FLUVASTATIN SODIUM CRYSTAL FORMS, PROCESSES FOR PREPARING
THEM, COMPOSITIONS CONTAINING THEM AND METHODS OF USING
THEM
PRIORITY
This application claims the benefit of U.S. Provisional Application Serial Nos.
60/479, 182 filed June 18,2003; 60/483,099 filed June 30, 2003; 60/485,748 filed July
10,2003; 60/493,793 filed August 11,2003; 60/507,954 filed October 3,2003 and
60/545,466 filed February 19,2004, all of which are incorporated herein by reference.
FIELD OF THE INVENTION
The present invention relates to the antihypercholesterolemia and antilipidemia
agent fluvastatin and, more particularly, to the solid state properties of its monosodium
salt.
BACKGROUND OF THE INVENTION
Complications of cardiovascular disease, such as myocardial infarction, stroke,
and peripheral vascular disease account for half of the deaths in the United States. A high
level of low density lipoprotein (LDL) in the bloodstream has been linked to the
formation of coronary lesions which obstruct the flow of blood and can rupture and
promote thrombosis. Goodman and Oilman, Tiie Pharmacological Basis of Therapeutics
'"879 (9th ed. 1996). Reducing plasma LDL levels has been shown to reduce the risk of
clinical events in patients with cardiovascular disease and in patients who are free of
cardiovascular disease but who have hypercholesterolemia. Scandinavian Simvastatin
Survival Study Group, 1994; Lipid Research Clinics Program, 1984a, 1984b.
Statin drugs are currently the most therapeutically effective drugs available for
reducing the level of LDL in the blood stream of a patient at risk for cardiovascular
disease. This class of drugs includes, inter alia, compactin, lovastatin, simvastatin,
pravastatin and fluvastatin. The mechanism of action of statin drugs has'teen elucidated
in some detail. They disrupt the synthesis of cholesterol and other sterols in the liver by
competitively inhibiting the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase enzyme
("HMG-CoA reductase"). HMG-CoA reductase catalyzes the conversion of HMG-CoA
to mevalonate, which is the rate determining step in the biosynthesis of cholesterol.
Consequently, its inhibition leads to a reduction in the rate of formation of cholesterol in
the liver.
[^*,1S'*-(£)]-(±)-7-[3-(4-fluoropheivyl)-l-(l-inethylethyl)-lF-indol-2-yl]-355-
dihyoroxy-6-heptenoic acid is a statin drug. It is known by the trivial name fluvastatin
and has the molecular formula (I):
depicted in free acid form,
Fluvastatin is commercially available under the trade name Lescol®. Fluvastatin
is supplied as a monosodium salt in capsules containing the equivalent of 20 and 40 mg
of fluvastatin and in extended-release tablets containing the equivalent of 80 mg of
fluvastatin. Fluvastatin and its sodium salt are described hi U.S. Patent No. 4,739,073. In
Example 6(a) of the ' 073 patent, a methyl ester precursor of (±) fluvastatin was
hydrolyzed with sodium hydroxide in methanol, which yielded, after evaporation of the
methanol, crude fluvastatin sodium. In Example 6(b), the fluvastatin methyl ester was
hydrolyzed with sodium hydroxide in ethanol. After evaporation of the ethanol, the
residue was taken up in water and lyophilized. The lyophilized product had a melting
pointrangeof 194°C-197°C. In Example 8, the sodium salt was prepared by ring
opening of fluvastatin lactone with sodium hydroxide in ethanol as described in Example
6(b). The product ofJBxample^S produced an infrared spectrum in a KBr pellet with
bands at: 3413,2978,2936,1572 and 1216 cm'1.
According to U.S. Patent No. 6,124,340, lyophilization of fluvastatin sodium as
was performed in Examples 6(b) and 8 of the '073 patent yields solid fluvastatin sodium
as a mixture of a crystalline form, designated as Form A, and amorphous material. The
'340 patent sets forth the spectroscopic properties of another crystal form of fluvastatin
sodium which is said to have low hygroscopicity and photostability. This other form is
called Form B in the '340 patent It is characterized by an infrared spectrum with bands
at 3343,2995,1587,15&, 1386,1337,1042 and 1014 cm'1 and by the following powder
X-ray diffraction peak positions and intensities.
°20 d (A) I/Io(%)
4.063
11.056 •
11.328
12.210
12.965
14.925
21.728
7.996
7.805
7.243
6.823
5.931
100
2.9
5.5
45.2
•34.6
9.3
15.277
15.750
16.350
17.760
18.320
18.875
19.396
19.701
20.395
21.329
21.785
22.610
23.868
24.281
24.463
25.446
25.655
26.357
27.040
28.747
29.940
32.165
35.173
37.131
5.795
5.622
5.417
4.990
4.839
4.698
4.573
4.503
4.351
4.163
4,076
3.929
3.725
3.663
3.636
3.498
3.470
3.379
3.295
3.103
2.982
2.781
2.549
2.419
4.5
18.5
10.6
17.6
14.3
11.3
7.0
13.4
13.5
8.5
15.9
7.5
5.4
3.6
3.6
5.6
3.6
3.3
2.8
3.4
2.8
1.6
1.0
1.3
Fluvastatin sodium Form A is said to have the following powder X-ray diffraction
peak positions and intensities.
O^Q jt f A \ T/T {®/ ^
3.965
7.936
10.554
10.645
11.931
12.215
14.496
14.812
15,916
17.769
18.640
19.856
20.518
20.908
21.389
21.722
22.675
24.089
22.265
11.131
8.375
8.304
7.412
7.240
6.106
5.976
5.564
4.988
4.756
4.468
4.325
4.245
4.151
4.088
3.918
3.691 •
100
0.9
1.7
1.5
44.5
14.5
1.1
0.8
0.3
3.2
5.3
5.8
2.9
1.2
1.3
1.1
0.8
1.0
24.533
26.519
27.973
28.861
3.626
3.358
3.187
3.091
0.5
0.2
0.9
U.S. Patent Application Publication No. 2003/0032666 reports the existence of
four crystal forms of fluvastatin monosodium called Forms C, D, E and F. The water
content of the forms ranges between 3 and 32 %. The new crystal forms of fluvastatin
sodium were obtained by storing the samples under atmospheres ranging between 20 and
90% relative humidity.
According to the '666 publication^ the PXRD pattern of fluvastatin sodium Form
C possesses characteristic peaks at the following ^-values and qualitative intensities: •
d (A) Intensity
23.8
11.8
7.8
7.6
7.4
6.4
6.1
5.90
5.00
4.88
4.73
4.56
4.40
4.12
4.03
3,96
3.50
3.36
2,93
(vs)
(w)
(vs)
(vw)
(vw)
(vw)
(vw)
(w)
(vw)
(w)
(m)
(w)
(vw)
(vw)
(vw)
(vw)
(vw)
(vw)
(vw)
wherein (vs)=very strong intensity; (s)=sfrxmg intensity; (m)=medium intensity;
(w)=weak intensity; and (vw)=very weak intensity.
According to the {666 publication, the PXRD pattern of fluvastatin sodium Form
D possesses characteristic peaks at the following ^-values and qualitative intensities:
d (A) Intensity
24.6
12.5
8.3
7.4
. 6.2
4.97
4.85
4.52
4.40
4.14
3.96
3.41
3.10
(vs)
(w)
(vs)
(vw)
(m)
(w)
(vw)
(vw)
(vw)
(vw)
(vw)
(vw)
(vw)
According to the '666 publication, the PXRJD pattern of fluvastatin sodium Form
E possesses characteristic peaks at the following ^-values and qualitative intensities:
d (A) Intensity
27.6
13.9
9.2
8.5
8.1
7.4
6.9
6.1 .
4.98
4.77
4.63
4.15
4.03
3.97
3.52
3.33
3.08
2.99
(m)
(vw)
(m)
(vw)
(vw)
(vw)
(s)
(vw)
(m)
(m)
(m)
(w)
(w)
(vw)
(vw)
(vw)
(vw)
(vw)
According to the '666 publication, the PXRD pattern of fluvastatin sodium Form
F possesses characteristic peaks at the following J-varues and qualitative intensities:
d (A) Intensity
29.6
14.8
9.9
8.6
8.3
7.4
6.6
6.2
5.93
5.03
4.94
4.35
4.23
3.98
. 3.54
2.98
(w)
(vw)
(w)
(vw)
(vw)
(8)
(vw)
(vw)
(w)
(m)
(m)
(vw)
(w)
(vw)
(vw)
(vw)
It also deserves mention that International Publication No. WO 02/36563
discloses crystal forms of enantiomericallypure [3J?,55] and [3S,5R] fluvastatm sodium.
The present invention also relates to fluvastatin sodium and the properties that it
can exhibit in the condensed phase. The occurrence of different crystal forms
(polymorphism) is a property of some molecules and molecular complexes. A single
molecule, like the fluvastatin in formula (I) or a salt complex like fluvastatin sodium, may
give rise to a variety of solids having distinct physical properties like melting point, X-ray
diffraction pattern, infrared absorption fingerprint and NMR spectrum. The crystalline
form may give rise to thermal behavior different from that of the amorphous material or
another crystalline form. Thermal behavior is measured in the laboratory by such
techniques as capillary melting point, thermogravimetric analysis ("TGA") and
differential scanning calorimetry ("DSC") and can be used to distinguish some
polymorphic forms from others. The differences in the physical properties of different
crystalline forms result from the orientation and intermolecular interactions of adjacent
molecules (complexes) in the bulk solid. Accordingly, polymorphs are distinct solids
sharing the same molecular formula yet having distinct advantageous and/or,
disadvantageous physical properties compared to other forms in the polymorph family.
These properties can be influenced by controlling the conditions under which the salt is
obtained in solid form.
Exemplary solid state physical properties include the flowability of the milled
solid. Flowability affects the ease with which the material is handled during processing
into a pharmaceutical product. When particles of the powdered compound do not flow
past each other easily, a formulation specialist must take that fact into account in
developing a tablet or capsule formulation, which may necessitate the use of glidants such
as colloidal silicon dioxide, talc, starch or tribasic calcium phosphate.
One of the most important physical properties of pharmaceutical polymorphs is
their solubility in aqueous solution, particularly their solubility in the gastric juices of a
patient. For example, where absorption through the gastrointestinal tract is slow, it is
often desirable for a drug that is unstable to conditions in the patient's stomach or
intestine to dissolve slowly so that it does not accumulate in a deleterious environment.
On the other hand, the method is not advantageous where the effectiveness of a drug
correlates with peak bloodstream levels of the drug, as in the case of statin drugs. With a
statin drug, provided the drug is rapidly absorbed by the GI system, a more rapidly
dissolving form is likely to exhibit increased effectiveness over a comparable amount of a
more slowly dissolving form.
It is often the case that the most rapidly dissolving solid state of a compound is
amorphous. Amorphous forms are often less stable than crystalline forms because they
do not have many of the stabilizing intennolecular interactions that are present in
crystalline forms. With an amorphous form, therefore, stabilizing intermolecular
interactions do not have to be broken when the compound goes into solution, and so the
dissolution rate is not retarded. Although they are more rapidly dissolving than
crystalline forms, amorphous forms of a compound can have disadvantages, A
compound, when it is in an amorphous state, is frequently more hygroscopic than a
crystalline form of the same compound (although exceptions abound, such as when the
crystal has wide channels that allow water to enter and leave the crystal in response to
changes in moisture density outside the crystal). Water has been implicated in drug
stability problems.' For instance the decomposition of aspirin which leads to the
characteristic smell of vinegar when an old bottle of aspirin is opened is a hydrolysis
reaction catalyzed by water. It is thus prudent when selecting a solid state form of a
compound that is to be used as a drug, and possibly stored for a long time between
packaging and use, to select a form that has low permeability to water. In the case of
fluvastatin monosodium, a crystalline form designated Form B has already been
discovered that is purportedly less hygroscopic than the partially crystalline/partially
amorphous form of the salt that is obtained by following procedures in U.S. Patent No.
4,739,073.
Although six distinct crystalline forms of racemic fluvastatin sodium have been
reported to date, and at least one of them is purported to be less hygroscopic1 that the solid
state form originally reported by the discovers of the compound, the discovery of yet
other crystalline forms of fluvastatin sodium is desirable. The discovery of new
crystalline forms and solvates of a pharmaceutically useful compound provides a new
opportunity to improve the performance characteristics of a pharmaceutical product by
enlarging the repertoire of materials that a formulation scientist has available for
designing. For example, new crystalline forms can be used to design a pharmaceutical
dosage form of a drug with low hygroscopicity, a targeted release profile, consistent
dosing (enabled by good flow of the tableting composition into the tableting die), or other
desired characteristic. New polymorphic forms and solvates of fluvastatin have now been
discovered.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 depicts a powder X-ray diffractogram of fluvastatin sodium Form I
FIG. 2 depicts a powder X-ray diffractogram of fluvastatin sodium Form n.
FIG. 3 depicts a powder X-ray diffractogram of fluvastatin sodium Form IE.
FIG. 4 depicts a powder X-ray diffractogram of fluvastatin sodium Form IV.
FIG. 5 depicts a DSC thermogram of fluvastatin sodium Form IV.
FIG. 6 depicts an JR. spectrum of fluvastatin sodium Form IV scanned from 4000
to 400 cm"1, while FIG. 6a expands the 4000-1500 cm"1 region of the spectrum and FIG.
6b expands the 1500-400 cm"1 region of the spectrum.
FIG. 7 depicts a powder X-ray diffractogram of fluvastatin sodium Form W-l.
FIG. 8 depicts a DSC thermogram of fluvastatin sodium Form W-l.
FIG. 9 depicts an IR spectrum of fluvastatin sodium Form IV-1 scanned from
4000 to 400 cm"1, while FIG. 9a expands the 4000-1500 cm"1 region of the spectrum and
FIG. 9b expands the 1500-400 cm"1 region of the spectrum.
FIG. 10 depicts a powder X-ray diffractogram of fiuvastatin sodium Form V.
FIG. 11 depicts a powder X-ray diffractogram of fiuvastatin sodium Form VI.
FIG. 12 depicts a DSC thermogram of fluvastatin sodium Form VI.
FIG. 13 depicts an IR spectrum of fluvastatin sodium Form VI scanned from 4000
to 400 cm"1, while FIG. 13a expands the 4000-1500 cm"1 region of the spectrum and FIG.
13b expands the 1500-400 cm"1 region of the spectrum, .FIG. 14 depicts a powder X-ray diffractogram of fluvastatin sodium Form Vn.
FIG. 15 depicts a DSC thermogram of fluvastatin sodium Form VII.
FIG. 16 depicts an IR. spectrum of fluvastatin sodium Form VH scanned from
4000 to 400 cm"1, while FIG. 16a expands the 4000-1500 cm"1 region of the spectrum and
FIG. 16b expands the 1500-400 cm"1 region of the spectrum.
FIG. 17 depicts a powder X-ray diffractogram of fluvastatin sodium Form DC.
FIG. 18 depicts a powder X-ray diffractogram of fluvastatin sodium Form IX-1.
FIG. 19 depicts a powder X-ray diffractogram of fluvastatin sodium Form XI.
FIG. 20 depicts a DSC thennogram of fluvastatin sodium Ponn XI
to 400 H? ^ .ft* " m SPeCtlUm °f flUV9Stafin S°diUm Foim » S—d fetoo 4«00O cTm ,',« weklmeFIaG2.2I1aa«emrdasialse *4„0/m0nMn_5i 0<™0c _n_.-i, .r..e ^. ^o ft.h.. -m»d 4™000
aifcfepand! the 1500-400 cm'1 regio, of the spectaun.
-FIG. 23 depicts a DSC thermogram of fluvastatin sodium Fonn XI2
*ooo t !™ 24-.d"?? " m SPeCtnm °ffUVaStatin s°dium Fom ^2 sca-^ from
000 to 400 cm wMe FIG. 24a expands the 4000-1500 cm- region of the spectrum and
LXVH, LXVUI, LXIX, LXX; LXXI, LXXH, LXXIV,
LXXV, LXXVI, LXXVH, Lxxvin, xc, xci, xcn, xcin, xcrv, xcv, xcvi,
XCVII, XCVm,'XCIX, C, CI, CD, Can, CIV, and CV. In so doing we have opted to use
Roman numerals as labels for the crystals instead of the Roman alphabetical labels used
by others working in the field to label other crystalline forms of fluvastatin sodium.
Fluvastatin sodium crystal forms XTV, LXXIII, LXXK, LXXX and LXXXVH
appear in the priority applications of the present invention, and are present in another
application filed on the same day.
Whether the two enantiomers of [R*J>*-(£)]-(*:) fluvastatin sodium co-crystallize
in a single unit cell or whether they crystallize in separate unit cells that are mirror images
of each other has yet to be determined for all of the new crystals forms. Accordingly, the
crystal forms of this invention are considered to include crystals that exhibit substantially
the same PXRD patterns as those depicted in the figures whether they are prepared
starting from pure or enriched [fl*,iS*-(.fi)J-(+) and [R*,S''-(£)]-(-) fluvastatin sodium or
racemic fluvastatin sodium.
Many of the novel forms can be obtained by crystallization methods and are stable
under normal humidity conditions. Those skilled in the art, after reading tins disclosure
will appreciate that some of the crystallization processes by which the new forms can be
made share certain traits. Generally speaking, in those processes fluvastatin sodium is
dissolved in a solvent, the selection of which is taught with reference to each particular
crystalline form in the sections of this disclosure that follow. While the solution of
fluvastatin sodium in the solvent is refluxing, a selected anti-solvent (the selection of
which also is taught below) is added to the solution to induce precipitation of fluvastatin
sodium in the crystalline form desired. The anti-solvent addition and precipitation can be
performed, and preferably are performed, at elevated temperature. Additional
precipitation, of course, will occur in many cases during subsequent cooling of the
mixture. It will also be seen that in other processes heating of the solvent is not preferred.
By the crystallization processes of this invention, each of the novel crystal forms
of fluvastatin sodium is obtained substantially free from other crystal forms, which means
less than 5 % of any other crystal form as measured by X-ray powder diffraction.
Although these processes have been found to yield the novel crystal forms, and yield
them in high purity, other processes that produce the crystal forms of this invention in
either greater or lesser purity may yet be found.
The yields of the various processes for preparing the new fluvastatin sodium
crystal ftfrms vary greatly depending upon the form desired. As those skilled in the art
will appreciate, a low yield of the desired crystal form does not necessarily mean that
13
precious unconverted starting material is lost. It, or another crystalline or amorphous
form of fluvastatin sodium or fluvastatin free acid or lactone can be recovered from the
separated solve'nt or diluent, such as by evaporating the separated diluent or solvent used
in the process to leave a residue containing fluvastatin.
Some of the new forms of fluvastatin sodium are hydrated. The level of water in
fluvasjatin sodium is measured by Karl Fisher using methods known in the art. Some of
the new crystal forms of fluvastatin sodium contain residual solvent in addition to water,
which is seen by the fact that the TGA weight loss value is significantly larger than the
Karl Fisher value. Some of the solvated crystal forms, contain only small quantities of
residual solvent. In this latter group fluvastatin sodium can be found in the following
hydrated states: hemihydrate (water content about 2%); monohydrate (water content
about 3-4%}; sesquihydrate (water content about 5-6%); dihydrate (water content about
7-8%); hemipentahydrate (water content about 9-10%); trihydrate (water content about
11-13%); tetrahydrate (water content about 14-16%); pentahydrate (water content
17-18%); hexahydrate (water content about 19-20%); 8-hydrate (water content about
25%); 9-hydrate (water content about 27-28%).
Fluvastatin is a known compound that can be purchased from commercial sources
or synthesized by known processes such as the process disclosed in U.S. Patent No.
4,739,073, which is incorporated herein by reference in its entirety. In particular, U.S.
Patent No. 4,739,0731s incorporated herein for its disclosure of how to prepare fluvastatin
and fluvastatin sodium. In the processes of this invention that use fluvastatin sodium as a
starting material, fluvastatin sodium Form B is the preferred starting material unless
otherwise indicated.
As used in this disclosure, the term "elevated temperature" means a. temperature
above ambient temperature'or above about 25 °C. Preferred elevated temperatures are
50°C and above and especially preferred elevated temperatures, when used in reference
to contacting with particular liquids, are the boiling points of such liquids.
The term "anti-solvent" means a liquid that, when added to a solution of
fluvastatin sodium in a solvent, induces precipitation of fluvastatin sodium. Precipitation
of fluvastatin sodium is induced by the auti-solvent when addition of the anti-solvent
causes fluvastatin sodium to precipitate from the solution more rapidly or to a greater
extent than fluvastatin sodium precipitates from a solution containing an equal
concentration of fluvastatin in the same solvent when the solution is maintained under the
same conditions for the same period of time but without adding the anti-solvent.
Precipitation can be perceived visually as a clouding of the solution or formation of
distinct particles of fluvastatin sodium suspended in or on the surface of the solution or
collected on the walls or at the bottom of the vessel containing the solution.

Fluvastatin Sodium Crystal Form I
Fluvastatin sodium Form I produces a PXRD diffractogram with characteristic
peaks at 3.7,11.3,13.1,17.9,18.4 and 21.8 degrees two-theta (FIG. 1).
Fluvastatin sodium Form I can be prepared directly from a lower alkyl ester of
fluvastatin such as fluvastatin methyl ester. The ester is dissolved in a solution of about
one molar equivalent of sodium in a solvent selected from acetone and acetonitriie. The
sodium can be conveniently provided by dissolving the appropriate quantity of sodium
hydroxide pellets in water, acetone or acetonitrile, while exercising caution since the
dissolution in water is highly exottiermic. Fluvastatin sodium Form I forms as a
precipitate in the solvent and can be conventionally separated therefrom by a known
method of isolation such as filtering, decanting, centrifuging and the like, preferably
filtering under a nitrogen stream.
Form I can also be prepared by crystallization from acetone or a mixture of butan-
2-ol and water, with a 10:1 butan-2-ol:water mixture being especially preferred.
Preferably Form B is dissolved in the solvent at the solvent's reflux temperature a reflux
temperature by adding the Form B to the refluxiug solvent.
According to a preferred procedure about 0.05:1 (w/v) of Form B is added to
refluxing acetone. If Form B does not completely dissolve after a reasonable period of
time, the hot solution may be filtered to remove any undissolved particles. Next, about
1:3 (v/v) of MTBE is added to the solution. The mixture is then allowed to cool. If Form
I does not precipitate after cooling to ambient temperature, then an additional quantity of
MTBE can be added to the solution and it can be partially concentrated on a rotary
evaporator to induce precipitation. The product is then isolated using conventional
methods.
According to another preferred procedure, about 1:20 (w/v) of Form B is added to
a refluxing 10:1 butan-2-ol:water mixture. After dissolution is complete, the mixture is
cooled or allowed to cool to induce precipitation after'which Form I is isolated
conventionally.
Fluvastatin Sodium Crystal Form II
Fluvastatin sodium Form E produces a PXRD diffractogram (FIG. 2) with a
characteristic peak at 3.6±0.2 degrees two-theta and other peaks at 5.4, 5.7,10.7 and
20.3±0.2 degrees two-theta.
Form II can be prepared from either fluvastatin sodium such as Form B or
amorphous fluvastatin. Starting from Form B, the starting material is taken up in
refluxing butan-1-ol. The solution is then cooled or allowed to cool to ambient
temperature and is allowed to stand without seeding until a precipitate is observed.

Starting with amorphous fluvastatin sodium, about 1:21 (w/v) of the starting material is
suspended in refluxing propan-2-ol. The suspension is then allowed to cool and stand
until precipitation occurs.
Following either procedure, the precipitate is separated from the diluent by
conventional techniques such as filtering, decanting, centrifuging and the like. Drying
may be carried out at 50°C in a vacuum oven. :
Fluvastatin Sodium Crystal Form in
Fluvastatin sodium Form III produces a PXRD diffractogram with characteristic
peaks'at 3.5, 9.5, 10.1, 10.9 and 20.1 degrees two-theta (FIG. 2).
Like Form II, Form HI can be prepared from a form of fluvastatin sodium such as
either Form B or amorphous fluvastatin sodium. In addition, it can be prepared from
fluvastatin sodium Form XIV.
Starting from Form B, the starting material is dissolved in a solvent selected from
the group consisting of butan-l-ol, ethyl acetate and THF. Form B is preferably dissolved
at the reflux temperature of the solvent. If the Form B does not completely dissolve, the
hot solution can be filtered to obtain a clear filtrate. While at reflux temperature, an antisolvent
selected from the group consisting of MTBE, hexanes and cyclohexane, is slowly
added to the solution (dropwise addition on the bench scale). Addition of the anti-solvent
may induce precipitation at elevated temperature. If it does not, Form TTT should
precipitate upon cooling the solution to ambient temperature.
Starting from amorphous fluvastatin sodium, about 1:6 (w/v) of the starting
material is dissolved in refluxing ethanol. While the solution is refluxing, Form TH should
be seen to come out of solution. If it does not precipitate within about an hour, the
solution can be cooled to ambient temperature, which should induce precipitation of Form
m.
Starting from fluvastatin sodium Form XTV, about 1:7 (w/v) of the starting material
is suspended in refluxing ethanol for a period of time sufficient to effect the conversion to
Form HI, which may take several hours or days. Thereafter the suspension is cooled to
ambient temperature and the precipitate is isolated.
In each of these procedures for making fluvastatin sodium Form m, the product
maybe separated from the diluent by conventional techniques such as filtering, decanting,
centrifuging and the like. Drying may be carried out at 50°C in a vacuum oven.
Fluvastatin Sodium Crystal Form IV
Fluvastatin sodium Form IV produces a PXRD diffractogram with characteristic
peaks at 3.6,4.0, 9.8,10.8 and 22.0±0.2 degrees two-theta and additional peaks at6.5,

12.8,16.3,16.9,17.2,18.3,19.5,20.6 and 22.9±0.2 degrees two-theta (FIG. 4).
Fluvastatin sodium Form IV produced the DSC thermogram shown in FIG. 5, in which a
main endothermic peak can be seen below 70°C and at about 120°C. The water content
of the sample, measured by Karl Fisher, is about 4 wt. %. The weight loss by TGA is 8.3
%. The IR spectrum of fluvastatin sodium Form IV is shown in FIG.s 6, 6a and 6b.
Fluvastatin sodium Form TV,can be prepared by dissolving fluvastatin sodium in
refluxing tetrahydrofuran ("THF") and adding dropwise organic anti-solvents like
chloroform, dichloromethane, 1,2- dichloroethane, diethyl ether and n-pentane to the
refluxing solution. Form TV should precipitate from the refluxing mixture. The mixture
may be maintained at reflux temperature for any amount of time necessary to achieve the
desired yield of Form IV. Afterwards the mixture is allowed to cool to room temperature
and Form JV can be isolated by a known method of isolation such as.filtering, decanting,
centrifuging and the like, preferably filtering under nitrogen stream. Fluvastatin sodium
Form TV also can be prepared by the same procedure, but substituting butan-1-ol,
1,4-dioxane or propan-2-ol for the THF and using cyclohexane or methyl r-butyl ether
("MTBE") as the anti-solvent.
Fluvastatin Sodium Crystal Form IV-1
Fluvastatin sodium Form IV-1 produces a PXRD diffractogram with characteristic
peaks at 3.6,4.0, 9.6,18.5 and 22.2±0.2 degrees two-theta and other peaks at 6.6,10.4,
11.0, 17.3,19.5, 20.1,20.7 and 21.3±0.2 degrees two-theta (FIG. 7). Fluvastatin sodium
Form rV-1 produced the DSC thermogram shown in FIG. 8, in which the main
endothermic peaks can be seen below 70.°C and at about 120 °C. The water content
measured by Karl Fisher, is about 2.1-2.6 wt. %. The weight loss by TGA is about 10.5
wt. %. The IR spectrum of fluvastatin sodium Form TV-l is shown in FIG.s 9, 9a and 9b.
Fluvastatin sodium Form IV-1 can be prepared by dissolving fluvastatin sodium in
THF or 1,4-dioxane at reflux, and adding dropwise n-heptane or MTBE. Fluvastatin
sodium Form TV-1 can also be prepared by dissolving fluvastatin sodium in butan-2-ol
and recrystallizing it during reflux.
Fluvastatin Sodium Crystal Form V
Fluvastatin sodium Form V produces a PXRD diffractogram (FIG. 10) with
characteristic peaks at 3.8, 6.3, 9.5 and 21.2±0.2 degrees two-theta.
Two process for making Form V have been discovered to date, both of which
employ fluvastatin Form B as the starting material. According to one procedure, Form B
is dissolved in refluxing butan-1-ol. After a clear solution is obtained, either by complete
dissolution or filtering the solution, heptane is slowly added to the refluxing solution.

Thereafter, the solution is cooled and the precipitate is recovered. According to another
procedure, Form B is dissolved in a solvent system that is a 5:2:1 ternary mixture of
ethanol:ethyl acetate:propan-l-ol at reflux temperature. After a clear solution is obtained,
either by complete dissolution or filtering the solution, n-hexane is slowly added to the
refluxing solution. The solution is then cooled to ambient temperature and maintained
. until a precipitate is formed. In either procedure, the product may be separated from the
diluent by conventional techniques such as filtering, decanting, centrifuging and the like.
Drying may be carried out at 50°C in a vacuum oven.
Fluvastatin Sodium Crystal Form VI
Fluvastatin sodium Form VI produces a PXRD diffractogram with characteristic
peaks at 3.7,4.7, 5.7,10.9,12.2 and 19.9±0.2 degrees two-theta and other peaks at 9.1,
9.6, 14.3 16.3,16.9,20.4 and 21.3±0.2 degrees two-theta (FIG. 11). Fluvastatin sodium
Form VI produced the DSC thermogram shown in FIG. 12, in which the mam
endothermic peaks can be seen below 90°C and at about 130°C. The water content
measured by Karl Fisher is 5.0-5.6 wt. %. The weight loss by TGA is about 12 %.
Fluvastatin sodium Form VI was stable after exposure to relative humidities between 0-
40%RH for 12 days and equilibrated at water contents between 3-5%. At higher relative
humidities, it transformed to fluvastatin sodium form VII and Form D. The IR spectrum
of fluvastatin sodium Form VI is shown in FIGs 13,13a and 13b.
Fluvastatin sodium Form VI can be prepared by dissolving fluvastatin sodium in
• DMF at room temperature and adding dropwise organic anti-solvents like diethyl ether or
hexanes to precipitate the material. The mixture may be cooled using an ice-bath. Form
VI can be separated from the DMF and anti-solvent by methods known in the art such as
filtering, decanting centrifuging and the like, preferably filtering under nitrogen stream.
Fluvastatin sodium Form VI also can be prepared directly from a lower alkyl ester
of fluvastatin. The starting material is dissolved in a solution of about one molar
equivalent of sodium hydroxide in a solvent system selected from the group consisting of
methanol, ethanol, mixtures of methanol and water and mixtures of butan-1-ol and water.
The preferred methanol:water mixture is 91% methanol, 9% water and the preferred
butan-l-ol:water mixture is 94% butan-1-ol, 6% water. The solvent system is preferably
heated, e.g. to reflux temperature, to accelerate conversion of any lactone that maybe
present to the sodium salt, which process can be monitored by HPLC. Once the starting
material has completely dissolved, an anti-solvent selected from the group consisting of
acetonitrile and acetone is added dropwise to the solution at elevated temperature to
induce precipitation. After cooling the mixture to ambient temperature, Form VI can be

isolated by conventional techniques such as filtering, decanting, centrifuging and the like.
Drying may be carried out at 50° C in a vacuum oven.
Fluvastatin Sodium Crystal Form VII
Fluvastatin sodium Form VII produces a PXKD diffractogram with characteristic
peaks at 3.7, 4.3, 5.8, 8.6 and 20.7±0.2 degrees two-theta and other peaks at 10.8, 12.3,
13.7,15.8,17.3,19.4, 22.0,23.9, 25.2,26.2 and 27.6 degrees two-theta (FIG. 14).
Fluvastatin sodium Form VII produced the DSC thermogram shown in FIG. 15, in which
the main endothermic peaks can be seen below 90°C and at about 130°C. The water
content, measured by Karl Fisher is about_4.1-4.5 wt. %. The weight loss by TGA 13-14
wt. %. The IR spectrum of fluvastatin sodium Form VII is shown in FIGs 16, 16a and
16b.
Fluvastatin sodium Form VII Was stable after exposure to relative humidities
between 20-60 % RH for 11 days and equilibrated at water contents between 1.4-8.6%.
Afterexposure to 80 % RH for 11 days, Form VH transformed to novel Form XX (water
content: about 19%), and after exposure to 100 % RH for 11 days Form VH transformed
to novel Form XTV (water content: about 17%). The results are summarized in the next
table.
Water uptake (%) and crystal form of Fluvastatin sodium Form VH equilibrated at
different relative humidities for 1 1 days
RH (%)
20
40
60
80
100
Water Content by KF
(%)
1.4-4.8
3.5-4.8
6.6-8.6
18.7-19.5
16.6
Weight Loss by TGA (%)
8.4
10.1
9.6
19.0
17.6
Crystal Form
vn
vn
vn
XX
xrv
Fluvastatin sodium Form VII can be prepared by dissolving fluvastatin sodium in
jyN-dmethylformarnide ("DMF") at room temperature, and adding dropwise an organic
anti-solvent like chloroform, MTBE, dichloromethane, cyclohexane or 1,2-dichloroethane
to induce precipitation. The mixture may be cooled using an ice-bath to enhance recovery
of Form Vn. Form Vn can be isolated by methods known in the art such as filtering,
decanting, centrifuging and the like, preferably by filtering under a nitrogen stream.
Fluvastatin sodium Form VH also can be prepared by suspending fluvastatin
sodium, preferably Form B, in DMF at room temperature and isolating it by methods
known in the art such as filtering, decanting, centrifuging and the like, preferably by
filtering under a nitrogen stream.

Another way of making fluvastatin sodium Form VII starts from a lower alkyl
ester of fluvastatin. The starting material is dissolved in a solution containing about one
molar equivalent of sodium hydroxide in a solvent selected from the group consisting of
butan-1-ol and mixtures of water and propan-2-ol. The preferred mixture of water and
propan-2-ol contains about 8% water and 92% propan-2:ol. The starting material is
preferably dissolved at elevated temperature, e.g. the reflux temperature of the solvent.
Once a solution has been obtained, an anti-solvent, either acetone, acetonitrile or MTBE,
is added to the mixture at elevated temperature to induce precipitation.
Alternatively, the lower alkyl esler of fluvastatin can be taken up in methanol at
ambient or elevated temperature, preferably ambient temperature, to form a saturated
solution. A saturated solution can be prepared by forming an unsaturated solution and
then evaporating solvent until solids or turbidity appears. Then, the solution can be
heated, preferably to reflux temperature, until all of the solids are redissolved. Next in
this process, acetonitrile is added dropwise to the solution to induce precipitation of
fluvastatin sodium Form VIT.
In yet another alternative process starting from the lower alkyl ester of fluvastatin,
the starting material is dissolved in acetonitrile. To effect dissolution, the acetonitrile can
be heated to 40°C. Then, a solution of sodium hydroxide in ethanol is added to the
solution. The resulting mixture becomes turbid and over time an oily phase may separate.
If this occurs, the mixture should be heated until the oil goes into solution. Then, Form
VTI can be precipitated by cooling or allowing the solution to cool.
After allowing the mixture to cool to ambient temperature Form VTI can be
isolated by conventional techniques such as filtering, decanting, centrifuging and the like.
Preferably, the liquids are separated by vacuum filtration under an inert gas like nitrogen.
A suitable condition for drying the separated product is 50°C under vacuum.
Fluvastatin Sodium Crystal Form DC
Fluvastatin sodium Form DC produces a PXRD diffractograni (FIG. 17) with
characteristic peaks at 3.4,10.0 and 19.7 ±0.2 degrees two-theta.
Form DC can be prepared by crystallization from a variety of solvent systems
following procedures described in greater detail in the Examples. Briefly, Form DC can
be precipitated from a solution in 1,4-dioxane by addition of dichloromethane; from a
solution in ethanol by addition of ethyl acetate, diethyl ether or n-pentane; or from a
mixture of ethanol and methanol by addition of hexanes. In addition, Form DC can be
prepared by refluxing a suspension of Form B in ethyl acetate.
Alternatively, Form DC can be prepared directly from a lower alkyl ester of
fluvastatin such as fluvastatin methyl ester. The ester is dissolved in a solution of about

one molar equivalent of sodium in ethanol. The sodium can be conveniently provided by
1 dissolving the appropriate quantity of sodium hydroxide pellets in water, while exercising
caution since the dissolution in water is highly exothermic. The solution is heated for a
.sufficient period of time to hydrolyze the ester, typically several hours. Then, a large
excess (e.g. 7x v/v) of propan-2-ol is added to the solution. The mixture is then cooled to
ambient temperature and maintained until a precipitate forms in the flask.
Form IX can be conventionally separated from the solvent or diluent by a known
method of isolation such as filtering, decanting, centrifuging and the like, preferably
filtering under a nitrogen stream.
Fluvastatin Sodium Crystal Form DC-1
Fluvastatin sodium Form IX-1 produces a PXRD diffractogram (FIG. 18) with
characteristic peaks at 3.4, 6.6,10.0,13.2,19.8 ±0.2 degrees two-theta.
We have discovered a multitude of ways to make Form IX-1, which are
exemplified by starting from fluvastatin Form B. For the sake of brevity, please refer to
the Examples for the particulars of how it can be made.
Fluvastatin Sodium Crystal Form. XI
Fluvastatin sodium Form XI produces a PXRD diffractogram with characteristic
peaks at 3.3,3.8, 4.6, 8.3, 10.2 and 25.1±0.2 degrees two-theta and other peaks at 7.2,
11.4,12.4,13.6, 16.0,16.9,17.4,20.4,21.3,21.9 and 23.1±0.2 degrees two-theta (FIG.
19). Fluvastatin sodium Form XI produced the DSC thermogram shown in FIG. 20 in
which one main endothermic peak can be seen at about 150 °C. The water content of the
sample is about 4-6 wt. %. The weight loss by TGA is 6-8 %. The IR spectrum of
fluvastatin sodium Form XI is shown in FIG.s 21,21a and 21b.
Fluvastatin sodium Form XI was stable after exposure to relative humidities
between 20-60 % RH for 11 days and equilibrated at water contents between 1.1-5.6%.
After exposure to 80 % and 100 % RH for 11 days, Form XI transformed to novel Form
XTX (water content: about 19-28 %). The results are summarized in the next table.
Water uptake
Equilibrated
RH(%)
0
20
40
60
80
(%) and Crystal Form of Fluvastatin Sodium Crystal Form XI
at Different Relative Humidities for 1 1 Davs
Water Content by KF Weight Loss by TGA (%)
(%)
2.0-2.4 6.5
1.1-5.6 5.0
3.0-3.6 4.5
3.5-3.6 4.7
19.5-22.6 22.0
Crystal Form
XI
XI
XI
XI
XDC

100 28.0-28.4 26.2 XDC
Fluvastatin sodium Form XI can be prepared by dissolving fluvastatin sodium,
preferably Form B, in refluxing butan-2-ol. During reflux, the fluvastatin sodium
recrystallizes in Form XI. Addition of organic anti-solvents like hexanes, n-pentane,
MTBE, diethyl ether, n-heptane and chloroform at reflux tends to increase the yield of
precipitate. The mixture may be maintained at reflux temperature for any amount of time
necessary to achieve the desired yield of Form XL Afterwards, the mixture is allowed to
cool to room temperature and Form XI can be isolated by a known method of isolation
such as filtering, decanting, centrifuging and the like, preferably filtering under a nitrogen
stream.
Fluvastatin Sodium Crystal Form XI-2
Fluvastatin sodium Form XI-2 produces a PXRD diffractogram with characteristic
peaks at 3.5,3.8,4.6, 10.4 and 18.5±0.2 degrees two-theta and other peaks at 8.5,11.2,
12.1,16.4,17.0,17.7,20.9,21.2,21.7,22.2 and 23.6±0.2 degrees two-theta (FIG. 22). '
Fluvastatin sodium Form XI-2 produced the DSC thermogram shown in FIG. 23, in
which two main endothermic peaks can be seen below 80°C and at about 145 °C. The
water content of the sample is about 1.9-3.2 wt. %. The weight loss by TGA is 7.7 %.
Fluvastatin sodium form XI-2 was stable after exposure to relative humidities between 0-
60% RH for 11 days and equilibrated at water contents between 5-7%. At higher relative
humidities it transformed into Form D. The IR spectrum of fluvastatin sodium Form XI-2
is shown in FIG.s 24,24a and 24b.
Fluvastatin sodium Form XI-2 can be prepared by dissolving fluvastatin sodium in
refluxing propan-1-ol and adding dropwise organic anti-solvents like hexanes, MTBE and
dichloromethane. The mixture may be maintained at reflux temperature for any amount
of time necessary to achieve the desired yield of Form XI-2. Afterwards, the mixture is
allowed to cool to room temperature and Form XI-2 can be isolated fay a known method
of isolation like filtering, decanting, centrifuging and the like, preferably filtering under
nitrogen stream.
Fluvastatin Sodium Crystal Form XTI
Fluvastatin sodium Form XT! produces a PXRD diffractogram (FIG. 25) with
characteristic peaks at 3.1, 6.5,9.8,17.6,25.9 and 30.9±0.2 degrees two-theta,
, Form XII is prepared by crystallization from a mixture of butan-1-ol and 1,4-
dioxane. According to a preferred process, Form B is dissolved in refluxing butan-1-ol.
1,4-Dioxane is then added to the refluxing solution until it becomes turbid. Thereafter,
the mixture is cooled to ambient temperature at which point additional 1,4-dioxane may

be added to enhance recovery of Form XII. Form XII can be separated from the solvent
system by conventional techniques such as filtering, decanting, centrifuging and the like,
preferably filtering under an inert atmosphere like nitrogen. The separated Form Xn may
be dried. A suitable drying condition is 50 °C under vacuum.
Fluvastatin Sodium Crystal Form Xffl
Fluvastatin sodium Form XIII produces a PXRD diffractogram (FIG. 26) with
characteristic peaks at 3.8,5.6,12.3 and 20.6±0.2 degrees two-theta.
Form XIII can be prepared by suspending fluvastatin sodium Form B in
acetonitrile, which is preferably done at elevated temperature and then cooling the
suspension to reduced temperature such as 10°C. Form XIH can be separated from the
acetonitrile by conventional techniques such as filtering, decanting, centrifuging and the
like, preferably filtering under an inert atmosphere like nitrogen. The separated Form
XUI may be dried. A suitable drying condition is 50°C under vacuum.
Fluvastatin Sodium Crystal Form XV
The material that was received in Israel in response to a commercial order placed
to the Zhejiang Hisun Pharmaceutical Co., Ltd. 46 Waisha Rd.3 Jiaojiang District,
Taizhou City, Zhejiange Province, China, was subjected to PXRD analysis at our facility
in Israel and produced the PXRD diffractogram depicted in FIG. 30, which is distinct
from the diffractograms produced by each of the other solid state forms of fluvastatin
sodium disclosed herein. We have designated this solid state form of fluvastatin sodium
Form XV. Form XV has been found useful for producing certain novel solid state forms
of fluvastatin sodium, as described below.
Fluvastatin Sodium Crystal Form XVI
Fluvastatin sodium Form XVI produces a PXRD diffractogram with characteristic
peaks at 3.8 and 7.0±0.2 degrees two-theta and other peaks at 4.3,10.2,10.7,11.2,15.6,
17.8,18.4 and 19.5±0.2 degrees two-theta. (FIG. 31). Fluvastatin sodium Form XVI
produced the DSC thermogram shown in FIG. 32, in which broad endothermic peaks can
be seen below SO°C and between 100-150 °C. The water content of the sample is about
3-4 wt. %. The weight loss by TGA is 8.7 wt. %. The IR spectrum of fluvastatin sodium
Form XVI is shown in FIG.s 33, 33a and 33b.
Fluvastatin sodium Form XVI can be prepared by dissolving fluvastatin sodium in
refluxing propan-2-ol and adding dropwise an organic anti-solvent like dichloromethane.
The mixture may be maintained at reflux temperature for any amount of time necessary to
achieve the desired yield of Form XVI. Afterwards, the mixture is allowed to cool to

room temperature and Form XVI can be isolated by a known method of isolation like
filtering, decanting, centrifuging and the like.
Fluvastatin Sodium Crystal Form XVII
Fluvastatin sodium Form XVII produces a PXRD diffractogram with
characteristic peaks at 3.5 (broad), 5.4, 5.8 and 13.8±0.2 degrees two-theta and other
peaks at 10.8, 14.8,16.4,19.4, 21.5 and 22.7±0.2 degrees two-theta. (FIG. 34).
Fluvastatin sodium Form XVII produced the DSC thermogram shown in FIG. 35, in
which two broad endothermic peaks can be' seen at 80 and at about 113 °C respectively.
The weight loss by TGA is 8.4 wt. %.
Fluvastatin sodium Form XVII can be prepared by dissolving fluvastatin sodium
in propan-1-ol and recrystallizing it from the stirred solution. In a preferred embodiment,
the recrystallization is carried out at elevated temperature.

Fluvastatin Sodium Crystal Form XVHI
Fluvastatin sodium Form XVffi produces a PXRD diffractogram with
characteristic peaks at 3.4, 8.4,10.0 and 10.9i0.2 degrees two-theta and other peaks at
11.7,12.6,15.8,17.4,18.0,18.8,20.0,20.7 and 21.3±0.2 degrees two-theta. (FIG. 36).
Fluvastatin sodium Form XVffl produced the DSC thermogram shown in FIG. 37, in
which two endothermic peaks can be seen below 70 °C and at about 180 °C. The water
content of the sample is about 4 wt. %. The loss on drying shown by TGA is about 4 wt.
%. Fluvastatin sodium form XVHI is a monohydrate. The IR spectrum of fluvastatin
sodium Form XVHI is shown in FIG.s 38, 38a and 38b.
xFluvastatin sodium Form XVTfl can be prepared by suspending fluvastatin sodium
in refluxing methylethyl ketone (MEK). The mixture may be maintained at reflux
temperature for any amount of time necessary to achieve the desired yield of Form XVIII.
Afterwards, the mixture is allowed to cool to room temperature and Form XVHI can be
isolated by a known method of isolation such as filtering, decanting, centrifuging,
distilling and the like, preferably filtering under a nitrogen stream or distillation.
Fluvastatin Sodium Crystal Form XIX
Fluvastatin sodium Form XIX produces a PXRD diffractogram with characteristic
peaks at 3.4., 10.1,13.5 and 18.0±0.2 degrees two-theta and other peaks at 6.8,20.1,21.8
and 25.6±0.2 degrees two-theta. (FIG. 39). Fluvastatin sodium Form XIX produced the
DSC thermogram shown hi FIG. 40, in which one main endothermic peak can be seen at
about 80 °C. The water content of the sample is 19-28 wt. %. The weight loss by TGA is
22-26 wt. %. Fluvastatin sodium Form XK is in hexahydrate, 8-hydrate, and 9-hydrate

forms. The IR spectrum of fluvastatin sodium Form XIX is shown in FIG.s 41, 41a and
41b.
Fluvastatin sodium Form XIX can be prepared by exposing Form XI, TV-l or XVI
to an atmosphere of elevated humidity ranging of about 60 % to about 100% RH.
Fluvastatin Sodium Crystal Form XDC-1
Fluvastatin sodium Form XDC-1 produces a PXRD diffractogram (FIG. 42) with
characteristic peaks at 3.5,10,4,11.9,14.0,22.5±0.2 degrees two-theta and other peaks at
17.5,17.8,18.0,18.3., 25.4±0.2 degrees two-theta. The water content offluvastatinForm
XIX-1 measured by Karl Fisher analysis is about 8% by weight. The weight loss by TGA
is about 7% by weight. Fluvastatin sodium Form XIV is a dihydrate.
Fluvastatin sodium Form XDC-1 can be prepared by forming a heterogeneous
mixture of fluvastatin sodium Form XI and water and maintaining the mixture for a
period of time sufficient to achieve the desired yield of Form XDC-1. The mixture may be
stirred and preferably is stirred for about 2 hours to about 15 hours, with about 5 hours
being especially preferred. The product may then be recovered from the mixture by
conventional techniques such as filtration.
The recovered wet product may then be optionally dried. Drying may be carried
out at a preferred temperature range of from about 40°C to about 60°C, for about 12 to
about 48 hours.
Fluvastatin Sodium Crystal Form XX
Fluvastatin sodium Form XX produces a PXRD diffractogram with characteristic
peaks at 3.5,10.1,13.5,18.0 and 20.8±0.2 degrees two-theta and other peaks at 5.9 and
12.4 degrees two-theta. (FIG. 43). Fluvastatin sodium Form XX produced the DSC
thermegram shown in FIG. 44, in which one main endothermic peak is seen below about
130°C. The water content of the sample is about 19 wt. %. The loss on drying by TGA is
about 19 wt. %. Fluvastatin sodium Form XX is a hexahydrate. The IR spectrum of
fluvastatin sodium Form XX is shown in FIG.s 45,45a and 45b.
Fluvastatin Form XX can be prepared by exposing fluvastatin sodium Form VII to
an atmosphere of relative humidity of 80% or higher for a period of time sufficient to,
effect the conversion of Form XX.
In the case of fluvastatin sodium Forms XI, XIV, XVIII, XIX and XX, the TGA
and Karl Fisher analyses were in close agreement, which is taken as an indication that
those samples are mainly hydrated forms.
In fiuvastatin sodium Forms TV, IV-1, VI, VH and XI-2, the TGA analysis
exceeded that of Karl Fisher, which is taken as an indication that a considerable quantity

of organic solvent was present. After exposure at 60% relative humidity for 11 days, the
gap between TGA and KF results decreased (see below Forms VII and XI stored at
different relative humidities), indicating that the level of organic solvent decreased. As a
consequence, exposure to humidity is a useful method minimize the organic solvent
present in fluvastatin sodium.
Fluvastatin Sodium Crystal Fonn XXII
Fluvastatin sodium Form XXII produces a PXRD diffractogram (FIG. 46) with
characteristic peaks at 3.2,12.4, and 18.3±0.2 degrees two-theta and other peaks at 6.4,
9.5,15.6 and 21.4 degrees two-theta.
Form XXII can be prepared by exposing fluvastatin sodium Form XV to water
vapor. Preferably, Form XV is maintained under an atmosphere of 100% relative
humidity at ambient temperature. Substantially complete conversion is achieved over a
period of weeks, typically about two weeks.
Fluvastatin Sodium Crystal Form XXIII
Fluvastatin sodium Form XXIII produces a PXRD diffractogram (FIG. 47) with
characteristic peaks at 3.6, 4.0,4.4, 17.1 and 19.3±0.2 degrees two-theta and other peaks
at 6.2, 7.2, 9.3, 10.2 and 18.6 degrees two-theta.
Form XXin can be prepared by dissolving about 1:20 (w/v) of fluvastatin sodium
Form B in refluxing propan-1-ol. In a matter of hours after complete dissolution,
fluvastatin sodium should begin to precipitate in Form XXIII. After the initial crystals
form, the mixture can be cooled or allowed to cool to ambient temperature to complete
the crystalli2ation yielding Form XXHI. Form XXIII can be separated from the propan-1-
ol by conventional techniques such as filtering, decanting, centrifuging and the like,
preferably filtering under an inert atmosphere like nitrogen. The separated Form XXIII
may be dried. A suitable drying condition is 50°C under vacuum.

Fluvastatin Sodium Crystal Form XXTV
Fluvastatin sodium Form XXIV produces a PXRD diffractogram (FIG. 48) with
characteristic peaks at 3.4,10.2,13.6,17.9 and 18.7±0.2 degrees two-theta and other
peaks at 6.9,10.7,12.0,22.5 and 25.4 degrees two-theta.
Form XXrV can be prepared from fluvastatin sodium Form B and fluvastatin
Form XV. Form XXTV can be obtained from these forms by crystallization from water.
When starting from Form XV, the starting material is dissolved in refluxing water. After
a period of hours to a few days following cooling of the solution to ambient temperature,
Fonn XXIV crystalKzes out of solution. Form XXTV can be separated from the water by
26
conventional techniques such as filtering, decanting, centrifiiging and the like, preferably
filtering under an inert atmosphere like nitrogen. The separated Form XXIV may be
dried. A suitable drying condition is 50°C under vacuum. When starting from Form B,
the starting material can be dissolved in the water at ambient temperature. If Form XXIV
does not crystallize, the procedure can be modified as follows. Diethyl ether is added to
the vessel containing the solution and contacted with the solution for several minutes.
Then, the phases are separated and the aqueous phase is lyopliilized to obtain a residue
that is fluvastatin sodium Form XXIV.
Fluvastatin Sodium Crystal Form XXVI
Fluvastatin sodium Form XXVI produces a PXRD diffractogram (FIG. 49) with
characteristic peaks at 3.8,15.0,18.5,21.6 and 25.8±0.2 degrees two-theta and other
peaks at 11.7,15.9,16.2,24.3 and 35.2 degrees two-theta.
Form XXVI can be prepared by dissolving about 1:7 (w/v) of fluvastatin sodium
Form B in a 20:1 mixture of 1,4-dioxane: water. The mixture is refluxed until a clear
solution is obtained. Then the mixture is cooled or allowed to cool to induce precipitation
of fluvastatin sodium in Form XXVI Form XXVI can be separated from the water and
1,4-dioxane by conventional techniques such as filtering, decanting, centrifuging and the
like, preferably filtering under an inert atmosphere like nitrogen. The separated Form
XXVI may be dried. A suitable drying condition is 50 °C under vacuum.
Fluvastatin Sodium Crystal Form XXVII
Fluvastatin sodium Form XXVE produces a PXRD diffractogram (FIG. 50) with
characteristic peaks at 3.3, 3.9,15.9, 18.4 and21.6±0.2 degrees two-theta and other peaks
at 8.4,15.0,17.9, 24.3 and 25.7±0.2. degrees two-theta.
The initial steps for preparing Form XXVII are the same as for preparing Form
XXVI. Form B is dissolved in a refluxing 20:1 mixture of l,4-dioxane:water. However,
at reflux temperature 1.5 volumes of hexanes is slowly added to the solution. Thereafter,
the mixture is cooled to ambient temperature after which fluvastatin sodium crystalizes in
Form"XXVII from the mixture. Form XXVn can be separated from the solution by
conventional techniques such as filtering, decanting, centrifuging and the like, preferably
filtering under an, inert atmosphere like nitrogen. The separated Form XXVII may be
dried. A suitable drying condition is 50 ° C under vacuum.
Fluvastatin Sodium Crystal Form XXTX

Fluvastatin sodium Form XXDC produces a PXRD dif&actogram with
characteristic peaks at 4.4, 5.9, 6.8, 7.9,10.8±0.2 degrees two-theta and other peaks at
14.3,15.6,17.5,19.7,21.3,22.7±0.2 degrees two-theta (FIG. 51).
Fluvastatin sodium Form XXIX can be prepared by forming a heterogeneous
mixture of fluvastatin sodium Form XV and 1,4-dioxane and maintaining the
heterogeneous mixture until substantially all of the Form XV is converted into Form
XXDC. Preferably, the conversion is accelerated by heating the heterogeneous mixture.
Under an especially preferred set of conditions, the heterogeneous mixture is
heated to the reflux temperature of 1,4-dioxane and maintained at reflux for about 16
hours. Then, Form XXDC is separated from the 1,4 dioxane by cooling the mixture and
filtering the mixture under a nitrogen flow. Thereafter, Form XXDC may be
conventionally dried.
Fluvastatin Sodium Crystal Form XXX
Fluvastatin sodium Form XXX produces a PXRD diffractogram with
characteristic peaks at 5.4,5.8,10.8,13.8,14.8±0.2 degrees two-theta and other peaks at
16.4,19.0,19.5, 20.2,20.8,21.5,22.7±0.2 degrees two-theta (FIG. 52). The water
content of the sample, measured by Karl Fisher, is about 4% by weight The weight loss
by TGA is about 10%.
Fluvastatin sodium Form XXX can be prepared by forming a heterogeneous
mixture of fluvastatin sodium Form XV and one or a mixture of certain selected organic
liquids. Liquids that have been found suitable include methylethylketone ("MEK"),
tetrahydrofuran ("THF"), acetone, butan-2-ol and butan-1-ol. The heterogeneous
mixture is maintained until substantially all of the Form XV is converted into Form XXX.
Preferably, the conversion is accelerated by heating the heterogeneous mixture.
Under an especially preferred set of conditions, the heterogeneous mixture is
heated to the reflux temperature of organic liquid used and maintained at reflux for about
16 hours. Then, Form XXX is separated from the organic liquid by cooling the mixture
and filtering the mixture under a nitrogen flow. Thereafter, Form XXX may be
conventionally dried.
Fluvastatin sodium Form XXX also can be prepared directly from a lower alkyl
ester of fluvastatin by precipitation from a solution containing an excess of sodium. The
preferred excess of sodium is about 1.5 molar equivalents. According to a preferred
procedure, the starting material is added to a solution of sodium hydroxide in mixture
containing water as a minor component and methanol as a major component and the
resulting mixture is heated, e.g. to the reflux temperature of the solvent, until a clear
solution is obtained. Acetone is then added to the solution at elevated temperature to

induce precipitation of Form XXX. After cooling to ambient temperature. Form XXX
can be separated from the methanol and water by conventional techniques such as
filtering, decanting, centrifuging and the like. Preferably, the water is separated by
vacuum filtration under an inert gas like nitrogen. A suitable condition for drying the
separated product is 50°C under vacuum.
Fluvastatin Sodium Crystal Form XXXI
Fluvastatin sodium Form XXXI produces a PXRD diffractogram with
characteristic peaks at 5.3, 6.1, 6.5,11.9,13.2±0.2 degrees two-theta, and other peaks at
8.0,8.5,9.3,16.3,18.3,20.2,20.6,21.1iO,2 degrees two-theta (FIG. 53). The water
content of fluvastatin sodium Form XXXI measured by Karl Fisher analysis is about 16%
by weight. The weight loss by TGA is about 10% by weight. Fluvastatin sodium Form
XXXI is a tetrahydrate.

Fluvastatin sodium Form XXXI can be prepared by forming a heterogeneous
mixture of fluvastatin sodium Form XV and ethanol and maintaining the heterogeneous
mixture until substantially all of the Form XV is converted into Form XXXI. Preferably,
the conversion is accelerated by heating the heterogeneous mixture.
Under an especially preferred set of conditions, the heterogeneous mixture is
heated to the reflux temperature of ethanol and maintained at reflux for about 23 hours.
Then, Form XXXI is separated from the ethanol by cooling the mixture and filtering the
mixture under a nitrogen flow. Thereafter, Form XXXI may be conventionally dried.
Fluvastatin Sodium Crystal Form XXXDI
. Fluvastatin sodium Form XXXIH produces a PXRD diffractogram (FIG. 54) with
characteristic peaks at 4.0,5.5, 8.0,9.1,13.4,16.6,21.2±0.2 degrees two-theta and other
peaks at 6.6, 8.8,10.4,11.6,12.0,14.1,14.8,16.1,17.9,18.5,19.7, 20.3,24.3,24.9,
26.7±0,2 degrees two-theta. The water content of the sample measured by Karl Fisher is
about 7% by weight. The weight loss by TGA is about 7%. The water content measured
may reach about 10% by weight. Fluvastatin sodium Form XXXIII is in dihydrate and
hemipentahydrate form.
Fluvastatin sodium Form XXXIH can be prepared by forming a heterogeneous
mixture of fluvastatin sodium Form XV or Form B and ethanol, preferably absolute
ethanoland maintaining the mixture for a period of time sufficient to achieve the desired
yield of Form XXXDI. The mixture preferably is stirred for about 5 hours to about 48
hours and heated to reflux temperature while stirring. The product may then be recovered
from the mixture by conventional techniques such as filtering, decanting, centrifuging and
the like. The recovered wet product may then be optionally dried. Drying may be carried

out at a preferred temperature range of from about 40°C to about 60°C, for about 12 to
about 48 hours.
Fluva&atin sodium Form XXXIV
Fluvastatin sodium Form XXXIV produces a PXRD diffractogram (FIG. 55) with
characteristic peaks at 5.4, 6.1,7.6,18.5,21,1±0.2 degrees rwo-theta and other peaks at
8.8,9.3,12.4,13.1,14.3,15.2,15.9,17.2,17.6, 20.5, 22.2,24.1,25.4, 26.2±0.2 degrees
rwo-theta. The water content of Form XXXIV as measured by Karl Fisher analysis is
about 10% by weight. The weight loss by TGA is abW 20%.
Fluvastatin sodium Form XXXTV can be prepared by forming a heterogeneous
mixture of fluvastatin Form XV and dimethyl sulfoxide ("DMSO") and maintaining the
mixture for a period of time sufficient to achieve the desired yield of Form XXXIV. The
mixture preferably is stirred about 5 hours to about 48 hours and heated while stirring, yet
more preferably heated to about 80°C or higher temperature. The product may then be
recovered from the slurry by conventional techniques such as filtering, decanting,
centrifuging and the like. The recovered wet product may then be optionally dried.
Drying maybe carried out at a preferred temperature range of from about 40 °C to about
60 °C, for about 12 to about 48 hours.
Fluvastatin sodium Form XXXV
Fluvastatin sodium Form XXXV produces a PXRD diffractogram (FIG. 56) with
characteristic peaks at S.4, 6.0, 9.9,14.8,2LO±0.2 degrees 2 theta and other peaks at
16.7,18.6, 19.8,22.6±0.2 degrees two-theta. The water content of this sample measured
by Karl Fisher is about 15% by weight. The weight loss by TGA is about 31% by weight.
Fluvastatin sodium Form XXXVII is a hemipentahydrate.
Fluvastatin sodium Form XXXV may be prepared by forming a heterogeneous
mixture of fluvastatin sodium Form XV inN,N dimethyl formamide ("DMF") and
maintaining the mixture for a period of time sufficient to achieve the desired yield of
Form XXXV. The mixture preferably is stirred for about 5 hours to about 48 hours. The
mixture is preferably heated while stirring. Yet more preferably, the stirred mixture is
heated to a temperature of about 80°C or higher. The product may then be recovered
from the mixture by conventional techniques such as filtering, decanting, centrifuging and
the like. The recovered wet product may then be optionally dried. Drying may be carried
out at a preferred temperature range of from about 40°C to about 60°C, for about 12 to
about 4.8xhours.
Fiuvastatin Sodium CrystalFormXXXVI

Fluvastatin sodium Form XXXVI produces a PXRD diffractogram (FIG. 57)
having characteristic peaks at 3.0, 9.2,11.5, 14.4 and 20.2±0.2 degrees two-theta, and
other peaks at 9.6, 12.3 and 12.8±0.2 degrees two-theta.
Form XXXVI can be prepared by suspending fluvastatin sodium Form Xl-wet
(obtained after filtration, but before drying) in water for a sufficient period time to effect
the conversion (typically about 6 h). The product may then be recovered from the
suspension by conventional techniques such as filtering, decanting, centrifuging and the
like. The recovered wet product may then be optionally dried. A suitable condition for
drying the separated product is 50°C under vacuum.
Fluvastatin Sodium Crystal Form XXXVII.
Fluvastatin sodium Form XXXVn produces a PXRD diffractogram having
characteristic peaks at 3.63,10.36,13.74,17.93,18.34±0.2 degrees two-theta, and other
peaks at 11.26,12.16,12.91,19.44, 20.57±0.2 degrees two-theta (FIG. 58). The water
content of this sample measured by Karl Fisher is about 9% by weight. The weight loss
by TGA is about 31 % by weight.
Fluvastatin sodium Form XXXVn can be prepared by forming a heterogeneous
mixture of fluvastatin sodium Form XI and water. The weight ratio of Form XI to water
is preferably about 0.5:1. The mixture should be maintained at ambient temperature. The
conversion takes about 5h, 45 min. at 22 °C. Form XXXVII can then be separated from
the water by conventional means such as filtering, decanting, centrifuging and the like.
Preferably, the water is separated by vacuum filtration under an inert gas like nitrogen. A
suitable condition for drying the separated product is 50°C under vacuum.
Fluvastatin Sodium Crystal Form XXXVm
Fluvastatin sodium Form XXXVTH produces a PXRD diffractogram having
characteristic peaks at 3.64,4.66, 7.30, 8.84,11.61±0.2 degrees two-theta, and other
peaks at 19.08,19.65,21.15,22.59,24.20±0.2 degrees two-theta (FIG. 59). The water
content of this sample measured by Karl Fisher is about 6-7% by weight. The weight loss
by TGA is about 10-11% by weight.
Fluvastatin sodium Form XXXVIII can be prepared by forming a heterogeneous
mixture of fluvastatin sodium Form XI and ethanol. To obtain a product of highest
polymorphic purity it is preferable to use absolute ethanol. The ratio of Form XI to
ethanol is preferably about 0.2 g nil"1, more preferably about 0.19 g ml"1.
Under a particular preferred set of conditions the heterogeneous mixture is heated
until the ethanol boils and is maintained at that temperature for several hours until the
conversion of Form XI to Form XXXVIfl is complete. The conversion can be monitored

by powder X-ray diffractometry. If the conversion is still not complete after several
hours (it took 16 hours in one of our experiments) then the mixture can be held at
elevated or ambient temperature until the conversion is considered to be sufficiently
complete.
Form XXXVIII can then be separated from the ethanol by conventional means
such as filtering, decanting, centrifuging and the like. Preferably, the ethanol is separated

by vajmum filtration under an inert gas like nitrogen. A suitable condition for drying the
separated product is 50 °C under vacuum.
Fluvastatin sodium Fotai XXXVIH also can be prepared from a lower alkyl ester
of fluvastatin by taking it up in a solution of about one molar equivalent of sodium
hydroxide in ethanol and then precipitating it by addition-of ethyl acetate to the mixture.
Thereafter, Form XXXVIH can then be separated from the ethanol and ethyl acetate by
conventional means such as filtering, decanting, centrifuging and the like. Preferably, the
ethanol and ethyl acetate are separated by vacuum filtration under an inert gas like
nitrogen. A suitable condition for drying the separated product is 50°C under vacuum.
Yet further, Form XXXVIII can be prepared by suspending fluvastatin sodium
Form XI-wet in refluxing absolute ethanol, preferably for about 16 h. Then the
suspension is cooled to reduced temperature and the product is isolated by conventional
means.
Fluvastatin Sodium Crystal Form XXXIX
Fluvastatin sodium Form XXXDC produces a PXRD diffractogram (FIG. 60)
having characteristic peaks at 3.7,4.5, 8.5,17.8, 20,1±0.2 degrees two-theta and other
peaks at 6.9, 11.2, 16.8,19.6 and 21.6±0.2 degrees two-theta.
•Form XXXIX can be prepared directly from a lower alkyl ester of fluvastatin such
as fluvastatin methyl ester. The ester is dissolved in a solution of about one molar
equivalent of sodium in ethanol. The sodium can be conveniently provided by dissolving
the appropriate quantity of sodium hydroxide pellets in water, while exercising caution
since the dissolution in water is highly exothermic. The solution is heated for a sufficient
period of time to hydrolyze the ester, typically several hours. Then, a large excess (e.g.
8x v/v) of propan-2-ol is added to the solution. The mixture is men cooled to ambient
temperature and maintained until a precipitate forms in the flask.
Form XXXDC can then be separated from the solution by conventional means. Form
XXXIX unlike Form IX is obtained without use of water.
Fluvastatin Sodium Crystal Form XLI

Fluvastatin sodium Form XLI produces a PXRD diffractogram having
characteristic peaks at 3.75,4.31, 9.10,11.00±0.2 degrees two-theta and other peaks at
5.60, 7.30, 7.55,14.50,18.04±0.2 degrees two-theta (FIG. 61). The water content of this
sample measured by Karl Fisher is about 9% by weight. The weight loss by TGA is
about 9% by weight. Fluvastatin sodium Form XLI is a hemipentahydrate.
Fluvastatin sodium Form XLI can be prepared by precipitating fluvastatin sodium
from a mixture of water and acetonitrile. Fluvastatin sodium- should first be dissolved in
water. The water may be heated in order to produce a more concentrated solution and
maximized recovery of Form XLI. Fluvastatin sodium can be dissolved to produce a
solution of 0.375 g ml"1 or greater in water at 100°C. Of course, if all of the fluvastatin
sodium does not go into solution or reprecipitates, additional water should be added.
Once a homogeneous solution-has been formed, acetonitrile is added to the solution to
induce precipitation of the fluvastatin sodium. The addition is done at whatever elevated
temperature was used to dissolve the starting material or at higher temperature. The
addition is dropwise and will generally require adding a excess of acetonitrile over the
amount of water that was used. For example, we used a little less than four volumes of
acetonitrile. The resulting heterogeneous mixture is then allowed to cool. Before
isolating the fluvastatin sodium Form XLI that precipitates. The recovery can be
improved by adding an addition portion of acetonitrile after cooling.
Form XLI can then be separated from the water and acetonitrile by conventional
means such as filtering, decanting, centrifuging and the like. Preferably, the liquids are
separated by vacuum filtration under an inert gas like nitrogen and washed with
acetonitrile. A suitable condition for drying the separated product is 50°C under vacuum.
Fluvastatin Sodium Crystal Form XLII
Fluvastatin sodium Form XLH produces a PXRD diffractogram having
characteristic peaks at 3,4,9.7,11.0,18.9±0.2 degrees two-theta and other peaks at 5.7,
14.8,16.1, 17.0,22.6±0.2 degrees two-theta (FIG. 62). The water content of this sample
measured by Karl Fisher is about 4% by weight. The weight loss by TGA is about 5% by
weight. Fluvastatin sodium Form XLH is a monohydrate.
Form XLH can be prepared from a fiuvastatin-diol by dissolving fluvastatin-diol
in methyl ethyl ketone and then filtering the solution. Sodium hydroxide dissolved in
methanol is then added to the solution and the solution is stirred at room temperature to
obtain a gelatinous precipitate. The product is recovered by any conventional means such
as filtering, decanting, centrifuging and the like. Preferably, the liquids are separated by
vacuum filtration under an inert gas like nitrogen. A suitable condition for drying the
separated product is 50°C under vacuum.

According to another process for preparing fiuvastatin sodium Form XLH,
fluvastatin diol is dissolved in methanol at reflux temperature and solid sodium hydroxide
is added to the solution. The solution is stirred at room temperature to obtain a precipitate
having a paste-like consistency. Ethyl acetate is added dropwise to the stirred solution.
Then, the solution is cooled to form a slurry. The product is separated from the solution
by any conventional means such as filtering, decanting, centrifuging and the like.
Preferably, the liquids are separated by vacuum filtration under an inert gas like nitrogen.
A suitable condition for drying the separated product is 50°C under vacuum.
Abpording to yet another process for preparing fluvastatin sodium form XLU,
fluvastatin-diol is completely dissolved in dichloromethane and the solution is filtered.
An ethanolic or methanolic solution of NaOH is added to the solution. The solution is
stirred at room temperature to obtain a precipitate and the product is separated by any
conventional means such as' filtering, decanting, centrifuging and the like. Preferably, the
liquids are separated by vacuum filtration under an inert gas like nitrogen. A suitable
condition for drying the separated product is 50 °C under vacuum.
Fluvastatin Sodium Crystal Form XLIII
Fluvastatin sodium Form XLIII produces a PXRD diffractogram having
characteristic peaks at 4.25, 5.29, 6.59, 8,60±0.2 degrees two-theta and other peaks at
12.75,14.26±0.2 degrees two-theta (FIG. 63). The water content of this sample measured
by Karl Fisher is about 9-11% by weight The weight loss by TGA is about 12% by
weight. '
We have discovered two ways of making Form XL/in. If can be made by inducing
precipitation from an aqueous solution by dropwise addition of propan-2-ol at elevated
temperature. The preferred procedure is similar to that used to prepare Form.XLI, except
that propan-2-ol is used instead of acetonitrile. We prepared an aqueous solution with a
three fold excess of water to fluvastatin sodium (ml g"1). After obtaining a homogenous
solution, a three-fold excess of propan-2-ol to water (ml ml"1) was added to it at elevated
temperature. The initial addition of propan-2-ol at elevated temperature causes crystals of
Form XLIII to form. However, addition of another portion of propan-2-ol of about the
same amount after the mixture has cooled should be done to maximize recovery of Form
XLffl.
According to another process for preparing fluvastatin sodium Form XLHI, a
lower alkyl ester of fluvastatin is dissolved in a solution containing about one molar
equivalent of sodium hydroxide in water. Once a homogeneous solution of fluvastatin
sodium is obtained, precipitation of the sodium salt is induced by addition of propan-2-
ol. Formation of the salt and the initial addition of propan-2-ol are preferably conducted

at elevated temperature, e.g. 70°C. After cooling the solution to ambient temperature,
additional portions of propan-2-ol can be added to increase recovery of Form XLIQ.
There is a tendency for the solution to gel. As described in the examples, the gel can be
broken by reheating the mixture and then cooling again.
Form XLffl can then be separated from the water and propan-2-ol in either of the
processes just described by conventional means such as filtering, decanting, centrifuging
and the like. Preferably, the liquids are separated by vacuum filtration under an inert gas
like nitrogen. A suitable condition for drying the separated product is 50°C under
vacuum.
Fluvastatin Sodium Crystal Form XLIV
Fluvastatin sodium Form XLTV produces a PXRD diffractogram having
characteristic peaks at 3.46,4.05, 9.19,10.14, 20.56±0.2 degrees two-theta and other
peaks at 6.26,10.91, 11.12,11.38,15.98,20.02, 22.21, 23.52,25.45±0.2 degrees
two-theta (FIG. 64). The water content of this sample measured by Karl Fisher is about
4-6% by weight. The weight loss by TGA is about 8-10% by weight.
Fluvastatin sodium Form XLIV can be prepared by forming a heterogeneous
mixture of amorphous fluvastatin sodium in propan-2-ol. Preferably the two are used in a
ratio of about 20 ml g "l. The suspension should be heated to accelerate conversion.
After cooling, Form XLIV can be separated from the propan-2-ol by conventional means
such as filtering, decanting, centrifuging and the like. Preferably, the propan-2-ol is
separated by vacuum filtration under an inert gas like nitrogen. A suitable condition for
drying the separated product is 50 ° G under vacuum.
Alternatively Form XLIV can be prepared directly from fluvastatin free acid.
According to a preferred embodiment of this method, the free acid is dissolved in acetone
and a molar equivalent of ethanolic sodium (preferably prepared by dissolving an
equivalent of sodium hydroxide in ethanol) is added to the solution and the resulting
mixture is maintained until fluvastatin sodium Form XLIV precipitates. Form XLIV may
men be separated from the acetone and ethanol by conventional means and dried. A
suitable condition for drying the separated product is 50°C under vacuum.
Fluvastatin Sodium Crystal Form XLV
Fluvastatin sodium Form XLV produces a PXRD pattern (FIG, 65) having
characteristic peaks at 3.7,5.1,10.7,17.8 and 20.3±0.2 degrees two-theta, and other
peaks at 6.2,14.5, 21.6,22.6 and 25.2±0.2 degrees two-theta.
Form XLV can be prepared by suspending amorphous fluvastatin sodium in
propan-2-ol at room temperature for a period of time sufficient to effect the conversion to

Form XLV, which typically requires about 25 h. Form XLV can then be separated from
propan-2-ol by conventional means such as filtering, decanting, centrifuging and the like.
Preferably, the liquids are separated by vacuum filtration under an inert gas like nitrogen.
After optionally washing with for example propan-2-ol, the crystals can be dried. A
suitable condition for drying the separated product is 50°C under vacuum.
Fluvastatin Sodium Crystal Form XLVI
Fluvastatin sodium Form XLVI produces a PXRD pattern (FIG. 66) having
characteristic peaks at 3.3, 3.5, 10.2,11.2 and 21.1±0.2 degrees two-theta, and other
peaks at 9.7,12.1, .17.2 and 19.0±0.2 degrees two-theta.
Form XLVI can be prepared directly from a lower alkyl ester of fluvastatin such
as fluvastatin methyl ester. The ester is dissolved in a solution of about one molar
equivalent of sodium in ethanol. The sodium can be conveniently provided by dissolving
the appropriate quantity of sodium hydroxide pellets in water, while exercising caution
since the dissolution in water is highly exothermic. The solution is heated for a sufficient
period of time to hydrolyze the ester, typically several hours. Then, a large excess (e.g.
lOx v/v) of acetonitrile is added to the solution to induce precipitation of Form XLVI
The resulting slurry is then cooled to ambient temperature and Form XLVI is separated
from the ethanol and acetonitrile by conventional means such as filtering, decanting,
centrifuging and the like. Preferably, the liquids are separated by vacuum filtration under
an inert gas like nitrogen. A suitable condition for drying the separated product is 50°C
under vacuum,
Fluvastatin Sodium Crystal Form XLVII
Fluvastatin sodium Form XLVII produces a PXRD (FIG. 67) pattern having
characteristic peaks at 3.3,10.2 and 18.0±0.2 degrees two-theta, and other peaks at 8.3,
10.8,13.6,20.7 and 21.3±0.2 degrees two-theta.
Fluvastatin sodium Form XLVII can be prepared by exposing fluvastatin sodium'
Form XVin to water vapor. Preferably, Form XVITI is maintained under an atmosphere
of 80% relative humidity at ambient temperature. Substantially complete conversion is
achieved over a period of weeks, typically about three and a half weeks.
Fluvasfatin Sodium Crystal Form XLVHI
Fluvastatin sodium Form XLVEI produces a PXRD pattern having characteristic
peaks at 4.5, 6.7, 7.0,10.9,19.1, 21.7±0.2 degrees two-theta, and other peaks at 8.9,12.9,
13.1,13.5,15.2,16.8,17.6,18.3,19.7,20.6±0.2 degrees two-theta. The water content of
this sample measured by Karl Fisher is about 6-8% by weight. The weight loss by TGA
is about 8% by weight. Fluvastatin sodium Form XLn is a dihydrate.

Fluvastatin sodium Form XLVIII can be made by dissolving a lower alkyl ester of
fluvastatin in a solution containing about one molar equivalent of sodium hydroxide in
methanol. Once a homogeneous solution of fluvastatin sodium is obtained, precipitation
of the sodium salt is induced by addition of acetonitrile. Formation of the salt and the
addition of acetonitrile are preferably conducted at elevated temperature. After cooling
and being allowed to stand for a sufficient time for crystallization to go substantially to
completion, Form XLIII can then be separated from the methanol and acetonitrile by
conventional means such as filtering, decanting, cenrrifuging and the like. Preferably, the
liquids are separated by vacuum filtration under an inert gas like nitrogen. A suitable
condition for drying the separated product is 50°C under vacuum.
Fluvatastin sodium Form XLVffl can also be prepared from fluvastatin sodium
Form B. Fluvastatin sodium Form B is slurried in methanol at elevated temperature for a
period of time sufficient to effect the conversion to Form XLVTDL The slurry is then
cooled to ambient temperature and Form XLVDI is separated by conventional means
known to one of skill in the art such as filtering, decanting, centrifuging, and the like.
Preferably, the liquids are separated by vacuum filtration under an inert gas like nitrogen.
A suitable condition for drying the separated product is 50°C under vacuum.
In another process for preparing fluvastatin sodium Form XLVIH, fluvastatin
sodium Form B is dissolved in methanol at room temperature and the solution is heated to
reflux temperature to obtain a precipitate. The methanol stays in solution for a short
amount of time. The resulting slurry is cooled and stirred at room temperature /and Form
XLVIII is separated by conventional means known to one of skill in the art such as
filtering, decanting, centrifuging, and the like. Preferably, the liquids are separated by
vacuum filtration under an inert gas like nitrogen. A suitable condition for drying the
separated product is 50°C under vacuum.
hi another process for preparing fluvastatin sodium Form XLVm, fluvastatin diol
is completely dissolved in methanol at reflux temperature and the solution is filtered to
obtain a clear solution and heated to reflux again. Solid NaOH is added to the solution at
reflux temperature to obtain a precipitate. The resulting slurry is cooled to room
temperature to obtain a mixture having a paste-like consistency. Acetone is added
dropwise to the mixture at room temperature. The solution is stirred at room temperature
to obtain Form XLVIII as a precipitate. Form XLVm is separated by conventional
means known to one of skill in the art such as filtering, decanting, centrifuging, and the
like. Preferably, the liquids are separated by vacuum filtration under an inert gas like
nitrogen. A suitable condition for drying the separated product is 50°C under vacuum.
Fluvastatin Sodium Crystal Form XLIX
37
FJuvastatin sodium Form XLIX produces a PXRD pattern (FIG. 69) having
characteristic peaks at 3.5, 5.0,12.1,33.5 and 20.2±0.2 degrees two-theta and other peaks
at 6.3,10.1 and 17.U0.2 degrees two-theta.
Form XLIX can be prepared from fhivastatin sodium Form B. According to a
preferred process, about 1:8 (w/v) of Form B is dissolved in methanol at ambient
temperature. After dissolution, the solution is heated to reflux and then MTBE is slowly
added (dropwise on a bench scale) to the refluxing solution. The addition causes
fluvastatin Form XLIX to precipitate from solution. After precipitation, the suspension
can be cpoled to ambient temperature and Form XLIX can be separated from the methanol and MTBE by conventional means known to one of skill in the art such as
filtering, decanting, centrifuging, and the like. Preferably, the liquids are separated by
vacuum filtration under an inert gas like nitrogen. After optional washing, for example
with MTBE, the crystals can be dried. A suitable condition for drying the separated
product is 50°C under vacuum.

Fluvastatin Sodium Crystal Form L
Fluvastatin sodium Form L (50) produces a PXRD pattern (FIG. 70) having
characteristic peaks at 6.48, 6.92, 9.72,12.64,21.49±0.2 degrees two-theta and other
peaks at 4.53,12.06,13.50,14.79,15.79,16.32,19.15,23.19±0.2 degrees two-theta. The
water content of this sample measured by Karl Fisher is about 5-6% by weight. The
weight loss by TGA is about 7% by weight. Fluvastatin sodium Form L is a
sesquihydrate.
Fluvastatin sodium Form L can be prepared by precipitation from a mixture of
methanol and ethyl acetate. The fluvastatin sodium starting material, in any crystalline
form or amorphous, should first be dissolved in the methanol. One gram of fluvastatin
sodium will dissolve in 7 ml of methanol or more at room temperature. The starting
material can be dissolved either at ambient or elevated temperature, e.g. the boiling point
of methanol. Once dissolved, precipitation of Form L is induced by dropwise addition of
ethyl acetate to the solution at elevated temperature. The amount of ethyl acetate used is
preferably about three times the volume of methanol. Once precipitation has started, the
mixture can then be allowed to cool and after an optional period of.time for further
crystallization at ambient temperature, Form L can be separated from the methanol and
ethyl acetate by conventional means such as such as filtering, decanting, centrifuging and
the like. Preferably, the liquids are separated by vacuum filtration under an inert gas like
nitrogen. A suitable condition for drying the separated product is 50 °C under vacuum.
Pluvastatin Sodium Crystal Form LI

Fluvastatin sodium Form XLIX produces a PXRD pattern (FIG. 71) having
characteristic peaks at 6.2,10.8,14.5 and 20.7±0.2 degrees two-theta and other peaks at
8.9,11.5 and 23.1±0.2 degrees two-theta.
Form LI can be prepared from fluvastatin sodium Form B by a procedure
analogous to the one used to prepare Form XLIX, but substituting acetonitrile for MTBE.
Fluvastatin Sodium Crystal Form LIII
Fluvastatin sodium Form XLIX produces a PXKD pattern (FIG. 72) having
characteristic peaks at 5.6,6.3,10.5,20.9±0.2 degrees two-theta and other peaks at!4.3,
15.1,15.6 and 17.1±0.2 degrees two-theta.
Form LDI can be prepared .from fluvastatin sodium Form B by a procedure
analogous to the one used to prepare Form XLIX, but substituting ethyl acetate for
MTBE.
Fluvastatin Sodium Crystal Form LIV
Fluvastatin sodium Form LIV produces a PXRD pattern (FIG. 73) having
characteristic peaks at 3.4,10.4,18.2,19.6,21.3±0.2 degrees two-theta and other peaks at
6.9,12.1,13.8,17.7,19.0±0.2 degrees two-theta. The water content of a sample of Form
LIV measured by Karl Fisher was about 11% by weight. The weight loss by TGA is
about 11% by weight. Fluvastatin sodium Form LIV is a trihydrate.
Fluvastatin sodium Form LIV can be prepared from by mixing fluvastatin in an
aqueous solution of sodium hydroxide to obtain a suspension having a mud-like
consistency. The suspension is stirred at room temperature and the product can be
separated by conventional means such, as filtering, decanting, centrifuging and the like.
Preferably, the liquids are separated by vacuum filtration under an inert gas like nitrogen.
A suitable condition for drying the separated product is 50°C under vacuum.
Fluvastatin Sodium Crystal Form LV
Fluvastatin sodium Form LV produces a PXRD pattern having characteristic
peaks at 3.7,5.0,5.9,12.2±0.2 degrees two-theta and other peaks at 5.6,8.7,10.1,
11.2±0.2 degrees two-theta. The water content of this sample measured by Karl Fisher is
about 7% by weight. The weight loss by TGA is about 7% by weight, Fluvastatin
sodium Form LV is a dihydrate.
Fluvastatin sodium Form LV can be prepared by precipitation from a mixture of
methanol and acetonitrile, Preferred mixtures contain from about 10% to about 12%,
more preferably about 12.5% by volume (methanol volume/acetonitrile volume X 100).
39
A preferred procedure starts with a lower alkyl ester of fluvastatin. The
fhrvastatin ester is added to acetonitrile and the mixture is heated until the ester dissolves.
The solution is then cooled and a solution of sodium hydroxide in methanol is added to it.
Form LV can be separated from the methanol and acetonitrile by conventional means
such as filtering, decanting, centrifuging and the like. Preferably, the liquids are
separated by vacuum filtration under an inert gas like nitrogen. A suitable condition for
drying the separated product is 50°C under vacuum.
Fluvastatin Sodium Crystal Form LVI
Fluvastatin sodium Form LVI produces a PXRD pattern (FIG. 75) having
characteristic peaks at 3.4,22.1 and 27.4±0.2 degrees two-theta and other peaks at 6.8,
10.2,13.6,18.5 and 20.0±0.2 degrees two-theta.
Form LVI can be prepared directly from a lower alkyl ester derivative of
fluvastatin having a ketal protecting group on the P and 6 hydroxyl groups, such as an
acetonide protected fluvastatin methyl ester. The starting material is taken up in THF and
the acetonide is hydrolyzed with HC1, preferably 1.5% (aq.) HC1. The time required will
be dependent upon the concentration of the starring material and acid concentration used,
but cap.-be readily determined by reaction-monitoring techniques such as thin layer
chromatography. Thereafter, a sufficient excess of NaOH is added to neutralize the HC1.
The THF is then evaporated and the residue is taken up in acetone. About a molar
equivalent of sodium hydroxide is added to the solution. Over time, fluvastatin sodium
precipitates as Form LVI. Form LVI can be separated by conventional means such as
filtering, decanting, centrifuging and the like. Preferably, the acetone is separated by
vacuum filtration under an inert gas like nitrogen. After optional washing, for example
with acetone, the crystals can be dried. A suitable condition for drying is 50°C under
vacuum.
Fluvastatin Sodium Crystal Form LVn
Fluvastatin sodium Form LVII produces a PXRD pattern (FIG. 76) having
characteristic peaks at 3.7,5.0, 5.5,10.1,12.1±0.2 degrees two-theta and other peaks at
8.6,11.1,14.9,21.7,22.8±0.2 degrees two-theta. The water content of this sample
measured by Karl Fisher is about 2% by weight. The weight loss by TGA is about 2% by
weight. Fluvastatin sodium Form LVII is a hemihydrate.
Fluvastatin sodium Form LVn can be prepared by forming a heterogeneous
mixture of fluvastatin sodium Form VII and ethanol and maintaining the heterogeneous
mixture until substantially all of the Form VII is converted into Form LVH. Preferably,
the ethanol is anhydrous ("absolute") and the suspension is maintained under dry

conditions. Form LVII can be separated from the ethanol by conventional means such as
filtering, decanting, centrifuging and the like. Preferably, the ethanol separated by'
vacuum filtration under an inert gas like nitrogen. A suitable condition for drying the

separated product is 50 °C under vacuum.
Fluvastatin Sodium Crystal Form LVI3I
Fluvastatin sodium Form LVIII produces a PXRD pattern (FIG. 77) having
characteristic peaks at 3.4,3.8, 5.4,5.7,10.3±0.2 degrees two-theta and other peaks at
4.7, 7.2, 8.4, 11.5,17.5, 20.4,2\\4,23.1±0.2 degrees two-theta. The water content of this
sample measured by Karl Fisher is about 4-5% by weight. The weight loss by TGA is
about 6-7% by weight.
Fluvastatin sodium Form LVHI can be prepared by forming a heterogeneous
mixture of fluvastatin sodium and propan-2-ol and maintaining the heterogeneous mixture
for a period of time sufficient to substantially convert the fluvastatin sodium into Form
LVTII. A preferred starting material is fluvastatin sodium Form B. The conversion can
be accelerated by heating the suspension, preferably to reflux temperature of the diluent.
Form LVUI can be separated from the propan-2-ol by conventional means such as
filtering, decanting, centrifuging and the like. Preferably, the liquids are separated by
vacuum filtration under an inert gas like nitrogen. A suitable condition for drying the
separated product is 50°C under vacuum.
Fluvastatin Sodium Crystal Form LX
Fluvastatin sodium Form LX produces a PXRD pattern (FIG. 78) having
characteristic peaks at 5.6, 6.3 and 10.5±0.2 degrees two-theta and other peaks at 4.1,5.0,
11.0,15.7,17.2 and 19.6±0.2 degrees two-theta. Form LX may be prepared by adding
ethyl acetate to solution of fluvastatin sodium in methanol. In the exemplified
embodiment, the solution is heated, followed by portion-wise addition of ethyl acetate.
Form LX then precipitates, and is stirred and recovered by conventional techniques.
Fluvastatin Sodium Crystal Form LXIV
Fluvastatin sodium Form LXIV produces a PXRD pattern (FIG. 79) having
characteristic peaks at 5.8, 13.9 and 14.7±0.2 degrees two-theta and other peaks at 5.1,
9.3,11.7 and 19.4±0.2 degrees two-theta.
Form LXTV can be prepared directly from a lower alkyl ester of fluvastatin such
as fluvastatin methyl ester. Two different processes have been discovered. According to
a preferred embodiment of one process, about 0.1:1 (w/v) of the starting material is
dissolved in methanol while heating the mixture to reflux. About one equivalent of
sodium hydroxide is then added to the refluxing solution. During hydrolysis, fluvastatin

sodium begins to precipitate. After the hydrolysis is complete, which can be determined
by thin layer chromatography, the slurry is cooled to ambient temperature. Cooling
causes the precipitate to redissolve. Acetone is then added to the solution to reprecipitate
fluvastatin sodium in Form LXIV. Thereafter Form LXIV can be separated from the
methanol and acetone by conventional means such as filtering, decanting, centrifuging
and the like. Preferably, the liquids are separated by vacuum filtration under an inert gas
like nitrogen. A suitable condition for drying, the separated product is 50°C under
vacuum.
According to an alternative process for making Form LXTV, about 1:15 (w/v) of
the starting lower alkyl ester of fluvastatin is dissolved in acetone. Then an' excess of
sodium hydroxide dissolved in methanol is added to the solution. Over time, fluvastatin
sodium precipitates from the solution as Form LXTV. Form LXIV can be separated from
the acetone and methanol by conventional techniques such as filtering, decanting,
centrifuging and the like, preferably filtering under an inert atmosphere like nitrogen.
After optional washing, for example with acetone, the separated Form LXTV may be
dried. A suitable drying condition is 50 °C under vacuum.
Fluvastatin Sodium Crystal Form LXV

Fluvastatiu sodium Form LXV produces a PXRD pattern (FIG. 80) having
characteristic peaks at 5.8, 13.9 and 14.7±0.2 degrees two-theta and other peaks at 5.1,
9.3,11.7 and 19.4±0.2 degrees two-theta.
Form LXV can be prepared directly from a lower alkyl ester of fluvastatin such
as fluvastatin methyl ester. According to a preferred process, about 1:7 (w/v) of the
starting material is dissolved in methanol containing about one equivalent of sodium at
ambient temperature. After the mixture becomes clear, about six volumes of propan-2-ol
is added to induce precipitation of fluvastatin sodium in Form LXV. Thereafter Form
LXV can be separated from the methanol and propan-2-ol by conventional means such as
filtering, decanting, centrifuging and the like. Preferably, the liquids are separated by
vacuum filtration under an inert gas like nitrogen. After optional washing, for example
with acetone, the crystals can be dried. A suitable condition for drying the separated
product is 50 °C under vacuum. In the process, five volumes of acetone can be
substituted for the six volumes of propan-2-ol.
Fluvastatin Sodium Crystal Form LXVI
Fluvastatin sodium Form LXVI produces a PXRD pattern (FIG. 81) having
characteristic peaks at 3.6,10.8,17.8,18.3 and 21.6±0.2 degrees two-theta and other
peaks at 7.2,12.2, 14.4 and 25.5±0.2 degrees two-theta.

We have been able to produce Form LXVI from several other crystal forms of
fluvastatin sodium by similar processes. In general terms either fluvastatin sodium Form
VI, B or XV is dissolved in water either at ambient temperature or elevated temperature
to obtain a clear solution. The solution is refluxed, preferably for one to two hours and
then is cooled or allowed to cool to ambient temperature. After a period of time, Form
LXVT precipitates from the solution. Form LXVI can be separated from the water by
conventional means such as by filtering, decanting, centrifuging and the like. Preferably,
the water is separated by vacuum filtration under an inert gas like nitrogen. After
optional washing, for example with water, the crystals can be dried. A suitable condition
for drying the separated product is 50°C under vacuum.
Pluvastatin Sodium Crystal Form LXVH
Fluvastatin sodium Form LXVII produces a PXRD pattern (FIG. 82) having
characteristic peaks at 3.7 and 4.4±0.2 degrees two-theta and other peaks at 5.6 and
10.8±0.2 degrees two-theta.
Form LXVII can be prepared directly fronra lower alkyl ester of fluvastatin such
as fluvastatin methyl ester. According to a preferred process, 1:15 (w/v) of the starting
material is dissolved in acetone. An excess of sodium hydroxide in methanol is added
and the mixture is maintained at ambient temperature until hydrolysis of the ester is
complete. Thereafter, fluvastatin sodium precipitates in Form LXVTI. Thereafter Form

LXVII can be separated from the methanol and acetone by conventional means such as by
filtering, decanting, centrifuging and the like. Preferably, the methanol and acetone is
separated by vacuum filtration under an inert gas like nitrogen. After optional washing,
for example with acetone, the crystals can be dried. A suitable condition for drying the
separated product is 50°C under vacuum.
Fluvastatin Sodium Crystal Form LXVm
Fluvastatin sodium Form LXVEE produces a PXRD pattern (FIG. 83) having
characteristic peaks at 3.6, 5.9,10.8 and 11.6±0.2 degrees two-theta and other peaks at
1 9.3,15.4,17.0,18.4 and 23.0±0.2 degrees two-theta.
Form LXVIII can be prepared directly from a lower alkyl ester of fluvastatin such
as fluvastatin methyl ester. According to a preferred process, 1:15 (w/v) of the starting
material is dissolved in acetone. An excess of sodium hydroxide in methanol as added to
the solution. The solution is maintained at ambient temperature for a period of time
sufficient to hydrolyze the ester, which can be determined by thin layer chromatography.
Thereafter, Form LXVIII crystallizes either spontaneously or with cooling and can be
separated from the methanol and acetone by conventional means such as by filtering,

decanting, centrifuging and the like. Preferably, the methanol and acetone are separated
by vacuum filtration under an inert gas like nitrogen. After optional washing, for
example with acetone, the crystals can be dried. A suitable condition for drying the
separated product, is 50 °C under vacuum.
Fluvastatin Sodium Crystal Form LXIX
Fluvastatin sodium Form LXIX produces a PXRD pattern (FIG. 84) having
characteristic peaks at 3.5, 5.7, 10.8,18.2 and 21.6±0.2 degrees two-theta and other peaks
at 12.4,14.7,20.4,22.4 and 25.4±0.2 degrees two-theta. ^
Form LXIX can be prepared by slurrying fluvastatin sodium Form VI in propan-2-
ol at reflux temperature for a period of time sufficient to effect the conversion. After
cooling the solution, Form LXIX can be separated from the propan-2-ol by conventional
means such as filtering, decanting, centrifuging and the like. Preferably, the propan-2-ol
is separated by vacuum filtration under an inert gas like nitrogen. After optional washing,
for example with propan-2-ol, the crystals can be dried. A suitable condition for drying
the separated product is 50°C under vacuum..
Fluvastatin Sodium Crystal Form LXX
Fluvastatin sodium Form LXX produces a PXRD pattern (FIG. 85) having
characteristic peaks at 3.0,3 A', 5.9, and 13.8±0.2 degrees two-theta and other peaks at
8.2, 8.9, 18.6, 21.1 and 22.4±0.2 degrees two-theta.
Form LXX can be prepared from fluvastatin sodium such as Form LXVII by
dissolving in water at reflux temperature and adding a ten fold excess of acetone to
induce precipitation of fluvastatin sodium in Form LXX. After cooling the resulting
mixture to ambient temperature, Form LXX can be separated from the water and acetone
by conventional means such as by filtering, decanting, centrifuging and the like.
Preferably, the water and acetone are separated by vacuum filtration under an inert gas
like nitrogen. After optional washing, for example with acetone, the crystals can be dried.
A suitable condition for drying the separated product is 50 °C under vacuum.
Fmvastatin Sodium Crystal Form LXXI
Fluvastatin sodium Form LXXI produces a PXRD pattern (FIG. 86) having
characteristic peaks at 3.9, 7.8,11.6 and 15.5±0.2 degrees two-theta and other peaks at
9.2, 13.3,19.0 and 23.2±0.2 degrees two-theta.
Form LXXI can be prepared by refluxing a 1:1 (w/v) mixture of fluvastatin
sodium Form LXVn and water and then adding a large excess of acetone and maintaining
the mixture for a period of time sufficient to effect the conversion to Form LXXI. After

cooling the resulting mixture to ambient temperature, Form LXXI can be separated from
the water and acetone by conventional means such.as by filtering, decanting, centrifuging
and the like. Preferably, the water and acetone are separated by vacuum filtration under
an inert gas like nitrogen. After optional washing, for example with acetone, the crystals
can be dried. A suitable condition for drying the separated product is 50 °C under
vacuum.
Fluvastatin Sodium Crystal Form LXXII
Fluvastatin sodium Form LXXII produces a PXRD pattern (FIG. 87) having
characteristic peaks at 3.7, 5.7 and 12.1±0.2 degrees two-theta and other peaks at 5.0,
10.8,16.8 and 20.1±0.2 degrees two-theta.
Form LXXII can be prepared from fluvastatin sodium Form VI. According to one
preferred procedure, the starting material is suspended in an about 40:1 mixture of
acetone and water and heated to reflux for a period of time sufficient to effect the
conversion to Form LXXJQ. After the mixture has cooled to ambient temperature, Form
LXXII can be separated from the water and acetone by conventional means such as by
filtering, decanting, centrifuging and the like. Preferably, the water and acetone are
separated by vacuum filtration under an inert gas like nitrogen. After optional washing,
for example with acetone, the crystals can be dried. A suitable condition for drying the
separated product is 50 °C under vacuum.
According to another preferred procedure, Form VI is suspended in acetonitrile
and heated to reflux for a period of time sufficient to effect the conversion. After the
mixture has cooled to ambient temperature, Form LXXII can be separated from the
acetonitrile by conventional means such as filtering, decanting, centrifuging and the like.
Preferably, the acetonitrile is separated by vacuum filtration under an inert gas like
nitrogen. After optional washing, for example with acetonitrile, the crystals can be dried.
A suitable condition for drying the separated product is 50°C under vacuum.
Fluvastatin Sodium Crystal Form LXXIV
Fluvastatin sodium Form LXXTV produces a PXRD pattern (FIG. 89) having
characteristic peaks at 4.0, 12.8,19.0,19.9 and 25.8 ±0.2 degrees two-theta and other
peaks at 5.4,11.8,13.4,18.0 and 24.6 ±0.2 degrees two-theta.
Form LXXrV can be prepared from fluvastatin sodium Form B by suspending
Form B in a refluxing about 10:1 mixture of propan-2-ol and water for a sufficient period
to effect the conversion. After cooling the solution, Form LXXTV can be separated from
the propan-2-ol and water by conventional means such as filtering, decanting,
centrifuging and the like. Preferably, the propan-2-ol and water are separated by vacuum

filtration under an inert gas like nitrogen. After optional washing, for example with
propan-2-ol, the crystals can be dried. A suitable condition for drying the separated
product is 50°C under vacuum.
Fluvastatin Sodium Crystal Form LXXV
Fluvastatin sodium Form LXXV produces a PXRD pattern (FIG. 90) having
characteristic peaks at 4.4, 6.6,10.8, 14.3 and 22.2±0.2 degrees two-theta and other peaks
at 7.8, 15.0,19.8, 20.4 and 21.4±0.2 degrees two-theta.
Form LXXV can be prepared from fluvastatin sodium Form XXX by refluxing
Form XXX in methanol for a period of time sufficient to effect the conversion. After
cooling the solution, Form LXXV can be separated from the methanol by conventional
means such as filtering, decanting, centriruging and the like. Preferably, the methanol is
separated by vacuum filtration under an inert gas like nitrogen. After optional washing,
for example with methanol, the crystals can be dried. A suitable condition for drying the
separated product is 50° C under vacuum.
Fluvastatin Sodium Crystal Form LXXVI
Fluvastatin sodium Form LXXVI produces a PXRD pattern (FIG. 91) having
characteristic peaks at 3.5, 7.0,10.5 and 13.0 ±0.2 degrees two-theta.
LXXVI can be prepared directly from a lower alkyl ester of fluvastatin such as
fluvastatin methyl ester. According to a preferred process, the starting material is
dissolved in an about 5:3 ethanol:water mixture containing about one equivalent of
sodium hydroxide. After the hydrolysis is complete, the mixture is partially concentrated
and additional water is added. The mixture is then extracted with a water immiscible
solvent,such as ethyl acetate. The aqueous phase is then distilled off leaving a residue
that is fluvastatin sodium Form LXXVI.
Fluvastatin Sodium Crystal Form LXXVII
Fluvastatin sodium Form LXXVII produces a PXRD pattern (FIG. 92) having
characteristic peaks at 3.6, 8.8,11.0,12.8 and 17.8±0.2 degrees two-theta and other peaks
at 7.3,20.2 and 31.0±0.2 degrees two-theta.
Form LXXVII can be prepared directly from a lower alkyl ester of fluvastatin
such as fluvastatin methyl ester. According to a preferred process, 1:30 (w/v) of the
starting material is dissolved in ethyl acetate. An excess of sodium hydroxide in water is
added to the solution. The solution is maintained at ambient temperature for a period of
time sufficient to hydrolyze the ester, which can be determined by thin layer
chromatography. Thereafter, Form LXXVII crystallizes and can be separated from the

ethyl acetate and water by conventional means such as filtering, decanting, centrifuging
and the like. Preferably, the ethyl acetate and water are separated by vacuum filtration
under an inert gas like nitrogen. After optional washing, for example with ethyl acetate,
the crystals can be dried. A suitable condition for drying the separated product is 50 °C
under vacuum.
Fluvastatin Sodium Crystal Form LXXVIII
Fluvastatin sodium Form LXXVIII produces a PXRJD pattern (FIG. 93) having
characteristic peaks at 8.8,19.1,27.2,29.6 and 30.9±0.2 degrees two-theta and other
peaks at 3.4,11.3,17.7,22.5 and 32.2±0.2 degrees two-theta.
Form LXXVIII can be prepared directly from a lower alkyl ester of fluvastatin
such as fluvastatin methyl ester. The starting material is hydrolyzed with sodium
hydroxide in water. Then, the reaction mixture is extracted with ethyl acetate. The
aqueous phase is concentrated. The residue is then contacted with either propan-2-oI or
acetonitrile for one or two days. After conventional separation of the propan-2-ol or
acetonitrile, the fluvastatin sodium is in Form LXXVIII. After optional washing, for
example with acetonitrile, the crystals can be dried. A suitable condition for drying the
separated product is 50°C under vacuum.
Summary of Distinctive Physical Properties of Fluvastatin Sodium Crystal Forms
A summary; of the water content of Forms IV, FV-1, VI, VH, XI, XI-2, XVIxvm,
xix, xix-i, xx, XXK, xxx, xxxi, xxxm, xxxiv, xxxv, XXXVH,
XXXVIH, XLI, XLH, XLHI, XLVffl, L,.LIV, LV, LIV, LV, LVH, and LVHI is provided
in the table below.
47
Form
rv
rv-i
VI
vn
XI
XI-2
XVI
XVII
xvm
XIX
XK-l
XX
XXIX
XXX
XXXI
XXXIII
XXXIV
XXXV
xxx vn
xxxvm
XLI
XLH
XLm
XLIV
XLvm
L
LIV
LV
LVH
LVffl
• Water Content
4%KF
2.1-2.6% KF
5.0-5.6%KF
4.1%-4.5%KF
4-6% KF
1. 9-3.2% KF
3-4% KF
4%KF
19-28%KF
8%KF
19% KF
4%KF
16% KF
7%KF
9.5% KF
10% KF
15%KF
9%KF
6-7% KF
9%KF
4%KF
9-11 %KF
4-6% KF
6-8% KF
5-6% KF
11% KF
7%KF
2%KF
4.6% KF
Weight Loss
8.3% TGA
10.5% TQA
12% TGA
13-14% TGA +
hygroscopicity
6-8% TGA
+ bygroscopicity
7.7% TGA
8.7% TGA
8.4% TGA
4% TGA
22-26% TGA
7% TGA
19% TGA
10% TGA
16% TGA
7% TGA
10.7% TGA
20.1% TGA
31% TGA
9% TGA
10-11 %TGA •
9%TGA
5% TGA
12% TGA
8-10% TGA
8% TGA
7% TGA
11%TGA
7%TGA
2% TGA
6.4 %TGA
Water Content Hydration
4
2-3
5-6%
1-9 - •
1-6
2-3
3-4
S
4 monohydrate
19-28 Hexahydrate
S:hydrate
9-hydrate
Dihydrate
19 hexahydrate
-
Tetrahydrate
Dihydrate
hemipemahydrate
-
Hemipentahydrate
-
monohydrate
monohydrate
-
-
Dihydrate
Sesquihydrate
Trihydrate
Dihydrate
hemihydrate
-
Jn addition to the crystalline polymorphic forms of fluvastatin sodium previously
described, we have discovered a number of semi-crystalline solid forms of fluvastatin that
can be reproducibly obtained by following certain procedures set forth below.

Fluvastatin Sodium Form XC
Fluvastatin sodium Form XC produces a PXRD pattern (FIG. 97) having
characteristic peaks at 3.2 and 9.6±0.2 degrees two-theta and other peaks at 11.8 and
19.S±0.2 degrees two-theta.
Fluvastatin sodium Form XC can be prepared from fluvastatin sodium Form B by
dissolving it in ethanol at ambient temperature and then adding cyclohexane to induce
precipitation. Afterwards, Form XC can be separated from the ethanol and cyclohexane
by conventional means such as by filtering, decanting, centrifuging and the like.
Preferably, the liquids are separated by vacuum filtration under an inert gas like nitrogen.
A suitable condition for drying the separated product is 50°C under vacuum.
Fluvastatin Sodium Form XCI
Fluvastatin sodium Form XCI produces a PXRD pattern (FIG. 98) having
characteristic peaks at 4.7, 5.6 and 13.8±0.2 degrees two-theta and other peaks at 7.3,9.6,
10.8,16.4,17.6,19.8, 20.8 and23.1±0.2 degrees two-theta.
Fluvastatin sodium Form XCI can be prepared from fluvastatin sodium Form XV
by suspending Form XV in ethyl acetate and maintaining the suspension at elevated
temperature for a sufficient period of time to convert Form XV into Form XCI. After
cooling the suspension to ambient temperature, Form XCI can be separated from the ethyl
acetate by conventional means such as filtering, decanting, centrifuging and the like.
Preferably, the ethyl acetate is separated by vacuum filtration under an inert gas like
nitrogen. A suitable condition for drying the separated product is 50°C under vacuum.

Fluvastatin Sodium Form XCII
Fluvastatin sodium Form XCII produces a PXRD pattern (FIG. 99) having
characteristic peaks at 3.4,10.1 and 11.8±0.2 degrees two-theta and other peaks at 4.1,
17.8,20.i; 21.7,23.4 and 25.3±0.2 degrees two-theta.
Fluvastatin sodium Form XCII can be prepared from fluvastatin sodium Form B by
dissolving it in a 10:1 ethanol:methanol at reflux temperature and then adding hexanes to
induce precipitation. Afterwards, Form XCH can be separated from the ethanol, methanol
and eyclohexane by conventional means such as filtering, decanting, centrifuging and the
like. Preferably, the liquids are separated by vacuum filtration under an inert gas like
nitrogen. A suitable condition for drying the separated product is 50°C under vacuum.
Fluvastatin Sodium Form XCIII
Fluvastatin sodium Form XCin produces a PXRD pattern (FIG. 100) having

characteristic peaks at 4.9, 5.9, 7.2 and 12.3±0.2 degrees two-theta and other peaks at 9.7,
10.9 and 13.9±0.2 degrees two-theta.
Fluvastatin sodium Form XCIII can be prepared from fluvastatin sodium^orm XV
by suspending it in propan-1-ol at ambient temperature and maintaining the suspension at
ambient temperature for a sufficient period of time to convert Form XV into Form XCIII.
Form XCffl can be separated from the propan-1-ol by conventional means such as
filtering, decanting, centrifuging and the like. Preferably, the propan-1-ol is separated by
vacuum filtration under an inert gas like nitrogen. A suitable condition for drying the
separated product is 50°C under vacuum.
Fluvastatin Sodium Form XCTV
Fluvastatin sodium Form XCIV produces a PXRD pattern (FIG. 101) having
characteristic peaks at 4.6, 9.2 and 20.3±0.2 degrees two-theta and other peaks at 4.1, 6.7,
13.0,15.8,17.7, 21.7 and23.0±0.2 degrees two-theta.
Fluvastatin sodium Form XCTV can be prepared from fluvastatin sodium Form XV
by suspending it in butan-1-ol at ambient temperature and maintaining the suspension at
ambient temperature for a sufficient period to convert Form XV into Form XCin. Form
XCIH can be separated from the butan-1-ol by conventional means such as by filtering,
decanting, centrifuging and the like. Preferably, the butan-1-ol is separated by vacuum
filtration under an inert gas like nitrogen. A suitable condition for drying the separated
product is 5 0 ° C under vacuum.
Fluvastatin. Sodium Form XCV
Fhivastatin sodium Form XCV produces a PXRD pattern (FIG. 102) having
characteristic peaks at 5.7,13.0,19.8 and20.5±0.2 degrees two-theta and other peaks at
4.2,4.7,12.3 and 15.9±0.2 degrees two-theta.
Fluvastatin sodium Form XCV can be prepared from fluvastatin sodium Form XV
by suspending it in either ethyl acetate, acetone, 1,4-dioxane or MEK at ambient
temperature and maintaining the suspension at ambient temperature for a sufficient period
of time to convert Form XV into Form XCV. Form XCV can be separated from the
diluent by conventional means such as filtering, decanting, centrifuging and the like.
Preferably, the diluent is separated by vacuum filtration under an Inert gas like nitrogen. A
suitabfe condition for drying the separated product is 50°C under vacuum.
Fluvastatin Sodium Form XCVI
Fluvastatin sodium Form XCVI produces a PXRD pattern (FIG. 103) having

characteristic peaks at 3.7,11.0,12.9 and 18.2±0.2 degrees two-theta and other peaks at
5.2, 8.3,17.7,21.5 and 25.5±0.2 degrees two-theta.
Fluvastatin sodium Form XCVI can be prepared from fluvastatin sodium Form XV
by suspending it in THF at ambient temperature and maintaining the suspension at ambient
temperature for a sufficient period of time to convert Form XV into Form XCVT. Form
XCV can be separated from the THF by conventional means such as filtering, decanting,
centrifuging and the like. Preferably, the THF is separated by vacuum filtration under an
inert gas like nitrogen. A suitable condition for drying the separated product is 50 °C
under vacuum.
Fhivastatin Sodium Form XCVH
Fluvastatin sodium Form XCVH produces a PXRD pattern (FIG. 104) having a
characteristic peak at 3.5±0.2 degrees two-theta and other peaks at 9.4,18.4,20.0,21.2
and 22.0±0.2 degrees two-theta.
Form XCVTJ can be prepared directly from a lower alkyl ester of fluvastatin such
as fluvastatin methyl ester. The starting material is hydrolyzed with sodium hydroxide in
cyclohexane. According to a preferred procedure, the sodium hydroxide is added as a
methanolic solution. Over time, fluvastatin sodium Form XCVII precipitates from the
mixture. Form XCVH can be separated from the cyclohexane by conventional means such
as filtering, decanting, centrifuging and the like. Preferably, the cyclohexane is separated
by vacuum filtration under an inert gas like nitrogen. A suitable condition for drying the
separated product is 50 °C under vacuum.
Fluvastatin Sodium Form XCVin ,,
Fluvastatin sodium Form XCVIII produces a PXRD pattern (FIG. 105) having
characteristic peaks at 3.8 and 10.8±0.2 degrees two-theta and other peaks at 6.4 and
14.4±0.2 degrees two-theta.
Form XCVIII can be prepared directly from a lower alkyl ester of fluvastatin such
as fluvastatin methyl ester. The starting material is hydrolyzed with sodium hydroxide in a
concentrated methanol solution at elevated temperature. After completion of the
hydrolysis, a large excess of acetonitrile (e.g. ~ 7x) is added to the methanol at elevated
temperature. The hot solution is then cooled or allowed to cool to ambient temperature
and held until Form XCVIII precipitates from the solution. Form XCVIII can be separated
from the methanol and acetonitrile by conventional means such as by filtering, decanting,
centrifliging and the like. Preferably, the methanol and acetonitrile are separated by
vacuum filtration under an inert gas like nitrogen. A suitable condition for drying the
separated product is 50 °C under vacuum.

Fluvastatin Sodium Form XCIX
Fluvastatin sodium Form XCIX produces a PXRD pattern (FIG. 106) having
characteristic peaks at 3.6,5.3, 8.7 and 10.4±0.2 degrees two-theta and other peaks at 17.9
and 21.5±0.2 degrees two-theta.
Fluvastatin sodium Form XCIX can be prepared from fluvastatin sodium Form VI
by suspending it in ethanol at ambient temperature and maintaining the suspension at
ambient temperature for a sufficient period to convert Form VI into Form XCIX. Form
XCIX can be separated from the ethanol by conventional means such as filtering,
decanting, centrifuging and the like. Preferably, the ethanol is separated by vacuum
filtration under an inert gas like nitrogen. A suitable condition for drying the separated
product is 50°C under vacuum.
Fluvastatin Sodium Form C
Fluvastatin sodium Form C (100) produces a PXRD pattern (FIG. 107) having
characteristic peaks at 3.3,9.8, 11.0, 19.0 and 22.7±0.2 degrees two-theta and other peaks
at 6.2,17.2 and 21.3±0.2 degrees two-theta.
Form C can be prepared directly from a lower alkyl ester of fluvastatin such as
fluvastatin methyl ester. The starting material is hydrolyzed with sodium hydroxide in
dichloromethane at room temperature. Over time, fluvastatin sodium precipitates from thereaction
mixture as Form C. Form C can be separated from the dichloromethane by
conventional means such as filtering, decanting, centrifuging and the like. Preferably, the
dichloromethane is separated by vacuum filtration under an inert gas like nitrogen. A
suitable condition for drying the separated product is 50 °C under vacuum.
Fluvastatin Sodium Form CI
Fluvastatin sodium Form CI produces a PXRD pattern (FIG. 108) having
characteristic peaks at 4.5 and 11.2±0.2 degrees two-theta and other peaks at 5.7 and
19.3±0.2 degrees two-theta.
Form CI can be prepared directly from a lower alkyl ester of fluvastatin such as
fluvastatin methyl ester. The starting material is hydrolyzed with sodium hydroxide in a
mixture of acetone and methanol. After completion of the hydrolysis and, where
applicable, cooling to ambient temperature, Form CI precipitates from the reaction
mixture. Form CI can be separated from the methanol and acetone by conventional means
such as filtering, decanting, centrifuging and the like. Preferably, the methanol and
acetone are separated by vacuum filtration under an inert gas like nitrogen. A suitable
S
condition for drying the separated product is 50°C under vacuum.

Fluvastatin Sodium Form CII
Fluvastathi sodium Form CII produces a PXRD pattern (FIG. 109) having a
characteristic peak at 4.3±0.2 degrees two-theta and other peaks at 8.7,11.0 and 19.2±0.2
degrees two-theta.
Form CII can be prepared directly from a lower alkyl ester of fluvastatin such as
fluvastatin methyl ester. The starting material is hydrolyzed with sodium hydroxide in a
mixture of acetone and methanol. After completion of the hydrolysis and, where
applicable, cooling to ambient temperature, Form CI precipitates from the reaction
mixture. Form C13 can he separated from the methanol and acetone by conventional
means such as filtering, decanting, centrifuging and the like. Preferably, the methanol and
acetone are separated by vacuum filtration under an inert gas like nitrogen. A suitable
condition for drying the separated product is 50°C under vacuum.

Fluvastatin Sodium Form CHI
Fluvastatin sodium Form GDI produces a PXRD pattern (FIG. 110) having
characteristic peaks at 4.5,20.4, 25.9 and 30.6±0.2 degrees two-theta and other peaks at
5.6,10.1, 12.5,19.0 and I9.7±0.2 degrees two-theta.
Form CHI can be prepared directly from a lower alkyl ester of fluvastatin such as
fluvastatin methyl ester. The starting material is hydrolyzed with sodium hydroxide in a
mixture of acetone and water. After completion of the hydrolysis and, where applicable,
cooling to ambient temperature, Form CHI precipitates from the reaction mixture. Form
CIE can be separated from the water and acetone by conventional means such as filtering,
decanting, centrifuging and the like. Preferably, the water and acetone are separated by
vacuum filtration under an inert gas like nitrogen. A suitable condition for drying the
separated product is 50°C under vacuum.
Fluvastatin Sodium Form CIV
Fluvastatin sodium Form CIV produces a PXRD pattern (FIG. Ill) having
characteristic peaks at 3.7, 9.7,18.3,19.9,21.8±0.2 degrees two-theta and other peaks at
5.6,11.3,14.8, 22.6±0.2 degrees two-theta. Form'CIV can be prepared directly from a
lower alkyl ester of fluvastatin such as fluvastatin methyl ester. The starting material is
hydrolyzed with sodium hydroxide in THF. After completion of the hydrolysis, hexanes is
added to the reaction mixture to induce precipitation of Form CIV. Form CIV can be
separated from the THF by conventional means such as filtering, decanting, centrifuging
and the like. Preferably, the THF is separated by vacuum filtration under an inert gas like
nitrogen. A suitable condition for drying the separated product is 50°C under vacuum.

Fluvastatin Sodium Form CV
Fluvastatin sodium Form CV produces a PXRD pattern (FIG. 112) having
characteristic peaks at 3.7, 8.9,19.1, 22.5,29.7±0.2 degrees two-theta and other peaks at
11.5,17.0,25.1,26.9,28.2 ±0.2 degrees two-theta. Form CV can be prepared directly
from a lower alkyl ester of fluvastatin such as fluvastatin methyl ester. The starting
material is hydrolyzed with sodium hydroxide in acetonitrile at elevated temperature.
After completion of the hydrolysis, the reaction mixture is cooled or allowed to cool. Over
time, fluvastatin sodium precipitates as Form CV. Form CV can be separated from the
acetonitrile by conventional means such as filtering, decanting, centrifuging and the like.
Preferably, the acetonitrile is separated by vacuum filtration under an inert gas like
nitrogen. A suitable condition for drying the separated product is 50 °C under vacuum.
Process for Preparing Amorphous Fluvastatin Sodium
We have discovered that fluvastatin sodium precipitates in an amorphous state
from 1,4-dioxane and cyclohexane. Accordingly, one preferred process for making,
amorphous fluvastatin sodium of the present invention is to dissolve fluvastatin sodium in
1,4-dioxane, more preferably at elevated temperature, yet more preferably at about 85 °C3
and cooling the resulting solution to induce precipitation of amorphous fluvastatin sodium.
In another preferred process, a lower alkyl ester of fluvastatin is suspended in
cyclohexane. Then, about one molar equivalent of sodium hydroxide dissolved in a
minimum of protic solvent like methanol, is added to the suspension. The addition should
cause the suspension to clarify. Upon standing, fluvastatin sodium may precipitate from
the solution in amorphous form. Otherwise, additional cyclohexane can be added to
induce precipitation.
In each of the foregoing processes, the precipitate is then separated from the 1,4-
dioxane or cyclohexane by conventional means such, as filtering, decanting, centrifuging
and the like. Preferably, the 1,4-dioxane is separated by vacuum filtration under an inert
gas like nitrogen. A suitable condition for drying the separated product is 50 °C under •
vacuum.
Pharmaceutical Compositions and Dosage Forms Containing-And Methods of Medical
Treatment Using The Novel Fluvastatin Sodium Forms
Fluvastatin exerts an antihypercholesterolemia and antihyperlipidemia effect in
mammals, especially humans. Accordingly, fluvastatin sodium Forms I, II, HI, IV, IV-1,
v, vi, vn, ix, K-I, xi, xi-2, xn, xm, xvi, xvn, xvrn, xix, XDC-I, xx, xxn,
xxnr, xxrv, xxvi, xxvn, xxix, xxx, xxxi, xxxm, xxxrv, xxxv, xxxvi,

XXXVH, xxxvin, xxxix, XLI, XLU, XLIII, XLIV, XLV, XLVI, XLVII, XLVIII,
XLIX, L, LI, LHI, LIV, LV, LVI, LVE, LVffl, LX, LXIV, LXV, LXVI, LXVH, LXVHI,
LXDC, LXX, LXXI, LXXH, LXXTV, LXXV, LXXVI, LXXVII, LXXVIU, XC, XCI,
XCII, XCni, XCIV, XCV, XCVI, XCVII, XCVm, XCIX, C, CI, CII, Cm, CIV, CV and
mixtures thereof with each other as well as with other crystalline forms of fluvastatin
sodium are useful for delivering fluvastatin to the gastrointestinal tract, bloodstream and
liver of humans and other mammals suffering from or at risk of atherosclerosis. In
particular, they are useful as active ingredients in pharmaceutical compositions and dosage
forms. ^For this purpose, they may be formulated into a variety of compositions and
dosage forms for administration to humans and animals.
Pharmaceutical compositions of the present invention contain fluvastatin sodium
Form I, II, III, IV, IV-1, V, VI, VII, DC, DC-1, XI, XI-2, XII, XHI, XVI, XVII, XVffl, XIX,
XK-I , xx, xxn, xxm, xxrv, xxvi, xxvn, xxix, xxx, xxxi, xxxin, xxxrv,
xxxv, xxxvi, xxxvn, xxxvin, XXXDC, XLI, XLH, XLIH, XLFV, XLV, XLVI,
xLvn, xLvm, XLDC, L, LI, Lin, LIV, LV, LVI, Lvn, Lvm, LX, LXIV, LXV, LXVI,
Lxvn, Lxvni, LXDC, LXX, LXXI, LXXH, LXXTV, LXXV, LXXVI, LXXVH,
Lxxvni, xc, xci, xcn, xcm, xcrv, xcv, xcvi, xcvn, xcvin, xcix, c, ci, en,
CHI, CIV, CV or mixtures thereof with each other or other crystalline forms of fluvastatin
sodium, optionally in mixtures with one or more other active ingredient(s). In addition to
the active ingredient(s), the pharmaceutical compositions of the present invention may
contain one or more excipients. Excipients are added to the composition for a variety of
purposes.
Diluents increase the bulk of a solid pharmaceutical composition and may make a
pharmaceutical dosage form containing the composition easier for the patient and care
giver to handle. Diluents for solid compositions include, for example, microcrystalline
cellulose (e.g. Avicel®), microfine cellulose, lactose, starch, pregelitinized starch, calcium
carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate
dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide,
maltodextrin, mannitol, polymethacrylates (e.g. Eudragit®), potassium chloride, powdered
cellulose, sodium chloride, sorbitol and talc.
Solid pharmaceutical compositions that are compacted into a dosage form like a
tablet may include excipients whose functions include helping to bind the active ingredient
and other excipients together after compression. Binders for solid pharmaceutical
compositions include acacia, alginic acid, carbomer (e.g. carbopol),
carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated
vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®),
hydroxypropyl methyl cellulose (e.g. Methocel®), liquid glucose, magnesium aluminum

silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon®,
Plasdone®), pregelatinized starch, sodium alginate and starch.
The dissolution rate of a compacted solid pharmaceutical composition in the
patient's stomach may be increased by the addition of a disintegrant to the composition.
Disintegrants include alginic acid, carboxymethylcellulose calcium,
carboxymethylcellulose sodium (e.g. Ac-Di-Sol®, Primellose®), colloidal silicon dioxide,
croscarmellose sodium, crospovidone (e.g. Kollidon®, Polyplasdone®), guar gum,
magnesium aluminum silicate, methyl cellulose, macrocrystalline cellulose, polacrilin
potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch
glycolate (e.g. Explotab®) and starch.
Glidants can be added to improve the flow properties of non-compacted solid
composition and improve the accuracy of dosing. Excipients that may function as glidants
include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc '
and tribasic calcium phosphate.
When ,a dosage form such as a tablet is made by compaction of a powdered
composition, the composition is subjected to pressure from a punch and die. Some
excipients and active ingredients have a tendency to adhere to the surfaces of the punch
and die, which can cause the product to have pitting and other surface irregularities. A
lubricant can be added to the composition to reduce adhesion and ease release of the
product from the die. Lubricants include magnesium stearate, calcium stearate, glyceryl
monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable
oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium
stearyl fumarate, stearic acid, talc and zinc stearate.
Flavoring agents and flavor enhancers make the dosage form more palatable to the
patient. Common flavoring agents and flavor enhancers for pharmaceutical products that
may be included in the composition of the present invention include maltol, vanillin, ethyl
vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.
Solid and liquid compositions may also be dyed using any pharmaceutically
acceptable colorant to improve their appearance and/or facilitate patient identification of
the product and unit dosage level.
In liquid pharmaceutical compositions of the present invention, fluvastatin sodium
Form I, H, IE, IV, IV-1, V, VI, VE, DC, IX-1, XI, XI-2, XE, XEI, XVI, XVE, XVEI, XIX,
XIX-1, XX, XXII, XXEI, XXTV, XXVI, XXVII, XXDC, XXX, XXXI, XXXIII, XXXTV,
xxxv, xxxvi, xxxvn, XXXVEI, XXXDC, XLI, XLE, XLEI, XLIV, XLV, XLVI;
XLVE, XLVIH, XLK, L, LI, LEI, LIV, LV, LVI, LVE, LVEI, LX, LXIV, LXV, LXVI,
LXVE, LXVEI, LXIX, LXX, LXXI, LXXE, LXXIV, LXXV, LXXVI, LXXVE,
56
LXXVDI and any other solid excipients are dissolved or suspended in a liquid carrier such
as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.
Liquid pharmaceutical compositions may contain emulsifying agents to disperse
uniformly throughout the composition an active ingredient or other excipient that is not
soluble in the liquid carrier. Emulsifying agents that may be useful in liquid compositions
of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia,
tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol and cetyl
alcohol.
Liquid pharmaceutical compositions of the present invention may also contain a
viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining
of the gastrointestinal tract. Such agents include acacia, alginic acid bentonite, carbomer,
carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose,
ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose,
hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene

carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch
tragacanth and xanthan gum.
Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose,
aspartame, fructose, mannitol and invert sugar may be added to improve the taste.
Preservatives and chelating agents such as alcohol, sodium benzoate, butylated
hydroxy toluene, butylated hydroxyanisole and ethylenediamine tetraacetic acid may be
added at levels safe for ingestion to improve storage stability.
A liquid composition according to the present invention may also contain a buffer
such as guconic acid, lactic acid, citric acid or acetic acid, sodium guconate, sodium
lactate, sodium citrate or sodium acetate.
Selection of excipients and the amounts to use may be readily determined by the
formulation scientist based upon experience and consideration of standard procedures and
reference works in the field.

The solid compositions of the present invention include powders, granulates,
aggregates and compacted compositions. The dosage forms include dosage forms suitable
for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and
intravenous), inhalant and ophthalmic administration. Although the most suitable route in
any given case will depend on the nature and severity of the condition being treated, the
most preferred route of the present invention is oral. The dosages may be conveniently
presented in unit dosage form and prepared by any of the methods well-known in the
pharmaceutical arts.
57
Dosage forms include solid dosage forms like tablets, powders, capsules,
suppositories, sachets, troches and lozenges as well as liquid syrups, suspensions and
elixirs.
An especially preferred dosage form of the present invention is a capsule
containing the composition, preferably a powdered or granulated solid composition of the
invention, within either a hard or soft shell. The shell may be made from gelatin and
optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or
colorant. An especially preferred capsule filling contains, in addition to one or more of the
fluvastatin sodium crystalline forms\)f this invention, the excipients magnesium stearate,
macrocrystalline cellulose, pregelatinized starch, sodium lauryl sulfate and talc.
Another especially preferred dosage form of this invention is a compressed tablet
that contains, in addition to one or more of the fluvastatin sodium crystalline forms of this
invention, the excipients rnicrocrystalline cellulose, hydroxypropyl cellulose,
hydroxypropylmethyl cellulose, potassium bicarbonate, povidone, magnesium stearate,
iron oxide yellow, titanium dioxide and polyethylene glycol 8000.
/The active ingredient and excipients may be formulated into compositions and
dosage forms according to methods known in the art.
A composition for tableting or capsule filing may be prepared by wet granulation.
In wet granulation some or all of the active ingredients and excipients in powder form are
blended and then further mixed in the presence of a liquid, typically water, that causes the
powders to clump up into granules. The granulate is screened and/or milled, dried and
then screened and/or milled to the desired particle size. The granulate may then be
tableted or other excipients may be added prior to tableting such as a glidant and or
lubricant.
A tableting composition may be prepared conventionally by dry blending. For
instance, the blended composition of the actives and excipients may be compacted into a
slug or a sheet and then comminuted into compacted granules. The compacted granules
may be compressed subsequently into a tablet.
As an alternative to dry granulation, a blended composition maybe compressed
directly into a compacted dosage form using direct compression techniques. Direct
compression produces a more uniform tablet without granules. Excipients that are
particularly well suited to direct compression tableting include rnicrocrystalline cellulose,
spray dried Jactose, dicalcium phosphate dihydrate and colloidal silica. The proper use of
these and other excipients in direct compression tableting is known to those in the art with
experience and skill in the particular formulation challenges of direct compression
tableting.

A capsule filling of the present invention may comprise any of the aforementioned
blends and granulates that were described with reference to tableting, only they are not
subjected to a final tableting step.
Capsules, tablets and lozenges and other unit dosage forms preferably contain a
dosage equivalent to from about 10 to about 100 mg fluvastatin. Preferably the dosage is
equivalent to from about 20 to about 80 mg of fluvastatin. More particularly, immediate
or uncontrolled release dosage forms preferably contain the equivalent of from abut 20 to
about 40 mg of fluvastatin and extended release dosage forms preferably contain the
equivalent of from about 60 to about 100 mg of fluvastatin, more preferably about 80' mg
of fluvastatin.
Process for Preparing Fluvastatin Sodium Crystal Form B
In another aspect, the present invention provides a process for preparing known
fluvastatin Form B. In the process, the free acid of fluvastatin, fluvastatin lactone or a
mixture of the two, is dissolved in a solution containing about one molar equivalent of
sodium hydroxide in a mixture of water and methanol. The most preferred solvent is a
10:1 mixture of methanohwater. Conversion of any lactone that may be present in the
starting material can be monitored by HPLC. Once a homogeneous solution of fluvastatin
sodium is obtained, precipitation of the sodium salt is induced by addition of methyl tertburyl
ether ("MTBE"). Formation of the salt and the initial addition of MTBE are
preferably conducted at elevated temperature, e.g. the reflux temperature of the solvent
system. Form B can be separated from the methanol, water and MTBE by conventional
means such as filtering, decanting, centrifuging and the like. Preferably, the liquids are
separated by vacuum filtration under an inert gas like nitrogen. A suitable condition for
drying the separated product is 50 °C under vacuum.
Having thus described the present invention with reference to certain preferred
embodiments, the processes for producing fluvastatin sodium I, II, IE, TV, TV-1, V, VI,
vii, DC, rx-i, xi, xi-2, xii, xm, xvr, xvn, xvm, xix, xix-i, xx, XXH, xxm,
xxrv, xxvi, xxvn, xxrx, xxx, xxxi, xxxm, xxxrv, xxxv, xxxvi, xxxvn,
xxxvm, XXXK, XLI, xm, XLIH, XLIV, XLV, XLVI, XLVH, XLVHI, XLIX, L, LI,
LIE, LIV, LV, LVI, LVH, LVHI, LX, LXFV, LXV, LXVI, LXVE, LXVHI, LXK, LXX,
LXXI, LXXH, LXXIV, LXXV, LXXVI, LXXVH, LXXVHI, xc, xci, xcn, xcni,
XCTV, XCV, XCVI, XCVH, XCVm, XCIX, C, CI, CII, CM, CIV, CV and B of the
present invention and techniques suitable for identifying them are further illustrated by the
examples which follow. These examples are provided for illustrative purposes only and
are not intended to limit the invention in any way.

EXAMPLES
General
Powder X-ray diffraction data were obtained using methods known in the art on a
SCINTAG powder X-ray diffractometer model X'TRA equipped with a solid state
detector. Copper radiation of 1.5418 A was used. A round aluminum sample holder with
zero background was used.
DSC analysis was done on a Mettler 821 Star e. The weight of the samples was
about 5 mg; theNsamples were scanned at a rate of 10°C/min from 30°C to 200°C. The
oven was constantly purged with nitrogen gas at a flow rate of 40 ml/min. Standard 40 jil
aluminum crucibles covered by lids with 3 holes were used.
TGA analysis was done using a Mettler M3 meter. The weight of the samples was
about 10 mg; the samples were scanned at a rate of 10°C/min from 25°C to 200°C. The
oven was constantly purged with nitrogen gas at a flow rate of 40 ml/min. Standard 70 \ialumina crucibles covered by lids with 1 hole were used.
IR analysis was done using a Perkin Elmer "Spectrum One" FT-IR spectrometer in
DRIFTt mode. The samples in the 4000-400 cm-1 interval were scanned 16 tunes with 4.0
cm-1 resolution.
-The water content of fluvastatin sodium is measured by the methods known in the
art like Karl Fisher or thermogravimetric analysis.
Those skilled in the art will recognize the abbreviations used in the disclosure, as
they are in widespread use in the fields of medicinal and organic chemistry. The
abbreviations used include the following:
ACN acetonitrile
DMF N,N-dimethyl formamide
DMSO dimethyl sulfoxide
EtOH ethanol
Et20 diethyl ether
EtOAc ethyl acetate
IPA isopropyl alcohol
MeOH methanol
MTBE methyl tot-butyl ether
MEK methyl ethyl ketone
THF tetrahydrofuran

Preparative
All the preparations described below were carried out on fluvastatin sodium Form
B except where indicated otherwise. Fluvastatin sodium Forms XTX-1, XXXIII, XXXIV,
XXXV were prepared using as starting material fluvastatin sodium Form XV which was
purchased from Zhejiang Hisun Pharmaceutical Company Limited; 46 Waisha Road,
Jiaojiang District, Taizhou City, Zhejiang Province, China.
1) Preparation of Fluvastatin Sodium Crystal Form I
Example 1
Fluvastatin methyl ester (3.0 g) was dissolved in acetone (30 ml) and NaOH (0.29
g) partially dissolved in acetone (0.75 ml) was added. The mixture was stirred at room
temperature overnight. The product was isolated by filtration under nitrogen, washed with
acetone (40 ml) and dried at 50 °C in a vacuum oven for 24 h to obtain 2.31 g (76.2%) of
fluvastatin sodium crystal Form I.
Example 2
Fluvastatin methyl ester (3.01 g) was dissolved in acetonitrile (60 ml) by heating
and NaOH (0.28 g) was added. The mixture was stirred at about 60 °C for 1 h, cooled to
room temperature, heated again to about 75 °C for 2h, then cooled to room temperature
and stirred overnight. The product was isolated by filtration under nitrogen, washed with
acetonifrile (40 ml) and dried at 50°C in a vacuum oven for 24 h to obtain 1.07 g (34.9%)
i
of fluvastatin' sodium crystal Form I.
Example 3
Fluvastatin methyl ester (3.01 g) was dissolved in acetonitrile (60 ml) by heating
and a solution of NaOH (0.28 g) in water (0.75 ml) was added at about 50 °C. The mixture
was stirred at about 40 °C for 2 h, cooled to room temperature and stirred for another h.
The product was isolated by filtration under nitrogen, washed with acetonitrile (40 ml) and
dried at 50 °C in a vacuum oven for 24 h to obtain 2.52 g (82.2%) of fluvastatin sodium
crystal Form I.
Example 4
Fluvastatin sodium crystal Form B (3.0 g) was dissolved in acetone (600 ml) at
reflux temperature. The obtained solution was filtered and MTBE (200 ml) was added at
reflux temperature. The solution was cooled to room temperature and MTBE (100 ml) was
added. The mixture was concentrated under reduced pressure to obtain precipitate. The
product was then filtered, washed with MTBE (2x18 ml) and dried at 50°C in a vacuum '
oven for 24 h to obtain 1.7 g (58%) of fluvastatin sodium crystal Form I.

Examples
Fluvastatin sodium crystal Form B (3.0 g) was dissolved in butan-2-ol (60 ml) and
water (6 ml) at reflux temperature. The solution was cooled to 15 °C for 2 h to obtain a
precipitate. The product was then filtered under nitrogen flow, washed with butan-2-ol
(1x15 ml) and dried at 50°C in a vacuum oven for 24 h to obtain 0.05 g (2%) of fluvastatin
sodium crystal Form I.
2) Preparation of Fluvastatin Sodium Crystal Form II
Example 6
Fluvastatin sodium crystal Form B (3.0 g) was almost completely dissolved in
butan-1-ol (90 ml) at reflux temperature. The mixture was stirred at reflux temperature for
2.5 h. Then, it was cooled to room temperature and stirred at this temperature for 16 h. The
product was filtered, washed with butan-1-ol (1x5 ml) and dried at 50°C in a vacuum oven
for 52 h to obtain 1.7 g (56%) of fluvastatin sodium crystal Form E.
3) Preparation of Fluvastatin Sodium Crystal Form in
Example 7 Fluvastatin sodium crystal Form B (3.0 g) was dissolved in butan-1-ol (70
ml) at reflux temperature. MTBE (70 ml) was added dropwise and the mixture was stirred
at reflux temperature for 3 h. The solution was cooled to room temperature and MTBE (70
ml) was added to obtain a massive precipitate after 2 h. The product was filtered, washed
with MTBE (3x10 ml) and dried at 50°C in a vacuum oven for 24 h to obtain 1.5 g (49%)
of fluvastatin sodium crystal Form HI.
Example 8
Fluvastatin sodium crystal Form B (3.0 g) was dissolved in butan-1-ol (70 ml) at
reflux temperature. The solution was filtered and n-hexane (70 ml) was added dropwise.
The mixture was stirred at reflux temperature for 3.5 h. The solution was cooled to room
temperature to obtain precipitate. The product was filtered, washed with n-hexane (2x20
ml) and dried at 50 °C in a vacuum oven for 23 h to obtain 1.0 g (34%) of fluvastatin
sodium crystal Form HI.
Example 9
Fluvastatin sodium crystal Form B (3.0 g) was dissolved in 1,4-dioxane (75 ml) at
reflux temperature. The solution was cooled to room temperature to obtain precipitate. The
product was filtered, washed with 1,4-dioxane (1x25 ml) and dried at 50°C in a vacuum
oven for 24 h to obtain 2.2 g (75%) of fluvastatin sodium crystal Form ffi.
Example 10
A suspension of fluvastatin sodium crystal Form B (3.0 g) in ethyl acetate (150 ml)
was stirred at reflux temperature. Hexanes (150 ml) were added dropwise at reflux

temperature. The mixture was stirred at reflux temperature for 3 h. The suspension was
cooled to room temperature. The product was filtered under nitrogen flow, washed with
hexanes (1x20 ml) and dried at 50°C in a vacuum oven for 22 h to obtain 2.7 g (91%) of
fluvastatin sodium crystal Form III.
Example 11 Amorphous fluvastatin sodium (1.7 g) was dissolved in ethanol (10 ml) at
reflux temperature. After 0.5 h the product was recrystallized at reflux temperature. The
suspension was stirred at reflux temperature for additional 1 h. Then, the suspension was
cooled to room temperature and additional amount of ethanol (10 ml) was added. The
product was filtered under nitrogen flow, washed with ethanol (2x10 ml) and dried at
50°C in a vacuum oven for 24 h to obtain 0.9 g (53%) of fluvastatin sodium crystal Form
m.
Example 12
Fluvastatin sodium crystal Form B (3.0 g) was dissolved in THF (50 ml) at reflux
temperature. Cyclohexane (65 ml) was added dropwise at reflux temperature to obtain a
precipitate. The mixture was cooled to room temperature. The product was filtered,
washed with cyclohexane (2x20 ml) and dried at 50°C in a vacuum oven for 19.5 h to
obtain 2.7 g (91%) of fluvastatin sodium crystal Form HI.
Example 13
A suspension of fluvastatin sodium crystal Form XTV (3.0 g) was stirred in ethanol
(20 ml) at reflux temperature for 7 h. The suspension was cooled to room temperature. The
product was filtered under nitrogen flow, washed with ethanol (2x25 ml) and dried at
50°Cin a vacuum oven for 21 h to obtain 2.3 g (77%) of fluvastatin sodium crystal Form
m.
4) Preparation of Fluvastatin Sodium Crystal Form IV
Example 14
Fluvastatin sodium (3.0 g) was dissolved in tetrahydrofuran (THF) (50 ml) at
reflux temperature. Chloroform (50 ml) was added dropwise at reflux temperature and the
resulting mixture was stirred at this temperature for 40 minutes. A precipitate was obtained
during reflux. Then, the mixture was cooled to room temperature. The product was
isolated by filtration under nitrogen, washed with Chloroform (2x20 ml) and dried at 50°C
in a vacuum oven for 19 h to obtain 2.7 g (89%) of fluvastatin sodium crystal Form IV.

Examplel5
Fluvastatin sodium (3.0 g) was dissolved in THF (50 ml) at reflux temperature.
Dichloromethane (65 ml) was added dropwise at reflux temperature and the resulting
mixture was stirred at this temperature for 1 h. Then, the mixture was cooled to room
temperature. The product was isolated by filtration under nitrogen, washed with
dichloromethane (2x20 ml) and dried at 50°C in a vacuum oven for 20 h to obtain 2.6 g
(87%) of fluvastatin sodium crystal Form IV.
Example 16
Fluvastatin sodium (3.0 g) was dissolved in THF (50 ml) at reflux temperature.
1,2-Dichloroethane (50 ml) was added dropwise at reflux temperature and the resulting
mixture was stirred at this temperature for 1 h. A precipitate was obtained during the
reflux. Then, the mixture was cooled to room temperature. The product was isolated by
filtration under nitrogen and dried at 50 °C in a vacuum oven for 24 h to'obtain 0.7 g
(24%) of fluvastatin sodium crystal Form IV.
Example 17
Fluvastatin sodium (3.0 g) was dissolved in THF (50 ml) at reflux temperature.
Diethyl ether (50 ml) was added dropwise at reflux temperature and the resulting mixture
was stirred at this temperature for 1 h. A precipitate was obtained during the reflux. Then,
the mixture was cooled to room temperature. The product was isolated by filtration under
nitrogen, washed with diethyl ether (2x25 ml) and dried at 50°C in a vacuum oven for
24.5 h to obtain 2.1 g (69%) of fluvastatin sodium crystal Form IV,
Example: 18 Fluvastatin sodium (3.0 g) was dissolved in THF (50 ml) at reflux
temperature. n-Pentane (50 ml) was added dropwise at reflux temperature and the resulting
mixture was stirred at this temperature for 8 minutes. A massive precipitate was obtained
during reflux. Then, the mixture was cooled to room temperature. The product was
isolated by filtration under nitrogen, washed with n-pentane (2x25 ml) and dried at 50°C
in a vacuum oven for 25 h to obtain 2.8 g (93%) of fluvastatin sodium crystal Form IV.
Example 19
Fluvastatin sodium (3.0 g) was dissolved in butan-1-ol (70 ml) at reflux
temperature, Cyclohexane (70 ml) was added at reflux temperature and the resulting
mixture was stirred at this temperature for 3 h. Then, the mixture was cooled to room
temperature. The product was isolated by filtration, washed with cyclohexane (2x20 ml)
and dried at 50°C in a vacuum oven for 25.5 h to obtain 2.1 g (69%) of fluvastatin sodium
crystal Form IV.
Example 20
Fluvastatin sodium (3.0 g) was dissolved in 1,4-dioxane (75 ml) at reflux
temperature. Cyclohexane (70 ml) was added at reflux temperature and the resulting

mixture was stirred at this temperature for 3.5 h. A precipitate was obtained during the
reflux. Then, the mixture was cooled to room temperature. The product was isolated by
filtration, washed with cyclohexane (2x10 ml) and dried at 50° C in a vacuum oven for
22.5 h to obtain 2.7 g (89%) of fluvastatin sodium crystal Form IV.
Example 21
Fluvastatin sodium (3.0 g) was dissolved in propan-2-ol (70 ml) at reflux
temperature. MTBE (70 ml) was added dropwise at reflux temperature and the resulting
mixture was stirred at this temperature for 15 minutes. A precipitate was obtained during
the reflux. Then, the mixture was cooled to room temperature. The product was isolated by
filtration under nitrogen, washed with MTBE (3x20 ml) and dried at 50° C in a vacuum
oven for 25.5 h to obtain 2.4. g (81%) of fluvastatin sodium crystal Form IV.
5) Preparation of Fluvastatin Sodium Crystal Form IV-1
Example 22
Fluvastatin sodium (3.0 g) was dissolved in THF (50 ml) at reflux temperature.
n-Heptane (50 ml) was added dropwise at reflux temperature and the resulting mixture was
stirred at this temperature for 1 h. A massive precipitate was obtained during reflux. Then,
the mixture was cooled to room temperature. The product was isolated by filtration under
nitrogen, washed with n-heptane (2x50 ml) and dried at 50°C in a vacuum oven for 24 h to
obtain 2.9 g (97%) of fluvastatin sodium crystal Form TV-1.
Example 23
Fluvastatin sodium (3.0 g) was almost completely dissolved in butan-2-ol (70 ml)
at reflux temperature. During this time the material was recrystallized. Cyclohexane (70
ml) was added at reflux temperature and the resulting mixture was stirred at this temperature for 5 h. Then, the mixture was cooled to room temperature. The product was
isolated by filtration, washed with cyclohexane (1x20 ml) and dried at 50°C in a vacuum
oven'for 24 h to obtain 3.0 g (100%) of fluvastatin sodium crystal Form IV-1.
Example 24
Fluvastatin sodium (3.0 g) was dissolved in 1,4-dioxane (75 ml) at reflux
temperature. MTBE (75 ml) was added dropwise at reflux temperature and the resulting
mixture was stirred at this temperature for 4 h. A massive precipitate was obtained during
the reflux. Then, the mixture was cooled to room temperature. The product was isolated by
filtration, washed with MTBE (2x10 ml) and dried at 50° C in a vacuum oven for 22 h to
obtain 2.7 g (89%) of fluvastatin sodium crystal Form IV-l.

6) Preparation of Fluvastatin Sodium Crystal Form V
Example 25
Fluvastatin sodium crystal Form B (3.0 g) was dissolved in butan-1-ol (70 ml) at
reflux temperature. The solution was filtered and n-heptane (70 ml) was added dropwise at
reflux temperature. The mixture was stirred at reflux temperature for additional 3 h. The'
mixture was cooled to room temperature and stirred at this temperature for 25 h. The
product was filtered, washed with n-Heptane (1x20 ml) and dried at 50°C in a vacuum
oven for 24 h to obtain 1.8 g (61%) of ftuvastatin sodium crystal Form V.
Example 26
Fluvastatin sodium crystal Form B (3.0 g) was dissolved in a mixture of ethanol
(50 ml), ethyl acetate (20 ml) andpropan-1-ol (10 ml) at reflux temperature. The solution
was filtered and n-hexane (200 ml) was added dropwise. The mixture was cooled to room
temperature and stirred at this temperature for 16 h. The product was filtered under
nitrogen flow, washed with n-hexane (2x25 ml) and dried at 50°C in a vacuum oven for, 24
h to obtain 2.3 g (77%) of fluvastatin sodium crystal Form V.
7) Preparation of Fluvastatin Sodium Crystal Form VI
Example 27
Fluvastatin sodium (3.0 g) was dissolved in DMF (83 ml) at room temperature.
Diethyl ether (100 ml) was added gradually at room temperature and the resulting mixture
was stirred at this temperature for 1 h. Then, the mixture was cooled using an ice-bath. The
product was isolated by filtration under nitrogen and dried at 50°C in a vacuum oven for
24 h to obtain 1.7 g (55%) of fluvastatin sodium crystal Form VI.
Example 28
Fluvastatin sodium (3.0 g) was dissolved in DMF (120 ml) at room temperature.
Then, hexanes (10 ml) were added. The solvent and the anti-solvent were evaporated to
dryness and the obtained solid was suspended in DMF (80 ml) at room temperature for 16
h. Thelnixture was cooled using an ice-bath. The'product was isolated by filtration under
nitrogen and dried at 50° C in a vacuum oven for 24 h to obtain 1.3 g (42%) of a mixture of
fluvastatin sodium crystal Forms VI and VII.

Example 29
Fluvastatin methyl ester (3.0 g) was added to a solution of NaOH (1 eq.) in water
(0.75 ml) and methanol (7.5 ml). The mixture was stirred at about 60°C for 4 hr, after
which the starting material was no longer detectable by HPLC. Then, acetonitrile (58 ml)
was dripped into the solution over 1.5 h. Turbidity appeared in the solution which as it
was allowed to cool slowly to room temperature. The mixture was stirred overnight. The
product was isolated by filtration under nitrogen, washed with acetonitrile (50 ml) and
dried at 50°C in a vacuum oven for 24 h to obtain 2.23 g (73%) of fiuvastatin sodium
FofcmVL
Example 30
Fluvastatin methyl ester (2.0 g) was added to a solution of NaOH (1 eq.) in
methanol (5 ml). The mixture was heated to reflux and stirred for 2.25 h after which the
starting material was not longer detected by HPLC. Then, acetonitrile (40 ml) was dripped
into the solution in two portions over 1.5 h. The mixture was cooled slowly to room
temperature and stirred for another 1.75 h. The product was isolated by filtration under
nitrogen, washed with acetonitrile (20 ml) and dried at 50 °C in a vacuum, oven for 23 h to
obtain 1.7 g (83.4%) of fiuvastatin sodium Form VI.
Example 31
Fluvastatin methyl ester (2.0 g) was added to a solution of NaOH (1 eq.) in ethanol
(15 ml). The mixture was stirred at about 70°C for 1.75 h, after which the starting material
was not detected by HPLC. Then, acetone (40 ml) was dripped into the solution and the
mixture was cooled slowly to room temperature and stirred overnight. The product was
isolate'd by filtration under nitrogen, washed with acetone (20 ml) and'dried at 50°C in a
vacuum oven for 24 h to obtain 1.54 g (75.6%) of fiuvastatin sodium Form VI.
Example 32
Fluvastatin methyl ester (2.0 g) was added to a solution of NaOH (1 eq.) in water
(0. 5 ml) and butan-1-ol (8 ml). The mixture was stirred at about 80°C for 4 h, after which
the starting material was not detected by HPLC. Then, acetonitrile (40 ml) was dripped
into the solution and the mixture was cooled slowly to room temperature and stirred
overnight. The product was isolated by filtration under nitrogen, washed with acetonitrile
(15 ml) and dried at 50°C in a vacuum oven for 24 h to obtain fiuvastatin sodium Form VI
(1.65 g, 81%).
8) Preparation of Fluvastatin Sodium Crystal Form VH
Example 33
Fluvastatin sodium (3.0 g) was dissolved in DMF (83 ml) at room temperature.
Chloroform (100 ml) was added gradually at room temperature and the resulting mixture

was stirred at this temperature for 4 days. Then, the mixture was cooled using an ice-bath.
The product was isolated by filtration under nitrogen, washed with dichloromethane (1x35
ml) and dried at 50°C in a vacuum oven for 24 h to obtain 2.0 g (65%) of fluvastatin
sodium crystal Form VII.,
Example 34
Fluvastatin sodium (3.0 g) was dissolved in DMF (80 ml) at room temperature.
MTBE (100 ml) was added gradually at room temperature and the resulting mixture was
stirred at this temperature for 5 h. Then, the mixture was cooled using an ice-bath. The
product was isolated by filtration under nitrogen and dried at 50°C in a vacuum oven for
22 h to obtain 1.8 g (59%) of fluvastatin sodium crystal Form VH.
Example 35
Fluvastatin sodium (3.0 g) was dissolved in DMF (80 ml) at room temperature.
Dichloromethane (100 ml) was adHed gradually at room temperature and the resulting
mixture was stirred at this temperature for 16 h. Then, the mixture was cooled using an
ice-bath. The product was isolated by filtration under nitrogen and dried at 50°C in a
vacuum oven for 23 h to obtain 2.4 g (79%) of fluvastatin sodium crystal Form Vn.
Example 36
Fluvastatin sodium (3.0 g) was dissolved in DMF (120 ml) at room temperature.
Then, cyclohexane (20 ml) was added. The solvent and the anti-solvent were evaporated to
dryness and the obtained solid was suspended in DMF (80 ml) at room temperature for 16
h. The mixture was cooled using an ice-bath. The product was isolated by filtration under
nitrogen and dried at 50°C in a vacuum oven for 23 h to obtain 1.9 g (64%) of fluvastatin
sodium crystal Form VII.
Example 37
Fluvastatin sodium (3.0 g) was dissolved in DMF (80 ml) at room temperature.
1,2-Dichloroethane (100 ml) was added at room temperature and the resulting mixture was
stirred at this temperature for 5 h. Then, the mixture was cooled using an ice-bath. The
product was isolated by filtration under nitrogen and dried at 50 °C in a vacuum oven for
21 h to obtain 1.8 g (60%) of fluvastatin sodium crystal Form VII.
Example 3 8
Fluvastatin sodium (3.0 g) was suspended in DMF (40 ml) at room temperature for
16 h. The product was isolated by filtration under nitrogen, washed with DMF (1x20 ml)
and dried at 50°C in a vacuum oven for 28 h to obtain 1.1 g (37%) of fluvastatin sodium
crystal Form VH.

Example 39 Fluvastatin methyl ester (2.0 g) was added to a mixture of NaOH (1 eq.)
and butan-l-ol (15 ml). The mixture was stirred at about 80°C for 1.5 h, after which the
starting material was not detected by HPLC. Then, 40 ml of acetone was dripped into the
solution and the mixture was cooled slowly to room temperature and stirred overnight. The
product was isolated by filtration under nitrogen, washed with acetone (20 ml) and dried at
50 °C in a vacuum oven for 24 h to obtain 1.09 g (53.5%) of fluvastatin sodium Form VII.
Example 40
Fluvastatin methyl ester (2.0 g) was added to a mixture of NaOH (1 eq.) and butanl-
ol (15 ml). The mixture was stirred at about 80°C for 2.5 h, after which the starting
material was not detected by HPLC. Then, 40 ml of acetonitrile was dripped into the
solution. The mixture was then cooled slowly to room temperature and stirred overnight.
The product was isolated by filtration under nitrogen, washed with acetonitrile (45 ml) and
dried at 50 °C in a vacuum oven for 24 h to obtain 1.96 g (96.2%) of fluvastatin sodium
Form YE. .i
Example 41
Fluvastatin methyl ester (3.0 g) was added to a solution of NaOH (1 eq.) in water
(0.75 ml) and propan-2-ol (7.5 ml). The mixture was heated to reflux and 1 ml of propan-
2-ol was added. After 2 h the mixture was cooled to room temperature and stirred for 2 h.
MTBE (60 ml) was dripped into the solution over 20 min and it was stirred for another 1.5
h. The_product was isolated by filtration under nitrogen, washed with MTBE and dried at
50°C in a vacuum oven for 24 h to obtain 1.9 g (62%) of fluvastatin sodium Form VII.
Example 42
Fluvastatin methyl ester (3.0 g) was added to a solution of NaOH (1 eq.) in MeOH
(30 ml). The mixture was stirred at room temperature for 4.5 h. Then, it was filtered and
concentration by vacuum distillation until a solid appeared. The concentrated solution was
heated to reflux and 60 ml of acetonitrile was dripped into the mixture over 50 min.
Turbidity was observed and the mixture was cooled slowly to room temperature and
stirred over night. The product was isolated by filtration under nitrogen, washed with
acetonitrile (60 ml) and dried at 50° C in a vacuum oven for 24 h to obtain fluvastatin
sodium Form VII (2.54 g, 83.1%).
Example 43
Fluvastatin methyl ester (3.0 g) was added to acetonitrile (60 ml) and the mixture
was heating to about 40°C for dissolution. A solution of NaOH (1 eq.) in EtOH (7.5 ml)
was added and turbidity was immediately observed. The mixture then was heated to about
65 °C. The mixture was cooled slowlv to room temperature and stirred overnight. The
product was isolated by filtration under nitrogen, washed with acetonitrile (40 ml) and

dried at 50°C in a vacuum oven for 24 h to obtain fluvastatin sodium Form VII (1.99 g,
64.9%).
9) Preparation of Fluvastatin Sodium Crystal Form IX
Example 44
Into a 100 ml flask were placed fluvastatin methyl ester (3.0 g), BtOH (7.5 ml) and
a solution of NaOH (0.28 g) in water (0.75 ml). The mixture was heated to reflux for two
h, propan-2-ol was added (58 ml) and the mixture was cooled to room temperature and
stirred over night. The product Vas isolated by filtration under nitrogen, washed with
propan-2-ol (50 ml) and dried at 50 °C in a vacuum oven for 24 h to obtain 1,92 g (62.8%)
of fluvastatin sodium crystal Form IX.
Example 45
Fluvastatin sodium crystal Form B (3.0 g) was dissolved in 1,4-dioxane (75 ml) at .
reflux temperature. Dichloromethane (75 ml) was added dropwise to obtain a precipitate
and the mixture was stirred at reflux temperature for 2.5 h. The suspension was cooled to
room temperature and stirred at this temperature for 20 h. The product was filtered,
washed with Dichloromethane (1x20 ml) and dried at 50°C in a vacuum oven for 24 h to
obtain 1.5 g (51%) of fluvastatin sodium crystal Form IX.
Example 46
A suspension of fluvastatin sodium crystal Form B (3.0 g) in ethyl acetate (100 ml)
was stirred at reflux temperature for 2.5 h. The suspension was cooled to room
temperature. The product was filtered, washed with ethyl acetate (1x20 ml) and dried at
50°C in a vacuum oven for 23 h to obtain 2.0 g (66%) of fluvastatin sodium crystal Form
rx.
Example 47
Fluvastatin sodium crystal Form B (5.0 g) was almost completely dissolved in
ethanol (100 ml) at 45 °C. The solution was filtered arid cooled to room temperature, ethyl
acetate (250 ml) was added and the mixture was stirred at room temperature for 63 h to
obtain precipitate. The product was filtered under nitrogen flow, washed with ethyl acetate
(1x20 ml) and dried at 50°C in a vacuum oven for 23 h to obtain 2.2 g (44%) of fluvastatin
sodium crystal Form IX.
Example 48
Fluvastatin sodium crystal Form B (3.0 g) was dissolved in ethanol (130 ml) at
room temperature. The solution was filtered and Diethyl ether (260 ml) was added. The
mixture was stirred at room temperature for 16 h to obtain precipitate. The product was
filtered and dried at 50 °C in a vacuum oven for 22 h to obtain 1.7 g (56%) of fluvastatin
sodium crystal Form IX.

Example 49
Fluvastatin sodium crystal Form B (3.0 g) was dissolved in ethanol (130 ml) at
room temperature. The solution was filtered and n-pentane (260 ml) was added. The
.mixture was stirred at room temperature for 17 h to obtain precipitate. The product was
filtered, washed with n-pentane (2x35 ml) and dried at 50°C in a vacuum oven for 24 h to
obtain 1.9 g (63%) of fluvastatin sodium crystal Form DC.
Example 50

Fluvastatin sodium crystal Form B (5.0 g) was almost completely dissolved in a
mixture of ethanol (130 ml) and methanol (5 ml) at room temperature. The solution was
filtered and hexanes (200 ml) were added dropwise. The mixture Avas stirred at room
temperature for 19 h to .obtain precipitate. The product was filtered under nitrogen flow
and dried at 50°C in a vacuum oven for 22 h to obtain 3.6 g (73%) of fluvastatin sodium
crystal Form IX.
10) Preparation of Fluvastatin Sodium Crystal Form IX-1
Example 51
Fluvastatin sodium crystal Form B (3.0 g) was dissolved in butan-1-ol (70 ml) at
reflux temperature. The solution was filtered and n-pentane (70 ml) was added dropwise at
reflux temperature. The mixture was stirred at reflux temperature for 1.5 h. The mixture
was cooled to room temperature. The product was filtered, washed with n-pentane (2x10
ml) and dried at 5Q-°C in a vacuum oven for 21 h to obtain 2.2 g (73%) of fluvastatin
sodium crystal Form IX-1.
Example 52
Fluvastatin sodium crystal Form B (3.0-g) was dissolved in butan-1-ol (70 ml) at
reflux temperature. The solution was filtered and Diethyl ether (70 ml) was added
dropwise at reflux temperature. The mixture was stirred at reflux temperature for 0.5 h.
The mixture was cooled to room temperature. The product was filtered, washed with
Diethyl ether (2x5 ml) arid dried at 50°C in a vacuum oven for 24 h to obtain 2.0 g (65%)

of fluvastatin sodium crystal Form IX-1.
71
Example 53 A slurry of fluvastatiri sodium crystal Form B (3.0 g) in ethyl acetate (240
ml) was heated to reflux temperature. Additional amount of ethyl acetate (80 ml) was
added at reflux temperature. The material was recrystallized during reflux and the mixture
was stirred at reflux temperature for 2.5 h to obtain a massive precipitate. The mixture was
cooled to room temperature. The product was filtered under nitrogen flow, washed with
ethyl acetate (2x10 ml) and dried at 50°C in a vacuum oven for 23 h to obtain 2.7 g (89%)
of fluvastatin sodium crystal Form IX-1.
Example 54
/A slurry of fluvastatin sodium crystal Form B (3.0 g) in isobutyl acetate (70 ml)
was heated to reflux temperature. The material was recrystallized during reflux and MTBE
(70 ml) was added dropwise to obtain a massive precipitate. The mixture was stirred at
reflux temperature for additional 0.5 h. The mixture was cooled to room temperature. The
product was filtered under nitrogen flow, washed with MTBE (2x10 ml) and dried at 50°C
in a vacuum oven for 22 h to obtain 2.74 g (91%) of fluvastatin sodium crystal Form IX-1.
Example 55
Fluvastatin sodium crystal Form B (3.0 g) was almost completely dissolved in
isobutyl acetate (70 ml) at reflux temperature. Dichloromethane (70 ml) was added
dropwise to obtain precipitate. The mixture was cooled to room temperature. The product
was filtered, washed with Dichloromethane (2x10 ml) and dried at 50°C in a vacuum oven
for 25 h to obtain 2.5 g (82%) of fluvastatin sodium crystal Form IX-1.
Example 56
Fluvastatin sodium crystal Form B (3.0 g) was dissolved in ethanol (130ml) at
room temperature. The solution was filtered and hexanes (200 ml) were added dropwise.
The mixture was stirred at room temperature for 19 h. The product was filtered under
nitrogen flow, washed with hexanes (2x25 ml) and dried at 50 °C in a vacuum oven for 24
h to obtain 1.2 g (41%) of amorphous fluvastatin sodium. A precipitate was observed in
the mother-liquid after 20 days. The precipitate was dried at 50°C in a vacuum oven for 26
h to obtain fluvastatin sodium crystal Form DC-1.
Example 57
A slurry of fluvastatin sodium crystal Form B (3.0 g) in toluene (60 ml) and
Cyclohexane (60 ml) was heated to reflux temperature for 22 h. The mixture was cooled to
room temperature. The product was filtered under nitrogen flow and dried at 50°C in a
vacuum oven for 24 h to obtain 2.6 g (85%) of fluvastatin sodium crystal Form IX-1.
Example 58
Fluvastatin sodium crystal Form B (3.0 g) was dissolved in THF (100 ml) at reflux
temperature. The solution was filtered and hexanes (100 ml) were added dropwise at
reflux temperature. The mixture was stirred at reflux temperature for 1 h and then was

cooled to room temperature. The product was filtered under nitrogen flow, washed with
haxanes (2x20 ml) and dried at 50°C in a vacuum oven for 19 h to obtain 2.5 g (83%) of
fluvastatin sodium crystal Form DC-1.
Example 59
Fluvastatin sodium crystal Form B (3.0 g) was dissolved in THF (60 ml) at reflux
temperature. The solution was filtered and MTBE (60 ml) was added dropwise at reflux
temperature. The mixture was stirred at reflux temperature for 1 h and then was cooled to
room temperature. The product was filtered under nitrogen flow, washed with MTBE
(2x20 ml) and dried at 50°C in a vacuum oven for 18 h to obtain 1.9 g (63%) of fluvastatin
sodium crystal Form DC-1.
Example 60 Fluvastatin sodium crystal Form B (3.0 g) was dissolved in MEK (70 ml) at
reflux temperature. MTBE (70 ml) was added dropwise at reflux temperature. The mixture
was cooled to room temperature. The product was filtered under nitrogen flow and dried at
50°C in a vacuum oven for 29 h to obtain 0.7 g (24%) of fluvastatin sodium crystal Form
rx-i.
11) Preparation of Fluvastatin Sodium Crystal Form XT
Example 61
Fluvastatin sodium (3.0 g) was almost completely dissolved in butan-2-ol (70 ml)
at reflux temperature. During this time the material was recrystallized. Hexanes (70 ml)
were added at reflux temperature to obtain a massive precipitate. The resulting suspension
was stirred at reflux temperature for 4.5 h. Then, the mixture was cooled to room
temperature. The product was isolated by filtration, washed with hexanes (2x15 ml) and
dried at 50°C in a vacuum oven for 23.5 h to obtain 2.8 g (93%) of fluvastatin sodium
crystal Form XL
Example 62
Fluvastatin sodium (3.0 g) was almost completely dissolved in butan-2-ol (70 ml)
at reflux temperature. During this time the material was recrystallized. n-pentane (70 ml)
was added at reflux temperature to obtain a massive precipitate. The resulting suspension
was stirred at reflux temperature for 4 h. Then, the mixture was cooled to room
temperature. The product was isolated by filtration, washed with n-pentane (2x10 ml) and
dried at 50 °C in a vacuum oven for 23.5 h to obtain 2.76 g (92%) of fluvastatin sodium
crystal Form XL
Example 63
Fluvastatin sodium (3.0 g) was dissolved in butan-2-ol (70 ml) at reflux
temperature. MTBE (70 ml) was added at reflux temperature to obtain a massive
precipitate. The resulting suspension was stirred at reflux temperature for 5 h. Then, the

mixture was cooled to room temperature. The product was isolated by filtration, washed
with MTBE (2x10 ml) and dried at 50°C in a vacuum oven for 21 h to obtain 2.7 g (90%)
of fluvastatin sodium crystal Form XL
Example 64
Fluvastatin sodium (3.0 g) was almost completely dissolved in butan-2-ol (70 ml)
at reflux temperature. During this time the material was recrystallized. Diethyl ether (70
ml) was added at reflux temperature to obtain a massive precipitate. The resulting
suspension was stirred at reflux temperature for 4.5 h. Then, the mixture was cooled to
room temperature. The product was isolated by filtration, washed with diethyl ether (2x10
ml) and dried at 50 °C in a vacuum oven for 24 h to obtain 2.8 g (94%) of fluvastatin
sodium crystal Form XI.
Example 65
Fluvastatin sodium (3.0 g) was almost completely dissolved in butan-2-ol (70 ml)
at reflux temperature. During this time the material was recrystallized. n-heptane (70 ml)
was added at reflux temperature to obtain a massive precipitate. The resulting suspension
was stirred at reflux temperature for 4.5 h. Then, the mixture was cooled to room
temperature. The product was isolated by filtration, washed with n-heptane (2x10 ml) and
dried at 50°C in a vacuum oven for 24 h to obtain 2.8 g (94%) of fluvastatin sodium '.
crystal Form XL
Example 66
Fluvastatin sodium (3.0 g) was almost completely dissolved in butan-2-ol (70 ml)
at reflux temperature. During this time the material was recrystallized. Chloroform (70 ml)
was added dropwise at reflux temperature to obtain a massive precipitate. The resulting
suspension was stirred at reflux temperature for 4 h. Then, the mixture was cooled to room
temperature. The product was isolated by filtration, washed with Chloroform (2x10 ml)
and dried at 50°C in a vacuum oven for 24 h to obtain 1.7 g (57%) of fluvastatin sodium
crystal Form XI.
12) Preparation of Fluvastatin Sodium Crystal Form XI-2
Example 67
Fluvastatin sodium (3.0 g) was dissolved in propan-1-ol (60 ml) at reflux
temperature. Hexanes (60 ml) were added dropwise at reflux temperature and the resulting
mixture was stirred at this temperature for 1.5 h. Then, the mixture was cooled to room
temperature. The product was isolated by filtration under nitrogen, washed with hexanes
(2x20 ml) and dried at 50°C in a vacuum oven for 28 h to obtain 2.3 g (78%) of fluvastatin
sodium crystal Form XI-2.

Example 68
Fluvastatin sodium (3.0 g) was dissolved in propan-1-ol (60 ml) at reflux
temperature. MTBE (60 ml) was added dropwise at reflux temperature and the resulting
mixture was stirred at this temperature for 40 minutes. Then, the mixture was cooled to
room temperature. The product was isolated by filtration under nitrogen, washed with
MTBE (2x30 ml) and dried at 50°C in a vacuum oven for 28 h to obtain 2.5 g (82%) of
fluvastatin sodium crystal Form XI-2.
Example 69
Fluvastatin sodium (3.0 g) was dissolved in propan-1-ol (60 ml) at reflux
temperature. Dichloromethane (60 ml) was added dropwise at reflux temperature and the
resulting mixture was stirred at this temperature for 30 minutes. Then, the mixture was
cooled to room temperature. The product was isolated by filtration under nitrogen,' washed
. with dichloromethane (2x20 ml) and dried at 50°C in a vacuum oven for 24 h to obtain 0.3
g (11%1 of fluvastatin sodium crystal Form XI-2.
13) Preparation of Fluvastatin Sodium Crystal Form X3I
Example 70
Fluvastatin sodium crystal Form B (3.0 g) was dissolved in butan-l-ol (70 ml) at
reflux temperature. 1,4-dioxane (140 ml) was added in two portions (2x70 ml) at reflux
temperature during 18 h. Then, the turbid solution was cooled to room temperature and
another portion of 1,4-dioxane (70 ml) was added. The mixture was stirred at room
temperature for 23 h. Then, it was concentrated under reduced pressure and was stirred at
room temperature for 9.5 h to obtain a precipitate. The product was filtered under nitrogen
flow, washed with 1,4-dioxane (2x15 ml) and dried at 50° C in a vacuum oven for 20 h to
obtain 0.35 g.(12%) of fluvastatin sodium crystal Form XH
14) Preparation of Fluvastatin Sodium Crystal Form XIII '
Example 71
A suspension of fluvastatin sodium crystal Form B (3.0 g) in acetonitrile (600 ml)
was stirred at reflux temperature for 2 h. The suspension was then cooled to 10°C using an
ice-bath. The product was filtered under nitrogen flow and dried at 50° C in a vacuum oven
for 24 h to obtain 2.1 g (70%) of fluvastatin sodium crystal Form XDI.
15) Preparation of Fluvastatin Sodium Crystal form XVI
Example 72
Fluvastatin sodium (3.0 g) was almost completely dissolved in propan-2-ol (70 ml)
at reflux temperature. Dichloromethane (70 ml) was added dropwise at reflux temperature.

The resulting solution was stirred at reflux temperature for 3 h. Then, the mixture was
cooled to room temperature and stirred at this temperature for 16 h. The product was
isolated by filtration, washed with dichloromethane (2x10 ml) and dried at 50° C in a
vacuum oven for 22 h to obtain 1.3 g (44%) of fluvastatin sodium crystal Form XVI.
16) Preparation of Fluvastatin Sodium Crystal Form XVII
Example 73
Fluvastatin sodium (3.0 g) was dissolved in propan-1-ol (60 ml) at reflux
temperature. The resulting solution was stirred at reflux temperature for 3 h. During this
time the material was recrystallized. Then, the mixture was cooled to room temperature.
The product was isolated by filtration under nitrogen, washed with propan-1-ol (1x10 ml)
and dried at 50° C in a vacuum oven for 21 h to obtain 0.2 g (7%) of fluvastatin sodium
•crystal Form XVII.
17) Preparation of Fluvastatin Sodium Crystal Form XVffl
Example 74
Fluvastatin sodium (3.0 g) was suspended in MEK (30 ml) at reflux temperature
for 16 h. Then, the solvent was distilled out and the residue was dried in a vacuum oven
for 24 h to obtain 2.7 g (90%) of fluvastatin sodium crystal Form XVIII
Example 75
'Fluvastatin sodium (3.0 g) was suspended in MEK (30 ml) at reflux temperature
for 2.5 h. Then, the mixture was cooled to room temperature. The product was isolated by
filtration under nitrogen, washed with MEK (2x15 ml) and dried at 50 °C in a vacuum
oven for 25.5 h to obtain 2.6 g (86%) of fluvastatin sodium crystal Form XVIII.
18) Preparation of Fluvastatin Sodium Crystal Form XIX
Example 76
Fluvastatin sodium Form XI (~ 300 nig) was placed on flat dishes with a diameter
of 35 mm and introduced in a chamber with controlled relative humidity of about 80% for
11 days. Fluvastatin sodium Form XIX was recovered.
Example 77
Fluvastatin sodium Form XI (~ 300 nig) was placed on flat dishes with a diameter
of 35 mm and introduced in a chamber with controlled relative humidity of about 100%
for 11 days. Fluvastatin sodium Form XTX was recovered.

Example 78
Fluvastatin sodium Form IV-1 (~ 300 mg) was placed on flat dishes with a
diameter of 35 mm and introduced in a chamber with controlled relative humidity of about
80% for 11 days. Fluvastatin sodium Form XIX was recovered.
Example 79 Fluvastatin sodium Form IV-1 (~ 300 mg) was placed on flat dishes with a
diameter of 35 mm and introduced in a chamber with controlled relative humidity of about
100% for 11 days. Fluvastatin sodium Form XIX was recovered.
Example 80
Fluvastatin^odium Form XVI (~ 300 mg) was placed on flat dishes with a
diameter of 35 mm and introduced in a chamber with controlled relative humidity of about
80% for 24 days. Fluvastatin sodium Form XIX was recovered.
Example 81
Fluvastatin sodium Form XVI (~ 300 mg) was placed on flat dishes with a
diameter of 35 mm and introduced in a chamber with controlled relative humidity of about
100% for 24 days. Fluvastatin sodium Form XIX was recovered.
19) Preparation of Fluvastatin Sodium Crystal Form XDC-1
Example 82
Wet fluvastatin sodium crystal form XI (10.0 g) was stirred in water (10 ml) at
room temperature for 6 h. Then,, the product was filtered under nitrogen flow, washed
with water (2 ml) and dried at 50°C in a vacuum oven for 21.5 h to obtain 3.8 g of
fluvastatin sodium crystal form XIX-1.
20) Preparation of Fluvastatin Sodium Crystal Form XX
Example 83
Fluvastatin sodium Form XVI (~ 300 mg) was placed on flat dishes with a
diameter of 35 mm and introduced in a chamber with controlled relative humidity of about
80% for 1 days. Fluvastatin sodium Form XX was recovered.
21) Preparation of Fluvastatin Sodium Crystal Form XXII
Example 84
About 300 mg fluvastatin sodium Form XV was placed on flat dishes with a
diameter of 35 mm and introduced in a chamber with controlled relative humidity of about
100% for 14 days, and fluvastatin sodium Form XXII was recovered.

22) Preparation of Fluvastatin Sodium Crystal Form XXHI
Example 85
Fluvastatin sodium crystal Foim B (5.0 g) was dissolved in propan-1-ol (100 ml) at
reflux temperature. The material was recrystallized at reflux temperature after 1 h. The
suspension was stirred at reflux temperature for additional 2 h. Then, the mixture was
cooled to room temperature and stirred at this temperature for 16 h to obtain a massive
precipitation. The product was filtered under nitrogen flow, washed with propan-1-ol
(2x25 ml) and dried at 50°C in a vacuum oven for 72 h to obtain 3.3xg (66%) of fluvastatin
sodium crystal Form XXHI.
23) Preparation of Fluvastatin Sodium Crystal Form XXIV
Example 86
Fluvastatin sodium crystal Form XV (5.0 g) was dissolved in water (14 ml) at
reflux temperature. The mixture was stirred at reflux temperature for 1.5 h and then was
cooled to room temperature. The mixture was stirred at room temperature for 16 h to
obtain a massive precipitate. The product was filtered under nitrogen flow, washed with
water (2x3 ml) and dried at 50°C in a vacuum oven for 22 h to obtain 4.5 g (90%) of
fluvastatin sodium crystal Form XXIV.
Example 87
Fluvastatin sodium crystal Form XV (5.0 g) was dissolved in water (9 ml) at reflux
temperature. The mixture was stirred at reflux temperature for 1.5 h and then was cooled
to room temperature. The mixture was stirred at room temperature for 16 h to obtain a
massive precipitate. The product was filtered under nitrogen flow, washed with water
(1x5 ml) and dried at 50°C in a vacuum oven for 24 h to obtain 4.2 g (84%) of fluvastatin
sodium crystal Form XXTV.
Example 88
Fluvastatin sodium crystal Form B (5.0 g) was dissolved in water (5 ml) at reflux
temperature. The mixture was stirred at reflux temperature for 2 h and then was cooled to
room temperature. The product was dried (without filtration) at 50 °C in a vacuum oven foi
24 h to obtain 4.4 g (88%) of fluvastatin sodium crystal Form XXTV.
Example 89
A slurry of fluvastatin sodium crystal Form B (8.0 g) in water (200 ml) was stirred
at room temperature for 1 h. Diethyl ether (100 ml) was added and the mixture was stirred
for 5 minutes. The organic and aqueous phases were separated. Traces of diethyl ether
were removed from the aqueous phase under reduced pressure. The aqueous solution was
lyophilized for 72 h to obtain fluvastatin sodium crystal Form XXTV.

Example 90
A slurry of fluvastatin sodium crystal Form B (8.0 g) in water (200 ml) was stirred
at room temperature for 1 h. Diethyl ether (100 ml) was added and the mixture was stirred
for 15 minutes. The organic and aqueous phases were separated. Traces of Diethyl ether
were removed from the aqueous phase under reduced pressure. The aqueous solution was
lyophilized for 96 h to obtain fluvastatin sodium crystal Form XXIV.
24) Preparation of Fluvastatin Sodium Crystal Form XXVI
•'Example 91
Fluvastatin sodium crystal Form B (3.0 g) was dissolved in 1,4-dioxane (20 ml)
and water (1 ml) at reflux temperature. The solution was stirred at reflux temperature for 1
h. Then, the mixture was cooled to room temperature and stirred at this temperature for 1.5
h to obtain a massive precipitation. The product was dried at 50° C in a vacuum oven
(without isolation by filtration) for 22 h to obtain 3.2 g (107%) of fluvastatin sodium
crystal Form XXVI.
25) Preparation of Fluvastatin Sodium Crystal Form XXVII
Example 92 ' Fluvastatin sodium crystal Form B (3.0 g) was dissolved in 1,4-dioxane (20
ml) and water (1 ml) at reflux temperature, Hexanes (30 ml) were added dropwise at reflux
temperature and the obtained mixture was stirred at this temperature for additional 1 h.
Then, the mixture was cooled to room temperature and stirred at this temperature for 1 h to
obtain a massive precipitation. The product was isolated by filtration, washed with
hexanes (3x20 ml) and dried at 50°C in a vacuum oven for 22 h to obtain 2.5 g (82%) of
fluvastatin sodium crystal Form XXVII.
26) Preparation of Fluvastatin Sodium Crystal Form XXIX
Example 93
Fluvastatin sodium crystal Form XV (5.0 g) was stirred in 1,4-dioxane (80 ml) at
reflux temperature for 16 h. Then, the suspension was cooled to room temperature. The
product was filtered under nitrogen flow, washed with 1,4-dioxane (4x25 ml) and dried at
50 °C in a vacuum oven for 24 h to obtain 3.8 g (76%) of fluvastatin sodium crystal Form
xxrx.
27) Preparation of Fluvastatin Sodium Crystal Form XXX
Example 94
fluvastatin sodium crystal Form XV (5.0 g) was stirred in methylethylketone
(MEK) (70 ml) at reflux temperature for 16 h. Then, the suspension was cooled to room

temperature. The product was filtered under nitrogen flow, washed with MEK (4x15 ml)
and dried at 50°C in a vacuum oven for 22 h to obtain 4.2 g (84%) of fluvastatin sodium
crystal Form XXX.
Example 95
Fluvastatin sodium crystal Form XV (5.0 g) was stirred in tetrahydrofuran (THF)
(50 ml) at reflux temperature for 16 h. Then, the suspension was cooled to room
temperature. The product was filtered under nitrogen flow, washed with THF (2x15 ml)
and dried at 50°C in a vacuum oven for 21 h to obtain 3.9 g (78%) of fluvastatin sodium
crystal Form XXX. ^"
Example 96
Fluvastatin sodium crystal Form XV (5.0 g) was stirred in acetone (75 ml) at reflux
temperature for 16 h. Then, the suspension was cooled to room temperature. The product
was filtered under nitrogen flow, washed with acetone (3x25 ml) and dried at 50°C in a
vacuum oven for 24 h to obtain 4.0 g (80%) of fluvastatin sodium crystal Form XXX.
Example 97
Fluvastatin sodium crystal Form XV (5.0 g) was stirred butan-2-ol (60 ml) at reflux
temperature for 16 h. Then, the suspension was cooled to room temperature. The product
was filtered under nitrogen flow, washed with butan-2-ol (3x25 ml) and dried at 50° C in a
vacuum oven for 25 h to obtain 4.2 g (84%) of fluvastatin sodium crystal Form XXX.
Example 98 i
Fluvastatin sodium crystal Form XV (5.0 g) was stirred butan-1-ol (60 ml) at reflux
temperature for 16 h. Then, the suspension was cooled to room temperature. The product
was filtered under nitrogen flow, washed with butan-2-ol (4x25 ml) and dried at 50°C hi a
vacuum oven for 24 h to obtain 4.2 g (84%) of fluvastatin sodium Form XXX.
Example 99
Fluvastatin methyl ester (3.0 g) was added to a solution of NaOH (1 eq.) hi water
(0.75 ml) and methanol (7.5 ml). The mixture was stirred at about 65°C for 3.5 h. Then,
another portion of NaOH (O.Seq.) hi water (0.4 ml) was added. After another 40 min the
starting material was no longer detectable by HPLC. Acetone (58 ml) was dripped into the
solution over 25 min. Turbidity appeared in the solution. The mixture was cooled slowly
to room temperature and stirred overnight. The product was isolated by filtration under
nitrogen, washed with acetone (20 ml) and dried at 50° C in a vacuum oven for 24 h to
obtain 0.25 g (8.2%) of fluvastatin sodium Form XXX.
28) Preparation of Fluvastatin Sodium Crystal Form XXX3
Example 100

Fluvastatin sodium crystal Form XV (5.0 g) was stirred ethanol (100 ml) at reflux
temperature for 23 h. Then, the suspension was cooled to room temperature. The product
was filtered under nitrogen flow, washed with ethanol (2x10 ml) and dried at 50° C in a
vacuum oven for 21 h to obtain 4.4 g (88%) of fluvastatin sodium crystal Form XXXI.
29) Preparation of Fluvastatin Sodium Crystal Form XXXIII
Example 101
Fluvastatin sodium crystal Form XV (5.0 g) was stirred in absolute ethanol (40 ml)
at reflux temperature for 16 h. Then, the suspension was cooled to ro^om temperature. The
product was filtered under nitrogen flow, washed with absolute ethanol (4x20 ml) and
dried at 50 °C in a vacuum oven for 24 h to obtain 4.2 g (84%) of fluvastatin sodium
crystal Form XXXIH.
Example 102
Absolute ethanol was added in 4 portions (1x60 ml, 3x20 ml) to fluvastatin sodium
Form B (5.0 g). The heterogeneous mixture was at reflux temperature for 1.25 h. Then,
the suspension was cooled to room temperature and stirred at this temperature for 23 h.
The product was filtered under nitrogen flow, washed with absolute ethanol (2x20 ml) and
dried at 50°C in a vacuum oven for 22 h to obtain 2.3 g (45%) of fluvastatin sodium Form
xxxni..
Example 103
Absolute ethanol was added in two portions (2x100 ml) to fluvastatin sodium Form
B (5.0 g). The heterogeneous mixture was at reflux temperature for 3 h. Then, the
suspension was cooled to room temperature and stirred at this temperature for 18 h. The
product was filtered under nitrogen flow, washed with absolute ethanol (1x20 ml) and
dried at 50°C in a vacuum oven for 24 h to obtain 0.8 g (16%) of Fluvastatin sodium Form
xxxni.
30) Preparation of Fluvastatin Sodium Crystal Form XXXTV
Example 104
Fluvastatin sodium crystal Form XV (5,0 g) was stirred in DMSO (50 ml) at 100°C
for 16 h. Then, the suspension was cooled to room temperature. The product was filtered
under nitrogen flow, washed with DMSO (2x25 ml) and dried at 50 °C in a vacuum oven
for 24 h to obtain 3.6 g (71%) of fluvastatin sodium crystal Form XXXrV.
31) Preparation of Fluvastatin Sodium Crystal Form XXXV
Example 105

Fhivastatin sodium crystal Form XV (5.0 g) was stirred in DMF (50 ml) at 95°C
for 16 h. Then, the suspension was cooled to room temperature. The product was filtered
under nitrogen flow, washed with DMF (2x25 ml) and dried at 50° C in a vacuum oven for
24 h to obtain 4.9 g (98%) of fluvastatin sodium crystal form XXXV.
32) Preparation of Fluvastatin Sodium Crystal Form XXXVI
Example 106
A suspension of fluvastatin sodium crystal Form XI wet (10.0 g) in water (10 ml)
vWas stirred at room temperature for 6 h. The product was then filtered under nitrogen flow
and washed with water (1x2 ml) to obtain 9.6 g (88%) of wet fluvastatin sodium crystal
Form XXXVI
33) Preparation of Fluvastatin Sodium Crystal Form XXXVn
Example 107
Fluvastatin sodium Form XI (6.0 g) was suspended in water (12 ml) at room
temperature for 5.75 h. Then, the product was filtered under nitrogen flow and dried at
50 °C in a vacuum oven for 23 h to obtain 4.1 g (68%) of fluvastatin sodium crystal Form
XXXVII.
34) Preparation of Flnvastatin Sodium Crystal Form XXXVIII
Example 108
Fluvastatin sodium Form XI (2.5 g) was suspended in absolute ethanol (13.5 ml) at
reflux temperature for 16 h. Then, the suspension was cooled to room temperature and
stirred at this temperature for 3 h. The product was filtered under nitrogen flow, washed
with absolute ethanol (2x10 ml) and dried at 50°C in a vacuum oven for 23 h to obtain 2.0
g (79%) of fluvastatin sodium crystal Form XXXVIH.
Example 109
Fluvastatin methyl ester (2.0 g) was added to a solution of NaOH (1 eq.) in EtOH
(15 ml). The mixture was stirred at about 70 °C for 4 h (it became clear and turned to a
slurry), after which the starting material was not detected by HPLC. Then, 40 ml of ethyl
acetate was dripped into the mixture and it was cooled slowly to room temperature and
stirred overnight. The product was isolated by filtration under nitrogen, washed with ethyl
acetate (10 ml) and dried at 50°C in a vacuum oven for 24 h to obtain fluvastatin sodium
Form XXXVin (1.78 g, 87.4%).
Example 110
Fluvastatin sodium crystal Form XI (2.5 g) was suspended in absolute ethanol
(13.5 ml) at reflux temperature for 16 h. The suspension was cooled to room temperature

and stirred at this temperature for 3 h. The product was filtered under nitrogen flow,
washed with absolute ethanol (2x10 ml) and dried at 50°C in a vacuum oven for 23 h to
obtain 2.0 g (79%) of fluvastatin sodium crystal Form XXXVIII.
35) Preparation of Fluvastatin Sodium Crystal Form XXXIX
Example 111
In a 100 ml flask were placed Fluvastatin methyl ester (2.0 g) and a solution of
NaOH (0.19 g) in EtOH (5 ml). The mixture was stirred at reflux for 3.5 h and propan-2-ol
(40 ml) was added. The slurry was^cooled to room temperature and stirred over night. The
product was isolated by filtration under nitrogen, washed with propan-2-ol (20 ml) and
dried at 50 °C in a vacuum oven for 24 h to obtain 1.93 g (95%) of fluvastatin sodium
crystal Form XXXK.
36) Preparation of Fluvastatin Sodium Crystal Form XLI
Example 112
Fluvastatin sodium Form XV (6.0 g) was dissolved in water (16 ml) at reflux
temperature. Acetonitrile (60 ml) was added dropwise and the mixture was stirred at reflux
)
temperature for 1 h. Then, the mixture was cooled to room temperature and stirred at this
temperature for 16 h. Another portion of acetonitrile (70 ml) was added to obtain
precipitation. After 3.5 h, the product was isolated by filtration under nitrogen, washed
with acetonitrile (2x20 ml) and dried at 50°C in a vacuum oven for 25 h to obtain 2.96 g
(49%) of fluvastatin sodium crystal Form XLI.
37) Preparation of Fluvastatin Sodium Crystal Form XLn
Example 113
Fluvastatin (3.0 g) was completely dissolved in MEK (40 ml) at room temperature.
The solution was filtered to obtain a clear solution and 97% NaOH (0.29 g) dissolved in
MeOH (3 ml) was added to the solution. The solution was stirred at room temperature for
94 h to obtain a gelatinous precipitate. The product was filtered under nitrogen flow
washed with MEK (2x11 ml) and dried at 50°c is a vacuum oven for 25.5 h to obtain 2.6
(g) (85.5%) of fluvastatin sodium crystal Form XIII.
Example 114
Fluvastatin (2.0 g) was completely dissolved in MeOH (5 ml) at reflux temperature
and NaOH (s) (0.19 g) was added. The solution was stirred at reflux temperature for 3 h to
obtain a precipitate having a paste-like consistency, ethyl acetate (40 ml) was added
dropwise at reflux temperature and then the solution was cooled to room temperature and
the slurry was stirred for 3 h. The product was filtered under nitrogen flow, washed with

ethyl acetate (2 x 10 ml) and dried at 50 °C in a vacuum oven for 23 h to obtain 1.58 g
(77.5%) of fluvastatin-sodium form XLII.
Example 115
Fluvastatin (3.0 g) was completely dissolved in dichloromethane (35 ml) at room
temperature and the solution was filtered to obtain clear solution. NaOH (s) (0.29 g)
dissolved in MeOH (3 ml) was added to the solution and the solution was then stirred at
room temperature for 23 h to obtain-a precipitate. The product was filtered under nitrogen
flow, washed with dichloromethane (2x10 ml) and dried at 50°C in a vacuum oven for 42
h to obtain 2.3 g (75%) of Fluvastatin-sodium form XLII.
Example 116
Fluvastatin-diol (3.0 g) was completely dissolved in dichloromethane (35 ml) at
room temperature and the solution was filtered to obtain clear solution. NaOH (s) (0.29 g)
dissolved in EtOH (5 ml) was added to the solution and the solution was then stirred at
room temperature for 23 h to obtain a precipitate. The product was filtered under nitrogen
flow, washed with dichloromethane (2 x 10 ml) and dried at 50°C in a vacuum oven for 42
h to obtain 1.88 g (61.5%) of fluvastatin-sodium form XLII.
38) Preparation of Fluvastatin Sodium Crystal Form XLITI
Example 117
Fluvastatin sodium Form B (5.0 g) was dissolved in water (15 ml) at reflux
temperature. Propan-2-oI (45 ml) was added dropwise and the mixture was stirred at
reflux temperature for 2 h. Then, the mixture was cooled to room temperature and stirred
at this temperature for 16 h. Another portion of propan-2-ol (50 ml) was added to obtain a
massive precipitation. After 7.5 h, the product was isolated by filtration under nitrogen,
washed with propan-2-ol (2x25 ml) and dried at 50° C in a vacuum oven for 24 h to obtain
0.74 g (15%) of fluvastatin sodium Form XLffl.

Example 118
Fluvastatin methyl ester (2.0 g) was added to a solution of NaOH (1 eq.) in water.
The mixture was stirred at about 70°C for 2 h until the raw material wasn't observed by
HPLC. After this time, propan-2-ol (10 ml) was dripped and the solution was cooled
slowly to room temperature. Another 40 ml of propan-2-ol (in 3 portions) were added at
room temperature to the solution but no precipitation was °Ccurred. The solution was
stirred overnight and a gel-like precipitate formed. The mixture was heated to reflux to
dissolve the gel. The mixture was then allowed to cool to room temperature. A yellow
slurry was obtained. After stirring overnight, another 15 ml of propan-2-ol were added
dropwise. The product was isolated by filtration under nitrogen, washed with propan-2-ol
(25 ml) and dried at 50 °C in a vacuum oven for 24 h to obtain 0.46 g (22.6%) of
fluvastatin sodium Form XLIII.
• 39) Preparation of Fluvastatin Sodium Crystal Form XLJV
Example 119
Amorphous fluvastatin sodium (1.5 g) was suspended in propan-2-ol (31 ml) at
reflux temperature for 4.25 h. Then, the suspension was cooled to room temperature and
stirred at this temperature for 1 h. The product was filtered under nitrogen flow, washed
with propan-2-ol (2x35 ml) and dried at 50°C in a vacuum oven for 23 h to obtain 0.4 g
(25%) of fluvastatin sodium Form XLIV.
Example 120
Fluvastatin methyl ester (3.0 g) was added to acetone (30 ml) and the solution was
stirred at room temperature. NaOH (1 eq.) in EtOH (3 ml) was added to the solution. The
mixture was stirred overnight. The product that precipitated was isolated by filtration
under nitrogen, washed with acetone (100 ml) and dried at 50°C in a vacuum oven for 24
h to obtain 2.45 g (80.8%) of fluvastatin sodium Form XLIV.
40) Preparation of Fluvastatin Sodium Crystal Form XLV
Example 121
A suspension of fluvastatin sodium Form Ami (2.6 g) in propan-2-ol (36 ml) was
stirred at room temperature for 25 h. The product was then filtered under nitrogen fio\v,
washed with propan-2-ol (2x20 ml) and dried at 50°C in a vacuum oven for 20.5 h to
obtain 2.4 g (92%) of fluvastatin sodium crystal Form XLV.
Preparation of Form Ami
Fluvastatin -diol -methyl ester (FDME) (3.0g) was added to cyclohexane (60 ml)
and the mixture was heated to reflux. NaOH (1 eq.) dissolved in MeOH (3 ml) was added

to the slurry solution which became clear. After 15 min precipitant was appeared. After
another hour the mixture was cooled to rt, cyclohexane (40 ml) was added and it was
stirred overnight. The product was isolated by filtration under nitrogen, washed with
cyclohexane (90 ml) and dried at 50*C in a vacuum over for 24 hours to obtain 2.73 gr
(90%) of Fluvastatin sodium Ami.
41) Preparation of Fluvastatin Sodium Crystal Form XLVI
Example 122
In a 100 ml flask were placed fluvastatin methyl ester (2.42 g), EtOH (5 ml) and a
solution of NaOH (0.23 g) in EtOH (7 ml). The mixture was stirred at reflux for 2.5 h and
acetonitrile (50 ml) was added. The slurry was stirred at reflux for another 3 h then cooled
to room temperature and stirred over night. The product was isolated by filtration under
nitrogen and dried at 50°C in a vacuum oven for 24 h to obtain 2.02 g (83%) of fluvastatin
sodium crystal Form XLVI.
42) Preparation of Fluvastatin Sodium Crystal Form XLVII
Example 123
About 300 mg fluvastatin sodium Form XVIII was placed on flat dishes with a
diameter of 35 mm and introduced in a chamber with controlled relative humidity of about
80% for 25 days, and fluvastatin sodium form XLVII was recovered.
43) Preparation of Fluvastatin Sodium Crystal Form XLVIH
Example 124
To a three necked flask was added fluvastatin methyl ester (3.0 g) and NaOH (1
eq.) dissolved in MeOH (7.5 ml). The mixture refluxed for 6.5 h. Then, acetonitrile (50
ml) was added dropwise to the refluxing solution over 10 min. The mixture was then
cooled to room temperature and stirred for 46 h. The product was isolated by filtration
under nitrogen, washed with acetonitrile (50 ml) and dried at 50°C in a vacuum oven for
24 h to obtain 1.84 g (60.7%) of fluvastatin sodium Form XLVm.
Example 125
Fluvastatin sodium Form B (5.0 g) was stirred in MeOH (40 ml) at reflux for 5 h.
The slurry was cooled to room temperature and stirred at room temperature for 17 h. The
product was filtered under nitrogen flow, washed with MeOH (2x20 ml) and dried at 50°C
in a vacuum oven for 21.5 h to obtain 0.28 g (5.6%) of fluvastatin sodium Form XLVIIL
Example 126
Fluvastatin sodium Form B (5.0 g) was dissolved in MeOH (24 ml) at room
temperature. The solution was heated to reflux temperature to obtain a precipitate. The

slurry formed was cooled to room temperature and stirred at room temperature for 19.5 h.
The product was filtered under nitrogen flow, and dried at 50°C in a vacuum oven for 24 h
to obtain 0.53 g (10.6%) of fluvastatin sodium Form XLVIII.
Example 127
Fluvastatin (3 g) was completely dissolved in MeOH (15 ml) at reflux temperature.
Then, the solution was filtered to obtain a clear solution and heated to reflux again. NaOH
(s) (0.29 g) was added at reflux temperature to obtain a precipitate. The slurry was cooled
to room temperature to obtain a paste-like mixture. Acetone (30 g) was added dropwise at
room "temperature and the solution stirred at room temperature for 21 h to obtain a massive
precipitate. The product was filtered under nitrogen flow, washed with acetone (2x15 ml)
and dried at 50°C in a vacuum oven for 22.5 h to obtain 1.89 g (62%) of fluvastatin
sodium Form XLVHI.
44) Preparation of Fluvastatin Sodium Crystal Form XLDC
Example 128
Fluvastatin sodium crystal Form B (5.0 g) was dissolved in methanol (40 ml) at
room temperature. The solution was heated to reflux temperature and MTBE (100 ml) was
added dropwise to obtain a precipitate. The obtained suspension was stirred at reflux
temperature for 1 h. Then, the mixture was cooled to room temperature and stirred at this
temperature for 16 h. The product was filtered under nitrogen flow, washed with MTBE
(2x10 ml) and dried at 50°C in a vacuum oven for 24 h to obtain 3.2 g (64%) of fluvastatin
sodium crystal Form XLBC
45) Preparation of Fluvastatin Sodium Crystal Form L
Example 129
Fluvastatin sodium (5.0 g) was dissolved in methanol (35 ml) at room temperature.
The solution was heated to reflux temperature and ethyl acetate (100 ml) was added
dropwise. A precipitation was obtained during addition of ethyl acetate. The mixture was
stirred at reflux temperature for 1.5 h. Then, the suspension was cooled to room
temperature and stirred at this temperature for 16 h. The product was filtered under
nitrogen flow and dried at 50°C in a vacuum oven for 24 h to obtain 0.7 g (14%) of
Fluvastatin sodium Form L.
46) Preparation of Fluvastatin Sodium Crystal Form LI
Example 130
Fluvastatin sodium crystal Form B (5.0 g) was dissolved in methanol (50 ml) at
room temperature. The solution was heated to reflux temperature and acetonitrile (100 ml)

was added dropwise to obtain a precipitate. The obtained suspension was stirred at reflux
temperature for 1 h. Then, the mixture was cooled to room temperature and stirred at this
temperature for 16 h. The product was filtered under nitrogen flow, washed with
acetonitrile (2x15 ml) and dried at 50°C in a vacuum oven for 23 h to obtain 0.73 g (15%)
of fluvastatin sodium crystal Form LI.
47) Preparation of Fluvastatin Sodium Crystal Form LIII
Example 131
Fluvastatin sodium crystal Form B (16.0 g) was dissolved in methanol (112 ml) at
room temperature. The solution was heated to reflux temperature and ethyl acetate (320
ml) was added dropwise to obtain a precipitate. The obtained suspension was stirred at
reflux temperature for 1.5 h. Then, the mixture was cooled to room temperature and stirred
at this temperature for 16 h. The product was filtered under nitrogen flow, washed with
ethyl acetate (1x25 ml) and dried at 50°C in a vacuum oven for 23.5 h to obtain 2.1 g
(13%) of fluvastatin sodium crystal Form LIII.
48) Preparation of Fluvastatin Sodium Crystal Form LIY
Example 132
Fluvastatin (3.52 g) was stirred in a solution of H2O (9.9 ml) and NaOH (s) (0.32
g) at room temperature to obtain a mud-like suspension. The suspension was stirred at
room temperature over night. The product was filtered under nitrogen flow, washed with
H2O (2 x 3 ml) and dried at 50°C in a vacuum oven for 24 h to obtain 3.36 g (65.8%) of
fluvastatin sodium Form LIV.
49) Preparation of Fluvastatin Sodium Crystal Form LV
Example 133
Fluvastatin methyl ester (3.0 g) was added to acetonitrile (60 ml) and dissolved by
heating the mature to reflux. The solution was then cooled to about 40°C and NaOH (1
eq.) dissolved in MeOH (7.5 ml) was added. Turbidity appeared immediately. After 30
minutes an oil residue separated from the mixture. The mixture was heated again to aboui
5 5 ° C for 3 h to dissolve the oil. The product was isolated by filtration under nitrogen,
washed with acetonitrile (40 ml) and dried at 50 °C in a vacuum oven for 24 h to obtain
2.48 g (81.1 %) of fluvastatin sodium Form LV.
50) Preparation of Fluvastatin Sodium Crystal Form LVI
Example 134
In a 250 ml flask were placed Fluvastatin-acetonide-methylester (4.4 g), THF (44
ml) and 1.5% HC1 solution (0.67 ml). The mixture was stirred at room temperature for 10
h, then NaOH (0.25 g) was added and the solvents were evaporated. The residue was
dissolved in acetone (80 ml), NaOH (0.43 g)was added and the mixture was stirred at
room temperature over night. The product was isolated by filtration under nitrogen,
washed with acetone (50 ml).and dried a.V50°C in a vacuum oven for 24 h to obtain 1.37 g
of iluvastatin sodium crystal Form LVI.
51) Preparation of Fluvastatin Sodium Crystal Form LVII
Example 135
Fluvastatin sodium Form VII (20.5 g) was suspended in absolute ethanol (246 ml)
at room temperature for 21 h. The product was then filtered under nitrogen flow, washed
with absolute ethanol (2x40 ml) and dried at 50 °C in a vacuum oven for 24 h to obtain
11.8 g (58%) of fluvastatin sodium Form LVII
52) Preparation of Fluvastatin-Sodium Crystal Form LVDI
Example 136
Propan-2-ol (120 ml) was heated to reflux temperature. Fluvastatin sodium (5.0 g)
was added to the boiled solvent. The mixture was stirred at reflux temperature for 3 h.
Then, the suspension was cooled to room temperature and stirred at this temperature for 16
h. The product was filtered under nitrogen flow, washed with propan-2-ol (2x25 ml) and
dried at 50 °C in a vacuum oven for 22 h to obtain 4.7 g (95%) of fluvastatin sodium Form
LVIIL
53) Preparation of Fluvastatin-Sodium Crystal Form LX
Example 137
Fluvastatin sodium crystal Form B (16.0 g) was dissolved in methanol (112 ml) at
room temperature. The solution was heated to reflux temperature and ethyl acetate (320
ml) was added dropwise to obtain a precipitate. The obtained suspension was stirred at
reflux temperature for 1.5 h. Then, the mixture was cooled to room temperature and stirred
at this temperature for 16 h. The product was filtered under nitrogen flow, washed with
ethyl acetate (1x20 ml) and dried at 50°C in a vacuum oven for 24 h to obtain 2.3 g (14%)
of fluvastatin sodium crystal Form LX.

54) Preparation of Fhivastatin-Sodium Crystal Form LXFV
Example 138
la a 3 neck flask were placed fluvastatin methyl ester (3.0 g) and MeOH (30 ml).
The mixture was heated to reflux for dissolution and NaOH (0.42) was added in two
portions. Precipitant was appeared at reflux temperature and wasn't dissolved after
addition of another 45 ml of MeOH during 4 h. The slurry mixture was cooled to room
temperature and stirred overnight. The precipitant was dissolved, acetone (150ml) was
added and the mixture was stirred at room temperature for 22 h. The product was isolated
by filtration under nitrogen, washed with acetone (35 ml) and dried at 50°C in a vacuum
oven for 22.5 h to obtain 1.68g of fluvastatin sodium crystal Form LXIV.
Example 139
Fluvastatin methyl ester (15.0 g) was dissolved in'acetone (225 ml) and filtered. A
solution of NaOH (1.46 g) in MeOH (15 ml) was added and the solution was stirred at
room temperature. After 2 h a solution of NaOH (0.73 g) in MeOH (15 ml) was added and
the mixture was stirred over night. The product was isolated by filtration under nitrogen,
- washed with acetone and dried at 50°C in a vacuum oven for 24 h to obtain fluvastatin
sodium form LXIV.
Example 140
Fluvastatin methyl ester (15.0 g) was dissolved in acetone (225 ml) and filtered. A
solution of NaOH (1.46 g) in MeOH (15 ml) was added and the solution was stirred at
room temperature. After 2 h a solution of NaOH (0.73 g) in MeOH (15 ml) was added.
After 2 h the mixture was cooled to 14°C and stirred at this temperature over night. The
product was isolated by filtration under nitrogen, washed with acetone and dried at 50 °C
in a vacuum oven for 24 h to obtain fluvastatin sodium form LXIV.
55) Preparation of Fluvastatin-Sodium Crystal Form LXV
Example 141
hi a 100 ml flask were placed Fluvastatin methyl ester (3.0 g), MeOH (20 ml) and
NaOH (0.29 g). After a clear solution was obtained propan-2-ol (80 ml) was added and the
solution was stirred at room temperature over night. A little precipitation occurred,
propan-2-ol (40 ml) was added and the solution was stirred at room temperature for
another night. The product was isolated by filtration under nitrogen, washed with acetone
(35 ml) and dried at 50°C in a vacuum oven for 22.5 h to obtain 0.92g of fluvastatin
sodium crystal Form LXV.

Example 142
Fluvastatin methyl ester (3.0 g) was dissolved in MeOH (15 ml) by heating to
reflux. NaOH (0.29 g) was added and the clear solution was stirred at reflux for 30 min,
then acetone (75 ml) was added. The solution was cooled to room temperature and stirred
over night. The product was isolated by filtration under nitrogen, washed with acetone (35
ml) and dried at 50°C'in a vacuum oven for 21.5 h to obtain 1.34 g of fluvastatin sodium
crystal Form LXV.
56) Preparation of Fluvastatin-Sodium Crystal Form LXVI
Example 143
la a 50 ml flask were placed fluvastatin sodium crystal Form VI (1.98 g) and water
(4 ml), then the mixture was heated to reflux for dissolution. After 2 h the solution was
cooled to room temperature and stirred over night. The product was isolated by filtration
under nitrogen, washed with water (3 ml) and dried at 50°C hi a vacuum oven for 24 h to
obtain 1.25 g (63%) of fluvastatin sodium crystal Form LXVI.
Example 144
Fluvastatin sodium crystal Form B (5.0 g) was dissolved in water (10 ml) at reflux
temperature. The solution was stirred at reflux temperature for 2 h. Then, the solution was
cooled to room temperature and stirred at this temperature for 16 h to obtain a precipitate.
The product was filtered under nitrogen flow, washed with water (2x2 ml) and dried at
50 °C in a vacuum oven for 24.5 h to obtain 4.4 g (89%) of fluvastatin sodium crystal
Form LXVI.
Example 145
Fluvastatin sodium crystal Form XV (5.0 g) was dissolved in water (14 ml) at
reflux temperature. The solution was stirred at reflux temperature for 1.25 h. Then, the
solution was cooled to room temperature and stirred at this temperature for 16 h to obtain a
precipitate. The product was filtered under nitrogen flow, washed with water (2x3 ml) and
dried at 50° C in a vacuum oven for 24 h to obtain 4.2 g (84%) of fluvastatin sodium
crystal Form LXVI.
57) Preparation of Fluvastatin-Sodium Crystal Form LXVII
Example 146
Fluvastatin methyl ester (3.0 g) was dissolved in acetone (45 ml) and a solution of
NaOH (0.36 g) in MeOH (5 ml) was added. After 3 h NaOH (0.072 g) was added and the
mixture was stirred at room temperature for another 21 h. NaOH (0.073 g) was added and
the mixture was stirred for another 4 h. The product was isolated by filtration under

nitrogen, washed with acetone (55 ml) and dried at 50°C in a vacuum oven for 24 h to
obtain 2.64 g of fluvastatin sodium crystal Form LXVII.
Example 147
Fluvastatin methyl ester (3.0 g) was dissolved in acetone (45 ml), a solution of
NaOH (0.58 g) in MeOH (8 ml) was added and the mixture was stirred at room
temperature for another 3.75 h. The product was isolated by filtration under nitrogen,
washed with acetone (40 ml) and dried at 50°C in a vacuum oven for 21 h to obtain 2.54 g
of fluvastatin sodium crystal Form LXVII.
Example 148 x
Fluvastatin methyl ester (10.0 g) was dissolved in acetone (150 ml) and a solution
of NaOH (0.94 g) in MeOH (10 ml) was added. After 26.5 h, NaOH (0.47 g) was added
and the mixture was stirred at room temperature over night. The product was isolated by
filtration under nitrogen, washed with acetone (20 ml) and dried at 50 °C in a vacuum oven
for 23 h to obtain 8.01 g of fluvastatin sodium crystal Form LXVII.
58) Preparation of Fluvastatin-Sodium Crystal Form LVffl
Example 149
Fluvastatin methyl ester (3.0 g) was dissolved in acetone (45 ml) and a solution of
NaOH (0.44 g) in MeOH (6 ml) was added. After 29 h, NaOH (0.14 g) was added and the
mixture was stirred at room temperature for another 1 h, then it was cooled with ice bath
for 30 nun. The product was isolated by filtration under nitrogen, washed with acetone (38
ml) and dried at 50°C in a vacuum oven for 22 h to obtain 2.76 g of fluvastatin sodium
crystal Form LXVHL
Example 150
Fluvastatin methyl ester (15.0 g) was dissolved in acetone (225 ml) and filtered. A
solution of NaOH (1.46 g) in MeOH (15 ml) was added and the solution was stirred at
room temperature. After 27 h, a solution of NaOH (0.73 g) in MeOH (15 ml) was added
and the mixture was stirred over night. The product was isolated by filtration under
nitrogen, washed with acetone and dried at 50° C in a vacuum oven for 24 h to obtain
fluvastatin sodium form LXVIH.
59) Preparation" of Fluvastatin Sodium Crystal Form LXIX
Example 151
In a 50 ml flask were placed fluvastatin sodium crystal Form VI (1.63 g) and
propan-2-ol (28 ml) then the mixture was heated to reflux. After 2 h, propan-2-ol (4 ml)
was added, the slurry was stirred at reflux for another 20 min, cooled to room temperature
and stirred over night. The product was isolated by filtration under nitrogen, washed with

propan-2-ol (30 ml) and dried at 50 °C in a vacuum oven for 24 h to obtain 1.52 g (93%) of
fluvastatin sodium crystal Form LXIX.
60) Preparation of Fluvastatin Sodium Crystal Form LXX
Example 152
In a 100 ml flask were placed fluvastatin sodium crystal Form LXVII (2.0 g) and
water (3.4 ml). The mixture was heated to reflux for dissolving and acetone (34 ml) was
added. After 2 h, the mixture was cooled to room temperature and stirred over night. The
product was isolated by filtration under nitrogen, washed with acetone (20 ml) and dried at
50°C in a vacuum oven for 24 h to obtain 1.69 g (84.5%) of fluvastatin sodium crystal
Form LXX.
61) Preparation of Fluvastatm Sodium Crystal Form LXXI
Example 153
In a 100 ml flask were placed fluvastatin sodium crystal Form LXVII (2.0 g) and
water (2 ml). The mixture was heated to reflux and acetone (74 ml) was added. After 2 h,
the mixture was cooled to room temperature and stirred over night. The product was
isolated by filtration under nitrogen, washed with acetone (20 ml) and dried at 50°C in a
vacuum oven for 24 h to obtain 1.85 g (92.5%) of fluvastatin sodium crystal Form LXXI.
62) Preparation of Fluvastatin Sodium Crystal Form LXXII
Example 154
In a 100 ml flask were placed fluvastatin sodium crystal Form VI (1.33 g), acetone
(28 ml) and water (0.7 ml). The mixture was heated to reflux for 2 h, then cooled to room
temperature and stirred over night. The product was isolated by filtration under nitrogen,
washed with acetone (20 ml) and dried at 50°C in a vacuum oven for 24 h to obtain 1.26 g
(95%) of fluvastatin sodium crystal Form LXXH.
Example 155
In a 100 ml flask were placed fluvastatin sodium crystal' Form VI (1.12 g) and
acetonitrile (19 ml). The mixture was heated to reflux for 2 h, then cooled to room
temperature and stirred over night. The product was isolated by filtration under nitrogen,
washed with acetonitrile (20 ml) and dried at 50°C in a vacuum oven for 24 h to obtain
1.02 g (86%) of fluvastatin sodium crystal Form LXXII.

63) Preparation of Fluvastatin Sodium Crystal Form LXXIV
Example 156
A suspension of fluvastatin sodium crystal Form B (30.0 g) in a mixture of propan-
2-ol (501 ml) and water (51 ml) was heated to reflux temperature for 16 h. The suspension
was then cooled to room temperature. The product was filtered under nitrogen flow,
washed with propan-2-ol (2x25 ml) and dried at 50°C in a vacuum oven for 21.5 h to
obtain 4.7 g (16%) of fluvastatin sodium crystal Form LXXTV.
^Example 157
A suspension of fluvastatin sodium crystal Form B (2.0 g) in a mixture of propan-
2-ol (33.3 ml) and water (4.3 mi) was heated to reflux temperature for 4 h. The suspension
was then cooled in an ice-bath. The product was filtered under nitrogen flow, washed with
propan-2-ol (2x10 ml) and dried at 50°C in a vacuum oven for 17:5 h to obtain 0.4g (20%)
of fluvastatin sodium crystal Form LXXIV.
64) Preparation of Fluvastatin Sodium Crystal Form LXXV

Example 158
Fluvastatin sodium crystal Form XXX (2.0 g) was refluxed in MeOH (10 ml) for
15 h, cooled to room temperature and stirred for another 2 h. The product was isolated by
filtration under nitrogen, washed with MeOH (15 ml) and dried at 50° C in a vacuum oven
for 24 h to obtain 0.48 g (24%) of fluvastatin sodium crystal Form LXXV.
65) Preparation of Fluvastatin Sodium Crystal Form LXXVI
Example 159
A 250 round bottom flask was loaded with fluvastatin methyl ester (12.0 g), EtOH
(60 ml), water (36 ml) and NaOH (1 eq.). After 2 h the ethanol was evaporated and the
residue was divided to 4 fractions. Water was added (completing to 20 vol) and extracted
twice with ethyl acetate. The product was isolated by distillation of water to obtain wet
fluvastatin sodium crystal Form LXXVI. (the sample was kept at room temperature for 3
days).
66) Preparation of Fluvastatin Sodium Crystal Form LXXVII
Example 160
Fluvastatin methyl ester (3,0 g) was dissolved in ethyl acetate (90 ml), a solution of
NaOH (0.2 g) in water (1 ml) was added and the mixture was stirred at room temperature
over night. The product was isolated by filtration under nitrogen, washed with ethyl

acetate (50 ml) and dried at 50 °C in a vacuum oven for 24 h to obtain 1.52 g (49.7%) of
fluvastatin sodium crystal Fonn LXXVTL
67) Preparation of Fluvastatin Sodium Crystal Form LXXVIII
Example 161
A 100 ml round bottom flask was loaded with fluvastatin methyl ester (4.0 g, 9.4
mmole), water (32 ml) and NaOH (0.39 g). The mixture was stirred for 3 days at room
temperature then extracted with ethyl acetate (32 ml, 16 ml). The aqueous solution was
evaporated, propan-2-ol (40 ml) was added and the mixture was stirred at room
temperature over night. Precipitation occurred after scraping the mixture with spatula and
stirring for another day. The product was isolated by filtration under nitrogen flow, washed,
with propan-2-ol (20 ml) and dried at 5Q°C in a vacuum oven for 24 h to obtain 1.28 g
(31%) of fluvastatin sodium crystal Form LXXVTfl.
Example 162
A 100 ml round bottom flask was loaded with Fluvastatin methyl ester (3.0 g, 7.08
mmole), water (30 ml) and NaOH (0.29 g). The mixture was stirred for 3 h at room
temperature then extracted with ethyl acetate (30 ml). The aqueous solution was
evaporated, acetonitrile (12 ml) was added and the mixture was stirred at room
temperature over night. The product was isolated by filtration under nitrogen flow, washed
with acetonitrile (20 ml) and dried at 40°C in a vacuum oven for 24 h to obtain 0.37 g
(12°/o) of fluvastatin sodium crystal Form LXXVIQ.
68) Preparation of Fluvastatin Sodium Form XC
Example 163
Fluvastatin sodium crystal Form B (3.0 g) was dissolved in ethanol (140 ml). The
obtained solution was filtered and cyclohexane (2x140 ml) was added in two portions. The
mixture was stirred at room temperature for 26 h to obtain a massive precipitate. Then, the
product was filtered, washed with cyclohexane (2x25 ml) and dried at 50 °C in a vacuum
oven for 21.5 h to obtain 1.7 g (55%) of fluvastatin sodium Form XC.
69) Preparation of Fluvastatin Sodium Form XCI
Example 164
A suspension of fluvastatin sodium crystal Fonn XV (5.0 g) in ethyl acetate (75
ml) was stirred at reflux temperature for 16 h. Then, the suspension was cooled to room
temperature. The product was filtered under nitrogen flow, washed with ethyl acetate
(4x25 ml) and dried at 50°C in a vacuum oven for 21 h to obtain 3.9 g (78%) of fluvastatin
sodium Form XCI.

70) Preparation of Fluvastatin Sodium Form XCn
Example 165
Fluvastatin sodium crystal Form B (1.0 g) was dissolved in ethanol (10 ml) and
methanol (1 ml) at reflux temperature. Hexanes (10 ml) were added in one portion and the
turbid solution was stirred at reflux temperature for 4 h. A precipitation was obtained
during this time. Then, the suspension was cooled to room temperature and stirred at this
temperature for 16 h. The product was filtered under nitrogen flow, washed with hexanes
(3x7 ml) and dried at 50° (S, in a vacuum oven for 19 h to obtain 0.67 g (67%) of fluvastatin
sodium Form XCII.
71) Preparation of Fluvastatin Sodium Form XCHI
Example 166
A suspension of fluvastatin sodium crystal Form XV (5.0 g) in propan-1-ol (50 ml)
was stirred at room temperature for 25 h. The product was then filtered under nitrogen
flow, washed with propan-1-ol (3x40 ml) and dried at 50°C in a vacuum oven for 24 h to
obtain 3.8 g (76%) of fluvastatin sodium Form XCHI.
72") Preparation of Fluvastatin Sodium Form XCIV
Example 167
A suspension of fluvastatin sodium crystal Form XV (5.0 g) in butan-1-ol (50 ml)
was stirred at room temperature for 24 h. The product was then filtered under nitrogen
flow, washed with butan-1-ql (2x20 ml) and dried at 50°C in a vacuum oven for 24 h to
obtain 6.0 g (120%) of fluvastatin sodium Form XCIV.
73) Preparation of Fluvastatin Sodium Form XCV
Example 168
A suspension of fluvastatin sodium crystal Form XV (5.0 g) in ethyl acetate (90
ml) was stirred at room temperature for 19 h. The product was then filtered under nitrogen
flow, washed with ethyl acetate (2x20 ml) and dried at 50° C in a vacuum oven for 22 h to
obtain 5.2 g (104%) of fluvastatin sodium Form XCV.
Example 169
A suspension of fluvastatin sodium crystal Form XV (5.0 g) in acetone (70 ml) was
stirred at room temperature for 23 h. The product was then filtered under nitrogen flow,
washed with acetone (2x15 ml) and dried at 50°C in a vacuum oven for 20 h to obtain 4.6
g (92%) of fluvastatin sodium Form XCV.

Example 170
A suspension of fluvastatin sodium crystal Form XV (5.0 g) in 1,4-dioxane (50 ml)
was stirred at room temperature for 24 h. The product was then filtered under nitrogen
flow, washed with 1,4-dioxane (2x30 ml) and dried at 50°C in a vacuum oven for 23 h to
obtain 4.4 g (88%) of fluvastatin sodium Form XCV.
Example 171
A suspension of fluvastatin sodium crystal Form XV (5.0 g) in MEK (70 ml) was
stirred at room temperature for 30 h. The product was then filtered under nitrogen flow,
washed with MEK (2x20 ml) and dried at 50°C in a vacuum oven for 21 hxto obtain 4.7 g
(93%) of fluvastatin sodium Form XCV.
74) Preparation of Fluvastatin Sodium Form XCVI
Example 172
A suspension of fluvastatin sodium crystal Form XV (5.0 g) in THF (70 ml) was
stirred at room temperature for 29 h. Then, the product was filtered under nitrogen flow,
washed with THF (2x20 ml) and dried at 50°C in a vacuum oven for 20 h to obtain 4.1 g
(82%) of fluvastatin sodium Form XCVI.
75) Preparation of Fluvastatin Sodium Form XCVn
Example 173
In a 3 neck flask were placed fluvastatin methyl ester (3.0 g) and cyclohexane (60
ml) then the mixture was heated to reflux. A solution of NaOH (0.29 g) in MeOH (3 ml)
was added and the mixture was stirred at reflux for 1.6 h. The slurry was cooled to room
temperature, cyclohexane (40 ml) was added and the mixture was stirred over night The
product was isolated by filtration under nitrogen, washed with cyclohexane (90 ml) and
dried at 50°C in a vacuum oven for 24 h to obtain 2.81 g (93%) of fluvastatin sodium
FormXCVn.
76) Preparation of Fluvastatin Sodium Form XCVIU
Example 174
Fluvastatin methyl ester (3.0 g).was dissolved in a solution of NaOH (0.29 g) in
MeOH (7.5 ml) by heating to reflux. The clear solution was stirred at reflux for 85 min and
acetonitrile (50 ml) was added. The solution was cooled to room temperature and stirred
over night. The product was isolated by filtration under nitrogen, washed with acetonitrile
(50 ml) and dried at 50° C in a vacuum oven for 25.5 h to obtain 0.97 g of fluvastatin
sodium Form XCVffl.

77) Preparation of Fluvastatin Sodium Form —- XCIX
Example 175
In a 50 ml flask were placed fluvastatin sodium crystal Form VT (1.02 g) and ElOH
(10 ml). After 2.5 h EtOH (15 ml) was added and the mixture was stirred at room
temperature over night. The product was isolated by filtration under nitrogen, washed with
EtOH (20 ml) and dried at 50°C in a vacuum oven for 24 h to obtain 0.14 s (14%) of
fluvastatin sodium Form XCIX.
78) Preparation of Fluvastatin Sodium Form C
Example 176
Fluvastatia methyl ester (3.0 g) was dissolved in dichloromethane (35 ml). NaOH
(0.29 g) was added and the mixture was stirred at room over night. The product was
isolated by filtration under nitrogen, washed with dichloromethane (20 ml) and dried at
50°C in a vacuum oven for 24 h to obtain 1.89 g (62%) of fluvastatin sodium Foim C.
79) Preparation of Fluvastatin Sodium Form CI
Example 177
Fluvastatin methyl ester (3.0 g) was dissolved in acetone (45 ml), a solution of
NaOH (0.58 g) in MeOH (8 ml) was added and the mixture was stirred at room
temperature for another 3.5 h. The product was isolated by filtration under nitrogen,
washed with acetone (40 ml) and dried at 50°C in a vacuum oven for 22.5 h to obtain 2.37
g of fluvastatin sodium Form CI.
Example 178
Fluvastatin methyl ester (8.0 g) was dissolved in acetone (120 ml) and a solution of
NaOH (0.75 g) in MeOH (8 ml) was added. The mixture was heated to 50°C for 4.25 h,
•cooled to room temperature and stirred over night. NaOH (0.2 g) was added and the
mixture was heated again to 50°C. After 5.5 h a solution of NaOH (0.2 g) in MeOH (8 ml)
was added and stirred for 1.5 h, men the mixture was cooled to room temperature and.
stirred for 1 h. The product was isolated by filtration under nitrogen, washed with acetone
(100 ml) and dried at 50°C in a vacuum oven for 21.5 h to obtain 7,26 g of fluvastatin
sodium Form CI,
80). Preparation of Fluvastatin Sodium Form CH
Example 179
Fluvastatin methyl ester (8.0 g) was dissolved in acetone (120 ml), filtered and
cooled to 10°C. A solution of NaOH (0.75 g) in MeOH (8 ml) was added and the mixture

was stirred at 10°C for 10 h. A solution of NaOH (0.4 g) in MeOH (4 ml) was added to the
mixture in 3 portions during this time. The product was isolated by filtration under
nitrogen, washed with acetone (120 ml), and dried at 50°C in a vacuum oven for 22.5 h to
obtain 5.04 g of fluvastatin sodium Form CII.
81) Preparation of Fluvastatin Sodium Form CIII
Example 180
Fluvastatin methyl ester (3.0 g) was dissolved in acetone (30 ml) and filtered. A
solution of NaOH (0.29 g) in watch (1 ml) was added and the mixture was stirred at room
temperature over night. The product was isolated by filtration under nitrogen, washed with
acetone (40 ml) and dried at 50°C in a vacuum oven for 25.5 h to obtain 1.08 g of
fluvastatin sodium Form CIII.
82) Preparation of Fluvastatin Sodium Form CIV
Example 181
Fluvastatin methyl ester (3.0 g) was dissolved in THF (30 ml) and the NaOH (1
eq.) was added. After 2.5 h hexanes (60 ml) was added and the slurry stirred at room
temperature over night. The product was isolated by filtration under nitrogen, washed with
hexanes (30 ml) and dried at 50°C in a vacuum oven for 24 h to obtain 1.2 g (39%) of
fluvastatin sodium Form CIV.
83) Preparation of Fluvastatin Sodium Form CV
Example 182
Fluvastatin methyl ester (5,0 g) was dissolved in acetonitrile (100 ml) by heating.
At 50 °C a solution of NaOH (1 eq.) in water (1.25 ml) was added and the mixture was
stirred at this temperature for 2 h, then cooled to room temperature and stirred over night.
The product was isolated by filtration under nitrogen, washed with acetonitrile (30 ml) and
dried at 50 °C in a vacuum oven for 24 h to obtain 1.75 g (34.5%) of fluvastatin sodium
Form CV.
84) Preparation of Fluvastatin Sodium Crystal Form B
Example 183
Fluvastatin methyl ester (3.0 g) was added to a solution of NaOH (1 eq.) in water
(0.75 ml) and methanol (7.5 ml). The mixture was stirred at reflux temperature for 2 h.
After this time the raw material was not observed by HPLC. MTBE (58 ml) was dripped
into the solution over 2 h. The solution was cooled slowly to room temperature and was
stirred overnight. The product was isolated by filtration under nitrogen, washed with

MTBE (50 ml) and dried at 50°C in a vacuum oven for 24 h to obtain 2.78 g (91.3%) of
fluvastatin sodium Form B.
85) Preparation of Amorphous Fluvastatin Sodium
Example 184
Fluvastatin sodium (3.0 g) was dissolved in 1,4-dioxane (40 ml) at 85 °C. Then,
the solution was cooled to room temperature and stirred at this temperature for 70 h. The
product was filtered under nitrogen flow and dried at 50° C in a vacuum oven for 25 h to
obtain 2.7 g (90%) of amoiphous^fiuvastatin sodium. s
Example 185
Fluvastatin methyl ester (3.0 g) was added to cyclohexane (60 nil) and the slurry
was heated to reflux. A solution of NaOH (1 eq.) inMeOH (3 ml) was added to the slurry
solution which became clear. After 15 min. a precipitate formed. After another hour, the
mixture was cooled to room temperature and cyclohexane (40 ml) was added. The
mixture was stirred over night. The product was isolated by filtration under nitrogen,
washed with cyclohexane (90 ml) and dried at 50°C in a vacuum oven for 24 h to yield
2.73 g (90%) of amorphous fluvastatin sodium.
Example 186
A suspension of amorphous fluvastatin (5.0 g) in propan-2-ol (104 ml) was stirred
at reflux temperature for 4.5 h. Then, the suspension was cooled to room temperature and
stirred at this "temperature for 16 h. The product was filtered under nitrogen flow, washed
with propan-2-ol (2x10 ml) and dried at 50°C in a vacuum oven for 24 h to obtain 3.8 g
(76 %) of amorphous fluvastatin sodium.

Example 187
A 100 ml round bottom flask was loaded with Fluvastatin -diol-t-butyl ester (20.0g,
43mmole), MeOH (120ml) and NaOH (1.82gr) in water (10ml). The mixture was heated
to 35°C. The solution became clear and water (50ml) was added. The mixture was stirred
for 3 hr then the MeOH was evaporated. The volume of the water was completed to 8 vol.
and the mixture was extracted with MTBE (120ml). The organic solvents residue was
evaporated and solution was divided to two portions of 68ml. NaCl (0.7gr) was added to
one of the solutions and it was cooled to 4oC during 1 hr. The product was isolated after 1
hr by filtration under nitrogen and dried at 40°C in a vacuum oven for 24 hours to obtain
6.04 gr (65%) of Fluvastatin sodium crystal form D.
Example 188
Fluvastatin -diol -methyl ester (FDME) (4.0g) was dissolved in acetone (40ml). A
solution of NaOH (0.38gr) in MeOH (4ml) was added and the mixture was stirred at room
temperature for 20 hr. The product was isolated by filtration under nitrogen, washed with
acetone (20ml) and dried at 50°C in a vacuum oven for 26 hours to obtain 3.35gr (82.2%)
of Fluvastatin sodium crystal form VI.
Example 189
Fluvastatin -diol -methyl ester (FDME) (3.5g) was dissolved in acetone (35ml). A
solution of NaOH (0.34gr) in MeOH (4ml) was added and the mixture was stirred at room
temperature for 22.5 hr. The product was isolated by filtration under nitrogen, washed with
acetone (20mIX2) and dried at 50°C in a vacuum oven for 26 hours to obtain 3.22gr
(90.3%) of Fluvastatin sodium crystal form VI.

What is claimed is:
1. A crystalline form of fiuvastatin sodium characterized by a PXRD pattern with peaks
at 3.7, 11.3,13.1,17.9, 18.4 and 21.8±0.2 degrees two-theta.
2. The crystalline form of claim 1 wherein the crystalline form is characterized by a
PXRD pattern substantially as depicted in Figure 1.
3. The crystalline form of claim 1 wherein the crystalline form is fiuvastatin sodium
Form I.
4. A process for preparing crystalline fluvastatin sodium Form I comprising:

a) contacting a lower alkyl ester of fiuvastatin and sodium in a solvent selected from
the group consisting of acetone and acetonitrile,
b) precipitating fiuvastatin sodium Form I from the solvent, and
c) separating the solvent from Form I.
5. A process for preparing crystalline fiuvastatin sodium Form I comprising:
a) dissolving fiuvastatin sodium in a solvent selected from acetone and mixtures of
butan-2-ol and water,
b) crystallizing Form I from the solvent, and
c) separating the solvent from. Form I.

6. A crystalline form of fiuvastatin sodium characterized by a PXRD pattern with peaks
at 3.6±0.2 degrees two-theta.
7. The crystalline form of claim 6 further characterized by peaks at 5.4, 5.7,10.7 and
20.3±0.2 degrees two-theta.
8. The crystalline form of claim 7 wherein the crystalline form is characterized by a
PXRD pattern substantially as depicted in Figure 2.
9. The crystalline form of claim 6 wherein the crystalline form is fiuvastatin sodium
FormII.
10. A process for preparing crystalline fluvastatin sodium Form II comprising:

a) dissolving solid fluvastatin sodium in a solvent selected from butan-1-ol and
propan-2-ol,
b) crystallizing Fom II from the solvent, and
c) separating the solvent from Form II,
11. A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks
at 3.5, 9.5, 10.1,10.9 and 20.1±0.2 degrees two-theta.
12. The crystalline form of claim 11 wherein the crystalline form is characterized by a
PXRD pattern substantially as depicted in Figure 3.
13. The crystalline form of claim 11 wherein the crystalline form is fluvastatin sodium
Form III.
14. A process for preparing crystalline fluvastatin sodium Form III comprising:

a) dissolving fluvastatin sodium in a solvent selected from the group consisting of
butan-1-ol, ethyl acetate and THF.
b) slowly adding an anti-solvent selected from the group consisting of MTBE,
hexanes and cyclohexane to the solvent to induce precipitation of Form HI, and
c) separating the solvent and anti-solvent from Form III.
15. A process for preparing crystalline fluvastatin sodium Form III comprising:
a) dissolving amorphous fluvastatin sodium in refluxing ethanol.
b) precipitating Form III from the ethanol, and
c) separating the ethanol from the Form III..
16. A process for preparing crystalline fluvastatin sodium Form III comprising:
a) suspending fluvastatin sodium Form XIV in refluxing ethanol for a period of time
sufficient to effect the conversion to Form III,
b) cooling the ethanol to ambient temperature, and
c) separating the ethanol from the Form III.

17. A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks
at 3.6, 4.0, 9.8, 10.8 and 22.0±0.2 degrees two-theta.
18. The crystalline form of claim 17 wherein the crystalline form is characterized by a
PXRD pattern substantially as depicted in Figure 4.

19. The crystalline form of claim 17 wherein the crystalline form is fluvastatin sodium
Form IV.
20. The fluvastatin sodium of claim 17 having a water content of about 4 percent by
weight.
21. A process for preparing crystalline fluvastatin sodium Form IV comprising the steps
of:
a) dissolving fluvastatin sodium in solvent selected from the group consisting of
THF, propan-2-ol, 1,4-dioxane and butan-1-ol to form a solution,
b) refluxing the solution by heating the solvent, the heating being commenced either
before or after dissolving the fluvastatin sodium,
c) adding an organic anti-solvent to the refluxing solution to induce precipitation of
fluvastatin sodium Form IV, and
d) and separating the fluvastatin sodium Form IV from the solvent and anti-solvent.

22. The process of claim 20 where the anti-solvent is selected from the group consisting
of chlorofonn, dichloromethane, 1,2- dichloroethane, diethyl ether, n-pentane,
cyclohexane and methyl t-butyl ether.
23. A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks
at 3.6,4.0, 9.6, 18.5 and 22.2±0.2 degrees two-theta.
24. The crystalline form of claim 23 further characterized by peaks at 6.6,10.4, 11.0,
17.3,19.5,20.1,20.7 and 21.3±0.2 degrees two-theta.
25. The crystalline form of claim 24 further characterized by a PXRD pattern
substantially as depicted in Figure 7.
26. The crystalline form of claim 23 wherein the crystalline form is fluvastatin sodium
FormIV-1.
27. A process for preparing fluvastatin sodium Form IV-1 comprising the steps of:
a) dissolving fluvastatin sodium in a solvent selected from the group consisting of THF, butan-2-ol and 1,4-dioxane to form a solution,

b) refluxing the solution by heating the solvent the heating being commenced either
before or after dissolving the fluvastatin sodium,
c) adding an organic anti-solvent to the refluxing solution to induce precipitation of
fluvastatin sodium Form IV-1, and
d) separating the fluvastatin sodium Form IV-1 from the solvent and anti-solvent.

28. The process of claim 27 wherein the anti-solvent is selected from the group consisting
of n-heptane, cyclohexane and MTBE.
29. Fluvastatin-sodium Form IV-1 having a water content of from about 2 to about 3
weight percent.
30. A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks
at 3.8, 6.3, 9.5 and 21.2±0.2 degrees two-theta.
31. The crystalline form of claim 30 wherein the crystalline form is characterized by a
PXRD pattern substantially as depicted in Figure 10.
32. The crystalline form of claim 29) wherein the crystalline form is fluvastatin sodium
Form V.
33. A process for preparing crystalline fluvastatin sodium Form V comprising:

a) dissolving fluvastatin sodium in refluxing butan-1-ol,
b) slowly adding heptane to the refluxing solution,
c) precipitating Form V from the solution, and
d) separating the butan-1-ol and heptane from the Form V.
34. A process for preparing crystalline fluvastatin sodium Form V comprising:
a) dissolving fluvastatin sodium in a ternary solvent system of ethanol:ethyl
acetate:propan-l-ol at reflux temperature,
b) adding n-hexane to the solution,
c) precipitating Form V from the solution,
d) separating the ethanol, ethyl acetate, propan-1-ol and n-hexane from the Form V.
35. A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks
at 3.7, 4.7, 5.7,10.9,12.2 and 19.9±0.2 degrees two-theta.

36. The crystalline form of claim 35 further characterized by peaks at 9.1, 9.6, 14.3 16.3,
16.9,20.4 and 21.3±0.2 degrees two-theta.
37. The crystalline form of claim 36 further characterized by a PXRD pattern
substantially as depicted in Figure 11.
38. The crystalline form of claim 35 wherein the crystalline form is fluvastatin sodium
Form VI.
39. A process for preparing fluvastatin sodium Form VI comprising the steps of:

a) dissolving fluvastatin sodium in DMF at room temperature to form a solution,
b) adding an organic anti-solvent to the solution to induce precipitation of fluvastatin
sodium Form VI, and
c) separating the fluvastatin sodium Form VI from the DMF and anti-solvent.
40. A process for preparing fluvastatin sodium Form VI comprising:
a) dissolving a lower alkyl ester of fluvastatin in a solution of about one molar
equivalent of sodium hydroxide in a solvent system selected from the group
consisting of methanol, ethanol and mixtures of methanol and water and butan-1-
ol and water,
b) adding an anti-solvent selected from the group consisting of acetonitrile and
acetone to the solution at elevated temperature, and
c) separating Form VI from the solvent system.

41. The process of claim 40 wherein the anti-solvent is selected from the group consisting
of diethyl ether and hexanes.
42. Fluvastatin sodium Form VI having a water content of from about 5 to about 6 weight
percent.
43. A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks
at 3.7,4.3, 5.8, 8.6 and 20.7±0.2 degrees two-theta.
44. The crystalline form of claim 43 further characterized by peaks at 10.8,12.3, 13.7,
15.8,17.3, 19.4, 22.0, 23.9,25.2,26.2 and 27.6±0.2 degrees two-theta.

45. The crystalline form of claim 44 further characterized by a PXRD pattern
substantially as depicted in Figure 14.
46. The crystalline form of claim 43 wherein the crystalline form is fluvastatin sodium
Form VII.
47. A process for preparing fluvastatin sodium Form VII comprising the steps of:
a) dissolving fluvastatin sodium in DMF at room temperature to form a solution,
b) adding an organic anti-solvent to induce precipitation of fluvastatin sodium Form
VII from the solution, and
c) separating the fluvastatin sodium Form VII from the DMF and anti-solvent.

48. The process of claim 47 wherein the anti-solvent is selected from the group consisting
of chloroform, MTBE, dichloromethane, cyclohexane and 1,2-dichloroethane.
49. A process for preparing fluvastatin sodium Form VII comprising the steps of:

a) dissolving a lower alkyl ester of fluvastatin in a solution of about one molar
equivalent of sodium hydroxide in a solvent system selected from the group
consisting of methanol, butan-1-ol and mixtures of butan-1-ol and propan-2-ol,
b) adding an anti-solvent selected from the group consisting of acetone, acetonitrile
and methyl tert-butyl ether to induce precipitation of Form VII, and
c) separating the solvent system arid anti-solvent from the Form VII.
50. A process for preparing fluvastatin sodium Form VII comprising the steps of:
a) dissolving a lower alkyl ester of fluvastatin in acetonitrile,
b) adding a solution of about one molar equivalent of sodium hydroxide in ethanol
to induce precipitation of Form VII, and
c) separating the acetonitrile and ethanol from the Form VII.

51. Fluvastatin sodium Form VII having a water content of from about 1 to about 9
weight percent.
52. A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks
at 3.4, 30.0 and 19.7 ±0.2 degrees two-theta.
53. The crystalline form of claim 52 wherein the crystalline form is characterized by a
PXRD pattern substantially as depicted in Figure 17.

54. The crystalline form of claim 52 wherein the crystalline form is fluvastatiii sodium
Form IX.
55. A process for preparing crystalline fluvastatin sodium Form IX comprising:
a) dissolving fluvastatin sodium in 1,4-dioxane
b) adding dichloromethane to the solution to induce precipitation of Form IX, and
c) separating the 1,4-dioxane and dichloromethane from the Form IX.
56. A process for preparing crystalline fluvastatin sodium Form IX comprising:
a) dissolving fluvastatin sodium in ethanol,
b) adding ethyl acetate to the solution to induce precipitation of Form IX, and
c) separating the ethanol and ethyl acetate from Form IX.
57. A process for preparing crystalline fluvastatin sodium Form IX comprising:
a) dissolving fluvastatin sodium in a solvent system selected from the group
consisting of diethyl ether, n-pentane and mixtures of ethanol and methanol,
b) adding hexanes to induce precipitation of Form DC, and
c) separating the solvent system from the Form JX.
58. A process for preparing crystalline fluvastatin sodium Form IX comprising:
a) suspending fluvastatin sodium Form B in refluxing ethyl acetate for a period of
time sufficient to effect its conversion to Form IX, and
b) separating the ethyl acetate from the Form DC.
59. A process for preparing crystalline fluvastatin sodium Form IX comprising:
a) hydrolyzing a lower alkyl ester of fluvastatin with about one molar equivalent of
sodium hi ethanol at elevated temperature.
b) adding-an excess of propan-2-ol with respect to the ethanol to the ethanol,
c) precipitating Form IX, and
d) separating the ethanol and propan-2-ol from the Form IX.

60. A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks
at 3.4, 6.6,10.0, 13.2,19.8 ±0.2 degrees two-theta.
61. The crystalline form of claim 60 wherein the crystalline form is characterized by a
PXRD pattern substantially as depicted in Figure 18.

62. The crystalline form of claim 60 wherein the crystalline form is fluvastatin sodium
Form DC-1.
63. A process for preparing crystalline fluvastatin sodium Form IX-1 comprising:
a) dissolving fluvastatin sodium in a solvent selected from the group consisting of
butan-1-ol, ethyl acetate, isobutyl acetate, ethanol, toluene, tetrahydrofuran and
methyl ethyl ketone,
b) inducing precipitation of Form IX-1 by adding of an anti-solvent selected from
the group consisting of n-pentane, diethyl ether, methyl tert-butyl ether,
dichloromethane, hexanes and cyclohexane to the solvent, and
c) separating the solvent and anti-solvent from the FormIX-1.

64. A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks
at 3.3, 3.8,4.6, 8.3,10.2 and 25.1±0.2 degrees two-theta.
65. The crystalline form of claim 64 further characterized by peaks at 7.2, 11.4,12.4,
13.6,16.0,16.9,17.4,20.4,21.3, 21.9 and 23.1±0.2 degrees two-theta.
66. The crystalline form of claim 65 further characterized by a PXRD pattern
substantially as depicted in Figure 19.
67. The crystalline form of claim 64 wherein the crystalline form is fluvastatin sodium
Form XI.
68. A process for preparing fluvastatin sodium Form XI comprising the steps of:

a) dissolving fluvastatin sodium in butan-2-ol to form a solution,
b) refluxing the solution by heating the butan-2-ol, the heating being commenced
either before or after dissolving the fluvastatin sodium,
c) precipitating fluvastatin sodium Form XI from the solution, and
d) separating the fluvastatin sodium Form XI from the butan-2-ol.

69. The process of claim 68 wherein precipitating is induced by adding an organic anti-
solvent to the solution.
70. The process of claim 68 wherein the organic anti-solvent is selected from the group
consisting of hexanes, n-pentane, methyl ^-butyl ether, diethyl ether and chloroform.

71. Fluvastatin sodium Form XI having a water content of from about 1 to about 6 weight
percent.
72. A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks
at 3.5, 3.8, 4.6, 10.4 and 18.5±0.2 degrees two-theta.
73. The crystalline form of claim 72 further characterized by peaks at 8.5,11.2,12.1,
16.4,17.6,17.7,20.9,21.2, 21.7, 22.2 and 23.6^0.2 degrees two-theta.
74. The crystalline form of claim 73 further characterized.by a PXRD pattern
substantially as depicted in Figure 22. ;
75. The crystalline form of claim 72 wherein the crystalline form is fluvastatin sodium
FormXI-2.
76. A process for preparing fluvastatin sodium Form XI-2 comprising the steps of:

a) dissolving fluvastatin sodium in propan-l-ol to form a solution,
b) refluxing the solution by heating the propan-l-ol, the heating being commenced
either before or after dissolving the fluvastatin,
c) adding an organic anti-solvent to the refluxing solution to induce precipitation of
fluvastatin sodium Form XI-2, and
d) and separating the fluvastatin sodium Form XI-2 from the propan-l-ol and anti-
solvent.

77. The process of claim 76 wherein the anti-solvent is selected from the group consisting
of hexanes, MTBE, and dichloromethane.
78. Fluvastatin sodium Form XI-2 having a water content of from about 2 to about 3%.
79. A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks
at 3.1,6.5, 9.8, 17.6, 25.9 and 30.9±0.2 degrees two-theta.
80. The crystalline form of claim 79 wherein the crystalline form is characterized by a
PXRD pattern substantially as depicted in Figure 25.
81. The crystalline form of claim 79 wherein the crystalline form is fluvastatin sodium
Form XII.
82. A process for preparing crystalline fluvastatin sodium Form XII comprising:
a) dissolving fluvastatin sodium in butan-1-ol,
b) inducing precipitation of Form XII by adding 1,4-dioxane to the butan-1-ol, and
c) separating the 1,4-dioxane and butan-1-ol from the Form XII.

83. A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks
at 3.8, 5.6, 12.3 and 20.6±0.2 degrees two-theta.
84. The crystalline form of claim 83 wherein the crystalline form is characterized by a
PXRD pattern substantially as depicted in Figure 26.
85. The crystalline form of claim 83 wherein the crystalline form is fluvastatin sodium
Form XIII.
86. A process for preparing crystalline fluvastatin sodium Form XIII comprising:

a) suspending fluvastatin sodium Form B in acetonitrile at elevated temperature,
b) cooling the suspension to induce precipitation of Form XIII, and
c) separating the acetonitrile from the Form XIII.

87. A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks
at 3.8 and 7.0±0.2 degrees two-theta.
88. The crystalline form of claim 87 further characterized by peaks at 4.3,10.2, 10.7,
11.2,15.6,17.8, 18.4 and 19.5±0.2 degrees two-theta.
89. The crystalline form of claim 88 further characterized by a PXRD pattern
substantially as depicted in Figure 31.
90. The crystalline form of claim 87 wherein the crystalline form is fluvastatin sodium
Form XVI.
91. A process for preparing fluvastatin sodium Form XVI of any of claims - comprising
the steps of:
a) dissolving fluvastatin sodium in propan-2-ol to form a solution

b) refluxing the solution by heating the propan-2-ol, the heating being commenced
either before or after dissolving the fluvastatin sodium,
c) adding dichloromethane to the refluxing solution to precipitate fluvastatin Form
XVI, and
d) separating the fluvastatin sodium Form XVI from the propan-2-ol.

92. Fluvastatin sodium Form XVI having a water content of from about 3 to about 4
weight percent.
93. A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks
at 3.5 (broad), 5.4, 5.8 and 13.8±0.2 degrees two-theta.
94. The crystalline form of claim 93 further characterized by peaks at 10.8, 14.8,16.4,
19.4, 21.5 and 22.7±0.2 degrees two-theta.
95. The crystalline form of claim 94 further characterized by a PXRD pattern
substantially as depicted in Figure 34.
96. The crystalline form of claim 93 wherein the crystalline form is fluvastatin sodium
FormXVII
97. A process for preparing the fluvastatin sodium Form XVII of any of claims - '
comprising the steps of:

a) dissolving fluvastatin sodium in propan-1-ol at elevated temperature,
b) crystallizing fluvastatin sodium from the propan-1-ol at elevated temperature, and
c) separating the fluvastatin sodium Form XVII from the propan-1-ol.

98. A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks
at 3.4, 8.4,10.0 and 10.9±0.2 degrees two-theta.
99. The crystalline form of claim 98 further characterized by peaks at 11.7, 12.6,15.8,
17.4,18.0,18.8, 20.0,20.7 and 2I.3±0.2 degrees two-theta.
lOO.The crystalline form of claim 99 further characterized by a PXRD pattern substantially as depicted in Figure 36.

101. The crystalline fonn of claim 98 wherein the crystalline form is fluvastatin sodium
Fonn XVIII
102. A process for preparing fluvastatin sodium Form XVIII comprising the steps of:
a) forming a slurry of fluvastatin sodium in methylethylketone,
b) refluxing the slurry for a period of time sufficient to substantially convert
fluvastatin sodium to fluvastatin sodium Form XVIII, and
c) separating the fluvastatin sodium Form XVIII from the slurry.

103. Fluvastatin sodium Form XVIII having a water content of about 4 weight p ercent.
104. A .crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks
at 3.4,10.1,13.5 and 18.0±0.2 degrees two-theta.
105. The crystalline form of claim 104 further characterized by peaks at 6.8,20.1, 21.8
and 25.6±0.2 degrees two-theta.
106. The crystalline form of claim 105 further characterized by a PXRD pattern
substantially as depicted in Figure 39.
107. The crystalline form of claim 104 wherein the crystalline form is fluvastatin sodium
Form XIX.
108. A process for preparing fluvastatin sodium Form XIX comprising the steps of:

a) maintaining a crystalline form of fluvastatin sodium selected from the group
consisting of Form XI, Form IV-1 and Form XVI under conditions of 60%
relative humidity or higher for a period of time sufficient to effect conversion to
fluvastatin sodium Form XIX, and
b) removing the fluvastatin sodium Form XIX from the conditions of 60% relative
humidity or higher.

109. Fluvastatin sodium Form XIX having a water content of from about 19 to about 28
weight percent.
110. A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks
at 3.5, 10.4, 11.9,14.0, 22.5±0.2 degrees two-theta.

111. The crystalline form of claim 110 further characterized by peaks at 17.5, 17.8,18.0,
18.3, 25.4±0.2 degrees two-theta.
112. The crystalline form of claim 111 further characterized by a PXRD pattern
substantially depicted in Figure 42.
113. The crystalline form of claim 110 wherein the crystalline form is fluvastatin sodium
FormXIX-1.
114. A process for preparing crystalline fluvastatin sodium Form XIX-1 comprising:

a) forming a heterogeneous mixture of fluvastatin sodium Form XI and water
b) maintaining the heterogeneous mixture to obtain Form XIX-1, and
c) recovering fluvastatin sodium Form XTX-1 from the mixture.

115. A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks
at 3.5,10.1, 13.5,18.0 and 20.8±0.2 degrees two-theta
116. The crystalline form of claim 115 further characterized by peaks at 5.9 and 12.4±0.2
degrees two-theta.
117. The crystalline form of claim 116 further characterized by a PXRD pattern
substantially as depicted in Figure 43.
118. The crystalline form of claim 115 wherein the crystalline form is fluvastatin sodium
Form XX.
119. A process for preparing fluvastatin sodium Form XX comprising the steps of:

a) maintaining fluvastatin sodium Form VII under conditions of 80% relative
humidity for a period of time sufficient to effect conversion to fluvastatin
sodium Form XX and
b) removing the fluvastatin sodium Form XX from the conditions of 80% relative
humidity.

120. Fluvastatin sodium Form XX having a water content of about 19 percent by weight.
121. A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks
at 3.2, 12.4, and 18.3±0.2 degrees two-theta.

122. The crystalline form of claim 121 further characterized by peaks at 6.4, 9.5,15.6 and
21.4±0.2 degrees two-theta.
123. The crystalline form of claim 122 wherein the crystalline form is characterized by a
PXRD pattern substantially as depicted in Figure 46.
124. The crystalline form of claim 121 wherein the crystalline form is fluvastatm sodium
FormXXII.
125. A process for preparing crystalline fluvastatin sodium Form XXII comprising:

a) contacting fluvastatin sodium Form XV with water vapor in a vessel containing
an atmosphere of controlled elevated humidity relative to the atmosphere
outside of the vessel for a period of time effective to convert the Form XV into
Form XXII, and
b) ceasing control of the humidity within the vessel or removing the Form XV
from the vessel.

126. A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks
at 3.6, 4.0, 4.4,17.1 and 19.3±0.2 degrees two-theta.
127. The crystalline form of claim 126 further characterized by peaks at 6.2, 7.2, 9.3, 10.2
and 18.6±0.2 degrees two-theta.
128. The crystalline form of claim 127 wherein the crystalline form is characterized by a
PXRD pattern substantially as depicted in Figure 47.
129. The crystalline form of claim 126 wherein the crystalline form is fluvastatin sodium
FormXXIII.
130. A process for preparing crystalline fluvastatin sodium Form XXIII comprising:

a) dissolving fluvastatin sodium in propan-1-ol at elevated temperature,
b) precipitating Form XXIII from the propan-1-ol,
c) separating the propan-1-pl from the Form XXIII
131. A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks
at 3.4,10.2, 13.6, 17.9 and 18.7 ±0.2 degrees two-theta.

132. The crystalline form of claim 131 further characterized by peaks at 6.9, 10.7,12.0,
22.5 and 25.4±0.2 degrees two-theta.
133. The crystalline form of claim 132 wherein the crystalline form is characterized by a
PXRD pattern substantially as depicted in Figure 48.
134. The crystalline form of claim 131 wherein the crystalline form is fluvastatin sodium
FormXXIV.
135. A process for preparing crystalline fluvastatin sodium Form XXIV comprising:

a) dissolving a fluvastatin sodium in water,
b) precipitating Form XXIV from the water, and
c) separating the water from the Form XXIV.

136. A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks
at 3.8,15.0, 18.5, 21.6 and 25.8±0.2 degrees two-theta.
137. The crystalline form of claim 136 further characterized by peaks at 11.7, 15.9,16.2,
24.3 and 35.2±0.2 degrees two-theta.
138. The crystalline form of claim 137 wherein the crystalline form is characterized by a
PXRD pattern substantially as depicted in Figure 49.
139. The crystalline form of claim 136 wherein the crystalline form is fluvastatin sodium
Form XXIV.
140. A process for preparing crystalline fluvastatin sodium Form XXVI comprising:

a) dissolving fluvastatin sodium in a mixture of l,4-dioxane:water at elevated
temperature,
b) cooling the mixture to indue precipitation of Form XXVI, and
c) separating the mixture from Form XXVI.
141. A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks
at 3.3,3.9,15.9,18.4 and 21.6 ±0.2 degrees two-theta.

142. The crystalline form of claim 141 further characterized by peaks at 8.4,15.0, 17.9,
24.3 and 25.7±0.2 degrees two-theta.
143. The crystalline form of claim 142 wherein the crystalline form is characterized by a
PXRD pattern substantially as depicted in Figure 50.
144. The crystalline form of claim 141 wherein the crystalline form is fluvastatin sodium
Form XXVII.
145. A process for preparing crystalline fluvastatin sodium Form XXVII comprising:

a) dissolving fluvastatin sodium in a mixture of l,4-dioxane:water at elevated
temperature,
b) adding hexanes to the mixture at elevated temperature,
c) cooling the mixture,
d) precipitating Form XXVII, and
e) separating the 1,4-dioxane, water and hexanes from the Form XXVII.

146. A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks
at 4.4, 5.9, 6.8, 7.9, 10.8±0.2 degrees two-theta.
147. The crystalline form of claim 146 further characterized by peaks at 14.3, 15.6,17.5,
19.7, 21.3, 22.7±0.2 degrees two-theta.
148. The crystalline form of claim 147 further characterized by a PXRD pattern
substantially as depicted in Figure 51.
149. The crystalline form of claim 146 wherein the crystalline form is fluvastatin sodium
Form XXIX.
150. A process for preparing fluvastatin sodium Form XXIX comprising the steps of:

a) forming a heterogeneous mixture of fluvastatin sodium Form XV and 1,4-
dioxane,
b) maintaining the heterogeneous mixture for a period of time sufficient to
substantially convert Form XV to Form XXIX, and
c) separating the Form XXIX from the 1,4-dioxane.

151. A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks
at 5.4, 5.8,10.8,13.8 and 14.B±0.2 degrees two-theta.
152. The crystalline form of claim 151 further characterized by peaks at 16.4,19.0,19.5,
20.2, 20.8, 21.5, 22.7±0.2 degrees two-theta.
153. The crystalline form of claim 152 further characterized by a PXRD pattern
substantially as depicted in Figure 52.
154. The crystalline form of claim 151 wherein the crystalline form is fluvastatin sodium
Form XXX.
155. A process for preparing fluvastatin sodium Form XXX comprising:

a) forming a heterogeneous mixture of fluvastatin sodium Form XV and a diluent
selected from the group consisting of methyl ethyl ketone, tetrahydrofuran,
acetone, butan-2-ol and butan-1-ol,
b) maintaining the heterogeneous mixture to convert Form XV to Form XXX, and
c) separating the diluent from Form XXX.
156. A process for preparing fluvastatin sodium Form XXX comprising:
a) dissolving a lower alkyl ester of fluvastatin in a solution containing a molar
excess of sodium hydroxide relative to the fluvastatin in a mixture of methanol
and water,
b) adding acetone to the solution at elevated temperature to induce precipitation of
Form XXX, and
c) separating the methanol and water from the Form XXX.

157. A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks
at 5.3, 6.1, 6.5, 11.9,13.2±0.2 degrees two-theta.
158. The crystalline form of claim 157 further characterized by peaks at 8.0, 8.5, 9.3,
16.3,18.3,20.2, 20.6,21.1±0.2 degrees two-theta.
159. The crystalline form of claim 158 further characterized by a PXRD pattern
substantially as depicted in Figure 53.

160. The crystalline form of claim 157 wherein the crystalline form is fluvastatin sodium
Form XXXI.
161. A process for preparing fluvastatin sodium Form XXXI comprising:
a) forming a heterogeneous mixture of fluvastatin sodium Form XV and ethanol,
b) maintaining the mixture for a period of time sufficient to effect conversion of
Form XV to Form XXXI, and
c) separating the ethanol from Form XXXI.

162. A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks
at 4.0, 5.5, 8.0,9.1, 13.4,. 16.6,21.2±0.2 degrees two-theta.
163. The crystalline form of claim 162 further characterized by peaks at 6.6, 8.8,10.4,
11.6, 12.0,14.1,14.8,16.1, 17.9,18.5,19.7,20.3,24.3,24.9,26.7±0.2 degrees two-
theta.
164. The crystalline form of claim 163 further characterized by a PXRD pattern as
substantially depicted in Figure 54.
165. The crystalline form of claim 162 wherein the crystalline form is fluvastatin sodium
Form XXXIII.
166. The crystalline form of claim 162 having a water content of about 7 weight percent.
167. A process for preparing crystalline fluvastatin sodium Form XXXIII comprising:

a) forming a heterogeneous mixture of fluvastatin sodium Form XV or Form B and
ethanol,
b) maintaining the mixture for a period of time sufficient to substantially convert
the Form XV or Form B to Form XXXIII, and
c) recovering the fluvastatin sodium Form XXXIII from the mixture.

168. The process of claim 167 wherein the heterogeneous mixture is maintained at
elevated temperature and then cooled or allowed to cool before recovering Form
XXXIH.
169. A crystalline form of fluvastatin sodium characterized by a PXRD pattern having
peaks at 5.4, 6.1, 7.6, 18.5, 21.1±0.2 degrees two-theta.

170. The crystalline form of claim 169 further characterized by peaks at 8.8, 9.3, 12.4,
13.1, 14.3, 15.2, 15.9, 17.2,17.6, 20.5, 22.2, 24.1,25.4,26.2±0.2 degrees two-theta.
171. The crystalline form of claim 170 further characterized by a PXRD pattern
substantially as depicted in Figure 55.
172. The crystalline form of claim 169 wherein the crystalline form is fluvastatin sodium
FormXXXIV.
173. A process for preparing crystalline fluvastatin sodium. Form XXXIV comprising:

a) forming a heterogeneous mixture of fluvastatin sodium Form XV for a sufficient
time and DMSO,
b) maintaining the mixture for a period of time sufficient to substantially convert
Form XV to Form XXXIV, and
c) recovering fluvastatin sodium Form XXXIV from the mixture.

174. A crystalline form of fluvastatin sodium characterized by a PXRD pattern having
peaks at 5.4, 6.0, 9.9, 14.8, 21.0±0.2 degrees two-theta.
175. The crystalline form of claim 174 further characterized by peaks at 16.7, 18.6, 19.8,
22.6±0.2 degrees two-theta.
176. The crystalline form of claim 175 further characterized by a PXRD pattern
substantially as depicted in Figure 56.
177. The crystalline form of claim 174 wherein the crystalline form is fluvastatin sodium
Form XXXV
178. A process for preparing the crystalline fluvastatin sodium Form XXXV comprising:

a) forming a heterogeneous mixture of fluvastatin sodium Form XV and DMF,
b) maintaining the heterogeneous mixture for a period of time sufficient to
substantially convert Form XV to Form XXXV, and
c) recovering Form XXXV from the heterogeneous mixture.
179. A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks
at 3.0,9.2,11.5, 14.4 and 20.2±0.2 degrees two-theta.

180. The crystalline form of claim 179 further characterized by peaks at 9.6, 12.3 and
12.8±0.2 degrees two-theta.
181. The crystalline form of claim 180 wherein the crystalline form is characterized by a
PXRD pattern substantially as depicted in Figure 57.
182. The crystalline form of claim 179 wherein the crystalline form is fluvastatin sodium
Form XXXVI.
183. A process for preparing crystalline fluvastatin sodium Form XXXVI comprising:

a) suspending fluvastatin sodium Form Xl-wet in water for a period time sufficient
to effect the conversion of Form XI-wet to Form XXXVI, and
b) separating the water from Form XXXVI.

184. A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks
at 3.63,10.36, 13.74,17.93,18.34±0.2 degrees two-theta.
185. The crystalline form of claim 184 further characterized by peaks at 11.26, 12.16,
12.91, 19.44, 20.57±0.2 degrees two-theta.
186. The crystalline form of claim 185 further characterized by a PXRD pattern
substantially as depicted in Figure 58.
187. The crystalline form of claim 184 wherein the crystalline form is Fluvastatin sodium
FonnXXXVII.
188. A process for preparing crystalline fluvastatin sodium Form XXXVII comprising:

a) forming a heterogeneous mixture of fluvastatin sodium Form XI and water at
ambient temperature,
b) maintaining the heterogeneous mixture at ambient temperature to convert Form
XI to Form XXXVII, and
c) recovering fluvastatin sodium Form XXXVII from the mixture.
189. A crystalline form of fluvastatin sodium characterized by aPXRD pattern having
peaks at 3.64, 4.66,7.30, 8.84,11.61+0.2 degrees two-theta.

190. The crystalline form of claim 189 further characterized by peaks at 19.08,19.65,
21.15,22.59,24.20±0.2 degrees two-theta.
191. The crystalline form of claim 190 further characterized by a PXRD pattern
substantially as depicted in Figure 59.
192. The crystalline form of claim 189 wherein the crystalline form is fluvastatin sodium
FormXXXVIII
193. A process for preparing crystalline fluvastatin sodium Form XXXVIII comprising:

a) forming a heterogeneous mixture of fluvastatin sodium Form XI and absolute
ethanol,
b) maintaining the mixture to convert Form XI to Form XXXVIII, and
c) recovering Form XXXVIII from the mixture.
194. A process for preparing crystalline fluvastatin sodium Form XXXVIII comprising;
a) dissolving a lower alkyl ester of fluvastatin in a solution of about one molar
equivalent of sodium hydroxide in ethanol,
b) inducing precipitation of Form XXXVIII by addition of ethyl acetate, and
c) separating Form XXXVIII from the ethanol and ethyl acetate.

195. A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks
at 3.7, 4.5, 8.5,17.8,20.1±0.2 degrees two-theta.
196. The crystalline form of claim 195 further characterized by peaks at 6.9,11.2,16.8,
19.6 and 21.6±0.2 degrees two-theta.

197. The crystalline form of claim 196 wherein the crystalline form is characterized by a
PXRD pattern substantially as depicted in Figure 60.
198. The crystalline form of claim 195 wherein the crystalline form is fluvastatin sodium
Form XXXIX.
199. A process for preparing crystalline fluvastatin sodium Form XXXIX comprising:

a) hydrolyzing a lower alkyl ester of fluvastatin with about one molar equivalent of
sodium hydroxide in ethanol,
b) adding an excess of propan-2-ol with respect to the ethanol to the ethanol,

c) precipitating Form XXXIX, and
d) separating the ethanol and propan-2-ol from the Form XXXIX.
200. A crystalline form of fluvastatin sodium characterized by a PXRD pattern having
peaks at 3.75,4.31, 9.10, 11.00±0.2 degrees two-theta.
201. The crystalline form of claim 200 farther characterized by peaks at 5.60, 7.30, 7.55,
14.50,18.04±0.2 degrees two-theta.
202. The crystalline form of claim 201 further characterized by a PXRD pattern
substantially as depicted in Figure 61.
203. The crystalline form of claim 200 wherein the crystalline form is fluvastatin sodium
form XLI. .
204. A process for preparing crystalline fluvastatin sodium Form XLI comprising:

a) dissolving fluvastatin sodium in water,
b) adding acetonitrile to the water to induce precipitation of Form XLI, and
c) separating the acetonitrile and water from Form XLI.

205. A crystalline form of fluvastatin sodium characterized by a PXRD pattern having
peaks at 3.4, 9.7,11.0, 18.9±0.2 degrees two-theta.
206. The crystalline form of claim 205 further characterized by peaks at 5.7,14.8,16.1,
17.0, 22.6±0.2 degrees two-theta.
207. The crystalline form of claim 206 wherein the crystalline form is characterized by a
PXRD pattern substantially as depicted in Figure 62.
208. The crystalline form of claim 205 wherein the crystalline form is fluvastatin sodium
Form XLII
209. A process for preparing fluvastatin sodium Form XLII comprising:

a) dissolving fluvastatin in methyl ethyl ketone,
b) adding a solution of sodium hydroxide in methanol to the solution to induce
precipitation of Form XLII; and
c) separating the solution from Form XLII.
210. A process fdr preparing fluvastatin sodium Form XLII, comprising:
a) dissolving fluvastatin in methanol,
b) adding solid sodium hydroxide to the solution at elevated temperature,
c) cooling the solution,
d) adding ethyl acetate to' form a slurry of Form XLII in the methanol, and
e) separating Form XLII from the methanol.
211. A process for preparing fluvastatin stidium Form XLII comprising:
a) dissolving fluvastatin diol in a solution of dichloromethane,
b) adding NaOH (s) dissolved in methanol to the solution to induce precipitation of
Form XLII; and
c) separating the solution from Form XLII.
212. A process for preparing fluvastatin sodium Form XLII comprising:
a) dissolving fluvastatin in dichloromethane,
b) adding ethanolic or methanolic sodium hydroxide to the solution,
c) precipitating Form XLII from the solution, and
d) separating Form XLII from the solution.

213. A crystalline form of fluvastatin sodium characterized by a PXRD pattern having
peaks at 4.25,-5.29, 6.59, 8.60±0.2 degrees two-theta.
214. The crystalline form of claim 213 further characterized by peaks at 12.75, 14.26±0.2
degrees two-theta.
215. The crystalline form of claim 214 further characterized by a PXRD pattern
substantially as depicted in Figure 63.
216. The crystalline form of claim 213 wherein the crystalline form is fluvastatin sodium
Form XLIII.
217. A process for preparing crystalline fluvastatin sodium Form XLIII comprising:

a) dissolving fluvastatin sodium in water,
b) adding propan-2-ol to induce precipitation of Form XLIII, and
c) separating the water and propan-2-ol from the Form XLIII.
218. A process for preparing crystalline fluvastatin sodium Form XLIII comprising:
a) dissolving a lower alkyl ester of fluvastatin in a solution of NaOH in water,
b) adding propan-2-ol to the solution to induce precipitation of Form XLIII, and
c) separating the solution from Form XLIII.

219. A crystalline form of fluvastatin sodium characterized by a PXRD pattern having
peaks at 3.46,4.05, 9.19, 10.14, 20.56±0.2 degrees two-theta.
220. The crystalline form of claim 219 further characterized by peaks at 6.26, 10.91,
11.12, 11.38, 15.98, 20.02, 22.21, 23.52, 25.45±0.2 degrees two-theta.
221. The crystalline form of claim 220 further characterized by a PXRD pattern
substantially as depicted in Figure 64.
222. The crystalline form of claim 219 wherein the crystalline form is Fluvastatin sodium
formXLIV.
223. A process for preparing crystalline fluvastatin sodium Form XLIV comprising:

a) forming a heterogeneous mixture of amorphous fluvastatin sodium and propan-
2-ol,
b) maintaining the heterogeneous mixture at reflux temperature for a period of time
to substantially convert amorphous fluvastatin sodium to Form XLIV, and
c) recovering Form XLIV from the mixture.
224. A process for preparing crystalline fluvastatin sodium Form XLIV comprising:
a) dissolving fluvastatin free acid, lactone or mixture thereof in acetone to form a
solution,
b) mixing an ethanolic solution of sodium with the solution,
c) maintaining the mixture for a period of time sufficient to precipitate fluvastatin
sodium Form XLIV, and
d) separating Form XLIV from the acetone and ethanol.
225. A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks
at 3.7, 5.1, 10.7, 17.8 and 20.3±0.2 degrees two-theta.
226. • The crystalline form of claim 225 further characterized by peaks at 6.2,14.5, 21.6, /
22.6 and 25.2±0.2 degrees two-theta.
227. The crystalline form of claim 226 wherein the crystalline form is characterized by a
PXRD pattern substantially as depicted in Figure 65.
228. The crystalline form of claim 225 wherein the crystalline form is fluvastatin sodium
FormXLV.
229. A process for preparing crystalline fluvastatin sodium Form XLV comprising:

a) suspending amorphous fluvastatin sodium in propan-2-oI at room temperature to
obtain Form XLV, and
b) separating the propan-2-ol from the Form XLV.

230. A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks
at 3.3, 3.5,10.2,11.2 and 21.1 ±0.2 degrees two-theta.
231. The crystalline form of claim 230 further characterized by peaks at 9.7,12.1,17.2
and 19.0±0.2 degrees two-theta.
232. The crystalline form of claim 231 wherein the crystalline form is characterized by a
PXRD pattern substantially as depicted in Figure 66.
233. The crystalline form of claim 230 wherein the crystalline form is fluvastatin sodium
Form XLVI
234. A process for preparing crystalline fluvastatin sodium Form XLVI comprising:

a) contacting a lower alkyl ester of fluvastatin with about one molar equivalent of
sodium in ethanol,
b) adding an excess of acetonitrile relative to the ethanol,
c) precipitating Form XLVI from the mixture of ethanol and acetonitrile, and
d) separating the ethanol and acetonitrile from the Form XLVI.
235. A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks
at 3.3, 10.2 and 18.0 ±0.2 degrees two-theta.
236. The crystalline form of claim 235 further characterized by peaks at 8.3,10.8, 13.6,
. 20'. 7 and 21.3±0.2 degrees two-theta.
237. The crystalline form of claim 236 wherein the crystalline form is characterized by a
PXRD pattern substantially as depicted in Figure 67.
238. The crystalline form of claim 235 wherein the crystalline form is fluvastatin sodium
Form XLVII.
239. A process for preparing crystalline fluvastatin sodium Form XLVII comprising:
a) contacting fluvastatin sodium Form XVIII with water vapor in a vessel
containing"an atmosphere of controlled elevated humidity relative to the atmosphere outside of the vessel to convert the Form XV into Form XII, and
b) ceasing control of the humidity within the vessel or removing the Form XV
from the vessel.
240. A crystalline form of fluyastatin sodium characterized by a PXRD pattern having
peaks at 4.5, 6.7, 7.0,10.9, 19.1, 21.7±0.2 degrees two-theta.
241. The crystalline form of claim 240 further characterized by peaks at 8.9, 12.9, 13.1,
13.5, 15.2,16.8,17.6,18.3, 19.7, 20.6 ±0.2 degrees two-theta.
242. The crystalline form of claim 241 further characterized by a PXRD pattern
substantially as depicted in Figure 68.
243. The crystalline form of claim 240 wherein the crystalline form is fluvastatin sodium
FormXLVIII
244. A process for preparing crystalline fluvastatin sodium Form XLVIII comprising:

a) dissolving a lower alkyl ester of fluvastatin in a solution of NaOH in methanol
to hydrolyze the ester,
b) adding acetom'trile to the solution to induce precipitation of fluvastatin sodium,
and
c) separating fluvastatin sodium from the methanol and acetonitrile.
245. A process for preparing crystalline fluvastatin sodium Form XLVIII comprising:
a) slurrying fluvastatin sodium Form B in methanol at reflux temperature,
b) cooling the slurry,
c) stirring the slurry solution at room temperature,
d) separating fluvastatin sodium from the methanol as Form XL VIII
246. A process for preparing crystalline fluvastatin sodium Form XLVIII comprising:
a) dissolving fluvastatin sodium in methanol at ambient temperature,
b) heating the solution to reflux temperature to induce precipitation of Form
XLVIII,
c) cooling the resulting slurry to room temperature,
d) stirring the slurry solution at room temperature, and
e) separating Form XLVIII from the methanol.
247. A process for preparing crystalline fluvastatin sodium Form XLVIII comprising:
a) dissolving fluvastatin in refluxing methanol,
b) adding solid sodium hydroxide to the solution at reflux temperature to induce
precipitation of Form XLVIII,
c) cooling the resulting slurry to ambient temperature,
d) stirring the slurry at room temperature; and •
e) separating Form XLVIII from the methanol.
248. A process for preparing crystalline fluvastatin sodium Form XLVIII comprising:
a) dissolving fluvastatin in methanol at reflux temperature,
b) adding solid sodium hydroxide to the resulting solution at reflux temperature to
induce precipitation of Form XLVIII,
c) cooling the resulting slurry to ambient temperature,
d) adding acetone to the slurry, and
e) separating Form XLVIII from the methanol and acetone.

249. A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks
at 3.5, 5.0, 12.1,13.5 and 20.2±0.2 degrees two-theta.
250. The crystalline form of claim 249 further characterized by peaks at 6.3,10.1 and
17.1±0.2 degrees two-theta.
251. The crystalline form of claim 250 wherein the crystalline form is characterized by a
PXRD pattern substantially as depicted in Figure 69.
252. The crystalline form of claim 249 wherein the crystalline form is fluvastatin sodium
FormXLIX.
253. A process for preparing crystalline fluvastatin sodium Form XLIX comprising:
a) heating a solution of fluvastatin sodium in methanol to an elevated temperature,
b) adding methyl tert-'butyl ether to the methanol at elevated temperature to induce
precipitation of Form XLIX, and
c) separating the methanol and methyl tert-butyl ether from the Form XLIX.

254. A crystalline form of fluvastatin sodium characterized by a PXRD pattern having
peaks at 6.48,6.92, 9.72,12.64,21.49±0.2 degrees two-theta
255. The crystalline form of claim 254 further characterized by peaks at 4.53, 12.06,
13.50,14.79,15.79, 16.32,19.15,23.19±0.2 degrees two-theta.
256. The crystalline form of claim 255 further characterized by a PXRD pattern
substantially as depicted in Figure 70.
257. The crystalline form of claim 254 wherein the crystalline form is fluvastatin sodium
FormL.
258. A process for preparing crystalline fluvastatin sodium Form L comprising:

a) dissolving fluvastatin sodium in methanol,
b) adding ethyl acetate to the solution at ambient temperature to induce
precipitation of Form L, and
c) separating the methanol and.ethyl acetate from Form L.
259. A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks
at 6.2,10.8,14.5 and 20.7 ±0.2 degrees two-theta.
260. The crystalline form of claim 259 further characterized by peaks at 8.9,11.5 and
.23.1 ±0.2 degrees two-theta.
261. The crystalline form of claim 260 wherein the crystalline form is characterized by a
PXRD pattern substantially as depicted in Figure 71.
262. The crystalline form of claim 259 wherein the crystalline form is fluvastatin sodium
Form LI.
263. A process for preparing crystalline fluvastatin sodium Form LI comprising:
a) heating a solution of fluvastatin sodium in methanol to an elevated temperature,
b) adding acetonitrile to the methanol at elevated temperature to induce
precipitation of Form LI, and
c) separating the methanol and acetonitrile from the Form LI.

264. A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks
at 5.6, 6.3,10.5,20.9±0.2 degrees two-theta.
265. The crystalline form of claim 264 further characterized by peaks at 14.3,15.1,15.6
and 17.1±0.2 degrees two-theta.
266. The crystalline form of claim 265 wherein the crystalline form is characterized by a
PXRD pattern substantially as depicted in Figure 72.
267. The crystalline form of claim 264 wherein the crystalline form is fluvastatin sodium
Form LIII.
268. A process for preparing crystalline fluvastatin sodium Form Lin comprising:

a) heating a solution of fluvastatin sodium in methanol to an elevated temperature,
b) adding ethyl acetate to the methanol at elevated temperature to induce
precipitation of Form LIII., and
c) separating the methanol and ethyl acetate from, the Form Lin.

269. A crystalline form of fluvastatin sodium, wherein the crystalline form is
characterized by aPXRD pattern with peaks at 3.4, 10.4, 18,2, 19.6, 21.3.±0.2
degrees two-theta.
270. The crystalline form of claim 269 wherein the crystalline form is further
characterized by a PXRD pattern with peaks at 6.9, 12.1,13.8,17.7,19.0 ±0.2
degrees two-theta.
271. The crystalline form of claim 270 wherein the crystalline form is characterized by a
PXRD pattern substantially as depicted in FIG. 73.
272. The crystalline form of claim 269 wherein the crystalline form is fluvastatin form
LIV.

273. A process for preparing crystalline fluvastatin sodium Form LIV comprising:
a) contacting fluvastatin with an aqueous sodium hydroxide for a period of time
sufficient to form a suspension, and
b) separating Form LIV from the water.

274. A crystalline form of fluvastatin sodium characterized by a PXRD pattern having
peaks at 3.7, 5.0, 5.9, 12.2±0.2 degrees two-theta.
275. The crystalline form of 274 claim wherein the crystalline form is further
characterized by peaks at 5.6, 8.7,10.1, 11.2±0.2 degrees two-theta.
276. The crystalline form of claim 275 wherein the crystalline form is characterized by a
PXRD pattern substantially as depicted in Figure 74.
277. The crystalline form of claim 274 wherein the crystalline form is Fluvastatin sodium
formLV.
278. A process for preparing crystalline fluvastatin sodium Form LV comprising:

a) dissolving a lower alkyl ester of fluvastatin in acetonitrile,
b) adding a solution of about one equivalent of sodium hydroxide in methanol,
c) precipitating fluvastatin sodium Form LV from the solution, and
d) separating fluvastatin sodium Form LV from the solution.

279. A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks
at 3.4,22.1 and 27.4 ±0.2 degrees two-theta.
280. The crystalline form of claim 279 further characterized by peaks at 6.8,10.2,13.6,
18.5'and 20.0±0.2 degrees two-theta.
281. The crystalline form of claim 280 wherein the crystalline form is characterized by a
PXRD pattern substantially as depicted in Figure 75.
282. The crystalline form of claim 279 wherein the crystalline form is fluvastatin sodium
Form LVI.
283. A process for preparing crystalline fluvastatin sodium Form LVI comprising:

a) cleaving the ketal group a lower alkyl ester derivative of fluvastatin having a
ketal protecting group on the p and 6 hydroxyl groups in a tetrahydrofuran
solution under acidic conditions,
b) adding sodium hydroxide to neutralize the solution,
c) evaporating the tetrahydrofuran to leave a residue,
d) dissolving the residue in acetone,
e) adding about a molar equivalent of sodium hydroxide to the acetone,
f) precipitation Form LVI from the acetone, and
g) separating the acetone frorri the Form LVI.

284. A crystalline form of fluvastatin sodium characterized by a PXRD pattern having
peaks at 3.7, 5.0, 5.5,10.1,12.1 iO.2 degrees 2 theta.
285. The crystalline form of claim 284 wherein the crystalline form is further
characterized by peaks at 8.6,11.1,14.9,21.7, 22.8 ±0.2 degrees two-theta. .
286. The crystalline form of claim 285 wherein the crystalline form is characterized by a
PXRD pattern as substantially depicted in Figure 76.
287. The crystalline form of claim 284 wherein the crystalline form is fluvastatin sodium
Form LVII.
288. A process for preparing crystalline fluvastatin sodium Form LVn comprising;

a) forming a heterogeneous mixture of fluvastatin sodium Form VII in ethanol,
b) maintaining the heterogeneous mixture to convert Form VII into fluvastatin
sodium Form LVH, and
c) separating the Form LVII from the ethanol.

289. A crystalline form of Fluvastatin sodium characterized by a PXRD pattern having
peaks at 3.4, 3.8, 5.4, 5.7,10.3±0.2 degrees two-theta.
290. The crystalline form of claim 289 wherein the crystalline form is further
characterized by peaks at 4.7, 7.2, 8.4,11.5,17.5, 20.4,21.4,23.1±0.2 degrees
two-theta.
291. The crystalline form of claim 290 further characterized by a PXRD pattern
substantially as depicted in Figure 77.

292. The crystalline form of claim 289 wherein the crystalline form is fluvastatin sodium
form LVIII.
293. A process for preparing crystalline Fluvastatin Na Form LVIII comprising:
a) forming a heterogeneous mixture of fluvastatin sodium Form B in propan-2-ol,
b) maintaining the mixture to convert Form B into fluvastatin sodium Form LVIII,
and
6.) separating Form LVIII from the propan-2-ol.
294. A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks
at 3.5, 5.7, 10.8,18.2 and 21.6 ±0.2 degrees two-theta.
295. The crystalline form of claim 294 further characterized by peaks at 12.4,14.7, 20.4,
22.4 and 25.4±0.2 degrees two-theta. '
296. The crystalline form of claim 295 wherein the crystalline form is characterized by a
PXRD pattern substantially as depicted in Figure 84.
297. The crystalline form of claim 294 wherein the crystalline form is fluvastatin sodium
Form LXIX.
298. A process for preparing crystalline-fluvastatin sodium Form LXIX comprising:

a) forming a heterogeneous mixture of fluvastatin sodium Form VI and propan-2-
ol,
b) maintaining the heterogeneous mixture for a period of time sufficient to convert
Form VI to Form LXIX, and
c) separating the propan-2-ol from the Form LXLX.

299. A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks
at 3.0,3.4, 5.9, and 13,8 ±0.2 degrees twq-theta.
300. The crystalline form of claim 299 further characterized by peaks at 8.2, 8.9, 18.6,
21.1 and 22.4±0.2 degrees two.-theta.
301. The crystalline form of claim 300 wherein the crystalline form is characterized by a
PXRD pattern substantially as depicted in Figure 85.

302. The crystalline form of claim 299 wherein the crystalline form is fluvastatin sodium
Form LXX.
303. A process for preparing crystalline fluvastatin sodium Form LXX comprising:
a) dissolving in water at elevated temperature,
b) adding an excess of acetone to the water to induce precipitation of Form LXX,
and
c) separating the water and acetone from the Forrrr LXX.
304. A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks
at 3.9,7.8,11.6 and 15.5±0.2 degrees two-theta.
305. The crystalline form of claim 304 further characterized by peaks at 9.2,13.3, 19.0
and 23.2±0.2 degrees two-theta,
306. The crystalline form of claim 305 wherein the crystalline form is characterized by a
PXRD pattern substantially as depicted in Figure 86.
307. The crystalline form of claim 304 wherein the crystalline form is fluvastatin sodium
FormLXXI.
308. A process for preparing crystalline fluvastatin sodium Form LXXI comprising:

a) dissolving fluvastatin sodium in water at elevated temperature,
b) adding an excess of acetone to the water to induce precipitation of Form LXXI,
and
c) separating the water and acetone from the Form LXXI.

309. A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks
at 3.7,5.7 and 12.1 ±0.2 degrees two-theta.
310. The crystalline form of claim 309 further characterized by peaks at 5.0,10.8,16.8
and 20.1±0.2 degrees two-theta,
311. The crystalline form of claim 310 wherein the crystalline form is characterized by a
PXRD pattern substantially as depicted in Figure 87.

312. The crystalline form of claim 309 wherein the crystalline form is fluvastatin sodium
FormLXXII.
313. A process for preparing crystalline fluvastatin sodium Form LXXII comprising:
a) forming a heterogeneous mixture of fluvastatin sodium Form VI and a diluent
selected from the group consisting of acetonitrile and mixtures of acetone and
water,
b) maintaining the heterogeneous mixture at elevated temperature for a period of
time sufficient to convert Form VI to Form LXXII, and
c) separating the diluent from Form LXXII.

314. A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks
at 4.0,12.8, 19.0,19.9 and 25.8 ±0.2 degrees two-theta.
315. The crystalline form of claim 314 further characterized by peaks at 5.4, 11.8, 13.4,
18.0 and 24.6±0.2 degrees two-theta.
316. The crystalline form of claim 315 wherein the crystalline form is characterized by a.
PXRD pattern substantially as depicted in Figure 89.
317. The crystalline form of claim 314 wherein the crystalline form is fluvastatin sodium
Form LXXIV.
318. A process for preparing crystalline fluvastatin sodium Form LXXIV comprising:

a) forming a heterogeneous mixture of fluvastatin sodium Form B and a mixture of
propan-2-ol and water,
b) maintaining the mixture for a period of time sufficient to effect the conversion
to Form LXXIV, and
c) separating the propan-2-ol and water from the Form LXXIV. .

319. A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks
at 4.4, 6.6,10.8,14.3 and22.2±0.2 degrees two-theta.
320. The crystalline form of claim 319 further characterized by peaks at 7.8, 15.0, 19.8,
20.4 and 21.4±0.2 degrees two-theta.

321. The crystalline form of claim 320 wherein the crystalline form is characterized by a
PXRD pattern substantially as depicted in Figure 90.
322. The crystalline form of claim 320 wherein the crystalline form is fluvastatin sodium
FormLXXV.
323. A process for preparing crystalline fluvastatin sodium Form LXXV comprising:
a) forming a heterogeneous mixture of fluvastatin sodium Form XXX and
methanol,
b) maintaining the mixture for a period of time sufficient to convert Form XXX to
Form LXV, and
c) separating the methanol from the Form LXV.

324. A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks
at 3.5, 7.0, 10.5 and 13.0±0.2 degrees two-theta.
325. The crystalline form of claim 324 wherein the crystalline form is characterized by a
PXRD pattern substantially as depicted in Figure 91.
326. The crystalline form of claim 324 wherein the crystalline form is fluvastatin sodium
FormLXXVI.
327. A process for preparing crystalline fluvastatin sodium Form LXXVI comprising:

a) hydrolyzing a lower alkyl ester of fluvastatin with about a molar equivalent of a
sodium base catalyst in a mixture of ethanol and water,
b) evaporating a portion of the ethanol and water mixture,
c) adding water to the remaining mixture,
d) extracting the mixture with a water immiscible extraction solvent,
e) evaporating the ethanol and water to leave a residue that is Form LXXVI.

328. A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks
at 3.6, 8.8,11.0,12.8 and 17.8±0.2 degrees two-theta.
329. The crystalline fonn of claim 328 further characterized by peaks at 7.3,20.2 and
31.0±0.2 degrees two-theta.

330. The crystalline form of claim 329 wherein the crystalline form is characterized by a
PXRD pattern substantially as depicted in Figure 92.
331. The crystalline form of claim 328 wherein the crystalline form is fluvastatin sodium
Form LXXVIII
332. A process for preparing crystalline fluvastatin sodium Form LXXVII comprising:
a) hydrolyzing a lower alkyLester of fluvastatin with a molar excess of sodiimbase catalyst in a mixture of water and ethyl acetate,
b) precipitating Form LXXVII from the mixture, and
c) separating Form LXXVII from the water, ethyl acetate and residual sodium base
catalyst.

333. A crystalline form of fluvastatin sodium characterized by a PXRD pattern with peaks
at 8.8,19.1, 27.2, 29.6 and 30.9±0.2 degrees two-theta.
334. The crystalline form of claim 333 further characterized by peaks at 3.4,11.3, 17.7,
22.5 and 32.2±0.2 degrees two-theta.
335. The crystalline form of claim 334 wherein the crystalline form is characterized by a
PXRD pattern substantially as depicted in Figure 93.
336. The crystalline form of claim 333 wherein the crystalline form is fluvastatin sodium
Form LXXVIII.
337. A process for preparing crystalline fluvastatin sodium Form LXXVIII comprising:

a) hydrolyzing a lower alkyl ester of fluvastatin with a sodium base catalyst in
water,
b) contacting the water with a water-immiscible extraction solvent,
c) evaporating the water to leave a residue,
d) contacting the residue with a liquid selected from the group consisting of
propan-2-ol and acetonitrile to convert the residue into Form LXXVIII, and
e) separating the liquid from the Form LXXVIII.
338. A semi-crystalline form of fluvastatin sodium characterized by a PXRD pattern with
peaks at 3.2 and 9.6±0.2 degrees two-theta.

339. The semi-crystalline form of fluvastatin sodium of claim 338 further characterized
by peaks at 11.8 and 19.8±0.2 degrees two-theta.
340. The semi-crystalline form of claim 339 wherein the semi-crystalline form is
characterized by a PXRD pattern substantially as depicted in Figure 97.
341. The semi-crystalline form of claim 338 wherein the semi-crystalline form is
fluvastatin, sodium Form XC.
342. A process for preparing semi-crystalline fluvastatin sodium Form XC comprising:

a) dissolving fluvastatin sodium in ethanol,
b) adding cyclohexane to the ethanol to induce precipitation of Form XC, and
c) separating the ethanol and cyclohexane from the Form XC.

343. A semi-crystalline form of fluvastatin sodium characterized by a PXRD pattern with
peaks at 4.7,5.6 and 13.8±0.2 degrees two-theta.
344. The semi-crystalline form of fluvastatin sodium of claim 343 further characterized
by peaks at 7.3, 9.6, 10.8, 16.4,17.6, 19.8, 20.8 and 23.1±0.2 degrees two-theta.
345. The semi-crystalline form of claim 344 wherein the semi-crystalline form is
characterized by a PXRD pattern substantially as depicted in Figure 98.
346. The semi-crystalline form of claim 343 wherein the semi-crystalline form is
fluvastatin sodium Form XCI.
347. A process for preparing semi-crystalline fluvastatin sodium Form XCI comprising:

a) forming a heterogeneous mixture of Form XV and ethyl acetate,
b) maintaining the mixture for a period of time sufficient to effect the conversion
to Form XCI, and
c) separating the ethyl acetate from the Form XCI.

348. A semi-crystalline form of fluvastatin sodium characterized by a PXRD pattern with
peaks at 3.4,10.1 and 11.8±0.2 degrees two-theta.
349. The semi-crystalline form of fluvastatin sodium of claim 348 further characterized
by peaks at 4.1,17.8, 20.1,21.7, 23.4 and 25.3±0.2 degrees two-theta.

350. The semi-crystalline form of claim 349 wherein the semi-crystalline form is
characterized by a PXRD pattern substantially as depicted in Figure 99.
351. The semi-crystalline form of claim 348 wherein the semi-crystalline form is
fluvastatin sodium Form XCH.
352. A process for preparing semi-crystalline fluvastatin sodium,Form XCII comprising:
a) dissolving fluvastatin sodium Form B in an ethanol:methanol mixture at
elevated temperature,
b) adding hexanes to the mixture to induce precipitation of fluvastatin sodium in
Form XCH, and
c) separating the ethanol, methanol and hexanes from the Form XCII.

353. A semi-crystalline form of fluvastatin sodium characterized by a PXRD pattern with
peaks at 4.6, 9.2 and 20.3±0.2±0.2 degrees two-theta.
354. The semi-crystalline form of fluvastatin sodium of claim 353 further characterized
by peaks at 4.1,6.7, 13.0, 15.8, 17.7, 21.7 and 23.0±0.2 degrees two-theta.
355. The semi-crystalline form of claim 354 wherein the semi-crystalline form is
characterized by a PXRD pattern substantially as depicted in Figure 101.
356. The semi-crystalline form of claim 353 wherein the semi-crystalline form is
fluvastatin sodium Form XCIV.
357. A process for preparing semi-crystalline fluvastatin sodium Form XCIV comprising:

a) forming a heterogeneous mixture of fluvastatin sodium Form XV in butan-1-ol
at ambient temperature,
b) maintaining the heterogeneous mixture at ambient temperature for a sufficient
period to convert Form XV into Form XCIV, and
c) separating the butan-1-ol from the Form XCIV.
358. A semi-crystalline form of fluvastatin sodium characterized by a PXRD pattern with
peaks at 5.7,13.0,19.8 and 20.5±0.2 degrees two-theta.

359. The semi-crystalline form of fluvastatin sodium of claim 358 further characterized
by peaks at 4.2, 4.7,12.3 and 15.9±0.2 degrees two-theta.
360. The semi-crystalline form of claim 359 wherein the semi-crystalline form is
characterized by a PXRD pattern substantially as depicted in Figure 102.
361. The semi-crystalline form of claim 358 wherein the semi-crystalline form is
fluvastatin sodium Form XCV.
362. A process for preparing semi-crystalline fluvastatin sodium Form XCV comprising:

a) forming a heterogeneous mixture of fluvastatin sodium Form XV in a diluent
selected from the group consisting of ethyl acetate, acetone, 1,4-dioxane and
MEK at ambient temperature,
b) maintaining the mixture at ambient temperature for a sufficient period to convert
Form XV into Form XCV, and
c) separating the diluent from the Form XCV.

363. A semi-crystalline form of fluvastatin sodium characterized by a PXRD pattern with
peaks at 3.7, 11.0,12.9 and 18.2±0.2 degrees two-theta.
364. The semi-crystalline form of fluvastatin sodium of claim 363 further characterized
by peaks at 5.2, 8.3,17.7,21.5 and 25.5±0.2 degrees two-theta.
365. The semi-crystalline form of claim 364 wherein the semi-crystalline form is
characterized by a PXRD pattern substantially as depicted in Figure 103.
366. The semi-crystalline form of claim 363 wherein the semi-crystalline form is
fluvastatin sodium Form XCVI.
367. A process for preparing semi-crystalline fluvastatin sodium Form XCVI comprising:

a) forming a heterogeneous mixture of fluvastatin sodium Form XV and THF at
ambient temperature,
b) maintaining the suspension at ambient temperature for a sufficient period to
convert Form XV into Form XCVI, and
c) separating the THF from the Form XCV.

368. A semi-crystalline form of fiuvastatin sodium characterized by a PXRD pattern with apeak at 3.5±0.2 degrees two-theta.
369. The semi-crystalline form of fiuvastatin sodium of claim 368 further characterized
by peaks at 9.4, 18.4,20.0, 21.2 and 22.0±0.2 degrees two-theta.
370. The semi-crystalline form of claim 369 wherein the semi-crystalline form is
characterized by a PXRD pattern substantially as depicted in Figure 104..
371. The semi-crystalline form of claim 368 wherein the semi-crystalline form is
fiuvastatin sodium Form XCVII.
372. A process for preparing semi-crystalline fiuvastatin sodium Form XCVII
comprising:

a) hydrolyzing a lower alkyl ester of fiuvastatin with sodium hydroxide in
cyclohexane,
b) precipitating Form XCVII from the cyclohexane, and
c) separating the cyclohexane from the Form XCVII.

373. A semi-crystalline form of fiuvastatin sodium characterized by a PXRD pattern with '
peaks at 3.8 and 10.8±0.2 degrees two-theta.
374. The semi-crystalline form of fiuvastatin sodium of claim 373 further characterized
by peaks at 6.4 and 14.4±0.2 degrees two-theta.
375. The semi-crystalline form of claim 374 wherein the semi-crystalline form is
characterized by a PXRD pattern substantially as depicted in Figure 105.
376. The semi-crystalline form of claim 373 wherein the semi-crystalline form is
fiuvastatin sodium Form XCVIII
377. A process for preparing semi-crystalline fiuvastatin sodium Form XCVIII
comprising:

a) hydrolyzing a lower alkyl ester of fiuvastatin with sodium-hydroxide in a
concentrated methanol solution at elevated temperature,
b) adding a large excess of acetonitrile to the methanol at elevated temperature,
c) precipitating Form XCVHI from the methanol and acetonitrile, and

d) separating themethanol and acetonitrile from the Form XCVIII
378. A semi-crystalline form of fluvastatin sodium characterized by a PXRD pattern with
peaks at 3.6, 5.3, 8.7 and 10.4+0.2 degrees two-theta.
379. The semi-crystalline form of fluvastatin sodium of claim 378 further characterized
by peaks at 17.9 and 21.5±0.2 degrees two-theta.
380. The semi-crystalline form of claim 379 wherein the semi-crystalline form is
characterized by a PXRD pattern substantially as depicted in Figure 106.
381. The semi-crystalline form of claim 378 wherein the semi-crystalline form is
fluvastatin sodium Form XCIX.
382. A process for preparing semi-crystalline fluvastatin sodium Form XCIX comprising:

a) forming a heterogeneous mixture of fluvastatin sodium Form VI and ethanol at
ambient temperature,
b) maintaining the heterogeneous mixture at ambient temperature for a sufficient
period to convert Form VI into Form XCIX, and •
c) separating the ethanol from the Form VI.

383. A semi-crystalline form of fluvastatin sodium characterized by a PXRD pattern with
peaks at 3.3, 9.8,11.0,19.0 and 22.7±0.2 degrees two-theta.
384. The semi-crystalline form of fluvastatin sodium of claim 383 further characterized
by peaks at 6.2,17.2 and 21.3±0.2 degrees two-theta.
385. The semi-crystalline form of claim 384 wherein the semi-crystalline form is
characterized by a PXRD pattern substantially as depicted in Figure 107.
386. The semi-crystalline form of claim 383 wherein the semi-crystalline form is
fluvastatin sodium Form C.
387. A process for preparing semi-crystalline fluvastatin sodium Form C comprising:

a) hydrolyzing a lower alkyl ester of fluvastatin with sodium hydroxide in
dichloromethane at room temperature,
b) precipitating fluvastatin sodium Form C from the dichloromethane, and

c) separating the dichloromethane from the Form C.
388. A semi-crystalline form of fiuvastatin sodium characterized by a PXRD pattern with
peaks at 4.5 and 11.2±0.2 degrees two-theta.
389. The semi-crystalline form of fiuvastatin sodium of claim 388 further characterized
by peaks at 5.7 and 19.3±0.2 degrees two-theta.
390. The semi-crystalline form of claim 389 wherein the semi-crystalline form is
characterized by a PXRD pattern substantially as depicted in Figure 108.
391. The semi-crystalline form of claim 388 wherein the semi-crystalline form is
fiuvastatin sodium Form CI.
392. A process for preparing semi-crystalline fiuvastatin sodium Form CI comprising:

a) hydrolyzing a lower alkyl ester of fiuvastatin with sodium hydroxide in a
mixture of acetone and methanol.
b) precipitating Form CI from the mixture, and
c) separating the mixture from the Form CI.

393. A semi-crystalline form of fiuvastatin sodium characterized by a PXRD pattern with
a peak at 4.3±0.2 degrees two-theta.
394. The semi-crystalline form of fiuvastatin sodium of claim 393 further characterized
by peaks at 8.7, 11.0 and 19.2±0.2 degrees two-theta.
395. The semi-crystalline form of claim 394 wherein the semi-crystalline form is
characterized by a PXRD pattern substantially as depicted in Figure 109.
396. The semi-crystalline form of claim 393 wherein the semi-crystalline form is
fiuvastatin sodium Form CII.
397. A process for preparing semi-crystalline fiuvastatin sodium Form CII comprising:

a) hydrolyzing a lower alkyl ester of fiuvastatin with sodium hydroxide in a
mixture of acetone and methanol,
b) precipitating Form CII from the mixture, and
c) separating the mixture from the Form CII.

398. A semi-crystalline form of fluvastatin sodium characterized by a PXRD pattern with
peaks at 4.5, 20.4, 25.9 and 30.6±0.2 degrees two-theta.
399. The semi-crystalline form of fluvastatin sodium of claim 398 further characterized
by peaks at 5.6,10.1,12.5,19.0 and 29.7±0.2 degrees two-theta.
400. The semi-crystalline form of claim 399 wherein the semi-crystalline form is
characterized by a PXRD pattern substantially as depicted in Figure 110.
401. The semi-crystalline form of claim 398 wherein the semi-crystalline form is
fluvastatin sodium Form CHI.
402. A process for preparing semi-crystalline fluvastatin sodium Form CHI comprising:

a) hydrolyzing a lower alkyl ester of fluvastatin with sodium hydroxide in a
mixture of acetone and water,
b) precipitating Form CIII from the mixture, and
c) separating the mixture from the Form CIII.

403. A semi-crystalline form of fluvastatin sodium characterized by a PXRD pattern with
peaks at 3.7, 9.7,18.3,19.9,21.8±0.2 degrees two-theta.
404. The semi-crystalline form of fluvastatin sodium of claim 403 further characterized
by peaks at 5.6,11,3,14.8,22.6±0.2 degrees two-theta.
405. The semi-crystalline form of claim 404 wherein the semi-crystalline form is
characterized by a PXRD pattern substantially as depicted in Figure 111.
406. The semi-crystalline form of claim 403 wherein the semi-crystalline form is
fluvastatin sodium Form CIV.
407. A process for preparing semi-crystalline fluvastatin sodium Form CIV comprising:

a) hydrolyzing a lower alkyl ester of fluvastatin with sodium hydroxide in THF,
b) adding hexanes to the THF to induce precipitation of Form CIV, and
c) separating the THF and hexanes from the Form CIV.

408. A semi-crystalline form of fluvastatin sodium characterized by a PXRD pattern with
peaks at 3.7, 8.9,19.1,22.5,29.7±0.2 degrees two-theta.
409. The semi-crystalline form of fluvastatin sodium of claim 408 further characterized
by peaks at 11.5,17.0,25.1,26.9, 28.2±0.2 degrees two-theta.
410. The semi-crystalline form of claim 409 wherein the semi-crystalline form is
characterized by a PXRD pattern substantially as depicted in Figure 112.
411. The semi-crystalline form of claim 408 wherein the semi-crystalline form is
fluvastatin sodium Form GV.
412. A process for preparing semi-crystalline fluvastatin sodium Form CV comprising:
a) hydrolyzing a lower alkyl ester of fluvastatin with sodium hydroxide in
acetonitrile at elevated temperature, . b) cooling the acetonitrile,
c) precipitating Form CV from the acetonitrile, and
d) separating the acetonitrile from the Form CV.
413. A pharmaceutical composition comprising an effective amount of a fluvastatin
sodium form selected from the group consisting of Form I, II, III, IV, IV-1, V, VI,
vII vIII, Ix, Ix-I, xI, xI-2, xII, xIII, xIII, xVII, xvIII, xIx, xIx-I, xx, XXII, xxIII, xxIv, xxvI, xxvII, xxrx, xxx, xxxI, xxxIII, xxxIv, xxxv, xxxvI, xxxvII, xxxvm, xxxIx, XLI, xLII, xLIII, xLIv, XLV, XLVI, XLVII, XLvIII, XLIX, L, LI, LIII, LIV, LV, LVI, LVII, LvIII, LX, LXIV, LXV, LXVI, LXVII, Lxvm, LXDC, LXX, LXXI, LXXII, LXXIV, LXXV, LXXVI, LxxvII, LXXVIIII; xc, xcI, xcII, xcIII, xcIv, xcv, xcvI, xcvII, xcvIII,
XCIX, C, CI, CII, CIII, CIV, CV and mixtures thereof and a pharmaceutically acceptable excipient.
414. A phannaceutical dosage form comprising an effective amount of a fluvastatin
sodium form selected from the group consisting of Form I, II, III, IV, IV-1, V, VI,
vII, vIII, Ix,Ix-I, xI, xI-2, xII, xIII, xvI, xvII, XVIII, xIx, xIx-I xx, xxII, xxIII, xxrv, xxvI, xxvII, xxrx, xxx, xxxI, xxxIII, xxxIv, xxxv, xxxvI, xxxvII, xxxvIII, XXXI,X XLI, xxII; XLIII, XLIV, XLV, XLVI, XLvII XLVIII XLIX, L, LI, LIII, LIV, LV, LVI, LVII, LVIII, LX, LXIV, LXV, LXVI, LXVII, LXVIII, LXIX, LXX, LXXI, LXXII, LXXIV, LXXV, LXXVI,

LXXVII, LxxvIII, XC, XCI, XCII, XCIII, XCIV, XCV, XCVI, XCVII, XCVIII,
XCIX, C, CI, CII, CIII, CIV, CV and mixtures thereof and a pharmaceuticalLy acceptable excipient.
415. A method of treating a patient suffering from hyperch.olesterolem.ia or
hyperlipidemia comprising the step of administering to the patient an effective amount of a fhivastatin sodium form selected from the group consisting of Form I,
II, III, Iv,IV-1, v, vI, vII, vIII, Ix, DC-I, xI, xI-2, xII, xIII, xvI, xvII, xvIII, x1x, x1x-1, xx, xxII, xxIII, xxIv, xxvI, xxvII, xxIx, xxx, xxxI, xxxIII, xxxIv, xxxv, xxxvI, xxxvII, xxxvIII, xxxIx, XLI, xII, XLIII,
XLIV, XLV, XLVI, XLVII, XLVIII, XLIX, L, LI, LIII, LIV, LV, LVI, LVII, LVIII, LX, LXIV, LXV, LXVI, LXVII, LXVIII, LXIX, LXX, LXXI, LXXII, LXXIV,
LXXV, LXXVI, LxxvII, LXXVIII, xc, xcI, xcII, xcIII, xcIv, xcv, xcvI,
XCVII, XCVm, XCIX, C, CI, CII, CIII, CIV, CV and mixtures thereof.
416. A process for preparing fiuvastatin sodium Form B comprising:
a) dissolving fiuvastatin free acid, lactone or mixture thereof in a mixture of
methanol and water,
b) adding methyl tert-butyl ether to the solution to induce precipitation of Form B,
and
c) separating the methanol, water and methyl tert-butyl ether from the Form B.
417. A process for preparing amorphous fiuvastatin sodium comprising:
a) dissolving fiuvastatin sodium in 1,4-dioxane at elevated temperature,
b) cooling the solution to induce precipitation of amorphous fiuvastatin sodium,
and
c) separating the amorphous fiuvastatin sodium from the 1,4-dioxane.

418. A crystalline form of fiuvastatin sodium characterized by a PXRD pattern with peaks
at 3.7 and 4.410.2 degrees two-theta.
419. The crystalline form of claim 418 further characterized by peaks at 5.6 and 10,8±0.2
degrees two-theta.
420. A process for preparing crystalline fiuvastatin sodium Form LXVn comprising
combining a solution of a lower alkyl ester of fiuvastatin in acetone with a sodium
hydroxide and methanol to precipitate the crystalline form.

421. A crystalline form of fluvastatin characterized by an PXRD pattern with peaks at
5.6, 6.3 and 10.5±0.2 degrees two-theta.
422. The crystalline form of claim 421, further characterized by peaks at 4.1, 5.0, 11.0,
15.7,17.2 and 19.6±0.2 degrees two-theta.
423. A process for preparing fluvastatin sodium Form LX comprising heating a solution
of fluvastatin sodium in methanol and combining the solution with ethyl acetate to
precipitate the crystalline form.
424. A crystalline form of fluvastatin sodium characterized by an PXRD pattern with
peaks at 5.8, 13.9 and 14.7±0.2 degrees two-theta.
425. The crystalline form of claim 424, further characterized by peaks at 5.1, 9.3,11.7
and 19.4±0.2 degrees two-theta.
426. A process for preparing crystalline fluvastatin Form LXIV comprising precipitating
the crystalline form from a mixture of acetone and methanol.
427. A crystalline form of fluvastatin sodium characterized by an PXRD pattern with
peaks at 5.8,13.9 and 14.7±0.2 degrees two-theta.
428. The crystalline form of claim 427, further characterized by peaks at 5.1, 9.3, 11.7
and 19.4±0.2 degrees two-theta.
429. A process for preparing fluvastatin sodium Form LXV comprising adding propan-2-
ol to a solution of fluvastatin sodium in methanol to precipitate the crystalline form.
430. A crystalline form of fluvastatin sodium characterized by an PXRD pattern with
peaks at 3.6,10.8,17.8, 18.3 and 21.6±0.2 degrees two-theta.
431. The crystalline form of claim 430 further characterized by peaks at 7.2,12.2, 14.4
and 25.5±0.2 degrees two-theta.

432. A process for preparing crystalline fluvastatin Form LXVI comprising heating a
solution of fluvastatin sodium in water and cooling the solution to precipitate the
crystalline form.
433. A crystalline form of fluvastatin sodium characterized by an PXRD with peaks at
3.6, 5.9,10.8 and Il.6+0.2 degrees two-theta.
434. The crystalline form of claim 433, further characterized by peaks at 9.3,15.4,17.0,
18.4 and 23.0±0.2 degrees two-theta.
43 5. A process for preparing crystalline fluvastatin sodium Form LXVIII comprising combining a solution of a lower alkyl ester of fluvastatin in acetone with a sodium hydroxide and methanol to precipitate the crystalline form.
436.. A process for preparing crystalline fluvastatin sodium Form II comprising:
a) heating solid fluvastatin sodium in a solvent selected from butan-1-ol
and propan-2-ol,
b) crystallizing Form II from the solvent, and
c) separating the solvent from Form II
437. A process for preparing crystalline fluvastatin sodium Form III comprising:
a) heating fluvastatin sodium in a solvent selected from the group
consisting of butan-1-ol, ethyl acetate and THF.
b) slowly adding an anti-solvent selected from the group consisting of
MTBE, hexanes and cyclohexane to the solvent to induce precipitation
of Form in, and
c) separating the solvent and anti-solvent from Form III.
438. A process for preparing crystalline fluvastatin sodium Form III comprising:
a) heating amorphous fluvastatin sodium in refluxing ethanol.
b) precipitating Form III from the ethanol, and
c) separating the ethanol from the Form III.
439. A process for preparing crystalline fluvastatin sodium Form V comprising:
a) heating fluvastatin sodium in refluxing butan-1 -ol,
b) slowly adding heptane to the refluxing solution,

c) precipitating Form V from the solution, and
d) separating the butan-1-ol and heptane from the Form V,
440. A process for preparing crystalline iluvastatin sodium Form V comprising:
a) heating iluvastatin sodium in a ternary solvent -system of ethanol:ethyl
acetate:propan-l-ol at reflux temperature,
b) adding n-hexane to the solution,
e) precipitating-sForm V from the solution, separating the'ethanbl ethyl
acetate, propan-1-ol and n-hexane from the Form V.
441 . A process for preparing crystalline fluvastatin sodium Form IX-1 comprising:
a) heating fluvastatin sodium in a solvent selected from the group
consisting of butan-1-ol, ethyl acetate, isobutyl acetate, ethanol, toluene,
tetrahydrofuran and methyl ethyl ketone,
b) inducing precipitation of Form IX-1 by adding of an anti-solvent
selected from the group consisting of n-pentane, diethyl ether, methyl
terf-butyl ether, dichloromethane, hexanes and cyclohexane to the
solvent, and
c) separating the solvent and anti-solvent from the Form IX-1 .
442. A process for preparing crystalline fluvastatin sodium Form XH comprising:
- a) heating fluvastatin sodium in butan-1-ol,
b) inducing precipitation of Form XII by adding 1,4-dioxane to the butan-
1-ol, and
c) separating the 1 ,4-dioxane and butan-1-ol from the Form XII.

443. A crystalline form of iluvastatin sodium characterized by an PXRD pattern with
peaks at 4.9, 5.9, 7.2 and 12.3±0.2 degrees two-theta.
444. The crystalline form of claim 443, further characterized by peaks at 9.7, 10.9 and
13.9±0.2 degrees two-theta.
445. A process for preparing fluvastatin sodium Form XCIII comprising suspending
fluvastatin sodium Form XV in propan-I-ol to obtain Form XCIII