FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
COMPLETE SPECIFICATION
(SECTION 10, rule 13)
"PROCESSES FOR THE PREPARATION OF
SUBSTANTIALLY PURE AMORPHOUS FLUVASTATIN"
Glenmark Pharmaceuticals Limited
an Indian Company, registered under the Indian company's Act 1957 and having
its registered office at
Glenmark House,
HDO - Corporate Bldg, Wing -A,
B.D. Sawant Marg, Chakala,
Andheri (East), Mumbai - 400 099
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION AND
THE MANNER IN WHICH IT IS TO BE PERFORMED


1


PRIORITY
[0001] This application claims the benefit under Indian Provisional Application No.
460/MUM/2005, filed on April 12, 2005, and entitled "PROCESS FOR THE
PREPARATION OF SUBSTANTIALLY PURE AMORPHOUS FLUVASTATIN", the
contents of each of which are incorporated by reference herein.
BACKGROUND OF THE INVENTION
1. Technical Field
J0002] The present invention generally relates to processes for the preparation of
substantially pure fluvastatin or a pharmaceutically acceptable salt thereof in an amorphous
form.
2. Description of the Related Art
[0003] Fluvastatin, also known as R*,S*-(E)-(±)-3,5-dihydroxy-7-[3-(4-
fluorophenyl)-l-(l-methylethyl)-lH-indoI-2-yl]-6-heptenoic acid, is represented by the
structure of Formula I.

Generally, fluvastatin is a synthetic lipid-lowering agent that acts as an inhibitor of 3-
hydroxy-3-methyIglutaryl-coenzyme A (HMG-CoA) reductase (HMG-CoA reductase
inhibitor). This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and
rate-limiting step in cholesterol biosynthesis. HMG-CoA reductase inhibitors are commonly
referred to as "statins." Statins are therapeutically effective drugs used for reducing low
density lipoprotein (LDL) particle concentration in the blood stream of patients at risk for
2

cardiovascular disease. Fluvastatin is indicated for use for reducing elevated total cholesterol
(total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), and high
plasma triglycerides (TG) in patients with primary hypercholesterolemia and mixed
hyperlipidemia (Fredrickson types IIa and IIb). Fluvastatin sodium is sold under the trade
nam LESCOL®: ' See, e.g., The Merck Index, Thirteenth Edition, 2001, p. 747-48,
monograph 4244; and Physician's Desk Reference, "Lescol," 58th Edition, pp. 2274-2278
(2004).
[0004] U.S. Patent No. 4,739,073 ("the '073 patent"), incorporated by reference
herein, discloses fluvastatin as a racemate and as a sodium salt. The '073 patent further
discloses that fluvastatin can be prepared by lyophilization.
[00051 U.S. Patent No. 5,354,772 ("the '772 patent"), incorporated by reference
herein, discloses fluvastatin as a racemate, (3S, 5R) and (3R, 5S) enantiomers, a sodium salt
and a lactone. The '772 patent further discloses various processes for the preparation for
fluvastatin. One such process includes the stereo-selective reduction of the compound 7-[3-
(4-fluorophenyl)-l-(l -methylethyl)-lH-indol-2-yl]-5-hydroxy-3-oxo-6-heptenoic acid alkyl
ester using sodium borohydride and triethyl borane in presence of air to obtain a dihydroxy
ester. The dihydroxy ester is then saponified and acidified to obtain a mixture of the
dihydroxy acid isomers. This mixture is lactonized using N-cyclohexyl-N'-[2-(N"-methyl
mopholinium) ethyl] carbodiimide p-toluene suJfonate to obtain a mixture of the trans and cis
lactones. The trans and cis lactones are separated by chromatography and treated with a
sodium hydroxide solution to get the corresponding ervthro and three forms. The '772 patent
also discloses that the racemic product may be resolved into two optically pure enantiomers
(3R, 5S) and (3S, 5R) with the (3R, 5S) being the preferred compound.
[0006] U.S. Patent No. 6,124,340 ("the '340 patent"), incorporated by reference
herein, discloses polymorphic form B of racemic fluvastatin sodium. The '340 patent further
discloses that lyophilization of fluvastatin sodium yields a mixture of amorphous fluvastatin
and polymorphic form A of fluvastatin.
[0007] U.S. Patent No. 6,696,479 ("the '479 patent"), incorporated by reference
herein, discloses polymorphic forms C, D, E and F of racemic fluvastatin sodium hydrates.
3

The '479 patent further discloses a process for preparing highly crystalline fluvastatin sodium
Form A.
[0008] U.S. Patent No. 6,858,643 ("the '643 patent"), incorporated by reference
herein, discloses polymorphic forms A, Bl, B2, C, D and E of the (3R, 5S) or (3S, 5R)
enantiomers of fluvastatin and processes for their preparation.
[0009] Efforts are made to prepare pharmaceutical products of a high grade and with a
minimum amount of impurities present. The control of impurities requires a study of various
options to decide upon the reaction conditions and testing protocols necessary to insure that
drugs which are administered to the public are substantially pure. Accordingly, there remains
a need for an improved process for preparing amorphous fluvastatin or a pharmaceutically
acceptable salt thereof that eliminates or substantially reduces the impurities in a convenient
and cost efficient manner to provide highly purified amorphous fluvastatin or a
pharmaceutically acceptable salt thereof.
SUMMARY OF THE INVENTION
[0010] In accordance with one embodiment of the present invention, a process for
preparing substantially pure amorphous fluvastatin or a pharmaceutically acceptable salt
thereof is provided comprising (a) providing a solvent solution comprising substantially non-
amorphous fluvastatin or a pharmaceutically acceptable salt thereof and a solvent capable of
dissolving the fluvastatin; and (b) recovering substantially pure fluvastatin or a
pharmaceutically acceptable salt thereof in a substantially pure amorphous form other than by
spray drying.
[0011] In accordance with a second embodiment of the present invention, a process
for preparing substantially pure amorphous fluvastatin or a pharmaceutically acceptable salt
thereof is provided comprising (a) providing a solvent solution comprising substantially non-
amorphous fluvastatin or a pharmaceutically acceptable salt thereof and a solvent capable of
dissolving the fluvastatin; and (b) recovering substantially pure fluvastatin or a
pharmaceutically acceptable salt thereof in a substantially pure amorphous form by (i)
concentrating the solution or (ii) evaporating the solution.
4

[0012] In accordance with a third embodiment of the present invention, a process for
preparing substantially pure amorphous fluvastatin or a pharmaceutically acceptable salt
thereof is provided comprising (a) providing a solvent solution comprising a straight or
branched CpC4 alkyl ester of substantially non-amorphous fluvastatin in a lower alcoholic
solvent or cyclic ether solvent capable of dissolving the fluvastatin; (b) hydrolyzing the
fluvastatin ester solution with an aqueous solution comprising an alkali metal hydroxide; and
(c) recovering fluvastatin or a pharmaceutically acceptable salt thereof in a substantially pure
amorphous form.
[0013] In accordance with a fourth embodiment of the present invention, substantially
pure amorphous fluvastatin or a pharmaceutically acceptable salt thereof containing less than
about 5% crystalline fluvastatin salt is provided.
[0014] In accordance with a fifth embodiment of the present invention, a
pharmaceutical composition is provided comprising substantially pure amorphous fluvastatin
or a pharmaceutically acceptable salt thereof containing less than about 5% crystalline
fluvastatin salt, and a pharmaceutically acceptable excipient.
[0015] The processes of the present invention advantageously provide amorphous
fluvastatin in an efficient manner at a high yield and in relatively high purity.
BRIEF DESCRIPTION OF DRAWINGS
[0016] Figure 1 shows the X-ray powder diffraction pattern which demonstrates the
amorphous nature of the fluvastatin prepared according to Example 28 of the present
invention.
[0017] Figure 2 shows the infra-red spectrum of the amorphous fluvastatin prepared
according to Example 28 of the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0018] The present invention involves a process for producing fluvastatin or a
pharmaceutically acceptable salt thereof in a substantially pure amorphous form. The
substantially pure amorphous fluvastatin prepared according to the present invention may be
5

prepared as the racemic form or the (3S, 5R) or (3R, 5S) enantiomer of fluvastatin or a
pharmaceutically acceptable salt thereof,
[0019] Generally, one embodiment of the process of the present invention includes at
least (a) providing a solvent solution comprising substantially non-amorphous fluvastatin or a
salt thereof and a solvent capable of dissolving the fluvastatin; (b) optionally filtering the
solution of any impurities; and (c) recovering fluvastatin or a pharmaceutically acceptable salt
thereof in a substantially pure amorphous form other than by spray drying. In step (a) of this
process, a solvent solution of fluvastatin or salt thereof and/or a derivative thereof is prepared.
The substantially non-amorphous fluvastatin or salt thereof used as a starting material can be
any substantially non-amorphous form of fluvastatin known to the skilled artisan including
any hydrates, solvates, corresponding free acid, esters, salts, and the like as well as mixtures
of amorphous and non-amorphous forms of fluvastatin. Examples of such starting material
include polymorph forms A and B of fluvastatin sodium. The starting substantially non-
amorphous fluvastatin or salt thereof can be prepared by well known techniques such as those
disclosed in, e.g., U.S. Patent Nos. 6,124,340, 6,696,479 and 6,858,643.
[0020] A suitable solvent includes, but is not limited to, water, organic solvents such
as a lower aliphatic alcohol, e.g., a C1-C6 alcohol such as methanol and ethanol, and the like
and mixtures thereof. Preferably, the solvent is methanol. The amount of solvent present can
range from about 5 to about 30 volumes per volume of fluvastatin, and preferably about 10
volumes. The temperature employed in step (a) will ordinarily range from about 20°C to
about60°C.
[0021] The resulting clear solution can then be filtered to substantially remove any
impurities present in the solution utilizing standard filtration techniques. If desired, a filtering
aid, such as celite, is added and the solution can then be filtered with a 5 micron cartridge
filter.
[0022] After filtration, the substantially pure amorphous form of fluvastatin or a
pharmaceutically acceptable salt thereof is recovered, for example, by removing the solvent
from the solution. Removal of the solvent may be carried out by, for example, (1)
concentrating the solution and drying, or (2) evaporating the solvent. The solution may be
6

concentrated under vacuum above about 720 mm Hg. The reaction mass is concentrated to
about 2 to about 5 volumes as compared to the initial fluvastatin. The concentration may also
take place in, for example, a reactor with stirring, a rotavapor, or in a vacuum paddle dryer
with stirring. After concentrating the solution, the solution can be cooled to a temperature of
about 0°C to obtain a slurry. The slurry is then filtered under controlled conditions using
standard filtration techniques such as, for example, over a nutsche filter, agitated nutsche
filter, centrifugation, through a filter press or in a sparkler filter. Filtration is typically carried
out under controlled conditions including, for example, a nitrogen atmosphere, a temperature
of about 25°C and a relative humidity ranging from about 45% to about 50%. The wet
product is then dried at a temperature below about 60°C.
[0023] Alternatively, the solvent may be removed by evaporation. The solvent may
be completely evaporated in, for example, a pilot plant rotavapor, a vacuum paddle dryer or in
a conventional reactor under vacuum above about 720 mm Hg, by flash evaporation
techniques at a temperature of about 90°C, using an agitated thin film dryer ("ATFD"), or by
spray drying at a temperature ranging from about room temperature to about 65°C to obtain a
dry amorphous fluvastatin powder. When the solvent is water, the solvent may be removed
by distillation under vacuum in a pilot plant rotavapor.
[0024] In another embodiment of the present invention, a process for preparing
substantially pure amorphous fluvastatin or a salt thereof involves at least (a) preparing an
organic solvent solution comprising a straight or branched C1-C4 alkyl ester of substantially
non-amorphous fluvastatin in a lower alcoholic solvent or cyclic; ether solvent, e.g.,
tetrahydrofuran, capable of dissolving the crude fluvastatin; (b) hydrolyzing the fluvastatin
ester solution with an aqueous solution of an alkali metal hydroxide, e.g., sodium hydroxide,
to provide a clear solution in which the homogeneity of the clear solution is maintained; (c)
optionally filtering the clear solution to remove impurities; and (d) recovering the
substantially pure amorphous form of fluvastatin or a salt thereof. Step (b) of this
embodiment may be carried out at a temperature ranging from about 20° C to about 45° C.
The amorphous form of fluvastatin or a salt thereof can be recovered, e.g., by concentration,
evaporation as described above.
7

[0025] The substantially pure amorphous form of fluvastatin or salt thereof obtained
by the above processes may be further dried in, for example, vacuum tray dryer, rotocon
vacuum dryer, vacuum paddle dryer or pilot plant rotavapor, to further lower residual
solvents, preferably below about 2% w/w. The time period for drying will depend on the
conditions employed and can range from about 12 hours to about 52 hours.
[0026] The amorphous form of fluvastatin obtained herein is substantially amorphous,
i.e., contains less than about 5% crystalline fluvastatin or salt thereof, preferably less than
about 2% crystalline fluvastatin or salt thereof and most preferably 0% crystalline fluvastatin
or salt thereof, i.e., 100% amorphous fluvastatin or salt thereof. The amorphous form of
fluvastatin obtained herein is also substantially pure, e.g., has a purity great than or equal to
about 99%.
[0027] Yet another aspect of the present invention is directed to pharmaceutical
compositions containing at least the substantially pure amorphous form of fluvastatin or salt
thereof disclosed herein. Such pharmaceutical compositions may be administered to a
mammalian patient in any dosage form, e.g., liquid, powder, elixir, injectable solution, etc.
Dosage forms may be adapted for administration to the patient by oral, buccal, parenteral,
ophthalmic, rectal and transdermal routes. Oral dosage forms include, but are not limited to,
tablets, pills, capsules, troches, sachets, suspensions, powders, lozenges, elixirs and the like.
The amorphous form of fluvastatin or salt thereof disclosed herein also may be administered
as suppositories, ophthalmic ointments and suspensions, and parenteral suspensions, which
are administered by other routes. The dosage forms may contain the substantially pure
amorphous form of fluvastatin or salt thereof disclosed herein as is or, alternatively, may
contain the substantially pure amorphous form of fluvastatin or salt thereof disclosed herein as
part of a composition. The pharmaceutical compositions may further contain one or more
pharmaceuticaHy acceptable excipients. Suitable 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, e.g., the buffering agents, sweetening
agents, binders, diluents, fillers, lubricants, wetting agents and disintegrants described
hereinabove.
8

[0028] Capsule dosages will contain the amorphous form of fluvastatin or salt thereof
disclosed herein within a capsule which may be coated with gelatin. Tablets and powders
may also be coated with an enteric coating. The enteric-coated powder forms may have
coatings comprising phthalic acid cellulose acetate, hydroxypropylmethyl cellulose phthalate,
polyvinyl alcohol phthalate, carboxy methyl ethyl cellulose, a copolymer of styrene and
maleic acid, a copolymer of methacrylic acid and methyl methacrylate, and like materials, and
if desired, they may be employed with suitable plasticizers and/or extending agents. A coated
capsule may have a coating on the surface of the capsule or may be a capsule comprising a
powder or granules with an enteric-coating,
[0029] Tableting compositions may have few or many components depending upon
the tableting method used, the release rate desired and other factors. For example, the
compositions of the present invention may contain diluents such as cellulose-derived
materials like powdered cellulose, microcrystalline cellulose, microfine cellulose, methyl
cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose,
hydroxypropylmethy) cellulose, carboxymethyl cellulose salts and other substituted and
unsubstituted celluloses; starch; pregelatinized starch; inorganic diluents such calcium
carbonate and calcium diphosphate and other diluents known to one of ordinary skill in the
art. Yet other suitable diluents include waxes, sugars (e.g. lactose) and sugar alcohols like
mannitol and sorbitol, acrylate polymers and copolymerSj as well as pectin, dextrin and
gelatin.
[0030] Other excipients contemplated by the present invention include binders, such
as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet
and dry granulation and direct compression tableting processes; disintegrants such as sodium
starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose and others; lubricants
like magnesium and calcium stearate and sodium stearyl fumarate; flavorings; sweeteners;
preservatives; pharmaceutically acceptable dyes and glidants such as silicon dioxide.
[0031] In one embodiment, the substantially pure amorphous form of fluvastatin or
salt thereof obtained herein for use in the pharmaceutical compositions of the present
invention can have a D50 and D90 particle size of less than about 400 microns, preferably less
9

than about 200 microns, more preferably less than about 150 microns, still more preferably
less than about 50 microns and most preferably less than about 15 microns. The particle sizes
can be obtained by, for example, any milling, grinding, micronizing or other particle size
reduction method known in the art to bring the solid state amorphous form of fluvastatin or
salt thereof into any of the foregoing desired particle size range.
[0032] Actual dosage levels of the substantially pure amorphous form of fluvastatin or
salt thereof obtained herein may be varied to obtain an amount of the amorphous form of
fluvastatin or salt thereof that is effective to obtain a desired therapeutic response for a
particular composition and method of administration for treatment of a mammal. The
selected dosage level therefore depends upon such factors as, for example, the desired
therapeutic effect, the route of administration, the desired duration of treatment, and other
factors. The total daily dose of the amorphous form of fluvastatin or salt thereof obtained
herein administered to a host in single or divided dose and can vary widely depending upon a
variety of factors including, for example, the body weight, general health, sex, diet, time and
route of administration, rates of absorption and excretion, combination with other drugs, the
severity of the particular condition being treated, etc.
[0033] The following examples are provided to enable one skilled in the art to practice
the invention and are merely illustrative of the invention. The examples should not be read as
limiting the scope of the invention as defined in the features and advantages,
EXAMPLE 1
[0034] Preparation of Amorphous Fluvastatin
[0035] Fluvastatin tert-butyl ester (crystalline) (10 kg) and methane! (200 L) were
charged into a reactor with stirring. An aqueous solution of sodium hydroxide pellets (0.86
kg of pellets dissolved in 21 L of purified water) was slowly run into the reaction mass by
maintaining the batch temperature between about 20°C to about 25°C. The contents were
reacted for about 12 hours at a temperature of about 25°C until the ester was completely
hydrolyzed as determined by HPLC. The clear solution of the reaction mass was filtered over
a celite bed prepared in methanol to remove any impurities. The solution was further filtered
10

through a 5 micron cartridge filter and evaporated completely under vacuum better than about
720 mm Hg in a vacuum paddle dryer until a free flowing solid product was obtained. The
vacuum was broken with nitrogen, and the product was milled to get a uniform particle size
and re-dried under vacuum in a vacuum paddle dryer until the product was below residual
solvent limits as per The International Conference on Harmonisation of Technical
Requirements for Registration of Pharmaceuticals for Human Use ("ICH") and as determined
by gas chromatography. The moisture content was also below the limit of detection (about 2
to about 4% w/w) as determined by Karl-Fischer titration.
[0036] Yield - 8 kg; HPLC - greater than 99% pure.
[0037] The PXRD pattern showed that the dried sample was found to be amorphous.
The sample was also found to comply with USP forum specifications.
EXAMPLE 2
[0038] Preparation of Amorphous Fluvastatin
[0039] Fluvastatin tert-butyl ester (crystalline) (10 kg) and methanol (200 L) were
charged into a reactor with stirring. An aqueous solution of sodium hydroxide pellets (0.86
kg of pellets dissolved in 21 L of purified water) was slowly run into the reaction mass by
maintaining the batch temperature between about 20°C to about 25°C. The contents were
reacted for about 12 hours at a temperature of about 25°C until the ester was completely
hydrolyzed as determined by HPLC. The clear solution of the reaction mass was filtered over
a celite bed prepared in methanol to remove any impurities. The solution was further filtered
through a 5 micron cartridge filter and evaporated completely under vacuum better than about
720 mm Hg in a pilot plant Rota vapor until a free flowing solid product was obtained. The
vacuum was broken with nitrogen, and the product was milled to get a uniform particle size
and re-dried under vacuum in a vacuum paddle dryer until the product was below residual
solvent limits as per ICH and the moisture content was below the limit of detection (about 2 to
about 4% w/w).
[0040] Yield - 8 kg; HPLC - greater than 99% pure.
11

[0041] The PXRD pattern showed that the dried sample was found to be amorphous.
The sample was also found to comply with USP forum specifications,
EXAMPLE 3
[0042] Preparation of Amorphous Fluvastatin
[0043] Fluvastatin tert-butyl ester (crystalline) (10 kg) and methanol (200 L) were
charged into a reactor with stirring. An aqueous solution of sodium hydroxide pellets (0.86
kg of pellets dissolved in 21 L of purified water) was slowly run into the reaction mass by
maintaining the batch temperature between about 20°C to about 25°C. The contents were
reacted for about 12 hours at a temperature of about 25°C until the ester was completely
hydrolyzed as determined by HPLC. The clear solution of the reaction mass was filtered over
a celite bed prepared in methanol to remove any impurities. The solution was further filtered
through a 5 micron cartridge filter and evaporated completely under vacuum better than about
720 mm Hg in a vacuum paddle dryer until a free flowing solid product was obtained. The
vacuum was broken with nitrogen, and the product was milled to get a uniform particle size
and re-dried under vacuum in a rotocone vacuum dryer until the product was below residual
solvent limits as per ICH and the moisture content was below the limit of detection (about 2 to
about 4% w/w).
[0044] Yield - 8 kg; HPLC - greater than 99% pure.
[0045] The PXRD pattern showed that the dried sample was found to be amorphous.
The sample was also found to comply with USP forum specifications.
12

EXAMPLE 4
[0046] Preparation of Amorphous Fluvastatin
(0047] Fluvastatin tert-butyl ester (crystalline) (10 kg) and methanol (200 L) were
charged into a reactor with stirring. An aqueous solution of sodium hydroxide pellets (0,86
kg of pellets dissolved in 21 L of purified water) was slowly run into the reaction mass by
maintaining the batch temperature between about 20°C to about 25°C, The contents were
reacted for about 12 hours at a temperature of about 25°C until the ester was completely
hydrolyzed as determined by HPLC. The clear solution of the reaction mass was filtered over
a celite bed prepared in methanol to remove any impurities. The solution was further filtered
through a 5 micron cartridge filter and evaporated completely under vacuum better than about
720 mm Hg in a pilot plant Rota vapor until a free flowing solid product was obtained. The
vacuum was broken with nitrogen, and the product was milled to get a uniform particle size
and re-dried under vacuum in a rotocone vacuum dryer until the product was below residual
solvent limits as per ICH and the moisture content was below the limit of detection (about 2 to
about 4% w/w).
[0048] Yield - 8 kg; HPLC - greater than 99% pure.
[0049] The PXRD pattern showed that the dried sample was found to be amorphous.
The sample was also found to comply with USP forum specifications.
EXAMPLE 5
[0050] Preparation of Amorphous Fluvastatin
[0051] Fluvastatin tert-butyl ester (crystalline) (10 kg) arid methanol (200 L) were
charged into a reactor with stirring. An aqueous solution of sodium hydroxide pellets (0.86
kg of pellets dissolved in 21 L of purified water) was slowly run into the reaction mass by
maintaining the batch temperature between about 20°C to about 25°C. The contents were
reacted for about 12 hours at a temperature of about 25°C until the ester was completely
hydrolyzed as determined by HPLC. The clear solution of the reaction mass was filtered over
a celite bed prepared in methanol to remove any impurities. The solution was further filtered
through a 5 micron cartridge filter and evaporated completely under vacuum better than about
13

720 mm Hg in a vacuum paddle dryer until a free flowing solid product was obtained. The
vacuum was broken with nitrogen, and the product was milled to get a uniform particle size
and re-dried under vacuum in a pilot plant rotavapor until the product was below residual
solvent limits as per ICH and the moisture content was below the limit of detection (about 2 to
about 4% w/w).
[0052] Yield - 8 kg; HPLC - greater than 99% pure.
[0053] The PXRD pattern showed that the dried sample was found to be amorphous.
The sample was also found to comply with USP forum specifications.
EXAMPLE 6
[0054] Preparation of Amorphous Fluvastatin
[0055] Fluvastatin tert-butyl ester (crystalline) (10 kg) and methanol (200 L) were
charged into a reactor with stirring. An aqueous solution of sodium hydroxide pellets (0.86
kg of pellets dissolved in 21 L of purified water) was slowly run into the reaction mass by
maintaining the batch temperature between about 20°C to about 25°C. The contents were
reacted for about 12 hours at a temperature of about 25°C until the ester was completely
hydrolyzed as determined by HPLC. The clear solution of the reaction mass was filtered over
a celite bed prepared in methanol to remove any impurities. The solution was further filtered
through a 5 micron cartridge filter and evaporated completely under vacuum better than about
720 mm Hg in a pilot plant Rota vapor until a free flowing solid product was obtained. The
vacuum was broken with nitrogen, and the product was milled to get a uniform particle size
and re-dried under vacuum in a pilot plant rotavapor until the product was below residual
solvent limits as per ICH and the moisture content was below the limit of detection (about 2 to
about 4% w/w).
[0056] Yield - 8 kg; HPLC - greater than 99% pure.
[0057] The PXRD pattern showed that the dried sample was found to be amorphous.
The sample was also found to comply with USP forum specifications.
14

EXAMPLE 7
[0058] Preparation of Amorphous Fluvastatin
[0059] Fluvastatin tert-butyl ester (crystalline) (10 kg) and methanol (200 L) were
charged into a reactor with stirring. An aqueous solution of sodium hydroxide pellets (0.86
kg of pellets dissolved in 21 L of purified water) was slowly run into the reaction mass by
maintaining the batch temperature between about 20°C to about 25°C. The contents were
reacted for about 12 hours at a temperature of about 25°C until the ester was completely
hydrolyzed as determined by HPLC. The clear solution of the reaction mass was filtered over
a celite bed prepared in methanol to remove any impurities. The solution was further filtered
through a 5 micron cartridge filter and evaporated completely under vacuum better than about
720 mm Hg in a vacuum paddle dryer until a free flowing solid product was obtained. The
vacuum was broken with nitrogen, and the product was milled to get a uniform particle size
and re-dried under vacuum in a conventional vacuum tray dryer until the product was below
residual solvent limits as per ICH and the moisture content was below the limit of detection
(about 2 to about 4% w/w).
[0060] Yield - 8 kg; HPLC - greater than 99% pure.
[0061] The PXRD pattern showed that the dried sample was found to be amorphous.
The sample was also found to comply with USP forum specifications.
EXAMPLE 8
[0062] Preparation of Amorphous Fluvastatin
[0063] Fluvastatin tert-butyl ester (crystalline) (10 kg) and methanol (200 L) were
charged into a reactor with stirring. An aqueous solution of sodium hydroxide pellets (0.86
kg of pellets dissolved in 21 L of purified water) was slowly run into the reaction mass by
maintaining the batch temperature between about 20°C to about 25oC. The contents were
reacted for about 12 hours at a temperature of about 25°C until the ester was completely
hydrolyzed as determined by HPLC. The clear solution of the reaction mass was filtered over
a celite bed prepared in methanol to remove any impurities. The solution was further filtered
through a 5 micron cartridge filter and evaporated completely under vacuum better than about
15

720 mm Hg in a pilot plant rota vapor until a free flowing solid product was obtained. The
vacuum was broken with nitrogen, and the product was milled to get a uniform particle size
and re-dried under vacuum in a conventional vacuum tray dryer until the product was below
residual solvent limits as per ICH and the moisture content was below the limit of detection
(about 2 to about 4% w/w).
(0064] Yield - 8 kg; HPLC - greater than 99% pure.
[0065] The PXRD pattern showed that the dried sample was found to be amorphous.
The sample was also found to comply with USP forum specifications.
EXAMPLE 9
[0066] Preparation of Amorphous Fluvastatin
[0067] Fluvastatin sodium (crystalline Form A) (10 grams) was dissolved in about 10
volumes of methanol at temperature ranging of about 30°C, filtered over a celite bed and
passed through a 5 micron cartridge filter. The solvent was completely distilled off under
vacuum in substantially the same manner as in Example 1 until a free flowing solid product
was obtained. The vacuum was broken with nitrogen, and the product was milled to get a
uniform particle size and re-dried under vacuum in substantially the same manner as in
Example 1 until the product was below residual solvent limits as per ICH and the moisture
content was below the limit of detection (about 2 to about 4% w/w). Fluvastatin sodium in
the amorphous form was obtained at a yield of about 75% w/w (HPLC - greater than 99%
pure).
r
EXAMPLE 10
[006S] Preparation of Amorphous Fluvastatin
[0069] Fluvastatin sodium (crystalline Form A) (10 grams) was dissolved in about 10
volumes of methanol at temperature ranging of about 30°C; filtered over a celite bed and
passed through a 5 micron cartridge filter. The solvent was completely distilled off under
vacuum in substantially the same manner as in Example 2 until a free flowing solid product
was obtained. The vacuum was broken with nitrogen, and the product was milled to get a
16

uniform particle size and re-dried under vacuum in substantially the same manner as in
Example 2 until the product was below residual solvent limits as per ICH and the moisture
content was below the limit of detection (about 2 to about 4% w/w). Fluvastatin sodium in
the amorphous form was obtained at a yield of about 75% w/w (HPLC - greater than 99%
pure).
EXAMPLE 11
[0070] Preparation of Amorphous Fluvastatin
[0071] Fluvastatin sodium (crystalline Form A) (10 grams) was dissolved in about 10
volumes of methanol at temperature ranging of about 30°C, filtered over a celite bed and
passed through a 5 micron cartridge filter. The solvent was completely distilled off under
vacuum in substantially the same manner as in Example 3 until a free flowing solid product
was obtained. The vacuum was broken with nitrogen, and the product was milled to get a
uniform particle size and re-dried under vacuum in substantially the same manner as in
Example 3 until the product was below residual solvent limits as per ICH and the moisture
content was below the limit of detection (about 2 to about 4% w/w). Fluvastatin sodium in
the amorphous form was obtained at a yield of about 75% w/w (HPLC - greater than 99%
pure).
EXAMPLE 12
[0072] Preparation of Amorphous Fluvastatin
[0073] Fluvastatin sodium (crystalline Form A) (10 grams) was dissolved in about 10
volumes of methanol at temperature ranging of about 30°C, filtered over a celite bed and
passed through a 5 micron cartridge filter. The solvent was completely distilled off under
vacuum in substantially the same manner as in Example 4 until a free flowing solid product
was obtained. The vacuum was broken with nitrogen, and the product was milled to get a
uniform particle size and re-dried under vacuum in substantially the same manner as in
Example 4 until the product was below residual solvent limits as per ICH and the moisture
content was below the limit of detection (about 2 to about 4% w/w). Fluvastatin sodium in
17

the amorphous form was obtained at a yield of about 75% w/w (HPLC - greater than 99%
pure).
EXAMPLE 13
[0074] Preparation of Amorphous Fluvastatin
[0075] Fluvastatin sodium (crystalline Form A) (10 grams) was dissolved in about 10
volumes of methanol at temperature ranging of about 30°C, filtered over a celite bed and
passed through a 5 micron cartridge filter. The solvent was completely distilled off under
vacuum in substantially the same manner as in Example 5 until a free flowing solid product
was obtained. The vacuum was broken with nitrogen, and the product was milled to get a
uniform particle size and re-dried under vacuum in substantially the same manner as in
Example 5 until the product was below residual solvent limits as per ICH and the moisture
content was below the limit of detection (about 2 to about 4% w/w). Fluvastatin sodium in
the amorphous form was obtained at a yield of about 75% w/w (HPLC - greater than 99%
pure).
EXAMPLE 14
[0076] Preparation of Amorphous Fluvastatin
[0077] Fluvastatin sodium (crystalline Form A) (10 grams) was dissolved in about 10
volumes of methanol at temperature ranging of about 30°C, filtered over a celite bed and
passed through a 5 micron cartridge filter. The solvent was completely distilled off under
vacuum in substantially the same manner as in Example 6 until a free flowing solid product
was obtained. The vacuum was broken with nitrogen, and the product was milled to get a
uniform particle size and re-dried under vacuum in substantially the same manner as in
Example 6 until the product was below residual solvent limits as per ICH and moisture
content was below the limit of detection (about 2 to about 4% w/w). Fluvastatin sodium in
100% amorphous form was obtained at a yield of about 75% w/w (HPLC - greater than 99%
pure).
18

EXAMPLE 15
[0078] Preparation of Amorphous Fluvastatin
[0079] Fluvastatin sodium (crystalline Form A) (10 grams) was dissolved in about 10
volumes of methanol at temperature ranging of about 30°C, filtered over a celite bed and
passed through a 5 micron cartridge filter. The solvent was completely distilled off under
vacuum in substantially the same manner as in Example 7 until a free flowing solid product
was obtained. The vacuum was broken with nitrogen, and the product was milled to get a
uniform particle size and re-dried under vacuum in substantially the same manner as in
Example 7 until the product was below residual solvent limits as per ICH and the moisture
content was below the limit of detection (about 2 to about 4% w/w). Fluvastatin sodium in
the amorphous form was obtained at a yield of about 75% w/w (HPLC - greater than 99%
pure).
EXAMPLE 16
[0080] Preparation of Amorphous Fluvastatin
[0081] Fluvastatin sodium (crystalline Form A) (10 grams) was dissolved in about 10
volumes of methanol at temperature ranging of about 30°C, filtered over a celite bed and
passed through a 5 micron cartridge filter. The solvent is completely distilled off under
vacuum in substantially the same manner as in Example 8 until a free flowing solid product
was obtained. The vacuum was broken with nitrogen, and the product was milled to get a
uniform particle size and re-dried under vacuum in substantially the same manner as in
Example 8 until the product was below residual solvent limits as per ICH and the moisture
content was below the limit of detection (about 2 to about 4% w/w). Fluvastatin sodium in
100% amorphous form was obtained at a yield of about 75% w/w (HPLC - greater than 99%
pure).
19

EXAMPLE 17
[0082] Preparation of Amorphous Fluvastatin
[0083] Fluvastatin sodium (crystalline Form B) (10 grams) was dissolved in about 10
volumes of methanol at temperature of about 30°C, filtered over a celite bed and passed
through a 5 micron cartridge filter. The solvent was completely distilled off under vacuum in
substantially the same manner as in Example 1 until a free flowing solid product was
obtained. The vacuum was broken with nitrogen, and the product was milled to get a uniform
particle size and re-dried under vacuum in substantially the same manner as in Example 1
until the product was below residual solvent limits as per ICH and the moisture content was
below the limit of detection (about 2 to about 4% w/w). Fluvastatin sodium in 100%
amorphous form was obtained at a yield of about 75% w/w (HPLC - greater than 99% pure).
EXAMPLE 18
[0084] Preparation of Amorphous Fluvastatin
[0085] Fluvastatin sodium (crystalline Form B) (10 grams) was dissolved in about 10
volumes of methanol at temperature of about 30°C, filtered over a celite bed and passed
through a 5 micron cartridge filter. The solvent was completely distilled off under vacuum in
substantially the same manner as in Example 2 until a free flowing solid product was
obtained. The vacuum was broken with nitrogen, and the product was milled to get a uniform
particle size and re-dried under vacuum in substantially the same manner as in Example 2
until the product was below residual solvent limits as per ICH and the moisture content was
below the limit of detection (about 2 to about 4% w/w). Fluvastatin sodium in the amorphous
form was obtained at a yield of about 75% w/w (HPLC - greater than 99% pure).
EXAMPLE 19
[0086] Preparation of Amorphous Fluvastatin
[0087] Fluvastatin sodium (crystalline Form B) (10 grams) was dissolved in about 10
volumes of methanol at temperature of about 30°C, filtered over a celite bed and passed
through a 5 micron cartridge filter. The solvent was completely distilled off under vacuum in
20

substantially the same manner as in Example 3 until a free flowing solid product was
obtained. The vacuum was broken with nitrogen, and the product was milled to get a uniform
particle size and re-dried under vacuum in substantially the same manner as in Example 3
until the product was below residual solvent limits as per ICH and the moisture content was
below the limit of detection (about 2 to about 4% w/w). Fluvastatin sodium in the amorphous
form was obtained at a yield of about 75% w/w (HPLC - greater than 99% pure).
EXAMPLE 20
[0088] Preparation of Amorphous Fluvastatin
[0089] Fluvastatin sodium (crystalline Form B) (10 grams) was dissolved in about 10
volumes of methanol at temperature of about 30°C, filtered over a celite bed and passed
through a 5 micron cartridge filter. The solvent was completely distilled off under vacuum in
substantially the same manner as in example 4 until a free flowing solid product was obtained.
The vacuum was broken with nitrogen, and the product was milled to get a uniform particle
size and re-dried under vacuum in substantially the same manner as in example 4 until the
i'
product was below residual solvent limits as per ICH and the moisture content was below the
limit of detection (about 2 to about 4% w/w). Fluvastatin sodium in the amorphous form was
obtained at a yield of about 75% w/w (HPLC - greater than 99% pure).
EXAMPLE 21
[0090] Preparation of Amorphous Fluvastatin
[0091] Fluvastatin sodium (crystalline Form B) (10 grams) was dissolved in about 10
volumes of methanol at temperature of about 30°C, filtered over a celite bed and passed
through a 5 micron cartridge filter. The solvent was completely distilled off under vacuum in
substantially the same manner as in Example 5 until a free flowing solid product was
obtained. The vacuum was broken with nitrogen, and the product was milled to get a uniform
particle size and re-dried under vacuum in substantially the same manner as in Example 5
until the product was below residual solvent limits as per ICH and the moisture content was
21

below the limit of detection (about 2 to about 4% w/w). Fluvastatin sodium in the amorphous
form was obtained at a yield of about 75% w/w (HPLC - greater than 99% pure).
EXAMPLE 22
[0092] Preparation of Amorphous Fluvastatin
[0093] Fluvastatin sodium (crystalline Form B) (10 grams) was dissolved in about 10
volumes of methanol at temperature of about 30°C, filtered over a celite bed and passed
through a 5 micron cartridge filter. The solvent was completely distilled off under vacuum in
substantially the same manner as in Example 6 until a free flowing solid product was
obtained. The vacuum was broken with nitrogen, and the product was milled to get a uniform
particle size and re-dried under vacuum in substantially the same manner as in Example 6
until the product was below residual solvent limits as per ICH and moisture content was
below the limit of detection (about 2 to about 4% w/w). Fluvastatin sodium in the amorphous
form was obtained at a yield of about 75% w/w (HPLC - greater than 99% pure).
EXAMPLE 23
[0094] Preparation of Amorphous Fluvastatin
[0095] Fluvastatin sodium (crystalline Form B) (10 grams) was dissolved in about 10
volumes of methanol at temperature of about 30°C, filtered over a celite bed and passed
through a 5 micron cartridge filter. The solvent was completely distilled off under vacuum in
substantially the same manner as in Example 7 until a free flowing solid product was
obtained. The vacuum was broken with nitrogen, and the product was milled to get a uniform
particle size and re-dried under vacuum in substantially the same manner as in Example 7
until the product was below residual solvent limits as per ICH and the moisture content was
below the limit of detection (about 2 to about 4% w/w). Fluvastatin sodium in the amorphous
form was obtained at a yield of about 75% w/w (HPLC - greater than 99% pure).
22

EXAMPLE 24
[0096] Preparation of Amorphous Fluvastatin
[0097] Fluvastatin sodium (crystalline Form B) (10 grams) was dissolved in about 10
volumes of methanol at temperature of about 30°C, filtered over a celite bed and passed
through a 5 micron cartridge filter. The solvent was completely distilled off under vacuum in
substantially the same manner as in Example 8 until a free flowing solid product was
obtained. The vacuum was broken with nitrogen, and the product was milled to get a uniform
particle size and re-dried under vacuum in substantially the same manner as in Example 8
until the product was below residual solvent limits as per ICH and the moisture content was
below the limit of detection (about 2 to about 4% w/w). Fluvastatin sodium in the amorphous
form was obtained at a yield of about 75% w/w (HPLC - greater than 99% pure).
EXAMPLE 25
[0098] Preparation of Amorphous Fluvastatin
[0099] Fluvastatin tert-buty] ester (crystalline) (10 kg) and methanol (200 L) were
charged into a reactor with stirring. An aqueous solution of sodium hydroxide pellets (0.86
kg of pellets dissolved in 21 L of purified water) was slowly run into the reaction mass by
maintaining the batch temperature between about 20 °C to about 25 °C. The contents were
reacted for about 12 hours at a temperature of about 25°C until the ester was completely
hydrolyzed as determined by HPLC. The clear solution of the reaction mass was filtered over
a celite bed prepared in methanol to remove any impurities and passed through a 5 micron
cartridge filter. The solution was passed through agitated thin film dryer under vacuum as
high as about 0.5 Torr and the solvent was evaporated rapidly. The solid formed was
scrapped by the rotor and discharged from the equipment as a dry powder. This was further
dried under vacuum in a conventional vacuum oven until the water content fell below about
2% to about 4% and the residual solvents complied with ICH limits. Fluvastatin sodium in
the amorphous form was obtained (HPLC - greater than 99% pure).
23

EXAMPLE 26
[00100] Preparation of Amorphous Fluvastatin
[00101J Fluvastatin sodium (crystalline Form A) (10 grams) was dissolved in about 10
volumes of methanol at temperature ranging of about 30°C} filtered over a celite bed and
passed through a 5 micron cartridge filter. The solution was passed through agitated thin film
dryer under vacuum as high as about 0.5 Torr and the solvent was evaporated rapidly. The
solid formed was scrapped by the rotor and discharged from the equipment as a dry powder.
This was further dried under vacuum in a conventional vacuum oven until the water content
fell below about 2% to about 4% and the residual solvents complied with ICH limits.
Fluvastatin sodium in the amorphous form was obtained (HPLC - greater than 99% pure).
EXAMPLE 27
[00102] Preparation of Amorphous Fluvastatin
[00103] Fluvastatin sodium (crystalline Form B) (10 grams) was dissolved in about 10
volumes of methanol at temperature ranging of about 30°C5 filtered over a celite bed and
passed through a 5 micron cartridge filter. The solution was passed through agitated thin film
dryer under vacuum as high as about 0.5 Torr and the solvent was evaporated rapidly. The
solid formed was scrapped by the rotor and discharged from the equipment as a dry powder.
This was further dried under vacuum in a conventional vacuum oven until the water content
fell below about 2% to about 4% and the residual solvents complied with ICH limits.
Fluvastatin sodium in the amorphous form was obtained (HPLC - greater than 99% pure).
EXAMPLE 28
[00104] Preparation of Amorphous Fluvastatin
[00105] Tetrahydrofuran (330 L) was charged into a round bottom flask at room
temperature under a nitrogen atmosphere. Next, fluvastatin tert-butyl ester (crystalline) (50
kg) was charged in the flask at 25°C to 30°C and stirred for 15 minutes. An aqueous solution
of sodium hydroxide pellets (4.494 g of pellets dissolved in 25 ml of purified water) was
added to the reaction mass by maintaining the batch temperature between 25°C to 30°C. The
24

contents were stirred for 8-10 hours at a temperature of 25°C to 30°C until the reaction was
complete as determined by HPLC. After the reaction was complete, the solvent was distilled
out under high vacuum (greater than 740 mm of Hg) at a temperature between 20°C and 40°C
until a solid was obtained. A solution of water and methanol (350 ml and 1450 ml,
respectively) was added until a clear solution was obtained. The pH of the solution was
adjusted to 9.5 by adding a 1% acetic acid solution in methanol. The solution was filtered on
a highflow bed and then distilled under vacuum to obtain a semisolid material. The semi-
solid material was striped out (i.e., 250 ml methanol added to the semi-solid and distilled out
totally, this procedure was done 5 times) under vacuum at 50°C until a free flowing solid
product was obtained. The solid product was dried in a vacuum oven at 50°C.
[00106] Yield - 40 g; HPLC - greater than 99% pure.
[00107] The PXRD pattern and IR spectrum as set forth in Figures 1 and 2 showed that
the dried sample was found to be amorphous. The sample was also found to comply with
USP forum specifications.
EXAMPLE 29
[00108] Preparation of Amorphous Fluvastatin
[00109] Fluvastatin tert-butyl ester (crystalline) (10 kg) and methanol (200 L) were
charged into a reactor with stirring. An aqueous solution of sodium hydroxide pellets (0.86
kg of pellets dissolved in 21 L of purified water) was slowly added into the reaction mixture
while maintaining the temperature between about 20°C to about 25°C. The contents were
reacted for about 12 hours at a temperature of about 25°C until the ester was completely
hydrolyzed as determined by HPLC. The clear solution of the reaction mass was filtered over
a Celite bed prepared in methanol to remove any impurities. The solution was further filtered
through a 5 micron cartridge filter and evaporated completely under vacuum better than about
720 mm Hg in a vacuum paddle dryer until a free flowing solid product was obtained. This
product was dissolved in 20-30 volumes of purified water at room temperature to about 60°C
to obtain a clear solution. The solution was filtered through a 5 micron cartridge filter. The
solution was spray dried in a in a laboratory scale spray dryer (make: Labplant SD-06) with
25

an inlet temperature of about 90QC at a rate of about 5 kg per hour of water evaporation using
filtered air. The product obtained in the collector was further dried in a vacuum oven until the

water content was below about 2 to about 4% w/w.
[00110] Yield - 8 kg; HPLC - greater than 99% pure.
[00111] The PXRD pattern showed that the dried sample was found to be amorphous.
The sample was also found to comply with USP forum specifications.
EXAMPLE 30
[00112] Preparation of Amorphous Fluvastatin
[00113] Fluvastatin sodium (crystalline Form A) (5 kg) was dissolved in about 10 to
about 20 volumes of purified water at room temperature to about 60°C to obtain a clear
solution. The solution was filtered through a 5 micron cartridge filter. The solution is spray
dried in a laboratory scale spray dryer (make: Labplant SD-06) with an inlet temperature of
about 90°C at a rate of about 5 kg per hour of water evaporation using filtered air. The
product obtained in the collector was further dried in a vacuum oven until the water content
was below about 2 to about 4% w/w.
[00114] Yield - 3.5 kg w/w; HPLC - greater than 99% pure.
[00115] The PXRD pattern showed that the dried sample was found to be a mixture of
amorphous and a crystalline.
EXAMPLE 31
[00116] Preparation of Amorphous Fluvastatin
[00117] Fluvastatin sodium (crystalline Form B) (5 kg) was dissolved in about 20 to
about 30 volumes of purified water at room temperature to about 60°C to obtain a clear
solution. The solution was filtered through a 5 micron cartridge filter. The solution is spray
dried in a in a laboratory scale spray dryer (make: Labplant SD-06) with an inlet temperature
of about 90°C at a rate of about 5 kg per hour of water evaporation using filtered air. The
product obtained in the collector was further dried in a vacuum oven until the water content
was below about 2 to about 4% w/w.
26

[00118] Yield - 3.5 kg w/w; HPLC - greater than 99% pure.
The PXRD pattern showed that the dried sample was found to be a mixture of amorphous and
a crystalline form.
EXAMPLE 32
[00119] Milling of Amorphous Fluvastatin
[00120] Amorphous fluvastatin sodium (5 kg) obtained from Example 1 was subjected
to multi milling and Jet milling [micronization] under a nitrogen atmosphere to obtain desired
particle size limits.
[00121] Yield - 4.0 kg w/w
[00122] The PXRD pattern showed that the sample was found to be amorphous with
crystalline matter below the limit of detection. The sample was also found to comply with
USP forum specifications.
[00123] It will be understood that various modifications may be made to the
embodiments disclosed herein. Therefore the above description should not be construed as
limiting, but merely as exemplifications of preferred embodiments. For example, the
functions described above and implemented as the best mode for operating the present
invention are for illustration purposes only. Other arrangements and methods may be
implemented by those skilled in the art without departing from the scope and spirit of this
invention. Moreover, those skilled in the art will envision other modifications within the
scope and spirit of the features and advantages appended hereto.
27

WE CLAIM:
1. A process for preparing fluvastatin or a pharmaceutically acceptable salt thereof in
a substantially pure amorphous form, the process comprising:
(a) providing a solvent solution comprising substantially non-amorphous fluvastatin or
a pharmaceutically acceptable salt thereof and a solvent capable of dissolving the fluvastatin;
and
(b) recovering fluvastatin or a pharmaceutically acceptable salt thereof in a
substantially pure amorphous form.
2. The process of Claim 1, wherein the solvent is selected from the group consisting
of water, a lower alcohol, cyclic ether and mixtures thereof.
3. The process of Claim 1, wherein the solvent is a lower alcohol.
4. The process of Claim 1, wherein the solvent is methanol or tetrahydrofuran.
5. The process of Claims 1-4, wherein the amount of solvent is from 5 to 30 volumes
per volume of fluvastatin.
6. The process of Claims 1-5, wherein the substantially non-amorphous fluvastatin is
fluvastatin sodium in crystalline Form A or crystalline Form B.
7. The process of Claims 1-6, wherein step (b) comprises concentrating the solution.
8. The process of Claim 7, wherein the solution is concentrated under vacuum above
720 mm Hg.
9. The process of Claims 7 and 8, wherein the solution is concentrated to 2 to 5
volumes as compared to the initial fluvastatin.
28

10. The process of Claims 7-9, further comprising the step of cooling the concentrated
solution to obtain a slurry, filtering the slurry and drying the filtered product.
11. The process of Claim 10, wherein the filtered product is dried at a temperature
below 60°C.
12. The process of Claims 1-6, wherein step (b) comprises evaporating the solvent.
13. The process of Claims 1-6, wherein step (b) comprises evaporating the solvent,
and drying the product to recover fluvastatin or a pharrnaceutically acceptable salt thereof in a
substantially pure amorphous form.

14. The process of Claims 1-13, wherein the fluvastatin or a pharmaceutically
acceptable salt thereof in an amorphous form is a racemic form or the (3S, 5R) or (3R, 5S)
enantiomer.
15. The process of Claims 1-14, wherein the fluvastatin or a pharmaceutically
acceptable salt thereof in a substantially pure amorphous form contains less than 5%
fluvastatin or a pharmaceutically acceptable salt thereof in a crystalline form and has a purity
of greater than or equal to 99%.
16. The process of Claims 1-14, wherein the fluvastatin or a pharmaceutically
acceptable salt thereof in a substantially pure amorphous form contains less than 2%
fluvastatin or a pharmaceutically acceptable salt thereof in a crystalline form and has a purity
of greater than or equal to 99%.
29

17. The process of Claims 1-14, wherein the fluvastatin or a pharmaceutically
acceptable salt thereof in a substantially pure amorphous form contains 0% fluvastatin or a
pharmaceutically acceptable salt thereof in a crystalline form and has a purity of greater than
or equal to 99%.
18. Fluvastatin or a pharmaceutically acceptable salt thereof in a substantially pure
amorphous form prepared in accordance with the process of Claims 1-17.
19. The fluvastatin of Claim 18, which contains less than 5% fluvastatin or a
pharmaceutically acceptable salt thereof in a crystalline form and has a purity of greater than
or equal to 99%.
20. The fluvastatin of Claim 18, which contains less than 2% fluvastatin or a
pharmaceutically acceptable salt thereof in a crystalline form and has a purity of greater than
or equal to 99%.

21. The fluvastatin of Claim 18, which contains 0% fluvastatin or a pharmaceutically
acceptable salt thereof in a crystalline form and has a purity of greater than or equal to 99%.
22. A process for preparing fluvastatin or a pharmaceutically acceptable salt thereof
in a substantially pure amorphous form, the process comprising:

(a) providing a solvent solution comprising a straight or branched C1-C4 alkyl ester of
substantially non-amorphous fluvastatin in a lower alcoholic solvent or cyclic ether solvent
capable of dissolving the fluvastatin;
(b) hydrolyzing the fluvastatin ester solution with an aqueous solution comprising an
alkali metal hydroxide; and
(c) recovering fluvastatin or a pharmaceutically acceptable salt thereof in a
substantially pure amorphous form.
30

23. The process of Claim 22, wherein the solvent is methanol.
24. The process of Claim 22, wherein the solvent is tetrahydrofuran.

25. The process of Claims 22-24, wherein the amount of solvent is from 5 to 30
volumes per volume of fluvastatin.
26. The process of Claims 22-25, wherein the temperature maintained in step (a) is
from 20°C to 60°C.
27. The process of Claims 22-26, further comprising filtering the solution of any
impurities prior to step (c).

28. The process of Claims 22-27, wherein step (c) comprises concentrating the
solution.
29. The process of Claim 28, wherein the solution is concentrated under vacuum
above 720 mm Hg.
30. The process of Claims 28 and 29, wherein the solution is concentrated to 2 to 5
volumes as compared to the initial fluvastatin.
31. The process of Claims 28-30, further comprising the step of cooling the
concentrated solution to obtain a slurry, filtering the slurry and drying the filtered product.
32. The process of Claim 31, wherein the filtered product is dried at a temperature
below 60°C,
33. The process of Claims 22-27, wherein step (c) comprises evaporating the solvent.
31

34. The process of Claims 22-33, wherein the fluvastatin or a pharmaceutically
acceptable salt thereof in an amorphous form is a racemic form or the (3S, 5R) or (3R, 5S)
enantiomer.
35. The process of Claims 22-34, wherein the fluvastatin or a pharmaceutically
acceptable salt thereof in a substantially pure amorphous form contains less than 5%
fluvastatin or a pharmaceutically acceptable salt thereof in a crystalline form and has a purity
of greater than or equal to 99%.
36. The process of Claims 22-34, wherein the fluvastatin or a pharmaceutically
acceptable salt thereof in a substantially pure amorphous form contains less than 2%
fluvastatin or a pharmaceutically acceptable salt thereof in a crystalline form and has a purity
of greater than or equal to 99%.
37. The process of Claims 22-34, wherein the fluvastatin or a pharmaceutically
acceptable salt thereof in a substantially pure amorphous form contains 0% fluvastatin or a
pharmaceutically acceptable salt thereof in a crystalline form and has a purity of greater than
or equal to 99%.
38. Fluvastatin or a pharmaceutically acceptable salt thereof in a substantially pure
amorphous form prepared in accordance with the process of Claims 22-37,
39. The fluvastatin of Claim 38, which contains less than 5% fluvastatin or a
pharmaceutically acceptable salt thereof in a crystalline form and has a purity of greater than
or equal to 99%.
40. The fluvastatin of Claim 38, which contains less than 2% fluvastatin or a
pharmaceutically acceptable salt thereof in a crystalline form and has a purity of greater than
or equal to 99%.
32

41. The fluvastatin of Claim 38, which contains 0% fluvastatin or a pharmaceutically
acceptable salt thereof in a crystalline form and has a purity of greater than or equal to 99%.
42. Fluvastatin or a pharmaceutically acceptable salt thereof in a substantially pure
amorphous form and containing 0% fluvastatin or a pharmaceutically acceptable salt thereof
in a crystalline form and has a purity of greater than or equal to 99%.
43. The amorphous fluvastatin of Claim 42, which is amorphous fluvastatin sodium.
44. The amorphous fluvastatin of Claims 18-21 and 38-43, having a particle size of
less than 400 microns.
45. The amorphous fluvastatin of Claims 18-21 and 38-43, having a particle size of
less than 200 microns.
46. The amorphous fluvastatin of Claims 18-21 and 38-43, having a particle size of
less than 150 microns.
47. The amorphous fluvastatin of Claims 18-21 and 38-43, having a particle size of
less than 50 microns.
48. The amorphous fluvastatin of Claims 18-21 and 38-43, having a particle size of
less than 15 microns.
v49. A pharmaceutical composition comprising a therapeutically effective amount of
the substantially pure amorphous fluvastatin of Claims 18-21 and 38-48.
50. The pharmaceutical composition of Claim 49, further comprising one or more
pharmaceutically acceptable excipients.
33

51. The pharmaceutical composition of Claims 49 and 50, which is in the form of a
tablet or capsule.
34
Dated this Twelfth (12th) day of April, 2006