CRYSTALLINE FORM OF NATEGLINIDE
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation-in-part of U.S. Patent Applications Serial No.
10/622,905, filed July 18,2003; Serial No. 10/693,166, filed October 23,2003 and
International Application No. PCT/US03/22375, filed July 18, 2003, and claims the
benefit of U.S. Patent Application Serial No. 107 , filed December 24, 2003, U.S.
Provisional Applications Serial No. 60/442,109, filed January 23,2003; Serial No.
60/449,791, filed February 24,2003 and Serial No. 60/479,016, filed June 16,2003, the
contents of all of which are incorporated herein by reference.
FIELD OF THE INVENTION
The present invention relates to the solid state chemistry of nateglinide.
BACKGROUND OF THE INVENTION
Nateglinide, known as (-)-N-(trans-4-isopropylcyclohexanecarbonyl)-DPhenylalanine,
has the following structure and characteristics:
(Figure Removed)
Formula Cj9H27NO3
Molecular Weight 317.42
Exact Mass 317.199093
Composition c 71.89% H 8.57% N 4.41% O 15.12%
Nateglinide is marketed as STARLIX, which is prescribed as oral tablets having a
dosage of 60mg and 120mg for the treatment of type II diabetes. STARLIX may be used
as monotherapy or in combination with metaformin to stimulate the pancreas to secrete
insulin. According to the maker of STARLIX, nateglinide is a white powder that is freely
soluble in methanol, ethanol, and chloroform, soluble in ether, sparingly soluble in
acetonitrile and octanol, and practically insoluble in water.
Nateglinide may be crystallized out of a mixture of water and methanol, and
further dried, as disclosed in U.S. Pat. No. 4,816,484. The procedure of the '484 patent
results in a hydrate labeled by the present Applicant(s) as Form Z, or in a methanolate
lablelled by the Applicant(s) as Form E. Drying of the wet sample results in Form B.
The present invention relates to the solid state physical properties of nateglinide.
These properties may be influenced by controlling the conditions under which nateglinide
is obtained in solid Form. Solid state physical properties include, for example, 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.
Another important solid state property of a pharmaceutical compound is its rate of
dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient's
stomach fluid may have therapeutic consequences since it imposes an upper limit on the
rate at which an orally-administered active ingredient may reach the patient's bloodstream.
The rate of dissolution is also a consideration in formulating syrups, elixirs and other
liquid medicaments. The solid state Form of a compound may also affect its behavior on
compaction and its storage stability.
These practical physical characteristics are influenced by the conformation and
orientation of molecules in the unit cell, which defines a particular polymorphic Form of a
substance. The polymorphic Form may give rise to thermal behavior different from that of
the amorphous material or another polymorphic Form. Thermal behavior is measured in
the laboratory by such techniques as capillary melting point, thermogravimetric analysis
(TGA) and differential scanning calorimetry (DSC) and may be used to distinguish some
polymorphic forms from others. A particular polymorphic Form may also give rise to
distinct spectroscopic properties that may be detectable by powder X-ray crystallography,
solid state C NMR spectrometry and infrared spectrometry.
Nateglinide exists in various crystalline forms. U.S. Pat. Nos. 5,463,116 and
5,488,150 disclose two crystal forms of nateglinide, designated B-type and H-type, and
processes for their preparation. These patents are incorporated herein by reference for
their disclosure of the forms. Both forms are characterized by melting point, X-Ray
Powder Diffraction ("XRJPD") pattern, IR spectrum in KBr and DSC thermogram.
According to these patents, B-type has a melting point of 129-130 °C while H-type has a
melting point of 136-l42°C. The H-type crystals are characterized in these patents by an
XRPD pattern with peaks at 8.1, 13.1, 19.6 and 19.9 ±0.2 degrees 29, and a strong
reflection between 15 and 17 ±0.2 degrees 20. The B-type crystal is reported to lack these
peaks and have a weak reflection between 15 and 17 ±0.2 degrees 20. H-type crystals are
reported to have an IR spectrum with characteristic absorptions at about 1714, 1649,1542
and 1214cm"1. These absorptions are reported to be missing in the spectrum of B-type
crystals.
According to U.S. Pat. No. 5,463,116, B-type crystals are unstable and susceptible
to change during grinding as demonstrated by DSC. The DSC thermogram of B-type
shows a sharp endotherm at 131.4°C before grinding while that of H-type shows a sharp
endotherm at 140.3°C. After grinding, the DSC thermogram of B-type shows a second
endotherm at 138.2°C, suggesting a solid-solid transformation during grinding.
According to U.S. Pat. No. 5,463,116, the temperature during crystallization and
filtration determines whether the crystal Form is B-type or H-type. Temperatures above
10°C, more preferably above 15°C, lead to formation of H-type, while those below 10°C
lead to formation of B-type.
Another crystalline form of nateglinide designated Type-S is disclosed in two
Chinese articles: ACTA Pharm. Sinica 2001, 36(7), 532-34 and Yaowu Fenxi Zazhi, 2001,
21(5), 342-44. Form S is reported to be distinguisheable from Forms B and H by a
melting point of 172.0°C, a Fourier Transform IR with a peak at 3283cm"1 (as supposed to
3257cm"1 and 3306cm"1 for Forms B and H respectively) and an XRPD pattern with a
strong peak at 3.78 ±0.2 degrees 29.
U.S. Pat. No. 5,463,116 ("the '116 patent") lists the methanolate, ethanolate,
isopropanolate and acetonitrilate solvates of nateglinide. According to the '116 patent,
amorphous nateglinide may be obtained by drying the hydrate and the solvates. The
hydrate may be crystallized by dissolving B-type crystals in a 1.5:1 mixture of ethanol and
water, followed by crystallization, as disclosed in Example B-3 of the '116 patent.
The present Applicants obtained a hydrate of nateglinide which the Applicants
labeled as Form Z. However, repeating of Example B-3 or comparative Example A3 of
the ' 116 patent also results in Form Z, as well as the crystallization procedure of the '484
patent. Form Z is obtained when only water is present, but Form E methanolate or
ethanolate when both methanol or ethanol and water are present.
WO 02/34713, a PCT publication in Japanese, provides in its abstract: "A process
for preparing B form nateglinide crystals containing substantially no H-form crystals,
which comprises the step of drying wet crystals of a nateglinide solvate at a low
temperature until the solvent disappears and then causing them to undergo a crystal
transition." According to the Applicant's translation of Example 1 of the WO publication:
"Nateglinide H-form crystals (24.5 kg) were added to ethanol (360 L) and stirred to
dissolution at room temperature. After dissolution was confirmed (the mixture) was
cooled to 5 °C and allowed to mature at 5 °C for one hour. The deposited crystals were
separated and damp crystals (43.0 kg) obtained. These were dried at 45 °C in a rack drier
for 24 hours (water content ca. 1%) and then heated for 12 hours at 90 °C to bring about a
crystal transformation, when dry crystals (13.3 kg) were obtained. When these crystals
were measured by DSC, the characteristic B-form peak was detected (mp ca. 130°C) but
the characteristic H-form peak (mp ca. 139°C) was not detected. Hence the crystals
obtained were of the B-form only and the H-form was concluded to be essentially absent."
According to the Applicants' translation of Page 3, Line 2 of the WO publication:
"The moist solvate crystals obtained (BS: from the cooled solution) are dried till the
solvent disappears. The temperature for this will differ depending on the type and quantity
of solvent, but usually lies below 60 °C and preferably below 50 °C. Although there is no
lower limit to the temperature, [the drying] is usually carried out at 20 °C or more for
economic reasons. Drying is favorably carried out at usual reduced pressure; at
industrially attainable reduced pressures the drying will be complete in a short time.
Though the drying at low temperature can be continued to virtual disappearance of the
solvent it is not necessary to clear it completely. Even if solvent to the extent of 5% by
weight is present this is no problem because it will disappear during the crystal
transformation. By heating the dried crystals at 60-110°C, preferably 70-100°C, a crystal
transformation into the B-form is brought about. Though the crystal transformation is
usually favorably carried out in 0.5 to 48 hours, a period of 1-24 hours is most favored."
Another PCT publication, WO 03/022251 discloses a crystalline form of
nateglinide labeled "AL-type". The crystalline form is characterized as having a melting
point of 174-178°C, an XRPD pattern with peaks at 7.5, 15.5, 19.8 and 20.2 degrees 26,
and an infra red spectrum with absorption bands in the region 1711.5, 1646.5,1538.7,
1238.8, 1215.1 and 700.5 cm"1. The crystalline form is obtained in the examples from a
solution of acetonitrile under a specific temperature range.
Processes for preparation of nateglinide are disclosed in WO/0232854.
The discovery of new polymorphic forms of a pharmaceutically useful compound
provides a new opportunity to improve the performance characteristics of a
pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist
has available for designing, for example, a pharmaceutical dosage form of a drug with a
targeted release profile or other desired characteristic. New polymorphic forms of
nateglinide have now been discovered.
SUMMARY OF THE INVENTION
The present invention provides for a novel crystalline forms of nateglinide,
denominated pure Form U. As discussed in detail below, Form U can be prepared in a
pure form and an impure form. Basically these may be distinguished by the presence or
absence of the XRPD peak at 3.8 +/-0.2 shown in Figure 17. Co-pending PCT application
PCT/03US/22375 (filed 18 July 2003), from which the present application claims priority,
describes 25 other polymorphic forms of nateglinide which are discussed herein as pure
form U may be prepared from various of the other polymorphs, and may itself be used to
preare other polymorphic forms.
In summary, Crystalline form U does not have any significant amounts of bound
solvents, and is an anhydrate. As used herein, the term "anhydrate" refers to having a
bound solvate level of less than about 2% as measured by LOD. The characterization of
this anhydrate shows that it is stable towards grinding.
Some of the crystalline forms of nateglinide have bound solvents, that is solvents
that are part of the crystalline structure (solvates). These solvates having bound solvent
include Form A (xylene), C (dimethylacetamide- "DMA"), D (ethanol- "EtOH"), E
(ethanol and methanol-"MeOH"), F (n-propanol- "n-PrOH"), G (isopropyl alcohol-
"TPA"), 1 (n-butanol- "n-BuOH"), J (N-methylpyrrolidone- "NMP"), K
(dimethylformamide- "DMF"), M (carbon tetrachloride- "CTC"), N (dichloroefhane-
"DCE"), O (methanol), Q (chloroform- "CHC13"), T (methanol), V (dimethoxyethane-
"DME"), Y (chloroform; dichloromethane), P (N-methyl pyrolidone), y (Nmethylpyrolidone)
and t: (acetone; acetonitrile- "MeCN"; nitromethane-"NM") and 0
5
(heptane). Form Z is a hydrate, having water in the crystalline structure. Form Q is a
solvate of both water and isopropyl alcohol.
Other crystalline forms do not have bound solvents, i.e., less than about 2% as
measured by loss on drying ("LOD"), and are anhydrates. These anhydrates include
crystalline Forms L, P, U, a, 8 and a.
The XRPD pattern of these forms as substantially depicted is disclosed in Figures
1 -27,63 and 65-69, with the characteristic peaks listed in Table I. The DSC thermograms
for the forms is disclosed in Figures 36 to 62, and the characteristic DSC peaks are listed
in Table II. The FTIR spectrum of the anhydrate and hydrate Forms and their
characteristic peaks are also provided. The LOD values from the TGA analysis of some of
these Forms is listed in Table III. Preparation of the various Forms by crystallization
procedure is listed in Table IV, while preparation by trituration is listed in Tables V and
VI, data on absorption of solvent vapors is listed in Table VII, data on preparation by
solvent removal is listed in Table VIII and data on crystallization from a solvent/antisolvent
system is listed in Tables DC-XL Figure 28 summarizes the thermal stability of the
various forms.
The present invention also provides for pharmaceutical compositions of the novel
crystalline form U and their use in treating diabetes.
As used herein the term "Form U" is utilised interchangeabley with "pure Form U"
both referring to the novel form lacking a XRPD peak at 3.8 +/-0.2. The form U described
in crystallization examples of the priority applications is pure form U (including the FTIR
depicted in the priority application) despite Figure 17 showing the XRPD of the impure
form.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 is an XRPD pattern for nateglinide Form A.
Figure 2 is an XRPD pattern for nateglinide Form C.
Figure 3 is an XRPD pattern for nateglinide Form D.
Figure 4 is an XRPD pattern for nateglinide Form E.
Figure 5 is an XRPD pattern for nateglinide Form F.
Figure 6 is an XRPD pattern for nateglinide Form G.
Figure 7 is an XRPD pattern for nateglinide Form I.
Figure 8 is an XRPI) pattern for nateglinide Form J.
Figure 9 is an XRPI) pattern for nateglinide Form K.
Figure 10 is an XRPD pattern for nateglinide Form L.
Figure 11 is an XRPD pattern for nateglinide Form M.
Figure 12 is an XRPD pattern for nateglinide Form N.
Figure 13 is an XRPD pattern for nateglinide Form O.
Figure 14 is an XRPD pattern for nateglinide Form P.
Figure 15 is an XRPD pattern for nateglinide Form Q.
Figure 16 is an XRPD pattern for nateglinide Form T.
Figure 17 is an XRPD pattern for nateglinide Form U in impure form.
Figure 18 is an XRPD pattern for nateglinide Form V.
Figure 19 is an XRPD pattern for nateglinide Form Y.
Figure 20 is an XRPD pattern for nateglinide Form Z.
Figure 21 is an XRPD pattern for nateglinide Form a.
Figure 22 is an XRPD pattern for nateglinide Form p.
Figure 23 is an XRPD pattern for nateglinide Form y.
Figure 24 is an XRPD pattern for nateglinide Form 5.
Figure 25 is an XRPD pattern for nateglinide Form z.
Figure 26 is an XRPD pattern of nateglinide Form a.
Figure 27 is an XRPD pattern of nateglinide Form 0.
Figure 28 is a thermal stability chart showing transformation of the forms during drying,
and is a summary of a comparison between the wet and the dry forms illustrated in various
tables in the present invention.
Figure 29 is an FTIR spectrum of nateglinide Form L.
Figure 30 is an FTIR spectrum of nateglinide Form P.
Figure 31 is an FTIR spectrum of nateglinide Form U in pure form.
Figure 32 is an FTIR spectrum of nateglinide Form Z.
Figure 33 is an FTIR spectrum of nateglinide Form a.
Figure 34 is an FTIR spectrum of nateglinide Form 8.
Figure 35 is an FTIR spectrum of nateglinide Form u.
Figure 36 is a DSC therrnogram of nateglinide Form A.
Figure 37 is a DSC thermogram of nateglinide Form D.
7
Figure 38 is a DSC thermogram of nateglinide Form E.
Figure 39 is a DSC thermogram of nateglinide Form F.
Figure 40 is a DSC thermogram of nateglinide Form G.
Figure 41 is a DSC thermogram of nateglinide Form I.
Figure 42 is a DSC thermogram of nateglinide Form J.
Figure 43 is a DSC thermogram of nateglinide Form K.
Figure 44 is a DSC thermogram of nateglinide Form L.
Figure 45 is a DSC thermogram of nateglinide Form M.
Figure 46 is a DSC thermogram of nateglinide Form N.
Figure 47 is a DSC thermogram of nateglinide Form O.
Figure 48 is a DSC thermogram of nateglinide Form P.
Figure 49 is a DSC thermogram of nateglinide Form Q.
Figure 50 is a DSC thermogram of nateglinide Form T.
Figure 51 is a DSC thermogram of nateglinide Form U in impure Form.
Figure 52 is a DSC thermogram of nateglinide Form V.
Figure 53 is a DSC thermogram of nateglinide Form Y (chloroform solvate).
Figure 54 is a DSC thermogram of nateglinide Form Y (dichloromethane solvate).
Figure 55 is a DSC thremogram of nateglinide Form Z.
Figure 56 is a DSC thermogram of nateglinide Form a.
Figure 57 is a DSC thermogram of nateglinide Form p.
Figure 58 is a DSC thermogram of nateglinide Form y.
Figure 59 is a DSC thermogram of nateglinide Form 8.
Figure 60 is a DSC thermogram of nateglinide Form e.
Figure 61 is a DSC thermogram of nateglinide Form a.
Figure 62 is a DSC thermogram of nateglinide Form 0.
Figure 63 is a XRPD pattern of nateglinide Form Q.
Figure 64 is a determination of purity of Form B prepared by Example 15.
Figure 65 is a XRPD pattern of nateglinide pure Form U prepared according to Example
17, lacking the impurity at 3.8 +/-0.2 shown in Figure 17.
Figure 66 is a XRPD pattern of nateglinide pure Form U prepared according to Example
17, lacking the impurity at 3.8 +/-0.2 shown in Figure 17.
Figure 67 is a XRPD pattern of nateglinide pure Form U prepared according to Example
17, lacking the impurity at 3.8 +/-0.2 shown in Figure 17.
Figure 68 is a XRPD pattern of nateglinide pure Form U prepared according to Example
17, lacking the impurity at 3.8 47-0.2 shown in Figure 17.
Figure 69 is an XRPD pattern of pure Form U, lacking the impurity at 3.8 +/-0.2 shown in
Figure 17, prepared according to the refined processes disclosed in the specification.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect, the present invention provides for a novel crystalline form of
nateglinide ("NTG"), denominated pure Form U. This crystalline form is characterized by
its PXRD pattern, DSC thermogram and TGA analysis, among others.
The various crystalline forms are characterized by their XRPD pattern, which
differs from one polymorph to another. Form E is rather similar by XRPD to Form Z,
although some differences may be observed. The peak at 3.7 is characteristic of Form E
and is not observed in the XRPD of Form Z. The pattern in the range of 19-22 degrees
two theta is also somewhat different between these two forms. Table I lists the most
characteristic peaks for the new crystalline forms. The XRPD patterns are illustrated in
figures 1-27 and 63.
Table (Removed)
The various crystalline forms of nateglinide are also characterized by their DSC
thermograms. Table II lists the DSC peaks (endotherms). hi addition to the peaks listed
in Table II, many of the various crystalline forms show an exotherm at about 165°C
followed by an endothenn at about 174°C, probably due to recrystallization into S-Type
Form.
Table (Removed)
The various crystalline forms are also analyzed by Thermal Gravimetric Analysis
(TGA). TGA measurements show that Forms A, D, E, F, G, I, J, K, M, N, O, Q, T, U, V,
Y, Z, p, y, e, 0 and £3 contain significant amounts of bound solvents and may be
considered as solvated forms of nateglinide. The XRPD analysis of some of these
solvated forms show that some of them are unstable when left in an open bottle for 24
hours. In contrast to the above listed forms, TGA profiles of forms L, P, U, a, 5 and or
show no significant weight loss. These polymorphic forms of nateglinide are free of
bound solvents, i.e., less than about 2% LOD. Table III lists the solvents used for the
preparation for nateglinide solvated forms, as well as LOD values based on TGA analysis.
The ethanol solvate of nateglinide disclosed herein has an ethanol content of from
about 10% to about 30%) by weight. The ethanol solvate of nateglinide ethanol solvate is
represented by formula NTG-3/2 EtOH. Specifically, the solvate is nateglinide Form D.
The methanol solvates of nateglinide disclosed herein have a methanol content of
from about 2 to about 60% by weight. Specifically, nateglinide methanol solvate exists as
nateglinide Form E, Form O and Form T methanol solvate. Nateglinide methanol solvate
is represented by the formula NTG*l/4 MeOH (Form O) or by the formula NTG*l/2
MeOH (form E). Nateglinide Form T contains more than about 20% methanol by weight.
The methanol content of Form T is from about 20% to about 60% by weight.
The isopropyl solvate of nateglinide disclosed herein has an isopropyl alcohol
content of from about 12% to about 30% by weight. Specifically, isopropyl solvate of
nateglinide exists as nateglinide Form G.
A hydrate of nateglinide, Form Z, has a water content of about 10 to about 50%,
more preferably about 10% to about 40%, and most preferably from about 15% to about
25%, measured either by the Karl Fischer method or LOD. Form Q, is a hydrate-solvate
of isopropanol and contains about 50% LOD water and isopropanol.
The heptane solvated form of nateglinide, Form 6, has about 7 to about 8% heptane
by weight, and is represented by the formula NTG» l/4Heptane.
Table (Removed
The anhydrate forms and the hydrated Form Z, are also characterized by their
FTIR spectrum. Form Z is characterized by a FTIR spectrum (Figure 31) with peaks at
about 699, 1542, 1645, 1697, 2848, 2864,2929, 3279 and 3504 cm'1. The more
characteristic peaks are observed at about 1645, 1697, 3279 and 3504 cm"1. Characteristic
FTIR peaks are for the anhydrates, specifically Forms L, U, P, a, 8 and cr are disclosed in
the following table.
nateglinide form
Form Alfa:
Form L:
FormU:
Form 8:
Form cr
Form P:
Characteristic FTIR Peaks
3283, 1711, 1646, 1420, 1238 cm"1 (Fig. 32)
1741, 1726, 1621, 1600, 1538, 1211, 1191 cm'1 (Fig. 28)
3350, , 1701, 1646, 1291 cm"1 (Fig. 30)
3306, 1729, 1704, 1275 cm"1 (Fig. 34)
3303, 1705, 1640 cm"1 (Fig. 35)
3309, 1748, 1589 cm"1 (Fig. 29)
The various crystalline forms are related to each other in that drying of one form
may result in a transformation to another form, namely nateglinide Forms A, B, D, E, F,
G, H, I, J, K, L, M, N, Q, S, T, V, Z, a, p, 8, y, E, 9 and Q. The drying is carried out by
heating a sample under ambient or reduced pressure. Generally, a preferred temperature is
from about 40 °C to about 80 °C, more preferably under reduced pressure. Of these forms,
Forms B, H, L, U and sigma are thermally stable, and do not convert to another form upon
heating. Many of the above forms convert to Form B upon drying, namely Forms A, C, D,
B, F, G, J, K, P, Q, T, Z, a, (3, 8, Q and Q. Of these forms, Form a, 8, Y and O are
somewhat stable, and usually retain their crystalline structure after heating, unless heated
to a high temperature. For example, Form 8 is stable when heated to 60°C overnight (at
least about 8 hours), but heating of Form 8 at 120°C and 1 atmosphere results in Form B.
Thus, heating at a temperature above about 80 °C may cause a transformation in these
forms. The term "stable" as used herein refers to a polymorphic change of less than about
5% by weight, more preferably less than about 2%, particularly for Form 8.
The conversion of some of the forms to Form B goes through another form. For
example, the conversion of Form Q. and E to Form B may go through Form Z.
Form G may represent a link between Forms F, T on the one hand, and Form B on
the other hand. Forms T and F, upon drying, convert to a mixture of Form B and G, which
makes is probable that Forms F and T convert to Form B by going through Form G.
Of the forms that convert to Form B, some of them sometimes under drying
convert to other forms. Form K may convert to Forms a or S, while Form C may convert
to Form B or a. Form a may convert to Form S upon heating, but the presence of seeds of
Form B in the sample of Form a results in Form B. Probably Forms C and K transform to
Form a first, and that it is through Form a that they transform to Form B or S. Form J
may convert to Form B or p, though its conversion to Form B may go through Form p.
The Form J used in preparing Form p is preferably obtained by crystallization from Nmethylpyrrolidone.
When Form J contains some seeds of Form y, heating results in Form
The acetonitrile solvate of Form Epsilon, when dried, results in Form B. While the
nitromethane solvates of Form Epsilon when dried result in Forms H or P. When Form P
is dried, Form H is obtained, which makes it probable that conversion of Form Epsilon to
Form H goes through Form P.
Another thermally stable Form of nateglinide is Form L. Form L may be obtained
by heating Forms M, N and D. To obtain Form L, these various forms are preferably
heated for about 3-10 hours at a preferred temperature range of from about 40 °C to about
80°C, more preierably about 50 °C under reduced pressure. Form y may also be prepared
by heating Form J containing seeds of Form y under similar conditions.
Another thermally stable form of nateglinide is Form H which may be prepared by
heating nateglinide Forms P, V and e;. Form S may be prepared by heating Forms a and
K, though the transition of Form K to Form S may go through Form a.
Form U is another thermally stable Form of nateglinide, and does not undergo a
transition after being heated at about 100°C for at least about 8.5 hours.
Storage at room temperature and pressure may also cause a transition of one form
to another. Form A partially converts to Form B during storage at room temperature for
about a day. Form 1 converts to Form L under the same conditions. Also under the same
conditions, Form Q converts to Form Y (containing chloroform), while Form T converts to
Form E.
Form a is related to Forms F, G, I and E in that it may be crystallized out of the
same solvent as those forms, n-propanol, isopropyl alcohol, n-butanol and acetonitrile,
respectively. Form a however is crystallized under different conditions, see e.g., Table
IV. Form a is often obtained with prolonged crystallization step (at least about 2-3 days).
Not being bound by any theory, this phenomenon may point to a possible conversion of
another crystalline form, such as those obtained from the same solvent, to Form a
overtime in the solvent.
Forms E and D are also related in that both of the forms may be crystallized out of
ethanol; but these forms crystallize under different conditions, see e.g., Table IV. The
crystallization of Form E in ethanol is prolonged, for at least about 5 days, more preferably
at least about 1 month. Not being bound by any theory, it might be possible that initially
Form D crystallizes out, followed by a conversion to Form E overtime in the solvent.
To prepare Form S, the wet sample obtained after crystallization has to be dried.
Crystallization from a solution of nateglinide in n-butanol and DMF results in a solvate,
which needs to be dried to obtain Form S. The wet samples are nateglinide Forms K, I
and alpha.
Some of the forms may first appear as a gel, and then transform into crystals
during the filtration step (e.g. form epsilon from mtromethane, and form A from xylene) or
overtime (e.g. Form M from carbon tetrachloride and Form J from N-methylpyrrolidone).
Generally, gels are unstable forms which crystallize over time.
Some of the crystalline forms may be obtained by trituration. As used herein,
trituration refers to obtaining a solid from a mixture of nateglinide in a solvent without
complete dissolution. A form of nateglinide is mixed in a particular solvent and agitated
for a sufficient time to allow for transformation to another crystalline form. After
agitation, a suspension or a paste forms. A solid may then be separated from the
suspension by techniques well known in the art, such as filtration. The paste may be
filtered, to name one technique, to remove excess solvent. The result of this trituration
procedure is various forms of nateglinide.
The trituration of Form delta in water may result in Form Z after about 5 hours,
and Form E after about 8 hours, which may also point to a transition of Form Z to Form E.
All three forms may be heated to obtain Form B.
Some of the crystalline forms may be obtained by solvent removal. First a solution
of nateglinide in a suitable solvent is prepared. The solvent may be heated to obtain a
clear solution. The solvent may be heated from about 40 °C to about 70 °C, with about
55°C being preferred. The solvent is then removed to obtain a residue, preferably at
elevated temperature within the said range. The solvent is preferably removed by
evaporation, with evaporation under reduced pressure being particularly preferred. The
resulting residue is then examined. Suitable solvents include esters, ketones, amines,
amides, alcohols and nitriles. Removal of acetonitrile, acetone, ethyl acetate and isopropyl
alcohol as solvents results in nateglinide Form B.
Some of the crystalline forms are obtained by absorption of solvent vapors.
Nateglinide is contacted with vapors of a particular solvent, resulting in absorption of the
solvent. Absorption of ethanol results in Form D, methanol in Form O, and DCM in Form
Y. Form H was stable in the presence of vapors of water and acetone.
Some of the crystalline forms may be obtained by crystallization from a suitable
solvent. Form omega is obtained by crystallization of nateglinide out of a mixture of
water and isopropanol. Preferably, the ratio of the water to isopropanol is from about 1/2
to about 1/5, more preferably 1/3 (vol/vol).
Nateglinide Form Z is generally prepared by acidification of a solution of an alkali
metal or alkaline earth metal salt of nateglinide hi an aqueous solvent. Preferred solvent is
water free of a co-solvent. Preferred salts are sodium and potassium salts, with the sodium
salt being most preferred. Before acidification, the solution preferably has a pH of above
about 8, while after acidification, the pH is preferable from about 1 to about 5, most
preferably from about 2 to about 5. Acidification results in precipitation of nateglinide,
which may be recovered by techniques well known in the art, such as filtration.
Nateglinide Forms B and U may be prepared by crystallization from an organic
solvent such as ethyl acetate or acetone. In the procedure for the preparation of form B,
crystallization is preferably induced by concentration of the solvent, while for Form U, by
seeding of the solution.
Nateglinide Forms B, H, U, Z, 6, 0 and a are related in that all of them may be
prepared from a two solvent system. The two solvent system used is a mixture of a
solvent and an anti-solvent. Example of suitable antisolvents are €5 to C^ aromatic
hydrocarbons such as toluene and xylene, and Cs to Cn saturated hydrocarbons such as
hexane and heptane. Examples of suitable solvents are Ci to Cs alcohols such as
methanol, ethanol, isopropanol, n-butanol and n-propanol, lower ketones (€3 to Ce) such
as acetone and lower esters (€3 to Ce) such as ethyl acetate. After crystallization, the
crystals are recovered by techniques well known in the art, such as filtration and
centrifugation, and may be dried. To dry, the temperature may be increased or the
pressure reduced. In one embodiment, the crystals are dried at about 40 °c to 60 °C, at a
pressure of less than about 50 mmHg.
When nateglinide is crystallized out of a binary mixture, particularly in the absence
of stirring, the crystalline product is often Form B, as illustrated in Table IX. The binary
mixture is prepared by suspending nateglinide in the anti-solvent, and then adding the
solvent to form a solution. Nateglinide Form B may be obtained at different
crystallization temperatures, such as at room temperature and at about 0°C, particularly in
the absence of stirring.
Crystallization from a binary mixture of the above solvents and anti-solvents may
lead to other forms of nateglinide other than Form B. Crystallization out of a
toluene/methanol mixture may result in nateglinide Form E, which may be converted to
Form B by heating. Additionally, a heptane/ethyl acetate combination may sometimes
lead to a mixture of Forms B and Z, especially with longer period of crystallization (over
about 3 days), while a toluene/ethyl acetate mixture may result in a mixture of Form B and
II. A mixture of Form B and Z may be converted to one containing substantially Form B
through heating, since Form Z converts to Form B through heating.
In another embodiments, rather than preparing a solution by first suspending
nateglinide in the anti-solvent, a solution is prepared in the solvent, followed by
combining with the anti-solvent. The combining is carried out in this embodiment in such
a way where upon additon a solution is formed, and any precipitated solids go back into
solution. Preferrably, the anti-solvent is heated so that upon mixing of the solution and the
anti-solvent, immediate precipitation does not take place.
The different forms may be obtained depending on the solvent/anti-solvent ratio,
crystallization conditions and the time of stirring. Generally, Form Z is crystallized from
an ethyl acetate/heptane ratio of about 2 to 4, form H a ratio of about 4 to about 7, Form B
a ratio of about 6 to about 8, Form U a ratio of about 1 to about 2, Form 0 a ratio of about
1 and Form 8 a ratio of about 1 to about 8, more preferably from about 1 to about 2
(vol/vol).
Some of the crystalline forms may be obtained by solvent removal. First a solution
of nateglinide in a suitable solvent is prepared. The solvent may be heated to obtain a
clear solution. The solvent may be heated from about 40 °C to about 70 °C, with about
55°C being preferred. The solvent is then removed to obtain a residue, preferably at
elevated temperature within the said range. The solvent is preferably removed by
evaporation, with evaporation under reduced pressure being particularly preferred. The
resulting residue is then examined. Suitable solvents include esters, ketones, amines,
amides, alcohols and nitriles. Removal of acetonitrile, acetone, ethyl acetate and isopropyl
alcohol as solvents results in nateglinide Form B.
Some of the crystalline forms are obtained by absorption of solvent vapors.
Nateglinide is contacted with vapors of a particular solvent, resulting in absorption of the
solvent. Absorption of ethanol results in Form D, methanol in Form O, and DCM in Form
Y. Form H was stable in the presence of vapors of water and acetone.
Some of the crystalline forms may be obtained by crystallization from a suitable
solvent. Form omega is obtained by crystallization of nateglinide out of a mixture of
water and isopropanol. Preferably, the ratio of the water to isopropanol is from about 1/2
to about 1/5, more preferably 1/3 (vol/vol).
Nateglinide Form Z is generally prepared by acidification of a solution of an alkali
metal or alkaline earth metal salt of nateglinide in an aqueous solvent. Preferred solvent is
water free of a co-solvent. Preferred salts are sodium and potassium salts, with the sodium
salt being most preferred. Before acidification, the solution preferably has a pH of above
about 8, while after acidification, the pH is preferable from about 1 to about 5, most
preferably from about 2 to about 5. Acidification results in precipitation of nateglinide,
which may be recovered by techniques well known in the art, such as filtration.
Nateglinide Forms B and U may be prepared by crystallization from an organic
solvent such as ethyl acetate or acetone. In the procedure for the preparation of form B,
crystallization is preferably induced by concentration of the solvent, while for Form U, by
seeding of the solution.
Nateglinide Forms B, H, U, Z, 8, 0 and o are related in that all of them may be
prepared from a two solvent system. The two solvent system used is a mixture of a
solvent and an anti-solvent. Example of suitable antisolvents are Cj to Cu aromatic
hydrocarbons such as toluene and xylene, and Cs to Cia saturated hydrocarbons such as
hexane and heptane. Examples of suitable solvents are Q to €5 alcohols such as
Table X does not show a transition of Form B to other forms despite prolonged
stirring in the anti-solvent/solvent system due to use of a high ratio of ethyl acetate.
Preferably about a 1:1 ratio of solvent to anti-solvent is used for obtaining other forms
through stirring of Form B in a solvent/antisolvent mixture.
The results of the processes may vary when precipitating a solid after combining
the solution and the anti-solvent. In this embodiment, the solution is combined with the
anti-solvent in such a way to result in precipitation, in contrast with the other embodiments
that result in a solution after the combining step. To cause substantial precipitation,
preferably, the solution is combined with a cold anti-solvent. More preferably, the
antisolvent is from about 20 °C td about 40 °C colder than the solution, particularly when
an ethyl acetate/heptane system is used. Most preferably, the heptane has a temperature of
from about 0 UC to about 10 °C and the ethyl acetate a temperature of from about 30 °C to
about 40 °C.
hi this embodiment, Form U may be obtained within a wide range of solvent/antisolvent
ratios and crystallization temperatures. For example, table XI shows that Form U
may be obtained from a solvent to anti-solvent ratio of from about 1 to about 6, and final
crystallization temperatures from about 0 °C to about 30 °C. Not being bound by any
theory, the presence of other forms, particularly Form 6 and o, especially after long
crystallization step, points to possible a transition of Form U to these forms. The presence
of a mixture of Form B and U after 1 hour also points to the possibility that Form B might
be immediately crystallized out of the solution, followed by a transition to Form U, which
itself may change overtime to Forms 5 or o.
The following table provides guidance on obtaining Forms B, H, U, Z, 6, 6 and o
from a solvent: anti-solvent system:
V/V ratio
(EA/Heptane)
(about)
1:1
1:1
1:1
Filtration temp.
(about)
15°C ~30°C
preferably 20-25 °C
15 "C 30° C
preferably 20-25 °C
15°C-300C
preferably 20-25 °C
No stirring
With stirring
Precipitation
without going
Immediately after crystallization
Stirring for at least about 21h
Immediately after crystallization
Crystal
form
obtained
B
B
a
B
20
Of these, some forms may crystallize as other forms, and convert after being stirred
for a sufficient time in the solvents. Stirring the resulting slurry from crystallization at a
temperature of from about -15°C to about 10°C, preferably about 5 °C, may result in Form
8. Form 8 seems to result from stirring of forms such as Form U, Form 9, Form H and
even Form B. Preferably the stirring to obtain Form 8 is carried out for at least about 2-3
hours, more preferably for at least about 10 hours.
Other than a solventantisolvent ratio of about 1, formation of Form 0 seems to be
favored at lower crystallization and filtering temperatures, from about -15°C to about 10°C
preferably 5°C. As previously noted, stirring of Form 0, preferably at the specified
temperature range, results in Form 8.
Form U may be obtained by stirring with Form B or H in an organic solvent.
Stirring for about 1 hour is sufficient to obtain Form U. However, additional stirring, such
as above about 5 hours, may result in a transition to Form 8. Form U may also be obtained
by crystallization, preferably at the specified ratio, more preferably at a crystallization and
filtering temperature of about -15°C to about 10° C. Form U is generally favored when
starting with a temperature of from about 25°C to about 35°C, followed by cooling in less
than about 1 hour to a temperature of from about 0°C to about 10°C, with about 5°C being
preferred, followed by filtering in less than about 1 hour. Higher solvent to anti-solvent
ratio may favor form U over 0.
Form H may be obtained under both low and high crystallization temperatures,
preferably under the specified solvent/anti-solvent ratio. Form B, on the other hand, tends
to crystallize at a temperature of at least about 15°C.
Forms Z generally crystallizes after about a day at a final crystallization
temperature of at least about 15 °C, more preferably from about 15 °C to about 30 °C, and
most preferably from about 20 °C to about 25 °C. The initial crystallization temperature
for these forms is preferably above 35 °C, followed by cooling in a few hours, more
preferably about 1 hour, to about 20 °C to about 25 °C. These conditions may lead to Form
Z, which converts to Form B by drying.
Form or may also be obtained by stirring of crystals of Form B. Not being bound
by any theory, it may be possible that Form a is obtained through Form U, that is stirring
results in a transition of Form B to Form U followed to Form or. Prolonged crystallization
and filtration is preferred for obtaining Form a, i.e., preferably at least about 10 hours.
19
1:1
1.5:1
2:1 - 8:1
2:1 - 8:1
2:1 - 8:1
-15°C 10°C
preferably 5°C
-15°C 10° C
preferably 5°C
-15°C ]0°C
preferably 5°C
15°C 30°C
preferably 20-25 °C
15 °C 30 °C
preferably 20-25 °C
into solution
after combining
Wet crude
material
Dry crude
material
Stirring for at least about Ih
Immediately after crystallization
Stirring at about 5°C
Immediately after crystallization
Stirring at about 5°C
Immediately after crystallization
Stirring for about l-5h
Stirring for at least about 5h
U
Drying
6 ~> B
5
U
8
H (95%
yield)
U
8
Drying
Z -> B
H
In a refinement of the above processes for preparing Form U, nateglinide Form U may be
prepared by dissolving nateglinide (any form, crystalline or amorphous) in a relatively
small amount of ethyl acetate, in the ratio of about 3 to about 11 mL/g, more preferably
about 4 to about 6 mL/g ratio. A clear solution is obtained by heating the mixture to a
preferred temperature of about 25 °C to about 47°C. It is possible to use a larger quantity
of solvent to dissolve nateglinide without heating, however the range of about 3 to about
11 mL/g is preferred since inducing crystallization is simply done by seeding and
optionally cooling, while large volumes may involve more complicated ways of inducing
crystallization. The solution is preferably filtered to remove insoluble matter. The
solution is seeded with nateglinide crystals, preferably Form U crystals (in order to ensure
that the final material is consistently crystallized in form U), preferably at a temperature of
about 13 to about 35°C, more preferably a temperature of about 25°C to about 35°C.
Cooling to about --10°C to about +10°C may be used to increase the yield. Cooling may
be done beofre or after seeding. The crystals are isolated by conventional methods such as
filtration. The crystals obtained (form U) may be dried using conventional techniques,
such as vacuum drying (stirred or static). Nateglinide crystals obtained from this process
are chemically pure (More than 99% pure as area percentage HPLC). Table U-I
summarizes the main parameters ranges used for the preparation of nateglinide Form U in
ethyl acetate, and table U-II gives details of the parameters of the different experiments.
Table (Removed)
In another refinement of the above process for preparation of Form U, nateglinide (any
form, crystalline or amorphous) is dissolved in ethyl acetate (about 4 volumes). The
solution is heated, for instance to about 30°C to about 50°C, more preferably about 45 to
about 50°C, and a clear solution is obtained. The solution is preferably filtered to remove
insoluble matter. A €5 to C^ saturated hydrocarbon, such as heptane (about 5 to about 10
volumes), is added to the solution, while keeping the solution clear, for instance by
controlling the temperature or by controlling the addition rate. In this embodiment, the
solution is preferably in a container (e.g. reactor, flask), and the heptane is added to the
container. The solution is then cooled to about 25 to about 44 °C and seeded in this
temperature range with nateglinide crystals, while stirring. Cooling may be done before or
after seeding. It is recommended to seed with form U in order to ensure that the final
material is consistently crystallized as Form U. The mixture may be cooled to about 5 °C
lo about 10°C to increase the yield, and then the crystals are recovered. The crystals
obtained (Form U) may be dried using conventional techniques, such as vacuum drying
(stirred or static).
Addition of a small quantity of water (about 2 to about 10% mL/g based on solid NTG)
helps to improve the chemical quality (NMT about 0.15% of any impurity, preferably
NMT about 0.1% of any impurity). Nateglinide Form U from this process may be made
by dissolving nateglinide (any form, crystalline or amorphous) in ethyl acetate (4 volumes)
containing about 2 to about 10% water (based on solid nateglinide), preferably about 4 to
about 5%. The solution is heated, for instance to about 30 °C about 50°C, more preferably
about 45 °C to about 50 °C, and a clear solution is obtained. The solution is preferably
filtered to remove insoluble matter. Heptane (about 5 to about 10 volumes) is added,
keeping the solution clear, for instance by controlling the temperature or controlling the
addition rate. The solution is then preferably cooled to a temperature of about 25 °C to
about 44°C, and seeded at this temperature range with nateglinide crystals, while stirring.
Cooling may be done before or after seeding. It is recommended to seed with Form U in
order to ensure that the final material is consistently crystallized in Form U. The mixture
may be cooled to about 5 to about 10°C to increase the yield, and then the crystals are
isolated. The crystals obtained (Form U) may be dried using conventional techniques. By
using this process nateglinide crystals obtained are chemically pure (NMT about 0.15% of
any impurity, more preferably NMT about 0.1% of any impurity).
Table U-I1I summarizes the main parameters ranges used for the preparation of nateglinide
Form U using ethyl acetate and heptane (and water if chemical purification is needed).
(Table Removed)
The following table summarizes the yarious experiments used for the preparation of
nateglinide Form U by using ethyl acetate (EA) water and heptane as described above.
(Table Removed)

From all the crystallization procedures in tables U-I through U-IV, nateglinide Form U is
obtained with a purity of at least 99.5% (wt/wt) with respect to other polymorphic forms,
e.g.. Form H. The polymorphic purity of Form H, for example, can be monitored by XRay
powder diffraction, by monitoring the typical peak of Form H at about 5.4 deg 2-
theta.
Moreover form U is polymorphically stable (NMT 0.5 conversion to other
poylmorphic forms, for example Form H), even in the presence of considerable relative
humidity (75%), in particular under the conditions dictated by the ICH international
standard (Ql A, "Stability testing of new drug substances and new products, 1st edition oct
27,1997 and 2nd edition nov.8 2000), recognized for the evaluation of the stability of
pharmaceutical substances. Form U is polymorphically stable when stored for a period of
at least about 6 months at about 40°C/75% RH, or about 25°C/60% RH. In addition, Form
U is polymorphically stable at least 6 months when stored at a temperature of about 55°C.
Nateglinide Form U is characterized by peaks at 4.7, 7.4,13.8 and 17.0+/-0.2 theta
are disclosed in Table 1. The additional peak at 3.8 +/-0.2 disclosed in Figure 17 in an
impurity, and thus Figure 17 is a mixture of Form U with another crystalline Form.
Example 17 and refined processes for preparation of Form U do not produce the impurity
at 3.8 +/-0.2. Form U without such impurity is shown in Figures 65 through 69 and Figure
31. It should be noted that non-crystallization methods produce the impurity at 3.8 +/-0.2
for Form U.
Depending on the preparation procedure, nateglinide Form 8 may contain from
about 0.5% to about 3% of residual heptane by weight. The removal of heptane without
changing the crystal form may be carried out in a fluidized bed drier, preferably at a
temperature of from about 60 to about 70°C, more preferably for at least about 3 hours.
The residual Heptane may be also removed under stirring, preferably at a temperature of at
least about 40 °C under vacuum. The 5 Form is preferably polymorphically pure and
contains less than about 5% Form H (wt/wt), more preferably less than about 2% (wt/wt),
and most preferably less than about 0.5% (wt/wt).
Crystalline Form 8 is stable at a temperature of about 40 °C and a relative humidity
of about 75% for at least about 3 months.
Trituration of Form 8 in ethyl acetate may result in other polymorphic forms of
nateglinide. Triturating nateglinide Form 8 at a temperature of frpm about 20 to about
30°C in ethyl acetate results in Form U, while triturating at higher temperatures (above
40°C), such as at about 50°C, results in Form B.
The processes of the present invention allow for obtaining Forms 8 and B with a
purity of at least about 95%, more preferably at least about 98% wt/wt compared to other
polymorphic forms. These forms may be produced particularly free of the H Form.
The starting material used for the processes of the present invention may be any
crystalline or amorphous form of nateglinide, including various solvates and hydrates.
With crystallization processes, the crystalline form of the starting material does not usually
affect the final result With trituration, the final product may very depending on the
starting material. One of skill in the art would appreciate the manipulation of the starting
material within skill in the art to obtain a desirable form with trituration.
The processes of the present invention may also be practiced as the last step of
prior art processes that synthesize nateglinide.
Many processes of the present invention involve crystallization out of a particular
solvent, i.e., obtaining a solid material from a solution. One skilled in the art would
appreciate that the conditions concerning crystallization may be modified without
affecting the form of the polymorph obtained. For example, when mixing nateglinide in a
solvent to form a solution, warming of the mixture may be necessary to completely
dissolve the starting material. If warming does not clarify the mixture, the mixture may be
diluted or filtered. To filter, the hot mixture may be passed through paper, glass fiber or
other membrane material, or a clarifying agent such as celite. Depending upon the
equipment used and the concentration and temperature of the solution, the filtration
apparatus may need to be preheated to avoid premature crystallization.
The conditions may also be changed to induce precipitation. A preferred way of
inducing precipitation is to reduce the solubility of the solvent. The solubility of the
solvent may be reduced, for example, by cooling the solvent.
In one embodiment, an anti-solvent is added to a solution to decrease its solubility
for a particular compound, thus resulting in precipitation. Another way of accelerating
crystallization is by seeding with a crystal of the product or scratching the inner surface of
the crystallization vessel with a glass rod. Other times, crystallization may occur
spontaneously without any inducement. The present invention encompasses both
embodiments where crystallization of a particular form of nateglinide occurs
spontaneously or is induced/accelerated, unless if such inducement is critical for obtaining
a particular form.
Nateglinide of defined particle size may be produced by known methods of particle
size reduction starting with crystals, powder aggregates and course powder of the new
crystalline forms of nateglinide. The principal operations of conventional size reduction
are milling of a feedstock material and sorting of the milled material by size.
A fluid energy mill, or micronizer, is an especially preferred type of mill for its
ability to produce particles of small size in a narrow size distribution. As those skilled in
the art are aware, micronizers use the kinetic energy of collision between particles
suspended in a rapidly moving fluid stream to cleave the particles. An air jet mill is a
preferred fluid energy mill. The suspended particles are injected under pressure into a
recirculating particle stream. Smaller particles are carried aloft inside the mill and swept
into a vent connected to a particle size classifier such as a cyclone. The feedstock should
first be milled to about 150 to 850 um which may be done using a conventional ball,
roller, or hammer mill. One of skill in the art would appreciate that some crystalline forms
may undergo a transition to another form during particle size reduction.
Pharmaceutical compositions may be prepared as medicaments to be administered
orally, parenterally, rectally, transdermally, bucally, or nasally. Suitable forms for oral
administration include tablets, compressed or coated pills, dragees, sachets, hard or gelatin
capsules, sub-lingual tablets, syrups and suspensions. Suitable forms of parenteral
administration include an aqueous or non-aqueous solution or emulsion, while for rectal
administration suitable forms for administration include suppositories with hydrophilic or
hydrophobic vehicle. For topical administration the invention provides suitable
transdermal delivery systems known in the art, and for nasal delivery there are provided
suitable aerosol delivery systems known in the art.
Pharmaceutical formulationss of the present invention contain nateglinide Form U.
The pharmaceutical composition may contain only a single form of nateglinide, or a
mixture of various forms of nateglinide, with or without amorphous form. In addition to
the active ingredient(s), the pharmaceutical compositions of the present invention may
contain one or more excipients or adjuvants. 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.
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, such as
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.
Disintegrates 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, microcrystalline cellulose, polacrilin
potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch
glycolatc (e.g. Explotab®) and starch.
Glidants can be added to improve the flowability of a non-compacted solid
composition and to improve the accuracy of dosing. Excipients that may function as
glidants include colloidal silicon dixoide, magnesium trisilicate, powdered cellulose,
starch, talc and tribasic calcium phosphate.
When a dosage form such as a tablet is made by the compaction of a powdered
composition, the composition is subjected to pressure from a punch and dye. Some
excipients and active ingredients have a tendency to adhere to the surfaces of the punch
and dye, 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 the release of the
product from the dye. 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 iumarate, stearic acid, talc and zinc stearate.
Flavonng 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, nateglinide 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.
According to the present invention, a liquid composition 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 used 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 dosages include dosages suitable for oral,
buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous),
inhalant and ophthalmic administration. Although the most suitable administration 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.
Dosage forms include solid dosage forms like tablets, powders, capsules,
suppositories, sachets, troches and losenges, as well as liquid syrups, suspensions and
elixirs.
The dosage form of the present invention may be 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.
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 filling 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 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 a lubricant.
A tableting composition may be prepared conventionally by dry blending. For
example, the blended composition of the actives and excipients maybe compacted into a
slug or a sheet and then comminuted into compacted granules. The compacted granules
may subsequently be compressed into a tablet.
As an alternative to dry granulation, a blended composition may be 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 for direct compression tableting include microcrystalline cellulose,
spray dried lactose, 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 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, however, they are
not subjected to a final tableting step.
The dosage and formulation of STAJRJLIX may be used as a guidance. The dosage
used is preferably from about 30 to about 240 ing of nateglinide, more preferably from
about 60 to about 120 mg of nateglinide. The pharmaceutical compositions of the present
invention, preferably in the form of a coated tablet, are administered from about 10
minutes to about 1 hours prior to a meal, more preferably about 15 minutes before each
meal. The dose is not taken if the meal is skipped. The pharmaceutical compositions may
also be used in combination with metaformin.
Instruments
X-Ray Powder Diffraction:
X-Ray diffraction was performed on X-Ray powder diffractometer, Scintag®, variable
goniometer, Cu-tube, solid state detector. Sample holder: A round standard aluminum
sample holder with round zero background quartz plate.
The sample was put on the sample holder and immediately analyzed as is.
Scanning parameters: Range: 2-40 deg 20, Continues Scan, Rate: 3deg./min.
DSC:
DSC82T Mettler Toledo®, Sample weight: 3-5mg, Heating rate: 10°C/min, Number of
holes in the crucible: 3
TGA:
Mettler TG50*, Sample weight: 7-15mg, Heating rate: 10°C/min
FTIR:
Perkin -Elmer"", Spectrum One FTIR spectrometer, Range: 4000-400cm-l, no. of scans:
16, resolution: 4.0cm-l, DRIFT technique.
EXAMPLES
Examples 1-7, 11,12,14-16 and 18-19 relate to the preparation of forms other than
form U, but may be used to preapre a form that is used as a precursor to form U as
describe above or in examples 8-10, 13 and 17
Example 1 - This example illustrates preparation of various forms of nateglinide from a
solution
Nateglinide (5 g) was placed into an erlenmeyer flask and heated to the specified
temperature. The solvent was added in 1 -ml portions (in some cases, the solvent was
added in 5-ml portions) until a clear solution was obtained. If a clear solution was not
obtained after addition of 150 ml of the solvent, the hot mixture was filtered.
The clear solution was left to crystallize at room temperature. If crystallization did
not happen or was poor, the solution was refrigerated at 3°C. The precipitate was filtered
off (at RT or at 5°C depending on the temperature of the crystallization), weighed and
31
divided into 2 equal parts. One part was dried at 50°C under reduced pressure (20-30
mmHg) to constant weight (±0.01 g) for about 3-10 hours. Details are presented in Table
IV.
(Table Removed)
Legend. L/S liquid/solid ratio: * - the solvent was added in 5-ml portions; T - starting
temperature; Ww - weight of wet sample after filtration, Wd - weight of the sample after
drying at 80-90°C/20 mbar.
Solvent abbreviations: MeOH- methanol, EtOH - ethanol, n-PrOH - n-propanol, IP A- 2-
propanol, n-BuOH- n-butanol, EA - ethyl acetate, NM - nitromethane, DMF - N,Ndimethylformamide,
DMA - N,N-dimethylacetamide, NMP - N-methylpyrrolidone,
MeCN - acetonitrile. Ether - diethyl ether, DME - dimethoxyethane, DCM -
dichloromethane, DCE - 1,2-dichloroethane and CTC -carbon tetrachloride.
Example 2- This example illustrates trituration of nateglinide Form H and U in various
solvents
Nateglinide (5 g) was placed into an Erlenmeyer flask. Solvent was added in 1-ml
portions to prepare a stirrable mixture. The flask was stirred with a magnetic stirrer at
room temperature. A solid was filtered off at room temperature, weighted, and divided
into 2 equal parts. One part was dried at 55°C under 20-30 mm/Hg pressure to constant
weight (±0.01 g).
Details are presented in Tables V and VI.
(Table Removed)
Example 3- This Example illustrates Absorption of solvent vapors by nateglinide.
Nateglinide (3.50 g) was added to a polypropylene can and weighed. The can was
introduced into a bigger polypropylene container containing a solvent, and stored at room
temperature. The can was removed from the container and weighed (Wfrnal). The can
content was divided into 2 portions. One portion was dried at a temperature of 55°C and a
pressure of 20-30 mmHg to constant weight (±0.01 g). Details are presented in Table VII.
(Table Removed)
Legend. Brutto - starting weight of the can with NTG; Wfinal - final weight of the can
with NTG after the exposure; A - overweight
Example 4- This example illustrates preparation of various forms of nateglinide by
solvent removal.
Nateglinide (5g) was dissolved in the following solvents at about 55 C in over
about 15 minutes until a clear solution was obtained. The solvent was removed to dryness
by evaporation at about 55 C/20-30 mmHg to give dry nateglinide.
(Table Removed)
Example 5- This example illustrates preparation of Form Z.
D-Phenylalanine (PheOH, 7.73 g) was treated with 3.5% NaOH (185 ml, 3.5
equivalents), at room temperature to afford a clear solution of the corresponding Na-salt.
A solution of neat trans-4-isopropylcyclohexanecarboxyl chloride (IPCHAC, 9.02 g, 1.01
equivalent) was added to the solution of Phe-OH obtained above, over 3 minutes, while
stirring at room temperature. The rest of the IPCHAC in the runnel was washed with
toluene (1 ml) and added. The resulting mixture was stirred for 1 hour, and was treated
with 10% HC1 (32 ml) to adjust the pH to 3, while stirring. The mixture was stirred for 1
hour, and filtered. The solid was washed with water (200 ml) and sucked well to afford
33.3 g of the moist product, which lost weight after drying at 78°C/2.2 mbar. Assay
98.4%, purity >99%, yield 86%.
Example 6- This example illustrates preparation of nateglinide by crystallization from
binary mixtures (solvent/anti-solvent),
Nateglinide (5g) and an anti-solvent (20 ml) were placed into an Erlenmayer flask.
The mixture was heated at about 55°C over about 15 minutes, followed by addition of
solvent in 0.25-1 ml portions until a clear solution was obtained. The clear solution was
left to crystallize without stirring at room temperature.
36
If crystallization did not happen or was poor after 24 hours, the solution was
refrigerated at 3-5°C. The precipitate was filtered off (at RT or at 5°C depending on the
temperature of crystallization) to give Form B. The wet material was dried at 50°C under
reduced pressure (20-30 mmHg) to give dry Form B.
(Table Removed)
L/S- liquid/solid ratio (liquid= solvent+anti-solvent); / - symbol RT->3 means that
crystallization was started at room temperature then the mixture was cooled to 3°C to
complete precipitation.
Example 7- Preparation of Form delta
37
(A) Tliis example illustrates preparation of nateglinide Form delta by crystallization
from an ethyl acetate-heptane solvents system:
Preparation of nateglinide form 5
D-Phenylalanine (15.44 g) was added all at once to a 3.5% NaOH solution (370 ml, 3.5
equivalents), at 20°C, under stirring, 230 min"1. A clear solution was immediately formed.
A neat trans-4-isopropylcYclohexylcarboxychloride (18.03 g) was added for 5 minutes to
the reaction solution. A solid was formed and the temperature rose to 32°C. The mixture
was stirred for 1 hour at 20°C, under stirring. A 15% HaSC^ (56.1 g) was added all at
once to the reaction mixture to adjust the pH to 1-2. The mixture was stirred for 1 h at
20°C and the solid product was filtered off to afford cake- 76 g of a wet product (moisture
65%). The product was dissolved in EA (200 ml), and the aqueous phase was removed.
The organic phase was concentrated at 50°C under reduced pressure to afford 104 g of a
turbid solution, containing 95 ml of EA. The solution was filtered and added for 30
minutes to hot heptane (54°C, 250 ml). The initially formed solid completely dissolved
after addition of 2/3 of the EA solution. The clear solution was allowed to cool to 25°,
seeded with B-form, and left for crystallization overnight, under stirring at 215 revolutions
min"1. The solid was filtered off and washed with heptane (30 ml). The cake was dried at
60°C/20 mbar to afford 6.84 g of the 8-form. Yield 33%.
Preparation of nateglinide Form S
D-Phenylalanine (20.00 g) was added all at once to a 3.5% NaOH solution (370.12 g, 2.7
equivalents), heated to 35°C, under stirring, 200 min'1. A clear solution was immediately
formed. A neat trans-4-isopropylcyclohexylcarboxychloride (23.3 g) was added all at
once to the hot reaction mixture for 1 minute. A turbid solution was formed and the
temperature rose to 40°C. The mixture was stirred for 20 minutes at 40-43°C under
stirring. An 85% solution of H2SO4 (11.94 g) was added all at once to the RM to adjust
pH 1-2. The solid product was extracted with EA (140 ml). The hot organic extract was
washed with warm water (100 ml), followed by brine (25 ml, 30.0 g) at 40°C, and dried
with anhydrous magnesium sulfate (3.05 g) over 1.5 hours. The organic solution was
filtered through a PTFE 0.45 jam filter, heated to 38°C and to which was added hot
heptane (40°C, 125 ml). The resulting clear solution was gradually cooled for 45 minutes
to 13°C and seeded with NTG in B-form. The crystallization started. The mixture was
then cooled for 17 min to 5°C and stirred for 16 h. The solid was filtered off and washed
with a cold (5°C) mixture of heptane-EA mixture (5:1, total 180 ml) to afford 36.49 g of a
wet product (wetness 42.5%). The wet product was dried at 60°C/13 mbar to afford 20.38
g of the product, Form 8, with a purity >99.8%. Yield 55%.
Preparation of nateglinide form 5
D-Phenylalanine (20.02 g) was added all at once to a 3.5% NaOH solution (total 410.5 g,
2.99 equivalents), heated to 39°C, under stirring 150 min" . A clear solution was
immediately formed. A neat trans-4-isopropylcyclohexylcarboxychloride (24.73 g) was
added all at once to the hot reaction mixture. The mixture (clear solution) was stirred for
25 minutes at 44-45°C, under stirring. Ethyl acetate (140 ml), followed by an 85%
solution of HiSQi (14.08 g) were added all at once to the reaction mixture to adjust the pH
to 1-2. The hot organic layer was separated, washed twice with water (100 ml) at 30°C,
and filtered through a PTFE 0.45 urn filter. The clear solution (141 g) was heated to 46°C
and to which was added hot heptane (46°C, 153 ml), under stirring at 150 min"1. The
clear solution was gradually cooled to 28°C and seeded with Form delta. The
crystallization occurred at 24°C. The mixture was stirred for 30 minutes at 24°C,
gradually cooled to 5°C and stirred overnight at 5°C. The solid was filtered off and
washed with a cold (5°C) heptane-EA mixture (6:1, total 30 ml) to afford 49.1 g of a wet
product in form delta (wetness 50%). The wet product was dried for 24 h at 23°C/20 mbar
to afford 24.65 g of the product in a form delta with a purity >99.8%. Yield 65%.
(B) This example illustrates the preparation of form 5 crystallization
Crude nateglinide (50 grams) was dissolved in ethyl acetate (200 ml) and water (2.5 ml) at
45°C. Hot heptane (260 ml) at 50°C was added. The mixture was still fully dissolved.
The mixture was cooled to 30°C and seeded with nateglinide Form 8 (0.1 grams). The
mixture was stirred for 30 minutes and then cooled to less than 10°C in 2 hours. The
mixture was stirred at 5-10°C overnight and then filtered with vacuum. The wet product
was washed with ethyl acetate (100 ml) heptane mixture (ratio 1:3 v/v). The wet product
was dried in a vacuum oven at 50°C overnight. Both the wet and dry samples were Form
Starting material: Wet nateglinide (40% total wetness. 2 ml water, 10 ml ethyl acetate,
ml of heptane). Wet crude nateglinide (83 grams) and dry nateglinide (50 grams) were
dissolved in ethyl acetate (190 ml) at 45 °C. Hot heptane (239 ml) at 50°C was added.
The solution was cooled to 30°C and a seeded with nateglinide (0.1 grams) Form 8.
mixture was stirred for 30 minutes and men cooled to less than 10°C in 2 hours. The
mixture was stirred at 5-10°C overnight and then filtered with vacuum. The wet product
was washed with ethyl acetate-heptane mixture (100 ml) (ratio 1:3 v/v). The wet product
was dried in a vacuum oven at 50°C overnight. Both the wet and dry samples were Form
8.
(C) This example illustrates the drying of form 5 by fluidized bed dryer
Nateglinide Form delta (10 grams), with about 3 % heptane (wt/wt), was dried in a
fluidized bed drier for 4 hours at 60°C. Residual heptane was 1578 ppm af. Ethyl acetate
is under detection limit. Polymorphic form of the dry product is delta.
According to these procedures, a series of experiments were carried out under
various heptane/ethyl ratios, liquid/solid ratios, temperature and seeding. The results are
summarized in Table X:
(Table Removed)
Temperature profile: crystallization temperature (h)-^ final temperature (h); L,tamount
of L,trans-isomer.
Example 8 This example illustrates preparation of forms of nateglinide by precipitation
without going to solution after combining
Preparation of Nateglinide form U
D-Phenylalanine (20.02 g) was added all at once to a 3.5% NaOH solution (369.73 g, 2.7
equivalents), at 20°C, under stirring, 200 revolutions min"'. A clear solution was
immediately formed. A neat trans-4-isopropylcyclohexylcarboxychloride (23.9 g) was
added all at once to the hot reaction solution for 1 minute. A solid was formed and the
temperature rose to 32°C. The mixture was stirred for 40 minutes at 20°C, under stirring.
An 85% solution of H2SO4 (11.55 g) was added all at once to the reaction mixture to
adjust the pH to 1-2. The solid product was extracted with EA (150 ml) at 55°C for 55
minutes. The hot organic extract was washed with warm water (100 ml), followed by
brine (40°C, 50 ml), dried with anhydrous sodium sulfate (10 g) over 1.5 h, and filtered.
The excess of EA was removed under reduced pressure to afford 86 g of the solution,
containing -54 g (60 ml) of EA. The EA solution was finally filtered through a PTFE
0.45 jam filter into a clean dropping funnel heated to 35°C. Heptane (320 ml) was placed
into the reactor, cooled to 5°C, and seeded with B-form. The clear hot EA-solution was
added for 5 minutes to the cold heptane, under stirring. Precipitation immediately
happened to afford a solid. The mixture was stirred for 2.5 hours at 5°C. The solid was
filtered off and washed with a cold (5°C) mixture of heptane-EA mixture (4.5:1, total
-120 ml) to afford 63.62 g of a wet product (wetness 54%). The cake (62.4 g) was dried
at 60°C/10 mbar to afford 28.6 g of the product, containing -0.6% of L,trans-isomer (other
impurities <0.1%) in the U-form. Yield 77%.
(Table Removed)
TEA - temperature of the EA solution; TAs(time) - temperature of anti-solvent (exposure
time)-^ final temperature (exposure time); L,t - amount of L,trans-isomer.
Example 9- Heating of nateglinide Form U
Sample of nateglinide form U (~1 g) was introduced into a 6-gram vial and heated over
8.5 h in a 100°C oil bath. The vial were extracted from the bath. The resulted sample
showed Form U by XRPD.
Sample of nateglinide form U (-0.5 g) was heated to 120°C for Ih in an atmospheric
pressure. The resulted sample showed Form U by XRPD.
Example 10- heating of nateglinide Form 5
Sample of nateglinide form 8 (-0.5 g) was heated to 120°C for Ih in an atmospheric
pressure. The resulted sample showed Form B by XRPD.
Example 11 ^Preparation of Form Omega
Nateglinide Form delta (5 grams) was dissolved in isopropanol (15 ml) at room
temperature. The solution was cooled to ~ 0°C. Water (6 ml) was added. A white solid
precipitated suddenly The solid was heated to 35°C, resulting in complete dissolution.
42
The solution was cooled to ~7°C and the product precipitated. The product was filtered
with vacuum. XRPD confirmed the presence of Form omega.
Example 12- Drying of a wet sample of Form Omega
The product of example 11 was dried at 50 °C in a vacuum oven overnight, and analyzed
by XRD. A mixture of Form omega and Form Z was obtained.
Example 13- This example illustrates the preparation of Form U by triturating form 5 in
Ethyl-Acetate
Nateglinide Form 6 (5 grams) was triturated in ethyl acetate (10 ml) at 25 °C for 2 hours.
The wet material was filtered with vacuum and washed with ethyl acetate (10 ml). The
wet product was dried at 50 °C in a vacuum oven overnight. The wet and dry products
were Form U,
Example 14- This example illustrates the preparation of form B by triturating Form 5 in
ethyl-acetate
Nateglinide Form 6 (5 grams) was triturated in ethyl acetate (10 ml) at 50 °C for 1 hour.
The mixture was cooled to 20 °C and triturated for 1 hour. The wet material was filtered
with vacuum and washed with ethyl acetate (10ml). The wet product was dried at 50 °C in
a vacuum oven overnight. The wet and dry products were obtained as Form B.
Example 15-process for the Preparation of Nateglinide Form B
Nateglinide Form B may also be obtained by precipitation of nateglinide Form G,
from isopropanol followed by conversion of Form G to Form B. In this embodiment, a
form of nateglinide, such as nateglinide Form 5 (about 3% LOD) is dissolved in a mixture
of rPA/H2O at a preferred temperature range of about 40 to about 50°C. Preferably, the
I PA concentration in the solvent mixture is in the range of about 50% to about 70% (v/v),
and the volume of the solvent mixture is about 5 to about 20 volumes/unit weight of
nateglinide.
The solution obtained after dissolution is preferably cooled to a temperature of
about 30 °C for seeding with crystals of Form B. The seeded solution is preferably stirred
at the seeding temperature for about 30 minutes to about 3 hours. The solution is
preferably then cooled to about 0 °C plus/minus 5 °C for at preferably least about 5 hours,
and preferably stirred at 5 °C for at least about 30 minutes. The precipitated nateglinide
crystals may be recovered and dried under reduced pressure at a preferred temperature of
about 70 to about 90 °C to obtain nateglinide Form B.
43
Example 16 Process for the Preparation of Nateglinide Form B by Trituration in Water
Nateglinide Form 8 was triturated in 5 volumes water at about 25 °C for about 7 hours.
The crystals were isolated and dried under reduced pressure at 90°C
Example (A): Trituration of wet starting material
50 gr Nateglinide form 5 wet (about 37% LOD) was triturated in 250 ml water at 25°C.
After 4 hrs trituration, the slurry was sampled and dried under reduced pressure at 90°C.
The wet crystals were tested by XRD and found to be 5 type. The dry crystals were tested
by XRD and found to be B type. After 7 hours of trituration, the product was isolated and
dried under reduced pressure at 90°C. The wet crystals were tested by XRD and found to
be 8 type. The dry crystals were tested by XRD and found to be B type.
Example (B): Trituration of dry starting material
50 gr Nateglinide form 8 dry was triturated in 250 ml water at 25°C. After 4.5 hrs
trituration, the slurry was sampled and dried under reduced pressure at 90°C. The wet
crystals were tested by XRD and found to be Z type. The dry crystals were tested by XRD
and found to be B type. After 7.5 hours of trituration, the product was isolated and dried
under reduced pressure at 90°C. The wet crystals were tested by XRD and found to be E
type. The dry crystals were tested by XRD and found to be B type.
Example 17- Preparation of Nateglinide form U
Example (A) Crystallization from Acetone
Nateglinide (50 grams) Form 8 was dissolved in acetone (175 ml) at 42°C. The clear
solution was cooled to 10 °C for seeding. After seeding with type B crystals, the seeded
solution was stirred for an additional 3 hours at a temperature of 10 °C and cooled to -10
°C for 10 hours, and stirred at -10 °C over night. The crystals were isolated and dried at
90°C. The wet crystals were tested by XRD and found to be U type. The dry crystals were
tested and found to be U type.
Example (B) Crystallization from Ethyl Acetate
Nateglinide (20 grams) were dissolved in ethyl acetate (560 ml) at 40°C. The solution was
filtered to remove insoluble matter. The clear solution was evaporated under reduced
pressure, and Ethyl Acetate (460 ml) was evaporated (the solvent volume in the reactor
was 5 volumes/unit weight Nateglinide). The solution was cooled to 20 °C and seeded
with type B crystals. The seeded solution was stirred at 20 °C for an additional 30
minutes, cooled to 0 °C for 1.5 hours, and stirred at 0°C for an additional 30 minutes. The
crystals were isolated and dried under reduced pressure at 30°C, 50°C, 90°C. The wet
45
crystals were tested by XRD and found to be U type. The dry crystals were tested by
XRD and found to be U type.
Example 18- Removal of residual solvent from Form delta
Nateglinide (40 grams) Form delta (1.5% heptane) was dried in a stirred reactor (7-10
rpm) under 60 mmHg vacuum and at 60°C. After 6 hours of drying, the residual solvent
of the material was 613 ppm of heptane. The polymorph of the dried material remained
delta form, as the starting material.
Example 19- Preparation of nateglim'de Form B from ethyl acetate
Nateglinide form 8 is dissolved in ethyl acetate at 25°C. The solvent is evaporated under
reduced pressure, until turbidity appears. The turbid solution is cooled to 0 °C plus/minus
5 °C for 1 hour and stirred for 1 hour. The product was isolated and dried under reduced
pressure at 50°C.
Example (A)
Nateglinide (12 grams) Form 8 was dissolved in 165 ml of ethyl acetate at 25°C.
The solvent was evaporated under reduced pressure at 25°C, until turbidity appeared. At
the end of evaporation, the volume in the reactor was 90-95 ml. The mixture was cooled
from 25 °C to 5 °C for 1 hour and stirred at 5 °C for 1 hour. The product was isolated and
dried under reduced pressure at 50°C. Both the wet and the dry crystals were tested by
XRD and DSC and found to be B type.
Having thus described the invention with reference to particular preferred
embodiments and illustrative examples, those in the art may appreciate modifications to
the invention as described and illustrated that do not depart from the spirit and scope of the
invention as disclosed in the specification. The Examples are set forth to aid in
understanding the invention but are not intended to, and should not be construed to, limit
its scope in any way. The examples do not include detailed descriptions of conventional
methods. Such methods are well known to those of ordinary skill in the art and are
described in numerous publications. Polymorphism in Pharmaceutical Solids, Drugs and
the Pharmaceutical Sciences, Volume 95 may be used as a guidance. All references
mentioned herein are incorporated in their entirety.

What is claimed is:
1. Nateglinide Form U wherein the crystalline form is substantially free of a peak at
3.8+/-0.2 theta.
2. Nateglinide having a XRPD pattern with peaks at about 4.7, 7.4, 13.8 and 17.0 ±0.2
degrees 26, wherein the crystalline form is substantially free of a peak at 3.8+/-0.2
theta.
3. A nateglinide composition having a XRPD pattern as substantially depicted in a figure
selected from the group consisting of Fig. 31 and 65-69.
4. A pharmaceutical composition comprising of a nateglinide U and an effective amount
of an excipient.
5. A method for lowering blood sugar level comprising administering the pharmaceutical
composition of claim 4.
6. A method for treating diabetes type II comprising administering the pharmaceutical
composition of claim 4.
7. A process for preparing nateglinide Form U comprising the steps of:
a) preparing a solution of nateglinide in ethyl acetate at a temperature of about 40°C
to about 45°C;
b) adding in any order a €5 to a C^ aliphatic hydrocarbon having a temperature of
about 5°C as an anti-solvent to precipitate nateglinide.
8. The process of claim 7, wherein the antisolvent is heptane.
9. Crystalline nateglinide form U characterized by a FTIR spectrum with peaks at about
3350, 1701, 1646, 1291 cm"1.
10. A process for preparing crystalline form of nateglinide having an XRPD pattern with
peaks at 4.7, 7.4,13.8 and 17.0+/-0.2 theta comprising the steps of:

a) preparing a solution of nateglinide in ethylacetate;
b) seeding the solution with nateglinide crystals; and
c) recovering the crystalline form as a precipitate.

11. The process of claim 10, where the volume of ethyl acetate compared to weight of
nateglinide is about 3 to about 11 mL/g.
12. The process of claim 11, where the volume of ethyl acetate compared to weight of
nateglinide is about 4 to about 6 mL/g.
13. The process of claim 10, wherein the solution is seeded with the same crystalline form.
14. The process of claim 13, further comprising the step of cooling before or after seeding.

15. The process of claim 10, wherein the nateglinide obtained is more than about 99%
pure as area percentage HPLC.
16. The process of claim 10, wherein nateglinide obtained is 99% free of other crystalline
forms by weight.
17. A process for preparing crystalline form of nateglinide having an XRPD pattern with
peaks at 4.7, 7.4, 13.8 and 17.0+/-0.2 theta comprising the steps of:

a) preparing a container holding a solution of nateglinide in ethyl acetate;
b) adding a C5 to C\2 hydrocarbon to the container holding the solution;
c) recovering the crystalline form as a precipitate.

18. The process of claim 17, wherein the hydrocarbon is a Cs to Cg hydrocarbon.
19. The process of claim 18, wherein the hydrocarbon is heptane.
20. The process of claim 17, wherein precipitation is carried out in the presence of water.
21. The process of claim 17, further comprising seeding before precipitation.
22. The process of claim 21, wherein the same crystalline form is used for seeding.
23. The process of claim 17, wherein the hydrocarbon is added in such manner to avoid
precipitation upon addition.
24. A process for preparing crystalline form of nateglinide having an XRPD pattern with
peaks at 4.7, 7.4, 13.8 and 17.0+/-0.2 theta comprising the steps of:

a) preparing a container holding a solution of nateglinide in ethyl acetate;
b) adding heptane to the container holding the solution in such manner to
avoid precipitation upon addition;
c) cooling the solution and seeding the solution with the same crystalline form
of nateglinide, in any order; and
d) filtering the crystalline nateglinide as a precipitate.

25. The process of claim 24, wherein the ethyl acetate is mixed with water at about 2% to
about 10% water as percentage of milliliters of water to grams of nateglinide.
26. A process for preparing crystalline form of nateglinide having an XRPD pattern with
peaks at 4.7, 7.4, 13.8 and 17.0+/-0.2 theta comprising the steps of:

a) preparing a solution of nateglinide in a mixture of water and ethyl acetate;
b) combining the solution with an anti-solvent; and
c) recovering the crystalline nateglinide as a precipitate.

27. The process of claim 26, wherein the anti-solvent is a €5 to C\ 2 hydrocarbon.
28. The process of claim 27, wherein the hydrocarbon is heptane.

29. The process of claim 28, further comprising seeding before precipitation.
30. The process of claim 29, wherein the same crystalline form is used for seeding.
31. The process of claim 28, wherein the anti-solvent is added in such manner to avoid
precipitation upon addition.
32. A process for purifying crystalline form of nateglinide having an XRPD pattern with
peaks at 4.7, 7.4, 13.8 and 17.0+/-0.2 theta comprising the step of crystallizing the
crystalline nateglinide from a solution in the presence of water, thereby resulting in the
crystalline form being 99% pure as area percentage HPLC.
33. The process of claim 32, wherein ratio of water to nateglinide is about 2% to about
10% as percentage of milliliters of water to grams of nateglinide.
34. The process of claim 32, wherein the rest of the solution is comprised of ethyl acetate.
35. A process for preparing crystalline form of nateglinide having an XRPD pattern with
peaks at 4.7, 7.4, 13,8 and 17.0+/-0.2 theta comprising the steps of:

a) preparing a solution of nateglinide in ethyl acetate at a temperature of about
25 °C to about 50 °C at an ethyl acetate/nateglinide ratio of about 3 to about
! I ml/g;
b) seeding the solution with the same crystalline nateglinide at a temperature
of about 10°C to about 35 °C;
c) stirring the seeded solution;
d) cooling the seeded solution at a rate of about 1 °C to 10 °C per hour to a
temperature of about negative 10°C to about 10°C; and
e) filtering the crystalline nateglinide as a precipitate; and
f) drying the precipitate.

36. A crystalline form of nateglinide characterized by an XRPD pattern with peaks at 4.7,
7.4, 13.8 and 17.0+/-0.2 theta, wherein the crystalline form is substantially free of a
peak at 3.8+/-0.2 theta.
37. The crystalline form of claim 36, wherein the crystalline form is 99% pure as area
percentage HPLC".
38. The crystalline form of claim 37, wherein crystalline form is obtained 99% free of
other crystalline forms by weight.
39. A crystalline form of nateglinide characterized by an XRPD pattern or an FTIR
spectrum as substantially depicted in a figure selected from the group consisting of
figure 31, figure 65, figure 66, figure 67, figure 68 and figure 69.

40. A pharmaceutical formulation comprising the crystalline form of claim 39 and a
pharmaceutically acceptable excipient.
41. Use of a crystalline form U of nateglinide as defined in or prepared by a process
defined in any prededing claim in the manufacture of a medicament for lowering blood
glucose level in a mammal in need thereof.