Field of the Invention
The field of the invention relates to processes for the preparation of a polymorph of
zolpidem hemitartrate. More particularly, it relates to the preparation of a non-hygroscopic
polymorphic form of zolpidem hemitartrate and pharmaceutical compositions that include the
non-hygroscopic polymorphic form, designated as Form I of zolpidem hemitartrate. The
invention also relates to use of the compositions for treating anxiety, sleep disorders and
convulsions. The field of the invention also relates to a process for the preparation of zolpidem
or pharmaceutically acceptable salts thereof.
Background of the Invention
Chemically, zolpidem is N,N,6-trimethyl-2-(4-methylphenyl)-imidazo[l,2-a]pyridine-3-
acetamide of Formula I. It is useful in the treatment of anxiety, sleep disorders and convulsions.
FORMULA I
Zolpidem is commercially available as its hemitartrate salt of Formula II,
(Figure Removed) FORMULA II
having 2:1 ratio of zolpidem base to L-(+)-tartaric acid.
The pharmacological profile of zolpidem is characterized by a strong hypnotic effect,
together with weak anticonvulsant and muscle-relaxant properties, showing selectivity for
benzodiazepine receptors with the biochemical characteristics and regional distribution of the
benzodiazepine one subtype. While zolpidem is a hypnotic agent with a chemical structure
unrelated to benzodiazepines, barbiturates, or other drugs with known hypnotic properties, it
interacts with gamma-aminobutyric acid (GABA)-benzodiazepine receptor complex and shares
some of the pharmacological properties of the benzodiazepines. The selective binding of
zolpidem on the omega-1 receptor may explain the relative absence of myorelaxant and
anticonvulsant effects in animal studies. Zolpidem shows both high affinity and selectivity
toward non-benzodiazepine-2 receptors which results in improved activity and/or fewer side
effects for the treatment of anxiety, sleep disorders and convulsions.
A general method for the synthesis of 2-phenylimidazo[l,2-a]pyridine is reported in J.
Med. Chem.. 40, 3109 - 3118 (1997). The preparation of zolpidem is, however, not discussed in
this article. The reaction conditions employed therein are stringent and require higher
temperatures.
Several processes have been reported for the preparation of zolpidem or its salt for
example, in U.S. Patent Nos. 4,382,938; 4,794,185; 4,356,283; 4,460,592; 4,501,745; 4,675,323;
4,808,594; 4,847,263; 6,281,360; 6,407,246; and 6,384,226; and International (PCT) Publication
Nos. WO 01/38327 and WO 02/14316.
U.S. Patent No. 4,382,938 discloses a process for the preparation of zolpidem base by
treating zolpidic acid with dimethylamine in the presence of carbonyldiimidazole and
tetrahydrofuran, followed by treating the mass with base and recrystallizing from ethanol to get
zolpidem base. The product is not obtained with a high purity profile, thus making the process
commercially difficult to implement.
U.S. Patent No. 4,794,185 discloses a method for the preparation of zolpidem
hemitartrate. The method involves treating zolpidem base with L-(+)-tartaric acid in methanol
and allowing the hemitatrate salt to crystallize. The product obtained has a melting point of
197°C (hereinafter designated as Form A of zolpidem hemitartrate).
Form A has some characteristic physico-chemical properties. It is very hygroscopic
under normal storage conditions and can absorb up to about 5% w/w of moisture after exposure
to atmospheric conditions. It is therefore difficult for a formulation scientist to prepare a
pharmaceutical composition of Form A because the absorption of water results in problems of
weight variation and content uniformity in the formulation.
Form A is further characterized by X-Ray diffraction (XRD) pattern. A typical XRD of
Form A shows characteristic absorption peaks at two-theta values of 6.5, 9.0, 16.1, 16.6, 24.6
and 27.3. After micronization, the Form A exhibits seme additional characteristic peaks than
those mentioned above at two-theta values of 6.7, 8.6, 11.2, 15.4 and 17.3.
Form A exhibits a characteristic Differential Scanning Calorimetry (DSC) profile. Four
endothermic peaks are observed at 70.3°C, 113.2°C, 188.73°C and 200.42°C and two exothermic
peaks are obtained at 126.06°C and 168.00°C.
The Thermal Gravimetric Analysis (TGA) and Karl Fischer Analysis of Form A shows
that initially Form A has about 1.0% w/w of moisture, which after absorption of water rises up
to 5%. The Karl Fischer analysis suggests that Form A can have up to 3% w/w to 5% w/w of
moisture. TGA analysis supports this data. The endotherm at 110°C in TGA analysis suggests
partial desorption of water with an overall water content of about 3% w/w to 5% w/w.
U.S. Patent Application No. 20020077332 discloses various polymorphic forms of
zolpidem hemitartrate, for example, anhydrous, hydrated, or solvated forms having specific XRay
diffraction patterns, TGA profile and moisture or solvent content. These polymorphic forms
are designated as anhydrous, monohydrate, dihydrate, trihydrate and tetrahydrate of zolpidem
hemitartrate along with Forms B, C, D, E, F, G, H and L. With the stricter regulatory norms of
solvent content and water content (e.g., European Pharmacopoeia specifies a water content of
not more than 3% for zolpidem hemitartrate), it is very difficult to formulate the solvated and
hydrated polymorphic forms disclosed in this application.
International (PCT) Patent Application No. PCT/IB01/01558 relates to processes for the
preparation of N,N-dimethyl-3-(4-methyl) benzoyl propionamide of Formula III, which is a key
intermediate in the synthesis of zolpidem.
H3C'
(Figure Removed)International (PCT) Patent Application No. PCT/IB2004/00245 discloses a process for
the preparation of zolpidem hemitartrate by treating N,N-dimethyl-3-(4-methyl) benzoyl
propionamide of Formula III with bromine to get bromo amide of Formula IV,
H3C
(Figure Removed)followed by treatment of the bromo amide of Formula IV with 2-amino-5-methylpyridine to
obtain zolpidem base of Formula I, which is then converted to zolpidem hemitartrate of Formula
II.
The present inventors have surprisingly found that zolpidem or a salt thereof can be
prepared in high yield and purity by condensing bromo amide of Formula IV with 2-amino
methylpyridine in the presence of an organic solvent at a temperature of above 80°C. The
inventors have also found that a novel polymorph of zolpidem hemitartrate can be obtained
which is stable and non-hygroscopic when studied under extensive stability studies.
Thus, the present invention provides a process which does not result in a hygroscopic
form; rather, a pure stable non-hygroscopic form is obtained. The non-hygroscopic zolpidem
hemitartrate when made by the process of the present invention is easy to isolate and formulate
thus making the process amenable for commercial scale use.
Summary of the Invention
In one general aspect there is provided a process for the preparation of zolpidem of
(Figure Removed)FORMULA I
or a pharmaceutically acceptable salt thereof. The process steps include
a) condensing bromo amide of Formula IV,
(Figure Removed)with 2-amino-5-methylpyridine in one or more polar aprotic solvents, at a temperature
above 80°C; and
b) isolating zolpidem of Formula I or a pharmaceutically acceptable salt thereof, by
removal of the solvent.
The polar aprotic solvent may include one or more of methyl isobutyl ketone, ethyl
methyl ketone, diisobutyl ketone, 1,4-dioxane, sulpholane, N,N-dimethylformamide, N,Ndimethylacetamide,
acetonitrile, and N-methylpyrrol:idone. Mixtures of all of these solvents are
also contemplated.
Removing the solvent may include, for example, one or more of distillation, distillation
under vacuum, evaporation, filtration, filtration under vacuum, decantation and centrifugation.
The product obtained may be further or additionally dried to achieve the desired moisture
values. For example, the product may be further or additionally dried in a tray drier, dried under
vacuum and/or in a Fluid Bed Drier.
The process may include further forming the product so obtained into a finished dosage
form.
In one general aspect, the condensation of the bromo amide of Formula IV with 2-amino-
5-methylpyridine is carried out in a polar aprotic solvent at a temperature from about 80 °C to
about 120 °C, for example from about 80 °C to about 100°C. It may be heated from about 10
minutes to about 24 hours.
In another general aspect, the reaction mixture containing zolpidem may be cooled
before filtration to obtain better yields of the zolpidem or a salt thereof.
In another general aspect there is provided a non-hygroscopic polymorphic form of
zolpidem hemitartrate (hereinafter designated as Form I).
The polymorphic form of zolpidem hemitartrate may have, for example, the X-ray
powder diffraction pattern of Figure I, the differentia] scanning calorimetry profile of Figure II,
and infrared spectrum of Figure III.
In another general aspect there is provided a process for preparing polymorphic Form I
of zolpidem hemitartrate. The process includes obtaining a solution of zolpidem base in one or
more solvents; contacting the solution with L-(+)-tartaric acid to form a reaction mixture; adding
an anti-solvent to the reaction mixture; and isolating Form I of zolpidem hemitartrate from the
mixture thereof.
The process may include further drying of the product obtained.
In another general aspect there is provided a pharmaceutical composition that includes a
therapeutically effective amount of the non-hygroscopic polymorphic Form I of zolpidem
hemitartrate and one or more pharmaceutically acceptable carriers, excipients or diluents.
In another general aspect there is provided a method of treating anxiety, insomnia, sleep
disorders, and convulsions in a warm-blooded animal, the method including providing to the
warm-blooded animal a pharmaceutical composition lhat includes Form I of zolpidem
hemitartrate.
The details of one or more embodiments of the inventions are set forth in the description
below. Other features, objects and advantages of the inventions will be apparent from the
description and claims.
Description of the Drawings
Figure I is an X-ray powder diffraction pattern of Form I of zolpidem hemitartrate.
Figure II is a differential scanning calorimetry thermogram of Form I of zolpidem hemitartrate.
Figure III is an infrared spectrum of Form I of zolpidem hemitartrate.
Figure IV is a thermogravimetry curve of Form I of zolpidem hemitartrate.
Figure V is an X-ray powder diffraction pattern of Form A of zolpidem hemitartrate.
Figure VI is a differential scanning calorimetry thermogram of Form A of zolpidem
hemitartrate.
Detailed Description oi'the Invention
The inventors have developed a process for preparing zolpidem or its pharmaceutically
acceptable salts. The process provides benefits with respect to economics and convenience to
operate at a commercial scale.
The process steps include:
(a) condensing bromo amide of Formula IV,
(Figure Removed)with 2-amino-5-methylpyridine in one or more polar aprotic solvents, at a temperature
above 80°C; and
(b) isolating zolpidem of Formula I or a pharmaceutically acceptable salt thereof, by
removal of the solvent.
The starting material, the bromo amide of Formula IV, can be prepared as per the process
disclosed in International (PCT) Patent Application No. PCT/IB2004/00245, the disclosure of
which is incorporated herein by reference. The bromo amide intermediate of Formula IV is
treated with 2-amino-5-methylpyridine in the presence of a suitable solvent at a temperature
above 80°C to get zolpidem base. Zolpidem base may then be converted to a pharmaceutically
acceptable salt thereof by treating it with a suitable pharmaceutically acceptable acid. In
particular, it may be treated with L-(+)-tartaric acid to get zolpidem hemitartrate.
Suitable solvents include polar aprotic solvents. The polar aprotic solvent may include
one or more of methyl isobutyl ketone, ethyl methyl ketone, diisobutyl ketone, 1,4-dioxane,
sulpholane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, and Nmethylpyrrolidone.
Mixtures of all of these solvents are also contemplated. The reaction can be
carried out a temperature range of from about 80°C to about 120°C. In particular, it may be
carried out at a temperature from about 80°C to about 100°C.
The inventors have found a novel non-hygroscopic polymorphic form (designated Form
I) of zolpidem hemitartrate. The polymorphic Form I is characterized by its X-ray diffraction
pattern as shown in Figure I, differential scanning calorimetry profile as shown in Figure II,
infrared spectrum as shown in Figure III, and the thermogravimetry curve as shown in Figure
IV.
In general, the Form I of zolpidem hemitartrate may be characterized by X-ray
diffraction peaks at about 7.0, 7.8, 8.6, 8.9, 12.2, 15.6, 16.5, 17.3, 24.3 and 26.0 degrees twotheta
values.
Further, in general, Form I of zolpidem hemitartrate may be characterized by DSC
endothermic peaks at about 70°C, 109°C, 189°C and 204°C. It may be further characterized by
exothermic peaks at about 119°C and 157°C.
Further, Form I of zolpidem hemitartrate may be characterized by weight loss from about
1.0% upto about 1.75% w/w as determined by thermogravimetry.
In general, Form I of zolpidem hemitartrate has a moisture content of about 1.25% to
2.5% w/w as determined by Karl Fischer method.
The inventors also have developed a process for the preparation of the non-hygroscopic
Form I of zolpidem hemitartrate. The process involves obtaining a solution of zolpidem in one
or more alcoholic solvents; contacting the solution with L-(+)-tartaric acid to form a reaction
mixture; adding an anti-solvent to the reaction mixture; and isolating the Form I of zolpidem
hemitartrate from the mixture. The inventors also have developed pharmaceutical compositions
that contain Form I of zolpidem hemitartrate in admixture with one or more solid or liquid
pharmaceutical diluents, carriers, and/or excipients.
Alcoholic solvents include one or more of methanol, ethanol, isopropanol, and n-butanol.
Examples of anti-solvents that may be added to precipitate out salt of zolpidem include ketones
such as acetone, methyl isobutyl ketone, ethyl methyl ketone, diisobutyl ketone, and mixtures
thereof.
Zolpidem base may be prepared by any of the methods known in the art. In particular, it
may be prepared by the method described above.
In general, the solution of zolpidem base may be obtained by dissolving zolpidem in one
or more solvents. The solution of zolpidem in a solvent can be obtained by dissolving, slurrying,
stirring, or a combination thereof. The solution may be treated with animal charcoal before
precipitation of the zolpidem hemitartrate.
In general, an anti-solvent may be added to induce precipitation of zolpidem hemitartrate
from the reaction mixture. An anti-solvent is a solvent in which the salt of zolpidem is insoluble
or sparingly soluble to the solvent in which salt of zolpidem is prepared. The precipitation may
be spontaneous depending upon the solvents and the conditions used. The precipitation may also
be facilitated by adding seeds of the desired polymorphic form. Alternatively, precipitation may
also be induced by distilling off some solvent and/or reducing the temperature. For example, the
desired polymorphic form made according to the latter method may be used as the seed in the
former method at a subsequent time.
The product obtained may be further or additionally dried to achieve the desired moisture
values. For example, the product may be further or additionally dried in a tray drier, dried under
vacuum and/or in a Fluid Bed Drier.
For the purpose of this disclosure, a warm-blooded animal is a member of the animal
kingdom possessed of a homeostatic mechanism and includes mammals and birds.
The present invention is further illustrated by the following examples which are provided
merely to be exemplary of the invention and do not limit the scope of the invention. Certain
modifications and equivalents will be apparent to those skilled in the art and are intended to be
included within the scope of the present invention.
Methods
(a) X-Ray Powder Diffraction
X-ray powder diffraction patterns were recorded using the following instrument and
parameters:
X-Ray Difractometer, Rigaku Coorperation, RU-H3R
Goniometer CN2155A3
X-Ray tube with Cu target anode
Divergence slits 1°, receiving slit 0.15mm, Scatter slit 1°
Power: 40 KV, 50 mA
Scanning speed: 3 deg/min step: 0.02 deg
Wavelength: 1.5406 A
(b) Infrared Spectra
Infrared spectra were recorded using the following instrument and parameters:
SCAN: 16 scans, 4.0 cm'1
According to the USP 25, general test methods page 1920, infrared absorption spectrum
by potassium bromide pellet method.
(c) Differential Scanning Calorimetry
Differential scanning calorimetry plots were recorded using the following instrument and
parameters:
DSC821 e, Mettler Toledo
Sample weight: 8-10 mg
Temperature range: 25-300° C
Heating rate: 10° C/min
Nitrogen 20.0 mL/min
Number of holes in the crucible: 1
(d) TGA analysis was carried out using Perkin Elmer Instrument
(e) Moisture content determination was carried out by Karl-Fischer titration technique using
Mettler instrument.
Example 1; Preparation of zolpidem
3-bromo-N,N-dimethyl-4-oxo-4-p-tolyl-butyramide (50 gm) was dissolved in methyl
isobutyl ketone (350 ml) and stirred to get a solution. 2-amono-5-methylpyridine (18.1 gm) was
added to this solution. The reaction mixture was heated to 82-85°C and stirred at 82-85°C for
20 hours. The reaction mixture was then cooled to 25"C and the separated solids were filtered.
The wet cake was washed with methyl isobutyl ketons (2 x 100 ml). The wet solid was
suspended in de-ionized water (250 ml) and the pH was adjusted to 6.8-7.2 with aqueous sodium
carbonate solution (10% w/v, 60 ml). The resultant mixture was stirred at room temperature for
30 minutes and filtered. The filtered solids were washed with de-ionized water (2 x 100 ml) and
dried at 50°C under reduced pressure to get zolpidem base.
Yield: 12 g
Example 2: Preparation of zolpidem hemitartrate
Zolpidem base (35 gm) was dissolved in methanol (140 ml) and 1.75 gm activated
carbon was added to it. The resultant mass was stirred at room temperature for 15 minutes and
then filtered through a celite bed. To the clear filtrate, a solution of L-(+)-tartaric acid (8.55 gm)
dissolved in methanol (70 ml) was added under stirring at 45-50°C. Acetone (280 ml) was added
to the reaction mass. The reaction mixture was seeded with pure zolpidem tartarate (0.2 gm)
followed by cooling to -20 to -15°C. The resultant reaction mass was stirred at -20 to -15°C for
further 2 hours and separated solids were filtered. The wet cake was washed with acetone (2 x70
ml). The cake was dried at 45 to 50°C under reduced pressure for 6 to 8 hours to get pure
zolpidem hemitartarate.
Yield: 4.2 g (92.04%)
Example 3: Preparation of Form I of zolpidem hemitartrate
Zolpidem base (30 gm) was dissolved in methanol (120 ml) and activated carbon (1.5
gm) was added to it. The resultant mass was stirred at room temperature for 15 minutes and then
filtered through a celite bed and the bed was washed with methanol (2 x 30 ml). To the
combined, clear filtrate, a solution of L-(+)-tartaric acid (7.2 gm) dissolved in methanol (60 ml)
was added under stirring at 45-50°C. To the reaction mass, acetone (240 ml) was added. The
reaction mixture was cooled to -20 to -15°C. The resultant reaction mass was stirred at -20 to -
15°C for further 2 hours and separated crystals were filtered. The cake was washed with acetone
(2 x 55 ml). The cake was dried at 45 to 50°C under reduced pressure to get Form I of zolpidem
hemitartrate.
Yield:31.0g
Moisture Content: 2.33% w/w
TGA Analysis: Weight loss of 1.06% w/w
XRD pattern of Form I as depicted in Figure I
DSC profile of Form I as depicted in Figure II
IR Spectrum of Form I as depicted in Figure III.
While the present invention has been described in terms of its specific embodiments,
certain modifications and equivalents will be apparent to those skilled in the art and are intended
to be included within the scope of the present invention. For example, the resulting zolpidem
hemitartrate Form I can be used in pharmaceutical compositions with pharmaceutically
acceptable carriers, excipients or diluents, as known by those of ordinary skill in the art, to
prepare dosage forms that are suitable for administering to patients to treat the conditions
described herein or otherwise known to be suitable for treatment with zolpidem.

WE CLAIM;
1. A process for the preparation of zolpidem of Formula I,
(Figure Removed) FORMULA I
or a salt thereof, the process comprising:
a) condensing a bromo amide of Formula IV,
(Figure Removed)with 2-amino-5-methylpyridine in one or more polar aprotic solvents at a reaction
temperature above 80°C; and
b) isolating zolpidem of Formula I or a salt thereof, by the removal of the solvent.
2. The process of claim 1, wherein the solvent used in step a) has a boiling point above
80°C.
3. The process of claim 1, wherein the solvent comprises one or more of methyl isobutyl
ketone, ethyl methyl ketone, diisobutyl ketone, 1,4-dioxane, sulpholane,
dimethylformamide, dimethylacetamide, acetcne, acetonitrile, N-methylpyrrolidone, and
mixtures thereof.
4. The process of claim 1, wherein the reaction temperature is from about 80°C to about
120°C.
5. The process of claim 1, wherein removing the solvent comprises one or more of
distillation, distillation under vacuum, evaporation, filtration, filtration under vacuum,
decantation and centrifugation.
6. The process of claim 1, further comprising additional drying of the product obtained.
7. The process of claim 1, further comprising forming the product obtained into a finished
dosage form.
8. The process of claim 1, wherein the salt is zolpidem hemitartrate.
9. The process of claim 8, wherein the zolpidem hemitartrate is prepared from zolpidem by
treating it with L-(+)-tartaric acid.
10. A non-hygroscopic polymorphic Form I of zolpidem hemitartrate.
11. The Form I of zolpidem hemitartrate of claim 10 having characteristic X-ray diffraction
peaks at two-theta values of 7.0, 7.8, 8.6, 8.9, 12.2,15.6, 16.5, 17.3, 24.3 and 26.0.
12. The Form I of zolpidem hemitartrate of claim 10 having X-ray diffraction pattern of
Figure I.
13. The Form I of zolpidem hemitartrate of claim 10 having characteristic differential
scanning calorimetry endothermic peaks at about 70°C, 109°C, 189°C and 204°C.
14. The Form I of zolpidem hemitartrate of claim 13 having exothermic peaks at about
119°Candl57°C.
15. The Form I of zolpidem hemitartrate of claim 10 having differential scanning
calorimetry profile of Figure II.
16. The Form I of zolpidem hemitartrate of claim 10 having characteristic thermogravimetric
weight loss from about 1.0% w/w up to about 1.75% w/w.
17. The Form I of zolpidem hemitartrate of claim 10 having moisture content of about 1.25%
w/w to 2.5% w/w as determined by Karl Fischer method.
18. The Form I of zolpidem hemitartrate of claim 10 having infrared spectrum of Figure III.
(Figure Removed)19. A process for the preparation of Form I of zolpidem hemitartrate, the process
comprising:
a) obtaining a solution of zolpidem base in one or more alcoholic solvents;
b) contacting the solution with L-(+)-tartaric acid;
c) adding an anti-solvent to the reaction mixture; and
d) isolating Form I of zolpidem hemitartrate from the mixture thereof.
20. The process of claim 19, wherein temperature of the reaction mixture is from about
-50°C to about 25°C.
21. The process of claim 19, wherein the alcoholic solvent comprises one or more of
methanol, ethanol, isopropanol, n-butanol, and mixtures thereof.
22. The process of claim 19, wherein the anti-solvent comprises one or more of acetone,
methyl isobutyl ketone, ethyl methyl ketone, diisobutyl ketone, and mixtures thereof.
23. A pharmaceutical composition comprising:
a therapeutically effective amount of Form I of zolpidem hemitartrate; and
one or more pharmaceutically acceptable carriers, excipients or diluents.
24. A method of treating anxiety, insomnia, sleep disorders, and convulsions in a warmblooded
animal, the method comprising providing a pharmaceutical composition to the
warm-blooded animal, the pharmaceutical composition comprising Form I of zolpidem
hemitartrate.