The present invention relates to a novel polymorphic form of zolpidem hemitartrate and a method for preparation thereof using supercritical fluid technology.
N,N,6-trimethyl-2-(4-methylphenyl)-imidazo[1,2-a]pyridine-3-acetamide, commonly
known as zolpidem of Formula I is used for the treatment of anxiety, sleep disorders and convulsions. Zolpidem is commercially available in the form of its hemitartrate salt having 2:1 ratio of zolpidem base to tartaric acid.
(Formula Removed)
US Patent No. 4,382,938 discloses a process for preparation of zolpidem or pharmaceutically acceptable salt thereof. The pharmacological profile of this compound 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 means 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[1,2-a]pyridine is reported by Trapani et al. in J. Med. Chem., 40, 3109-3118 (1997). Preparation of Zolpidem is
however not discussed in the same. The reaction conditions employed therein are stringent and require higher temperature.
There are several processes reported for preparation of zolpidem hemitartrate in the literature. US 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; 6,384,226 and PCT Patent Applications WO 01/38327; WO 02/14316 disclose various processes for preparation of zolpidem or zolpidem hemitartrate.
US Patent No. 4,382,938 provides a process for preparation of zolpidem base by treating zolpidic acid with dimethylamine in presence of carbonyldiimidazole and tetrahydrofuran, followed by treating the mass with base and recrystallization from ethanol to get zolpidem base. The product obtained is characterized by high impurity profile and the process is not suitable on commercial scale.
US Patent No. 4,794,185 discloses alternative method for preparation of zolpidem hemitartrate, which 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 upto about 5% w/w of moisture after exposure to atmospheric conditions. It is therefore difficult to prepare a pharmaceutical composition of Form A as due to absorption of water there are problems of weight variation and content uniformity.
Form A is further characterized by X-Ray diffraction (XRD) pattern. A typical XRD of Form A shows characteristic absorption peaks at 20 values of 6.5, 9.0, 16.1, 16.6, 24.6 and 27.3. After micronization Form A exhibits some additional characteristic peaks than those mentioned above which are at 20 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 raises upto 5%. Karl Fischer analysis suggests that Form A can have upto 3 to 5% of moisture. TGA analysis supports this data. A 110°C endotherm in TGA analysis suggest partial desorption of water with an overall water content of about 3 to 5% w/w.
US Patent Application No. 20020077332 provides polymorphic forms of zolpidem hemitatrate which are mainly anhydrous or hydrated or solvated forms having particular X-Ray diffraction pattern, TGA profile and moisture or solvent content. These polymorphic forms are designated as anhydrous, monohydrate, dihydrate, trihydrate and tetrahydrate of zolpidem hemitartrate along with Form B, C, D, E, F, G, H and L.
Indian patent application 782/DEL/2000 relates to an improved and industrially advantageous process for the preparation of N,N-dimethyl-3-(4-methyl) benzoyl propionamide of Formula II which is a key intermediate in the synthesis of Zolpidem.
Indian Patent Application No. 951/DEL/2003 which is patent of addition of Indian Patent Application No. 782/DEL/2000 provides a process for preparation of zolpidem hemitartrate which comprises of treating N,N-dimethyl-3-(4-methyl) benzoyl propionamide of Formula II with bromine to get bromo amide of Formula III which is then treated with 2-amino-5-methylpyridine to obtain zolpidem base.
(Formula Removed)
The so obtained zolpidem base is dissolved in a mixture of methanol/acetone and treated with L-(+)-tartaric acid solution in methanol. Zolpidem hemitartrate of Formula I crystallize out from the methanol solution, which is then dried under reduced pressure.
Form I of zolpidem hemitartrate has characteristic XRD peaks at 29 values of 7.0, 7.8, 8.6, 8.9, 12.2, 15.6, 16.5, 17.3, 24.3 and 26.0. Form I of zolpidem hemitartrate has characteristic DSC endothermic peaks at about 70°C, 109°C, 189°C and 204°C along with exothermic peaks at about 119°C and 157°C. Form I of zolpidem hemitartrate has characteristic TGA weight loss from about 1.0% upto about 1.75% w/w.
The present inventors have found a novel polymorphic form of zolpidem hemitatrate. The novel polymorphic form of zolpidem hemitatrate is prepared by using supercritical fluid technology. The novel polymorphic form of zolpidem hemitatrate has a high melting point and is thermodynamically more stable. The present inventors have further found that the polymorphic form of zolpidem hemitartrate obtained according to the process of the present invention has particle size distribution wherein 90% of the particles have diameter of 34 microns or less.
Supercritical fluid technology has been used in the pharmaceutical industry for extraction of natural products like caffeine, essential oils etc., purification of surfactants
and also for designing new drug delivery systems. Supercritical fluids are gases or liquids that exist beyond their critical point. They possess density similar to gases and flow properties similar to liquids. Supercritical fluid technology offers tremendous advantages over the conventional crystallization processes as it enables preparation of Pharmaceuticals with targeted properties such as particle size distribution, purity enhancement. It also enables a single stage scalable process eliminating the use of additional solvents and reagents, which reduces process complexity and cost of production when compared with traditional methods of crystallization, harvesting and micronizing or milling processes. In contrast to formation of from high energy milling in most cases supercritical fluid technology enables preparation of crystalline, non-cohesive easy flowing particles with desired size distribution and having low residual solvents.
The preparation of novel polymorphic form of zolpidem hemitartrate according to the present invention is based on the antisolvent effect of supercritical fluid. It is similar to that of antisolvent induced precipitation in the conventional solvent-based crystallization processes. The technique involves spraying a solution of a compound into a bulk of supercritical fluid whereby the compound interacts and mixes with the supercritical fluid and gets precipitated due to the antisolvent effect of the latter. The important parameters in this technique are solubility of the compound in the organic solvent, insolubility of the compound in the supercritical fluid, physical conditions of the precipitation chamber (temperature, pressure) and rate of addition of the solution of the compound to the supercritical fluid. Supercritical carbon dioxide is non-toxic and non-hazardous and thus can be employed without any safety concerns. The present process is environment friendly, uses cheaply available raw materials and is easy to operate on an industrial scale. Moreover
A first aspect of the present invention provides novel polymorphic Form II of zolpidem hemitartrate.
A second aspect of the present invention provides novel polymorphic Form II of zolpidem hemitartrate having characteristic XRD pattern as depicted in Figure 1. The XRD of Form II shows characteristic 29 values at 7.24°, 9.38°, 10.54°, 11.60°, 12.40°, 12.92°, 13.66°, 13.98°, 14.50°, 15.04°, 15.52°, 16.42°, 17.00°, 17.70°, 18.08°, 18.68° 19.22°, 19.44° 19.68°, 20.16° 20.60°, 21.22° 22.00°, 23.32° 23.52° 23.72°, 24.34°, 25.02°, 25.66°, 26.60°, 26.94°, 27.60°, 27.82°, 29.50°, 30.10°, 30.74°, 30.90°, 31.50°, 32.34°, 32.50°, 33.00°, 33.38°, 33.60°, 34.40°, 34.62°, 35.64°, 36.34°, 37.40, 37.96°, 38.26°, 38.46°. The most prominent peaks in the XRD of Form II of zolpidem hemitartrate are at 29 values of 7.24, 17.7, 18.68, 23.32, 23.52 and 23.72.
A third aspect of the present invention provides novel polymorphic Form II of zolpidem hemitartrate having characteristic DSC thermogram as depicted in Figure 2. Form II of zolpidem hemitartrate has characteristic DSC endothermic peak observed between about 205°C and 211°C.
A fourth aspect of the present invention provides novel polymorphic Form II of zolpidem hemitartrate having characteristic TGA profile as depicted in Figure 3. Form II of zolpidem hemitartrate exhibits characteristic weight losses in TGA, of about 2.0% at around 70°C and of about 33% w/w at around 225°C.
A fifth aspect of the present invention provides novel polymorphic Form II of zolpidem hemitartrate having a particle size distribution wherein 90% of particles have diameter of 70 microns or less, 50% of particles have diameter of 50 microns or less and 10% of particles have diameter of 30 microns or less. More preferably Form II of zolpidem hemitartrate has a particle size distribution wherein 90% of particles have diameter of 40 microns or less.
A sixth aspect of the present invention provides a process for preparation of crystalline zolpidem hemitartrate wherein the said process comprises of,
a) spraying a solution of zolpidem hemitartrate in an organic solvent in a supercritical
fluid,
b) isolating crystalline zolpidem hemitartrate.
Zolpidem hemitartrate can be prepared by methods known in the art. A solution of zolpidem hemitartrate in a suitable organic solvent is sprayed in supercritical carbon dioxide whereby crystalline zolpidem hemitartrate precipitates due to the antisolvent effect of supercritical carbon dioxide. The precipitated crystalline zolpidem hemitartrate was cooled and analyzed by XRD, DSC and TGA and its particle size was determined. The suitable organic solvent is the one in which zolpidem hemitartrate is soluble and can be selected for example from C3-10 ketone, C1-4 alkanol, C3-6 ethers, nitriles and the like or mixtures thereof. The solution of zolpidem in the suitable organic solvent is sprayed at a rate of about 0.2-3.0 kg/hour.
Powder XRD of the samples were determined by using X-Ray Diffractometer, Rigaku Corporation, RU-H3R, Goniometer, X-Ray tube with Cu K alpha target anode, Divergence slits 1°, Receiving slit 0.15mm, Scatter slit 1°, Power: 40 KV, 100 mA, Scanning speed: 2 deg/min step: 0.02 deg, Wave length: 1.5406 A.
The thermal profiles were recorded using Differential Scanning Calorimeter DSC821 e, Mettler Toledo, Sample weight: 3.1 mg, Temperature range: 20-350° C, Heating rate: 10° C/min, Nitrogen 50.0 mL/min, Number of holes in the crucible: 1.
The percentage weight loss was recorded using a thermogravimetric analyzer (TGA) Perkin Elmer, Model Pyris 1, Temperature range: 20-350°C, Heating rate: 10° C/min, purged with Nitrogen.
Particle size was determined using Malvern Mastersizer 2000.
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.
Example
Preparation of Form II of Zolpidem hemitartarate using supercritical fluid technology A solution of Zolpidem hemitartarate in acetone (1.5% w/w) was sprayed at a rate of 0.57 kg/hour in vessel (10 L) containing supercritical carbon dioxide maintained at a temperature of 58°C, pressure of 100 bars and flowrate of 25 kg/hour. The precipitated solid was cooled to ambient temperature and analyzed by XRD, DSC and TGA and its particle size was determined. XRD as per Figure 1. DSC as per Figure 2. TGA as per Figure 3.
Particle size (microns): D(v,0.9) D(v,0.5) D(v,0.1)
34 10 2

WE CLAIM:
1. Polymorphic Form II of zolpidem hemitartrate.
2. Form II of zolpidem hemitartrate having characteristic XRD pattern as depicted in
Figure 1 wherein characteristic 29 values are obtained at 7.24°, 9.38°, 10.54°, 11.60°,
12.40° 12.92°, 13.66°, 13.98°, 14.50° 15.04°, 15.52°, 16.42°, 17.00°, 17.70°,
18.08°, 18.68° 19.22°, 19.44°, 19.68° 20.16° 20.60°, 21.22°, 22.00°, 23.32°
23.52°, 23.72°, 24.34°, 25.02°, 25.66°, 26.60°, 26.94°, 27.60°, 27.82°, 29.50°,
30.10°, 30.74°, 30.90°, 31.50° 32.34°, 32.50° 33.00°, 33.38°, 33.60°, 34.40°,
34.62°, 35.64°, 36.34°, 37.40, 37.96°, 38.26°, 38.46°.
3. Form II of zolpidem hemitartrate having characteristic DSC thermogram as depicted
in Figure 2 wherein characteristic endothermic peak is observed between about 205°C
and211°C.
4. Form II of zolpidem hemitartrate having characteristic TGA profile as depicted in
Figure 3 exhibiting characteristic weight losses in TGA, of about 2.0% at around 70°C
and of about 33% w/w at around 225°C.
5. Form II of zolpidem hemitartrate having particle size distribution wherein 90% of
particles have diameter of 70 microns or less.
6. Form II of zolpidem hemitartrate according to claim 5 wherein 90% of particles have
diameter of 40 microns or less.
7. A process for preparation of crystalline zolpidem hemitartrate wherein the said process comprises of,
a) spraying a solution of zolpidem hemitartrate in an organic solvent in a supercritical
fluid,
b) isolating crystalline zolpidem hemitartrate.
8. A process according to claim 7 wherein the organic solvent is selected from C3-10 ketone, C1-4 alkanol, C3-6 ethers, nitriles or mixtures thereof.
9. A process according to claim 7 wherein the supercritical fluid is carbon dioxide.
10. A process according to claim 7 wherein the solution of zolpidem hemitartrate is
sprayed at a rate of 0.2-3.0 kg/hour.