FIELD OF INVENTION
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The present invention is directed to novel crystalline form of rimonabant and to the processes for crystallizing the novel crystalline form of rimonabant.
BACKGROUND OF THE INVENTION
Rimonabant is 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-jV-(piperidin-l-yl)pyrazole- 3-carboxamide, having structural formula-I.
(Figure Remove)
Formula-I
Rimonabant is a selective antagonist of cannabinoid typel (CB1) receptor and a new class of compounds that target a potential treatment for obesity, smoking cessation, Alzheimer's disease, Parkinson's disease etc. The drug, formulated as 20 rng film coated tablets, is typically given once daily to the patients.
Rimonabant was first disclosed in U.S. Patent No. 5, 624,941, and is still under FDA review to approve for marketing in US. In a method described in U.S. Patent No. 5,624,941, crude rimonabant was purified by column chromatography, and the concentrated desired fractions were crystallized from isopropyl ether while in an another exemplified process, the product was crystallized from methyl cyclohexane to give purified rimonabant.
Recently, two novel crystalline forms of rimonabant, referred to as forms 1 and II, were characterized and described in U.S. patent application 2005/0043356.

According to this application, the method claimed in U.S. Patent No. 5, 624,941 allows the preparation of rimonabant in crystalline form-1.
The crystalline form-II of rimonabant, described in U.S. App. No. 2005/0043356 is prepared by dissolving rimonabant in the hot state in a solvent selected from methyl cyclohexane (containingl-10% water), acetone, acetonitrile or 4-methyl-2-pentanone or mixture thereof. The medium is cooled to 5-25°C to get crystalline form-II.
In recent years, solid-state properties of drugs have received great attention in the pharmaceutical industry, as a major contributing factor to both bio-availability and formulation characteristics. The ability of some substances to exist in more than one crystalline form, called polymorphism, was accredited as one of the most important solid-state property of drugs. While polymorphs have the same chemical composition, they differ in the packing and geometrical arrangement thereof, and exhibit different physical properties such as melting point, shape, color, X-ray diffraction pattern, infrared absorption, and solid state NMR spectrum, density, hardness, deformability, stability, dissolution, and the like. Depending on their temperature-stability relationship, one crystalline form may give rise to thermal behavior different from that of another crystalline form. Thermal behavior can be measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis ("TGA"), and differential scanning calorimetry ("DSC"), which have been used to distinguish polymorphic forms.
One of the most important physical properties of pharmaceutical compounds is their solubility in aqueous solution, particularly their solubility in the gastric juices of a patient. For example, where absorption through the gastrointestinal tract is slow, it is often desirable for a drug that is unstable to conditions in the patient's stomach or intestine to dissolve slowly, so that it does not accumulate in a deleterious environment. Different crystalline forms or polymorphs of the same pharmaceutical

compounds can and reportedly do have different aqueous solubilities or different dissolution rates (release profile) in-vivo. Therefor, 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. However, any failure to predict the bioavailability of a drug may result in administration of either too small or too large undesired doses, which may be dangerous to patients and in extreme cases, lethal.
Other examples are known, where different crystalline forms behave differently during physical processing like milling and pressing. Many process-induced solid-solid transitions of substances are known, that lead to either other crystalline forms or an amorphous form of the substance. The solid-state experts are in a constant search for crystalline forms that can withstand physical stress and still retain their original properties.
Consequently, there is an ongoing search for new polymorphic forms of drugs, which may provide for improved performance thereof. A single molecule, such as rimonabant, may give rise to a variety of crystalline forms having distinct crystal structures and physical properties.
Rimonabant free base is in itself a pharmaceutical agent in addition to being a precursor for production of rimonabant hydrochloride.
As taught in the art, the purification of rimonabant require tedious methods to yield a product with high purity, hence the process may suffer from relatively low yield.

Some of the methods used for obtaining the novel crystalline form-II of rimonabant described in U.S. App. No. 2005/0043356 are cumbersome.
Thus, there is a widely recognized need for, and it would be highly advantageous to have new and distinct crystalline forms of rimonabant.
The general techniques that may lead to the discovery of a novel crystalline form of a certain compound are well known to those who are skilled in the art. Such techniques may include crystallization, thermal treatment, and sublimation. Those who are skilled in the art appreciate that in a search for new polymorphic forms of a certain compound, anyone of these techniques is expected to fail. The search is an empirical exercise that involves series of trial and error experiments with different techniques and conditions. For these reasons, it is impossible to predict the experimental conditions that will produce a new rimonabant crystalline form. It is, however, possible to provide methods that have successfully and selectively produced rimonabant in one of these desired forms after conducting a series of trial and error experiments.
SUMMARY OF THE INVENTION
Thus, the present invention provides a novel crystalline form of rimonabant and processes for the preparation thereof.
Herein, novel crystalline form of rimonabant that is suitable for pharmaceutical use is presented.
Thus, according to one embodiment of the present invention there is provided a crystalline rimonabant form-Ill, characterized by X-ray powder diffraction peaks at about 7.2, 9.3, 10.5, 13.4, 14.5, 15.2, 16.0, 17.0, 17.7, 18.9, 20.7, 21.1, 22.4, 22.9, 24.6, 27.2 and 29.5 degrees two-theta, ± 0.2 degrees two-theta and infrared spectrum

having peaks at about 3641, 3385, 3207, 3080, 2935, 2806, 1657, 1554, 1496, 1383, 1263, 1138, 1091, 970, 917, 833, 814,and 634 cm'1.
Another embodiment of the invention provides processes for preparing the above crystalline form of rimonabant. Preferably, the crystalline form of rimonabant of the invention is polymorphically pure.
Another embodiment of the invention encompasses process for converting the rimonabant crystal form-Ill to rimonabant form-I.
Yet another embodiment of the invention encompasses pharmaceutically acceptable salts of rimonabant, prepared by obtaining one of crystalline form of rimonabant as described above, and converting the rimonabant crystal form to pharmaceutically acceptable salts of rimonabant. Preferably, rimonabant crystal form is converted to rimonabant hydrochloride.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 illustrates the powder X-ray diffraction pattern for crystalline rimonabant Form-Ill.
Figure 2 illustrates the powder X-ray diffraction pattern for crystalline rimonabant Form-1
Figure 3 illustrates the infrared spectra for crystalline rimonabant Form-Ill.

DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to a novel crystal form of 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-Af-(piperidin-l-yl)-l//-pyrazole-3-carboxamide (rimonabant), processes for the preparation of the crystal form of rimonabant, and pharmaceutical compositions comprising the new crystal form of rimonabant.
One embodiment of the invention encompasses a novel crystalline form of rimonabant, characterized by X-ray powder diffraction peaks at about 7.2, 9.3, 10.5, 13.4, 14.5, 15.2, 16.0, 17.0, 17.7, 18.9, 20.7, 21.1, 22.4, 22.9, 24.6, 27.2 and 29.5 degrees two-theta, ± 0.2 degrees two-theta. This form is herein denominated as form III as depicted in figure 1. Further the novel crystalline form III of rimonabant is characterized by infrared spectrum having peaks at about 3641, 3385, 3207, 3080, 2935, 2806, 1657, 1554, 1496, 1383, 1263, 1138, 1091, 970, 917, 833, 814,and 634 cm"'as identified by figure 3.
Crystalline form III of rimonabant is further characterized by melting point of about 106-111°C.
The X-ray diffraction patterns of crystalline Form I and Form III of rimonabant are measured on a PANalytical X'Pert Pro diffractometer with Cu radiation and expressed in terms of two-theta, d-spacings and relative intensities. One of ordinary skill in the art understands that experimental differences may arise due to differences in instrumentation, sample preparation, or other factors.
All infrared measurements are made on Perkin Elmer Spectrum 100 spectrometer using KBr pellets having the characteristic absorption bands expressed in reciprocal centimeter.

Melting point was conducted using a Polmon MP Apparatus MP 96 with a sample weight of about 10 mg.
Another embodiment of the invention encompasses a process for preparing rimonabant crystalline Form III. The process comprises providing slurry of rimonabant or any other crystalline form of rimonabant in protic organic solvent like alcohols. The alcohols can be selected from methanol, ethanol, n-propanol, isopropanol, butanol, isobutanol and the like.
The crude rimonabant or any crystalline form of rimonabant is stirred for a sufficient period of time and at temperature sufficient to form rimonabant crystalline form-Ill.
Preferably, the slurry is stirred for about 30 minutes to 3 hours, at a temperature of from about 10°C to reflux temperature. Thereafter product is isolated by conventional methods such as filtration or centrifugation and dried to obtain pure crystalline form III of rimonabant.
Generally crude rimonabant or other crystalline forms are prepared by the methods reported in the prior art. Preferably, rimonabant is prepared by reaction of 1-aminopiperidine with 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid or reactive derivative thereof. Typically prior to condensation, acid is converted to acid chloride (figure-II) using thionyl chloride and thereafter acid chloride is treated with 1-aminopiperidine in the presence of base in suitable solvent. The solvent may be selected from chlorinated solvents such as methylene chloride, chloroform, ethylene chloride, aromatic solvents, such as toluene, tetrahydrofuran, ethers like 1,4-dimethoxy ethane and the like or mixture thereof.

(Figure Remove)

Figurc-II
Another embodiment of the invention encompasses a process for preparing rimonabant crystalline Form I as depicted in figure 2. The process comprises stirring of rimonabant form-Ill or crude rimonabant in a suitable solvent selected from isopropylether, cyclohexane or methyl cyclohexane under refluxing conditions for about 15 minutes to 4 hours.
It is advantageous to prepare form-I using cyclohexane or isopropyl ether, as these are very cheap solvents as compared to methylcyclohexane used for the preparation of form-I.
Specifically, the process comprises providing a solution of rimonabant form-Ill in ethereal solvent such as isopropyl ether at the reflux temperature of the solvent, and cooling to a temperature sufficient to form crystals of rimonabant. Preferably, the solution is cooled to about room temperature and further to about 5-15°C. Preferably, prior to cooling, the solution is maintained, while stirring, for about 30 minutes to 2 hours at reflux temperature.
Yet another embodiment of the present invention provides pharmaceutically acceptable salts of rimonabant, prepared by obtaining crystalline form III of rimonabant, and converting the same to pharmaceutically acceptable salts of rimonabant. In the preferred embodiment crystalline form III of rimonabant is converted to its pharmaceutically acceptable salts by the reaction with mineral acids.

Preferably, the crystalline form III of rimonabant is converted to rimonabant hydrochloride by reaction with hydrochloric acid.
Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail the preparation of the composition and methods of use of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
EXAMPLES
Example 1
PREPARATION OF RIMONABANT FORM-II1 Step 1: Preparation of Rimonabant
To a suspension of 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH-pyrazole-3-carboxylic acid (40g, 0.Imol) in 200 ml of toluene, was added thionyl chloride (24.79g, 0.2mol) at 30±5°C. The reaction mass was stirred for 4 hours at reflux temperature and then evaporated to dryness under vacuum to give the expected acid chloride. The acid chloride was dissolved in methylene chloride (200 ml) and treated with a solution of 1-aminopiperidine (12.16g, 0.12mol) in methylene chloride (700 ml) in presence of triethyl amine (13.29g, 0.13mol ) at 5-10°C and progress of the reaction was monitored by high performance liquid chromatography. After completion of the reaction, the reaction mass was quenched with demineralized water (160 ml) and the organic layer was washed with IN hydrochloric acid and demineralized water followed by drying over anhydrous sodium sulphate. The organic layer was evaporated under vacuum to give the crude product.

Step 2- Preparation of Rimonabant Form-Ill
The crude rimonabant obtained above was slurried in methanol (120ml) at ambient temperature for one hour and was filtered and dried to give 38g of off white crystalline rimonabant which displayed XRD pattern as depicted in Fig. 1.
Example 2
PREPARATION OF RIMONABANT FORM-III
Crude rimonabant (5g) was added to methanol (10ml) and the reaction medium was heated to reflux for 30 minutes and cooled to 5-10°C. The reaction mass was stirred for 1 hours at the same temperature. The precipitated product was filtered, washed with chilled methanol and dried under vacuum at 40-45°C for 4 hours to afford 4.4 g of rimonabant form-Ill.
Example 3
PREPARATION OF RIMONABANT FQRM-III
Rimonabant form-I (5 g) was added to ethanol (10 ml) and the reaction mixture was heated to reflux for 30 minutes and cooled to 5-10°C.The reaction mass was stirred for 1 hours at the same temperature. The precipitated product was filtered, washed with chilled ethanol and dried under vacuum at 40-45°C for 4 hours to afford 4.4 g of rimonabant form-Ill.
Example 4
PREPARATION OF RIMQNABANT FORM-III
Rimonabant form-I (5 g) was added to methanol (10 ml) and the reaction medium was heated to reflux for 30 minutes and cooled to 5-10°C. The reaction mass was stirred for 1 hours at the same temperature. The precipitated product was filtered,

washed with chilled methanol and dried under vacuum at 40-45°C for 4 hours to yield 4.5 g of rimonabant form-Ill.
Example 5
PREPARATION OF RIMONABANT FQRM-I
Rimonabant form-Ill (38g) was slurried in isopropyl ether (200ml) and heated to reflux temperature (60-65°C). The reaction mixture was stirred at 60-65°C for 1.3 hours. The mass was cooled to 10-15°C, filtered and washed with isopropyl ether (3x100 ml). The product was dried under vacuum at 45-50°C for 4 hours to give 30 g of almost white crystalline product as form-I (yield 78.94 %).

WE CLAIM
1. A novel crystalline form III of rimonabant, characterized by an X-ray powder
diffraction pattern having peaks at about 7.2, 9.3, 10.5, 13.4, 14.5, 15.2, 16.0,
17.0, 17.7, 18.9, 20.7, 21.1, 22.4, 22.9, 24.6, 27.2 and 29.5 degrees two-theta, ±
0.2 degrees two-theta and as depicted in figure 1.
2. The crystalline form III of rimonabant of claim 1, further characterized by
infrared spectrum having peaks at about 3641, 3385, 3207, 3080, 2935, 2806,
1657, 1554, 1496, 1383, 1263, 1138, 1091, 970, 917, 833, 814, and 634 cm'1 and
as depicted in figure 3.
3. The crystalline form III of rimonabant of claim 1 and 2, characterized by a
melting point of 106-111 °C.
4. A process for preparing the crystalline form III of rimonabant of claim 1,
comprising:
slurring/ dissolving crude rimonabant or any other form of rimonabant in
alcoholic solvent at temperature of 10°C to reflux for sufficient time to convert
to form-Ill,
cooling the reaction mass,
filtering and isolating crystalline form III of rimonabant.
5. The process according to claim 4, wherein the solution is heated at a temperature
of about 10°C to reflux for 30 minutes to 3 hours.
6. The process according to claim 4, wherein the solvent used is methanol, ethanol,
n-propanol, isopropanol, butanol, isobutanol and the like.
7. The process according to claim 4, wherein the solvent used is preferably
methanol.
8. A process for preparing rimonabant form I, comprising:
providing a solution of crystal form Illof rimonabant in a solvent selected from diisopropyl ether, cyclohexane or methylcyclohexane, and refluxing for sufficient time to convert to form-I,

cooling the reaction mass,
filtering and isolating crystalline form I of rimonabant.
9. Pharmaceutically acceptable salts of rimonabant, prepared by obtaining
rimonabant crystalline form of claim 1, and converting the same to
pharmaceutically acceptable salts of rimonabant.
10. The pharmaceutically acceptable salts of claim 9, wherein the rimonabant
crystalline form is converted to rimonabant hydrochloride.