WO2008130630A2 - Polymorphic form of rimonabant hydrochloride and processes for preparation thereof - Google Patents

Abstract

Provided is a crystalline form of Rimonabant hydrochloride, processes for its preparation and pharmaceutical compositions containing such crystalline form of Rimonabant hydrochloride.

Description

POLYMORPHIC FORM OF RIMONABANT HYDROCHLORIDE AND PROCESSES FOR PREPARATION THEREOF

CROSS REFERENCE TO RELA TED APPLICA TIONS

[0001] The present application claims the benefit of the following United States Provisional Patent Application No.: 60/923,830, filed April 16, 2007. The contents of this application are incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The present invention encompasses a crystalline form of Rimonabant HCl as well as processes for preparation thereof.

BACKGROUND OF THE INVENTION

[0003] 5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)-4-methyl-N-(l -piperidinyl)- lH-pyrazole-3-carboxamide, whose international nonproprietary name is Rimonabant, has the following chemical structure.

[0004] Rimonabant is an antagonist of CBi receptors cannabinoid receptors. This active pharmaceutical ingredient (CAS number 1583681-13-1 [HCl] and 168273-06-1 [free base]) has been introduced for the treatment of obesity and related diseases, smoking cessation, Alzheimer's disease, Parkinson's, etc. Its therapeutical application has been described in U.S. Patent No. 6,344,474, U.S. Patent No. 6,642,258 and others. Oral tablets have been developed by Sanofi-Aventis under the Tradename: Acomplia™.

[0005] Rimonabant was first described in EP Patent No. 656354 and parallel U.S. Patent No. 5,624,941, herein U.S. Patent '941, where the base, salt and solvate forms are described. U.S. Patent Application 2005/0043356, hereby incorporated by reference, names the crystalline form described in U.S. Patent '941 as Rimonabant hydrochloride salt Form I and characterizes this form, based on an IR spectrum and peaks, an XRD diffractogram and peaks, solubility, melting point, and by a single- crystal X-ray diffraction, see pages 1 and 2.

[0006] U.S. Patent Application 2005/0043356 and parallel application No. WO 2003/040105 apparently describes a crystalline form of Rimonabant base, designated as Form II. Form II is described therein to be obtained from pure methylcyclohexane, methylcyclohexane containing 1-10% water by volume, acetonitrile, 4-methyl-2- pentanone, acetone, or mixtures of these solvents. Form II is characterized by an IR spectrum and peaks, an XRD diffractogram and peaks, solubility, melting point and a single-crystal X-ray diffraction.

[0007] International Patent Application No. WO2006/087732 apparently describes an amorphous form of Rimonabant HCl and three crystalline forms (Forms II, III, and FV) of Rimonabant HCl. The amorphous Rimonabant HCl is described as either an hydrate or anhydrous amorphous form of Rimonabant HCl. Rimonabant HCl Forms II, III, and IV are characterized based on an XRD diffractogram and peaks and their melting point.

[0008] Further, US Patent Application published as US 2008/004313, which has a publication date after the priority date of the present invention, describes crystalline forms of Rimonabant HCl designated as forms A, B, C, D, and E.

[0009] WO2008035023 describes a crystalline form of rimonabant base (designated Form C) and amorphous rimonabant, processes for their preparation and pharmaceutical compositions thereof.

[00010] WO2008032330 provides a process for the preparation of rimonabant substantially free of an amide impurity.

[00011] WO2008026219 describes a polymorph of rimonabant base, its hydrates and solvates.

[00012] The present invention relates to the solid state physical properties of Rimonabant HCl. These properties can be influenced by controlling the conditions under which Rimonabant HCl is obtained in solid form. Solid state physical properties include, for example, the flow-ability of the milled solid. Flow-ability 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.

[00013] 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 can have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered active ingredient can 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.

[00014] 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.

[00015] 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.

[00016] Thus, there is a need in the art for the discovery of addition polymorphic forms of Rimonabant HCl.

SUMMARY OF THE INVENTION

[00017] The present invention presents a crystal form of Rimonabant hydrochloride, methods of preparing such crystal form, as well as pharmaceutical compositions comprising such crystal form. [00018] The present invention provides a crystalline form of Rimonabant hydrochloride, characterized by a powder XRD pattern with peaks at about 13.4, 13.9, 14.9 and 18.1 ± 0.2 degrees two-theta. Preferably, the crystalline form of the present invention is substantially pure.

[00019] The present invention provides a method of preparing the above crystalline Rimonabant HCl form comprising: combining Rimonabant hydrochloride and ethanol to a heterogeneous mixture thereby forming the crystalline Rimonabant hydrochloride.

[00020] The present invention comprises a pharmaceutical composition comprising the Rimonabant hydrochloride form of the present invention and at least one pharmaceutically acceptable excipient.

[00021] The present invention comprises a pharmaceutical composition comprising the Rimonabant hydrochloride form made by the processes of the present invention, and at least one pharmaceutically acceptable excipient.

[00022] The present invention further encompasses a process for preparing a pharmaceutical formulation comprising combining the Rimonabant hydrochloride form of the present invention with at least one pharmaceutically acceptable excipient.

[00023] The present invention further encompasses a process for preparing a pharmaceutical formulation comprising combining the Rimonabant hydrochloride form made by the processes of the present invention, and at least one pharmaceutically acceptable excipient.

[00024] The present invention further encompasses the use of the Rimonabant hydrochloride form of the present invention for the manufacture of a pharmaceutical composition.

[00025] The present invention further encompasses the use of the Rimonabant hydrochloride form made by the processes of the invention, for the manufacture of a pharmaceutical composition. BRIEF DESCRIPTION OF THE FIGURES

[00026] Figure 1 illustrates a powder X-ray diffraction pattern for Rimonabant hydrochloride Form VI.

DETAILED DESCRIPTION

[00027] Rimonabant hydrochloride used throughout the present application in preparing a crystalline form of Rimonabant hydrochloride may be prepared, for example, according to the process described in U.S. Patent 5,624,941 or may be purchased. In U.S. Patent 5,624,941 Rimonabant hydrochloride may be obtained by adding a saturated solution of gaseous HCl in ether to a solution of Rimonabant in ether until pH =1 and filtering of the precipitate obtained.

[00028] As used herein the term purity refers to crystalline purity. Crystalline purity may refer to the presence or absence of one or more crystalline forms other than the referenced crystalline form of the compound.

[00029] As used herein, the term "water content" refers to the content of water based upon the Loss on Drying method (the "LOD" method) as described in UPS 29-

NF 24, official August 1, 2006, Physical Test and Determinations, <731> LOSS ON

DRYING or in Pharmacopeial Forum, Vol. 24, No. 1, p. 5438 (Jan - Feb 1998), the

Karl Fisher assay for determining water content or thermogravimetric analysis (TGA).

All percentages herein are by weight unless otherwise indicated.

[00030] As used herein, "solvate" is meant to include any crystalline form which incorporates a solvent in a level of more than about 1%.

[00031] Those skilled in the art will understand that the term "hemiethanolate" when used in reference to Rimonabant hydrochloride describes Rimonabant hydrochloride having an ethanol content of about 4.4% w/w.

[00032] Those skilled in the art will understand that the term "Monoethanolate" when used in reference to Rimonabant hydrochloride describes Rimonabant hydrochloride having an ethanol content of about 8.4% w/w.

[00033] Those skilled in the art will understand that the term "Sesquethanolate" when used in reference to Rimonabant hydrochloride describes Rimonabant hydrochloride having an ethanol content of about 12.1% w/w.

[00034] The present invention provides a crystalline form of Rimonabant hydrochloride, designated Form VI, characterized by a powder XRD pattern with peaks at about 13.4, 13.9, 14.9 and 18.1 ± 0.2 degrees two-theta. Preferably, the crystalline form may be further characterized by a powder XRD pattern with peaks at about 16.8, 24.6, 29.6 and 30.5 ± 0.2 degrees two-theta or a powder XRD pattern substantially as depicted in Figure 1. Preferably, Form VI is substantially pure, having more than 80% of Form VI, more preferably, more than 90% of Form VI, and most preferably more than 99% of Form VI in a given sample as measured by XRD. [00035] Form VI has a weight loss, as measured by TGA, of between about 6.4- 11.8% by weight, while it has water content, as measured by KF of about 0.8% by weight. This corresponds to Rimonabant HCl ethanolate.

[00036] The present invention further encompasses a process for preparing the crystalline Rimonabant hydrochloride Form VI comprising: combining Rimonabant hydrochloride and ethanol to a heterogeneous mixture (for example a slurry or suspension) thereby forming the crystalline Rimonabant hydrochloride. [00037] The ratio of Rimonobant HCl to ethanol is preferably about 5 to about 50, preferably about 5 to about 15, more preferably about 5 to about 10. Combining Rimonabant hydrochloride and ethanol to a heterogeneous mixture, for example a slurry or suspension, can be carried out at a temperature of preferably about 0°C to about 55°C, preferably at about 20°C to about 45°C more preferably at room temperature (RT, 20°C-25°C). The heterogeneous mixture (slurry or suspension) can be maintained for a period of about 36 to about 60 hours, such as about 48 hours. The crystalline Form VI may be isolated and dried. Isolation can be carried out by filtration. To accelerate the filtration, the filtration can be carried out under vacuum (pressure of less than 100 mmHg). The isolated Form VI can then be dried. Drying can be carried out at a temperature of about 25°C to about 65°C, such as about 55⁰C. A pressure of less than one atmosphere, such as vacuum (pressure of less than 100 mmHg), can be used to accelerate the drying process. Drying under vacuum can be carried out for about 24 hours.

[00038] The present invention comprises a pharmaceutical composition comprising the Rimonabant hydrochloride form of the present invention and at least one pharmaceutically acceptable excipient.

[00039] The present invention comprises a pharmaceutical composition comprising the Rimonabant hydrochloride form made by the processes of the present invention, and at least one pharmaceutically acceptable excipient. [00040] The present invention further encompasses a process for-preparing a pharmaceutical formulation comprising combining the Rimonabant hydrochloride form of the present invention with at least one pharmaceutically acceptable excipient. [00041 ] The present invention further encompasses a process for preparing a pharmaceutical formulation comprising combining the Rimonabant hydrochloride form made by the processes of the present invention, and at least one pharmaceutically acceptable excipient.

[00042] The present invention further encompasses the use of the Rimonabant hydrochloride form of the present invention for the manufacture of a pharmaceutical composition.

[00043] The present invention further encompasses the use of the Rimonabant hydrochloride form made by the processes of the invention, for the manufacture of a pharmaceutical composition.

[00044] Methods of administration of a pharmaceutical composition of the present invention may comprise administration in various preparations depending on the age, sex, and symptoms of the patient. The pharmaceutical compositions can be administered, for example, as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, injection preparations (solutions and suspensions), and the like. When the pharmaceutical composition comprises the crystalline Rimonabant hydrochloride Form VI, the liquid pharmaceutical composition is a suspension or emulsion, wherein Form VI retains its crystalline form. [00045] Pharmaceutical compositions of the present invention can optionally be mixed with other forms of Rimonabant and/or other active ingredients. In addition, pharmaceutical compositions of the present invention can contain inactive ingredients such as diluents, carriers, fillers, bulking agents, binders, disintegrants, disintegration inhibitors, absorption accelerators, wetting agents, lubricants, glidants, surface active agents, flavoring agents, and the like.

[00046] Diluents increase the bulk of a solid pharmaceutical composition and can 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^®), micro fine 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, or talc.

[00047] Carriers for use in the pharmaceutical compositions may include, but are not limited to, lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, or silicic acid.

[00048] Binders help bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include for example 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, or starch.

[00049] Disintegrants can increase dissolution. Disintegrants include, for example, alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g.

Ac-Di-SoI , 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 glycolate (e.g.

Explotab^®) and starch.

[00050] Disintegration inhibitors may include, but are not limited to, white sugar, stearin, coconut butter, hydrogenated oils, and the like.

[00051] Absorption accelerators may include, but are not limited to, quaternary ammonium base, sodium laurylsulfate, and the like.

[00052] Wetting agents may include, but are not limited to, glycerin, starch, and the like. Adsorbing agents may include, but are not limited to, starch, lactose, kaolin, bentonite, colloidal silicic acid, and the like.

[00053] A lubricant can be added to the composition to reduce adhesion and ease release of the product from a punch or dye during tableting. Lubricants include for example 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 fumarate, stearic acid, talc and zinc stearate. [00054] Glidants can be added to improve the flowability of non-compaeted solid composition and improve the accuracy of dosing. Excipients that can function as glidants include for example colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.

[00055] Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that can be included in the composition of the present invention include for example maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

[00056] Tablets can be further coated with commonly known coating materials such as sugar coated tablets, gelatin film coated tablets, tablets coated with enteric coatings, tablets coated with films, double layered tablets, and multi-layered tablets.

Capsules can be coated with shell made, for example, from gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.

[00057] Solid and liquid compositions can also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.

[00058] In liquid pharmaceutical compositions of the present invention, the crystalline Rimonabant hydrochloride of the present invention is suspended together with and any other solid ingredients, which may be dissolved or suspended, in a liquid carrier, such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.

[00059] Liquid pharmaceutical compositions can 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 can 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.

[00060] Liquid pharmaceutical compositions of the present invention can also contain viscosity enhancing agents to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract. Such agents include for example 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.

[00061] Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol and invert sugar can be added to improve the taste.

Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxy toluene, butylated hydroxyanisole and ethylenediamine tetraacetic acid can be added at safe levels to improve storage stability.

[00062] A liquid pharmaceutical composition according to the present invention can also contain a buffer such as guconic acid, lactic acid, citric acid or acetic acid, sodium guconate, sodium lactate, sodium citrate or sodium acetate.

[00063] Selection of excipients and the amounts to use can be readily determined by an experienced formulation scientist in view of standard procedures and reference works known in the art.

[00064] A composition for tableting or capsule filing can 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, which causes the powders to clump up into granules. The granulate is screened and/or milled, dried and then screened and/or milled to the desired particle size. The granulate can then be tableted or other excipients can be added prior to tableting, such as a glidant and/or a lubricant.

[00065] A tableting composition can be prepared conventionally by dry blending.

For instance, the blended composition of the actives and excipients can be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules can be compressed subsequently into a tablet.

[00066] As an alternative to dry granulation, a blended composition can 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 to 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. [00067] A capsule filling of the present invention can comprise any of the aforementioned blends and granulates that were described with reference to tableting, only they are not subjected to a final tableting step.

[00068] When shaping the pharmaceutical composition into pill form, any commonly known excipient used in the art can be used. For example, carriers include, but are not limited to, lactose, starch, coconut butter, hardened vegetable oils, kaolin, talc, and the like. Binders used include, but are not limited to, gum arabic powder, tragacanth gum powder, gelatin, ethanol, and the like. Disintegrating agents used include, but are not limited to, agar, laminalia, and the like. [00069] For the purpose of shaping the pharmaceutical composition in the form of suppositories, any commonly known excipient used in the art can be used. For example, excipients include, but are not limited to, polyethylene glycols, coconut butter, higher alcohols, esters of higher alcohols, gelatin, semisynthesized glycerides, and the like.

[00070] When preparing injectable pharmaceutical compositions, solutions and suspensions are sterilized and are preferably made isotonic to blood. Injection preparations may use carriers commonly known in the art. For example, carriers for injectable preparations include, but are not limited to, water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and fatty acid esters of polyoxyethylene sorbitan. One of ordinary skill in the art can easily determine with little or no experimentation the amount of sodium chloride, glucose, or glycerin necessary to make the injectable preparation isotonic. Additional ingredients, such as dissolving agents, buffer agents, and analgesic agents may be added. If necessary, coloring agents, preservatives, perfumes, seasoning agents, sweetening agents, and other medicines may also be added to the desired preparations during the treatment of schizophrenia.

[00071 ] The amount of Rimonabant hydrochloride of the present invention contained in a pharmaceutical composition according to the present invention is not specifically restricted; however, the dose should be sufficient to treat, ameliorate, or reduce the condition.

[00072] 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 disclosures of the references referred to in this patent application are incorporated herein by reference. The invention is further defined by reference to the following examples describing in detail the process and compositions 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

Instruments

XRD

[00073] XRD diffraction was performed on X-Ray powder diffractometer: Philips X 'pert Pro powder diffractometer, Cu-tube, scanning parameters: CuK_a radiation, λ = 1.5418 A.

TGA analysis

[00074] TGA analysis was preformed using Mettler 3M with Mettler TG 50 thermobalance.

[00075] The weight of the samples was about 10 mg; the samples were scanned at a rate of 10°C/min from 25⁰C to 200°C or 25O⁰C. The oven was constantly purged with nitrogen gas at a flow rate of 40 ml/min. Standard alumina crucibles covered by lids with 1 hole were used

Water content

[00076] Water content was determined by Karl Fisher analysis using Mettler

Toledo DL 38 Karl Fisher Titrator

Example 1: Process for the preparation of Rimonabant HCl Form VI:

[00077] Slurry of Rimonabant HCl (2.0gr) in EtOH (14ml) was stirred at room temperature for 48 hours. The product was isolated by vacuum filtration and dried at 55⁰C in a vacuum oven for 24 hours to obtain 2.03gr of Rimonabant HCl crystalline form VI.

Example 2: Process for the preparation of Rimonabant according to the '941 patent [00078] A solution of 3.3 g of KOH in 70 ml of water is added tσ a solution of 9.6 g of Ethyl 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-pyrazole-3- carboxylate in 70 ml of methanol. The mixture is refluxed for 3 hours, poured into 200 ml of iced water and the reaction mixture is acidified to pH=l upon addition of a 10% solution of HCl. The precipitate formed is filtered off, washed with water and dried under vacuum to give 8.8 g of 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4- methyl-pyrazole-3-carboxylic acid. 5 ml of thionyl chloride are added to a suspension of 8.8 g of the above acid in 90 ml of toluene, the mixture is refluxed for 3 hours and then evaporated to dryness under vaccum. The residue is taken up in 90 ml of toluene and the solvent is evaporated off again to give 8.0 g of 5-(4-chlorophenyl)-l-(2,4- dichlorophenyl)-4-methyl-pyrazole-3-carboxylic acid chloride. A solution of 8.0 g of this acid chloride in 80 ml of dichloromethane is added dropwise to a solution of 2.8 ml of 1-aminopiperidine and 3.6 ml of triethylamine in 100 ml of dichloromethane, cooled to 0°C. The reaction mixture is stirred for 3 hours while allowing the temperature to rise to room temperature and then poured into 200 ml of iced water. The mixture is extracted with dichloromethane, washed with water and then a saturated solution of NaCl, dried over MgSO₄ and evaporated under vaccum. The residue is purified by chromatography on silica gel using AcOEt/toluene (10/90; v/v) as the eluent. Crystallization in isopropyl ether gives 5.9 g of Rimonabant.

Example 4: Process for the preparation of Rimonabant HCl

[00079] A saturated solution of gaseous HCl in ether is added dropwise to a solution of 5.9 g of Rimonabant in 50 ml of ether until pH=l. The precipitate formed is filtered off, washed with ether and dried under vacuum to give 6.0 g of the expected hydrochloride.

Claims

What is claimed is:

1. A crystalline Rimonabant hydrochloride, characterized by a powder XRD pattern with peaks at about 13.4, 13.9, 14.9 and 18.1 ± 0.2 degrees two-theta.

2. The crystalline Rimonabant hydrochloride of claim 1, further characterized by a powder XRD pattern with peaks at about 16.8, 24.6, 29.6 and 30.5 ± 0.2 degrees two-theta.

3. The crystalline Rimonabant hydrochloride of claims 1 or 2, having a powder XRD pattern substantially as depicted in Figure 2.

4. The crystalline Rimonabant hydrochloride of any one of claims 1 to 3, having a purity of more than 80% of the crystalline Rimonabant hydrochloride in a given sample as measured by XRD.

5. The crystalline Rimonabant hydrochloride of claim 4 having a purity of more than 90% of the crystalline Rimonabant hydrochloride in a given sample as measured by XRD.

6. The crystalline Rimonabant hydrochloride of claim 5 having a purity of more than 99% of the crystalline Rimonabant hydrochloride in a given sample as measured by XRD.

7. A method of preparing crystalline Rimonabant HCl characterized by a powder XRD pattern with peaks at about 16.8, 24.6, 29.6 and 30.5 ± 0.2 degrees two-theta comprising: combining Rimonabant hydrochloride and ethanol thereby forming a heterogeneous mixture to obtain the crystalline Rimonabant hydrochloride.

8. The method of claim 7, wherein the heterogeneous mixture is a slurry or suspension.

9. The method of claims 7 or 8, wherein the ratio of Rimonobant HCl to ethanol is about 5 to about 50.

10. The method of claim 9, wherein the ratio is about 5 to about 15.

11. The method of any one of claims 7 to 10, wherein combining Rimonabant hydrochloride and ethanol is carried out at a temperature of about 0°C to about 55°C.

12. The method of claim 11, wherein the temperature is about 2Θ°G to about 45°C.

13. The method of claim 12, wherein the temperature is about room temperature.

14. The method of any one of claims 7 to 13, wherein the heterogeneous mixture is maintained for a period of about 36 to about 60 hours.

15. The method of claim 14, wherein the heterogeneous mixture is maintained for about 48 hours.

16. The method of any one of claims 7 to 15, further comprising isolating and drying the crystalline Form.

17. A pharmaceutical composition comprising the crystalline Rimonabant hydrochloride form of any one of claims 1-6 and at least one pharmaceutically acceptable excipient.

18. A pharmaceutical composition comprising the crystalline Rimonabant hydrochloride form made by the processes of any one of claims 7-16, and at least one pharmaceutically acceptable excipient.

19. A process for preparing a pharmaceutical formulation comprising combining the crystalline Rimonabant hydrochloride form of any one of claims 1-6 with at least one pharmaceutically acceptable excipient.

20. A process for preparing a pharmaceutical formulation comprising combining the crystalline Rimonabant hydrochloride form made by the processes of any one of claims 7-16, and at least one pharmaceutically acceptable excipient.

21. Use of the crystalline Rimonabant hydrochloride form of any one of claims 1- 6 for the manufacture of a pharmaceutical composition.

22. Use of the crystalline Rimonabant hydrochloride form made by the processes of any one of claims 7-16, for the manufacture of a pharmaceutical composition.