WO2007103711A2 - Polymorphic forms of rimonabant - Google Patents

Polymorphic forms of rimonabant Download PDF

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Publication number
WO2007103711A2
WO2007103711A2 PCT/US2007/063042 US2007063042W WO2007103711A2 WO 2007103711 A2 WO2007103711 A2 WO 2007103711A2 US 2007063042 W US2007063042 W US 2007063042W WO 2007103711 A2 WO2007103711 A2 WO 2007103711A2
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rimonabant
solution
amorphous
process
crystalline form
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PCT/US2007/063042
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French (fr)
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WO2007103711A3 (en
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Vijayabhaskar Bolugoddu
Vijaya Kumar Kotagiri
Sashikanth Suthrapu
Purandhar Kolkonda
Ramulu Akula
Anuradha Bhimireddy
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Dr. Reddy's Laboratories Ltd.
Dr. Reddy's Laboratories, Inc.
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Priority to IN358CH2006 priority Critical
Priority to IN358/CHE/2006 priority
Priority to IN611CH2006 priority
Priority to IN611/CHE/2006 priority
Priority to US60/805,679 priority
Priority to US80567906P priority
Priority to US80778506P priority
Priority to US60/807,785 priority
Application filed by Dr. Reddy's Laboratories Ltd., Dr. Reddy's Laboratories, Inc. filed Critical Dr. Reddy's Laboratories Ltd.
Publication of WO2007103711A2 publication Critical patent/WO2007103711A2/en
Publication of WO2007103711A3 publication Critical patent/WO2007103711A3/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

Polymorphic crystalline Forms III, IV, V, and VI of rimonabant, amorphous rimonabant, and amorphous rimonabant in an intimate dispersion with a pharmaceutically acceptable carrier.

Description

POLYMORPHIC FORMS OF RIMONABANT

INTRODUCTION TO THE INVENTION

The present invention relates to polymorphic forms of rimonabant and processes for their preparation. In particular, it relates to crystalline Forms III, IV, V, Vl of rimonabant, an amorphous form of rimonabant, an amorphous combination of rimonabant with a pharmaceutically acceptable carrier, and processes for their preparation.

Rimonabant has the chemical name N-piperidino-5-(4-chlorophenyl)-1 -(2,4- dichlorophenyl)-4-methylpyrazole-3-carboxamide, has the research designation SR 141716, and is structurally represented by Formula I.

Figure imgf000003_0001

Formula I

Rimonabant is an antagonist of the CB1 cannabinoid receptors and is useful as an antiobesity agent. Rimonabant is currently in the pre-registration stage in the United States for the treatment of obesity. It is available in the European market under the trademark ACOMPLIA as 20 mg oral film-coated tablets.

U.S. Patent No. 5,624,941 discloses rimonabant and its related compounds and their pharmaceutically acceptable salts. It also describes a process for the preparation of rimonabant, which in the final step crystallizes the product in isopropyl ether (Example 95) or in methylcyclohexane (Example 211 ). The patent does not mention the polymorphic form obtained. The patent also describes a process for the preparation of a solvate of rimonabant hydrochloride with ethanol, and a hemisolvate of rimonabant methanesulfonate with acetone.

U.S. Patent Application Publication No. US 2005/0043356 A1 describes a stable crystalline Form Il of rimonabant, and it also characterizes the crystalline polymorph obtained in U.S. Patent No. 5,624,941 described above and designates it as Form I. It also gives the methods for preparation of Form Il and pharmaceutical compositions containing the same. It also states that rimonabant Form Il is less soluble at all temperatures between 10 0C and 70 0C, which shows that Form Il is thermodynamically more stable than rimonabant Form I. International Application Publication No. 2004/009057 A1 discloses a process for the preparation of nano-crystalline particle dispersions. The process described in this application does not isolate amorphous rimonabant, but it describes a suspension of amorphous rimonabant which can be utilized for the production of crystalline nano-particulate dispersions of rimonabant. International Application Publication No. WO 2006/087732 discloses crystalline forms of rimonabant hydrochloride designated as Form II, Form III, and Form IV and an amorphous form of the salt. It also designates the crystalline form of rimonabant hydrochloride obtained by the process described in U.S. Patent No. 5,624,941 as crystalline Form I. Regulatory authorities throughout the world require that all possible crystalline forms of the same active compound be synthesized and characterized as completely as possible. There is thus a continuing need to prepare new polymorphic forms of pharmacologically active compounds of commercial interest such as rimonabant or its salts, which provide the pharmaceutical formulation scientist with a broader spectrum of crystalline forms of an active ingredient to choose from, based on their differing physiochemical properties.

Different morphological forms of the same compound may exhibit significantly different properties such as for example enhanced thermodynamic stability or improved dissolution characteristics among other properties. The discovery of such novel forms and processes to make these forms are of interest to the pharmaceutical formulation scientist as these improved properties could help in developing pharmaceutical dosage forms with improved stability or handling characteristics. There is no way to predict the physicochemical properties of different polymorphic forms or whether a given compound could exist in different polymorphic forms.

The present invention provides polymorphic forms of rimonabant and processes for their preparation that are robust and reproducible. SUMMARY OF THE INVENTION

The present invention relates to polymorphic forms of rimonabant and processes for their preparation. In particular, it relates to crystalline Forms III, IV, V, Vl of rimonabant, an amorphous form of rimonabant, an amorphous combination of rimonabant with pharmaceutically acceptable carriers, and processes for their preparation.

An aspect of the present invention provides crystalline Forms III, IV, V, Vl of rimonabant characterized by their X-ray powder diffraction ("XRPD") patterns. Another aspect of the present invention provides amorphous rimonabant and an amorphous combination of rimonabant with a pharmaceutically acceptable carrier characterized by their XRPD patterns, differential scanning calohmetry ("DSC") curves, and/or infrared ("IR") absorption spectra.

A further aspect of the present invention provides a process for the preparation of crystalline Form III and Form IV of rimonabant which comprises: a) providing a solution of rimonabant hydrochloride in an alcoholic solvent; b) adjusting pH of the solution obtained in step b); c) combining with water; and d) recovering the solid.

A still further aspect of the present invention provides a process for the preparation of crystalline Form V of rimonabant, which comprises heating crystalline Form IV.

Yet another aspect of the invention provides a process for the preparation of crystalline Form Vl of rimonabant, which comprises recrystallizing rimonabant in an aromatic hydrocarbon solvent. An additional aspect of the present invention provides a process for the preparation of amorphous rimonabant and an amorphous combination of rimonabant with a pharmaceutically acceptable carrier which comprises: a) providing a solution of rimonabant either alone or in combination with a pharmaceutically acceptable carrier; b) removing the solvent; and c) optionally, drying the solid.

Further, an aspect of the present invention provides a pharmaceutical composition comprising crystalline Form III, Form IV, Form V, Form Vl, or an amorphous form of rimonabant, either alone or in combination with a pharmaceutically acceptable carrier, and one or more pharmaceutically acceptable excipients.

In an embodiment, the invention provides crystalline Form III of rimonabant.

Another embodiment of the invention provides a process for preparing crystalline Form III of rimonabant, comprising adjusting pH of a solution comprising rimonabant hydrochloride and an alcohol, to a value more than about 9.5, and adding water.

An embodiment of the invention provides crystalline Form IV of rimonabant.

Another embodiment of the invention provides a process for preparing crystalline Form IV of rimonabant, comprising adjusting pH of a solution comprising rimonabant hydrochloride and an alcohol, to about 7 to about 9, and adding water.

An embodiment of the invention provides crystalline Form V of rimonabant.

Another embodiment of the invention provides a process for preparing crystalline Form V of rimonabant, comprising heating Form IV of rimonabant to about 150 to about 2000C.

A further embodiment of the invention provides crystalline Form Vl of rimonabant.

Another embodiment of the invention provides a process for preparing crystalline Form Vl of rimonabant, comprising crystallizing from a solution comprising rimonabant and an aromatic hydrocarbon solvent.

In an additional embodiment, the invention provides amorphous rimonabant.

In a still further embodiment, the invention provides a process for preparing amorphous rimonabant, comprising removing solvent from a solution comprising rimonabant.

An additional embodiment of the invention provides an intimate dispersion comprising amorphous rimonabant and a pharmaceutically acceptable hydrophilic carrier. A further embodiment of the invention provides a process for preparing an intimate dispersion comprising amorphous rimonabant and a pharmaceutically acceptable carrier, comprising removing solvent from a solution comprising rimonabant and a pharmaceutically acceptable hydrophilic carrier. Yet another embodiment of the invention comprises a pharmaceutical composition comprising: one or more of crystalline Forms III, IV, V, and Vl of rimonabant, amorphous rimonabant, and amorphous rimonabant in an intimate dispersion with a pharmaceutically acceptable carrier; and at least one pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is an X-ray powder diffraction pattern of crystalline Form III of rimonabant prepared in Example 1. Fig. 2 is an X-ray powder diffraction pattern of crystalline Form IV of rimonabant prepared in Example 2.

Fig. 3 is an X-ray powder diffraction pattern of crystalline Form V of rimonabant prepared in Example 3.

Fig. 4 is an X-ray powder diffraction pattern of crystalline Form Vl of rimonabant prepared in Example 4.

Fig. 5 is an X-ray powder diffraction pattern of amorphous rimonabant prepared in Example 5.

Fig. 6 is a differential scanning calohmethc curve of amorphous rimonabant prepared in Example 5. Fig. 7 is an infrared absorption spectrum of amorphous rimonabant prepared in Example 5.

Fig. 8 is an X-ray powder diffraction pattern of an amorphous combination of rimonabant with povidone prepared in Example 8.

Fig. 9 is a differential scanning calorimetric curve of an amorphous combination of rimonabant with povidone prepared in Example 8.

Fig. 10 is an infrared absorption spectrum of an amorphous combination of rimonabant with povidone prepared in Example 8.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to polymorphic forms of rimonabant and processes for their preparation. In particular, it relates to crystalline Forms III, IV, V, Vl of rimonabant, an amorphous form of rimonabant, an amorphous combination of rimonabant with a pharmaceutically acceptable carrier, and processes for their preparation. An aspect of the present invention provides crystalline Forms III, IV, V, Vl of hmonabant characterized by their X-ray powder diffraction ("XRPD") patterns.

All XRPD data reported herein were obtained using Cu Ka radiation, having the wavelength 1.541 A and were obtained using a Bruker AXS D8 Advance Powder X-ray Diffractometer.

Crystalline Form III of rimonabant is characterized by an XRPD pattern substantially in accordance with the pattern of Fig. 1. Crystalline Form III of rimonabant is also characterized by an XRPD pattern having significant peaks at about 9.3, 10.5, 13.5, 16.1 , 17.1 , 17.8, 20.8, 22.4, 22.9, and 27.3, ± 0.2 degrees 2Θ. The pattern is also characterized by the additional XRPD peaks at about 7.3 and 19.2, ± 0.2 degrees 2Θ.

Crystalline Form IV of rimonabant is characterized by an XRPD pattern substantially in accordance with the pattern of Fig. 2. Crystalline Form IV of rimonabant is also characterized by an XRPD pattern having significant peaks at about 6.6, 10.9, 12.8, 15.5, 16.9, 18.6, 19.4, 19.7, 20.1 , 20.3, 25.0, 27.7, and 27.9, ± 0.2 degrees 2Θ. The pattern is also characterized by the additional XRPD peaks at about 21.2 and 22.0, ± 0.2 degrees 2Θ.

Crystalline Form V of rimonabant is characterized by an XRPD pattern substantially in accordance with the pattern of Fig. 3. Crystalline Form V of rimonabant is also characterized by an XRPD pattern having significant peaks at about 6.2, 6.7, 7.0, 7.9, 9.0, 9.7, 16.2, 17.07, 19.41 , 20.2, 20.4, 21.3, and 27.8, ± 0.2 degrees 2Θ. The pattern is also characterized by the additional XRPD peaks at about 10.0 and 11.7, ± 0.2 degrees 2Θ.

Crystalline Form Vl of rimonabant is characterized by an XRPD pattern substantially in accordance with the pattern of Fig. 4. Crystalline Form Vl of rimonabant is also characterized by an XRPD pattern having significant peaks at about 4.8, 5.5, 7.2, 7.9, 9.7, 16.4, 18.3, 19.9, 20.5, 21.0, and 25.5, ± 0.2 degrees 2Θ. The pattern is also characterized by the additional XRPD peaks at about 26.1 and 21.7, ± 0.2 degrees 2Θ. Another aspect of the present invention provides amorphous rimonabant, and an amorphous combination of rimonabant with a pharmaceutically acceptable carrier, characterized by their X-ray powder diffraction ("XRPD") patterns, differential scanning calorimetry ("DSC") curves, and/or infrared ("IR") absorption spectra. Amorphous rimonabant and an amorphous combination of hmonabant with at least one pharmaceutically acceptable carrier are characterized by their XRPD patterns showing a plain halo with no peaks, which is characteristic of an amorphous solid, substantially in accordance with Fig. 5 and Fig. 8, respectively. The infrared (IR) spectra of the amorphous form of rimonabant or an amorphous combination of rimonabant with pharmaceutically acceptable carriers have been recorded on a Perkin Elmer System Spectrum 1 model spectrophotometer, between 450 cm"1 and 4000 cm"1, with a resolution of 4 cm"1 in a potassium bromide pellet, the test compound being at the concentration of 1 % by mass.

Amorphous rimonabant is characterized by an infrared absorption spectrum in potassium bromide comprising peaks at about 522, 732, 783, 814, 833, 968, 1101 , 1092, 1137, 1245, 1358, 1529, 1485, 1497, 1682, 2791 , and 2937, ± 5 cm"1. Amorphous rimonabant is also characterized by its infrared absorption spectrum in potassium bromide substantially in accordance with the spectrum of Fig. 7.

An amorphous combination of rimonabant with povidone is characterized by an infrared absorption spectrum in potassium bromide comprising peaks at about 732, 814, 835, 1091 , 1269, 1287, 1421 , 1496, 1680, 2856, 2943, and 3346, ± 5 cm"1, The amorphous combination of rimonabant with povidone is characterized by its infrared absorption spectrum in potassium bromide substantially in accordance with the spectrum of Fig. 10.

Differential scanning calorimetric analysis was carried out in a DSC Q1000 model from TA Instruments with a ramp of 5 °C/minute with a modulation time of 60 seconds and a modulation temperature of ± 1 0C. The starting temperature was 0 0C and ending temperature was 200 0C.

Amorphous rimonabant has a characteristic differential scanning calohmetry curve substantially in accordance with Fig. 6, having an onset of glass transition at about 74 0C, a half point glass transition at about 76 0C and ending of glass transition at about 80 0C. An amorphous combination of rimonabant with a pharmaceutically acceptable carrier has a characteristic differential scanning calorimetry curve substantially in accordance with Fig. 9, having an onset of the glass transition at about 1000C, a half point glass transition at about 108 0C and ending of glass transition at about 117 0C.

A further aspect of the present invention provides a process for the preparation of crystalline Form III and Form IV of hmonabant. In an embodiment, the process comprises: a) providing a solution of rimonabant hydrochloride in an alcoholic solvent; b) adjusting pH of the solution obtained in step a); c) combining with water; and d) recovering the solid. Step a) involves providing a solution of rimonabant hydrochloride in an alcoholic solvent.

The solution of rimonabant hydrochloride may be obtained by dissolving rimonabant hydrochloride in a suitable alcoholic solvent, or such a solution may be obtained directly from a reaction in which rimonabant hydrochloride is formed. Suitable alcoholic solvents which can be used include, but are not limited to, methanol, ethanol, isopropanol, n-butanol, n-propanol, tertiary butyl alcohol and the like, and mixtures thereof.

Addition of the alcoholic solvent can be carried out at any temperature ranging from about 20 0C to about 50 0C. Step b) involves adjusting the pH of the solution obtained in step a). pH of the solution obtained above containing the hydrochloride salt is made alkaline to break the hydrochloride salt and release free rimonabant.

Suitable bases which can be used for adjusting the pH include, but are not limited to: alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate and the like; bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate, and the like; ammonia; and mixtures thereof. These bases can be used in the form of solids or in the form of aqueous solutions. Suitably, aqueous solutions containing about 5% to 50%, or about 10% to

20%, (w/v) of the corresponding base can be used. Any concentration is useful, which will convert the acid addition salt to a free rimonabant. The pH value of the solution determines the nature of polymorphic form obtained from the solution.

When the pH of the solution is adjusted to above about 9.5, such as in the range of from about 9.5 to about 14, the polymorphic form obtained is Form III. When the pH of the solution is adjusted to about 7 to about 9, the polymorphic form obtained is Form IV.

Step c) involves combining with water.

After adjusting the pH, water is used as an anti-solvent for separation of the product. The quantity of water used generally ranges from about 5 to about 20 times the weight of hmonabant, although different amounts can be used.

Optionally, the solution obtained in step b) can be treated to remove the solvent before addition of the anti-solvent. The solvent can be partially or completely removed, and this option can provide the benefits of improved product yield and a reduction in the amount waste materials generated. Solvent may be removed by distillation under a vacuum, such as below about 100 mm Hg to below about 600 mm Hg, at elevated temperatures such as about 20 0C to about 70 0C. Any temperature and vacuum conditions can be used as long as there is no increase in the impurity levels of the product.

The anti-solvent addition can be carried out at temperatures of the range of 10 to about 50 0C of from about 10 to about 30 0C.

The reaction mass may be maintained further at temperatures lower than the concentration temperatures, such as for example below about 10 0C to about 25 0C, for a period of time as required for a more complete separation of the product. The exact cooling temperature and time required for complete separation can be readily determined by a person skilled in the art and will also depend on parameters such as concentration and temperature of the solution or slurry.

Optionally separation may be enhanced by methods such as cooling, partial removal of the solvent from the mixture, or by adding an anti-solvent to the reaction mixture or a combination thereof. Step d) involves recovering the solid obtained in step c).

The methods by which the solid material is recovered from the final mixture, with or without cooling below the operating temperature, can be any of techniques such as filtration by gravity, or by suction, centrifugation, and the like. If desired the crystals can be washed with a solvent to wash out the mother liquor.

The wet cake obtained above optionally may be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying can be carried out at temperatures of about 35 0C to about 70 0C. The drying can be carried out for any desired time periods such as from about 1 to 20 hours, or longer, until a desired purity is obtained.

Rimonabant crystalline Form III and Form IV obtained above typically have a moisture content of about 3% to about 5%.

Rimonabant hydrochloride that is used in the process of the present invention can be prepared by a process comprising reacting a solution of rimonabant with hydrochloric acid.

The solution of rimonabant can be prepared by dissolving rimonabant in a suitable solvent, or such a solution may be obtained directly from a reaction in which rimonabant is formed. Any form of rimonabant such as any crystalline form of rimonabant including any salts, solvates and hydrates may be utilized for preparing the solution.

Suitable solvents which can be used for dissolution include, but are not limited to: ketones such as acetone, methyl isobutyl ketone, and cyclohexanone; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, tertiary- butyl alcohol, ethylene glycol, and the like; chlorinated solvents such as dichloromethane, chloroform, carbon tetrachloride and the like; and mixtures thereof. The dissolution temperatures can range from about 20 to 120 0C depending on the solvent used for dissolution. Any other temperature is also acceptable as long as a clear solution of rimonabant is provided.

The quantity of solvent used for dissolution depends on the solvent and the dissolution temperature adopted. The concentration of rimonabant in the solution may generally range from about 0.1 to about 1 g/ml in the solvent.

A rimonabant solution is then reacted with hydrochloric acid, in an amount about 1 to about 1.2 moles of hydrogen chloride per mole of rimonabant. Larger amounts of hydrogen chloride can be used, but this will adversely affect the economics of the process.

Hydrochloric acid can be added directly, or its solution in an appropriate solvent can be used. Solutions of hydrochloric acid in water or any of the alcohols like isopropanol may be used. Suitably, solutions containing about 5% to 50%, or about 10% to 20%, (w/v) of the acid can be used.

Hydrochloric acid can be added at temperatures as high as about 80 to about 30 0C, or addition can be done at lower temperatures of the range of 0 to 30 0C. The reaction mixture may be maintained further at temperatures lower than the temperatures of hydrochloric acid addition such as for example below about 10 0C to about 25 0C, for a period of time for isolation of the product. The exact cooling temperature and time required for complete isolation can be readily determined by a person skilled in the art and will also depend on parameters such as concentration and temperature of the solution.

Optionally, isolation may be enhanced by methods such as cooling, partial removal of the solvent from the mixture, by adding an anti-solvent to the reaction mixture or a combination thereof.

After isolation, the solid material is recovered from the final mixture, with or without cooling below the operating temperature by any of the techniques such as filtration by gravity, or by suction, centhfugation, and the like. If desired, the crystals can be washed with a solvent to wash out the mother liquor.

The wet hydrochloride salt obtained can be optionally dried further before dissolving it in an alcoholic solvent. Drying can be carried out at temperatures of about 35 0C to about 70 0C.

The drying can be carried out for any desired time periods from about 1 to 20 hours.

A still further aspect of the present invention relates to a process for the preparation of crystalline Form V of rimonabant. In an embodiment, the process comprises heating crystalline Form IV.

Crystalline Form V of Rimonabant can be obtained by heating crystalline Form IV of rimonabant to temperatures of the range of about 150 0C to about 200 0C. Heating can be carried out using any type of device, such as an oven.

Yet another aspect of the invention provides a process for the preparation of crystalline Form Vl of rimonabant. In an embodiment, the process comprises recrystallization of rimonabant from its solution in an aromatic hydrocarbon solvent.

Recrystallization involves providing a solution of rimonabant in an aromatic hydrocarbon solvent and isolating the solid from the solution.

The solution of rimonabant may be obtained by dissolving rimonabant in the solvent, or such a solution may be obtained directly from a reaction in which rimonabant is formed.

When the solution is prepared by dissolving rimonabant in an aromatic hydrocarbon solvent, any form of rimonabant such as any crystalline form of rimonabant including any salts, solvates and hydrates may be utilized for preparing the solution. Suitable aromatic hydrocarbon solvents which can be used include, but are not limited to, benzene, toluene, xylene and the like, and mixtures thereof.

The dissolution temperatures can range from about 20 0C to 150 0C depending on the solvent used for dissolution. Any other temperature is also acceptable as long as a clear solution of rimonabant is provided. The quantity of solvent used for dissolution depends on the solvent and the dissolution temperature adopted. The concentration of rimonabant in the solution may generally range from about 0.1 to about 1 g/ml in the solvent.

For isolation to occur, the reaction mass may be maintained further at temperatures lower than the concentration temperatures such as for example below about 10 0C to about 25 0C, for a period of time as required for a more complete isolation of the product. The exact cooling temperature and time required for complete isolation can be readily determined by a person skilled in the art and will also depend on parameters such as concentration and temperature of the solution or slurry. Optionally isolation may be enhanced by methods such as cooling, partial removal of the solvent from the mixture, by adding an anti-solvent to the reaction mixture or a combination thereof. The solid material isolated is recovered from the final mixture, with or without cooling below the operating temperature, can be any of techniques such as filtration by gravity, or by suction, centrifugation, and the like. The crystals so isolated will carry a small proportion of occluded mother liquor containing a higher percentage of impurities. If desired the crystals can be washed with a solvent to wash out the mother liquor.

Optionally, the solid isolated may be further dried. Drying can be carried out at reduced pressures, such as below about 200 mm Hg or below about 50 mm Hg, at temperatures such as about 35 0C to about 70 0C. The drying can be carried out for any desired time period that achieves a desired purity, such as times about 1 to 20 hours, or longer. Drying may also be carried out for shorter or longer periods of time depending on the product specifications.

An additional aspect of the present invention provides a process for the preparation of amorphous hmonabant, or an amorphous combination of rimonabant with a pharmaceutically acceptable carrier. In an embodiment the process comprises: a) providing a solution of rimonabant either alone or in combination with a pharmaceutically acceptable carrier; b) removing the solvent; and c) optionally, drying the solid.

Step a) involves providing a solution of rimonabant either alone or in the presence of a pharmaceutically acceptable carrier.

The solution of rimonabant may be obtained by dissolving rimonabant in a suitable solvent, or a solution may be obtained directly from a reaction in which rimonabant is formed.

When the solution is prepared by dissolving rimonabant in a suitable solvent, any form of rimonabant such as any crystalline form of rimonabant including any salts, solvates and hydrates may be utilized for preparing the solution. When the solution of rimonabant is prepared along with a pharmaceutically acceptable carrier, the order of charging the different materials is not critical for the product obtained. A specific order may be preferred with respect to the equipment actually used and will be easily determined by a person skilled in the art. In any case, the rimonabant must be completely soluble in the solvent of the invention and should provide a clear solution. The presence of undissolved crystals could lead to the formation of a material which is not completely amorphous. Suitable solvents which can be used for dissolving rimonabant either alone or along with a pharmaceutically acceptable carrier include but are not limited to: alcohols such as methanol, ethanol, isopropyl alcohol, n-propanol, and the like; halogenated hydrocarbons such as dichloromethane, 1 ,2-dichloroethane, chloroform, carbon tetrachloride and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; ethers such as diethyl ether, dimethyl ether, diisopropyl ether, 1 ,4-dioxane and the like; hydrocarbons such as toluene, xylene, n-heptane, cyclohexane, n-hexane and the like; nithles such as acetonithle, propionitrile and the like; and mixtures thereof or their combinations with water in various proportions.

The pharmaceutically acceptable carriers that can be used for the preparation of amorphous combinations of rimonabant include but are not limited to hydrophilic carriers such as polyvinylpyrrolidone (homopolymers or copolymers of N-vinyl pyrrolidone, also called "povidone"), gums, cellulose derivatives (including hydroxypropyl methylcellulose, hydroxypropyl cellulose and others), cyclodextrins, gelatins, hypromellose phthalate, sugars, polyhydhc alcohols, polyethylene glycol, polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohol, propylene glycol derivatives, and the like. The use of mixtures of more than one of the pharmaceutical carriers to provide desired release profiles or for the enhancement of stability is within the scope of this invention. Also, all viscosity grades, molecular weights, commercially available products, their copolymers, mixtures are all within the scope of this invention without limitation.

These lists of solvents and pharmaceutically acceptable carriers are merely representative of those that can be used, and the lists are not intended to be exhaustive.

The ratio of rimonabant to the pharmaceutically acceptable carrier can range from about 1 :99 to about 99:1 w/w, or from about 1 : 10 to about 10:1 w/w. The dissolution temperature can range from about 20 to 120 0C depending on the solvent used for dissolution. Any other temperature is also acceptable as long as a clear solution of rimonabant either alone or together with a pharmaceutically acceptable carrier is provided. The quantity of solvent used for dissolution depends on the solvent and the dissolution temperature adopted. The concentration of rimonabant in the solution may generally range from about 0.1 to about 1 g/ml in the solvent.

Rimonabant and the pharmaceutically acceptable carrier used can be dissolved either in the same solvent or they may be dissolved in different solvents and then combined to form a mixture.

The solution may optionally be treated with materials such as carbon or with sodium sulfate for clarification.

Optionally, the solution obtained above can be treated to remove undissolved particles, followed by further processing. Any undissolved particles can be removed suitably by filtration, centrifugation, decantation, and other techniques. The solution can be filtered by passing through paper, glass fiber, or other membrane material, or a bed of 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.

Step b) involves removal of the solvent from the solution obtained from step a), using a suitable technique.

Removal of the solvent may be carried out suitably using evaporation, atmospheric distillation, or distillation under vacuum. Distillation of the solvent may be conducted under a vacuum, such as below about 100 mm Hg to below about 600 mm Hg, at elevated temperatures such as about 20 0C to about 70 0C. Any temperature and vacuum conditions can be used as long as there is no increase in the impurity levels of the product.

Suitable techniques which can be used for the distillation include, distillation using a rotational evaporator device such as a Buchi Rotavapor, spray drying, agitated thin film drying ("ATFD"), and the like. These techniques are applicable to both aqueous and organic solutions of rimonabant and mixtures of rimonabant with a pharmaceutically acceptable carrier. However, solutions using the more volatile organic solvents are preferred.

Techniques such as Buchi Rotavapor drying and dry distillation under vacuum may be suitable for laboratory-scale processes such as for quantities less than about 100 g. Other techniques such as spray drying and ATFD are more suitable for industrial scale production with a batch size of at least about 100 g or about 1 kg, or greater.

The amorphous material obtained from step b) can be collected from the equipment using techniques such as by scraping, shaking the container, or by other methods specific to the equipment being used.

Step c) involves an optional drying of the product obtained from step b) to afford the amorphous rimonabant or amorphous combination of rimonabant with a pharmaceutically acceptable carrier, substantially free of residual solvents. Drying can be carried out under reduced pressure until the residual solvent content reduces to an amount that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use ("ICH") guidelines. The guideline solvent level depends on the type of solvent but is not more than about 5000 ppm, or about 4000 ppm, or about 3000 ppm.

The drying can be carried out at reduced pressures, such as below about 200 mm Hg or below about 50 mm Hg, at temperatures such as about 35 0C to about 70 0C. The drying can be carried out for any desired time period that achieves the desired result, such as times about 1 to 20 hours, or longer. Drying may also be carried out for shorter or longer periods of time depending on the product specifications.

Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, or using a fluidized bed drier, spin flash dryer, flash dryer and the like.

It is generally preferred that a rapid drying be utilized to provide the desired amorphous form free from organic solvent.

The dried product can optionally be milled to get the required particle size. Milling or micronization can be performed prior to drying, or after the completion of drying of the product. The milling operation reduces the size of particles and increases surface area of particles by colliding particles with each other at high velocities.

Drying is more efficient when the particle size of the material is smaller and the surface area is higher, hence milling can be performed prior to the drying operation.

Milling can be done suitably using jet milling equipment like an air jet mill, or using other conventional milling equipment.

The amorphous combinations of different active ingredients with different stabilizers show differences in their physical properties like flowability, solubility, stability, etc.

The amorphous combination of rimonabant with the pharmaceutically acceptable carrier obtained by the present process forms an intimate mixture of the amorphous rimonabant particles and the pharmaceutically acceptable carrier molecules in the matrix. While the invention should not be constrained by any particular theory, it is considered that the amorphous combinations of rimonabant with the pharmaceutically acceptable carrier are solid dispersions at a molecular level, or having the nature of solid solutions.

The process described in International Application Publication No. 2004/009057 A1 for the preparation of nano-crystalline particle dispersions comprises rapid mixing of a solution of a water-immiscible solid in an aqueous medium, optionally in combination with a water-miscible solvent in the presence or absence of a stabilizer, to form a dispersion of amorphous particles. This dispersion of amorphous particles is sonicated to form the dispersion of nano- crystalline particles. The process described in the published application does not isolate amorphous rimonabant, but it describes a suspension of amorphous rimonabant, which can be utilized for the production of crystalline nano-particulate dispersions of rimonabant. Material prepared using this process comprises independent particles having a deposition thereon of smaller particles. These particles are heterogeneous, that is, rimonabant and other components are not in an intimate mixture.

Amorphous rimonabant and amorphous combinations of rimonabant with pharmaceutically acceptable salts obtained in the present invention contain less than about 5000 ppm, or less than about 3000 ppm, or less than about 1000 ppm of methanol, and less than about 200 ppm, or less than about 100 ppm of individual residual organic solvents.

The D10, D50, and D90 values are useful ways for indicating a particle size distribution. D90 refers to the value for the particle size for which at least 90 volume percent of the particles have a size smaller than the value. Likewise D50 and Dio refer to the values for the particle size for which 50 volume percent, and 10 volume percent, of the particles have a size smaller than the value. Methods for determining Di0, D50, and D90 include laser light diffraction, such as using equipment sold by Malvern Instruments Ltd. of Malvern, Worcestershire, United Kingdom.

The polymorphic forms obtained according to the present invention typically have: a mean particle size less than about 100 μm; D10 less than about 10 μm, or less than about 5 μm; D50 less than about 50 μm, or less than about 40 μm; and D90 less than about 400 μm, or less than about 300 μm. A Malvern instrument calculates the mean particle size and gives it as D(4,3). It is the average particle size of the powder. There is no specific lower limit for any of the D values.

The amorphous hmonabant and amorphous combination of rimonabant with pharmaceutically acceptable carriers obtained according to the process described in this invention have a bulk density less than 0.8 g/ml, or less than 0.5 g/ml, before tapping, and a bulk density less than 1 g/ml, or less than 0.5 g/ml, after tapping. The bulk densities are determined using Test 616 "Bulk Density and Tapped Density," United States Pharmacopeia 24, pages 1913-4 (United States Pharmacopeial Convention, Inc., Rockville, Maryland, 1999). An additional aspect of the present invention provides a pharmaceutical composition comprising crystalline Form III, Form IV, Form V, Form Vl, or an amorphous form of rimonabant, either alone or in combination with a pharmaceutically acceptable carrier, together with one or more pharmaceutically acceptable excipients. The pharmaceutical composition comprising crystalline Form III, Form IV,

Form V, Form Vl, or an amorphous form of rimonabant either alone or in combination with a pharmaceutically acceptable carrier of this invention may be further formulated into solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as but not limited to solutions, dispersions, and freeze dried compositions. Formulations may be in the form of immediate release, delayed release or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared by direct blending, dry granulation or wet granulation or by extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated. Compositions of the present invention may further comprise one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients that find use in the present invention include, but are not limited to: diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, pregelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodexthns, resins; release rate controlling agents such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, methyl cellulose, various grades of methyl methacrylates, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but are not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.

In the compositions of the present invention, rimonabant is a useful active ingredient in the range of about 5 to about 50 mg, per dosage unit. Certain specific aspects and embodiments of this invention are described in further detail by the examples below, which examples are provided only for the purpose of illustration and are not intended to limit the scope of the appended claims in any manner.

EXAMPLE 1 PREPARATION OF RIMONABANT CRYSTALLINE FORM III

25.3 g of hmonabant was taken into a clean round bottom flask and 152 ml of acetone was added to it. The reaction mixture was heated to 55 0C. 6.26 g of 35% aqueous hydrochloric acid was added to the above solution at 55 0C. The reaction mass was then cooled to 0 0C and maintained at 0 to 3 0C for 15 minutes. The separated solid was filtered and washed with 38 ml of acetone. The wet solid was taken into another round bottom flask and 126 ml of methanol was added to it. The pH of the reaction mixture was adjusted to 11 with 6.95 ml of a 40 % aqueous solution of sodium hydroxide at 28 0C. 253 ml of demineralized water was then added to the reaction mass followed by stirring for 40 minutes at 30 0C. The separated solid was filtered and washed with 253 ml of demineralized water. The resultant solid was dried at 50 0C under a vacuum of 650 mm Hg for 8 hours to afford 22 g of the title compound. DSC thermogram: Endotherm at 111 0C.

Thermogravimetric Analysis (TGA) weight loss: 3.405%.

EXAMPLE 2 PREPARATION OF RIMONABANT CRYSTALLINE FORM IV 12 g of rimonabant and 300 ml of acetone were taken into a clean and dry round bottom flask and heated to 55 0C. 2.97 g of hydrochloric acid was added to it under stirring. The above reaction mixture was then cooled to 0 0C followed by stirring for 45 minutes. The reaction mass was stirred at 0 to 5 0C for 30 minutes and the separated solid was filtered and washed with 20 ml of precooled acetone. The wet solid was taken into a round bottom flask and 85 ml of methanol was added to it. pH of the reaction mixture was adjusted to 8.5 by adding 3.3 ml of aqueous sodium hydroxide (48%) solution under stirring. The reaction mass was then distilled completely at 64 0C under a reduced pressure of about 20 mbar. 125 ml of demineralized water was added to the obtained residue and stirred for 20 minutes. The separated solid was washed with 100 ml of demineralized water. The wet solid was dried under a reduced pressure of about 20 mbar to afford 9.3 g of the title compound. DSC: Endotherm at 249 0C.

Thermogravimetric Analysis (TGA) weight loss: 3.212%.

EXAMPLE 3 PREPARATION OF RIMONABANT CRYSTALLINE FORM V 18.15 g hmonabant crystalline Form IV was placed onto a TGA platinum pan (TA Instruments, Model number TGA Q500) and the pan was installed on the thermogravimetric analyzer, adjusting the balance nitrogen flow to 40 ml/minute and the sample nitrogen flow to 60 ml/minute. The sample was heated to 170 0C at a heating rate of 10 °C/minute for 5 minutes. The resultant solid was cooled to 30 0C and was recovered by conventional methods to afford the desired crystalline Form V of hmonabant.

EXAMPLE 4 PREPARATION OF RIMONABANT CRYSTALLINE FORM Vl 1.0 g of hmonabant was taken into a clean and dry round bottom flask equipped with a Dean-Stark apparatus and 25 ml of toluene was added to it. The resultant mixture was heated to 110 0C followed by stirring for about 3 hours. The reaction mixture was then cooled to 28 0C and was stirred for 10 minutes. The separated solid was filtered and the solid was washed with 5 ml of toluene. The wet solid was dried at 70 0C for about 8 hours to afford 0.72 g of the title compound.

Thermogravimetric analysis (TGA) weight loss: 0.327 %.

EXAMPLE 5 PREPARATION OF AMORPHOUS RIMONABANT USING DICHLOROMETHANE AS THE SOLVENT

4 g of rimonabant was dissolved in 80 ml of dichloromethane and the solution was filtered through a celite bed followed by washing of the bed with 4 ml of dichloromethane. The combined filtrate was taken into a Buchi Rotavapor flask and distilled under a vacuum of 20 mbar at a temperature of 50° C. The solid obtained was then dried in an air oven at 45° C for 9 hours to obtain 3.6 g of the title compound. Residual dichloromethane content: 487 ppm.

EXAMPLE 6

PREPARATION OF AMORPHOUS RIMONABANT USING ACETONE AS THE SOLVENT 25 g of hmonabant was dissolved in 1250 ml of acetone. 2.5 g of carbon was added to the reaction mass and stirred for 30 minutes at 27° C. The solution was then filtered through a celite bed and the filter bed was washed with 100 ml of acetone. The filtrate was taken into a Buchi Rotavapor flask and distilled under a vacuum of 20 mbar at a temperature of 50° C. The solid was recovered and dried at 40 ° C in an air oven for 8 hours to yield 23.2 g of the title compound. Particle Sizes: D10 5.9 μm, D50 30.5 μm, D90 275.9 μm. Bulk Density: Before tapping: 0.13 g/ml, after tapping: 0.26 g/ml.

EXAMPLE 7 PREPARATION OF AMORPHOUS RIMONABANT USING TOLUENE AS THE SOLVENT

0.5 g of hmonabant was dissolved in 10 ml of toluene and the solution was filtered through a Whatman No. 1 filter paper of dimensions 46^57 cm followed by filtration through a polypropylene cloth with a 5-10 micron pore size. The filtration cloth was washed with 5 ml of toluene. The combined filtrate was taken into a Buchi Rotavapor flask and distilled under a vacuum of 20 mbar at a temperature of 65° C. The obtained solid was recovered to yield 0.35 g of the title compound.

EXAMPLE 8 PREPARATION OF AN AMORPHOUS COMBINATION OF RIMONABANT WITH POVIDONE

5 g of rimonabant was dissolved in 75 ml of dichloromethane and the solution was checked for clarity. 10 g of povidone (PVP K30) was added to the above solution. The mixture was stirred at 27° C for 15 minutes to achieve a clear solution. The solution was filtered through a celite bed and the filter bed was washed with 10 ml of dichloromethane. The combined filtrate was taken into a Buchi Rotavapor flask and distilled under a vacuum of 20 mbar at a temperature of 45° C. The solid obtained was recovered and dried in an oven at 45° C for 6 hours to yield 8.5 g of the title composition.

EXAMPLE 9

PREPARATION OF AN AMORPHOUS COMBINATION OF RIMONABANT WITH POVIDONE

10 g of hmonabant was dissolved in 150 ml of dichloromethane and the solution was checked for clarity. 10 g of povidone (PVP K30) was added to the above solution. The mixture was stirred at 27° C for 15 minutes to obtain a clear solution. The solution was filtered through a celite bed and the filter bed was washed with 20 ml of dichloromethane. The combined filtrate was taken into a Buchi Rotavapor flask and distilled under a vacuum of 20 mbar at a temperature of 42° C. The solid obtained was recovered and dried in an oven at 40° C for 12 hours to yield 15.8 g of the title composition.

Particle Size Data: Di0 2.1 μm, D5o 39.2 μm, D90 253.7 μm, mean particle size 90.8 μm.

Bulk Density: Before tapping: 0.40 g/ml, after tapping: 0.47 g/ml.

EXAMPLE 10 TABLET COMPOSITION OF AMORPHOUS RIMONABANT

Figure imgf000025_0001
Rimonabant, starch, lactose monohydrate, croscarmellose sodium are sifted through an ASTM 40 mesh sieve. SLS and povidone K30 are dissolved in 50 ml of purified water. Granulate the dry mixture of rimonabant and other excipients above using a solution of SLS and povidone in water in a rapid mixer granulator. Granules are dried in a fluid bed drier at a temperature of 60 0C until the loss on drying ("LOD") of the dried granules is not more than 3% when measured using an infrared moisture balance at 105 0C. Dried granules are sifted through a ASTM 24 mesh sieve and lubricated by mixing with ASTM 40 mesh sifted magnesium stearate in a double cone blender for 5 minutes. Blended granules are compressed into tablets using 12.5 mm round tablet tooling wherein each tablet comprises 20 mg of rimonabant.

EXAMPLE 11 CAPSULE COMPOSITION OF AMORPHOUS RIMONABANT

Figure imgf000026_0001

Rimonabant, starch, dibasic calcium phosphate, sodium starch glycolate are sifted through an ASTM 40 mesh sieve. SLS and povidone K30 are dissolved in 50 ml of water. Granulate the dry mixture of rimonabant and other excipients above using solution of SLS and povidone in water in a rapid mixer granulator. Granules are dried in a fluid bed drier at a temperature of 60 0C until the LOD of the dried granules is not more than 3% when measured using an infrared moisture balance at 105 0C. Dried granules are sifted through an ASTM 24 mesh sieve and lubricated by mixing with ASTM 40 mesh sifted magnesium stearate in a double cone blender for 5 minutes. Blended granules are filled into size 1 hard gelatin capsules wherein each capsule comprises 30 mg of rimonabant. EXAMPLE 12

CAPSULE COMPOSITION OF AMORPHOUS COMBINATION OF RIMONABANT WITH POVIDONE

Figure imgf000027_0001

* Rimonabant-povidone 20 grams, prepared in Example 9, is equivalent to rimonabant 10 grams.

Rimonabant, starch, microcrystalline cellulose, sodium starch glycolate are sifted through an ASTM 40 mesh sieve. SLS and povidone K30 are dissolved in 50 ml of water. Granulate the dry mixture of rimonabant and other excipients above using a solution of SLS and povidone in water in a rapid mixer granulator. Granules are dried in a fluid bed drier at a temperature of 60 0C until the LOD of the dried granules is not more than 3% when measured using an infrared moisture balance at 105 0C. Dried granules are sifted through an ASTM 24 mesh sieve and lubricated by mixing with ASTM 40 mesh sifted magnesium stearate in a double cone blender for 5 minutes. Blended granules are filled into size 1 hard gelatin capsules where each capsule comprises 10 mg of rimonabant.

Claims

CLAIMS:
1. Crystalline Form III of rimonabant.
2. A process for preparing crystalline Form III of rimonabant, comprising adjusting pH of a solution comprising rimonabant hydrochloride and an alcohol, to a value more than about 9.5, and adding water.
3. The process of claim 2, wherein an alcohol comprises methanol.
4. The process of either of claims 2 or 3, wherein pH is adjusted to a value between about 9.5 and about 14.
5. The process of any one of claims 2-4, wherein an alcohol is partially or completely removed from a solution, before adjusting pH.
6. The process of any one of claims 2-5, wherein water is added in an amount about 5 to about 20 times the weight of rimonabant.
7. Crystalline Form IV of rimonabant.
8. A process for preparing crystalline Form IV of rimonabant, comprising adjusting pH of a solution comprising rimonabant hydrochloride and an alcohol, to about 7 to about 9, and adding water.
9. The process of claim 8, wherein an alcohol comprises methanol.
10. The process of either of claims 8 or 9, wherein an alcohol is partially or completely removed from a solution, before adjusting pH.
11. The process of any one of claims 8-10, wherein water is added in an amount about 5 to about 20 times the weight of rimonabant.
12. Crystalline Form V of rimonabant.
13. A process for preparing crystalline Form V of rimonabant, comprising heating Form IV of rimonabant to about 150 to about 2000C.
14. Crystalline Form Vl of rimonabant.
15. A process for preparing crystalline Form Vl of rimonabant, comprising crystallizing from a solution comprising rimonabant and an aromatic hydrocarbon solvent.
16. The process of claim 15, wherein an aromatic hydrocarbon solvent comprises toluene.
17. Amorphous rimonabant.
18. A process for preparing amorphous rimonabant, comprising removing solvent from a solution comprising rimonabant.
19. An intimate dispersion comprising amorphous hmonabant and a pharmaceutically acceptable hydrophilic carrier, wherein a weight ratio of rimonabant to carrier is about 1 :99 to about 99:1.
20. The intimate dispersion of claim 19, wherein a weight ratio of rimonabant to carrier is about 1 : 10 to about 10:1.
21. The intimate dispersion of either of claims 19 or 20, wherein a pharmaceutically acceptable hydrophilic carrier comprises polyvinylpyrrolidone.
22. A process for preparing an intimate dispersion comprising amorphous rimonabant and a pharmaceutically acceptable hydrophilic carrier, comprising removing solvent from a solution comprising rimonabant and a pharmaceutically acceptable hydrophilic carrier.
23. A pharmaceutical composition comprising: one or more of crystalline Forms III, IV, V, and Vl of rimonabant, amorphous rimonabant, and amorphous rimonabant in an intimate dispersion with a pharmaceutically acceptable carrier; and at least one pharmaceutically acceptable excipient.
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WO2008026219A3 (en) * 2006-09-01 2009-12-03 Hetero Drugs Limited Novel polymorphs of rimonabant
WO2008056377A3 (en) * 2006-11-06 2008-10-30 Cadila Healthcare Ltd Polymorphic forms of rimonabant
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