WO2008088900A2 - Polymorphic forms of rimonabant base and processes for preparation thereof - Google Patents

Polymorphic forms of rimonabant base and processes for preparation thereof Download PDF

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WO2008088900A2
WO2008088900A2 PCT/US2008/000726 US2008000726W WO2008088900A2 WO 2008088900 A2 WO2008088900 A2 WO 2008088900A2 US 2008000726 W US2008000726 W US 2008000726W WO 2008088900 A2 WO2008088900 A2 WO 2008088900A2
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rimonabant base
crystalline
rimonabant
base
hours
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PCT/US2008/000726
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French (fr)
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WO2008088900A3 (en
WO2008088900A9 (en
Inventor
Michal Rafilovich
Revital Lifshitz-Liron
Judith Aronhime
Marina Kalujny
Eli Lancry
Yaron Shmuely
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Teva Pharmaceutical Industries Ltd.
Teva Pharmaceuticals Usa, Inc.
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Publication of WO2008088900A2 publication Critical patent/WO2008088900A2/en
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Publication of WO2008088900A3 publication Critical patent/WO2008088900A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • Rimonabant was first described in EP Patent No. 656354 and corresponding U.S. Patent No. 5,624,941, herein the '941 patent, where the base, salt and solvate forms are described.
  • U.S. Patent Application 2005/0043356 and the corresponding published International Patent Application No. WO 2003/040105 describe an additional 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, a powder XRD diffractogram and peaks, solubility, melting point and a single-crystal X-ray diffraction.
  • the present invention provides amorphous Rimonabant base and crystalline forms of Rimonabant base, as well as crystalline Rimonabant base form I having a substantially reduced solvent content, methods of preparing these crystalline forms, and pharmaceutical compositions comprising such crystalline forms.
  • the present invention provides a process for preparing Rimonabant base Form I comprising: slurrying amorphous Rimonabant base in a C 5-8 hydrocarbon such as heptane to obtain Rimonabant Form I.
  • the present invention provides a process for preparing Rimonabant base Form II comprising: providing a solution of Rimonabant base and DMSO; admixing water; and recovering the Rimonabant base Form II.
  • the present invention provides a process for preparing Rimonabant base Form II comprising: providing a solution of Rimonabant base and a solvent selected from the group consisting acetone, ethylacetate or mixtures thereof; admixing pentane; and recovering the Rimonabant base Form II.
  • Figure 11 shows a powder X-ray diffraction pattern for Rimonabant base Form XII as prepared by example 52.
  • the amorphous Rimonabant base may be prepared by a process comprising: providing Rimonabant base and a solvent selected from the group consisting of: 1,4-dioxane, ethyl acetate, acetone and mixtures thereof to obtain a mixture; admixing the mixture with a C 5 to C 8 hydrocarbon, preferably heptane or pentane to obtain an amorphous Rimonabant base; and recovering the amorphous Rimonabant base.
  • the amorphous Rimonabant base is obtained by evaporating the solvents under reduced pressure.
  • 1,4- dioaxane and heptane are the solvents in the above process evaporation under reduced pressure may further include heating to a temperature of about 50°C to about 60 0 C for a period of about l ⁇ hours to about 32 hours, more preferably to a temperature of about 55°C for a period of about 24 hours.
  • the Rimonabant base and solvent are in solution.
  • the amorphous form of Rimonabant base may be recovered by filtration.
  • solvent weight loss as measured by standard TGA procedures may be about 7 weight % to about 8 weight %, preferably about 7.7 weight %.
  • the water content, as measured by KF, may be about 0.1 weight % to about 1 weight %, preferably about 0.2 weight %.
  • Rimonabant Form III crystals are relatively small in size when compared to Forms I and II.
  • the present invention provides a crystalline form of Rimonabant base, designated Form FV characterized by a powder XRD pattern with peaks at about 6.6, 8.4, 13.4 and 14.3 ⁇ 0.2 degrees two-theta.
  • Rimonabant base Form IV may be further characterized by a powder XRD pattern with an additional peak at about 21.8 ⁇ 0.2 degree two-theta.
  • Crystalline Form FV may have a powder XRD pattern substantially as depicted in Figure 3.
  • Rimonabant base Form IV may be prepared by a process comprising: combining ethanol and Rimonabant base to obtain a mixture; mixing the mixture for about 1 to about 10 minutes to obtain Rimonabant base Form IV; and recovering the Rimonabant base Form IV without drying the obtained crystalline Rimonabant base.
  • the Rimonabant base and ethanol are mixed for about 1 to about 5 minutes.
  • Rimonabant base Form V may be prepared by a process comprising: providing a solution of Rimonabant base and 1,4-Dioxane; admixing water, preferably in more than one portion, more preferably in three portions; maintaining for a period sufficient to obtain Rimonabant base Form V. Preferably, maintaining is for about 6 hours to about 48 hours, preferably for about 12 to about 24 hours. Once obtained, the Rimonabant base Form V can be recovered by removal of the solvent for example by drying under vacuum.
  • the present invention provides a crystalline form of Rimonabant base, designated Form VI characterized by a powder XRD pattern with peaks at about 10.2, 13.8, 15.6, 23.3 and 24.4 ⁇ 0.2 degrees two-theta.
  • Rimonabant base Form VI may be further characterized by a powder XRD pattern with one or more additional peaks at about 18.9, 20.4 and 22.9 ⁇ 0.2 degree two-theta.
  • Crystalline Form VI may have a powder XRD pattern substantially as depicted in Figure 5.
  • the present invention provides a crystalline form of Rimonabant base, designated Form VII characterized by a powder XRD pattern with peaks at about 4.0, 8.0, 10.4 and 15.7 ⁇ 0.2 degrees two-theta.
  • Rimonabant base Form VII may be further characterized by a powder XRD pattern with one or more additional peaks at about 19.2, 19.7 and 21.4 ⁇ 0.2 degree two-theta.
  • Crystalline Form VII may have a powder XRD pattern substantially as depicted in Figure 6.
  • the present invention provides a crystalline form of Rimonabant base, designated Form IX, characterized data selected from the list consisting of: a powder XRD pattern with peaks at about 13.7, 14.6, 16.2, 20.8 and 21.6 ⁇ 0.2 degrees two-theta; a solid-state 13 C NMR spectrum with signals at about 161.9, 145.4, 143.5, 136.0 and 129.6 ⁇ 0.2 ppm; a solid-state 13 C NMR spectrum having chemical shifts differences between the signal exhibiting the lowest chemical shift and another in the chemical shift range of 100 to 180 ppm of about 45.5, 29, 27.1, 19.6 and 13.2 ⁇ 0.1 ppm.
  • Rimonabant base Form IX may be further characterized by a powder XRD pattern with one or more additional peaks at about 6.9, 8.6, 19.4, 22.1, 22.5 and 24.3 ⁇ 0.2 degrees two-theta.
  • Crystalline Form DC may have a powder XRD pattern substantially as depicted in Figure 8, a 13 C NMR spectrum substantially as depicted in Figure 15, or a solid-state 13 C NMR spectrum substantially as depicted in Figure 16.
  • Crystalline Form DC may have a solvent weight loss as measured by standard TGA procedures of about 8 to 9 weight percent, preferably about 8.3 weight %.
  • the water content may be about 0.05 to 0.5 weight %, preferably about 0.1 weight %.
  • the crystalline Rimonabant base Form IX may be a solvated form being a solvate of n-propanol/n-pentane.
  • the present invention provides a crystalline form of Rimonabant base, designated Form X characterized by a powder XRD pattern with peaks at about 7.7, 8.3, 9.4 and 16.4 ⁇ 0.2 degrees two-theta.
  • Rimonabant base Form X may be further characterized by a powder XRD pattern with one or more additional peaks at about 4.6, 10.7, 17.6, 18.4 and 27.9 ⁇ 0.2 degree two-theta.
  • Crystalline Form X may have a powder XRD pattern substantially as depicted in Figure 9.
  • Rimonabant base Form X can be prepared by a process comprising: providing a solution of Rimonabant base and butanol; admixing the solution with an C 5-8 hydrocarbon anti-solvent, preferably n-heptane to obtain a precipitate; and recovering Rimonabant base Form X.
  • a precipitate may be obtained by cooling the solution of Rimonabant base in stead of adding an anti-solvent to the solution. Preferably cooling to about 15° to 30°C, more preferably to about 20°C to about 25°C.
  • Rimonabant base Form XII may be prepared by a process comprising: combining ethanol and Rimonabant base to obtain a mixture; mixing the mixture for about 1 to about 10 minutes; recovering the Rimonabant base; and drying to obtain Rimonabant base Form XII.
  • the Rimonabant base and ethanol are mixed for about 1 to about 5 minutes.
  • the Rimonabant base is dried at a temperature of about 30 to about 70°C for 16 to about 36 hours. More preferably, drying is about 55°C for about 24 hours.
  • each individual form has a polymorphic purity of more than 80%, preferably more than 90% and more preferably more than 99%.
  • each of the above crystalline forms of Rimonabant base in pure form are substantially free of known other polymorphic forms.
  • each pure form contains less than 20%, more preferably less than 10%, even more preferably less than 5%, and most preferably less than 1% of known polymorphic forms as measured by their identifying peak.
  • the present invention provides a process for preparing Rimonabant base Form I comprising: providing a solution of Rimonabant base and a solvent selected from the group consisting of: chloroform, dichloromethane [DCM], 1,2-dichloroethane, xylene, toluene and mixtures thereof; admixing the solution with an anti-solvent preferably a C 5-8 hydrocarbon, more preferably pentane or heptane; and recovering the Rimonabant base Form I.
  • the solution of Rimonabant base and a solvent may be heated.
  • the admixture with pentane or heptane is also heated at such temperature.
  • the present invention provides a process for preparing Rimonabant base Form I comprising: providing a solution of Rimonabant base and a solvent selected from the group consisting of: acetone, ethylacetate, or mixtures thereof; admixing the solution with an anti-solvent selected from water, heptane, or mixtures thereof; and recovering the Rimonabant base Form I.
  • the solution of Rimonabant base and a solvent may be heated.
  • the admixture with water or heptane is also heated at such temperature.
  • Rimonabant base Form I characterized by PXRD peaks at about: 9.2, 16.9, 26.2 and 27.3 ⁇ 0.2 degrees 2 ⁇ and having a substantially reduced residual solvent content.
  • the reduced amount of residual solvent content is in comparison to Rimonabant base form I as prepared by the process described in the '941 patent.
  • the Rimonabant base Form I having a substantially reduced residual solvent content contains less that 1% (wt/wt) solvent, preferably less than 0.5% (wt/wt) solvent, most preferably less than 0.2% (wt/wt) solvent.
  • the present invention provides a process for preparing Rimonabant base Form II comprising: providing a solution of Rimonabant base and a solvent selected from the group consisting of: acetone, ethylacetate, DMSO or mixtures thereof; admixing the solution with pentane or water; and recovering the Rimonabant base Form II.
  • 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.
  • a tableting composition can be prepared conventionally by dry blending.
  • 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.
  • Example 1 Rimonabant base (2.0gr) was dissolved in 1,4-Dioxane (20ml) at room temperature and stirred for 1 hour. Then n-Heptane (38ml) was added in one portion and the mixture was stirred at room temperature for about 16 hours. The solvent was removed under reduce pressure and the obtained solid was dried at 55 0 C in a vacuum oven for 24 hours to obtain 1.8gr of Rimonabant base amorphous form, as displayed in Figure 1.
  • Example 2 Rimonabant base (2.0gr) was dissolved in EtOAc (26ml) at room temperature and stirred for 1 hour. Then n-Pentane (40ml) was added in one portion and the mixture was stirred at room temperature for about 16 hours. The solvent was removed under reduce pressure to obtain 1.8gr of Rimonabant base amorphous form.
  • Example 5 A mixture of Rimonabant base Form I and Form II (3.0gr) was slurried in IPA (15ml) at room temperature for about 16 hours. The product was isolated by vacuum filtration, dried at 55 0 C in a vacuum oven for 24 hours to obtain 1.8 gr of Rimonabant base crystal form III, as displayed in Figure 2.
  • Example 11 Rimonabant base (3.0gr) was dissolved in xylene (21ml) at room temperature and stirred for 3 hour. Then water (30ml) was added in one portion and the mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure to obtain 1.83gr of Rimonabant base form V.
  • Example 16 A slurry of Rimonabant base (4.0gr) in methanol (40ml) was stirred at room temperature for 16 hours. The product was isolated by vacuum filtration to obtain 3.28 gr. of Rimonabant base. The wet solid was analyzed by XRD and found to be Form VI. ( Figure 5)
  • Example 18 A slurry of Rimonabant base (2.0gr) in cyclohexane (26ml) was stirred at room temperature for 16 hours. The product was isolated by vacuum filtration to obtain 3.09 gr. of Rimonabant base crystals. The wet solid was analyzed by XRD and found to be Form VII.
  • Example 20 Rimonabant base (2.0gr) was dissolved in n-Propanol (24ml) at room temperature and stirred for 1 hour. Then n-Heptane (40ml) was added in one portion and the mixture was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure and dried at 55 0 C in a vacuum oven for 24 hours to obtain 2.00 gr. of Rimonabant base crystal Form IX. ( Figure 8) [000143]
  • Example 21 Rimonabant base (2.0gr) was dissolved in n-Propanol (24ml) at room temperature and stirred for 1 hour.
  • Example 22 Rimonabant base (3.0gr) was dissolved in EtOAc (30ml) at room temperature and stirred for 3 hour. Then water (36ml) was added in three portions and the mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and dried at 55°C in a vacuum oven for 24 hours to obtain 2.05gr of Rimonabant base Form I.
  • Example 23 Rimonabant base (2.0gr) was dissolved in Ethyl acetate (EtOAc) (26ml) at room temperature and stirred for 1 hour. Then n-Heptane (46ml) was added in one portion and the mixture was stirred at room temperature for 64 hours. The solvent was removed under reduced pressure and dried at 55 0 C in a vacuum oven for 24 hours to obtain 1.52gr of Rimonabant base Form I.
  • EtOAc Ethyl acetate
  • Example 24 Rimonabant base (2.0gr) was dissolved in Xylene (20ml) at room temperature and stirred for 1 hour. Then n-Heptane (26ml) was added in one portion and the mixture was stirred at room temperature for 64 hours. The product was isolated by vacuum filtration and dried at 55 0 C in a vacuum oven for 24 hours to obtain 0.67gr of Rimonabant base Form I.
  • Example 25 Rimonabant base (2.0gr) was dissolved in Xylene (20ml) at room temperature and stirred for 1 hour. Then n-Pentane (46ml) was added in one portion and the mixture was stirred at room temperature for 16 hours. The product was isolated by vacuum filtration and dried at 55 0 C in a vacuum oven for 24 hours to obtain 0.94gr. of Rimonabant base Form I.
  • Example 26 Rimonabant base (2.0gr) was dissolved in 1,2 - Dichloroethane (16ml) at room temperature and stirred for 1 hour. Then n-Heptane (50ml) was added in one portion and the mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and dried at 55 0 C in a vacuum oven for 24 hours to obtain 1.67gr of Rimonabant base Form I.
  • Example 27 Rimonabant base (2.0gr) was dissolved in Chloroform (10ml) at room temperature and stirred for 1 hour. Then n-Heptane (50ml) was added in one portion and the mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and dried at 55 0 C in a vacuum oven for 24 hours to obtain 1.71gr of Rimonabant base Form I.
  • Example 28 Rimonabant base (2.0gr) was dissolved in Dichloromethane (10ml) at room temperature and stirred for 1 hour. Then n-Heptane (50ml) was added in one portion and the mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and dried at 55 0 C in a vacuum oven for 24 hours to obtain 1.85gr of Rimonabant base Form I.
  • Example 30 Rimonabant base (2.0gr) was dissolved in n-Butyl acetate (20ml) at room temperature and stirred for 1 hour. Then water (40ml) was added in one portion and the mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and dried at 55 0 C in a vacuum oven for 24 hours to obtain 1.64gr of Rimonabant base Form I.
  • Example 32 Rimonabant base (2.0gr) was dissolved in Acetone (30ml) at room temperature, stirred and heated to 45 0 C. Then n-Heptane (40ml) was added in one portion and the mixture was stirred at 45 0 C for 16 hours. The mixture was cooled to room temperature and stirred for 16 hours. The solvent was removed under reduced pressure and dried at 55 0 C in a vacuum oven for 24 hours to obtain 1.70gr of Rimonabant base Form I.
  • Example 33 Rimonabant base (2.0gr) was dissolved in Dichloromethane (8ml) at room temperature, stirred and heated to 45 0 C. Then n-Heptane (20ml) was added in one portion and the mixture was stirred at 45 0 C for 16 hours. The mixture was cooled to room temperature and stirred for 16 hours. The solvent was removed under reduced pressure and dried at 55 0 C in a vacuum oven for 24 hours to obtain 1.78gr of Rimonabant base Form I.
  • Example 34 Rimonabant base (2.0gr) was dissolved in Monochlorobenzene (10ml) at room temperature and stirred for 1 hour. Then n- Heptane (55ml) was added in one portion and the mixture was stirred at room temperature for 16 hours. The product was isolated by vacuum filtration and dried at 55 0 C in a vacuum oven for 24 hours to obtain 1.57g of Rimonabant base form I wit a reduced residual solvent content. The solid product was analyzed by TGA and GC.
  • Example 36 Rimonabant base (2.0gr) was dissolved in Toluene (10ml) at room temperature, stirred and heated to 85 0 C. Then n-Pentane (40ml) was added in one portion and the mixture was stirred at 85 0 C for 1 hour and then cooled to 40 0 C and stirred for 16 hours. Then the mixture was cooled to room temperature. The product was isolated by vacuum filtration, to obtain 1.35gr Rimonabant base Form I.
  • Example 43 Rimonabant base (2.0gr) was dissolved in MIBK (22ml) at room temperature and stirred for 1 hour. Then n-Heptane (40ml) for 64 hours. The product was isolated by vacuum filtration and dried at 55 0 C in a vacuum oven for 24 hours to obtain 0.42gr of Rimonabant base Form II.
  • Example 45 Rimonabant base (2.0gr) was dissolved in n-Butyl acetate (20ml) at room temperature and stirred for 1 hour. Then n-Pentane (40ml) was added in one portion and the mixture was stirred at room temperature for 72 hours. The product was isolated by vacuum filtration and dried at 55 0 C in a vacuum oven for 24 hours to obtain 0.63gr of Rimonabant base Form II.
  • Example 48 A slurry of amorphous Rimonabant base (2.0gr) in MTBE (20ml) was stirred at room temperature for 16 hours. The product was isolated by vacuum filtration, to obtain 0.47gr of Rimonabant base Form II.
  • Example 49 Rimonabant base (2.0gr) was dissolved in Toluene (10ml) at room temperature, stirred and heated to 85 0 C. Then n-Heptane (40ml) was added in one portion and the mixture was stirred at 85 0 C for 1 hour and then cooled to 40 0 C and stirred for 16 hours. Then the mixture was cooled to room temperature. The product was isolated by vacuum filtration, to obtain 1.49gr Rimonabant base Form II.
  • Example 50 Rimonabant base (2.0gr) was dissolved in n-Butanol (30ml) at room temperature, heated to 85 0 C and stirred at this temperature for 1 hour. Then n- Heptane (30ml) was added in one portion and the mixture was stirred at 4O 0 C over night (about 16 hours). The mixture was cooled to room temperature. The solvent was removed under reduced pressure to obtain 2.7gr of Rimonabant base crystalline Form X. [See Figure 9] K. Preparation of Rimonabant base Form XII

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Abstract

The present invention provides process for crystalline forms of Rimonabant base, including processes that prepare crystalline forms of Rimonabant base. Also provided is a crystalline Rimonabant base form I having a substantially reduced residual solvent content, including processes that prepare such crystalline Rimonabant form I. These crystalline forms of Rimonabant base may be in a pharmaceutical compositions further comprising at least one pharmaceutically acceptable excipient.

Description

POLYMORPHIC FORMS OF RIMONABANT BASE AND PROCESSES FOR
PREPARATION THEREOF
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims the benefit of the following United
States Provisional Patent Application Nos.: 60/881,242, filed January 18, 2007; 60/899,101, filed February 1, 2007; 60/903,198, filed February 22, 2007; 60/903,987, filed February 27, 2007; 60/918,978, filed March 19, 2007; 60/923,477, filed April 12, 2007; AWAITED (Attorney Docket No. 1662/A408P7), filed December 10, 2007; and 60/921,050, filed, March 29, 2007. The contents of these applications are incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to solid state chemistry of 5-(4- chlorophenyl)- 1 -(2,4-dichlorophenyl)-4-methyl-N-( 1 -piperidinyl)- 1 H-pyrazole-3 - carboxamide. More particularly, the present invention relates to polymorphic forms of Rimonabant base, processes for its preparation and pharmaceutical formulations comprising them.
BACKGROUND OF THE INVENTION
[0003] 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-N-(l- piperidinyl)-lH-pyrazole-3-carboxamide, whose international nonproprietary name is Rimonabant, has the following chemical structure.
Figure imgf000002_0001
[0004] Rimonabant is an antagonist for 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 containing Rimonabant as the active ingredient have been developed by Sanofi-Aventis under the Tradename: Acomplia™.
[0005] Rimonabant was first described in EP Patent No. 656354 and corresponding U.S. Patent No. 5,624,941, herein the '941 patent, 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 the '941 patent as Rimonabant base Form I and characterizes this form, based on an IR spectrum and peaks therein, a powder XRD diffractogram and peaks therein, its solubility, its melting point, and by a single-crystal X-ray diffraction see pages 1 and 2.
[0006] U.S. Patent Application 2005/0043356 and the corresponding published International Patent Application No. WO 2003/040105 describe an additional 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, a powder XRD diffractogram and peaks, solubility, melting point and a single-crystal X-ray diffraction.
[0007] WO2007/090949 reports a crystalline monohydrate form of rimonabant. The monohydrate form of Rimonabant is prepared from Rimonabant in methylcyclohexane, acetonitrile, methylpentanone, acetone, toluene or DMSO, to which water is added to precipitate the monohydrate.
[0008] WO2007/103711 reports according to its abstract polymorphic crystalline Forms of Rimonabant base. The crystalline forms herein are designated forms III, IV, V, and VI of Rimonabant and amorphous Rimonabant.
[0009] Further, WO2007/121466 describes a process for preparing Rimonabant and U.S. Publication No. 2008/0004313 describes crystalline forms of Rimonabant hydrochloride.
[00010] The present invention relates to the solid state physical properties of Rimonabant base. These properties can be influenced by controlling the conditions under which Rimonabant base 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.
[00011] 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.
[00012] 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.
[00013] 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.
[00014] Thus, there is a need in the art for the discovery of addition polymorphic forms of Rimonabant base.
SUMMARY OF THE INVENTION
[00015] The present invention provides amorphous Rimonabant base and crystalline forms of Rimonabant base, as well as crystalline Rimonabant base form I having a substantially reduced solvent content, methods of preparing these crystalline forms, and pharmaceutical compositions comprising such crystalline forms.
[00016] In one embodiment, the present invention provides amorphous Rimonabant base.
[00017] In another embodiment, the present invention provides a crystalline form of Rimonabant base, characterized by a powder XRD pattern with peaks at about 6.7, 8.5, 12.2 and 14.3 ± 0.2 degrees two-theta.
[00018] In another embodiment, the present invention provides a crystalline form of Rimonabant base, characterized by a powder XRD pattern with peaks at about 6.6, 8.4, 13.4 and 14.3 ± 0.2 degrees two-theta.
[00019] In yet another embodiment, the present invention provides a crystalline form of Rimonabant base, characterized by a powder XRD pattern with peaks at about 9.5, 13.7, 15.5 and 17.4 ± 0.2 degrees two-theta.
[00020] In yet another embodiment, the present invention provides a crystalline form of Rimonabant base, characterized by a powder XRD pattern with peaks at about 10.2, 13.8, 15.6, 23.3 and 24.4 ± 0.2 degrees two-theta.
[00021] In yet another embodiment, the present invention provides a crystalline form of Rimonabant base, characterized by a powder XRD pattern with peaks at about 4.0, 8.0, 10.4 and 15.7 ± 0.2 degrees two-theta.
[00022] In yet another embodiment, the present invention provides a crystalline form of Rimonabant base, characterized by a powder XRD pattern with peaks at about 13.7, 14.6, 16.2, 20.8 and 21.6 ± 0.2 degrees two-theta.
[00023] In yet another embodiment, the present invention provides a crystalline form of Rimonabant base, characterized by a powder XRD pattern with peaks at about 7.7, 8.3, 9.4 and 16.4 ± 0.2 degrees two-theta.
[00024] In yet another embodiment, the present invention provides a crystalline form of Rimonabant base, characterized by a powder XRD pattern with peaks at about 6.8 ± 0.3, 8.5, ± 0.3, 12.4 ± 0.2 and 22.1 ± 0.2 degrees two-theta.
[00025] In yet another embodiment, the present invention provides a crystalline form of Rimonabant base, characterized by a powder XRD diffraction pattern substantially as depicted in figure 13.
[00026] In yet another embodiment, the above crystalline forms of Rimonabant base are provided in pure form wherein each individual form is substantially free of known polymorphic forms. Preferably, each pure form contains less than 20%, more preferably less than 10%, even more preferably less than 5%, and most preferably less than 1% of known polymorphic forms as measured by their identifying peak.
[00027] In another embodiment of the present invention, there is provided Rimonabant Form I having a substantially reduced residual solvent content compared to the prior art. Preferably, the Rimonabant Form I having a substantially reduced residual solvent contains less than 1% (wt/wt) solvent, preferably less than 0.5% (wt/wt) solvent, most preferably less than 0.2% (wt/wt) solvent.
[00028] In another embodiment, Rimonabant Form I is provided having characteristic PXRD peaks at about: 9.2, 16.9, 26.2 and 27.3 ± 0.2 degrees 2Θ and a TGA thermogram wherein there is less than 1% weight loss in the range of 115-1800C (10°C/min), preferably less than 0.8% and more preferably less than 0.5% and most preferably less than 0.2% weight loss. The TGA thermogram of Rimonabant Form I with substantially no weight loss in the above temperature range is substantially as depicted in Figure 24.
[00029] Analysis by gas chromatography shows that this crystalline form I having a substantial reduced residual solvent content comprises less than 7000ppm residual solvent, preferably less than 6000ppm and most preferably less than 2000ppm. Thus, in another embodiment of the present invention, Rimonabant Form I is presented having characteristic PXRD peaks at about: 9.2, 16.9, 26.2 and 27.3 ± 0.2 degrees 2Θ and less than 7000ppm residual solvent, preferably less than 6000ppm, more preferably less than 4000ppm and most preferably less than 2000ppm solvent.
[00030] In another embodiment of the present invention, Rimonabant Form I is presented having characteristic PXRD peaks at about: 9.2, 16.9, 26.2 and 27.3 ± 0.2 degrees 2Θ and less than 6000ppm diisopropylether and 400ppm of dichloromethane, preferably less than 5000ppm diisopropylether and 300ppm of dichloromethane, more preferably less than 4000ppm diisopropylether and 200ppm of dichloromethane and most preferably less than 3000ppm diisopropylether and 200ppm of dichloromethane.
[00031 ] The present invention further comprises a pharmaceutical composition comprising any one of the Rimonabant base forms of the present invention, such as amorphous or any of the above crystalline forms of Rimonabant base, or Form I having a substantially reduced residual solvent content, and at least one pharmaceutically acceptable excipient.
[00032] The present invention further encompasses a process for preparing a pharmaceutical formulation comprising combining any one of Rimonabant base forms of the present invention with at least one pharmaceutically acceptable excipient.
[00033] The present invention further encompasses the use of any one of Rimonabant base forms of the present invention for the manufacture of a pharmaceutical composition.
[00034] In yet another embodiment, the present invention provides a process for preparing Rimonabant base Form I comprising: providing a solution of Rimonabant base and a solvent selected from the group consisting of: chloroform, dichloromethane (DCM), 1,2-dichloroethane, xylene, toluene and mixtures thereof; admixing an anti-solvent preferably pentane or heptane with the solution; and recovering the Rimonabant base Form I.
[00035] In yet another embodiment, the present invention provides a process for preparing Rimonabant base Form I comprising: providing a solution of Rimonabant base and a solvent selected from the group consisting of: acetone, ethylacetate, or mixtures thereof; admixing an anti-solvent selected from the group consisting of: water, heptane, or mixtures thereof; and recovering the Rimonabant base Form I.
[00036] In yet another embodiment, the present invention provides a process for preparing Rimonabant base Form I comprising: providing a solution of Rimonabant base and n-butylacetate; admixing water; and recovering the Rimonabant base Form I.
[00037] In yet another embodiment, the present invention provides a process for preparing Rimonabant base Form I comprising: slurrying amorphous Rimonabant base in a C5-8 hydrocarbon such as heptane to obtain Rimonabant Form I. [00038] In yet another embodiment, the present invention provides a process for preparing Rimonabant base Form II comprising: providing a solution of Rimonabant base and a solvent selected from the group consisting of: toluene, methyl isobutyl ketone (MIBK), n-butylacetate, tetrahydrofuran (THF), 1 ,4,-dioxane, dimethylsulfoxide (DMSO) and mixtures thereof; admixing pentane, heptane or a mixture thereof; and recovering the Rimonabant base Form II.
[00039] In yet another embodiment, the present invention provides a process for preparing Rimonabant base Form II comprising: providing a solution of Rimonabant base and DMSO; admixing water; and recovering the Rimonabant base Form II. In another embodiment, the present invention provides a process for preparing Rimonabant base Form II comprising: providing a solution of Rimonabant base and a solvent selected from the group consisting acetone, ethylacetate or mixtures thereof; admixing pentane; and recovering the Rimonabant base Form II.
[00040] In yet another embodiment, the present invention provides a process for preparing Rimonabant base Form II comprising: slurrying amorphous Rimonabant base in methyl tertiary butyl ether (MTBE), water or a mixture thereof to obtain Rimonabant Form II.
[00041] The present invention comprises a pharmaceutical composition comprising Rimonabant base of any one of the Rimonabant base forms made by the processes of the present invention, and at least one pharmaceutically acceptable excipient.
[00042] The present invention further encompasses the use of any one of Rimonabant base forms made by the processes of the invention, for the manufacture of a pharmaceutical composition.
BRIEF DESCRIPTION OF THE FIGURES
Figures 1 shows a powder X-ray diffraction pattern for amorphous Rimonabant base. Figure 2 shows a powder X-ray diffraction pattern for Rimonabant base Form III. Figure 3 shows a powder X-ray diffraction pattern for Rimonabant base Form IV. Figure 4 shows a powder X-ray diffraction pattern for Rimonabant base Form V. Figure 5 shows a powder X-ray diffraction pattern for Rimonabant base Form VI. Figure 6 shows a powder X-ray diffraction pattern for Rimonabant base Form VII. Figure 7 shows a powder X-ray diffraction pattern for Rimonabant base Form XII. Figure 8 shows a powder X-ray diffraction pattern for Rimonabant base Form IX. Figure 9 shows a powder X-ray diffraction pattern for Rimonabant base Form X.
Figure 10 shows a powder X-ray diffraction pattern for Rimonabant base Form XII as prepared by example 51.
Figure 11 shows a powder X-ray diffraction pattern for Rimonabant base Form XII as prepared by example 52.
Figure 12 shows a powder X-ray diffraction pattern for Rimonabant base Form V.
Figure 13 shows a solid-state 13C NMR spectrum of Rimonabant Form III in the 100- 180 ppm range.
Figure 14 shows a solid-state 13C NMR spectrum of Rimonabant Form III.
Figure 15 shows a solid-state 13C NMR spectrum of Rimonabant Form IX in the 100- 180 ppm range.
Figure 16 shows a solid-state 13C NMR spectrum of Rimonabant Form IX.
Figure 17 shows a solid-state 13C NMR spectrum of Rimonabant Form XII in the 100- 180 ppm range.
Figure 18 shows a solid-state 13C NMR spectrum of Rimonabant Form XII.
Figure 19 shows a solid-state 13C NMR spectrum of Rimonabant Form V in the 100- 180 ppm range.
Figure 20 shows a solid-state 13C NMR spectrum of Rimonabant Form V.
Figure 21 displays a PXRD of Rimonabant Form I having reduced residual solvents.
Figure 22 displays a TGA of Rimonabant Form I crystallized according to U.S. Patent No. 5,624,941.
Figure 23 displays a TGA of Rimonabant Form I recrystallized from various chlorinated alkanes and ester solutions.
Figure 24 displays a TGA of Rimonabant Form I having reduced residual solvents.
DETAILED DESCRIPTION
[00043] As used herein, "Rimonabant base" used as starting material may be prepared according to any of the methods described in US 5,624,941.
[00044] As used herein, "KF" is meant to refer to Karl Fisher procedure commonly used to measure water content. "TGA" is meant to refer to standard thermogravimetric analysis.
[00045] In one embodiment, the present invention provides amorphous Rimonabant base.
[00046] The amorphous Rimonabant base may be prepared by a process comprising: providing Rimonabant base and a solvent selected from the group consisting of: 1,4-dioxane, ethyl acetate, acetone and mixtures thereof to obtain a mixture; admixing the mixture with a C5 to C8 hydrocarbon, preferably heptane or pentane to obtain an amorphous Rimonabant base; and recovering the amorphous Rimonabant base. In this process of process the amorphous Rimonabant base is obtained by evaporating the solvents under reduced pressure. Preferably where 1,4- dioaxane and heptane are the solvents in the above process evaporation under reduced pressure may further include heating to a temperature of about 50°C to about 600C for a period of about lόhours to about 32 hours, more preferably to a temperature of about 55°C for a period of about 24 hours. Preferably, the Rimonabant base and solvent are in solution. The amorphous form of Rimonabant base may be recovered by filtration.
[00047] In one embodiment, the present invention provides a crystalline form of Rimonabant base, designated Form III, characterized data selected from the list consisting of: a powder XRD pattern with peaks at about 6.7, 8.5, 12.2 and 14.3 ± 0.2 degrees two-theta; solid-state 13C NMR spectrum with signals at about 161.8, 142.9, 135.9, 132.5 and 116.1 ± 0.2 ppm; a solid-state 13C NMR spectrum having chemical shifts differences between the signal exhibiting the lowest chemical shift and another in the chemical shift range of 100 to 180 ppm of about 45.7, 26.8, 19.8, 16.4 and 0.0 ± 0.1 ppm. The signal exhibiting the lowest chemical shift in the chemical shift area of 100 to 180ppm is preferably at about 116.1 ± lppm. Rimonabant base Form III may be further characterized by a powder XRD pattern with one or more additional peaks at about 15.6, 18.1, 21.9, 24.4 and 30.8 ± 0.2 degrees two-theta. Crystalline Form III may have a powder XRD pattern substantially as depicted in Figure 2, a solid state 13C NMR spectrum substantially as depicted in Figure 13, or a solid-state 13C NMR spectrum substantially as depicted in Figure 14. Crystalline Form III is an isopropanolate solvated form having a solvation of about hemi-isopropanolate to about a mono-isopropanolate. In one example, solvent weight loss as measured by standard TGA procedures may be about 7 weight % to about 8 weight %, preferably about 7.7 weight %. The water content, as measured by KF, may be about 0.1 weight % to about 1 weight %, preferably about 0.2 weight %. Rimonabant Form III crystals are relatively small in size when compared to Forms I and II.
[00048] Rimonabant base Form III may be prepared by a process comprising: combining isopropanol and Rimonabant base Form I, II or a mixture thereof to obtain a mixture; mixing the mixture for a period of time sufficient to convert the Rimonabant Form(s) to Form III, preferably about 16 to about 24 hours to obtain Rimonabant base Form III and recovering the Rimonabant base Form III. Preferably, the Rimonabant base and isopropanol are mixed for about 16 hours.
[00049] In one embodiment, the present invention provides a crystalline form of Rimonabant base, designated Form FV characterized by a powder XRD pattern with peaks at about 6.6, 8.4, 13.4 and 14.3 ± 0.2 degrees two-theta. Rimonabant base Form IV may be further characterized by a powder XRD pattern with an additional peak at about 21.8 ± 0.2 degree two-theta. Crystalline Form FV may have a powder XRD pattern substantially as depicted in Figure 3.
[00050] Rimonabant base Form IV may be prepared by a process comprising: combining ethanol and Rimonabant base to obtain a mixture; mixing the mixture for about 1 to about 10 minutes to obtain Rimonabant base Form IV; and recovering the Rimonabant base Form IV without drying the obtained crystalline Rimonabant base.. Preferably, the Rimonabant base and ethanol are mixed for about 1 to about 5 minutes.
[00051] In another embodiment, the present invention provides a crystalline form of Rimonabant base, designated Form V characterized by data selected from the list consisting of: a powder XRD pattern with peaks at about 9.5, 13.7, 15.5 and 17.4 ± 0.2 degrees two-theta, a solid-state 13C NMR spectrum with peaks at about 161.4, 159.4, 143.1, 127.8 and 118.6 ± 0.2 ppm and a solid-state 13C NMR spectrum having chemical shifts differences between the signal exhibiting the lowest chemical shift and another in the chemical shift range of 100 to 180 ppm of about 42.8, 40.8, 24.5, 9.2 and 0.0 ± 0.1 ppm. The signal exhibiting the lowest chemical shift in the chemical shift area of 100 to 180ppm is preferably at about 118.6 ± lppm. Rimonabant base Form V may be further characterized by a powder XRD pattern with one or more additional peaks at about 7.4, 14.7, 19.2, 23.5 and 29.7 ± 0.2 degree two-theta. Crystalline Form V may have a powder XRD pattern substantially as depicted in Figure 4 or 12, a 13C NMR spectrum substantially as depicted in Figure 19 or a solid- state 13C NMR spectrum substantially as depicted in Figure 20. Crystalline Form V may have about 3.5 to 4.0 weight percent water, preferable about 3.7 weight %. The crystalline form of Rimonbant base having about 3.7 weight percent water corresponds to a monohydrate form. The solvent weight loss for Form V as measured by standard TGA procedures may be about 3.5 to 4.0 weight %. The water content, as measured by KF, may be about 3.5 to 4.0, preferably about 3.6 weight %. Forms I and II crystallize in the shape of needles which shape negatively influences flowability. In contrast, Rimonabant Form V crystallizes as plate-like crystals.
[00052] Rimonabant base Form V may be prepared by a process comprising: combining Rimonabant base and a solvent selected from the group consisting of: ethyl acetate, THF, 1,4 dioxane, acetone, xylene and MEK, preferably until a solution is obtained; and admixing about 0.5 to about 4 volumes of an anti-solvent, preferably water (ml of water /g of Rimonabant base), preferably about 0.5 to about 1.5 volumes of water; and recovering the Rimonabant base Form V. Preferably, the Rimonabant base and solvent are in solution form. Preferably, the recovery may include a drying step.
[00053] Alternatively, Rimonabant base Form V may be prepared by a process comprising; combining Rimonabant base and toluene to obtain a mixture; admixing the mixture with heptane; recovering the Rimonabant base; and drying the Rimonabant base to obtain Form V.
[00054] In another method, Rimonabant base Form V may be prepared by a process comprising; combining Rimonabant base Form I, II or a mixture thereof and methanol to obtain a mixture, preferably a slurry; mixing the mixture for about 16 to about 24 hours; recovering the Rimonabant base; and drying Rimonabant base to obtain Rimonabant base Form V. Preferably, the Rimonabant base (weight) to solvent (volume) ratio is from about 1 :5 to about 1 :15, more preferably about 1 :10. Preferably, the Rimonabant base and ethanol are mixed for about 16 hours. Preferably, drying is at a temperature of about 30°C to about 60°C for about 6 to about 48 hours.
[00055] Rimonabant base Form V may be prepared by a process comprising: providing a solution of Rimonabant base and 1,4-Dioxane; admixing water, preferably in more than one portion, more preferably in three portions; maintaining for a period sufficient to obtain Rimonabant base Form V. Preferably, maintaining is for about 6 hours to about 48 hours, preferably for about 12 to about 24 hours. Once obtained, the Rimonabant base Form V can be recovered by removal of the solvent for example by drying under vacuum.
[00056] In yet another embodiment, the present invention provides a crystalline form of Rimonabant base, designated Form VI characterized by a powder XRD pattern with peaks at about 10.2, 13.8, 15.6, 23.3 and 24.4 ± 0.2 degrees two-theta. Rimonabant base Form VI may be further characterized by a powder XRD pattern with one or more additional peaks at about 18.9, 20.4 and 22.9 ± 0.2 degree two-theta. Crystalline Form VI may have a powder XRD pattern substantially as depicted in Figure 5.
[00057] Rimonabant base Form VI may be prepared by a process comprising; combining Rimonabant base Form I, II or a mixture thereof and methanol to obtain a mixture; mixing the mixture for about 16 to about 24 hours; and recovering the Rimonabant base, which is obtained without drying. Preferably, the Rimonabant (weight) to solvent (mL) ratio is from about 1 :5 to about 1 :15, more preferably about 1 :10. Preferably, the Rimonabant base and ethanol are mixed for about 16 hours.
[00058] Rimonabant base Form VI may additionally be prepared by a process comprising: providing a solution of a Rimonabant acid addition salt and methanol; admixing the solution with a base, preferably sodium hydroxide to obtain a precipitate; and recovering Rimonabant Form VI. Preferably, the Rimonabant acid addition salt is hydrochloride.
[00059] In yet another embodiment, the present invention provides a crystalline form of Rimonabant base, designated Form VII characterized by a powder XRD pattern with peaks at about 4.0, 8.0, 10.4 and 15.7 ± 0.2 degrees two-theta. Rimonabant base Form VII may be further characterized by a powder XRD pattern with one or more additional peaks at about 19.2, 19.7 and 21.4 ± 0.2 degree two-theta. Crystalline Form VII may have a powder XRD pattern substantially as depicted in Figure 6.
[00060] Rimonabant base Form VII may be prepared by a process comprising: combining cyclohexane and Rimonabant base to obtain a mixture; mixing the mixture for about 6 to about 48 hours, preferably for about 12 to about 24 hours, more preferably for about 16 hours to obtain Rimonabant base Form VII; and recovering the Rimonabant base Form VII.
[00061] In yet another embodiment, the present invention provides a crystalline form of Rimonabant base, designated Form IX, characterized data selected from the list consisting of: a powder XRD pattern with peaks at about 13.7, 14.6, 16.2, 20.8 and 21.6 ± 0.2 degrees two-theta; a solid-state 13C NMR spectrum with signals at about 161.9, 145.4, 143.5, 136.0 and 129.6 ± 0.2 ppm; a solid-state 13C NMR spectrum having chemical shifts differences between the signal exhibiting the lowest chemical shift and another in the chemical shift range of 100 to 180 ppm of about 45.5, 29, 27.1, 19.6 and 13.2 ± 0.1 ppm. The signal exhibiting the lowest chemical shift in the chemical shift area of 100 to 180ppm is preferably at about 116.4 ± lppm. Rimonabant base Form IX may be further characterized by a powder XRD pattern with one or more additional peaks at about 6.9, 8.6, 19.4, 22.1, 22.5 and 24.3 ± 0.2 degrees two-theta. Crystalline Form DC may have a powder XRD pattern substantially as depicted in Figure 8, a 13C NMR spectrum substantially as depicted in Figure 15, or a solid-state 13C NMR spectrum substantially as depicted in Figure 16. Crystalline Form DC may have a solvent weight loss as measured by standard TGA procedures of about 8 to 9 weight percent, preferably about 8.3 weight %. The water content, as measured by KF, may be about 0.05 to 0.5 weight %, preferably about 0.1 weight %. The crystalline Rimonabant base Form IX may be a solvated form being a solvate of n-propanol/n-pentane.
[00062] Rimonabant base Form IX may be prepared by a process comprising: providing a solution of Rimonabant base and n-propanol; admixing the solution with an anti-solvent selected from the group consisting of water, n-heptane, and n-pentane, to obtain a mixture; and maintaining the mixture for a period sufficient to obtain Rimonabant base Form IX, preferably about 6 to about 48 hours, more preferably for about 12 to about 24 hours, most preferably for about 24 hours; and recovering Rimonabant base Form IX. Preferably, the Rimonabant base Form IX is recovered by conventional methods including filtration and drying under vacuum.
[00063] In yet another embodiment, the present invention provides a crystalline form of Rimonabant base, designated Form X characterized by a powder XRD pattern with peaks at about 7.7, 8.3, 9.4 and 16.4 ± 0.2 degrees two-theta. Rimonabant base Form X may be further characterized by a powder XRD pattern with one or more additional peaks at about 4.6, 10.7, 17.6, 18.4 and 27.9 ± 0.2 degree two-theta. Crystalline Form X may have a powder XRD pattern substantially as depicted in Figure 9.
[00064] Rimonabant base Form X can be prepared by a process comprising: providing a solution of Rimonabant base and butanol; admixing the solution with an C5-8 hydrocarbon anti-solvent, preferably n-heptane to obtain a precipitate; and recovering Rimonabant base Form X. Alternatively, a precipitate may be obtained by cooling the solution of Rimonabant base in stead of adding an anti-solvent to the solution. Preferably cooling to about 15° to 30°C, more preferably to about 20°C to about 25°C.
[00065] In yet another embodiment, the present invention provides a crystalline form of Rimonabant base, designated Form XII, characterized by data selected from the list consisting of: a powder XRD pattern with peaks at about 6.8 ± 0.3, 8.5, ± 0.3, 12.4 ± 0.2 and 22.1 ± 0.2 degrees two-theta; a 13C NMR spectrum with signals at about 162.0 145.3, 135.9, 130.2 and 127.6 ± 0.2 ppm; a solid-state 13C NMR spectrum having chemical shifts differences between the signal exhibiting the lowest chemical shift and another in the chemical shift range of 100 to 180 ppm of about 45.8, 29.1, 19.7, 17 and 11.4 ± 0.1 ppm. The signal exhibiting the lowest chemical shift in the chemical shift area of 100 to 180ppm is preferably at about 116.2 ± lppm. Rimonabant base Form XII may be further characterized by a powder XRD pattern with one or more additional peaks at about 10.3, 14.6, 16.9 and 18.4 ± 0.2 degree two- theta. Crystalline Form XII may have a powder XRD pattern substantially as depicted in Figures 10 or 11. Crystalline Form XII may have a 13C NMR spectrum substantially as depicted in Figures 17, or a solid-state 13C NMR spectrum substantially as depicted in Figure 18. Crystalline Form XII is an ethanol solvate, having about 4.0 to about 5.0 weight %, preferably about 4.7 weight %, corresponding to a hemiethanolate. The solvent weight loss as measured by standard TGA procedures may be about 5.5 to about 6.5 weight %, preferably about 5.7 to about 6.3 weight %.The water content, as measured by KF, may be about 0.5 to about 2.5 weight %, preferably about 1 weight %.
[00066] Rimonabant base Form XII can be prepared by exposing amorphous Rimonabant base to ethanol until obtaining Rimonabant base Form XII. The time necessary may be determined by periodic PXRD measurements, preferably the time period is from about 6 hours to about 48 hours, more preferably from about 12 hours to about 30 hours, most preferably from about 16 hours to about 24 hours.
[00067] Rimonabant base Form XII may be prepared by a process comprising: combining ethanol and Rimonabant base to obtain a mixture; mixing the mixture for about 1 to about 10 minutes; recovering the Rimonabant base; and drying to obtain Rimonabant base Form XII. Preferably, the Rimonabant base and ethanol are mixed for about 1 to about 5 minutes. Preferably, the Rimonabant base is dried at a temperature of about 30 to about 70°C for 16 to about 36 hours. More preferably, drying is about 55°C for about 24 hours.
[00068] Although Forms I and II have relatively strong electrostatic charges which interfere with pharmaceutical preparations, Form III shows low electrostatic charges. In addition, Forms I and II crystallize in the shape of a needle which shape negatively influences flowability. In contrast, Rimonabant Form XIII crystallizes as plate-like crystals.
[00069] In yet another embodiment, pure Forms III, IV, V, VI, VII, IX, X, and XII are presented wherein each individual form has a polymorphic purity of more than 80%, preferably more than 90% and more preferably more than 99%. Each of the above crystalline forms of Rimonabant base in pure form are substantially free of known other polymorphic forms. Preferably, each pure form contains less than 20%, more preferably less than 10%, even more preferably less than 5%, and most preferably less than 1% of known polymorphic forms as measured by their identifying peak. [00070] In yet another embodiment, the present invention provides a process for preparing Rimonabant base Form I comprising: providing a solution of Rimonabant base and a solvent selected from the group consisting of: chloroform, dichloromethane [DCM], 1,2-dichloroethane, xylene, toluene and mixtures thereof; admixing the solution with an anti-solvent preferably a C5-8 hydrocarbon, more preferably pentane or heptane; and recovering the Rimonabant base Form I. In this process, the solution of Rimonabant base and a solvent may be heated. Preferably, when the solution is heated the admixture with pentane or heptane is also heated at such temperature. The temperature to which the solution is heated depends on the solvent used, which preferably is from about 40°C to about 900C, more preferably from about 45°C to about 85°C. The solution is heated for a sufficient amount of time prior to cooling, preferably for a period of about 1 hour to about 24 hours, more preferably for about 1 hour to about 16 hours. Cooling may involve a multi-step process of a first cooling step wherein the solution or mixture is maintained at such first cooling temperature for a sufficient amount of time before subsequent cooling, preferably for a period of time from about 1 hour to about 24 hours, more preferably from about 1 hour to about 16 hours. Such first cooling is preferably to a temperature of about room temperature to about 40°C and subsequent cooling is preferably to about 15°C to about 300C, more preferably to about room temperature.
[00071] Preferably, recovering of Rimonabant base Form I comprises evaporating the solvent(s) and anti-solvent under reduced pressure, preferably while heating to a temperature of about 500C to about 600C for a period of about 16 hours to about 32 hours, more preferably to a temperature of about 55°C for a period of about 24 hours. Preferably, the Rimonabant base and solvent are in solution. The crystalline form I of Rimonabant base may be recovered by filtration and drying.
[00072] In yet another embodiment, the present invention provides a process for preparing Rimonabant base Form I comprising: providing a solution of Rimonabant base and a solvent selected from the group consisting of: acetone, ethylacetate, or mixtures thereof; admixing the solution with an anti-solvent selected from water, heptane, or mixtures thereof; and recovering the Rimonabant base Form I. In this process, the solution of Rimonabant base and a solvent may be heated. Preferably, when the solution is heated the admixture with water or heptane is also heated at such temperature. The temperature to which the solution is heated depends on the solvent used, which preferably is about 40°C to about 55°C, more preferably about 45°C. The solution is heated for a sufficient amount of time prior to cooling, preferably for a period of about 1 hour to about 24 hours, more preferably for about 12 hours to about 16 hours, even more preferably for about 16 hours. Cooling is preferably to a temperature of about 15°C to about 30°C, more preferably to about room temperature.
[00073] Preferably, recovering of Rimonabant base Form I comprises evaporating the solvent(s) and anti-solvent(s) under reduced pressure, preferably while heating to a temperature of about 5O0C to about 600C for a period of about 16 hours to about 32 hours, more preferably to a temperature of about 55°C for a period of about 24 hours. Preferably, the Rimonabant base and solvent are in solution. The crystalline form I of Rimonabant base may be recovered by filtration and drying.
[00074] In yet another embodiment, the present invention provides a process for preparing Rimonabant base Form I comprising: providing a solution of Rimonabant base and n-butylacetate; admixing water; and recovering the Rimonabant base Form I.
[00075] In yet another embodiment, the present invention provides a process for preparing Rimonabant base Form I comprising: slurrying amorphous Rimonabant base in heptane for a period to obtain Rimonabant Form I. The period of slurrying is of a sufficient amount of time to obtain Rimonabant Form I from amorphous Rimonabant, preferably for a period of about 6 hours to about 24 hours, more preferably for about 12 hours to about 16 hours, even more preferably for about 16 hours.
[00076] As discussed above, the '941 patent describes a free base of Rimonabant Form I having a melting point of 156°C ±2°C and ΔH=65±2 J/g. Form I, as prepared by Example 195E of the '941 patent, was analyzed by TGA and found to include about 1% solvent. Crystallization using the above solvents such as those selected from the group consisting of: ethyl acetate, 1,2 dichloroethane and dichloromethane and heptane as an antisolvent yielded Rimonabant Form I having the same characteristic weight loss during melting, as can be seen in Figure 22. The gas chromato graph of Form I reveals that 6569 ppm of diisopropyl ether and 455 ppm of dichloromethane are present.
[00077] Further, the presence of unwanted residual solvents can cause the material to be inappropriate for pharmaceutical purposes. However, these solvents are difficult to remove, and are released only by melting of form I to about 155 to 158°C, making it very difficult to remove residual solvents without liquefying the solid material and decomposition of Form I.
[00078] In another embodiment of the present invention Rimonabant base form I can be produced with substantially low amount of residual solvents.
[00079] This Rimonabant base Form I having a substantially reduced residual solvent content may be prepared by a process comprising: combining Rimonabant base and monochlorobenzene and maintaining the mixture for about 30 minutes to about 5 hours, preferably about one hour; admixing the mixture with a C5-8 hydrocarbon, more preferably heptane; and maintaining the mixture at least for a period sufficient to obtain a solid form. Preferably, the monochlorobenzene is in an about 1 :5 to 1 :8, preferably 1 :5 weight to volume ratio compared to the Rimonabant base. Preferably, the heptane is in about 1 :20 to 1 :30 weight to volume ratio compared to the Rimonabant base. Preferably, maintaining for at least a sufficient time to obtain a solid form is about 12 to about 24 hours. Preferably, the solid form obtained is then dried. More preferably, drying is at about 40 to 70°C, more preferably about 50 to 60°C. Drying can be for about 16 to about 32 hours, preferably about 24 hours.
[00080] Another embodiment of the present invention provides Rimonabant base Form I characterized by PXRD peaks at about: 9.2, 16.9, 26.2 and 27.3 ± 0.2 degrees 2Θ and having a substantially reduced residual solvent content. The reduced amount of residual solvent content is in comparison to Rimonabant base form I as prepared by the process described in the '941 patent. Preferably, the Rimonabant base Form I having a substantially reduced residual solvent content contains less that 1% (wt/wt) solvent, preferably less than 0.5% (wt/wt) solvent, most preferably less than 0.2% (wt/wt) solvent.
[00081] In another embodiment, Rimonabant base Form I is provided having characteristic PXRD peaks at about: 9.2, 16.9, 26.2 and 27.3 ± 0.2 degrees 20 and a TGA thermogram wherein there is less than 1% weight loss in the range of 115-1800C (10°C/min), preferably less than 0.8% and most preferably less than 0.7% weight loss. The TGA thermogram of Rimonabant base Form I with substantially no weight loss in the above temperature range is substantially as depicted in Figure 24.
[00082] Analysis by gas chromatography shows that this crystalline form I having a substantially reduced residual solvent content comprises less than 7000ppm residual solvent, preferably less than 6000ppm and most preferably less than 2000ppm. Thus, in another embodiment of the present invention, Rimonabant base Form I is presented having characteristic PXRD peaks at about: 9.2, 16.9, 26.2 and 27.3 ± 0.2 degrees 2Θ and less than 7000ppm residual solvent, preferably less than 6000ppm, more preferably less than 4000ppm and most preferably less than 2000ppm solvent.
[00083] In another embodiment of the present invention, Rimonabant base Form 1 is provided having characteristic PXRD peaks at about: 9.2, 16.9, 26.2 and 27.3 ± 0.2Θ and less than 6000ppm diisopropylether and 400ppm of dichloromethane, preferably less than 5000ppm diisopropylether and 300ppm of dichloromethane, more preferably less than 4000ppm diisopropylether and 200ppm of dichloromethane and most preferably less than 3000ppm diisopropylether and 200ppm of dichloromethane.
[00084] In yet another embodiment, the present invention provides a process for preparing Rimonabant base Form II comprising: providing a solution of Rimonabant base and a solvent selected from the group consisting of: toluene, MEBK, n- butylacetate, THF, 1,4,-dioxane, DMSO and mixtures thereof; admixing an anti- solvent, preferably a C5-8 hydrocarbon, more preferably pentane, heptane or a mixture thereof with the solution to obtain a mixture; and recovering the Rimonabant base Form II. Preferably the mixture is maintained at a constant temperature for a sufficient period to obtain the crystalline form II. This period of time may be from about 12 hours to about 72 hours, preferably from about 16 hours to about 72 hours. In this process, the solution of Rimonabant base and a solvent may be heated. Preferably, when the solution is heated the admixture with pentane or heptane is also heated at such temperature. The temperature to which the solution is heated depends on the solvent used, which preferably is from about 40°C to about 90°C, more preferably from about 45°C to about 85°C. The solution is heated for a sufficient amount of time prior to cooling. Cooling may involve a multi-step process of a first cooling step wherein the solution or mixture is maintained at such first cooling temperature for a sufficient amount of time before subsequent cooling, preferably for a period of about 1 hour to about 16 hours. Such first cooling is preferably to a temperature of about room temperature to about 40°C and subsequent cooling is preferably to about 15°C to about 30°C, more preferably to about room temperature.
[00085] In yet another embodiment, the present invention provides a process for preparing Rimonabant base Form II comprising: providing a solution of Rimonabant base and a solvent selected from the group consisting of: acetone, ethylacetate, DMSO or mixtures thereof; admixing the solution with pentane or water; and recovering the Rimonabant base Form II.
[00086] In yet another embodiment, the present invention provides a process for preparing Rimonabant base Form II comprising: slurrying amorphous Rimonabant base in MTBE, water or a mixture thereof for a period to obtain Rimonabant Form II. The period of slurrying is of a sufficient amount of time to obtain Rimonabant Form II from amorphous Rimonabant, preferably for about 6 hours to about 24 hours, more preferably for about 16 hours.
[00087] The present invention further provides a pharmaceutical composition comprising any one of the Rimonabant base forms of the present invention, such as amorphous or Forms III, IV, V, VI, VII, IX, X, XII, and Form I having a reduced residual solvent content, and at least one pharmaceutically acceptable excipient.
[00088] The present invention provides a pharmaceutical composition comprising Rimonabant base of any one of the Rimonabant base forms made by the processes of the present invention, and at least one pharmaceutically acceptable excipient.
[00089] The present invention further encompasses a process for preparing a pharmaceutical formulation comprising combining any one of Rimonabant base forms of the present invention with at least one pharmaceutically acceptable excipient.
[00090] The present invention further encompasses the use of any one of Rimonabant base forms of the present invention for the manufacture of a pharmaceutical composition.
[00091] The present invention further encompasses the use of any one of Rimonabant base forms made by the processes of the invention, for the manufacture of a pharmaceutical composition.
[00092] 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 any one of the crystalline Rimonabant base Forms of the present invention, a liquid pharmaceutical composition is a suspension or emulsion, wherein Rimonabant base retains its crystalline form.
[00093] Pharmaceutical compositions of the present invention can optionally be mixed with other forms of Rimonabant base 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.
[00094] 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 ), microfine 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.
[00095] 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.
[00096] 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.
[00097] Disintegrants can increase dissolution. Disintegrants include, for example, alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-Sol®, 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.
[00098] Disintegration inhibitors may include, but are not limited to, white sugar, stearin, coconut butter, hydrogenated oils, and the like.
[00099] Absorption accelerators may include, but are not limited to, quaternary ammonium base, sodium laurylsulfate, and the like.
[000100] 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.
[000101] 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.
[000102] Glidants can be added to improve the flowability of non-compacted 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. [000103] 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.
[000104] 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.
[000105] 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.
[000106] In liquid pharmaceutical compositions of the present invention, the Rimonabant base of the present invention is suspended, retaining its crystalline form, together with 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.
[000107] 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.
[000108] 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.
[000109] Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol and invert sugar can be added to improve the taste.
[000110] Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxy toluene, butylated hydroxyanisole and ethylenedi amine tetraacetic acid can be added at safe levels to improve storage stability.
[000111] A liquid pharmaceutical composition according to the present invention can also contain a buffer such as gluconic acid, lactic acid, citric acid or acetic acid, sodium guconate, sodium lactate, sodium citrate or sodium acetate.
[000112] 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.
[000113] 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.
[000114] 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.
[000115] 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.
[000116] 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.
[000117] 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.
[000118] 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.
[000119] 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.
[000120] The amount of Rimonabant base 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. [000121] 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
[000122] Powder X-ray diffraction ("XRD") analysis can be carried out using any XRD powder diffractometer commonly used in the industry. The Rimonabant base samples of this invention were run in a SCESTTAG powder X-ray diffractometer model X'TRA equipped with a solid-state detector. Copper radiation of λ=l .5418 . The sample can be introduced using a round standard aluminum sample holder with round zero background quartz plate in the bottom and is scanned by a continuous scan at a rate of 3° per minute
A. Preparation of Amorphous Rimonabant base
[000123] Example 1 : Rimonabant base (2.0gr) was dissolved in 1,4-Dioxane (20ml) at room temperature and stirred for 1 hour. Then n-Heptane (38ml) was added in one portion and the mixture was stirred at room temperature for about 16 hours. The solvent was removed under reduce pressure and the obtained solid was dried at 550C in a vacuum oven for 24 hours to obtain 1.8gr of Rimonabant base amorphous form, as displayed in Figure 1.
[000124] Example 2: Rimonabant base (2.0gr) was dissolved in EtOAc (26ml) at room temperature and stirred for 1 hour. Then n-Pentane (40ml) was added in one portion and the mixture was stirred at room temperature for about 16 hours. The solvent was removed under reduce pressure to obtain 1.8gr of Rimonabant base amorphous form.
[000125] Example 3: Rimonabant base (2.0gr) was dissolved in 1,4-Dioxane (20ml) at room temperature and stirred for 1 hour. Then n-Pentane (40ml) was added in one portion and the mixture was stirred at room temperature for about 16 hours. The solvent was removed under reduce pressure to obtain 1.9gr of Rimonabant base amorphous form.
[000126] Example 4: Rimonabant base (2.0gr) was dissolved in Acetone (20ml) at room temperature and stirred for 1 hour. Then n-Pentane (46ml) was added in one portion and the mixture was stirred at room temperature for about 16 hours. The solvent was removed under reduce pressure to obtain 1.9gr of Rimonabant base amorphous form.
B. Preparation of Rimonabant base Form III
[000127] Example 5: A mixture of Rimonabant base Form I and Form II (3.0gr) was slurried in IPA (15ml) at room temperature for about 16 hours. The product was isolated by vacuum filtration, dried at 550C in a vacuum oven for 24 hours to obtain 1.8 gr of Rimonabant base crystal form III, as displayed in Figure 2.
C. Preparation of Rimonabant base Form IV
[000128] Example 6: Rimonabant base (3.0g) was partially dissolved in absolute Ethanol (30ml) at room temperature. The solution was gently shaken for 1 minute to obtain white crystals with almost no solvent in the flask. The product was isolated by vacuum filtration to obtain 3.9 gr of Rimonabant base crystals. The wet solid was analyzed by XRD and found to be Form IV, as displayed in Figure 3.
D. Preparation of Rimonabant base Form V
[000129] Example 7: Rimonabant base (3.0gr) was dissolved in EtOAc (30ml) at room temperature and stirred for 3 hour. Then water (36ml) was added in three portions and the mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure to obtain 2.05gr of Rimonabant base form V.
[000130] Example 8: Rimonabant base (3.0gr) was dissolved in THF (15ml) at room temperature and stirred for 3 hour. Then water (36ml) was added in three portions and the mixture was stirred at room temperature for 16 hours. The product was isolated by vacuum filtration and dried at 550C in a vacuum oven for 24 hours to obtain 2.86gr of Rimonabant base form V.
[000131] Example 9: Rimonabant base (3.0gr) was dissolved in 1,4-Dioxane (30ml) at room temperature and stirred for 3 hour. Then water (30ml) was added in three portions and the mixture was stirred at room temperature for 16 hours. The product was isolated by vacuum filtration and dried at 550C in a vacuum oven for 24 hours to obtain 2.35gr of Rimonabant base form V.
[000132] Example 10: Rimonabant base (3.0gr) was dissolved in Acetone (45ml) at room temperature and stirred for 3 hour. Then water (36ml) was added in three portions and the mixture was stirred at room temperature for 16 hours. The product was isolated by vacuum filtration to obtain 2.78gr of Rimonabant base form V, as displayed in Figure 4.
[000133] Example 11: Rimonabant base (3.0gr) was dissolved in xylene (21ml) at room temperature and stirred for 3 hour. Then water (30ml) was added in one portion and the mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure to obtain 1.83gr of Rimonabant base form V.
[000134] Example 12: Rimonabant base (3.0gr) was dissolved in MEK (30ml) at room temperature and stirred for 3 hour. Then water (40ml) was added in one portion and the mixture was stirred at room temperature for 16 hours. The product was isolated by vacuum filtration and dried at 550C in a vacuum oven for 24 hours to obtain 2.26gr of Rimonabant base form V.
[000135] Example 13: A mixture of Rimonabant base Form I and Form II (4.0gr) was slurried in MeOH (40ml) was stirred at room temperature for about 16 hours. The product was isolated by vacuum filtration and dried at 550C in a vacuum oven for 24 hours to obtain 1.79gr Rimonabant base form V.
[000136] Example 14: Rimonabant base (2.0gr) was dissolved in Toluene (20ml) at room temperature and stirred for 3 hour. Then n-Heptane (55ml) was added in one portion and the mixture was stirred at room temperature for 16 hours. The product was isolated by vacuum filtration to obtain 0.70gr of Rimonabant base form V. [000137] Example 15: Rimonabant base (3.0gr) was dissolved in 1,4-Dioxane (30ml) at room temperature and stirred for 3 hours. Then water (30ml) was added in three portions and the mixture was stirred at room temperature for additional 16 hours. The solvent was removed under reduced pressure and dried at 55°C in a vacuum oven for 24 hours to obtain 2.4gr of Rimonabant base Form V.
E. Preparation of Rimonabant base Form VI
[000138] Example 16: A slurry of Rimonabant base (4.0gr) in methanol (40ml) was stirred at room temperature for 16 hours. The product was isolated by vacuum filtration to obtain 3.28 gr. of Rimonabant base. The wet solid was analyzed by XRD and found to be Form VI. (Figure 5)
[000139] Example 17: Rimonabant HCl (2.Og) was dissolved in Methanol (8ml) at room temperature. Then NaOH (0.16 gr.) was added to obtain a white precipitation. The mixture was stirred at room temperature for 15 min. The product was isolated by vacuum filtration to obtain 2.46 gr. of Rimonabant base crystals. The wet solid was analyzed by XRD and found to be Form VI.
F. Preparation of Rimonabant base Form VII
[000140] Example 18: A slurry of Rimonabant base (2.0gr) in cyclohexane (26ml) was stirred at room temperature for 16 hours. The product was isolated by vacuum filtration to obtain 3.09 gr. of Rimonabant base crystals. The wet solid was analyzed by XRD and found to be Form VII.
G. Preparation of Rimonabant base Form IX
[000141] Example 19: Rimonabant base (2.0gr) was dissolved in n-Propanol (24ml) at room temperature and stirred for 1 hour. Then water (40ml) was added in one portion and the mixture was stirred at room temperature for 24 hours. The product was isolated by vacuum filtration and dried at 550C in a vacuum oven for 24 hours to obtain 1.97 gr. of Rimonabant base crystal Form IX.
[000142] Example 20: Rimonabant base (2.0gr) was dissolved in n-Propanol (24ml) at room temperature and stirred for 1 hour. Then n-Heptane (40ml) was added in one portion and the mixture was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure and dried at 550C in a vacuum oven for 24 hours to obtain 2.00 gr. of Rimonabant base crystal Form IX. (Figure 8) [000143] Example 21: Rimonabant base (2.0gr) was dissolved in n-Propanol (24ml) at room temperature and stirred for 1 hour. Then n-Pentane (40ml) was added in one portion and the mixture was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure and dried at 550C in a vacuum oven for 24 hours to obtain 2.00 gr. of Rimonabant base Form IX.
H. Preparation of Rimonabant base Form I
[000144] Example 22: Rimonabant base (3.0gr) was dissolved in EtOAc (30ml) at room temperature and stirred for 3 hour. Then water (36ml) was added in three portions and the mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and dried at 55°C in a vacuum oven for 24 hours to obtain 2.05gr of Rimonabant base Form I.
[000145] Example 23: Rimonabant base (2.0gr) was dissolved in Ethyl acetate (EtOAc) (26ml) at room temperature and stirred for 1 hour. Then n-Heptane (46ml) was added in one portion and the mixture was stirred at room temperature for 64 hours. The solvent was removed under reduced pressure and dried at 550C in a vacuum oven for 24 hours to obtain 1.52gr of Rimonabant base Form I.
[000146] Example 24: Rimonabant base (2.0gr) was dissolved in Xylene (20ml) at room temperature and stirred for 1 hour. Then n-Heptane (26ml) was added in one portion and the mixture was stirred at room temperature for 64 hours. The product was isolated by vacuum filtration and dried at 550C in a vacuum oven for 24 hours to obtain 0.67gr of Rimonabant base Form I.
[000147] Example 25: Rimonabant base (2.0gr) was dissolved in Xylene (20ml) at room temperature and stirred for 1 hour. Then n-Pentane (46ml) was added in one portion and the mixture was stirred at room temperature for 16 hours. The product was isolated by vacuum filtration and dried at 550C in a vacuum oven for 24 hours to obtain 0.94gr. of Rimonabant base Form I.
[000148] Example 26: Rimonabant base (2.0gr) was dissolved in 1,2 - Dichloroethane (16ml) at room temperature and stirred for 1 hour. Then n-Heptane (50ml) was added in one portion and the mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and dried at 550C in a vacuum oven for 24 hours to obtain 1.67gr of Rimonabant base Form I. [000149] Example 27: Rimonabant base (2.0gr) was dissolved in Chloroform (10ml) at room temperature and stirred for 1 hour. Then n-Heptane (50ml) was added in one portion and the mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and dried at 550C in a vacuum oven for 24 hours to obtain 1.71gr of Rimonabant base Form I.
[000150] Example 28: Rimonabant base (2.0gr) was dissolved in Dichloromethane (10ml) at room temperature and stirred for 1 hour. Then n-Heptane (50ml) was added in one portion and the mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and dried at 550C in a vacuum oven for 24 hours to obtain 1.85gr of Rimonabant base Form I.
[000151] Example 29: Rimonabant base (2.0gr) was dissolved in Toluene (10ml) at room temperature and stirred for 1 hour. Then n-Pentane (40ml) was added in one portion and the mixture was stirred at room temperature for 16 hours. The product was isolated by vacuum filtration and dried at 550C in a vacuum oven for 24 hours to obtain 1.44gr of Rimonabant base Form I.
[000152] Example 30: Rimonabant base (2.0gr) was dissolved in n-Butyl acetate (20ml) at room temperature and stirred for 1 hour. Then water (40ml) was added in one portion and the mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and dried at 550C in a vacuum oven for 24 hours to obtain 1.64gr of Rimonabant base Form I.
[000153] Example 31: Rimonabant base (2.0gr) was dissolved in EtOAc (22ml) at room temperature, stirred and heated to 450C. Then n-Heptane (40ml) was added in one portion and the mixture was stirred 45 0C for 16 hours. The mixture was cooled to room temperature and stirred for 16 hours. The solvent was removed under reduced pressure and dried at 550C in a vacuum oven for 24 hours to obtain 1.71gr of Rimonabant base Form I.
[000154] Example 32: Rimonabant base (2.0gr) was dissolved in Acetone (30ml) at room temperature, stirred and heated to 450C. Then n-Heptane (40ml) was added in one portion and the mixture was stirred at 450C for 16 hours. The mixture was cooled to room temperature and stirred for 16 hours. The solvent was removed under reduced pressure and dried at 550C in a vacuum oven for 24 hours to obtain 1.70gr of Rimonabant base Form I.
[000155] Example 33: Rimonabant base (2.0gr) was dissolved in Dichloromethane (8ml) at room temperature, stirred and heated to 450C. Then n-Heptane (20ml) was added in one portion and the mixture was stirred at 450C for 16 hours. The mixture was cooled to room temperature and stirred for 16 hours. The solvent was removed under reduced pressure and dried at 550C in a vacuum oven for 24 hours to obtain 1.78gr of Rimonabant base Form I.
[000156] Example 34: Rimonabant base (2.0gr) was dissolved in Monochlorobenzene (10ml) at room temperature and stirred for 1 hour. Then n- Heptane (55ml) was added in one portion and the mixture was stirred at room temperature for 16 hours. The product was isolated by vacuum filtration and dried at 550C in a vacuum oven for 24 hours to obtain 1.57g of Rimonabant base form I wit a reduced residual solvent content. The solid product was analyzed by TGA and GC.
[000157] Example 35: A slurry of amorphous Rimonabant base (2.0gr) in n- Heptane (22ml) was stirred at room temperature for 16 hours. The product was isolated by vacuum filtration, to obtain 1.37gr of Rimonabant base Form I.
[000158] Example 36: Rimonabant base (2.0gr) was dissolved in Toluene (10ml) at room temperature, stirred and heated to 85 0C. Then n-Pentane (40ml) was added in one portion and the mixture was stirred at 850C for 1 hour and then cooled to 400C and stirred for 16 hours. Then the mixture was cooled to room temperature. The product was isolated by vacuum filtration, to obtain 1.35gr Rimonabant base Form I.
I. Preparation of Rimonabant base Form II
[000159] Example 37: Rimonabant base (3.0gr) was dissolved in DMSO (36ml) at room temperature and stirred for 1 hour. Then water (36ml) was added in three portions and the mixture was stirred at room temperature for 16 hours. The product was isolated by vacuum filtration and dried at 550C in a vacuum oven for 24 hours to obtain 2.49gr of Rimonabant base Form II.
[000160] Example 38: Rimonabant base (2.0gr) was dissolved in THF (10ml) at room temperature and stirred for 1 hour. Then n-Heptane (30ml) was added in three portions and the mixture was stirred at room temperature for 16 hours. The product was isolated by vacuum filtration and dried at 55°C in a vacuum oven for 24 hours to obtain 0.47gr of Rimonabant base Form II.
[000161] Example 39: Rimonabant base (2.0gr) was dissolved in EtOAc (26ml) at room temperature and stirred for 1 hour. Then n-Pentane (40ml) was added in one portion and the mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and dried at 550C in a vacuum oven for 24 hours to obtain 1.5gr of Rimonabant base Form II.
[000162] Example 40: Rimonabant base (2.0gr) was dissolved in THF (10ml) at room temperature and stirred for 1 hour. Then n-Pentane (46ml) was added in one portion and the mixture was stirred at room temperature for 16 hours. The product was isolated by vacuum filtration and dried at 550C in a vacuum oven for 24 hours to obtain 0.33gr of Rimonabant base Form II.
[000163] Example 41: Rimonabant base (2.0gr) was dissolved in 1,4-Dioxane (20ml) at room temperature and stirred for 1 hour. Then n-Pentane (40ml) was added in one portion and the mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and dried at 550C in a vacuum oven for 24 hours to obtain 1.59gr of Rimonabant base Form II.
[000164] Example 42: Rimonabant base (2.0gr) was dissolved in Acetone (20ml) at room temperature and stirred for 1 hour. Then n-Pentane (46ml) was added in one portion and the mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and dried at 550C in a vacuum oven for 24 hours to obtain 1.76gr of Rimonabant base Form II.
[000165] Example 43: Rimonabant base (2.0gr) was dissolved in MIBK (22ml) at room temperature and stirred for 1 hour. Then n-Heptane (40ml) for 64 hours. The product was isolated by vacuum filtration and dried at 550C in a vacuum oven for 24 hours to obtain 0.42gr of Rimonabant base Form II.
[000166] Example 44: Rimonabant base (2.0gr) was dissolved in MIBK (22ml) at room temperature and stirred for 1 hour. Then n-Pentane (40ml) was added in one portion and the mixture was stirred at room temperature for 64 hours. The product was isolated by vacuum filtration and dried at 550C in a vacuum oven for 24 hours to obtain 0.32gr of Rimonabant base Form II.
[000167] Example 45: Rimonabant base (2.0gr) was dissolved in n-Butyl acetate (20ml) at room temperature and stirred for 1 hour. Then n-Pentane (40ml) was added in one portion and the mixture was stirred at room temperature for 72 hours. The product was isolated by vacuum filtration and dried at 550C in a vacuum oven for 24 hours to obtain 0.63gr of Rimonabant base Form II.
[000168] Example 46: Rimonabant base (2.0gr) was dissolved in n-Butyl acetate (20ml) at room temperature and stirred for 1 hour. Then n-Heptane (40ml) was added in one portion and the mixture was stirred at room temperature for 72 hours. The product was isolated by vacuum filtration and dried at 550C in a vacuum oven for 24 hours to obtain 0.59gr of Rimonabant base Form II.
[000169] Example 47: A slurry of amorphous Rimonabant base (2.0gr) in water (76ml) was stirred at room temperature for 16 hours. The product was isolated by vacuum filtration, to obtain 1.63gr of Rimonabant Form II.
[000170] Example 48: A slurry of amorphous Rimonabant base (2.0gr) in MTBE (20ml) was stirred at room temperature for 16 hours. The product was isolated by vacuum filtration, to obtain 0.47gr of Rimonabant base Form II.
[000171] Example 49: Rimonabant base (2.0gr) was dissolved in Toluene (10ml) at room temperature, stirred and heated to 850C. Then n-Heptane (40ml) was added in one portion and the mixture was stirred at 850C for 1 hour and then cooled to 400C and stirred for 16 hours. Then the mixture was cooled to room temperature. The product was isolated by vacuum filtration, to obtain 1.49gr Rimonabant base Form II.
J. Preparation of Rimonabant base Form X
[000172] Example 50: Rimonabant base (2.0gr) was dissolved in n-Butanol (30ml) at room temperature, heated to 850C and stirred at this temperature for 1 hour. Then n- Heptane (30ml) was added in one portion and the mixture was stirred at 4O0C over night (about 16 hours). The mixture was cooled to room temperature. The solvent was removed under reduced pressure to obtain 2.7gr of Rimonabant base crystalline Form X. [See Figure 9] K. Preparation of Rimonabant base Form XII
[000173] Example 51: Amorphous Rimonabant base (1.5g) was partially dissolved in absolute Ethanol (15ml) at room temperature and stirred at this temperature for 16 hours. The product was isolated by vacuum filtration and dried at 550C in a vacuum oven for 24 hours to obtain 0.65gr of Rimonabant base crystalline form XII. [See Figure 10]
[000174] Example 52: Amorphous Rimonabant base (1.5g) was partially dissolved in absolute Ethanol (15ml) at room temperature and stirred at this temperature for 16 hours. The product was isolated by vacuum filtration to obtain 0.80gr of Rimonabant base crystalline form XII. [See Figure 11]
[000175] Example 53: Rimonabant base (3.Og) was partially dissolved in absolute Ethanol (30ml) at room temperature. The solution was shaken gently for 1 minute to obtain white crystals with almost no solvent remained in the flask. The product was isolated by vacuum filtration, dried at 550C in a vacuum oven for 24 hours to obtain 1.82 gr. Rimonabant base Form VIII. (Figure 7)

Claims

What is claimed is:
1. A crystalline Rimonabant base Form I characterized by PXRD peaks at about: 9.2, 16.9, 26.2 and 27.3 ± 0.2 degrees 2Θ and having a substantially reduced residual solvent content.
2. The crystalline Rimonabant base Form I of claim 1, having a substantially reduced residual solvent content contains less that 1% (wt/wt) solvent.
3. The crystalline Rimonabant base Form I of claim 2, wherein the solvent content is less than 0.5% (wt/wt) solvent.
4. The crystalline Rimonabant base Form I of any one of claims 1 to 3, having a TGA thermogram wherein there is less than 1% weight loss in the range of 115- 180°C.
5. The crystalline Rimonabant base Form I of claim 4, wherein there is less than 0.8% weight loss.
6. The crystalline Rimonabant base Form I of any one of claims 4 and 5, having a TGA thermogram substantially as depicted in Figure 24.
7. The crystalline Rimonabant base Form I of any one of claims 1 to 6, having less than 7000 ppm residual solvent.
8. The crystalline Rimonabant base Form I of claim 7, having less than 6000 ppm residual solvent.
9. The crystalline Rimonabant base Form I of claim 8, having less than 2000 ppm residual solvent.
10. The crystalline Rimonabant base Form I of any one of claims 1 to 9, having less than 6000 ppm diisopropyl ether and 400 ppm of dichloromethane.
11. The crystalline Rimonabant base Form I of claim 10, having less than 5000 ppm diisopropylether and 300 ppm of dichloromethane.
12. The crystalline Rimonabant base Form I of claim 11, having less than 3000 ppm diisopropylether and 200 ppm of dichloromethane.
13. A process of preparing crystalline Rimonabant base Form I having a substantially reduced residual solvent content comprising:
a) combining Rimonabant base and monochlorobenzene to form a first mixture;
b) maintaining the first mixture for about 30 minutes to about 5 hours;
c) admixing the mixture with a C5-8 hydrocarbon to obtain a second mixture; and
d) maintaining the second mixture at least for a period sufficient to obtain a solid form.
14. The process of claim 13, wherein the first mixture is maintained for about 1 hour.
15. The process of any one of claims 13 and 14, wherein the C5-8 hydrocarbon is heptane.
16. The process of any one of claims 13 to 15, wherein the monochlorobenzene is in about 1 :5 to about 1 :8 weight to volume ratio compared to the Rimonabant base and the C5-8 hydrocarbon is in about 1 :20 to 1 :30 weight to volume ratio compared to the Rimonabant base.
17. The process of claim 16, wherein the monochlorobenzene is in about 1 :5 weight to volume ratio compared to the Rimonabant base.
18. The process of any one of claims 13 to 17, wherein the period in step d) is about 12 to about 24 hours.
19. The process of any one of claims 13 to 18, further comprising drying the solid form obtained in step d) at about 40°C to about 700C for a period of about 16 hours to about 32 hours.
20. A process for preparing crystalline Rimonabant base Form I comprising: a) providing a solution of Rimonabant base and a solvent selected from the group consisting of: chloroform, dichloromethane, 1,2- dichloroethane, xylene, toluene and mixtures thereof;
b) admixing the solution with an anti-solvent selected from a C5-8 hydrocarbon; and
c) recovering the Rimonabant base.
21. The process of claim 20, wherein the C5-8 hydrocarbon is pentane or heptane.
22. The process of any one of claims 20 and 21, wherein the solution of Rimonabant base and a solvent is heated.
23. The process of claim 22, wherein the temperature to which the solution is heated is from about 40°C to about 90°C.
24. The process of any one of claims 22 and 23, wherein the solution is heated for a sufficient period of time prior to cooling.
25. The process of claim 24, wherein the period is about 1 hour to about 24 hours.
26. The process of any one of claims 24 and 25, wherein cooling involves a multi- step process of a first cooling step wherein the solution or mixture is maintained at such first cooling temperature for a sufficient period of time before subsequent cooling.
27. The process of claim 26, wherein the period is about 1 hour to about 24 hours.
28. The process of any one of claims 26 and 27, wherein the first cooling is to a temperature of about room temperature to about 40°C and subsequent cooling is to about 15°C to about 30°C.
29. The process of any one of claims 20 to 28, wherein recovering of Rimonabant base Form I comprises evaporating the solvent(s) and anti-solvent(s) under reduced pressure while heating to a temperature of about 50°C to about 60°C for a period of about 16 hours to about 32 hours.
30. A process for preparing crystalline Rimonabant base Form I comprising: a) providing a solution of Rimonabant base and a solvent selected from the group consisting of: acetone, ethylacetate, or mixtures;
b) admixing the solution with an anti-solvent selected from water, heptane, or mixtures thereof; and
c) recovering the Rimonabant base.
31. The process of claim 30, wherein the solution of Rimonabant base and a solvent is heated.
32. The process of claim 31, wherein the temperature to which the solution is heated is about 40°C to about 550C.
33. The process of claim 32, wherein the solution is heated for a sufficient period of time prior to cooling.
34. The process of claim 33, wherein the period is about 1 hour to about 24 hours.
35. The process of any one of claims 33 and 34, wherein cooling is to a temperature of about 15°C to about 300C.
36. The process of any one of claims 30 to 35, wherein recovering of Rimonabant base Form I comprises evaporating the solvent(s) and anti-solvent(s) under reduced pressure while heating to a temperature of about 50°C to about 6O0C for a period of about 16 hours to about 32 hours.
37. A process for preparing crystalline Rimonabant base Form I comprising: providing a solution of Rimonabant base and n-butylacetate; admixing water; and recovering the Rimonabant base Form I.
38. The process of claim 37, wherein recovering of Rimonabant base Form I comprises evaporating n-butylacetate and water from the solution under reduced pressure while heating to a temperature of about 500C to about 600C for a period of about 16 hours to about 32 hours.
39. A process for preparing crystalline Rimonabant base Form I comprising: slurrying amorphous Rimonabant base in heptane for a period to obtain Rimonabant Form I.
40. The process of claim 39, wherein the period of slurrying is about 6 hours to about 24 hours.
41. A process of preparing amorphous Rimonabant base comprising:
a) providing Rimonabant base and a solvent selected from the group consisting of: 1 ,4-dioxane, ethyl acetate, acetone and mixtures thereof to obtain a mixture;
b) admixing the mixture with a C5 to C8 hydrocarbon to obtain an amorphous Rimonabant base; and
c) recovering the amorphous Rimonabant base, wherein recovering.
42. A crystalline form of Rimonabant base, characterized data selected from the list consisting of: a powder XRD pattern with peaks at about 6.7, 8.5, 12.2 and 14.3 ± 0.2 degrees two-theta; a solid-state 13C NMR spectrum with signals at about 161.8, 142.9, 135.9, 132.5 and 1 16.1 ± 0.2 ppm; a solid-state 13C NMR spectrum having chemical shifts differences between the signal exhibiting the lowest chemical shift and another in the chemical shift range of 100 to 180 ppm of about 45.7, 26.8, 19.8, 16.4 and 0.0 ± 0.1 ppm, wherein the signal exhibiting the lowest chemical shift in the chemical shift area of 100 to 180ppm is at about 116.1 ± lppm.
43. The crystalline Rimonabant base of claim 42, further characterized by a powder XRD pattern with one or more additional peaks at about 15.6, 18.1, 21.9, 24.4 and 30.8 ± 0.2 degrees two-theta.
44. The crystalline Rimonabant base of any one of claims 42 and 43, having a powder XRD pattern substantially as depicted in Figure 2, a solid state 13C NMR spectrum substantially as depicted in Figure 13, or a solid-state 13C NMR spectrum substantially as depicted in Figure 14.
45. The crystalline Rimonabant base of any one of claims 42 to 44, wherein the crystalline form is an isopropanolate solvated form.
46. The crystalline Rimonabant base of claim 45, wherein the isopropanolate solvated form is solvated from about hemi-isopropanolate to about a mono- isopropanolate.
47. The crystalline Rimonabant base of any one of claims 42 to 46, having a solvent weight loss as measured by standard TGA procedures of about 7-8 weight %.
48. The crystalline Rimonabant base of any one of claims 42 to 47, having a water content, as measured by KF, of about 0.1 to about 1 weight %.
49. The crystalline Rimonabant base of any one of claims 42 to 48, having a polymorphic purity of more than 80%.
50. The crystalline Rimonabant base of claim 50, wherein the purity is more than 90%.
51. A process for preparing crystalline Rimonabant base of any one of claims 42 to 50 comprising:
a) combining isopropanol and Rimonabant base Form I, II or a mixture thereof to obtain a mixture;
b) mixing the mixture for a period of time sufficient to convert the Rimonabant Form(s) to obtain Rimonabant base of claim 42; and
c) recovering the crystalline form of Rimonabant base.
52. A crystalline form of Rimonabant base, characterized by a powder XRD pattern with peaks at about 6.6, 8.4, 13.4 and 14.3 ± 0.2 degrees two-theta.
53. The crystalline Rimonabant base of claim 52, further characterized by a powder XRD pattern with an additional peak at about 21.8 ± 0.2 degree two-theta.
54. The crystalline Rimonabant base of any one of claims 52 and 53, having a powder XRD pattern substantially as depicted in Figure 3.
55. The crystalline Rimonabant base of any one of claims 52 to 54, having a polymorphic purity of more than 80%.
56. The crystalline Rimonabant base of claim 56, wherein the purity is more than 90%.
57. A process of preparing crystalline Rimonabant base of any one of claims 52 to 56 comprising:
a) combining ethanol and Rimonabant base to obtain a mixture;
b) mixing the mixture for about 1 to about 10 minutes to obtain the crystalline Rimonabant base; and
c) recovering the crystalline form of Rimonabant base.
58. A crystalline form of Rimonabant base, characterized by data selected from the list consisting of: a powder XRD pattern with peaks at about 9.5, 13.7, 15.5 and 17.4 ± 0.2 degrees two-theta, a solid-state 13C NMR spectrum with peaks at about 161.4, 159.4, 143.1, 127.8 and 118.6 ± 0.2 ppm and a solid-state 13C NMR spectrum having chemical shifts differences between the signal exhibiting the lowest chemical shift and another in the chemical shift range of 100 to 180 ppm of about 42.8, 40.8, 24.5, 9.2 and 0.0 ± 0.1 ppm. The signal exhibiting the lowest chemical shift in the chemical shift area of 100 to 180ppm is preferably at about 118.6 ± lppm.
59. The crystalline Rimonabant base of claim 58, further characterized by a powder XRD pattern with one or more additional peaks at about 7.4, 14.7, 19.2, 23.5 and 29.7 ± 0.2 degree two-theta.
60. The crystalline Rimonabant base of any one of claims 58 and 59, having a powder XRD pattern substantially as depicted in Figure 4 or 12, a 13C NMR spectrum substantially as depicted in Figure 19 or a solid-state 13C NMR spectrum substantially as depicted in Figure 20.
61. The crystalline Rimonabant base of any one of claims 58 to 60, having about 3.5 to 4.0 weight % water.
62. The crystalline Rimonabant base of claim 58 to 61, wherein the crystalline form is a monohydrate form.
63. The crystalline Rimonabant base of claim 58 to 62, having a solvent weight loss as measured by standard TGA procedures of about 3.5 to about 4.0 weight %.
64. The crystalline Rimonabant base of claim 58 to 63, having a water content, as measured by KF, may be about 3.5 to about 4.0 weight %.
65. The crystalline Rimonabant base of claim 58 to 64, having a polymorphic purity of more than 80%.
66. The crystalline Rimonabant base of claim 65, wherein the purity is more than 90%.
67. A process of preparing crystalline Rimonabant base of any one of claims 58 to 66 comprising:
a) combining Rimonabant base and a solvent selected from the group consisting of: ethyl acetate, tetrahydrofuran, 1,4 dioxane, acetone, xylene and methyl ethyl ketone;
b) admixing about 0.5 to about 4 volumes of water (ml of water per gram of Rimonabant base); and
c) recovering the crystalline form of Rimonabant base.
68. A process of preparing crystalline Rimonabant base of any one of claims 58 to 66 comprising; combining Rimonabant base and toluene to obtain a mixture; admixing the mixture with heptane; recovering the Rimonabant base; and drying the Rimonabant base.
69. A process of preparing crystalline Rimonabant base of any one of claims 58 to 66 comprising;
a) combining Rimonabant base Form I, II or a mixture thereof and methanol to obtain a mixture;
b) mixing the mixture for about 16 to about 24 hours; c) recovering the Rimonabant base; and
d) drying Rimonabant base to obtain the crystalline form of Rimonabant base,
wherein the Rimonabant base (weight) to methanol (volume) ratio is from about 1 :5 of about 1 :15.
70. A crystalline form of Rimonabant base, characterized by a powder XRD pattern with peaks at about 10.2, 13.8, 15.6, 23.3 and 24.4 ± 0.2 degrees two-theta.
71. The crystalline Rimonabant base of claim 70, further characterized by a powder XRD pattern with one or more additional peaks at about 18.9, 20.4 and 22.9 ± 0.2 degree two-theta.
72. The crystalline Rimonabant base of any one of claims 70 and 71, having a powder XRD pattern substantially as depicted in Figure 5.
73. The crystalline Rimonabant base of any one of claims 70 to 72, having a purity of more than 80%.
74. The crystalline Rimonabant base of claim 73, wherein the purity is more than 90%.
75. A process for preparing crystalline Rimonabant base of any one of claims 70 to 74 comprising;
a) combining Rimonabant base Form I, II or a mixture thereof and methanol to obtain a mixture;
b) mixing the mixture for about 16 to about 24 hours;
c) recovering the crystalline form of Rimonabant base;
wherein the crystalline form of Rimonabant base is obtained without drying and the Rimonabant (weight) to methanol (mL) ratio is from about 1 :5 to about 1 :15.
76. A crystalline form of Rimonabant base, characterized by a powder XRD pattern with peaks at about 4.0, 8.0, 10.4 and 15.7 ± 0.2 degrees two-theta.
77. The crystalline Rimonabant base of claim 76, further characterized by a powder XRD pattern with one or more additional peaks at about 19.2, 19.7 and 21.4 ± 0.2 degree two-theta.
78. The crystalline Rimonabant base of any one of claims 76 and 77, having a powder XRD pattern substantially as depicted in Figure 6.
79. The crystalline Rimonabant base of any one of claims 76 to 78, having a polymorphic purity of more than 80%.
80. The crystalline Rimonabant base of claim 79, wherein the purity is more than 90%.
81. A process for preparing crystalline Rimonabant base of any one of claims 76 to 80 comprising:
a) combining cyclohexane and Rimonabant base to obtain a mixture;
b) mixing the mixture for a period of about 6 to about 48 hours to obtain Rimonabant base of claim 76; and
c) recovering the crystalline form of Rimonabant base.
82. A crystalline form of Rimonabant base, characterized data selected from the list consisting of: a powder XRD pattern with peaks at about 13.7, 14.6, 16.2, 20.8 and 21.6 ± 0.2 degrees two-theta; a solid-state 13C NMR spectrum with signals at about 161.9, 145.4, 143.5, 136.0 and 129.6 ± 0.2 ppm; and a solid-state 13C NMR spectrum having chemical shifts differences between the signal exhibiting the lowest chemical shift and another in the chemical shift range of 100 to 180 ppm of about 45.5, 29, 27.1, 19.6 and 13.2 ± 0.1 ppm, wherein the signal exhibiting the lowest chemical shift in the chemical shift area of 100 to 180ppm is at about 116.4 ± lppm.
83. The crystalline Rimonabant base of claim 82, further characterized by a powder XRD pattern with one or more additional peaks at about 6.9, 8.6, 19.4, 22.1, 22.5 and 24.3 ± 0.2 degrees two-theta.
84. The crystalline Rimonabant base of any one of claims 82 and 83, having a powder XRD pattern substantially as depicted in Figure 8, a 13C NMR spectrum substantially as depicted in Figure 15, or a solid-state 13C NMR spectrum substantially as depicted in Figure 16.
85. The crystalline Rimonabant base of any one of claims 82 to 84, having a solvent weight loss as measured by standard TGA procedures of about 8-9 weight %.
86. The crystalline Rimonabant base of any one of claims 82 to 85, having a water content, as measured by KF, of about 0.05 to about 0.5 weight %.
87. The crystalline Rimonabant base of any one of claims 82 to 86, wherein the crystalline form is a solvate of n-propanol/n-pentane.
88. The crystalline Rimonabant base of any one of claims 82 to 87, having a polymorphic purity of more than 80%.
89. The crystalline Rimonabant base of claim 88, wherein the purity is more than 90%.
90. A process for preparing crystalline Rimonabant base of any one of claims 82 to 89 comprising:
a) providing a solution of Rimonabant base and n-propanol;
b) admixing with a solvent selected from the group consisting of water, n- heptane, and n-pentane, to obtain a mixture;
c) maintaining the mixture for a period sufficient to obtain the crystalline Rimonabant base; and
d) recovering Rimonabant base.
91. A crystalline form of Rimonabant base, characterized by a powder XRD pattern with peaks at about 7.7, 8.3, 9.4 and 16.4 ± 0.2 degrees two-theta.
92. The crystalline Rimonabant base of claim 91, further characterized by a powder XRD pattern with one or more additional peaks at about 4.6, 10.7, 17.6, 18.4 and 27.9 ± 0.2 degree two-theta.
93. The crystalline Rimonbant base of any one of claims 91 and 92, having a powder XRD pattern substantially as depicted in Figure 9.
94. The crystalline Rimonabant base of any one of claims 91 to 93, having a polymorphic purity of more than 80%.
95. The crystalline Rimonabant base of claim 94, wherein the purity is more than 90%.
96. A process for preparing crystalline Rimonabant base of any one of claims 91 to 95 comprising:
a) providing a solution of Rimonabant base and butanol;
b) admixing an anti-solvent to obtain a precipitate; and
c) recovering the crystalline form of Rimonabant base.
97. The process of claim 96, wherein the anti-solvent is n-heptane.
98. A crystalline form of Rimonabant base, characterized by data selected from the list consisting of: a powder XRD pattern with peaks at about 6.8 ± 0.3, 8.5, ± 0.3, 12.4 ± 0.2 and 22.1 ± 0.2 degrees two-theta; a 13C NMR spectrum with signals at about 162.0 145.3, 135.9, 130.2 and 127.6 ± 0.2 ppm; a solid-state 13C NMR spectrum having chemical shifts differences between the signal exhibiting the lowest chemical shift and another in the chemical shift range of 100 to 180 ppm of about 45.8, 29.1, 19.7, 17 and 1 1.4 ± 0.1 ppm, wherein the signal exhibiting the lowest chemical shift in the chemical shift area of 100 to 180ppm is at about 1 16.2 ± lppm.
99. The crystalline Rimonabant base of claim 98, further characterized by a powder XRD pattern with one or more additional peaks at about 10.3, 14.6, 16.9 and 18.4 ± 0.2 degree two-theta.
100. The crystalline Rimonabant base of any one of claims 98 and 99, having a powder XRD pattern substantially as depicted in Figures 10 or 11, a 13C NMR spectrum substantially as depicted in Figure 17, or a solid-state 13C NMR spectrum substantially as depicted in Figure 18.
101. The crystalline Rimonabant base of any one of claims 98 to 100, wherein crystalline form is an ethanol solvate.
102. The crystalline Rimonabant base of claim 101, wherein the ethanolate is an hemiethanolate.
103. The crystalline Rimonabant base of any one of claims 98 to 102, having a solvent weight loss as measured by standard TGA procedures of about 5.5 weight % to about 6.5 weight %.
104. The crystalline Rimonabant base of any one of claims 98 to 103, having a water content, as measured by KF, of about 0.5 weight % to about 2.5 weight %.
105. The crystalline Rimonabant base of any one of claims 98 to 104, having a polymorphic purity of more than 80%.
106. The crystalline Rimonabant base of claim 105, wherein the purity is more than 90%.
107. A process for preparing crystalline Rimonabant base of any one of claims 98 to 106 comprising exposing amorphous Rimonabant base to ethanol until obtaining Rimonabant base Form XII.
108. A process for preparing crystalline Rimonabant base Form II comprising:
a) providing a solution of Rimonabant base and a solvent selected from the group consisting of: toluene, MIBK, n-butylacetate, THF, 1,4,- dioxane, DMSO and mixtures thereof;
b) admixing pentane, heptane or a mixture thereof with the solution to obtain a mixture; and
c) recovering the Rimonabant base Form II.
109. The process of claim 108, wherein the mixture from step b) is maintained at a constant temperature for a sufficient period to obtain the crystalline form II.
110. The process of claim 109, wherein the period of time is from about 12 hours to about 72 hours.
111. The process of any one of claims 108 to 110, wherein the solution of Rimonabant base and a solvent is heated.
112. The process of claim 111, wherein the temperature to which the solution is heated is from about 40°C to about 90°C.
113. The process of claim 112, wherein the solution is heated for a period of time prior of about 1 hour to about 16 hours prior to cooling.
114. A process for preparing crystalline Rimonabant base Form II comprising: providing a solution of Rimonabant base and a solvent selected from the group consisting of: acetone, ethylacetate, DMSO or mixtures thereof; admixing pentane or water with the solution; and recovering the Rimonabant base Form II.
115. A process for preparing Rimonabant base Form II comprising: slurrying amorphous Rimonabant base in MTBE, water or a mixture thereof for a period to obtain Rimonabant Form II.
116. The process of claim 115, wherein the period of slurrying is about 6 hours to about 24 hours.
117. A pharmaceutical composition comprising any one of the Rimonabant base forms selected from the group consisting of crystalline Forms of claims 42-50, 52-56, 58-66, 70-74, 76-80, 82-89, 91-95, and 98-106, and Form I having a reduced solvent content, and at least one pharmaceutically acceptable excipient.
118. A pharmaceutical composition comprising Rimonabant base of any one of the Rimonabant base forms made by the processes of claims 13-41, 51, 57, 67-69, 75, 81, 90, 96, 97, and 107-116, and at least one pharmaceutically acceptable excipient.
119. A process for preparing a pharmaceutical formulation comprising combining any one of Rimonabant base forms selected from the group consisting of crystalline Forms of claims 42-50, 52-56, 58-66, 70-74, 76-80, 82-89, 91-95, and 98-106, and Form I having a reduced solvent content with at least one pharmaceutically acceptable excipient.
120. Use of any one of Rimonabant base forms selected from the group consisting of crystalline Forms of claims 42-50, 52-56, 58-66, 70-74, 76-80, 82-89, 91-95, and 98-106, and Form I having a reduced solvent content for the manufacture of a pharmaceutical composition.
121. Use of any one of Rimonabant base forms made by the processes of claims 13- 41, 51, 57, 67-69, 75, 81, 90, 96, 97, and 107-116, for the manufacture of a pharmaceutical composition.
PCT/US2008/000726 2007-01-18 2008-01-18 Polymorphic forms of rimonabant base and processes for preparation thereof WO2008088900A2 (en)

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US88124207P 2007-01-18 2007-01-18
US60/881,242 2007-01-18
US89910107P 2007-02-01 2007-02-01
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US90319807P 2007-02-22 2007-02-22
US60/903,198 2007-02-22
US90398707P 2007-02-27 2007-02-27
US60/903,987 2007-02-27
US91897807P 2007-03-19 2007-03-19
US60/918,978 2007-03-19
US92105007P 2007-03-29 2007-03-29
US60/921,050 2007-03-29
US92347707P 2007-04-12 2007-04-12
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