WO2008038143A2 - Novel solid forms of rimonabant and synthetic processes for their preparation - Google Patents

Novel solid forms of rimonabant and synthetic processes for their preparation Download PDF

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WO2008038143A2
WO2008038143A2 PCT/IB2007/003678 IB2007003678W WO2008038143A2 WO 2008038143 A2 WO2008038143 A2 WO 2008038143A2 IB 2007003678 W IB2007003678 W IB 2007003678W WO 2008038143 A2 WO2008038143 A2 WO 2008038143A2
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Prior art keywords
rimonabant
solvate
hydrate
approximately
amorphous
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PCT/IB2007/003678
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French (fr)
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WO2008038143A3 (en
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Monica Benito Velez
Stephen Winter
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Medichem, S.A.
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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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents

Definitions

  • the invention relates to novel solid forms of rimonabant and amorphous rimonabant and synthetic processes for their preparation.
  • Rimonabant a CBl cannabinoid receptor antagonist, is pharmaceutically useful for the treatment of obesity by reduction of appetite.
  • Rimonabant is the international common accepted name for 5-(4-chlorophenyI)-l-(2,4-dichlorophenyl)-4-methyI-N- piperidinopyrazole-3-carboxamide, which is represented in Formula I.
  • Rimonabant can be prepared by reaction of an activated form of 5-(4-chlorophenyl)-l- (2,4-dichlorophe ⁇ yl)-4-methy!-I H-pyrazole-3-carboxylic acid (compound [I) and 1-amino piperidine (compound 111) in an organic solvent in the presence of a base as shown in Scheme 1.
  • U.S. Patent No. 5,624,941 allows the preparation of rimonabant in crystalline form which is later designated by U.S. Patent Application No.2005/0043356 Al as Form I.
  • Form I is obtained from isopropyl ether and from methylcyclohexane.
  • U.S. Patent No. 5,624,941 describes also an ethanol solvate of rimonabant.
  • Example 212 the ethanol solvate is characterized by having a DSC with an endothermic peak centered at 102.7° C. According to the elemental analysis, the solvate obtained in Example 212 corresponds to a monoethanolate.
  • U.S. Patent Application No. 2005/0043356 Al describes a polymorphic form of rimonabant designated as Form II.
  • Form II can be prepared by recrystallization from solvents such as methylcyclohexane, methylcyclohexane - water, acetonitrile, 4-methyl-2-pentanone, acetone or mixtures thereof.
  • the invention relates to novel solid forms of rimonabant and amorphous rimonabant and synthetic processes for their preparation.
  • Figure 1 illustrates the X-ray powder diffractogram (XRD) of rimonabant ethanol solvate
  • Figure 2 illustrates the Infrared (IR) spectrum of rimonabant ethanol solvate
  • Figure 3 illustrates the XRD of rimonabant methanol solvate
  • Figure 4 illustrates the IR spectrum of rimonabant methanol solvate
  • Figure 5 illustrates the XRD of rimonabant hydrate
  • Figure 6 illustrates the IR spectrum of rimonabant hydrate
  • FIG. 7 illustrates the Differential Scanning Calorimetry (DSC) thermogram (open pan) of rimonabant hydrate
  • Figure 8 illustrates the Thermogravimetric Analysis (TG) of rimonabant hydrate
  • Figure 9 illustrates the XRD of rimonabant 1 -propanol solvate
  • Figure 10 illustrates the IR spectrum of rimonabant 1-propanol solvate
  • Figure 1 1 illustrates the XRD of rimonabant 3 -methyl- 1-butanol solvate
  • Figure 12 illustrates the IR spectrum of rimonabant 3-methyl- 1-butanol solvate
  • DSC Differential Scanning Calorimetry
  • TG Thermogravimetric Analysis
  • Figure 13 illustrates the XRD of rimonabant n-butanol solvate
  • Figure 14 illustrates the IR spectrum of rimonabant n-butanol solvate
  • Figure 15 illustrates the XRD of amorphous rimonabant
  • Figure 16 illustrates the IR spectrum of amorphous rimonabant.
  • rimonabant can exist and be prepared as an ethanol solvate, as a methanol solvate, as a 1-propanol solvate, as a 3-methyl- 1 -butanol solvate, as a n-butanol solvate, as a hydrate and as in amorphous form.
  • rimonabant ethanot solvate i.e., rimonabant ethanolate.
  • Figure 1 illustrates the X- Ray powder diffraction pattern (2 ⁇ ) ( ⁇ 0.2°) (XRD) of rimonabant ethanol solvate having its main peaks at approximately 6.7, 8.4, 10.1, 12.1, 13.5, 14.4, 16.7, 18.2, 19.3, 20.9 and 21.8°.
  • Figure 2 illustrates the infrared (IR) spectrum of rimonabant ethanol having its main peaks at approximately 3410, 3202, 3078, 2932, 2855, 2816, 1666, 1558, 1489, 1443, 1389, 1358, 1265, 121 1, 1 142, 1096, 1049, 101 1, 988, 972, 918, 833, 779, 725, 656, 556, 525, 494, 432 cm “1 .
  • the rimonabant ethanolate is further characterized by having a high purity according to high performance liquid chromatography (HPLC), and is generally free of insoluble materials/compounds.
  • HPLC high performance liquid chromatography
  • FIG. 3 illustrates the XRD (2 ⁇ ) ( ⁇ 0.2°) of rimonabant methanol solvate having its main peaks at approximately 7.6, 9.8, 13.3, 15.2, 18.4, 20.0, 21.1, 22.4, 22.8; 24.0 and 27.1°.
  • Figure 4 illustrates the IR spectrum of rimonabant methanolate having its main peaks at approximately 3641, 3395, 3209, 3078, 2939, 2855, 2808, 1659, 1551, 1489, 1435, 1381, 1358, 1304, 1265. 121 1. 1 142.
  • the rimonabant methanolate is further characterized by having a high purity according to HPLC, and is generally free of insoluble materials/compounds.
  • FIG. 5 illustrates the XRD (2 ⁇ ) ( ⁇ 0.2°) of rimonabant hydrate having its main peaks at approximately 7.2, 9.3, 10.4, 13.5, 15.2, 16.1, 16.3, 17.1, 17.8, 19.0, 19.2, 20.3, 20.8, 21.1, 21.6, 22.4 and 22.9°.
  • Figure 6 illustrates the IR spectrum of rimonabant hydrate having its main peaks at approximately 3642, 3387, 3209, 3078, 2939, 2855, 2808, 1659, 1551, 1489, 1435, 1381, 1358, 1304, 1265, 1211, 1134, 1096, 1057, 1033, 101 1, 987, 972, 918, 857, 833, 779, 718, 671, 633, 594, 548, 524, 494, 440 cm '1 .
  • Figure 7 illustrates the differential scanning calorimetry (open pan) (DSC) of rimonabant hydrate, which exhibits art endothermic peak at approximately 103.2° C (onset of 85.8° C).
  • DSC differential scanning calorimetry
  • FIG. 8 illustrates the thermogravimetric analysis (TG) of rimonabant hydrate.
  • This TG shows a loss of weight of approximately 3.3% which corresponds to rimonabant monohydrate.
  • the rimonabant hydrate is further characterized by having a high purity according to HPLC, with a low residual content, and is generally free of insoluble materials/compounds.
  • FIG. 9 illustrates the XRD (2 ⁇ ) ( ⁇ 0.2°) of rimonabant 1 -propanol solvate having its main peaks at approximately 6.7, 8.3, 9.9, 1 1.9, 13.4, 14.3, 15.9, 16.3, 16.7, 17.9, 18.1, 20.8 and 21.9°.
  • Figure 10 illustrates the IR spectrum of rimonabant 1-propanol solvate having its main peaks at approximately 3406, 3202, 3074, 2939, 2858, 2828, 1670, 1605, 1558, 1497, 1431, 1383, 1358, 1308.
  • the rimonabant 1-propanol solvate is further characterized by having a high purity according to HPLC, and is generally free of insoluble materials/compounds.
  • FIG. 1 1 illustrates the XRD (2 ⁇ ) ( ⁇ 0.2°) of rimonabant 3-methyl-l-buta ⁇ ol solvate having its main peaks at approximately 7.6, 8.0, 8.6, 1 1.1, 15.3, 16.2, 17.6, 17.8, 18.9, 19.4, 21.0, 22.1 , 22.3, 22.9, 23.6, 25.4°.
  • Figure 12 illustrates the IR spectrum of rimonabant 3-methyI-l-butanol solvate having its main peaks at approximately 3391, 3225, 3086, 3047, 2947, 2864, 2829, 1657, 1607, 1560, 1491, 1439, 1383, 1360, 1308, 1269, 1236, 1207, 1 167, 1 140, 1089, 1 103, 1090, 1065, 101 1, 994, 968, 918, 878, 859, 837, 814, 789, 745, 733, 671, 648, 613, 554, 523, 503, 492 and 738 cm "1 .
  • Rimonabant 3-methyl-l- butano! solvate is generally free of insoluble materials/compounds.
  • Another aspect of the invention is to provide a novel rimonabant n- butanol solvate.
  • Figure 13 illustrates the XRD (2 ⁇ ) ( ⁇ 0.2°) of rimonabant n-butanol solvate having its mean peaks at approximately 7.6, 8.1 , 8.7, 1 1.2, 15.3, 17.6, 19.0, 19.6, 21.1, 23.2, 23.4, 23.8 and 25.7°.
  • Figure 14 illustrates the JR spectrum of rimonabant n-butanol solvate having its main peaks at approximately 3391, 3225, 3086, 3047, 2949, 2860, 2824, 1661, 1607, 1560, 1497, 1441, 1383, 1360, 1308, 1267, 1209, 1 140, 1 102, 1090, 1054, 1037, 101 1, 994, 968, 918, 906, 878, 862, 837, 814, 787, 744, 733, 671, 613, 551 , 523, 503, 492, 438 cm-1.
  • Rimonabant n-butanol solvate is generally free of insoluble materials/compounds.
  • FIG. 15 illustrates the XRD (2 ⁇ ) ( ⁇ 0.2°) of amorphous rimonabant.
  • Figure 16 illustrates the infrared spectrum of amorphous rimonabant which has its main peaks at approximately 3408, 3317, 3082, 2939, 2854, 2795, 1684, 1497, 1383, 1246, 1094, 1013, 968, 918, 816, 733, 633, 503, 442 cm “ ' .
  • Amorphous rimonabant is further characterized by having a high purity according to HPLC. and is generally free of insoluble materials/compounds.
  • Another aspect of the invention includes a process for preparing rimonabant ethanol solvate including (i) combining rimonabant and ethanol; (ii) optionally adding water to the rimonabant and ethanol; and (iii) isolating the rimonabant ethanol solvate.
  • Another aspect of the invention includes a process for preparing rimonabant methanol solvate including (i) combining rimonabant and methanol; and (ii) isolating the rimonabant methanol solvate.
  • Another aspect of the invention includes a process for preparing rimonabant hydrate solvate including (i) combining rimonabant and 2-propanol; and (ii) isolating the rimonabant hydrate.
  • the invention also includes a process for preparing rimonabant hydrate solvate including (i) combining rimonabant and a volume of water in at least one organic solvent; and (ii) isolating the rimonabant hydrate.
  • the organic solvent is at least one of acetone, methyl isobutyl ketone, heptane, 1,4-dioxane, tetrahydrofuran, acetonitrile, dimethylsulfoxide, N,N-dimethylformamide . MN-dimethylacetamide and combinations thereof.
  • Another aspect of the invention includes a process for preparing rimonabant 1- propanol solvate including (i) combining rimonabant and 1-propanol; and (ii) isolating the rimonabant 1-propanol solvate.
  • Another aspect of the invention includes a process for preparing rimonabant 3-methyl- 1-butanol solvate including (i) combining rimonabant and 3-methyl-l-butanol; and (ii) isolating the rimonabant 3-methyl-l-butanol solvate.
  • Another aspect of the invention includes a process for preparing rimonabant n- butanol solvate including (i) combining rimonabant and n-butanol; and (it) isolating the rimonabant n-butanol solvate.
  • Another aspect of the invention includes a process for preparing amorphous rimonabant including (i) combining rimonabant and chloroform; and (ii) isolating the amorphous rimonabant.
  • Another aspect of the invention includes a process for preparing amorphous rimonabant including grinding rimonabant, solvates, or mixtures thereof.
  • Another aspect of the invention includes a process for preparing amorphous rimonabant from rimonabant hydrate, said process including heating rimonabant hydrate under vacuum.
  • Another aspect of the invention includes a process for preparing amorphous rimonabant from rimonabant etha ⁇ ol solvate, said process including heating rimonabant ethanol solvate under vacuum.
  • Another aspect of the invention includes a process for preparing rimonabant hydrate from amorphous rimonabant. said process including (i) combining amorphous rimonabant and water or cyclohexane or mixtures thereof; and (ii) isolating the rimonabant hydrate.
  • Another aspect of the invention includes a process for preparing rimonabant Form II from rimonabant Form I, said process including (i) combining rimonabant Form I and methylcyclohexane and water; (ii) adding seeds of rimonabant Form II; and (iii) isolating the rimonabant Form II.
  • Another aspect of the invention includes a process for preparing rimonabant Form I from rimonabant Form II. said process including (i) combining rimonabant Form II and toluene and heptane; (ii) adding seeds of rimonabant Form 1; and (iii) isolating the rimonabant Form I.
  • DSC measurements were carried out in vented pan at a scan rate of 10° C/minute from 25.0° C to 200.0° C under a nitrogen purge with a Pyris I DSC available from Mettler-Toledo.
  • TG Thermogravimetric Analysis
  • the chromatographic separation was carried out in a Symmetry Cl 8 , 5 ⁇ m, 250 x 4.6 mm I.D column: at room temperature (-25° C).
  • the mobile phase A was mixed and filtered through 0.22 ⁇ m nylon filter under vacuum.
  • the mobile phase B was acetonitrile.
  • the chromatograph was programmed as follows: Initial 0-2 minutes isocratic 60% mobile phase A, 2-13 minutes linear gradient to 30% mobile phase A, 13-40 minutes isocratic 30% mobile phase A, 40-45 minutes linear gradient to 60% mobile phase A and 45-50 minutes equilibration to 60% mobile phase A.
  • Test samples 10 ⁇ l were prepared by dissolving the appropriate amount of sample in acetonitrile in order to obtain 1 mg of sample per mL of acetonitrile.
  • Rimonabant (0.1 g) was dissolved in 0.7 mL of methanol. The mixture was heated at reflux temperature for 1 hour and then allowed to cool to room temperature while stirring. The solvent was allowed to evaporate at room temperature.
  • XRD methanol solvate, substantially identical to Figure 3.
  • Rimonabant (0.1 g) was dissolved in 3.2 mL of 2-propanol at room temperature. The solution was filtered, and the solvent was allowed to evaporate at room temperature. The solid obtained was ground.
  • Rimonabant (0.1 g) was dissolved in 0.7 mL of acetone at room temperature, and 2 mL of water were added. The suspension was stirred for 30 minutes at room temperature, and the resulting solid was collected by filtration.
  • Rimonaba ⁇ t (0.6 g) was dissolved in 4.2 mL of acetone at room temperature. The solution was filtered, and 18 mL of water were added slowly. The suspension was stirred for 1 hour and 30 minutes at room temperature, and the resulting solid was collected by filtration.
  • XRD hydrate, see Figure 5; IR: See Figure 6; DSC: See Figure 7,
  • Rimonabant (0.1 g) was dissolved in I mL of methyl isobutyl ketone at room temperature, and 0.1 mL of water and 4 mL of heptane were added. The suspension was stirred for 1 hour and 30 minutes at room temperature, and the resulting solid was collected by filtration.
  • Rimonabant (O. I g) was dissolved in 3.2 mL 2-propanol at room temperature, and 3 mL of water were added. The suspension was stirred for 30 minutes at room temperature, and the resulting solid was collected by filtration.
  • Rimonabant (0. Lg) was dissolved in 0.4 mL of tetrahydrofuran at room temperature, and 2 mL of water were added. The suspension was stirred for 30 minutes at room temperature, and the resulting solid was collected by filtration.
  • Rimonabant (0.1 g) was dissolved in 4.2 mL of acetonitrile at room temperature. The solution was filtered, and 3 mL of water were added. The suspension was stirred for 1 hour and 30 minutes at room temperature, and solid was collected by filtration.
  • Rimonabant (0.1 g) was dissolved in 0.5 mL of dimethylsulfoxide at room temperature, and I mL of water was added. The suspension was stirred for 1 hour and 30 minutes at room temperature, and solid was collected by filtration.
  • Rimonabant (0. 1 g) was dissolved in 0.5 mL of jV,N-dimethylformamide at room temperature, and 1 mL of water was added. The suspension was stirred for 1 hour and 30 minutes at room temperature, and solid was collected by filtration. Analytical data: XRD: hydrate, substantially identical to Figure 5. EXAMPLE 16: Preparation of Rimonabant Hydrate
  • Rimonabant (0.1 g) was dissolved in 0.5 mL of N,N-dimethylacetamide at room temperature, and I mL of water was added. The suspension was stirred for 1 hour and 30 minutes at room temperature, and solid was collected by filtration.
  • Rimonabant (0. ! g) was dissolved in 1 mL of 1-propanol at room temperature. The solution was filtered, and the solvent was allowed to evaporate at room temperature. The resulting solid was ground.
  • Rimonabant (0.1 g) was dissolved in 1.5 mL of 3-methyl-l-butanoI at room temperature. The mixture was filtered, and the solvent was allowed to evaporate at room temperature. The resulting solid was ground.
  • Rimonabant (0.1 g) was dissolved in 1.5 mL of n-butanol at room temperature. The mixture was filtered, and the solvent was allowed to evaporate at room temperature. The resulting solid was ground.
  • Rimonabant (0.1 g) was dissolved in 1.4 mL of chloroform at room temperature. The solvent was allowed to evaporate at room temperature. The resulting solid was ground.
  • Rimonabant Form I (0.15 g) was ground in a ball mill Retsch MM2 for 10 minutes at 27 Hz. The resulting solid was analysed again by XRPD.
  • Rimonabant hydrate (0.2 g) was ground in a ball mill Retsch MM2 for 10 minutes at 27 Hz. The resulting solid was analysed again by XRPD. Analytical data: XRD: amorphous, substantially identical to Figure 15.
  • Rimonabant Form 1 (5 g), methylcyclohexane (30 mL) and water (0.6 mL) were heated at 70° C for 4 days. The mixture was cooled and filtered. IR analysis showed a mixture of Forms I and H. The solids and liquors were recombined and heated at 70° C with added seeds of rimonabant Form (1 (spatula tip) for an additional 4 days at 70° C and then at ambient temperature for 3 days. The mixture was filtered, and the solid dried under vacuum at 65° C overnight. Yield: 4.04 g (81 %). IR and XRPD analysis: Form II.
  • Rimonabant Form II (2 g) was dissolved in toluene (6.5 mL) and heated with stirring to 65-70° C. Heptane (27 mL) was added dropwise over 10 minutes; the mixture was slightly turbid. Heating was continued until reflux was achieved and the solids completely dissolved. The mixture was cooled slowly and when the internal temperature was 70° C, the mixture was seeded with a spatula tip of rimonabant Form I. Slow cooling was continued causing abundant precipitation. When the mixture was at 30° C (after approximately 3 hours) an ice bath was applied, for one hour, and then the mixture fiUered and washed with heptane (2 x 7 mL). Analysis by IR showed that Form II was still the major component.
  • Amorphous rimonabant (100 mg ) was stirred ⁇ n 1 mL of water at ambient temperature for 4 hours, filtered, and washed with a little water. The resulting solid was analysed by XRPD and IR.
  • EXAMPLE 28 Preparation of Rimonabant hydrate lOOmg of amorphous Rimonabant was stirred in 1 mL of cyclohexane at ambient temperature for 4 hours, filtered, and washed with a little cyclohexane. The resulting solid was analysed by XRPD and IR. Analytical data: XRD: hydrate, substantially identical to Figure 5. IR: hydrate, substantially identical to Figure 6.

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Abstract

The invention relates to novel solid forms of rimonabant and amorphous rimonabant and synthetic processes for their preparation.

Description

NOVEL SOLID FORMS OF RIMONABANT AND SYNTHETIC PROCESSES FOR
THEIR PREPARATION
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims priority to United States Provisional Application No. 60/815,564, filed June 22, 2006. which application is expressly incorporated herein by reference in its entirety.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to novel solid forms of rimonabant and amorphous rimonabant and synthetic processes for their preparation. 2. Discussion of the Related Art
Rimonabant, a CBl cannabinoid receptor antagonist, is pharmaceutically useful for the treatment of obesity by reduction of appetite. Rimonabant is the international common accepted name for 5-(4-chlorophenyI)-l-(2,4-dichlorophenyl)-4-methyI-N- piperidinopyrazole-3-carboxamide, which is represented in Formula I.
Figure imgf000002_0001
Formula I
U.S. Patent No. 5,624,941 ("the '941 patent") generally describes rimonabant and its pharmaceutically acceptable acid addition salts and solvates thereof.
Rimonabant can be prepared by reaction of an activated form of 5-(4-chlorophenyl)-l- (2,4-dichloropheπyl)-4-methy!-I H-pyrazole-3-carboxylic acid (compound [I) and 1-amino piperidine (compound 111) in an organic solvent in the presence of a base as shown in Scheme 1.
Figure imgf000002_0002
Scheme 1 Until now, rimonabant was known to exist in at least two different crystalline forms.
The method described in U.S. Patent No. 5,624,941 allows the preparation of rimonabant in crystalline form which is later designated by U.S. Patent Application No.2005/0043356 Al as Form I. Form I is obtained from isopropyl ether and from methylcyclohexane. U.S. Patent No. 5,624,941 describes also an ethanol solvate of rimonabant. In
Example 212, the ethanol solvate is characterized by having a DSC with an endothermic peak centered at 102.7° C. According to the elemental analysis, the solvate obtained in Example 212 corresponds to a monoethanolate.
U.S. Patent Application No. 2005/0043356 Al describes a polymorphic form of rimonabant designated as Form II. This application discloses that Form II can be prepared by recrystallization from solvents such as methylcyclohexane, methylcyclohexane - water, acetonitrile, 4-methyl-2-pentanone, acetone or mixtures thereof.
SUMMARY OF THE INVENTION
The invention relates to novel solid forms of rimonabant and amorphous rimonabant and synthetic processes for their preparation.
BRIEF DESCRIPTION OF THE DRAWINGS
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the principles of the invention. In the drawings:
Figure 1 illustrates the X-ray powder diffractogram (XRD) of rimonabant ethanol solvate; Figure 2 illustrates the Infrared (IR) spectrum of rimonabant ethanol solvate; Figure 3 illustrates the XRD of rimonabant methanol solvate; Figure 4 illustrates the IR spectrum of rimonabant methanol solvate; Figure 5 illustrates the XRD of rimonabant hydrate; Figure 6 illustrates the IR spectrum of rimonabant hydrate;
Figure 7 illustrates the Differential Scanning Calorimetry (DSC) thermogram (open pan) of rimonabant hydrate; Figure 8 illustrates the Thermogravimetric Analysis (TG) of rimonabant hydrate; Figure 9 illustrates the XRD of rimonabant 1 -propanol solvate; Figure 10 illustrates the IR spectrum of rimonabant 1-propanol solvate; Figure 1 1 illustrates the XRD of rimonabant 3 -methyl- 1-butanol solvate; Figure 12 illustrates the IR spectrum of rimonabant 3-methyl- 1-butanol solvate;
Figure 13 illustrates the XRD of rimonabant n-butanol solvate; Figure 14 illustrates the IR spectrum of rimonabant n-butanol solvate; Figure 15 illustrates the XRD of amorphous rimonabant; and Figure 16 illustrates the IR spectrum of amorphous rimonabant. DESCRIPTION OF THE INVENTION
Reference will now be made in detail to the preferred embodiments of the invention. This invention may. however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. In addition, and as will be appreciated by one of skill in the art, the invention may be embodied as a method, system or process. It has been found that rimonabant can exist and be prepared as an ethanol solvate, as a methanol solvate, as a 1-propanol solvate, as a 3-methyl- 1 -butanol solvate, as a n-butanol solvate, as a hydrate and as in amorphous form.
One aspect of the invention includes rimonabant ethanot solvate (i.e., rimonabant ethanolate). In this regard. Figure 1 illustrates the X- Ray powder diffraction pattern (2Θ) (± 0.2°) (XRD) of rimonabant ethanol solvate having its main peaks at approximately 6.7, 8.4, 10.1, 12.1, 13.5, 14.4, 16.7, 18.2, 19.3, 20.9 and 21.8°. Figure 2 illustrates the infrared (IR) spectrum of rimonabant ethanol having its main peaks at approximately 3410, 3202, 3078, 2932, 2855, 2816, 1666, 1558, 1489, 1443, 1389, 1358, 1265, 121 1, 1 142, 1096, 1049, 101 1, 988, 972, 918, 833, 779, 725, 656, 556, 525, 494, 432 cm"1. The rimonabant ethanolate is further characterized by having a high purity according to high performance liquid chromatography (HPLC), and is generally free of insoluble materials/compounds.
Another aspect of the invention includes rimonabant methanol solvate (i.e., rimonabant methanolate). In this regard. Figure 3 illustrates the XRD (2Θ) (± 0.2°) of rimonabant methanol solvate having its main peaks at approximately 7.6, 9.8, 13.3, 15.2, 18.4, 20.0, 21.1, 22.4, 22.8; 24.0 and 27.1°. Figure 4 illustrates the IR spectrum of rimonabant methanolate having its main peaks at approximately 3641, 3395, 3209, 3078, 2939, 2855, 2808, 1659, 1551, 1489, 1435, 1381, 1358, 1304, 1265. 121 1. 1 142. 1096, 1055, 1034, 1010, 987, 972, 918, 833, 779, 718, 671, 633, 594, 556, 525, 494, 432 cm 1. The rimonabant methanolate is further characterized by having a high purity according to HPLC, and is generally free of insoluble materials/compounds.
Another aspect of the invention includes rimonabant hydrate. In this regard, Figure 5 illustrates the XRD (2Θ) (± 0.2°) of rimonabant hydrate having its main peaks at approximately 7.2, 9.3, 10.4, 13.5, 15.2, 16.1, 16.3, 17.1, 17.8, 19.0, 19.2, 20.3, 20.8, 21.1, 21.6, 22.4 and 22.9°. Figure 6 illustrates the IR spectrum of rimonabant hydrate having its main peaks at approximately 3642, 3387, 3209, 3078, 2939, 2855, 2808, 1659, 1551, 1489, 1435, 1381, 1358, 1304, 1265, 1211, 1134, 1096, 1057, 1033, 101 1, 987, 972, 918, 857, 833, 779, 718, 671, 633, 594, 548, 524, 494, 440 cm'1. Figure 7 illustrates the differential scanning calorimetry (open pan) (DSC) of rimonabant hydrate, which exhibits art endothermic peak at approximately 103.2° C (onset of 85.8° C). Figure 8 illustrates the thermogravimetric analysis (TG) of rimonabant hydrate. This TG shows a loss of weight of approximately 3.3% which corresponds to rimonabant monohydrate. The rimonabant hydrate is further characterized by having a high purity according to HPLC, with a low residual content, and is generally free of insoluble materials/compounds.
Another aspect of the invention includes rimonabant 1-propanol solvate. In this regard, Figure 9 illustrates the XRD (2Θ) (± 0.2°) of rimonabant 1 -propanol solvate having its main peaks at approximately 6.7, 8.3, 9.9, 1 1.9, 13.4, 14.3, 15.9, 16.3, 16.7, 17.9, 18.1, 20.8 and 21.9°. Figure 10 illustrates the IR spectrum of rimonabant 1-propanol solvate having its main peaks at approximately 3406, 3202, 3074, 2939, 2858, 2828, 1670, 1605, 1558, 1497, 1431, 1383, 1358, 1308. 1265, 121 1, 1 140, 1099, 1090, 1067, 1053, 101 1, 989, 968, 922, 905, 860, 837, 816, 789. 777, 746. 725, 714, 692, 672, 658, 615, 594, 554, 523,503, 486, 468, 445, 424 cm'1. The rimonabant 1-propanol solvate is further characterized by having a high purity according to HPLC, and is generally free of insoluble materials/compounds.
Another aspect of the invention includes rimonabant 3-methyl-l-butanoi solvate. In this regard, Figure 1 1 illustrates the XRD (2Θ) (± 0.2°) of rimonabant 3-methyl-l-butaπol solvate having its main peaks at approximately 7.6, 8.0, 8.6, 1 1.1, 15.3, 16.2, 17.6, 17.8, 18.9, 19.4, 21.0, 22.1 , 22.3, 22.9, 23.6, 25.4°. Figure 12 illustrates the IR spectrum of rimonabant 3-methyI-l-butanol solvate having its main peaks at approximately 3391, 3225, 3086, 3047, 2947, 2864, 2829, 1657, 1607, 1560, 1491, 1439, 1383, 1360, 1308, 1269, 1236, 1207, 1 167, 1 140, 1089, 1 103, 1090, 1065, 101 1, 994, 968, 918, 878, 859, 837, 814, 789, 745, 733, 671, 648, 613, 554, 523, 503, 492 and 738 cm"1. Rimonabant 3-methyl-l- butano! solvate is generally free of insoluble materials/compounds.
Another aspect of the invention is to provide a novel rimonabant n- butanol solvate.
Figure 13 illustrates the XRD (2Θ) (± 0.2°) of rimonabant n-butanol solvate having its mean peaks at approximately 7.6, 8.1 , 8.7, 1 1.2, 15.3, 17.6, 19.0, 19.6, 21.1, 23.2, 23.4, 23.8 and 25.7°. Figure 14 illustrates the JR spectrum of rimonabant n-butanol solvate having its main peaks at approximately 3391, 3225, 3086, 3047, 2949, 2860, 2824, 1661, 1607, 1560, 1497, 1441, 1383, 1360, 1308, 1267, 1209, 1 140, 1 102, 1090, 1054, 1037, 101 1, 994, 968, 918, 906, 878, 862, 837, 814, 787, 744, 733, 671, 613, 551 , 523, 503, 492, 438 cm-1. Rimonabant n-butanol solvate is generally free of insoluble materials/compounds.
Another aspect of the invention includes amorphous rimonabant. In this regard, Figure 15 illustrates the XRD (2Θ) (± 0.2°) of amorphous rimonabant. Figure 16 illustrates the infrared spectrum of amorphous rimonabant which has its main peaks at approximately 3408, 3317, 3082, 2939, 2854, 2795, 1684, 1497, 1383, 1246, 1094, 1013, 968, 918, 816, 733, 633, 503, 442 cm"' . Amorphous rimonabant is further characterized by having a high purity according to HPLC. and is generally free of insoluble materials/compounds. Another aspect of the invention includes a process for preparing rimonabant ethanol solvate including (i) combining rimonabant and ethanol; (ii) optionally adding water to the rimonabant and ethanol; and (iii) isolating the rimonabant ethanol solvate.
Another aspect of the invention includes a process for preparing rimonabant methanol solvate including (i) combining rimonabant and methanol; and (ii) isolating the rimonabant methanol solvate.
Another aspect of the invention includes a process for preparing rimonabant hydrate solvate including (i) combining rimonabant and 2-propanol; and (ii) isolating the rimonabant hydrate. Alternatively, the invention also includes a process for preparing rimonabant hydrate solvate including (i) combining rimonabant and a volume of water in at least one organic solvent; and (ii) isolating the rimonabant hydrate. The organic solvent is at least one of acetone, methyl isobutyl ketone, heptane, 1,4-dioxane, tetrahydrofuran, acetonitrile, dimethylsulfoxide, N,N-dimethylformamide . MN-dimethylacetamide and combinations thereof.
Another aspect of the invention includes a process for preparing rimonabant 1- propanol solvate including (i) combining rimonabant and 1-propanol; and (ii) isolating the rimonabant 1-propanol solvate.
Another aspect of the invention includes a process for preparing rimonabant 3-methyl- 1-butanol solvate including (i) combining rimonabant and 3-methyl-l-butanol; and (ii) isolating the rimonabant 3-methyl-l-butanol solvate.
Another aspect of the invention includes a process for preparing rimonabant n- butanol solvate including (i) combining rimonabant and n-butanol; and (it) isolating the rimonabant n-butanol solvate.
Another aspect of the invention includes a process for preparing amorphous rimonabant including (i) combining rimonabant and chloroform; and (ii) isolating the amorphous rimonabant.
Another aspect of the invention includes a process for preparing amorphous rimonabant including grinding rimonabant, solvates, or mixtures thereof.
Another aspect of the invention includes a process for preparing amorphous rimonabant from rimonabant hydrate, said process including heating rimonabant hydrate under vacuum.
Another aspect of the invention includes a process for preparing amorphous rimonabant from rimonabant ethaπol solvate, said process including heating rimonabant ethanol solvate under vacuum.
Another aspect of the invention includes a process for preparing rimonabant hydrate from amorphous rimonabant. said process including (i) combining amorphous rimonabant and water or cyclohexane or mixtures thereof; and (ii) isolating the rimonabant hydrate.
Another aspect of the invention includes a process for preparing rimonabant Form II from rimonabant Form I, said process including (i) combining rimonabant Form I and methylcyclohexane and water; (ii) adding seeds of rimonabant Form II; and (iii) isolating the rimonabant Form II. Another aspect of the invention includes a process for preparing rimonabant Form I from rimonabant Form II. said process including (i) combining rimonabant Form II and toluene and heptane; (ii) adding seeds of rimonabant Form 1; and (iii) isolating the rimonabant Form I.
The various embodiments of the invention having thus been generally described, several examples will hereafter be discussed to illustrate the inventive aspects more fully.
Specific Examples
The following examples are for illustrative purposes only and are not intended, nor should they be interpreted to, limit the scope of the invention.
General Experimental Conditions: I. X-ray Powder Diffraction (XRD)
The X-ray diffractograms were obtained using a RX SIEMENS D5000 diffractometer with a vertical goniometer and a copper anodic tube, radiation CuK0, λ=l .54056 A.
II. Infrared Spectra
Fourier transform infrared spectra were acquired on a Shimadzu FTIR-8300 spectrometer and solid forms were characterized in potassium bromide pellets.
III. Differential Scanning Calorimetry (DSC)
DSC measurements were carried out in vented pan at a scan rate of 10° C/minute from 25.0° C to 200.0° C under a nitrogen purge with a Pyris I DSC available from Mettler-Toledo.
IV. Thermogravimetric Analysis (TG) TG measurements were carried out in a vented pant at a scan of 10° C/minute from
25.0° C to 200° C under a nitrogen purge with a TG-50 available from Mettler-Toledo.
V. HPLC Method
The chromatographic separation was carried out in a Symmetry Cl 8 , 5μm, 250 x 4.6 mm I.D column: at room temperature (-25° C). The mobile phase A was prepared with 1000 mL of pH = 6.5 buffer, which was prepared from 0.77 g of ammonium acetate in 1000 mL of water adjusting the pH to 6.5 with acetic acid. The mobile phase A was mixed and filtered through 0.22 μm nylon filter under vacuum. The mobile phase B was acetonitrile.
The chromatograph was programmed as follows: Initial 0-2 minutes isocratic 60% mobile phase A, 2-13 minutes linear gradient to 30% mobile phase A, 13-40 minutes isocratic 30% mobile phase A, 40-45 minutes linear gradient to 60% mobile phase A and 45-50 minutes equilibration to 60% mobile phase A.
The chromatograph was equipped with a 230 nm detector and the flow rate was 1.0 mL per minute. Test samples ( 10 μl) were prepared by dissolving the appropriate amount of sample in acetonitrile in order to obtain 1 mg of sample per mL of acetonitrile.
EXAMPLE 1: Preparation of Rimonabant Ethanol Solvate Rimonabant (0.4 g) was dissolved in 4 mL of ethanol at room temperature. The solution was filtered and the solvent allowed to evaporate at room temperature. The resulting solid was ground.
Analytical data: XRD: ethanol solvate, see Figure 1 ; IR: See Figure 2; HPLC: 98.87% EXAMPLE 2: Preparation of Rimonabant Ethanol Solvate Rimonabant (0.1 g) was suspended in 3 mL of ethanol at room temperature. Water
(3 mL) was added, and the mixture was agitated for 30 minutes at room temperature. The resulting solid was collected by filtration.
Analytical data: XRD: ethanol solvate, substantially identical to Figure 1. EXAMPLE 3: Preparation of Rimonabant Ethanol Solvate Rimonabant (0.1 g) was suspended in 1 mL of ethanol at room temperature. Water
(3 mL) was added, and the mixture was agitated for 30 minutes at room temperature. The resulting solid was collected by filtration.
Analytical data: XRD: ethanol solvate, substantially identical to Figure 1. EXAMPLE 4: Preparation of Rimonabant Methanol Solvate Rimonabant (0.5 g) was dissolved in 27 mL of methanol at room temperature. The solution was filtered, and the solvent was allowed to evaporate at room temperature. The resulting solid was ground.
Analytical data: XRD: methanol solvate, see Figure 3; IR: see Figure 4; HPLC: 99.33%. EXAMPLE 5: Preparation of Rimonabaπt Methanol Solvate
Rimonabant (0.1 g) was dissolved in 0.7 mL of methanol. The mixture was heated at reflux temperature for 1 hour and then allowed to cool to room temperature while stirring. The solvent was allowed to evaporate at room temperature. Analytical data: XRD: methanol solvate, substantially identical to Figure 3.
EXAMPLE 6: Preparation of Rimonabant Hydrate
Rimonabant (0.1 g) was dissolved in 3.2 mL of 2-propanol at room temperature. The solution was filtered, and the solvent was allowed to evaporate at room temperature. The solid obtained was ground. Analytical data: XRD: hydrate, substantially identical to Figure 5.
EXAMPLE 7: Preparation of Rimonabant Hydrate
Rimonabant (0.1 g) was dissolved in 0.7 mL of acetone at room temperature, and 2 mL of water were added. The suspension was stirred for 30 minutes at room temperature, and the resulting solid was collected by filtration. Analytical data: XRD: hydrate, substantially identical to Figure 5.
EXAMPLE 8: Preparation of Rimonabant Hydrate
Rimonabaπt (0.6 g) was dissolved in 4.2 mL of acetone at room temperature. The solution was filtered, and 18 mL of water were added slowly. The suspension was stirred for 1 hour and 30 minutes at room temperature, and the resulting solid was collected by filtration. Analytical data: XRD: hydrate, see Figure 5; IR: See Figure 6; DSC: See Figure 7,
TG: See Figure 8: HPLC: 99.36%.
EXAMPLE 9: Preparation of Rimonabant Hydrate
Rimonabant (0.1 g) was dissolved in I mL of methyl isobutyl ketone at room temperature, and 0.1 mL of water and 4 mL of heptane were added. The suspension was stirred for 1 hour and 30 minutes at room temperature, and the resulting solid was collected by filtration.
Analytical data: XRD: hydrate, substantially identical to Figure 5. EXAMPLE 10: Preparation of Rimonabant Hydrate Rimonabant (0.1 g) was dissolved in 0.5 ml_ of 1 ,4-dioxane at room temperature, and 2 mL of water were added. The suspension was stirred for 30 minutes at room temperature, and the resulting solid was collected by filtration.
Analytical JcUa: XRD: hydrate, substantially identical to Figure 5; HPLC: 99.02%. EXAMPLE I l : Preparation of Rimonabant Hydrate
Rimonabant (O. I g) was dissolved in 3.2 mL 2-propanol at room temperature, and 3 mL of water were added. The suspension was stirred for 30 minutes at room temperature, and the resulting solid was collected by filtration.
Analytical data: XRD: hydrate, substantially identical to Figure 5. EXAMPLE 12: Preparation of Rimonabant Hydrate
Rimonabant (0. Lg) was dissolved in 0.4 mL of tetrahydrofuran at room temperature, and 2 mL of water were added. The suspension was stirred for 30 minutes at room temperature, and the resulting solid was collected by filtration.
Analytical delta: XRD: hydrate, substantially identical to Figure 5. EXAMPLE 13: Preparation of Rimonabant Hydrate
Rimonabant (0.1 g) was dissolved in 4.2 mL of acetonitrile at room temperature. The solution was filtered, and 3 mL of water were added. The suspension was stirred for 1 hour and 30 minutes at room temperature, and solid was collected by filtration.
Analytical data: XRD: hydrate, substantially identical to Figure 5. EXAMPLE 14: Preparation of Rimonabant Hydrate
Rimonabant (0.1 g) was dissolved in 0.5 mL of dimethylsulfoxide at room temperature, and I mL of water was added. The suspension was stirred for 1 hour and 30 minutes at room temperature, and solid was collected by filtration.
Analytical data: XRD: hydrate, substantially identical to Figure 5. EXAMPLE 15: Preparation of Rimonabant Hydrate
Rimonabant (0. 1 g) was dissolved in 0.5 mL of jV,N-dimethylformamide at room temperature, and 1 mL of water was added. The suspension was stirred for 1 hour and 30 minutes at room temperature, and solid was collected by filtration. Analytical data: XRD: hydrate, substantially identical to Figure 5. EXAMPLE 16: Preparation of Rimonabant Hydrate
Rimonabant (0.1 g) was dissolved in 0.5 mL of N,N-dimethylacetamide at room temperature, and I mL of water was added. The suspension was stirred for 1 hour and 30 minutes at room temperature, and solid was collected by filtration.
Analytical data: XRD: hydrate, substantially identical to Figure 5. EXAMPLE 17: Preparation of Rimonabant I-Propanoi Solvate
Rimonabant (0. ! g) was dissolved in 1 mL of 1-propanol at room temperature. The solution was filtered, and the solvent was allowed to evaporate at room temperature. The resulting solid was ground.
Analytical data: XRD: 1-propanol solvate, see Figure 9; IR: see Figure 10; HPLC: 98.98%.
EXAMPLE 18: Preparation of Rimonabant 3-Methyl-l-butanol Solvate
Rimonabant (0.1 g) was dissolved in 1.5 mL of 3-methyl-l-butanoI at room temperature. The mixture was filtered, and the solvent was allowed to evaporate at room temperature. The resulting solid was ground.
Analytical data: XRD: 3-methyl- l-butanol solvate, see Figure 11, IR: see Figure 12. EXAMPLE 19: Preparation of Rimonabant n-Butanol Solvate
Rimonabant (0.1 g) was dissolved in 1.5 mL of n-butanol at room temperature. The mixture was filtered, and the solvent was allowed to evaporate at room temperature. The resulting solid was ground.
Analytical data: XRD: n-butanol solvate, see Figure 13; IR: see Figure 14. EXAMPLE 20: Preparation of Amorphous Rimonabant
Rimonabant (0.1 g) was dissolved in 1.4 mL of chloroform at room temperature. The solvent was allowed to evaporate at room temperature. The resulting solid was ground.
Analytical data: XRD: amorphous, see Figure 15; IR: see Figure 16; HPLC: 99.36%. EXAMPLE 21 : Preparation of Amorphous Rimonabant Rimonabant hydrate (48.3 mg) was dried at 100° C for 16 hours under vacuum. The resulting solid was analyzed again by XRPD.
Analytical data: XRD: amorphous, substantially identical to Figure 15. EXAMPLE 22: Preparation of Amorphous Rimonabant Rimonabant ethanol solvate (77.1 mg) was dried at 60° C for 16 hours under vacuum. The resulting solid was analyzed again by XRPD.
Analytical data: XRD: amorphous, substantially identical to Figure 15. EXAMPLE 23: Preparation of Amorphous Rimonabant
Rimonabant Form I (0.15 g) was ground in a ball mill Retsch MM2 for 10 minutes at 27 Hz. The resulting solid was analysed again by XRPD.
Analytical data: XRD: amorphous, substantially identical to Figure 15. EXAMPLE 24: Preparation of Amorphous Rimonabant
Rimonabant hydrate (0.2 g) was ground in a ball mill Retsch MM2 for 10 minutes at 27 Hz. The resulting solid was analysed again by XRPD. Analytical data: XRD: amorphous, substantially identical to Figure 15.
EXAMPLE 25: Preparation of Rimonabant Form II
Rimonabant Form 1 (5 g), methylcyclohexane (30 mL) and water (0.6 mL) were heated at 70° C for 4 days. The mixture was cooled and filtered. IR analysis showed a mixture of Forms I and H. The solids and liquors were recombined and heated at 70° C with added seeds of rimonabant Form (1 (spatula tip) for an additional 4 days at 70° C and then at ambient temperature for 3 days. The mixture was filtered, and the solid dried under vacuum at 65° C overnight. Yield: 4.04 g (81 %). IR and XRPD analysis: Form II.
EXAMPLE 26: Conversion of Rimonabant Form II to Form I
Rimonabant Form II (2 g) was dissolved in toluene (6.5 mL) and heated with stirring to 65-70° C. Heptane (27 mL) was added dropwise over 10 minutes; the mixture was slightly turbid. Heating was continued until reflux was achieved and the solids completely dissolved. The mixture was cooled slowly and when the internal temperature was 70° C, the mixture was seeded with a spatula tip of rimonabant Form I. Slow cooling was continued causing abundant precipitation. When the mixture was at 30° C (after approximately 3 hours) an ice bath was applied, for one hour, and then the mixture fiUered and washed with heptane (2 x 7 mL). Analysis by IR showed that Form II was still the major component. The liquors and solid were combined and the mixture heated to reflux causing dissolution. The mixture was filtered through Celite, and cooled slowly. When the internal temperature was 70° C, the mixture was seeded with a spatula tip of rimonabant Form I. Slow cooling was continued causing abundant precipitation. When the mixture was at ambient temperature the mixture filtered to give 1.56 g of a white solid (78%). Analysis by IR and XRPD showed conversion to Form I. EXAMPLE 27: Preparation of Rimonabant hydrate
Amorphous rimonabant (100 mg ) was stirred ϊn 1 mL of water at ambient temperature for 4 hours, filtered, and washed with a little water. The resulting solid was analysed by XRPD and IR.
Analytical ikila: XRD: hydrate, substantially identical to Figure 5. IR: hydrate, substantially identical to Figure 6.
EXAMPLE 28: Preparation of Rimonabant hydrate lOOmg of amorphous Rimonabant was stirred in 1 mL of cyclohexane at ambient temperature for 4 hours, filtered, and washed with a little cyclohexane. The resulting solid was analysed by XRPD and IR. Analytical data: XRD: hydrate, substantially identical to Figure 5. IR: hydrate, substantially identical to Figure 6.
EXAMPLE 29; Hygroscopicity Stability Studies
Samples of rimonabant were stored under different temperature and humidity conditions and analysed by XRPD. The obtained results are shown in Table 1 below. 75% relative humidity was achieved using saturated sodium chloride solution in a chamber. 0% relative humidity was achieved using phosphorous pentoxide as desiccant in a chamber.
Figure imgf000015_0001
Table 1
It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention and specific examples provided herein without departing from the spirit or scope of the invention. Thus, it is intended that the present invention covers the modifications and variations of this invention that come within the scope of any claims and their equivalents.

Claims

I . Rimonabant ethanol solvate, wherein said rimonabant ethanol solvate is characterized by its X- Ray powder diffraction pattern (2Θ) (± 0.2°) having its main peaks at approximately 6.7, 8.4, 10.1, 12.1, 13.5, 14.4, 16.7, 18.2, 19.3, 20.9 and 21.8°.
2. Rimonabant ethanol solvate, wherein said rimonabant ethanol solvate is characterized by its infrared spectrum having its main peaks at approximately 3410, 3202, 3078, 2932, 2855, 2816, 1666, 1558, 1489, 1443, 1389, 1358, 1265, 121 1, 1 142, 1096, 1049, 1011, 988, 972. 918, 833, 779, 725, 656, 556, 525, 494, 432 cm"1.
3. The rimonabant ethanol solvate of either is claims 1 or 2, wherein said rimonabant ethanol has a high purity according to high performance liquid chromatography.
4. Rimonabant methanol solvate.
5. The rimonabant methanol solvate of claim 4, wherein said rimonabant methanol solvate is characterized by its X- Ray powder diffraction pattern (2θ) (± 0.2°) having its main peaks at approximately 7.6, 9.8, 13.3, 15.2, 18.4, 20.0, 21.1, 22.4, 22.8, 24.0 and 27.1°.
6. The rimonabant methanol solvate of claim 4, wherein said rimonabant methanol solvate is characterized by its infrared spectrum having its main peaks at approximately 3641, 3395, 3209, 3078, 2939, 2855. 2808, 1659, 1551. 1489, 1435, 1381, 1358, 1304, 1265, 121 1, 1142, 1096, 1055, 1034, 1010, 987, 972, 918, 833, 779, 718, 671, 633, 594, 556, 525, 494, 432 cm-1.
7. The rimonabant methanol solvate of claim 4, wherein said rimonabant methanol solvate has a high purity according to high performance liquid chromatography.
8. Rimonabant hydrate.
9. The rimonabant hydrate of claim 8, wherein said rimonabant hydrate is characterized by its X- Ray powder diffraction pattern (2Θ) (± 0.2°) having its main peaks at approximately 7.2, 9.3, 10.4, 13.5, 15.2, 16.1, 16.3, 17.1, 17.8, 19.0, 19.2, 20.3, 20.8, 21.1, 21.6, 22.4 and 22.9°.
10. The rimonabant hydrate of claim 8, wherein said rimonabant hydrate is characterized by its infrared spectrum having its main peaks at approximately 3642, 3387, 3209, 3078, 2939, 2855, 2808, 1659, 1551. 1489, 1435, 1381 , 1358, 1304, 1265, 121 1, 1 134, 1096, 1057, 1033, 101 1, 987, 972, 918, 857, 833, 779, 718, 671, 633, 594, 548, 524, 494, 440 cm"1.
1 1. The rimonabant hydrate of claim 8, wherein said rimonabant hydrate is characterized by its differential scanning calorimetry (open pan) exhibiting an endothermic peak at approximately 103.2° C and with an onset at approximately 85.8° C.
12. The rimonabant hydrate of claim 8. wherein said rimonabant hydrate is characterized by its thermogravimetric analysis (TG) having a loss of weight of approximately 3.3%.
13. The rimonabant hydrate of claim 8, wherein said rimonabant hydrate is rimonabant monohydrate.
14. The rimonabant hydrate of claim 8, wherein said rimonabant hydrate has a high purity according to high performance liquid chromatography.
15. Rimonabant 1-propanol solvate.
16. The rimonabant I-propanol solvate of claim 15, wherein said rimonabant 1-propanol solvate is characterized by its X- Ray powder diffraction pattern (2Θ) (± 0.2°) having its main peaks at approximately 6.7, 8.3, 9.9, 1 1.9, 13.4, 14.3, 15.9, 16.3, 16.7, 17.9, 18.1, 20.8 and 21.9°.
17. The rimonabant t-propanol solvate of claim 15, wherein said rimonabant 1-propanol solvate is characterized by its infrared spectrum having its main peaks at approximately 3406,
3202, 3074, 2939, 2858, 2828, 1670, 1605, 1558, 1497, 1431, 1383, 1358, 1308, 1265, 1211, 1140, 1099, 1090, 1067, 1053, 101 1, 989, 968, 922, 905, 860, 837, 816, 789, 777, 746, 725, 714, 692, 672, 658, 615, 594, 554, 523,503, 486, 468, 445, 424 cm'1.
18. The rimonabant I -propanol solvate of claim 15, wherein said rimonabant 1-propanol solvate has a high purity according to high performance liquid chromatography.
19. Rimonabant 3-methyl-l-butanol solvate.
20. The rimonabant 3-methyl-l -butanol solvate of claim 19, wherein said rimonabant 3- methyl-1 -butanol solvate is characterized by its X- Ray powder diffraction pattern (2Θ) (± 0.2°) having its main peaks at approximately 7.6, 8.0, 8.6, 1 1.1, 15.3, 16.2, 17.6, 17.8, 18.9, 19.4, 21.0, 22.1, 22.3. 22.9, 23.6, 25.4°.
21. The rimonabant 3-methyl-l-butanol solvate of claim 19, wherein said rimonabant 3- methyl-1-butanol solvate is characterized by its infrared spectrum having its main peaks at approximately 3391 , 3225, 3086, 3047, 2947, 2864, 2829, 1657, 1607, 1560, 1491, 1439, 1383, 1360, 1308, 1269, 1236, 1207, 1 167, 1 140, 1089, 1 103, 1090, 1065, 101 1, 994, 968, 918, 878, 859, 837, 814, 789, 745, 733, 671, 648, 613, 554, 523, 503, 492 and 738 cm"1.
22. Rimonabant n-butanol solvate.
23. The rimonabant n-butanol solvate of claim 22, wherein said rimonabant n-butanol solvate is characterized by its X- Ray powder diffraction pattern (2Θ) (± 0.2°) having its main peaks at approximately 7.6, 8.1, 8.7. 1 1.2. 15.3. 17.6, 19.0, 19.6, 21.1, 23.2, 23.4, 23.8 and 25.7°.
24. The rimonabant n-butanol solvate of claim 22, wherein said rimonabant n-butanol solvate is characterized by its infrared spectrum having its main peaks at approximately 3391, 3225, 3086, 3047, 2949, 2860, 2824, 1661, 1607, 1560, 1497, 1441, 1383, 1360, 1308, 1267, 1209, 1 140, 1 102, 1090, 1054, 1037, 101 1, 994, 968, 918, 906, 878, 862, 837, 814, 787, 744, 733, 671, 613, 551, 523, 503, 492, 438 cm"1.
25. Amorphous rimonabant.
26. The amorphous rimonabant of claim 25, wherein said amorphous rimonabant is characterized by its X- Ray powder diffraction pattern (2Θ) (± 0.2°) as illustrated in Figure 15.
27. The amorphous rimonabant of claim 25. wherein said amorphous rimonabant is characterized by its infrared spectrum having its main peaks at approximately 3408, 3317, 3082, 2939, 2854, 2795, 1684, 1497, 1383. 1246. 1094, 1013, 968, 918, 816, 733, 633, 503, 442 cm"1.
28. The amorphous rimonabant of claim 25, wherein said amorphous rimonabant has a high purity according to high performance liquid chromatography.
29. A process for preparing rimonabant ethanol solvate comprising (i) combining rimonabant and ethanol; (ii) optionally adding water to the rimonabant and ethanol; and (iii) isolating the rimonabant ethanol solvate.
30. A process for preparing rimonabant methanol solvate comprising (i) combining rimonabant and methanol; and (ii) isolating the rimonabant methanol solvate.
31. A process for preparing rimonabant hydrate solvate comprising (i) combining rimonabant and 2-propanol; and (ii) isolating the rimonabant hydrate.
32. A process for preparing rimonabant hydrate solvate comprising (i) combining rimonabant and a volume of water in at least one organic solvent; and (ii) isolating the rimonabant hydrate.
33. The process for preparing rimoπabant hydrate solvate of claim 32, wherein said at least one organic solvent is at least one of acetone, methyl isobutyl ketone, heptane, 1,4- dioxane, tetrahydrofuran, acetonitrile, dimethylsulfoxide, N,N-dimethylformamide , N,N- dimethylacetamide and combinations thereof.
34. A process for preparing rimonabant 1 -propanol solvate comprising (i) combining rimonabant and 1-propanol; and (ii) isolating the rimonabant 1-propanol solvate.
35. A process for preparing rimonabant 3-methyl-l -butanol solvate comprising (i) combining rimonabant and 3-methyl-l -butanol; and (ii) isolating the rimonabant 3-methyl-l -butanol solvate.
36. A process for preparing rimonabant n-butanol solvate comprising (i) combining rimonabant and n-butanol; and (ii) isolating the rimonabant n-butanol solvate.
37. A process for preparing amorphous rimonabant comprising (i) combining rimonabant and chloroform; and (ii) isolating the amorphous rimonabant.
38. A process for preparing amorphous rimonabant comprising grinding rimonabant, solvates, or mixtures thereof.
39. A process for preparing amorphous rimoπabant from rimonabant hydrate comprising heating rimonabant hydrate under vacuum.
40. A process for preparing amorphous rimonabant from rimonabant ethanol solvate comprising heating rimonabant ethanol solvate under vacuum.
41. A process for preparing rimonabant hydrate from amorphous rimonabant comprising (i) combining amorphous rimonabant and at least one of water, cyclohexaπe and mixtures thereof; and (ii) isolating the rimonabant hydrate.
42. A process for preparing rimonabant Form II from rimonabant Form I comprising (i) combining rimonabant Form I and methylcyclohexane and water; (ii) adding seeds of rimonabant Form II; and (iii) isolating the rimonabant Form II.
43. A process for preparing rimonabant Form I from rimonabant Form II comprising (i) combining rimonabant Form II and toluene and heptane; (ii) adding seeds of rimonabant Form I; and (iii) isolating the rimonabant Form I.
PCT/IB2007/003678 2006-06-22 2007-06-22 Novel solid forms of rimonabant and synthetic processes for their preparation WO2008038143A2 (en)

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