DESC:The following specification particularly describes the invention and the manner in which it is to be performed:
SUVOREXANT SALTS

INTRODUCTION
The present application relates to crystalline forms of suvorexant p-toluene sulfonate and suvorexant benzene sulfonate, processes for their preparation and pharmaceutical dosage form thereof.
BACKGROUND
Suvorexant is chemically described as 5-chloro-2-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1yl}-1,3-benzoxazole or [(R)-4-(5-chloro-benzooxazol-2-yl)-7-methyl-[1,4]diazepan-1-yl]-(5-methyl-2-[1,2,3]triazol-2-yl-phenyl)-methanone. It has the structure of Formula (I).

Suvorexant is an antagonist of orexin receptors and is under development for the potential oral treatment of chronic insomnia by Merck & Co. Breslin et al. U.S. Patent No. 7,951,797 B2 discloses suvorexant or a pharmaceutically acceptable salt thereof. International Application Publication No. WO 2012/148553 A1 discloses crystalline forms of suvorexant. WO 2015/164160 A1 discloses crystalline suvorexant salts.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is an illustration of a powder X-ray diffraction (PXRD) pattern of crystalline suvorexant p-toluene sulfonate, designated as Form ST1.
Figure 2 is an illustration of a powder X-ray diffraction (PXRD) pattern of crystalline suvorexant p-toluene sulfonate, designated as Form ST2.
Figure 3 is an illustration of a powder X-ray diffraction (PXRD) pattern of crystalline suvorexant p-toluene sulfonate, designated as Form ST3.
Figure 4 is an illustration of a powder X-ray diffraction (PXRD) pattern of crystalline suvorexant p-toluene sulfonate, designated as Form ST4.
Figure 5 is an illustration of a powder X-ray diffraction (PXRD) pattern of crystalline suvorexant benzene sulfonate, designated as Form SB1.
Figure 6 is an illustration of a powder X-ray diffraction (PXRD) pattern of crystalline suvorexant benzene sulfonate, designated as Form SB2.
Figure 7 is an illustration of crystal packing of Form ST2.
Figure 8 is an illustration of ORTEP diagram of Form ST2 at room temperature.
Figure 9 is an illustration of ORTEP diagram of Form ST2 at -153oC.
Figure 10 is an illustration of crystal packing of Form ST4.
Figure 11 is an illustration of ORTEP diagram of Form ST4 at 120oC.
Figure 12 is an illustration of crystal packing of Form SB3.
Figure 13 is an illustration of ORTEP diagram of Form SB3 at -153oC.

SUMMARY
In the first embodiment, the present application provides crystalline suvorexant p-toluene sulfonate, designated as Form ST1.
In the second embodiment, the present application provides crystalline suvorexant p-toluene sulfonate, designated as Form ST2.
In the third embodiment, the present application provides crystalline suvorexant p-toluene sulfonate, designated as Form ST3.
In the fourth embodiment, the present application provides crystalline suvorexant p-toluene sulfonate, designated as Form ST4.
In the fifth embodiment, the present application provides crystalline suvorexant benzene sulfonate, designated as Form SB1.
In the sixth embodiment, the present application provides crystalline suvorexant benzene sulfonate, designated as Form SB2.
In the seventh embodiment, the present application provides crystalline suvorexant benzene sulfonate, designated as Form SB3.
In the eighth embodiment, the present application provides a process for the preparation of crystalline suvorexant p-toluene sulphonate, designated as Form ST1, comprising:
a) slurrying suvorexant and p-toluene sulphonic acid (pTSA) in a solvent or mixture of solvents;
b) adding an anti-solvent; and
c) isolating crystalline suvorexant p-toluene sulphonate Form ST1.
In the ninth embodiment, the present application provides a process for the preparation of crystalline suvorexant p-toluene sulphonate, designated as Form ST2, comprising:
a) slurrying suvorexant and p-toluene sulphonic acid in a solvent or mixture of solvents; and
b) isolating crystalline suvorexant p-toluene sulphonate Form ST2.
In the tenth embodiment, the present application provides a process for the preparation of crystalline suvorexant p-toluene sulphonate, designated as Form ST3, comprising:
a) slurrying suvorexant and p-toluene sulphonic acid in a solvent or mixture of solvents; and
b) isolating crystalline suvorexant p-toluene sulphonate Form ST2.
c) drying crystalline suvorexant p-toluene sulphonate Form ST2 for a time sufficient to give ST3.
In the eleventh embodiment, the present application provides a process for the preparation of crystalline suvorexant p-toluene sulphonate, designated as Form ST4 comprising, drying suvorexant p-toluene sulphonate Form ST2.
In the twelfth embodiment, the present application provides a process for the preparation of crystalline suvorexant benzene sulfonate, Form SB1, comprising:
a) slurrying suvorexant and benzene sulfonic acid in a solvent or mixture of solvents; and
b) isolating crystalline suvorexant benzene sulfonate, Form SB1.
In the thirteenth embodiment, the present application provides a process for the preparation of crystalline suvorexant benzene sulfonate, designated as Form SB2, comprising:
a) slurrying suvorexant and benzene sulfonic acid in a solvent or mixture of solvents; and
b) isolating crystalline suvorexant benzene sulfonate, Form SB1;
c) drying crystalline suvorexant benzene sulfonate, Form SB1 for a time sufficient to give SB2.
In the fourteenth embodiment, the present application provides a process for the preparation of crystalline suvorexant benzene sulphonate, designated as Form SB3 comprising, growing a single crystal using vapor diffusion method.
DETAIL DESCRIPTION
The term "about" when used in the present application preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1% of its value. For example "about 10" should be construed as meaning within the range of 9 to 11, preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1.
Room temperature as used herein refers to ‘the temperatures of the thing close to or same as that of the space, e.g., the room or fume hood, in which the thing is located. Typically, room temperature is from about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C.
A process or step may be referred to herein as being carried out “overnight”. This refers to a time interval, e.g., for the process or step, that spans the time during the night, when that process or step may not be actively observed. This time interval is from about 8 to about 18 hours, typically about 16 hours.
The reactions of the processes described herein can be carried out in air or under an inert atmosphere. Typically, reactions containing reagents or products that are substantially reactive with air can be carried out using air-sensitive synthetic techniques that are well known to the person skilled in art.
For XRD, the relative intensities of the peaks can vary, depending upon the sample preparation technique, the sample mounting procedure and the particular instrument employed. Moreover, instrument variation and other factors can often affect the 2? values. Therefore, the peak assignments of diffraction patterns can vary by plus or minus about 0.2°.
In the first embodiment, the present application provides a crystalline suvorexant p-toluene sulfonate, designated as Form ST1 characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2? at about 5.61, 8.33, 12.34, 17.98, 24.82 and 25.03 ± 0.2° 2?.
Figure 1 shows typical X-ray powder diffraction pattern of Form ST1.
In the second embodiment, the present application provides a crystalline suvorexant p-toluene sulfonate, designated as Form ST2, characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2? located at about 6.09, 10.54, 12.21, 16.90 and 19.83 ± 0.2° 2?. It may be further characterized by XRD peaks located at about 11.37, 13.09, 17.57 and 22.79° ± 0.2° 2?. Form ST2 is observed to be a mono methanol solvate.
Figure 2 shows typical X-ray powder diffraction pattern of Form ST2.
In the third embodiment, the present application provides a crystalline suvorexant p-toluene sulfonate, designated as Form ST3, characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2? located at about 5.72, 11.49, 17.78, 20.69 and 23.12 ± 0.2° 2?.
Figure 3 shows typical X-ray powder diffraction pattern of Form ST3.
In the fourth embodiment, the present application provides a crystalline suvorexant p-toluene sulfonate, designated as Form ST4, characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2? located at about 5.63, 11.36, 13.30, 17.13, 20.08 and 23.13. ± 0.2° 2?.
Figure 4 shows typical X-ray powder diffraction pattern of Form ST4.
In the fifth embodiment, the present application provides a crystalline suvorexant benzene sulfonate, designated as Form SB1, characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2? located at about 5.25, 8.60, 15.28 and 23.85 ± 0.2° 2?. It may be further characterized by XRD peaks located at about 11.17, 12.16, 13.68, 21.14 and 21.66° ± 0.2° 2?.
Figure 5 shows typical X-ray powder diffraction pattern of Form SB1.
In the sixth embodiment, the present application provides a crystalline suvorexant benzene sulfonate, designated as Form SB2, characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2? located at about 5.43, 9.69, 17.65, 20.22 and 21.99° ± 0.2° 2?.
Figure 6 shows typical X-ray powder diffraction pattern of Form SB2.
In the seventh embodiment, the present application provides a crystalline suvorexant benzene sulfonate, designated as Form SB3, characterized by its single-crystal structure. Crystallographic data of SB3 obtained by single-crystal X-ray diffraction was established. The crystal structure corresponds to the monoclinic crystal system with a space group Pc. The data is shown in Table l.
Table 1: Crystallographic information of Forms-ST2, ST4 and SB3.
Form ST2 Form ST2 Form ST4 Form SB3
Chemical Formula C31 H35 Cl N6 O6 S C31 H35 Cl N6 O6 S C30 H31 Cl N6 O5 S C30 H31 Cl N6 O6 S
Formula weight 655.16 655.16 623.12 639.12
Crystal Mono MeOH solvate of Suvorexant p-toluene sulphonate (1:1 salt) Mono MeOH solvate of Suvorexant p-toluene sulphonate (1:1 salt) Anhydrous Suvorexant p-toluene sulphonate (1:1 salt) Anhydrous Suvorexant benzene sulphonate (1:1 salt)
X-ray data collection temperature 25?C -153?C 120?C -153?C
Crystal system Monoclinic Monoclinic Monoclinic Monoclinic
Space group P21 P21 P21 Pc
a [Å] 14.7389(17) 14.5891(8) 13.247(6) 15.4711(18)
b [Å] 7.5745(6) 7.5159(3) 7.6192(16) 7.0655(6)
c [Å] 15.7561(18) 15.6522(9) 15.469(10) 13.0349(12)
a [°] 90 90 90 90
ß [°] 113.119(14) 113.725(7) 92.42(6) 104.993(11)
? [°] 90 90 90 90
In the eighth embodiment, the present application provides a process for the preparation of crystalline suvorexant p-toluene sulphonate, Form ST1, comprising:
a) slurrying suvorexant and p-toluene sulphonic acid (pTSA) in a solvent or mixture of solvents;
b) adding an anti-solvent; and
c) isolating crystalline suvorexant p-toluene sulphonate, Form ST1.
Any physical form of suvorexant may be utilized in step a). Suvorexant that may be used as the input for the process of the present application may be obtained by any process including the processes described in the art. For example, suvorexant may be prepared by the processes described in the United States patent document US7951797B2, PCT application WO2012148553A1 or PCT application WO2014072961A2.
The solvents that may be used in step a) include, but are not limited to, water, alcohols like methanol, ethanol, isopropanol, butanol or mixtures thereof; ketones like acetone, buanone, ethyl isopropyl ketone or mixtures thereof; halogenated hydrocarbons like chloroform, dichloromethane, carbon tetrachloride or mixtures thereof; esters like ethyl acetate, propyl acetate, isopropyl acetate or mixtures thereof; nitriles like acetonitrile, propionitrile, C2-6 nitriles or mixtures thereof. Preferably methanol can be used.
The anti-solvent used in step b) include, but are not limited to hydrocarbon solvents like n-pentane, n-hexane, n-heptane, cyclohexane, methylcyclohexane, or mixtures thereof; ethers like diethyl ether, diisopropyl ether, methyl t-butyl ether, tetrahydrofuran, 1,4-dioxane, or mixtures thereof.
Step c) involves isolation of crystalline suvorexant p-toluene sulphonate, Form ST1.
The isolation may be effected by removing the solvent. The said isolation may be effected by methods such as, filtration, decantation, centrifugation, gravity filtration, suction filtration or any other techniques for the recovery of the solids. For filtration, equipment such as nutsche filter, centrifuge, agitated nutsche filter, leaf filter or any other suitable equipment for filtration may be used or any other suitable technique known in the art.
The solvent may be removed, optionally under reduced pressures, at temperatures less than about 150°C, less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, or any other suitable temperatures. The solvent may be removed optionally at atmospheric pressure at temperatures such as described above in this paragraph.
In the ninth embodiment, the present application provides a process for the preparation of crystalline suvorexant p-toluene sulphonate, Form ST2, comprising:
a) slurrying suvorexant and p-toluene sulphonic acid in a solvent or mixture of solvents; and
b) isolating crystalline suvorexant p-toluene sulphonate, Form ST2.
In an aspect, the solvent used in step (a) is methanol.
Step b) involves isolation of crystalline suvorexant p-toluene sulphonate, Form ST2.
The said isolation may be effected by methods such as, filtration, decantation, centrifugation, gravity filtration, suction filtration or any other techniques for the recovery of the solids. For filtration, equipment such as nutsche filter, centrifuge, agitated nutsche filter, leaf filter or any other suitable equipment for filtration may be used or any other suitable technique known in the art.
The solvent may be removed or concentrated, optionally under reduced pressures, at temperatures less than about 150°C, less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, or any other suitable temperatures. The solvent may be removed or concentrated optionally at atmospheric pressure at temperatures such as described above in this paragraph.
In the tenth embodiment, the present application provides a process for the preparation of crystalline suvorexant p-toluene sulphonate, Form ST3, comprising:
a) slurrying suvorexant and p-toluene sulphonic acid in a solvent or mixture of solvents; and
b) isolating crystalline suvorexant p-toluene sulphonate, Form ST2.
c) drying crystalline suvorexant p-toluene sulphonate, Form ST2 for a time sufficient to give ST3.
Step b) involves isolation of crystalline suvorexant p-toluene sulphonate, Form ST2.
The said isolation may be effected by methods such as, filtration, decantation, centrifugation, gravity filtration, suction filtration or any other techniques for the recovery of the solids. For filtration, equipment such as nutsche filter, centrifuge, agitated nutsche filter, leaf filter or any other suitable equipment for filtration may be used or any other suitable technique known in the art.
The solvent may be removed, optionally under reduced pressures, at temperatures less than about 150°C, less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, or any other suitable temperatures. The solvent may be removed optionally at atmospheric pressure at temperatures such as described above in this paragraph.
Step c) involves drying of Form ST2 obtained in step b) for a time sufficient to give Form ST3. The drying may take place over a period of about 30 minutes to about 12 hours. Preferably about 1 hour, or about 2 hours to about 4 hours, or any other suitable time period. The drying may be carried out at temperature of less than about 150°C, or less than about 120°C, or less than about 100°C, or less than about 70°C, or less than about 60°C, or less than about 50°C, or less than about 40°C, or less than about 20°C, or any other suitable temperature. The drying may be carried out under reduced pressure, that is, less than standard atmospheric pressure or at atmospheric pressure or any other suitable pressure.
In the eleventh embodiment, the present application provides a process for the preparation of crystalline suvorexant p-toluene sulphonate, Form ST4 comprising, drying suvorexant p-toluene sulphonate, Form ST2.
The drying may take place over a period of about 30 minutes to about 12 hours. Preferably about 1 hour, or about 2 hours to about 4 hours, or any other suitable time period. The drying may be carried out at temperature of less than about 150°C, or less than about 120°C, or less than about 100°C, or less than about 70°C, or less than about 60°C, or less than about 50°C, or less than about 40°C, or less than about 20°C, or any other suitable temperature. The drying may be carried out under reduced pressure, that is, less than standard atmospheric pressure or at atmospheric pressure or any other suitable pressure.
In the twelfth embodiment, the present application provides a process for the preparation of crystalline suvorexant benzene sulfonate, Form SB1, comprising:
a) slurrying suvorexant and benzene sulfonic acid in a solvent or mixture of solvents; and
b) isolating crystalline suvorexant benzene sulfonate, Form SB1.
The solvents that may be used in step a) include, but are not limited to, water, alcohols like methanol, ethanol, isopropanol, butanol or mixtures thereof; ketones like acetone, buanone, ethyl isopropyl ketone or mixtures thereof; halogenated hydrocarbons like chloroform, dichloromethane, carbon tetrachloride or mixtures thereof; esters like ethyl acetate, propyl acetate, isopropyl acetate or mixtures thereof; nitriles like acetonitrile, propionitrile, C2-6 nitriles or mixtures thereof. Preferably propyl acetate can be used.
Step b) involves isolation of crystalline suvorexant benzene sulfonate, Form SB1.
The said isolation may be effected by methods such as, filtration, decantation, centrifugation, gravity filtration, suction filtration or any other techniques for the recovery of the solids. For filtration, equipment such as nutsche filter, centrifuge, agitated nutsche filter, leaf filter or any other suitable equipment for filtration may be used or any other suitable technique known in the art.
The solvent may be removed, optionally under reduced pressures, at temperatures less than about 150°C, less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, or any other suitable temperatures. The solvent may be removed optionally at atmospheric pressure at temperatures such as described above in this paragraph.
Any physical form of suvorexant may be utilized in step a).
In the thirteenth embodiment, the present application provides a process for the preparation of crystalline suvorexant benzene sulfonate, Form SB2, comprising:
a) slurrying suvorexant and benzene sulfonic acid in a solvent or mixture of solvents; and
b) isolating crystalline suvorexant benzene sulfonate, Form SB1;
c) drying crystalline suvorexant benzene sulfonate, Form SB1 for a time sufficient to give SB2.
The solvents that may be used in step a) include, but are not limited to, water, alcohols like methanol, ethanol, isopropanol, butanol or mixtures thereof; ketones like acetone, buanone, ethyl isopropyl ketone or mixtures thereof; halogenated hydrocarbons like chloroform, dichloromethane, carbon tetrachloride or mixtures thereof; esters like ethyl acetate, propyl acetate, isopropyl acetate or mixtures thereof; nitriles like acetonitrile, propionitrile, C2-6 nitriles or mixtures thereof. Preferably propyl acetate can be used.
Step b) involves isolation of crystalline suvorexant benzene sulfonate, Form SB1.
The said isolation may be effected by methods such as, filtration, decantation, centrifugation, gravity filtration, suction filtration or any other techniques for the recovery of the solids. For filtration, equipment such as nutsche filter, centrifuge, agitated nutsche filter, leaf filter or any other suitable equipment for filtration may be used or any other suitable technique known in the art.
The solvent may be removed, optionally under reduced pressures, at temperatures less than about 150°C, less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, or any other suitable temperatures. The solvent may be removed optionally at atmospheric pressure at temperatures such as described above in this paragraph.
Step c) involves drying of Form SB1 obtained in step b) for a time sufficient to give Form SB2. The drying may take place over a period of about 30 minutes to about 12 hours. Preferably about 1 hour, or about 2 hours to about 4 hours, or any other suitable time period. The drying may be carried out at temperature of less than about 150°C, or less than about 120°C, or less than about 100°C, or less than about 70°C, or less than about 60°C, or less than about 50°C, or less than about 40°C, or less than about 20°C, or any other suitable temperature. The drying may be carried out under reduced pressure, that is, less than standard atmospheric pressure or at atmospheric pressure or any other suitable pressure.
In the fourteenth embodiment, the present application provides a process for the preparation of crystalline suvorexant benzene sulphonate, Form SB3 comprising, growing a single crystal using vapor diffusion method.
According to another aspect of the present application there is provided a pharmaceutical composition comprising one or more of Forms ST1, ST2, ST3, ST4, SB1, SB2 and SB3 and pharmaceutically acceptable carrier.
The pharmaceutical composition one or more of Forms ST1, ST2, ST3, ST4, SB1, SB2 and SB3 together with one or more pharmaceutically acceptable excipients of the present application may be further formulated as: solid oral dosage forms such as, but not limited to: powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as but not limited to solutions, dispersions, and freeze dried compositions. Formulations may be in the forms of immediate release, delayed release or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared using techniques such as direct blending, dry granulation, wet granulation, and extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated, and modified release coated. Compositions of the present application may further comprise one or more pharmaceutically acceptable excipients.
Pharmaceutically acceptable excipients that are useful in the present application include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar or the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starches or the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide or the like; lubricants such as stearic acid, magnesium stearate, zinc stearate or the like; glidants such as colloidal silicon dioxide or the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes or the like. Other pharmaceutically acceptable excipients that are of use include but are not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, or the like.
All PXRD data reported herein are obtained using a Powder X-ray Diffractometer (Example: PANalytical X-ray Diffractometer) using copper Ka radiation wavelength 1.5418Å.
In all ORTEP, the displacement ellipsoids are drawn at the 50% probability level for non-hydrogen atoms. All hydrogen atoms are shown by small spheres of arbitrary radii.
Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the following examples, which are provided for purposes of illustration only and should not be construed as limiting the scope of the present application in any manner.
Examples
Example 1: Preparation of Form ST1
In a reactor suvorexant (1 gm), p-toluenesulfonic acid (422 mg) and methanol (5 ml) were added at room temperature. The reaction mixture was heated to about 40oC and maintained for about 20 minutes at this temperature. Now cyclo hexane (10 ml) and diethylether (10 ml) were added to the reaction mixture and maintained for about 30 minutes. The obtained precipitate was filtered to give title compound.
Example 2: Preparation of Form ST2
In a reactor suvorexant (2 gm), p-toluenesulfonic acid (840 mg) and methanol (15 ml) were added at room temperature. The reaction mixture was heated to about 50oC and maintained for about 16 hours at this temperature. The obtained precipitate was filtered to give title compound.
Example 3: Preparation of Form ST3
In a reactor suvorexant (2 gm), p-toluenesulfonic acid (840 mg) and methanol (15 ml) were added at room temperature. The reaction mixture was heated to about 50oC and maintained for about 16 hours at this temperature. The obtained precipitate was filtered and dried at 100oC for about 1 hour to give title compound.
Example 4: Preparation of Form SB1
In a reactor suvorexant (2 gm), benzenesulfonic acid (700 mg) and propylacetate (15 ml) were added at room temperature. The reaction mixture was heated to about 50oC and maintained for about 4 hours at this temperature. The obtained precipitate was filtered to give title compound.

Example 5: Preparation of Form SB2
In a reactor suvorexant (2 gm), benzenesulfonic acid (700 mg) and propylacetate (15 ml) were added at room temperature. The reaction mixture was heated to about 50oC and maintained for about 4 hours at this temperature. The obtained precipitate was filtered and dried at 100oC for 1 hour to give title compound.
Example 6: Preparation of Form SB3
In a test tube SB1 was dissolved in a mixture of propyl acetate (3 ml) and ethanol (3 ml) at room temperature. The test tube was kept for vapor diffusion under n-hexane environment for 11 days to give Form SB3.
Example 7: Preparation of Form ST4
Form ST2 was dried at 120oC for about 6 hours and cooled to room temperature to give Form ST3. Form ST3 again dried at 120oC for about 4 hours to give Form ST4.
,CLAIMS:WE CLAIM:
1. A process for the preparation of crystalline suvorexant p-toluene sulphonate, designated as Form ST1, comprising:
a) slurrying suvorexant and p-toluene sulphonic acid in a solvent or mixture of solvents;
b) adding an anti-solvent; and
c) isolating crystalline suvorexant p-toluene sulphonate Form ST1.
2. A process for the preparation of crystalline suvorexant p-toluene sulphonate, designated as Form ST2, comprising:
a) slurrying suvorexant and p-toluene sulphonic acid in a solvent or mixture of solvents; and
b) isolating crystalline suvorexant p-toluene sulphonate Form ST2.
3. A process for the preparation of crystalline suvorexant p-toluene sulphonate, designated as Form ST3, comprising:
a) slurrying suvorexant and p-toluene sulphonic acid in a solvent or mixture of solvents; and
b) isolating crystalline suvorexant p-toluene sulphonate Form ST2.
c) drying crystalline suvorexant p-toluene sulphonate Form ST2 for a time sufficient to give ST3.
4. A process for the preparation of crystalline suvorexant p-toluene sulphonate, designated as Form ST4, comprising, drying suvorexant p-toluene sulphonate Form ST2.
5. A process for the preparation of crystalline suvorexant benzene sulfonate, designated as Form SB1, comprising:
a) slurrying suvorexant and benzene sulfonic acid in a solvent or mixture of solvents; and
b) isolating crystalline suvorexant benzene sulfonate, Form SB1.
6. A process for the preparation of crystalline suvorexant benzene sulfonate, designated as Form SB2, comprising:
a) slurrying suvorexant and benzene sulfonic acid in a solvent or mixture of solvents; and
b) isolating crystalline suvorexant benzene sulfonate, Form SB1;
c) drying crystalline suvorexant benzene sulfonate, Form SB1 for a time sufficient to give SB2.
7. A process for the preparation of crystalline suvorexant benzene sulphonate, designated as Form SB3, comprising, growing a single crystal by vapor diffusion method.