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

INTRODUCTION
Aspects of the present application relates to crystalline forms of Ozanimod, amorphous solid dispersions of Ozanimod and process for the preparation thereof.
The compound (S)-5-(3-(1-((2-hydroxyethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile, also known as Ozanimod.
Ozanimod is potentially best-in-class selective modulator that has demonstrated advantages over existing oral therapies for treatment of ulcerative colitis (UC), relapsing multiple sclerosis (RMS) and crohns disease.
U.S. Patent No. US8,796,318B2 discloses racemic Ozanimod or pharmaceutically acceptable salts thereof and pharmaceutical composition thereof. U.S. Patent No. US8,362,048B2 discloses (R) and (S) Ozanimod or a pharmaceutically acceptable salt thereof, pharmaceutical composition thereof and their use in the treatment of multiple sclerosis, ulcerative colitis and Crohn’s disease.
The physicochemical properties of a solid form is a critical parameter in the development of pharmaceutical dosage forms of and these properties can affect the bioavailability, stability and processability of the active pharmaceutical ingredient. It is known that a solid active pharmaceutical ingredient can exist in amorphous and crystalline state. Crystalline solids may further exist as various polymorphs and solvates.
The discovery of new polymorphs and solvates of a pharmaceutical active compound provides an opportunity to improve the performance of a drug product in terms of its bioavailability or release profile in vivo, or it may have improved stability or advantageous handling properties. Polymorphism is an unpredictable property of any given compound. This subject has been reviewed in recent articles, including A. Goho, "Tricky Business," Science News, August 21, 2004. In general, one cannot predict whether there will be more than one form for a compound, how many forms will eventually be discovered, or how to prepare any previously unidentified form.
The discovery of new forms of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, storage stability, and ease of purification. Accordingly, the present inventors have found three novel crystalline forms of Ozanimod and amorphous solid dispersions of Ozanimod having enhanced storage stability, solubility, and processability.
SUMMARY OF THE INVENTION
A first aspect of the present application provides different crystalline forms of Ozanimod, amorphous solid dispersions of Ozanimod, process for the preparation thereof and pharmaceutical formulations of crystalline forms of Ozanimod.
A second aspect of the present application provides a crystalline Ozanimod (Form AP1) having XRPD pattern comprising the peaks at about 5.8, 13.3, 16.1, 19.5, 23.3, 24.5, 25.3, 26.1, 26.9, 27.8 ±0.2°2?.
A third aspect of the present application provides a process for the preparation of crystalline Ozanimod (Form AP1), comprising the steps of;
a) providing a solution of Ozanimod in a methanol (or) mixture of dichlormethane and methanol;
b) optionally filtering the reaction mass obtained in step a);
c) isolating the crystalline Ozanimod (Form AP1).
A fourth aspect of the present application provides a crystalline Ozanimod (Form AP2) having XRPD pattern comprising the peaks at about 4.0, 18.5, 23.2, 26.6, 30.1 ±0.2°2?.
A fifth aspect of the present application provides a process for the preparation of crystalline Ozanimod (Form AP2), comprising the steps of;
a) providing a solution of Ozanimod in a methanol (or) mixture of acetone and water;
b) optionally filtering the reaction mass obtained in step a);
c) adding anti solvent to the solution obtained in step a) or b);
d) isolating the crystalline Ozanimod (Form AP2).
A sixth aspect of the present application provides a process for the preparation of crystalline Ozanimod (Form AP2), comprising the steps of;
a) providing a solution of Ozanimod in a mixture of acetone and water;
b) optionally filtering the reaction mass obtained in step a);
c) isolating the crystalline Ozanimod (Form AP2).
A seventh aspect of the present application provides a crystalline Ozanimod (Form AP3) having XRPD pattern comprising the peaks at about 4.4, 13.0, 17.0, 23.2, 26.0 ±0.2°2?.
An eighth aspect of the present application provides a process for the preparation of crystalline Ozanimod (Form AP3), comprising the steps of;
a) providing a solution of Ozanimod in a methanol;
b) optionally filtering the reaction mass obtained in step a);
c) isolating the crystalline Ozanimod (Form AP3) by evaporation of solvent under <100 mbar vacuum.
A ninth aspect of the present application provides amorphous solid dispersion of Ozanimod together with atleast one pharmaceutically acceptable excipient.
A tenth aspect of the present application provides a process for the preparation of an amorphous solid dispersion of Ozanimod, comprising the steps of:
a) providing a solution of Ozanimod in a suitable solvent;
b) adding atleast one pharmaceutically acceptable excipient to the solution obtained in step a);
c) optionally filtering the reaction mass obtained in step b);
d) isolating the amorphous solid dispersion of Ozanimod.
An eleventh aspect of the present application provides amorphous solid dispersion of Ozanimod with hydroxypropyl cellulose and is characterized by its X-ray powder diffractogram as substantially shown in FIG. 8

A twelfth aspect of the present application provides a process for the preparation of amorphous solid dispersion of Ozanimod with hydroxypropyl cellulose, comprising the steps of;
a) providing a solution of Ozanimod in a methanol;
b) adding hydroxypropyl cellulose to the solution obtained in step a);
c) optionally filtering the reaction mass obtained in step b);
d) isolating the amorphous solid dispersion of Ozanimod with hydroxypropyl cellulose.
A thirteenth aspect of the present application provides amorphous solid dispersion of Ozanimod with polyvinylpyrrolidone K 30 and is characterized by its X-ray powder diffractogram as substantially shown in FIG. 9
A fourteenth aspect of the present invention provides a process for the preparation of amorphous solid dispersion of Ozanimod with polyvinylpyrrolidone K 30, comprising the steps of;
a) providing a solution of Ozanimod in a methanol;
b) adding polyvinylpyrrolidone K30 to the solution obtained in step a);
c) optionally filtering the reaction mass obtained in step b);
d) isolating the amorphous solid dispersion of Ozanimod with polyvinylpyrrolidone K 30.
A fifteenth aspect of the present invention provides amorphous solid dispersion of Ozanimod with Eudragit S-100 and is characterized by its X-ray powder diffractogram as substantially shown in FIG. 10
A sixteenth aspect of the present application provides a process for the preparation of amorphous solid dispersion of Ozanimod with Eudragit S-100, comprising the steps of;
a) providing a solution of Ozanimod in a mixture of acetone and water;
b) adding Eudragit S-100 to the solution obtained in step a);
c) optionally filtering the reaction mass obtained in step b);
d) isolating the amorphous solid dispersion of Ozanimod with Eudragit S-100.

A seventeenth aspect of the present application provides a solid dispersion of Ozanimod comprising Ozanimod in substantially amorphous and preferably entirely in amorphous state.
An eighteenth aspect of the present application provides Ozanimod in amorphous state.
A nineteenth aspect of the present application provides pharmaceutical formulations comprising crystalline forms of Ozanimod (or) amorphous solid dispersion of Ozanimod together with one or more pharmaceutically acceptable excipients.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 illustrates an X-ray powder diffraction pattern of crystalline Ozanimod (Form AP1), obtained according to the procedure of example 1.
Figure 2 illustrates an X-ray powder diffraction pattern of crystalline Ozanimod (Form AP1), obtained according to the procedure of example 2.
Figure 3 illustrates an X-ray powder diffraction pattern of crystalline Ozanimod (Form AP2), obtained according to the procedure of example 3.
Figure 4 illustrates an X-ray powder diffraction pattern of crystalline Ozanimod (Form AP2), obtained according to the procedure of example 4.
Figure 5 illustrates an X-ray powder diffraction pattern of crystalline Ozanimod (Form AP2), obtained according to the procedure of example 5.
Figure 6 illustrates an X-ray powder diffraction pattern of crystalline Ozanimod (Form AP2), obtained according to the procedure of example 6.
Figure 7 illustrates an X-ray powder diffraction pattern of crystalline Ozanimod (Form AP3), obtained according to the procedure of example 7.
Figure 8 illustrates an X-ray powder diffraction pattern of amorphous solid dispersion of Ozanimod with hydroxypropyl cellulose, obtained according to the procedure of example 8.
Figure 9 illustrates an X-ray powder diffraction pattern of amorphous solid dispersion of Ozanimod with polyvinylpyrrolidone K 30, obtained according to the procedure of example 9.
Figure 10 illustrates an X-ray powder diffraction pattern of amorphous solid dispersion of Ozanimod with Eudragit S-100, obtained according to the procedure of example 10.
Figure 11 illustrates an X-ray powder diffraction pattern of crystalline Ozanimod (Form AP1), obtained according to the procedure of example 10.
DETAILED DESCRIPTION
A first aspect of the present application provides different crystalline forms of Ozanimod, amorphous solid dispersions of Ozanimod, process for the preparation thereof and pharmaceutical formulations of crystalline forms of Ozanimod.
A second aspect of the present application provides a crystalline Ozanimod (Form AP1) having XRPD pattern comprising the peaks at about 5.8, 13.3, 16.1, 19.5, 23.3, 24.5, 25.3, 26.1, 26.9, 27.8±0.2°2?. Crystalline Ozanimod (Form AP1) further characterized by PXRD pattern comprising peaks at about 8.7, 10.9, 11.6, 12.8, 13.8, 14.5, 15.3, 17.4, 17.7, 18.4, 18.9, 20.3, 21.6, 22.5, 23.8, 28.8, 30.9, 32.9, 35.5±0.2°2?. Crystalline Ozanimod (Form AP1) is also characterized by its X-ray powder diffractogram as substantially shown in FIG. 1 (or) 2 (or) 11
A third aspect of the present application provides a process for the preparation of crystalline Ozanimod (Form AP1), comprising the steps of;
a) providing a solution of Ozanimod in a methanol (or) mixture of dichlormethane and methanol;
b) optionally filtering the reaction mass obtained in step a);
c) isolating the crystalline Ozanimod (Form AP1).
Any physical form of Ozanimod may be utilized for providing the solution of Ozanimod in step a). Ozanimod that may be used as the input for the process of the present invention may be obtained by the processes described in the art. For example Ozanimod may be prepared by the processes described in US8,362,048B2 and US8,7963,18B2.
In an embodiment, providing a solution at step a) may be carried out by dissolving Ozanimod in a suitable solvent or by taking the reaction mixture containing Ozanimod directly. In an embodiment, a solution of Ozanimod can be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.
In embodiments of step a) involves the solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow), or any other suitable material to remove color and/or to clarify the solution.
In embodiments of step b) the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques. The solution may be filtered by passing thourough paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as celite or hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
In embodiments of step c), the isolation may be done using techniques such as direct filtration or by scraping, or by shaking the container, removal of the solvent include using a rotational distillation device such as a buchi rotavapor. Small quantity of solvent or anti solvent may be added to the reaction flask or the reactor to make the slurry or suspension when the solvent is completely removed, which will be useful for easy filtration.
The product thus isolated may be optionally further dried to afford crystalline Ozanimod (Form AP1).
Drying may be suitably carried out in a tray dryer, vacuum oven, buchi rotavapor, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to several hours.
A fourth aspect of the present application provides a crystalline Ozanimod (Form AP2) having XRPD pattern comprising the peaks at about 4.0, 18.5, 23.2, 26.6, 30.1 ±0.2°2? ±0.2°2?. Crystalline Ozanimod (Form AP2) further characterized by PXRD pattern comprising peaks at about 8.0, 13.0, 14.2, 15.9, 17.7, 18.9, 20.2, 24.7±0.2°2?. Crystalline Ozanimod (Form AP2) is also characterized by its X-ray powder diffractogram as substantially shown in FIG. 3 (or) 4 (or) 5 (or) 6
A fifth aspect of the present application provides a process for the preparation of crystalline Ozanimod (Form AP2), comprising the steps of;
a) providing a solution of Ozanimod in a methanol (or) mixture of acetone and water;
b) optionally filtering the reaction mass obtained in step a);
c) adding anti solvent to the solution obtained in step a) or b);
d) isolating the crystalline Ozanimod (Form AP2).
Any physical form of Ozanimod may be utilized for providing the solution of Ozanimod in step a). Ozanimod that may be used as the input for the process of the present invention may be obtained by the processes described in the art. For example Ozanimod may be prepared by the processes described in US8,362,048B2 and US8,7963,18B2.
In an embodiment, providing a solution at step a) may be carried out by dissolving Ozanimod in a suitable solvent or by taking the reaction mixture containing Ozanimod directly. In an embodiment, a solution of Ozanimod can be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.
In embodiments of step a) involves the solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow), or any other suitable material to remove color and/or to clarify the solution.
In embodiments of step b) the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques. The solution may be filtered by passing thourough paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as celite or hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
In embodiments of step c), adding suitable anti solvent to the reaction mass of step a) or b), wherein the anti-solvent include, but are not limited to water, hydrocarbon solvents.
In specific embodiment of step c), suitable antisolvents that may be used include, but are not limited to water.
In embodiment of step d), the isolation may be effected by combining the solution of step a) or b) with a suitable anti-solvent. Adding the solution obtained in step a) or b) to the anti-solvent, or adding an anti-solvent to the solution obtained in step a) or b), to effect the crystallization process are both within the scope of the present invention. Optionally, the addition may be carried out after concentrating the solution obtained in step a) or b). After adding anti-solvent, the reaction mass may be maintained from 15 minutes to 10 hours.
In embodiments of step d), the isolation may be done using techniques such as direct filtration or by scraping, or by shaking the container, removal of the solvent include using a rotational distillation device such as a buchi rotavapor. Small quantity of solvent or anti solvent may be added to the reaction flask or the reactor to make the slurry or suspension when the solvent is completely removed, which will be useful for easy filtration.
The product thus isolated may be optionally further dried to afford crystalline Ozanimod (Form AP2).
A sixth aspect of the present application provides a process for the preparation of crystalline Ozanimod (Form AP2), comprising the steps of;
a) providing a solution of Ozanimod in a mixture of acetone and water;
b) optionally filtering the reaction mass obtained in step a);
c) isolating the crystalline Ozanimod (Form AP2).
Any physical form of Ozanimod may be utilized for providing the solution of Ozanimod in step a). Ozanimod that may be used as the input for the process of the present invention may be obtained by the processes described in the art. For example Ozanimod may be prepared by the processes described in US8,362,048B2 and US8,7963,18B2.
In an embodiment, providing a solution at step a) may be carried out by dissolving Ozanimod in a suitable solvent or by taking the reaction mixture containing Ozanimod directly. In an embodiment, a solution of Ozanimod can be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.
In embodiments of step a) involves the solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow), or any other suitable material to remove color and/or to clarify the solution.
In embodiments of step b) the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques. The solution may be filtered by passing thourough paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as celite or hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
In embodiments of step c), the isolation may be done using techniques such as direct filtration or by scraping, or by shaking the container, removal of the solvent include using a rotational distillation device such as a buchi rotavapor. Small quantity of solvent or anti solvent may be added to the reaction flask or the reactor to make the slurry or suspension when the solvent is completely removed, which will be useful for easy filtration.
The product thus isolated may be optionally further dried to afford crystalline Ozanimod (Form AP2).
Drying of Ozanimod (Form AP2) obtained according to the process described herein may be suitably carried out in a tray dryer, vacuum oven, buchi rotavapor, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to several hours.
A seventh aspect of the present application provides a crystalline Ozanimod (Form AP3) having XRPD pattern comprising the peaks at about 4.4, 13.0, 17.0, 23.2, 26.0 ±0.2°2?. Crystalline Ozanimod (Form AP3) further characterized by PXRD pattern comprising peaks at about 7.9, 8.9, 11.0, 13.7, 18.4, 20.0, 22.4, 24.1, 25.3, 26.7, 28.4, 30.6±0.2°2?. Crystalline Ozanimod (Form AP3) is also characterized by its X-ray powder diffractogram as substantially shown in FIG. 7
An eighth aspect of the present application provides a process for the preparation of crystalline Ozanimod (Form AP3), comprising the steps of;
a) providing a solution of Ozanimod in a methanol;
b) optionally filtering the reaction mass obtained in step a);
c) isolating the crystalline Ozanimod (Form AP3) by evaporation of solvent under <100 mbar vacuum.
Any physical form of Ozanimod may be utilized for providing the solution of Ozanimod in step a). Ozanimod that may be used as the input for the process of the present invention may be obtained by the processes described in the art. For example Ozanimod may be prepared by the processes described in US8,362,048B2 and US8,7963,18B2.
In an embodiment, providing a solution at step a) may be carried out by dissolving Ozanimod in a suitable solvent or by taking the reaction mixture containing Ozanimod directly. In an embodiment, a solution of Ozanimod can be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.
In embodiments of step a) involves the solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow), or any other suitable material to remove color and/or to clarify the solution.
In embodiments of step b) the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques. The solution may be filtered by passing thourough paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as celite or hyflow.
In embodiments of step c), the isolation may be done by removal of the solvent include using a rotational distillation device such as a buchi rotavapor. Small quantity of solvent or anti solvent may be added to the reaction flask or the reactor to make the slurry or suspension when the solvent is completely removed, which will be useful for easy filtration.
The product thus isolated may be optionally further dried to afford crystalline Ozanimod (Form AP3).
Drying may be suitably carried out in a tray dryer, vacuum oven, buchi rotavapor, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to several hours.
A ninth aspect of the present application provides amorphous solid dispersion of Ozanimod together with atleast one pharmaceutically acceptable excipient.
In an embodiment, the present application provides amorphous solid dispersion of Ozanimod together with atleast one pharmaceutically acceptable excipient characterized by a powder X-ray diffraction (PXRD) pattern, substantially as illustrated by Figures 8, 9 or 10.
A tenth aspect of the present application provides a process for the preparation of an amorphous solid dispersion of Ozanimod, comprising the steps of:
a) providing a solution of Ozanimod in a suitable solvent;
b) adding atleast one pharmaceutically acceptable excipient to the solution obtained in step a);
c) optionally filtering the reaction mass obtained in step b);
d) isolating the amorphous solid dispersion of Ozanimod.
Any physical form of Ozanimod may be utilized for providing the solution of Ozanimod in step a). Ozanimod that may be used as the input for the process of the present invention may be obtained by the processes described in the art. For example Ozanimod may be prepared by the processes described in US 8,362,048B2 and US 8,796,318B2.
In an embodiment, providing a solution at step a) may be carried out by dissolving Ozanimod in a suitable solvent or by taking the reaction mixture containing Ozanimod directly. In an embodiment, a solution of Ozanimod can be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.
In an embodiment, suitable solvent at step a) of this aspect may be selected from C1-C6 alcohols, C3-C6 ketones, C5-C8 aliphatic or aromatic hydrocarbons, C3-C6 esters, C2-C6 aliphatic or cyclic ethers, C2-C6 nitriles, halogenated hydrocarbons, water or mixtures thereof.
In preferred embodiment, the suitable solvent may be selected from the group consisting of alcohol solvents such as methanol, ethanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-pentanol; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone; esters solvents such as methyl acetate, ethyl acetate, isopropyl acetate; water and mixtures thereof.
In an embodiment, pharmaceutically acceptable excipient at step b) of this aspect may be selected from the group consisting of polyvinyl pyrrolidone, povidone K-30, povidone K-60, Povidone K-90, polyvinylp yrrolidone vinylacetate, co-povidone NF, polyvinylacetal diethylaminoacetate (AEA®), polyvinyl acetate phthalate, polysorbate 80, polyoxyethylene–polyoxypropylene copolymers (Poloxamer® 188), polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer 188, pluronic F-68, methylcellulose, methacrylic acid copolymer (Eudragit), Eudragit S-100, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl ellulose acetate succinate, hydroxypropylmethyl ellulose, hydroxypropyl cellulose, hydroxypropyl cellulose SL, hydroxyethyl cellulose, gelucire 44/14, ethyl cellulose, D-alpha-tocopheryl polyethylene glycol 1000 succinate, cellulose acetate phthalate, carboxymethylethylcelluloseand the like; cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, and the like; water soluble sugar excipients, preferably having low hygroscopicity, which include, but are not limited to, mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol and the like; polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohols, propylene glycol derivatives and the like; organic amines such as alkyl amines (primary, secondary, and tertiary), aromatic amines, alicyclic amines, cyclic amines, aralkyl amines, hydroxylamine or its derivatives, hydrazine or its derivatives, and guanidine or its derivatives, or any other excipient at any aspect of present application. The use of mixtures of more than one of the pharmaceutical excipients to provide desired release profiles or for the enhancement of stability is within the scope of this invention. Also, all viscosity grades, molecular weights, commercially available products, their copolymers, and mixtures are all within the scope of this invention without limitation.
In embodiments of step c) the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques. The solution may be filtered by passing thourough paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as celite or hyflow.
In embodiments of step d), the isolation may be done using techniques such as direct filtration or by scraping, or by shaking the container, removal of the solvent include using a rotational distillation device such as a buchi rotavapor, spray drying, agitated thin film drying, freeze drying (lyophilization), and the like, or other techniques specific to the equipment used. Small quantity of solvent or anti solvent may be added to the reaction flask or the reactor to make the slurry or suspension when the solvent is completely removed, which will be useful for easy filtration.
The product thus isolated may be optionally further dried to afford amorphous solid dispersion of Ozanimod.
Drying may be suitably carried out in a tray dryer, vacuum oven, buchi rotavapor, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to several hours.
An eleventh aspect of the present application provides amorphous solid dispersion of Ozanimod with hydroxypropyl cellulose and is characterized by its X-ray powder diffractogram as substantially shown in FIG. 8
A twelfth aspect of the present application provides a process for the preparation of amorphous solid dispersion of Ozanimod with hydroxypropyl cellulose, comprising the steps of;
a) providing a solution of Ozanimod in a methanol;
b) adding hydroxypropyl cellulose to the solution obtained in step a);
c) optionally filtering the reaction mass obtained in step b);
d) isolating the amorphous solid dispersion of Ozanimod with hydroxypropyl cellulose.
The procedure as explained in details under the tenth aspect can be fallowed.
A thirteenth aspect of the present application provides amorphous solid dispersion of Ozanimod with polyvinylpyrrolidone K 30 and is characterized by its X-ray powder diffractogram as substantially shown in FIG. 9
A fourteenth aspect of the present invention provides a process for the preparation of amorphous solid dispersion of Ozanimod with polyvinylpyrrolidone K 30, comprising the steps of;
a) providing a solution of Ozanimod in a methanol;
b) adding polyvinylpyrrolidone K30 to the solution obtained in step a);
c) optionally filtering the reaction mass obtained in step b);
d) isolating the amorphous solid dispersion of Ozanimod with polyvinylpyrrolidone K 30.
The procedure as explained in details under the tenth aspect can be fallowed.
A fifteenth aspect of the present invention provides amorphous solid dispersion of Ozanimod with Eudragit S-100 and is characterized by its X-ray powder diffractogram as substantially shown in FIG. 10
A sixteenth aspect of the present application provides a process for the preparation of amorphous solid dispersion of Ozanimod with Eudragit S-100, comprising the steps of;
a) providing a solution of Ozanimod in a mixture of acetone and water;
b) adding Eudragit S-100 to the solution obtained in step a);
c) optionally filtering the reaction mass obtained in step b);
d) isolating the amorphous solid dispersion of Ozanimod with Eudragit S-100.
The procedure as explained in details under the tenth aspect can be fallowed.
The obtained crystalline forms of Ozanimod may be optionally milled to get desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller and hammer mills, and jet mills. etc., to produce a desired particle size distribution. Crystalline forms of Ozanimod obtained according to certain processes of the present application has a particle size distribution wherein: d(0.5) is less than about 100 µm, or less than about 25 µm, or less than about 10 µm; and d(0.9) is less than about 200 µm, or less than about 50 µm, or less than about 30 µm. Particle size distributions can be determined using any means, including laser light diffraction equipment sold by Malvern Instruments limited, Malvern, Worcestershire, United Kingdom, Coulter counters, microscopic procedures, etc. The term d(x) means that a particular fraction has particles with a maximum size being the value given; 0.5 represents 50% of the particles and 0.9 represents 90% of the particles.
Any crystalline forms (or) amorphous form of Ozanimod can be used as the input material for the processes of the present invention.
A seventeenth aspect of the present application provides a solid dispersion of Ozanimod comprising Ozanimod in substantially amorphous and preferably entirely in amorphous state.
An eighteenth aspect of the present application provides Ozanimod in amorphous state.
A nineteenth aspect of the present application provides pharmaceutical formulation comprising crystalline forms of Ozanimod (or) amorphous solid dispersion of Ozanimod together with one or more pharmaceutically acceptable excipients.
In an aspect of the application, crystalline forms of Ozanimod prepared according to the processes of the present application can be substantially pure having a chemical purity greater than about 99%, or greater than about 99.5%, or greater than about 99.9%, by weight, as determined using high performance liquid chouromatography (HPLC).
Crystalline forms of Ozanimod described herein are anhydrous, solvated or partially solvated or desolvated.
DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise. In general, the number of carbon atoms present in a given group or compound is designated “Cx-Cy”, where x and y are the lower and upper limits, respectively. For example, a group designated as “C1-C6” contains from 1 to 6 carbon atoms. The carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions and the like.
The term “anti-solvent” refers to a liquid that, when combined with a solution of Ozanimod, reduces solubility of the Ozanimod in the solution, causing crystallization or precipitation in some instances spontaneously.
The term “hydrocarbon solvents” refers to aliphatic or alicyclic hydrocarbon solvent.
An aliphatic or alicyclic hydrocarbon solvent refers to a liquid, non-aromatic, hydrocarbon, which may be linear, branched, or cyclic. It is capable of dissolving a solute to form a uniformly dispersed solution. Examples of a hydrocarbon solvents include, but are not limited to, cyclohexane, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, methylcyclohexane, cycloheptane, C5-C8 aliphatic hydrocarbons, petroleum ethers, or mixtures thereof.
As used herein, the term “isolated” refers to a compound that is at least 50%, preferably at least 90%, even more preferably at least5 95%, and most preferably at least 99% pure, as judged by GC or HPLC.
The term “solvate” refers to a complex formed by the combining of Ozanimod and a solvent.
The term “desolvated” refers to Ozanimod form that is a solvate as described herein, and from which solvent molecules have been partially or completely removed. Desolvation techniques to produce desolvated forms include, without limitation, exposure of Ozanimod form (solvate) to a vacuum, subjecting the solvate to elevated temperature, exposing the solvate to a stream of gas, such as air or nitrogen, or any combination thereof. Thus, a desolvated Ozanimod form can be anhydrous, i.e., completely without solvent molecules, or partially solvated wherein solvent molecules are present in stoichiometric or non-stoichiometric amounts.
The term "about" when used in the present invention 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 .
Certain specific aspects and embodiments of the present invention 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 invention in any manner.

EXAMPLES
EXAMPLE 1: Preparation of a crystalline Ozanimod (Form AP1).
Ozanimod (500 mg) and methanol (50 ml) were charged into a round bottom flask at 25°C. The reaction mass was stirred for 20 minutes at 40°C. The reaction mass temperature cooled to 25°C. The reaction mass was filtered to remove any insoluble particles. The reaction mass was evaporated under vacuum at 60°C for over 30 minutes.
EXAMPLE 2: Preparation of a crystalline Ozanimod (Form AP1).
Ozanimod (500 mg) and dichloromethane (50 ml) were charged into a round bottom flask at 25°C. The reaction mass was stirred for 10 minutes at 30°C. Methanol (5 ml) was added to the reaction mass. The reaction mass was filtered to remove any insoluble particles. The reaction mass was evaporated under vacuum at 40°C for over 30 minutes.
EXAMPLE 3: Preparation of a crystalline Ozanimod (Form AP2).
Ozanimod (500 mg) and acetone (50 ml) were charged into a round bottom flask at 25°C. The reaction mass was stirred for 10 minutes at 25°C. Water (5 ml) was added to the reaction mass. The reaction mass was filtered to remove any insoluble particles. The reaction mass was evaporated under vacuum at 50°C for over 30 minutes.
EXAMPLE 4: Preparation of a crystalline Ozanimod (Form AP2).
Ozanimod (500 mg) and methanol (50 ml) were charged into a round bottom flask at 25°C. The reaction mass was stirred for 15 minutes at 50°C. The reaction mass temperature cooled to 25°C. The reaction mass was filtered to remove any insoluble particles. Water (100 ml) was added to the reaction mass. The resulting slurry was filtered to produce crystalline Ozanimod (Form AP2).
EXAMPLE 5: Preparation of a crystalline Ozanimod (Form AP2). Ozanimod (500 mg), acetone (50 ml) and water (5 ml) were charged into a round bottom flask at 25°C. The reaction mass was stirred for 15 minutes at 40°C. The reaction mass temperature cooled to 25°C. The reaction mass was filtered to remove any insoluble particles. Water (100 ml) was added to the reaction mass. The resulting slurry was filtered to produce crystalline Ozanimod (Form AP2).
EXAMPLE 6: Preparation of a crystalline Ozanimod (Form AP2).
Ozanimod (500 mg), acetone (50 ml) and water (5 ml) were charged into a round bottom flask at 25°C. The reaction mass was stirred for 10 minutes at 50°C. The reaction mass temperature cooled to 25°C. The reaction mass was filtered to remove any insoluble particles. The reaction mass was evaporated under <100 mbar vacuum at 60°C for over 60 minutes.
EXAMPLE 7: Preparation of a crystalline Ozanimod (Form AP3).
Ozanimod (500 mg) and methanol (50 ml) were charged into a round bottom flask at 25°C. The reaction mass was stirred for 15 minutes at 50°C. The reaction mass temperature cooled to 25°C. The reaction mass was filtered to remove any insoluble particles. The reaction mass was evaporated under <100 mbar vacuum at 60°C for over 30 minutes.
EXAMPLE 8: Preparation of amorphous solid dispersion of Ozanimod with hydroxypropyl cellulose.
Ozanimod (500 mg), hydroxypropyl cellulose(500 mg) and methanol (50 ml) were charged into a round bottom flask at 25°C. The reaction mass was stirred for 15 minutes at 50°C. The reaction mass temperature cooled to 25°C. The reaction mass was filtered to remove any insoluble particles. The reaction mass was evaporated under vacuum at 50°C for over 60 minutes.
EXAMPLE 9: Preparation of amorphous solid dispersion of Ozanimod with polyvinylpyrrolidone K 30.
Ozanimod (500 mg), polyvinylpyrrolidone K 30(500 mg) and methanol (50 ml) were charged into a round bottom flask at 25°C. The reaction mass was stirred for 10 minutes at 40°C. The reaction mass temperature cooled to 25°C. The reaction mass was filtered to remove any insoluble particles. The reaction mass was evaporated under vacuum at 55°C for over 20 minutes.
EXAMPLE 10: Preparation of amorphous solid dispersion of Ozanimod with Eudragit S-100.
Ozanimod (500 mg), Eudragit S-100 (500 mg), acetone (50 ml) and water (5 ml) were charged into a round bottom flask at 25°C. The reaction mass was stirred for 10 minutes at 50°C. The reaction mass temperature cooled to 25°C. The reaction mass was filtered to remove any insoluble particles. The reaction mass was evaporated under vacuum at 50°C for over 30 minutes.
EXAMPLE 11: Preparation of a crystalline Ozanimod (Form AP1).
Mixture of (S)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)carbamate and (S)-tert-butyl 4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl) (2-hydroxyethyl) carbamate (65 gm), 1,4-dioxane (325 ml) were charged into a round bottom flask at 27°C. The reaction mass was stirred for 10 minutes under nitrogen atmosphere. The reaction mass was cooled to 0°C. 4N HCl in 1,4-dioxane (262.6ml) was added to the reaction mass at the same temperature for 20 minutes. The reaction mixture was warmed to room temperature and then heated to 50°C. for 1 h. The resulting suspension was cooled to room temperature and Et2O (350.7ml) was added. The reaction mass was stirred for 30 minutes. The precipitate was collected by filtration, washed with Et2O (150 ml) and dried to produce 39 g of an off-white solid. The obtained HCl salt of Ozanimod (39 gm) was diluted with MeOH (612 ml). The reaction mixture was warmed to room temperature and then heated to 70°C. for 1 h. The resulting suspension was cooled to 40°C. The precipitated solid was filtered off and washed with methanol (50 ml). The solid was dried under vacuum. The obtained product was diluted with 15% methanol in dichlormethane (1 L) and water (270 ml). The reaction mass was adjusted to pH 7 with aqueous NaHCO3 solution. The organic and aqueous layers were separated. The aqueous layer was extracted with 15% methanol in dichlormethane (1.8 L). The combined organic layer was washed with aqueous NaCl solution (500 ml)), and dried with Na2SO4. The reaction mass was evaporated under vacuum at 40°C. Product weight: 23 g; Chiral purity: 99.60% by HPLC.
,CLAIMS:We claim
1. An amorphous solid dispersion of Ozanimod with atleast one pharmaceutically acceptable excipient.
2. A process for the preparation of an amorphous solid dispersion of Ozanimod, comprising the steps of:
a) providing a solution of Ozanimod in a suitable solvent;
b) adding atleast one pharmaceutically acceptable excipient to the solution obtained in step a);
c) optionally filtering the reaction mass obtained in step b);
d) isolating the amorphous solid dispersion of Ozanimod.
3. The solid dispersion of Ozanimod according to claim 1 or 2, wherein the pharmaceutically acceptable excipient selected from hydroxypropyl cellulose, polyvinylpyrrolidone, Eudragit or mixture thereof.
4. The solid dispersion of Ozanimod according to claim 2, wherein the solvent selected from methanol, acetone, water or mixture thereof.
5. A process for the preparation of amorphous solid dispersion of Ozanimod with hydroxypropyl cellulose, comprising the steps of;
a) providing a solution of Ozanimod in a methanol;
b) adding hydroxypropyl cellulose to the solution obtained in step a);
c) optionally filtering the reaction mass obtained in step b);
d) isolating the amorphous solid dispersion of Ozanimod with hydroxypropyl cellulose.
7. A process for the preparation of amorphous solid dispersion of Ozanimod with polyvinylpyrrolidone K 30, comprising the steps of;
a) providing a solution of Ozanimod in a methanol;
b) adding polyvinylpyrrolidone K30 to the solution obtained in step a);
c) optionally filtering the reaction mass obtained in step b);
d) isolating the amorphous solid dispersion of Ozanimod with polyvinylpyrrolidone K 30.
8 A process for the preparation of amorphous solid dispersion of Ozanimod with Eudragit S-100, comprising the steps of;
a) providing a solution of Ozanimod in a mixture of acetone and water;
b) adding Eudragit S-100 to the solution obtained in step a);
c) optionally filtering the reaction mass obtained in step b);
d) isolating the amorphous solid dispersion of Ozanimod with Eudragit S-100.