DESC:INTRODUCTION
Aspects of the present application relates to crystalline forms of Ozanimod, process for the preparation thereof and pharmaceutical formulations of crystalline forms of Ozanimod.
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, The structure of Ozanimod is shown as formula I

Formula I
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 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 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 novel crystalline form of Ozanimod (AP5) with enhanced storage stability, solubility, and processability.
SUMMARY OF THE INVENTION
A first aspect of the present application provides a crystalline Ozanimod (Form AP5) having XRPD pattern comprising the peaks at about 5.71, 11.32 and 15.31±0.2°2?.
A second aspect of the present application provides a process for the preparation of crystalline Ozanimod (Form AP5), comprising the steps of;
a) combining Ozanimod with hot propanol;
b) stirring the reaction mixture obtained in step (a);
c) cooling the solution obtained in step (b);
d) optionally, repeat the step (b) and (c); and
e) isolating the crystalline Ozanimod (Form AP5).
A third aspect of the present application provides a process for the preparation of crystalline Ozanimod (Form AP2), comprising the steps of;
a) combining Ozanimod with solvent selected from DMSO, DMF or mixtures thereof;
b) heating the slurry obtained in step a);
c) optionally filtering the reaction mass obtained in step b);
d) adding anti solvent to the solution obtained in step b) or c);
e) isolating the crystalline Ozanimod (Form AP2).
A fourth aspect of the present application provides pharmaceutical formulations comprising crystalline forms of Ozanimod (Form AP2 and AP5) with one or more pharmaceutically acceptable excipients.
BRIEF DESCRIPTION OF THE DRAWING
Figure 1 illustrates an X-ray powder diffraction pattern of crystalline Ozanimod (Form AP5), obtained according to the procedure of example 2.
Figure 2 illustrates an X-ray powder diffraction pattern of crystalline Ozanimod (Form AP2), obtained according to the procedure of example 3.
DETAILED DESCRIPTION
A first aspect of the present application provides a crystalline Ozanimod (Form AP5) having XRPD pattern comprising the peaks at about 5.71, 11.32 and 15.31±0.2°2?. Crystalline Ozanimod (Form AP5) further characterized by PXRD pattern comprising peaks at about 19.52±0.2°2?. Crystalline Ozanimod (Form AP5) is also characterized by its X-ray powder diffractogram as substantially shown in FIG. 1
A second aspect of the present application provides a process for the preparation of crystalline Ozanimod (Form AP5), comprising the steps of;
a) combining Ozanimod with hot propanol;
b) stirring the reaction mixture obtained in step (a);
c) cooling the solution obtained in step (b);
d) optionally, repeat the step (b) and (c); and
e) isolating the crystalline Ozanimod (Form AP5).
Any physical form of Ozanimod may be utilized for 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 of step a), the combining Ozanimod with propanol at temperature ranging from about 45°C to 90°C.
In an embodiment of step b), stirring the reaction mixture for any time period, such as from about 5 minutes to 5 hours or longer. The solution may be filtered to make it particle free.
In an embodiment of step c), the cooling the solution may be carried out at temperature ranging from about -20°C to 30°C. The reaction mass may be maintained at the same temperature for any time period, such as from about 30 minutes to 10 hours or longer.
In an embodiment of step d), optionally repeat the step (b) and (c) any number of times.
In embodiments of step e), the isolation may be done using techniques such as direct filtration or by scraping, or by shaking the container. 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 isolated product may be optionally further dried to afford crystalline Ozanimod (Form AP5).
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 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 third aspect of the present application provides a process for the preparation of crystalline Ozanimod (Form AP2), comprising the steps of;
a) combining Ozanimod with solvent selected from DMSO, DMF or mixtures thereof;
b) heating the slurry obtained in step a);
c) optionally filtering the reaction mass obtained in step b);
d) adding anti solvent to the solution obtained in step b) or c);
e) isolating the crystalline Ozanimod (Form AP2).
Any physical form of Ozanimod may be utilized for 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 of step a), combining Ozanimod with solvent selected from DMSO, DMF or mixtures thereof (or) by taking the reaction mixture containing Ozanimod and DMSO (or) DMF (or) mixtures thereof.
In an embodiment of step b), the heating may be carried out at temperature ranging from about 45°C to 100°C. The reaction mass may be maintained at the same temperature for any time period, such as from about 5 minutes to 5 hours or longer.
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. 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 d), adding suitable anti solvent to the reaction mass of step b) or c), wherein the anti-solvent include, but are not limited to water, hydrocarbon solvents. In specific embodiment of step c), suitable antisolvent is water.
In embodiment of step e), the isolation may be effected by combining the solution of step b) or c) with a suitable anti-solvent. Adding the solution obtained in step b) or c) to the anti-solvent, or adding an anti-solvent to the solution obtained in step b) or c), to effect the crystallization process are both within the scope of the present invention. After adding anti-solvent, the reaction mass may be maintained from 15 minutes to 10 hours.
In embodiments of step e), the isolation may be done using techniques such as direct filtration or by scraping, or by shaking the container.
The isolated product may be optionally further dried to afford crystalline Ozanimod (Form AP2).
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 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.
The obtained crystalline forms of Ozanimod (Form AP2 and AP5) 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 (Form AP2 and AP5) 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 process of the present invention.
A fourth aspect of the present application provides pharmaceutical formulation comprising crystalline forms of Ozanimod (Form AP2 and AP5) with one or more pharmaceutically acceptable excipients. Crystalline forms of Ozanimod (Form AP2 and AP5) together with one or more pharmaceutically acceptable excipients of the present application may be formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, or capsules; liquid oral dosage forms such as, but not limited to, syrups, suspensions, dispersions, or emulsions; or injectable preparations such as, but not limited to, solutions, dispersions, or 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, or 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, or extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated, or modified release coated. Compositions of the present 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 methyl celluloses, 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 or 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.
In an aspect, the crystalline forms of Ozanimod (Form AP2 and AP5) may be used as an intermediate to produce amorphous form or alternate crystalline form or any targeted form.
In an aspect of the application, crystalline forms of Ozanimod (AP2 and Form AP5) 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).
DEFINITIONS
As used herein, the term “isolated” refers to a compound that is at least 50%, preferably at least 90%, even more preferably at least 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 Ozanimod and a solvent.
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 example, which are provided for purposes of illustration only and should not be construed as limiting the scope of the present invention in any manner.
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. 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.
EXAMPLES
EXAMPLE 1: Preparation of crystalline Ozanimod (Form-AP5)
1-Propanol (45 ml) was charged into an easymax reaction vessel and heated to 75°C. Ozanimod (1 gm) was added to 1-Propanol at 75°C. The reaction mixture was stirred for 10 minutes at 75°C. The resultant solution was cooled to 5°C at the rate of 0.5°C/min. The resultant precipitate was stirred at 0°C for 3 hours. The suspension was filtered under vacuum for 15 minutes and dried in vacuum tray dryer at 45°C for 3 hours to obtain crystalline Ozanimod (Form AP5).

EXAMPLE 2: Preparation of crystalline Ozanimod Form-AP5
2-Propanol (45 ml) was charged into an easymax reaction vessel and heated to 70°C. Ozanimod (1 gm) was added to 2-Propanol at 70°C. The reaction mixture was stirred for 20 minutes at 70°C. The resultant solution was cooled to 5°C at the rate of 0.5°C/min. The resultant precipitate was stirred at 0°C for 3 hours. The suspension was filtered under vacuum for 15 minutes and dried in vacuum tray dryer at 45°C for 3 hours to obtain crystalline Ozanimod (Form AP5).

EXAMPLE 3: Preparation of crystalline Ozanimod Form-AP2
Ozanimod (0.5g) and DMSO (1 ml) were charged into a round bottom flask at 30°C. The reaction mass was stirred for 5 minutes at 100°C. Water (10 ml) was added to the reaction mass. The resultant precipitate was stirred at 30°C for 3 hours. The suspension was filtered under vacuum to obtain crystalline Ozanimod (Form AP2).

EXAMPLE 4: Preparation of crystalline Ozanimod Form-AP2
Ozanimod (0.5g) and DMF (0.8 ml) were charged into a round bottom flask at 30°C. The reaction mass was stirred for 5 minutes at 100°C. Water (8 ml) was added to the reaction mass. The resultant precipitate was stirred at 30°C for 3 hours. The suspension was filtered under vacuum to obtain crystalline Ozanimod (Form AP2).
,CLAIMS:We claim
1. A crystalline Ozanimod (Form AP5) having XRPD pattern comprising the peaks at about 5.71, 11.32 and 15.31±0.2°2?.
2. The process for the preparation of crystalline Ozanimod (Form AP5) according to the claim 1, the process comprising the steps of;
a) combining Ozanimod with hot propanol;
b) stirring the reaction mixture obtained in step (a);
c) cooling the solution obtained in step (b);
d) optionally, repeating the steps (b) and (c); and
e) isolating the crystalline Ozanimod (Form AP5).
3. A process for the preparation of crystalline Ozanimod (Form AP2), the process comprising the steps of;
a) combining Ozanimod with a solvent selected from DMSO, DMF or mixtures thereof;
b) heating the slurry obtained in step a) ;
c) optionally filtering the reaction mass obtained in step b);
d) adding an anti-solvent to the solution obtained in step b) or c); and
e) isolating the crystalline Ozanimod (Form AP2).
4. The process according to the claim 3, wherein the anti-solvent is selected from water, hydrocarbon solvents or mixture thereof.
5. Pharmaceutical formulation comprising crystalline form of Ozanimod (Form AP5) with one or more pharmaceutically acceptable excipients.