POLYMORPHIC FORMS 5-[3-[(lS)-2,3-DIHYDRO-l-[(2-HYDROXYETHYL) AMINO]-lH-INDEN-4-YL]-l,2,4-OXADIAZOL-5-YL]-2-(l-METHYLETHOX Y)

BENZONITRILE CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of earlier Indian provisional patent application No. IN 201941003165, filed on January 25, 2019; the entire contents of each of which are incorporated by reference herein. FIELD OF THE INVENTION

The present invention relates to polymorphic forms of ozanimod and process for the preparation of the same.

BACKGROUND OF THE INVENTION

Ozanimod, 5- [3 - [( 1 S )-2, 3 -dihydro- 1 - [(2-hydroxy ethyl)amino] - 1 H-inden-4-yl] -1,2,4- oxadiazol-5-yl]-2-(l-methylethoxy)benzonitrile, having the structure shown in Formula-I is an immunomodulatory drug.

Ozanimod is reported in US 8,796,318 and US 8,481,573.

OBJECT AND SUMMARY OF THE INVENTION

The principle object of the present invention is to provide crystalline polymorphic form Ml, M2, M3 and amorphous solid dispersions of ozanimod.

In one aspect, the present invention provides a crystalline form Ml of ozanimod and process for the preparation of the same comprising the steps of: a) dissolving ozanimod in methyl ethyl ketone;

b) cooling the solution of ozanimod; c) maintaining the suspension for 40-45 hrs; and

d) isolating crystalline form Ml of ozanimod.

In another aspect, the present invention provides a crystalline form M2 of ozanimod and process for the preparation of the same comprising the steps of: a) dissolving ozanimod in methyl ethyl ketone;

b) adding an ether solvent to the solution;

c) optionally seeding with form M2 of ozanimod; and

d) isolating crystalline form M2 of ozanimod.

In one more aspect, the present invention provides a process for the preparation of crystalline form M2 of ozanimod comprising the steps of: a) drying form Ml of ozanimod at 95-105 °C; and

b) isolating crystalline form M2 of ozanimod.

In another aspect, the present invention provides a crystalline form M3 of ozanimod and process for the preparation of the same comprising the steps of: a) dissolving ozanimod in methyl ethyl ketone;

b) cooling the reaction mixture;

c) optionally seeding with crystalline form M3; and

d) isolating and drying at 40-60 °C to get crystalline form M3 of ozanimod.

In one more aspect, the present invention provides an amorphous form of ozanimod comprising the steps of: a) dissolving ozanimod in a solvent or mixtures thereof; and

b) lyophilizing the solution to isolate an amorphous ozanimod.

In one more aspect, the present invention provides an amorphous solid dispersion of ozanimod comprising the steps of: a) dissolving ozanimod in a solvent or mixtures thereof;

b) dissolving pharmaceutically acceptable an excipient in a solvent or mixtures thereof; c) mixing the solutions of step, a) and b);

d) lyophilizing the mixture of solution; and e) isolating an amorphous solid dispersion of ozanimod.

In one more aspect, the present invention provides an amorphous solid dispersion of ozanimod comprising the steps of: a) dissolving ozanimod in a solvent or mixtures thereof;

b) adding pharmaceutically acceptable an excipient;

c) lyophilizing the solution; and

d) isolating an amorphous solid dispersion of ozanimod. BRIEF DESCRIPTION OF THE DRAWINGS

Further aspects of the present disclosure together with additional features contributing thereto and advantages accruing therefrom will be apparent from the following description of embodiments of the disclosure which are shown in the accompanying figures wherein:

Figure 1: PXRD pattern of crystalline form Ml of ozanimod. Figure 2: PXRD pattern of crystalline form M2 of ozanimod.

Figure 3: PXRD pattern of crystalline form M3 of ozanimod.

Figure 4: PXRD pattern of an amorphous ozanimod.

Figure 5: PXRD pattern an amorphous solid dispersion of ozanimod-plasdone.

Figure 6: PXRD pattern an amorphous solid dispersion of ozanimod-silicon dioxide

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides polymorphic form Ml, M2, M3 and solid dispersions of ozanimod.

Instrumentation Details: The PXRD measurements were carried out using BRUKER D8 Discover powder diffractometer equipped with goniometer of Q/2Q configuration and Lynx Eye detector. The Cu-anode X-ray tube was operated at 40kV and 40mA. The experiments were conducted over the 2Q range of 2.0°-50.0°, 0.030° step size and 0.2 seconds step time. The PXRD measurements were carried out using PANalytical, X'Pert PRO powder diffractometer equipped with goniometer of Q/Q configuration and X'Celerator detector. The Cu- anode X-ray tube is operated at 40kV and 30mA. The experiments were conducted over the 2Q range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.

One embodiment of the present invention provides a crystalline form Ml of ozanimod.

Within the context of the present invention, the crystalline form Ml of ozanimod disclosed herein may be characterized by PXRD spectrum having peaks 4.09, 6.82, 8.28, 10.32, 11.84, 12.47, 13.07, 13.51, 14.73, 15.30, 15.97, 16.66, 18.90, 20.15, 20.88, 21.61, 22.56, 23.30, 25.01, 26.71 and 32.46 ±0.2° 20.

In another embodiment, the present invention provides a crystalline form Ml of ozanimod characterized by PXRD pattern substantially as depicted in FIG. 1

In another embodiment, the present invention provides a process for the preparation of crystalline form Ml of ozanimod comprising the steps of: a) dissolving ozanimod in methyl ethyl ketone;

b) cooling the solution of ozanimod;

c) maintaining the suspension for 40-45 hrs; and

d) isolating crystalline form Ml of ozanimod.

As per the above embodiment, ozanimod is dissolved in methyl ethyl ketone by heating at 65- 75°C and the reaction mixture is cooled to 20-30 °C. The obtained suspension was maintained at same temperature for 40-45 hrs, preferably for 42 hrs and the precipitated product is isolated.

The isolation may be carried out by methods well known in the art, for example, by filtering the reaction mixture to obtain a solid. The solid may be further processed by drying at 15-40 °C, preferably at 25-30 °C to obtain the final crystalline form Ml of ozanimod.

In another embodiment, the present invention provides a crystalline form M2 of ozanimod.

Within the context of the present invention, the crystalline form M2 of ozanimod disclosed herein may be characterized by PXRD spectrum having peaks 8.37, 11.811, 12.5, 13.04, 13.52, 19.09, 20.23, 20.86 and ±0.2° 2Q.

In one more embodiment of the present invention, the crystalline form M2 of ozanimod disclosed herein may be further characterized by PXRD spectrum having peaks 8.37, 11.81, 12.5, 13.04, 13.52, 13.82, 14.41, 14.72, 15.35, 16.14, 19.09, 20.23, 20.86, 21.66, 22.52, 23.35, 25.06, 25.34, 26.81 and 32.50 ±0.2° 20.

In another embodiment, the present invention provides a crystalline form M2 of ozanimod characterized by PXRD pattern substantially as depicted in FIG. 2.

In one embodiment, the present invention provides a process for the preparation of a crystalline form M2 of ozanimod comprising the steps of. a) dissolving ozanimod in methyl ethyl ketone;

b) adding an ether solvent to the solution;

c) optionally seeding with form M2 of ozanimod; and

d) isolating crystalline form M2 of ozanimod.

As per the above embodiment, ozanimod is dissolved in methyl ethyl ketone. To the resulting reaction mixture is added an ether solvent selected from tertiary butyl methyl ether, isopropyl ether, diethyl ether, cyclopentyl methyl ether, preferably tertiary butyl methyl ether. Optionally, the reaction mixture is seeded with crystal of form M2 of ozanimod and isolated .

In another embodiment, optionally the reaction mixture may be cooled to -5 to +5 °C, preferably 0-5 °C before isolation of the product.

The isolation may be carried out by methods well known in the art, for example, by filtering the reaction mixture to obtain a solid. The solid may be further processed by drying at 40-60 °C, preferably at 50-55 °C to obtain the final crystalline form M2 of ozanimod.

Yet another embodiment of the present invention provides a process for the preparation of crystalline form M2 of ozanimod comprising the steps of: a) drying form Ml of ozanimod at 95-105 °C; and

b) isolating crystalline form M2 of ozanimod.

As per the above embodiment, crystalline form Ml of ozanimod is dried at 95-105 °C; preferably 100-102°C and isolated. The isolation may be carried out by methods well known in the art, for example, by filtering the reaction mixture to obtain a solid. The solid may be further processed, for example, by drying, to obtain the final crystalline form M2 of ozanimod. In another embodiment, the present invention provides a crystalline form M3 of ozanimod.

Within the context of the present invention, the crystalline form M3 of ozanimod disclosed herein may be characterized by PXRD spectrum having peaks 7.13, 10.52, 11.08, 11.37, 12.8, 13.46, 25.30, 25.70 and ±0.2° 2Q. In one more embodiment of the present invention, the crystalline form M3 of ozanimod disclosed herein disclosed may be further characterized by PXRD spectrum having peaks 7.05, 7.13, 10.52, 10.98, 11.08, 11.33, 11.37, 12.8, 13.40, 13.46, 15.23, 16.00, 16.86, 17.83, 18.78, 20.18, 21.06, 22.17, 23.25, 23.99, 24.44, 25.30, 25.63, 25.70 and 26.18 ±0.2° 20.

In another embodiment, the present invention provides a crystalline form M3 of ozanimod characterized by PXRD pattern substantially as depicted in FIG. 3

In another embodiment, the present invention provides a process for the preparation of a crystalline form M3 of ozanimod comprising the steps of: a) dissolving ozanimod in methyl ethyl ketone;

b) cooling the reaction mixture;

c) optionally seeding with crystalline form M3; and

d) isolating and drying at 40-60 °C to get crystalline form M3 of ozanimod.

As per the above embodiment, ozanimod is dissolved in methyl ethyl ketone and the reaction mixture is cooled to 20-30 °C. Optionally the reaction mixture is seeded with crystalline form M3 and isolated. The isolation may be carried out by methods well known in the art, for example, by filtering the reaction mixture to obtain a solid.

In an additional embodiment, the reaction mixture may be further cooled to -5 to +5 °C before isolation of the product.

Next, the obtained solid is further processed by drying at 40-60 °C, preferably 50-55 °C to obtain crystalline form M3 of ozanimod.

Another embodiment of the present invention provides an amorphous form of ozanimod.

In another embodiment, the present invention provides an amorphous ozanimod characterized by PXRD pattern substantially as depicted in FIG. 4 In one more embodiment, the present invention provides a process for the preparation of an amorphous ozanimod comprising the steps of: a) dissolving ozanimod in a solvent or mixtures thereof; and

b) lyophilizing the solution to isolate an amorphous ozanimod.

As per the above embodiment, ozanimod is dissolved in a solvent includes but not limited to acetonitrile, acetone, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, IPA, t-butanol, water or mixtures thereof, preferably mixture of solvents, more preferably acetonitrile and water. The resulting solution is lyophilized to get an amorphous form of ozanimod.

In another embodiment, the present invention provides an amorphous solid dispersion of ozanimod.

In another embodiment, the present invention provides an amorphous solid dispersion of ozanimod characterized by PXRD pattern substantially as depicted in FIG. 5 & FIG. 6.

In one more embodiment, the present invention provides a process for the preparation of an amorphous ozanimod solid dispersion comprising the steps of: a) dissolving ozanimod in a solvent or mixtures thereof;

b) dissolving pharmaceutically acceptable excipient in a solvent or mixtures thereof; c) mixing the solutions of step, a) and b);

d) lyophilizing the mixture of solution; and

e) isolating an amorphous solid dispersion of ozanimod.

As per the above embodiment, ozanimod is dissolved in a solvent includes but not limited to acetonitrile, acetone, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, IPA, t-butanol, water or mixtures thereof, preferably mixture of solvents, more preferably acetonitrile and water. The pharmaceutically acceptable excipient is dissolved in a solvent includes but not limited to acetonitrile, acetone, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, IPA, t-butanol, water or mixtures thereof, preferably mixture of solvents, more preferably acetonitrile and water.

Pharmaceutically acceptable excipients of the present invention 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, povidones, crospovidones, croscarmellose sodium, silicon dioxide, 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.

Next, the ozanimod solution and the pharmaceutically acceptable excipient solutions are mixed and lyophilized to get an amorphous ozanimod solid dispersion.

In one more embodiment, the present invention provides a process for the preparation of an amorphous ozanimod solid dispersion comprising the steps of: a) dissolving ozanimod in a solvent or mixtures thereof;

b) adding an excipient;

c) lyophilizing the solution; and

d) isolating an amorphous solid dispersion of ozanimod.

As per the above embodiment, ozanimod is dissolved in a solvent includes but not limited to acetonitrile, acetone, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, IPA, t-butanol, water or mixtures thereof, preferably mixture of solvents, more preferably acetonitrile and water. To the solution added the pharmaceutically acceptable an excipient and lyophilized to get an amorphous ozanimod- silicon dioxide solid dispersion.

Pharmaceutically acceptable excipients of the present invention 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, povidones, crospovidones, croscarmellose sodium, silicon dioxide, 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. Indicative stability:

In yet another embodiment, the physical stability of ozanimod form M2 was determined by storing the samples at 40°C/75% relative humidity (RH) and at 25°C/60% relative humidity (RH) conditions for six months and the samples were analyzed by PXRD. The results are shown in table 1. The ozanimod form M2 was found to be physically stable at 40°C/75% relative humidity (RH) and at 25°C/60% relative humidity (RH) up to six months.

In yet another embodiment, the physical stability of ozanimod form M3 was determined by storing the samples at 40°C/75% relative humidity (RH) and at 25°C/60% relative humidity (RH) conditions for six months and the samples were analyzed by PXRD. The results are shown in table 1. The ozanimod form M3 was found to be physically stable at 40°C/75% relative humidity (RH) and at 25°C/60% relative humidity (RH) up to six months.

Table 1

In view of the above description and the examples below, one of the ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of molecules according to the present invention. All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure. EXAMPLES:

Example 1: Ozanimod (200 mg) was dissolved in methyl ethyl ketone (2 mL) at 70±5°C. The resulting clear solution was stirred for 30 min at 70±5°C. The clear solution was cooled to 25±5°C. The material started precipitating at 45±5°C. The suspension was maintained under stirring for 42 h at 25±5°C. The product obtained was filtered and suck dried at 25-30°C for 30 min. The solid obtained was identified as crystalline form Ml of ozanimod.

Yield: 100 mg

Example 2: Ozanimod crystalline form Ml (100 mg) obtained as per example 1 was dried at about 100±5°C for 30 minutes. The solid obtained was identified as crystalline form M2 of ozanimod.

Yield: 80 mg

Example 3: Ozanimod (500 mg) was dissolved in methyl ethyl ketone (5 mL) at 70±5°C. The resulting clear solution was stirred for 30 min at 70±5°C and filtered at same temperature to remove any undissolved particulates. The clear solution was added to methyl tertiary butyl ether (10 mL) solution at 25±5°C containing Ozanimod form M2 seeds (5 mg). The suspension was maintained under stirring for 4h at 25±5°C. The product obtained was filtered, suck dried at 25-30°C for 30 min and further dried the material at 50 °C under vacuum for 15h. The solid obtained was identified as crystalline form M2 of ozanimod. Yield: 280 mg

Example 4: Ozanimod (5.0 g) was dissolved in methyl ethyl ketone (50 mL) at 70±5°C. The resulting clear solution was stirred for 30 min at 70±5°C and filtered at same temperature to remove any undissolved particulate matter. The clear solution was added to methyl tertiary butyl ether (100 mL) solution at 25±5°C containing Ozanimod Form M2 seeds (10 mg). The suspension was maintained under stirring for 15h at 25±5°C. Cooled the reaction mass to 0±5°C and stirred for lh. The product obtained was filtered and dried at 50°C under vacuum for 24h. The solid obtained was identified as crystalline Form M2 of ozanimod.

Yield: 4.1g

Example 5:

Ozanimod (5.0 g) was dissolved in methyl ethyl ketone (100 mL) at 70±5°C. The resulting clear solution was stirred for 30 minutes at 70±5°C and filtered at same temperature to remove any undissolved particulate matter. The clear solution was cooled to 25±5°C, added Ozanimod Form M3 seeds (5 mg) and was maintained under stirring for 15h at 25±5°C. Cooled the reaction mass to 0±5°C and stirred for lh. The obtained product was filtered and dried at 50°C under vacuum for 24h. The solid obtained was identified as crystalline Form M3 of Ozanimod. Yield: 3.9g

Example 6: Ozanimod (500 mg) was dissolved in methyl ethyl ketone (5 mL) at 70±5°C. The resulting clear solution was stirred for 30 min at 70±5°C. The clear solution was cooled to 25±5°C. The material started precipitating at 45±5°C. The suspension was maintained under stirring for 24h at 25±5°C. The obtained product was filtered, suck dried at 25-30°C for 30 min and further dried the material at 50 °C under vacuum for 15h.The solid obtained was identified as crystalline form M3 of ozanimod.

Yield: 250 mg

Example 7: Ozanimod (500 mg) was dissolved in methyl ethyl ketone (10 mL) at 70±5°C. The resulting clear solution was stirred for 30 minutes at 70±5°C. The clear solution was cooled to 25±5°C. The material started precipitating at 45±5°C. The suspension was maintained under stirring for 24h at 25±5°C. The obtained product was filtered, suck dried at 25-30°C for 30 minutes and further dried the material at 50°C under vacuum for 15h. The solid obtained was identified as crystalline form M3 of ozanimod.

Yield: 250 mg Example 8: Ozanimod (0.5 g) was dissolved in a mixture of acetonitrile (15 mL) and water (5 mL) at 70+5 °C. The resulting clear solution was filtered through Hyflo filter aid to remove any undissolved particulate matter and subjected to lyophilization using Labocon lyophilized (Model: LFD-BT-104) to yield an amorphous form ozanimod.

Yield: 450 mg

Example 9: Ozanimod (0. 2g) was dissolved in a mixture of acetonitrile (7 mL) and water (3 mL) at 60±5°C. Plasdone S-630 (0.2 g) was dissolved in a mixture of acetonitrile (8 mL) and water (2 mL) at 60±5°C. Both the clear solutions were combined at 30±5°C and the resulting clear solution was filtered through Hyflo filter aid to remove any undissolved particulate and subjected to lyophilization using Labocon lyophilizer (Model: LFD-BT-104) to yield an amorphous solid dispersion of ozanimod with plasdone S-630.

Yield: 380 mg

Example 10: Ozanimod (0.2 g) was dissolved in a mixture of acetonitrile (15 mL) and water (5 mL) at 60±5°C. The resulting clear solution was filtered through Hyflo filter aid to remove any undissolved particulate, added silicon dioxide (0.2 g) and subjected to lyophilization using Labocon lyophilizer (Model: LFD-BT-104) to yield an amorphous solid dispersion of ozanimod with silicon dioxide.

Yield: 380 mg