CROSS REFERENCE TO THE RELATED APPLICATIONS

This application is a cognate in the benefit of earlier Indian provisional patent application No.’s: IN202241007473 filed on February 11, 2022, and IN202241010229 filed on February 25, 2022. 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 Hydrochloride. It also provides an improved process for the preparation of the same.

BACKGROUND OF THE INVENTION

Ozanimod, 5-[3-[(lS)-2,3-dihydro-l-[(2-hydroxyethyl)amino]-lH-inden-4- yl]-l,2,4-oxadiazol-5-yl]- 2-(l-methylethoxy)benzonitrile hydrochloride, having the structure shown in below is an immunomodulatory drug.

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

Ozanimod is approved under the brand name of ZEPOSIA. ZEPOSIA is a sphingosine 1 -phosphate receptor modulator indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.

Crystalline form of Ozanimod Hydrochloride CS2 is known in US 11,117,876, Form CS3 is known in US 10,882,830 and Form CS1 is known in US 20200157065 Al. OBJECT AND SUMMARY OF THE INVENTION

The principle object of the present invention is to provide polymorphic forms of ozanimod Hydrochloride.

In one object, the present invention provides a crystalline Form Ml, Form M2, Form M3, Form M4, Form M5 and Form M6 of Ozanimod Hydrochloride.

In another object, the present invention provides processes for the preparation of crystalline Form Ml, Form M2, Form M3, Form M4, Form M5 and Form M6 of Ozanimod Hydrochloride.

In one object, the present invention provides a process for the preparation of crystalline Form Ml of Ozanimod Hydrochloride comprising the steps of: a) dissolving Ozanimod hydrochloride in a hexafluoro-2-propanol; b) removing the solvent; c) optionally repeating step a), step b); and d) drying 10-20 mins to isolate crystalline Form Ml of Ozanimod Hydrochloride.

In one more object, the present invention provides a process for the preparation of crystalline Form M2 of Ozanimod Hydrochloride comprising the steps of: a) drying Form Ml of Ozanimod Hydrochloride and b) isolating crystalline Form M2 of Ozanimod Hydrochloride.

In one more object, the present invention provides a process for the preparation of crystalline Form M2 of Ozanimod Hydrochloride comprising the steps of: a) dissolving Ozanimod Hydrochloride in a polar solvent or mixtures thereof; b) removing the solvent; c) adding polar solvent, followed by a non-polar solvent to step b); and d) removing the solvent to isolate crystalline Form M2 of Ozanimod Hydrochloride.

In another object, the present invention provides a process for the preparation of crystalline Form M3 of Ozanimod Hydrochloride comprising the steps of: a) dissolving Ozanimod hydrochloride in a polar solvent or mixtures thereof; b) removing the solvent; c) optionally repeating step a), step b); and d) drying 50-70 mins to isolate crystalline Form M3 of Ozanimod Hydrochloride.

In another object, the present invention provides a process for the preparation of crystalline Form M3 of Ozanimod Hydrochloride comprising the steps of: a) dissolving Ozanimod Hydrochloride in a polar solvent or mixtures thereof; and b) removing the solvent to isolate crystalline Form M3 of Ozanimod Hydrochloride.

In another object, the present invention provides a process for the preparation of crystalline Form M3 of Ozanimod Hydrochloride comprising the steps of: a) dissolving Ozanimod Hydrochloride in an organic solvent or mixtures thereof; b) removing the solvent; c) adding a second solvent; and d) isolating crystalline Form M3 of Ozanimod Hydrochloride.

In another object, the present invention provides a process for the preparation of crystalline Form M4 of Ozanimod Hydrochloride comprising the steps of: a) dissolving Ozanimod Hydrochloride in a polar solvent or mixtures thereof; b) adding the solution of step a) to the second solvent or adding a second solvent to solution of step a) ; and c) isolating crystalline Form M4 of Ozanimod Hydrochloride.

In one object, the present invention provides a process for the preparation of crystalline Form M5 of Ozanimod Hydrochloride comprising the steps of: a) dissolving Ozanimod hydrochloride in trifluoroethanol; b) removing the solvent; c) optionally repeating step a), step b); and d) isolating crystalline Form M5 of Ozanimod Hydrochloride.

In another object, the present invention provides a process for the preparation of crystalline Form M5 of Ozanimod Hydrochloride comprising the steps of: a) dissolving Ozanimod Hydrochloride in trifluoroethanol; b) cooling the reaction solution to ambient temperature; c) adding a second solvent; and d) isolating crystalline Form M5 of Ozanimod Hydrochloride. In one more object, the present invention provides a process for the preparation of crystalline form M6 of Ozanimod Hydrochloride comprising the steps of: a) dissolving Ozanimod Hydrochloride in mixture of trifluoroethanol and halogenated solvent; and b) removing the solvent to isolate crystalline Form M6 of Ozanimod Hydrochloride.

In one more object, the present invention provides a process for the preparation of crystalline Form M6 of Ozanimod Hydrochloride comprising the steps of: a) taking Ozanimod Hydrochloride Form M5 ; and b) exposing to relative humidity to isolate crystalline Form M6 of Ozanimod Hydrochloride.

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 Hydrochloride.

FIGURE 2: DSC of crystalline Form Ml of Ozanimod Hydrochloride.

FIGURE 3: TGA of crystalline Form Ml of Ozanimod Hydrochloride.

FIGURE 4: PXRD pattern of crystalline Form M2 of Ozanimod Hydrochloride.

FIGURE 5: PXRD pattern of crystalline Form M3 of Ozanimod Hydrochloride.

FIGURE 6: PXRD pattern of crystalline Form M4 of Ozanimod Hydrochloride.

FIGURE 7 : PXRD pattern of crystalline Form M5 of Ozanimod Hydrochloride.

FIGURE 8: DSC of crystalline Form M5 of Ozanimod Hydrochloride.

FIGURE 9: TGA of crystalline Form M5 of Ozanimod Hydrochloride.

FIGURE 10: DSC of crystalline Form M2 of Ozanimod Hydrochloride.

FIGURE 11: TGA of crystalline Form M2 of Ozanimod Hydrochloride. FIGURE 12: DSC of crystalline Form M3 of Ozanimod Hydrochloride.

FIGURE 13: TGA of crystalline Form M3 of Ozanimod Hydrochloride.

FIGURE 14: DSC of crystalline Form M4 of Ozanimod Hydrochloride.

FIGURE 15: TGA of crystalline Form M4 of Ozanimod Hydrochloride.

FIGURE 16: PXRD pattern of crystalline Form M6 of Ozanimod Hydrochloride.

FIGURE 17: DSC of crystalline Form M6 of Ozanimod Hydrochloride.

FIGURE 18: TGA of crystalline Form M6 of Ozanimod Hydrochloride.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides crystalline polymorphic Form Ml , Form M2, Form M3, Form M4, Form M5 and Form M6 of Ozanimod Hydrochloride.

Instrumentation Details:

Powder X-ray Diffraction (PXRD)

The powder X-ray diffraction patterns of present invention were measured on BRUKER D-8 Advance powder X-ray diffractometer equipped with goniometer of 0/20 configuration and Lynx Eye detector. The Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 20 range of 2.0°-50.0°, 0.030° step size and 0.4 seconds step time.

Differential Scanning Calorimetry (DSC):

The DSC measurement was carried out on a TA Q2000 instrument. The experiment was conducted from 30°C to 250°C at a heating rate of 10.0°C/min with nitrogen purging at a flow rate of 50 mL/min. Standard aluminum pans covered by lids with three pinholes were used.

Thermogravimetric Analysis (TGA):

The TGA measurement was carried out on TA Q5000 instrument. The experiment was conducted from ambient temperature to 300°C at a heating rate of 10.0 °C/min and purging with nitrogen at a flow rate of 25 mL/min.

In one embodiment, the present invention provides crystalline Form Ml of Ozanimod Hydrochloride. In one embodiment, the present invention provides crystalline Form Ml of Ozanimod Hydrochloride characterized by a PXRD pattern that contains significant peaks at 20 angles at about 6.54, 13.14, 18.21 and 25.46 ± 0.2 degrees 20.

According to the present invention, the crystalline Form Ml of Ozanimod Hydrochloride may be further characterized by a PXRD pattern that contains significant peaks at 20 angles at about 6.54, 11.87, 13.14, 16.20, 17.27, 18.21, 18.80, 23.78, 25.46, 26.99 and 29.56 ± 0.2 degrees 20.

In one more embodiment, the present invention provides crystalline Form Ml of Ozanimod Hydrochloride disclosed herein may characterized by PXRD pattern substantially as depicted in FIG.1.

In one more embodiment, the present invention provides crystalline Form Ml of Ozanimod Hydrochloride disclosed herein may characterized by differential scanning calorimetry thermogram as depicted in FIG.2.

In one more embodiment, the present invention provides crystalline Form Ml of Ozanimod Hydrochloride disclosed herein may characterized by thermogravimetric analysis as depicted in FIG.3.

In another embodiment, the present invention provides a process for the preparation of crystalline Form Ml of Ozanimod Hydrochloride comprising the steps of: a) dissolving Ozanimod hydrochloride in a hexafluoro-2-propanol; b) removing the solvent; c) optionally repeating step a), step b); and d) drying 10-20 mins to isolate crystalline Form Ml of Ozanimod Hydrochloride.

According to the present invention, Ozanimod hydrochloride is dissolved in hexafluoro-2-propanol the solvent is removed from the resulting solution.

The resulting reaction solution is optionally further dissolved in hexafluoro-2-propanol and the solvent is removed.

The solvent removal of the above embodiment may carry out according to the methods well known in the art, for example, by distillation, or evaporation. Preferably by distillation.

In one embodiment, the resulting clear solution is distilled under controlled vacuum in a stepwise manner under 500mbar for lOmin, 400mbar for lOmin, 300mbar for lOmin, 200mbar for lOmin, lOOmbar for lOmin.

Next, the resulting solid is dried under reduced pressure for 10-20 mins to isolate crystalline Form Ml of Ozanimod Hydrochloride. Yet another embodiment, the present invention provides crystalline Form M2 of Ozanimod Hydrochloride.

In one embodiment, the present invention provides crystalline Form M2 of Ozanimod Hydrochloride characterized by a PXRD pattern that contains significant peaks at 20 angles at about 8.28, 18.37, 25.64 and 26.56 ± 0.2 degrees 20.

According to the present invention, the crystalline Form M2 of Ozanimod Hydrochloride may further be characterized by an PXRD pattern that contains significant peaks at 20 angles at about 8.28, 12.30, 13.26, 15.37,16.33, 18.37, 19.96, 21.50, 25.64 and 26.56 ± 0.2 degrees 20.

In one more embodiment, the present invention provides crystalline Form M2 of Ozanimod Hydrochloride disclosed herein may characterized by PXRD pattern substantially as depicted in FIG.4.

In one more embodiment, the present invention provides crystalline Form M2 of Ozanimod Hydrochloride disclosed herein may characterized by differential scanning calorimetry thermogram as depicted in FIG.10.

In one more embodiment, the present invention provides crystalline Form M2 of Ozanimod Hydrochloride disclosed herein may characterized by thermogravimetric analysis as depicted in FIG. 11.

In one more embodiment, the present invention provides a process for the preparation of crystalline Form M2 of Ozanimod Hydrochloride comprising the steps of: a) drying Form Ml of Ozanimod Hydrochloride and b) isolating crystalline Form M2 of Ozanimod Hydrochloride.

According to the present invention, crystalline form Ml of Ozanimod Hydrochloride is dried under vacuum at 45-65 °C; preferably 50-60 °C and isolated crystalline Form M2 of Ozanimod Hydrochloride.

Yet another embodiment, the present invention provides a process for the preparation of crystalline Form M2 of Ozanimod Hydrochloride comprising the steps of: a) dissolving Ozanimod HC1 in a polar solvent or mixtures thereof; b) removing the solvent; c) adding polar solvent, followed by a non-polar solvent to step b); and d) removing the solvent to isolate crystalline Form M2 of Ozanimod Hydrochloride.

According to the present invention, Ozanimod hydrochloride is dissolved in polar solvent or mixtures thereof and the solvent is removed from the resulting solution. The suitable polar solvent includes, but not limited to alcohols such as hexafluoro-2-propanol, trifluoroethanol, isopropyl alcohol, methanol, ethanol, 1-propoanol, 2-propanol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and esters such as ethyl acetate, isopropyl acetate; preferably hexafluoro-2-propanol.

The resulting reaction mixture is further dissolved in a polar solvent, followed by a non-polar solvent and the solvent is removed to isolate crystalline Form M2 of Ozanimod Hydrochloride.

The suitable polar solvent for further dissolution includes, but not limited to alcohols such as hexafluoro-2-propanol, trifluoroethanol, isopropyl alcohol, methanol, ethanol, 1-propoanol, 2- propanol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and esters such as ethyl acetate, isopropyl acetate; preferably the solvent which is used in step a), and more preferably hexafluoro-2-propanol.

The suitable non-polar solvent includes, but not limited to ethers such as methyl tertiary butyl ether, iso propyl ether, 2-methyl tetrahydrofuran; alkanes such as heptane, toluene; preferably methyl tertiary butyl ether.

The solvent removal of the above embodiment may carry out according to the methods well known in the art, for example, by distillation or evaporation. Preferably by distillation.

Next, the resulting reaction mass is cooled and dried to isolate crystalline Form M2 of Ozanimod Hydrochloride.

Yet another embodiment, the present invention provides crystalline Form M3 of Ozanimod Hydrochloride.

In one embodiment, the present invention provides crystalline Form M3 of Ozanimod Hydrochloride characterized by a PXRD pattern that contains significant peaks at 20 angles at about 3.93, 7.93, 12.67, 13.60 and 16.77 ± 0.2 degrees 20.

According to the present invention, the crystalline Form M3 of Ozanimod Hydrochloride may be further characterized by an PXRD pattern that contains significant peaks at 20 angles at about 3.93, 7.93, 12.67, 13.60, 16.77, 18.38, 20.06, 22.74 and 24.30± 0.2 degrees 20.

In one more embodiment, the present invention provides crystalline Form M3 of Ozanimod Hydrochloride disclosed herein may characterized by PXRD pattern substantially as depicted in FIG.5.

In one more embodiment, the present invention provides crystalline Form M3 of Ozanimod Hydrochloride disclosed herein may characterized by differential scanning calorimetry thermogram as depicted in FIG.12. In one more embodiment, the present invention provides crystalline Form M3 of Ozanimod Hydrochloride disclosed herein may characterized by thermogravimetric analysis as depicted in FIG. 13.

In another embodiment, the present invention provides a process for the preparation of crystalline Form M3 of Ozanimod Hydrochloride comprising the steps of: a) dissolving Ozanimod Hydrochloride in a polar solvent or mixtures thereof; b) removing the solvent; c) optionally repeating step a), step b); and d) drying 50-70 mins to isolate crystalline Form M3 of Ozanimod Hydrochloride.

According to the present invention, Ozanimod hydrochloride is dissolved in polar solvent or mixtures thereof and the solvent is removed from the resulting solution. The suitable polar solvent includes, but not limited to alcohols such as hexafluoro-2-propanol, trifluoroethanol, isopropyl alcohol, methanol, ethanol, 1-propoanol, 2-propanol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and esters such as ethyl acetate, isopropyl acetate; preferably hexafluoro-2-propanol.

In another embodiment, the above resulting Ozanimod Hydrochloride mass optionally dissolved in polar solvent or mixtures thereof and solvent removal similar to step a) and b) to isolate crystalline Form M3 of Ozanimod Hydrochloride.

The solvent removal of the above embodiments may carry out according to the methods well known in the art, for example, by distillation or evaporation. Preferably by distillation.

In one embodiment, the reaction mixture is distilled under controlled vacuum in a stepwise manner under 600mbar for 15min, 500mbar for 15min, 400mbar for 15min, 300mbar for 15min, 200mbar for 15min, lOOmbar for 15min.

Next, the resulting solid is dried under reduced pressure for 50-70 mins; preferably 60 mins to isolate crystalline Form M3 of Ozanimod Hydrochloride.

In another embodiment, the present invention provides a process for the preparation of crystalline Form M3 of Ozanimod Hydrochloride comprising the steps of: a) dissolving Ozanimod Hydrochloride in an organic solvent or mixtures thereof; b) removing the solvent; c) adding a second solvent; and d) isolating crystalline Form M3 of Ozanimod Hydrochloride.

According to the present invention, Ozanimod hydrochloride is dissolved in an organic solvent or mixtures thereof and the solvent is removed from the resulting solution. The suitable organic solvent is polar solvent includes, but not limited to alcohols such as hexafluoro-2-propanol, trifluoroethanol, isopropyl alcohol, methanol, ethanol, 1-propoanol, 2-propanol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and esters such as ethyl acetate, isopropyl acetate; halogenated solvent includes but not limited to dichloromethane, trichloromethane, dichloroethane; preferably mixture of hexafluoro-2-propanol and dichloromethane.

To the above embodiment resulting Ozanimod Hydrochloride reaction mass is added to a second solvent selected from non-polar solvent at room temperature and isolated crystalline Form M3 of Ozanimod Hydrochloride . The suitable non-polar solvent includes ethers such as methyl tertiary butyl ether, iso propyl ether, 2-methyl tetrahydrofuran; alkanes such as heptane, toluene; preferably methyl tertiary butyl ether.

In an additional embodiment, the resulting reaction may further washed with suitable solvent non-polar solvent includes ethers such as methyl tertiary butyl ether, iso propyl ether, 2-methyl tetrahydrofuran; alkanes such as heptane, toluene; preferably methyl tertiary butyl ether

The isolation of the above embodiments may carry out according to the methods well known in the art, for example, by filtration, centrifugation. Preferably by filtration..

Next, the resulting solid is dried under vacuum at 30-50 °C, preferably at 40 °C for 2-8 hrs; preferably 6 hrs to isolate crystalline Form M3 of Ozanimod Hydrochloride.

In one more embodiment, the present invention provides a process for the preparation of crystalline Form M3 of Ozanimod Hydrochloride comprising the steps of: a) dissolving Ozanimod Hydrochloride in a polar solvent or mixtures thereof; and b) removing the solvent to isolate crystalline Form M3 of Ozanimod Hydrochloride.

According to the present invention, Ozanimod hydrochloride is dissolved in polar solvent or mixtures thereof and the solvent is removed from the resulting reaction solution to isolate crystalline Form M3 of Ozanimod Hydrochloride. The suitable polar solvent includes, but not limited to alcohols such as hexafluoro-2-propanol, trifluoroethanol, isopropyl alcohol, methanol, ethanol, 1-propoanol, 2- propanol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and esters such as ethyl acetate, isopropyl acetate; preferably mixture of trifluoroethanol and ethanol.

The solvent removal of the above embodiment may carried out according to the methods well known in the art, for example, by distillation, or evaporation. Preferably by distillation and isolated crystalline Form M3 of Ozanimod Hydrochloride. Yet another embodiment, the present invention provides crystalline Form M4 of Ozanimod Hydrochloride.

In one embodiment, the present invention provides crystalline Form M4 of Ozanimod Hydrochloride characterized by a PXRD pattern that contains significant peaks at 20 angles at about 4.58, 9.18, 11.47, 16.42, 25.62 and 26.58 ± 0.2 degrees 20.

According to the present invention, the crystalline Form M4 of Ozanimod Hydrochloride may be further characterized by an PXRD pattern that contains significant peaks at 20 angles at about 4.58, 9.18, 11.47, 12.2, 13.8, 15.54, 16.42, 19.8, 22.65, 23.18, 23.91, 25.62 and 26.58± 0.2 degrees 20.

In one more embodiment, the present invention provides crystalline Form M4 of Ozanimod Hydrochloride disclosed herein may characterized by PXRD pattern substantially as depicted in FIG.6.

In one more embodiment, the present invention provides crystalline Form M4 of Ozanimod Hydrochloride disclosed herein may characterized by differential scanning calorimetry thermogram as depicted in FIG.14.

In one more embodiment, the present invention provides crystalline Form M4 of Ozanimod Hydrochloride disclosed herein may characterized by thermogravimetric analysis as depicted in FIG. 15.

Yet another embodiment, the present invention provides a process for the preparation of crystalline Form M4 of Ozanimod Hydrochloride comprising the steps of: a) dissolving Ozanimod Hydrochloride in a polar solvent or mixtures thereof; b) adding the solution of step a) to the second solvent or adding a second solvent to solution of step a) ; and c) isolating crystalline Form M4 of Ozanimod Hydrochloride.

According to the present invention, Ozanimod hydrochloride is dissolved in polar solvent or mixtures thereof at room temperature to reflux temperature. The suitable polar solvent includes, but not limited to alcohols such as hexafluoro-2-propanol, trifluoroethanol, isopropyl alcohol, methanol, ethanol, 1- propoanol, 2-propanol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and esters such as ethyl acetate, isopropyl acetate; preferably hexafluoro-2-propanol.

Next, the resulting reaction mixture optionally cooled to room temperature when dissolution takes place at higher temperature.

The above resulting Ozanimod Hydrochloride solution added a second solvent selected from non-polar solvent at room temperature to reflux temperature and isolated . In a preferred embodiment, reaction solution of step a) may added to the second solvent or a second solvent may be added to the reaction solution of step a).

The suitable non-polar solvent includes ethers such as methyl tertiary butyl ether, iso propyl ether, 2- methyl tetrahydrofuran; alkanes such as heptane, toluene; preferably methyl tertiary butyl ether.

In another embodiment, when the addition of second solvent carried out at reflux temperature, the reaction mixture optionally cooled to room temperature before isolation.

The isolation of crystalline Form M4 of Ozanimod Hydrochloride of the above embodiment may be carried out by removing the solvent by methods well known in the art, for example, by filtration, centrifugation, preferably by filtration. The resulting solid may be further processed by drying to obtain crystalline Form M4 of Ozanimod Hydrochloride.

In one more embodiment, the drying of the solid may carry out at stage wise from 50-70 °C for 2 hrs to 20 hrs, preferably at 50 °C for 2-3 hrs and at 70 °C for 16-18 hrs.

Yet another embodiment, the present invention provides crystalline Form M5 of Ozanimod Hydrochloride.

In one embodiment, the present invention provides crystalline Form M5 of Ozanimod Hydrochloride characterized by a PXRD pattern that contains significant peaks at 20 angles at about 4.43, 8.90, 18.02, 24.82 and 26.28 ± 0.2 degrees 20.

According to the present invention, the crystalline Form M5 of Ozanimod Hydrochloride may be further characterized by an PXRD pattern that contains significant peaks at 20 angles at about 4.43, 8.90, 11.22, 13.40, 16.08, 16.45, 18.02, 20.17, 22.66, 23.02, 23.58, 24.17, 24.82, 25.48 and 26.28 ± 0.2 degrees 20.

In one more embodiment, the present invention provides crystalline Form M5 of Ozanimod Hydrochloride disclosed herein may characterized by PXRD pattern substantially as depicted in FIG.7.

In one more embodiment, the present invention provides crystalline Form M5 of Ozanimod Hydrochloride disclosed herein may characterized by differential scanning calorimetry thermogram as depicted in FIG.8.

In one more embodiment, the present invention provides crystalline Form M5 of Ozanimod Hydrochloride disclosed herein may characterized by thermogravimetric analysis as depicted in FIG.9.

In one embodiment, the present invention provides a process for the preparation of crystalline Form M5 of Ozanimod Hydrochloride comprising the steps of: a) dissolving Ozanimod hydrochloride in trifluoroethanol; b) removing the solvent; c) optionally repeating step a), step b); and d) isolating crystalline Form M5 of Ozanimod Hydrochloride.

According to the present invention, Ozanimod hydrochloride is dissolved in trifluoroethanol the solvent is removed from the resulting solution.

The resulting reaction mass is optionally further dissolved in trifluoroethanol, and the solvent is removed in a process to isolate crystalline Form M5 of Ozanimod Hydrochloride.

The solvent removal of the above embodiment may carry out according to the methods well known in the art, for example, by distillation, or evaporation. Preferably by distillation.

In one embodiment, the resulting clear solution is distilled under controlled vacuum in a stepwise manner under 500mbar for lOmin, 400mbar for lOmin, 300mbar for lOmin, 200mbar for lOmin, lOOmbar for lOmin and finally at 10-15mbar for 15-25 min.

Next, the resulting solid is isolated as crystalline Form M5 of Ozanimod Hydrochloride.

Yet another embodiment, the present invention provides a process for the preparation of crystalline Form M5 of Ozanimod Hydrochloride comprising the steps of: a) dissolving Ozanimod Hydrochloride in trifluoroethanol; b) cooling the reaction solution to ambient temperature. c) adding a second solvent; and d) isolating crystalline Form M5 of Ozanimod Hydrochloride.

According to the present invention, Ozanimod hydrochloride is dissolved in trifluoroethanol at 45- 60°C, preferably 55-60 °C and the reaction solution is cooled to ambient temperature.

To the resulting reaction solution is added a second solvent and isolated crystalline Form M5 of Ozanimod Hydrochloride. A second solvent is selected from non-polar solvent includes ethers such as methyl tertiary butyl ether, iso propyl ether, 2-methyl tetrahydrofuran; alkanes such as heptane, toluene; preferably methyl tertiary butyl ether. In a preferred embodiment, the second solvent may contain crystalline Ozanimod Hydrochloride Form M5 seeds.

The isolation of crystalline Form M5 of Ozanimod Hydrochloride may carry out according to the methods well known in the art, for example, by filtration, centrifugation. Preferably by filtration and isolated crystalline form M5 of Ozanimod Hydrochloride. Yet another embodiment, the present invention provides crystalline Form M6 of Ozanimod Hydrochloride.

In one embodiment, the present invention provides crystalline Form M6 of Ozanimod Hydrochloride characterized by a PXRD pattern that contains significant peaks at 20 angles at about 4.44, 8.78, 13.12, 16.83 and 26.27 ± 0.2 degrees 20.

According to the present invention, the crystalline Form M6 of Ozanimod Hydrochloride may be further characterized by an PXRD pattern that contains significant peaks at 20 angles at about 4.44, 8.78, 13.12, 16.11, 16.83, 17.89, 18.61, 19.68, 23.39, 24.16, 24.85 and 26.27 ± 0.2 degrees 20.

In one more embodiment, the present invention provides crystalline Form M6 of Ozanimod Hydrochloride disclosed herein may characterized by PXRD pattern substantially as depicted in FIG. 16.

In one more embodiment, the present invention provides crystalline Form M6 of Ozanimod Hydrochloride disclosed herein may characterized by differential scanning calorimetry thermogram as depicted in FIG.17.

In one more embodiment, the present invention provides crystalline Form M6 of Ozanimod Hydrochloride disclosed herein may characterized by thermogravimetric analysis as depicted in FIG. 18.

In one more embodiment, the present invention provides a process for the preparation of crystalline Form M6 of Ozanimod Hydrochloride comprising the steps of: a) dissolving Ozanimod Hydrochloride in mixture of trifluoroethanol and halogenated solvent; and b) removing the solvent to isolate crystalline Form M6 of Ozanimod Hydrochloride.

According to the present invention, Ozanimod hydrochloride is dissolved in mixture of trifluoroethanol and halogenated solvent and the solvent is removed from the resulting Ozanimod Hydrochloride solution to isolate crystalline Form M6 of Ozanimod Hydrochloride. The halogenated solvent includes but not limited to dichloromethane, trichloromethane, dichloroethane, preferably dichloromethane.

The solvent removal of the above embodiment may carry out according to the methods well known in the art, for example, by distillation or evaporation. Preferably by distillation and isolated crystalline form M6 of Ozanimod Hydrochloride.

In one more embodiment, the present invention provides a process for the preparation of crystalline Form M6 of Ozanimod Hydrochloride comprising the steps of: a) taking Ozanimod Hydrochloride Form M5; and b) exposing to relative humidity to isolate crystalline Form M6 of Ozanimod Hydrochloride.

According to the present invention, the Ozanimod Hydrochloride Form M5 is exposed to 70-100% of relative humidity, preferably 80-90 of relative humidity for 12-18 hrs, preferably 14-17 hrs, more preferably for 16 hrs and isolated crystalline Form M6 of Ozanimod Hydrochloride.

In another embodiment, the input ozanimod Hydrochloride may be prepared as per the process known in the prior art, for example US 9388147.

DSC and TGA Analyses:

Form Ml: The DSC thermogram of ozanimod hydrochloride Form Ml (Fig. 2) is characterized by an initial endothermic peak at around 93.24°C attributing to the desolvation and a second broad endothermic event at around 188.61°C followed by a third endothermic peak at 237.30°C attributing to the final melting of the product. TGA data of Form Ml (Fig. 3) shows a weight loss of 23.61% attributing to solvent loss due to hexafluoro-2-propanol indicating that Form Ml is a solvate.

Form M2: The DSC thermogram of ozanimod hydrochloride Form M2 (Fig. 10) is characterized by a single melting endothermic peak at 240.75°C. The TGA data of Form M2 (Fig. 11) shows no significant weight loss till the melting of the product, indicating that Form M2 is an anhydrous form.

Form M3: The DSC thermogram of ozanimod hydrochloride Form M3 (Fig. 12) is characterized by a small endothermic event around 209.79 °C attributing to the phase transition followed by a sharp melting endothermic peak at 240.22°C corresponding to the final melting of the product. The TGA data of Form M3 (Fig. 13) shows no significant weight loss till the melting of the product, indicating that Form M3 is an anhydrous form.

Form M4: The DSC thermogram of ozanimod hydrochloride Form M4 (Fig. 14) is characterized by an exothermic peak at 189.37°C attributing to phase transition followed by a sharp endothermic peak at 241.87°C corresponding to final melting of the product. The TGA data of Form M4 (Fig. 15) shows no significant weight loss till the melting of the product, indicating that Form M4 is an anhydrous form.

Form M5: The DSC thermogram of ozanimod hydrochloride Form M5 (Fig. 8) is characterized by a small endo-exothermic events around 180-210°C attributing to phase transition followed by sharp endothermic peak at 241.21 °C corresponding to final melting of the product. The TGA data of Form M5 (Fig. 9) shows no significant weight loss till the melting of the product, indicating that Form M5 is an anhydrous form.

Form M6: The DSC thermogram of ozanimod hydrochloride Form M6 (Fig. 17) is characterized by a broad endothermic peak at 41.30°C attributing to desolvation event followed by an exothermic peak at 193.36°C attributing to phase transition and a sharp endothermic peak at 239.80°C attributing to final melting of the product. The TGA data of Form M6 (Fig. 18) shows a weight loss of around 2.5% till 100°C, which corresponds to desolvation, and above which no significant weight loss was observed. The moisture content analysis on Form M6 shows the water content in the range of 2-3%, indicating that Form M6 is a hydrate.

Indicative stability:

In yet another embodiment, the physical stability of Ozanimod hydrochloride Form M3 and Ozanimod hydrochloride Form M4 were determined by storing the samples at 25 °C and 60% RH, 40°C and 75% RH conditions for three months and the samples were analyzed by PXRD. The results are shown in Table 1. The Ozanimod hydrochloride Form M3 and Ozanimod hydrochloride Form M4 were found to be physically stable in all studied conditions.

Table 1

In view of the above description and the examples below, one of 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: Form Ml of Ozanimod Hydrochloride.

Ozanimod hydrochloride (0.1g) was dissolved in hexafluro-2-propanol (ImL) at 50-55°C. The resulting clear solution was distilled at 30-35°C on a rotary evaporator for 40 min under controlled vacuum in a stepwise manner i.e. under 500mbar for lOmin, 400mbar for lOmin, 300mbar for lOmin and finally at 200mbar for lOmin. To the resulting reaction mass was added hexafluro-2-propanol (ImL) and redissolved at 30-35°C. The resulting clear solution was redistilled at 30-35°C on a rotary evaporator for period of 65min under controlled vacuum in a stepwise manner i.e. under 500mbar for lOmin, 400mbar for lOmin, 300mbar for lOmin, 200mbar for lOmin, lOOmbar for lOmin and finally at 10- 15mbar for 15min. The solid obtained was identified by PXRD as novel crystalline Form Ml of Ozanimod hydrochloride. Yield: 0.1 g.

Example 2: Form M2 of Ozanimod Hydrochloride.

Ozanimod hydrochloride crystalline Form Ml (150 mg) obtained as per example 1 was dried under vacuum at 50-60°C for 16-24h. The resulting solid was identified by PXRD as novel crystalline Form M2 of Ozanimod hydrochloride.

Example 3: Form M2 of Ozanimod Hydrochloride.

Ozanimod hydrochloride (0.5g) was dissolved in Hexafluro-2-propanol (8mL) at 50-55°C. Filter the reaction mass through 0.45p filter to remove any undissolved particles. The resulting clear solution was distilled completely under vacuum at 33-35°C by downward distillation. To the resulting solid material added Hexafluro-2-propanol (4mL) at 33-35°C stirred to obtain clear solution. Then added Methyl tertbutyl ether (4ml) and the resulting clear solution was distilled completely under vacuum at 33-35°C by downward distillation. Cool the reaction mass to 25+3 °C and the isolated solid was dried under vacuum at 60°C for 16h. The product obtained was identified by PXRD as novel crystalline Form M2 of Ozanimod hydrochloride. Yield: 0.44 gm.

Example 4: Form M3 of Ozanimod Hydrochloride.

Ozanimod hydrochloride (0.59g) was dissolved in hexafluro-2-propanol (6 mL) at 50-55°C. The resulting clear solution was distilled at 30-35°C on a rotary evaporator for 50min under controlled vacuum in a stepwise manner i.e. under 500mbar for lOmin, 400mbar for lOmin, 300mbar for lOmin, 200mbar for lOmin and finally at lOOmbar for lOmin. To the resulting reaction mass was added hexafluro-2-propanol (6 mL) and redissolved at 30-35°C. The resulting clear solution was redistilled at 30-35°C on a rotary evaporator for period of 150min under controlled vacuum in a stepwise manner i.e. under 600mbar for 15min, 500mbar for 15min, 400mbar for 15min, 300mbar for 15min, 200mbar for 15min, lOOmbar for 15min and finally at 10-15mbar for 60min. The solid obtained was identified by PXRD as novel crystalline Form M3 of Ozanimod hydrochloride. Yield: 0.32 g.

Example 5: Form M3 of Ozanimod Hydrochloride.

Ozanimod hydrochloride (5g) was dissolved in a mixture of trifluoroethanol (105mL) and dichloromethane (35mL) at 25±2°C and filter through Whatman filter paper to remove any undissolved particulate matter at 25±2°C. The resulting clear solution was completely distilled under vacuum by downward distillation method at bath temperature 35±2°C. The reaction mass was then kept under vacuum at bath temperature 35±2°C for 30minutes. Cooled the reaction mass to 25±2°C, added methyl tertiary butyl ether (37mL) and stir the reaction mass at 25±2°C for 60minutes. The resulting reaction mass was filtered, washed with methyl tertiary butyl ether (5mL) and suck-dried for lOminutes under vacuum. The solid obtained was dried under vacuum at 40°C for 14h and further dried under vacuum at 60°C for 6h. The product obtained was identified by PXRD as novel crystalline Ozanimod hydrochloride Form M3. Yield: 4.5 g.

Example 6: Form M3 of Ozanimod Hydrochloride.

Ozanimod hydrochloride (3g) was dissolved in a mixture of trifluoroethanol (126mL) and methanol (54mL) at 57±2°C. The resulting clear solution was completely distilled under vacuum using rotary evaporator at bath temperature 40°C. The product obtained was identified by PXRD as novel crystalline Ozanimod hydrochloride Form M3. Yield: 2.85 g.

Example 7: Form M4 of Ozanimod Hydrochloride.

Dissolved Ozanimod hydrochloride (0.1g) in Hexafluro-2-propanol (ImL) at 55-60°C. To the clear solution added methyl tertiary butyl ether (ImL) for 5min and maintained under stirring at 55-60°C for 30min. Slowly cool reaction mass to 25-30°C in 30min, filter and suck-dried material for 30min. The solid obtained was identified by PXRD as novel crystalline Form M4 of Ozanimod hydrochloride. Yield: 90 mg.

Example 8: Form M4 of Ozanimod Hydrochloride.

Ozanimod hydrochloride (10g) was dissolved in hexafluoroisopropanol (lOOmL) at 25±2°C and filter through hyflo to remove any undissolved particulate matter at 25±2°C. The resulting clear solution was heated to 50-55°C, added methyl tertiary butyl ether (lOOmL) for 35min at 50-55°C and maintained under stirring for lOmin at 50-55°C. The reaction mass was slowly cooled to 50°C, filtered, washed with methyl tertiary butyl ether (5mL) and suck-dried under vacuum for 30min. The solid obtained was dried under vacuum at 50°C for 2h and further dried under vacuum 70°C for 17h. The product obtained was identified by PXRD as novel crystalline Ozanimod hydrochloride Form M4. Yield: 9.7g.

Example 9: Form MS of Ozanimod Hydrochloride.

Ozanimod hydrochloride (0.1g) was dissolved in trifluoroethanol (2 mL) at 60+3 °C. The resulting clear solution was distilled at 40+3 °C on a rotary evaporator for 50 min under controlled vacuum in a stepwise manner i.e. under 500mbar for 10 mins, 400mbar for 10 min, 300mbar for 10 mins, 200mbar for 10 mins and finally at lOOmbar for 10 mins. To the reaction mass was added trifluoroethanol (2 mL) and redissolved at 60+3 °C. The resulting clear solution was redistilled at 40+3 °C on a rotary evaporator for period of 70 min under controlled vacuum in a stepwise manner i.e. under 500mbar for 10 mins, 400mbar for 10 mins, 300mbar for 10 mins, 200mbar for 10 mins, lOOmbar for 10 mins and finally at 10-15mbar for 20 mins. The solid obtained was identified by PXRD as novel crystalline Form M5 of Ozanimod hydrochloride. Yield: 90 mg.

Example 10: Form M5 of Ozanimod Hydrochloride.

Ozanimod hydrochloride (0.1g) was dissolved in a trifluoroethanol (1.5mL) at 55+5°C and the clear solution was cooled to 27+2 °C. The resulting clear solution was added to methyl tertiary butyl ether (ImL) containing Ozanimod hydrochloride Form M5 seeds at 27+2°C. The reaction mass was maintained under stirring for 60min at 27+2°C, filter the reaction mass at 27+2°C. The product obtained was identified by PXRD as novel crystalline Ozanimod hydrochloride Form M5. Yield: 80 mg.

Example 11: Form M6 of Ozanimod Hydrochloride.

Ozanimod hydrochloride (1g) was dissolved in a mixture of trifluoroethanol (2 ImL) and dichloromethane (7mL) at 32+2°C. The resulting clear solution was completely distilled under vacuum by downward distillation method at bath temperature 35+2°C. The product obtained was identified by PXRD as novel crystalline Ozanimod hydrochloride Form M6. Yield: 870 mg.

Example 12: Form M6 of Ozanimod Hydrochloride.

Ozanimod hydrochloride Form M5 as per above example was exposed to 80-90% relative humidity (RH) for 16h. The resulting solid was identified by PXRD as novel crystalline Ozanimod hydrochloride Form M6.