DESC:The following specification particularly describes the invention and the manner in which it is to be performed:
CRYSTALLINE POLYMORPHIC FORMS OF SIPONIMOD FUMARATE

FIELD OF THE INVENTION
The present application relates to crystalline polymorphic forms of Siponimod fumarate, their preparative methods and pharmaceutical compositions thereof.

BACKGROUND OF THE INVENTION
The drug compound having the adopted name Siponimod, has a chemical name (E)-1-(4-(1-(((4-cyclohexyl-3-(trifluoromethyl)benzyl)oxy)-imino)ethyl)-2-ethylbenzyl)-azetidine-3-carboxylic acid, and is represented by the structure of formula I.

Siponimod is a selective sphingosine-1-phosphate receptor modulator drug approved in USA for the treatment of secondary progressive multiple sclerosis.
Siponimod base, its synthetic process and its pharmaceutical compositions are described in US patent No. 7,939,519 B2 (US ‘519). Siponimod hemifumarate salt and its pharmaceutical compositions are described in US patent application No. 20150175536 A1 (US ‘536).
The US ‘536 also describes crystalline forms of Siponimod hemifumarate salt and their pharmaceutical compositions.
Polymorphism, the occurrence of different crystal forms, is a phenomenon of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties. Polymorphs in general will have different melting points, thermal behaviors (e.g. measured by thermogravimetric analysis - "TGA", or differential scanning calorimetry - "DSC"), X-ray powder diffraction (XRPD or powder XRD) pattern, infrared absorption fingerprint, and solid state nuclear magnetic resonance (NMR) spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.
Discovering new polymorphic forms, hydrates and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New polymorphic forms and solvates of a pharmaceutically useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile, or improved shelf-life. For at least these reasons, there is a need for additional solid forms of Siponimod hemifumarate.

SUMMARY OF THE INVENTION
Aspects of the present application relate to novel crystalline polymorphic forms of Siponimod hemifumarate, Siponimod monofumarate, its preparative processes and pharmaceutical compositions thereof.
In one aspect, the present application provides a crystalline Form SHF5 of Siponimod hemifumarate, characterized by a PXRD pattern comprising the peaks at about 12.77, 13.01, 14.23, 16.68 and 24.80 ± 0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline Form SHF5 of Siponimod hemifumarate, comprising,
(a) dissolving Siponimod hemifumarate in a mixture of octanoic acid and dimethyl formamide,
(b) optionally stirring the solution of step (a) at below 20 °C,
(c) freezing the solution at below 0 °C, and
(d) isolating the crystalline Form SHF5 of Siponimod hemifumarate.
In another aspect, the present application provides a crystalline Form SF3 of Siponimod monofumarate, characterized by a PXRD pattern comprising the peaks at about 14.26, 17.85 and 28.82 ± 0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline Form SF3 of Siponimod fumarate, comprising,
(a) suspending Siponimod monofumarate crystalline Form SF2 in water,
(b) stirring the mixture of step (a), and
(c) isolating the crystalline Form SF3 of Siponimod monofumarate.
In another aspect, the present application provides use of the crystalline forms of Siponimod hemifumarate and Siponimod monofumarate to improve the purity of Siponimod hemifumarate.
In another aspect, the present application provides a pharmaceutical composition comprising any of the crystalline forms of Siponimod hemifumarate and at least one pharmaceutically acceptable carrier.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is powder X-ray diffraction ("PXRD") pattern of crystalline form SHF5 of Siponimod monofumarate prepared according to Example 1.
Figure 2 is powder X-ray diffraction pattern of crystalline form SF3 of Siponimod fumarate prepared according to Example 2.

DETAILED DESCRITPION
Aspects of the present application relate to novel crystalline forms of Siponimod hemifumarate, Siponimod monofumarate, their preparative processes and pharmaceutical compositions thereof. The present application also encompasses the use of novel crystalline forms of Siponimod fumarate provided herein, for the preparation of other solid forms of Siponimod hemifumarate, for the purification of Siponimod hemifumarate and for the preparation of pharmaceutical dosage forms.
In one aspect, the present application provides a crystalline Form SHF5 of Siponimod hemifumarate, characterized by a PXRD pattern comprising the peaks at about 12.77, 13.01, 14.23, 16.68 and 24.80 ± 0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline Form SHF5 of Siponimod hemifumarate, comprising,
(a) dissolving Siponimod hemifumarate in a mixture of octanoic acid and dimethyl formamide,
(b) optionally stirring the solution of step (a) at below 30 °C,
(c) freezing the solution at below 0 °C, and
(d) isolating the crystalline Form SHF5 of Siponimod hemifumarate.
The step (a) involves dissolving of Siponimod hemifumarate in a mixture of octanoic acid and N,N-dimethyl formamide . Any physical form of Siponimod hemifumarate may be used as starting material. The mixture may be heated to get complete dissolution. In step (b) the solution obtained in step (a) may be cooled to about 30 °C and stirred for about 2 hours to about 20 hours at below 30 °C.
In step (c) the solution is cooled to about -10 °C to about -25 °C and maintained the temperature for about 10 hours to about 3 days. The step (d) involves isolation of solid from the suspension obtained in step (c). Isolation of the solid may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, the solid may be isolated by filtration by gravity or suction. The isolated solid may be washed with a suitable solvent like methyl tert-butyl ether to obtain the crystalline Form SHF5 of Siponimod hemifumarate.
In another aspect, the crystalline Form SHF5 of Siponimod hemifumarate is further characterized by a PXRD pattern comprising the peaks at about 12.20, 15.58, 18.02 and 24.08 ± 0.2° 2?.
In another aspect, the crystalline Form SHF5 of Siponimod hemifumarate is characterized by the PXRD pattern of Figure 1.
In another aspect, the crystalline Form SHF5 of Siponimod hemifumarate may exist as a 2:1 co-crystal of siponimod and fumaric acid.
In another aspect, the present application provides a crystalline Form SF3 of Siponimod monofumarate, characterized by a PXRD pattern comprising the peaks at about 14.26, 17.85 and 28.82 ± 0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline Form SF3 of Siponimod fumarate, comprising,
(a) suspending Siponimod fumarate crystalline Form SF2 in water,
(b) stirring the mixture of step (a), and
(c) isolating the crystalline Form SF3 of Siponimod monofumarate.
The step (a) involves mixing crystalline Form SF2 of Siponimod fumarate with water. The water may be ultra-pure water such as MilliQ water. In step (b) the suspension obtained in step (a) is stirred for about 1 hour to about 15 hours at room temperature. The step (c) involves isolation of the crystalline Form SF3 of Siponimod monofumarate.
Isolation may be carried out by any methods known in the art or procedures described in the present application. In an embodiment, the solid may be isolated by filtration by gravity or suction.
In another embodiment, the crystalline Form SF3 of Siponimod monofumarate is further characterized by a PXRD pattern comprising the peaks at about 10.70, 16.67, 18.36 and 21.49 ± 0.2° 2?.
In another aspect, the crystalline Form SF3 of Siponimod fumarate is characterized by the PXRD pattern of Figure 2.
In another aspect, the crystalline Form SF3 of Siponimod monofumarate may exist as a 1:1 co-crystal of siponimod and fumaric acid.
In another aspect, the present application provides use of any of crystalline forms of Siponimod hemifumarate or Siponimod monofumarate of the present invention in the purification of Siponimod hemifumarate and in the preparation of other crystalline forms.
In another aspect, the present application provides pharmaceutical composition comprising any of crystalline forms of Siponimod fumarate described in this application and one or more pharmaceutically acceptable excipients.
In another aspect, the present application provides a method of treating multiple sclerosis, comprising administering to a subject in need thereof an effective amount of any one of crystalline forms of Siponimod fumarate of the present application, or a pharmaceutical composition comprising any of crystalline forms of Siponimod fumarate of the present invention.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.

DEFINITIONS
The following definitions are used in connection with the present invention unless the context indicates otherwise. The term “amorphous” refers to a solid lacking any long-range translational orientation symmetry that characterizes crystalline structures although; it may have short range molecular order similar to a crystalline solid.
The term "about" when used in the present application preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value. For example "about 10" should be construed as meaning within the range of 9 to 11, preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1.
All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, “comprising” means the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms “having” and “including” are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range “between” two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Reasonable variations of the described procedures are intended to be within the scope of the present invention. While particular aspects of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.
EXAMPLES
Example-1: Preparation of crystalline Form SHF5 of Siponimod hemifumarate
Siponimod hemifumarate (1.5 g), Octanoic acid (6 mL) and DMF (1 mL) were charged into a crystallization flask. The mixture was heated to 85 °C and stirred for 30 minutes. The clear solution was then cooled to 28 °C and stirred for 12 hours. The solution was then kept in the freezer and maintained at -20° C for 3 days. The solid formed was filtered and washed with MTBE (12.5 mL × 2) and suck dried to obtain crystalline Form SHF5 of Siponimod hemifumarate. PXRD as shown in Figure 1.

Example-2: Preparation of crystalline Form SF3 of Siponimod monofumarate
Siponimod fumarate crystalline Form SF2 (0.5 g) and MilliQ water (20 ml) were charged into a vial and stirred for 6 hours at 30 °C. The resultant suspension was filtered under vacuum to obtain crystalline 0.38 g of Form SF3 of Siponimod monofumarate. PXRD as shown in Figure 2.

Example-3: Preparation of crystalline Form SF3 of Siponimod monofumarate
Siponimod fumarate crystalline Form SF2 (3 g) and MilliQ water (100 ml) were charged into a crystallization flask and stirred for 12 hours at 25 °C. The resultant suspension was filtered under vacuum and suck dried to obtain 2 g of crystalline Form SF3 of Siponimod monofumarate. PXRD as shown in Figure 2.
,CLAIMS:We claim
1. A crystalline Form SF3 of Siponimod monofumarate, characterized by a PXRD pattern comprising the peaks at about 14.26, 17.85 and 28.82 ± 0.2° 2?.
2. The crystalline Form SF3 of Siponimod monofumarate of claim 1 is further characterized by a PXRD pattern comprising the peaks at about 10.70, 16.67, 18.36, and 21.49 ± 0.2° 2?.
3. The crystalline Form SF3 of Siponimod monofumarate of claim 1 is characterized by a PXRD pattern as depicted in Figure 2.
4. A process for preparation of crystalline Form SF3 of Siponimod monofumarate of claim 1, comprising,
(a) suspending Siponimod fumarate crystalline Form SF2 in water,
(b) stirring the mixture of step (a), and
(c) isolating the crystalline Form SF3 of Siponimod monofumarate.
5. A crystalline Form SHF5 of Siponimod hemifumarate, characterized by a PXRD pattern comprising the peaks at about 12.77, 13.01, 14.23, 16.68 and 24.80 ± 0.2° 2?.
6. The crystalline Form SHF5 of Siponimod hemifumarate of claim 1 is further characterized by a PXRD pattern comprising the peaks at about 12.20, 15.58, 18.02 and 24.08 ± 0.2° 2?.
7. The crystalline Form SHF5 of Siponimod hemifumarate of claim 1 is characterized by a PXRD pattern as depicted in Figure 1.
8. A process for preparation of crystalline Form SHF5 of Siponimod hemifumarate of claim 5, comprising,
(a) dissolving Siponimod hemifumarate in a mixture of octanoic acid and dimethyl formamide,
(b) optionally stirring the solution of step (a) at below 30 °C,
(c) freezing the solution at below 0 °C, and
(d) isolating the crystalline Form SHF5 of Siponimod hemifumarate.

9. A pharmaceutical composition comprising crystalline form SF3 of Siponimod monofumarate characterized by a PXRD pattern comprising the peaks at about 14.26, 17.85 and 28.82 ± 0.2° 2?, and at least one pharmaceutically acceptable carrier.
10. A pharmaceutical composition comprising crystalline form SHF5 of Siponimod hemifumarate characterized by a PXRD pattern comprising the peaks at about 12.77, 13.01, 14.23, 16.68 and 24.80 ± 0.2° 2?, and at least one pharmaceutically acceptable carrier.