DESC:The present application relates to crystalline polymorphic forms of Siponimod hemifumarate, 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 an investigational selective sphingosine-1-phosphate receptor modulator drug currently in phase III clinical trials for the therapy 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 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 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 forms of Siponimod hemifumarate, its preparative processes and pharmaceutical compositions thereof.
In one aspect, the present application provides a crystalline Form SHF3 of Siponimod hemifumarate, characterized by a PXRD pattern comprising the peaks at about 11.85, 15.64, and 23.74 ± 0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline Form SHF3 of Siponimod hemifumarate, comprising,
(a) suspending Siponimod hemifumarate in an alkane solvent at below 20 °C,
(b) optionally stirring the suspension of step (a) at below 20 °C, and
(c) isolating the crystalline Form SHF3 of Siponimod hemifumarate.
In another aspect, the present application provides a crystalline Form SHF4 of Siponimod hemifumarate, characterized by a PXRD pattern comprising the peaks at about 11.60, and 19.10 ± 0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline Form SHF4 of Siponimod hemifumarate, comprising drying the crystalline Form SHF3 of Siponimod hemifumarate.
In another aspect, the present application provides use of the crystalline forms of Siponimod hemifumarate 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 SHF3 of Siponimod hemifumarate prepared according to Example 1.
Figure 2 is powder X-ray diffraction pattern of crystalline form SHF4 of Siponimod hemifumarate prepared according to Example 2.

DETAILED DESCRITPION
Aspects of the present application relate to novel crystalline forms of Siponimod hemifumarate, their preparative processes and pharmaceutical compositions thereof. The present application also encompasses the use of novel crystalline forms of Siponimod hemifumarate 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 SHF3 of Siponimod hemifumarate, characterized by a PXRD pattern comprising the peaks at about 11.85, 15.64, and 23.74 ± 0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline Form SHF3 of Siponimod hemifumarate, comprising,
(a) suspending Siponimod hemifumarate in an alkane solvent at below 20 °C,
(b) optionally stirring the suspension of step (a) at below 20 °C, and
(c) isolating the crystalline Form SHF3 of Siponimod hemifumarate.
The step (a) involves mixing of Siponimod hemifumarate with an alkane solvent at below 20 °C. Any physical form of Siponimod hemifumarate may be used as starting material. The alkane solvent may be selected form the group comprising n-pentane, n-hexane, n-heptane, cyclohexane and the like. The alkane solvent may be about 2 volumes to about 60 volumes to the weight of Siponimod hemifumarate. In step (b) the suspension may be stirred for about 10 minutes to about 10 hours at below 20 °C.
The step (c) involves isolation of crystalline Form SHF3 of Siponimod hemifumarate from the suspension. 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.
In another aspect, the crystalline Form SHF3 of Siponimod hemifumarate is further characterized by a PXRD pattern comprising the peaks at about 12.7, 14.22, 18.80, 21.60 and 25.87 ± 0.2° 2?.
In another aspect, the crystalline Form SHF3 of Siponimod hemifumarate is characterized by the PXRD pattern of Figure 1.
In another aspect, the crystalline Form SHF3 of Siponimod hemifumarate of the present application can also exist as Siponimod fumaric acid (2:1) co-crystal.
In another aspect, the present application provides a crystalline Form SHF4 of Siponimod hemifumarate, characterized by a PXRD pattern comprising the peaks at about 11.60 and 19.10 ± 0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline Form SHF4 of Siponimod hemifumarate, comprising drying the crystalline Form SHF3 of Siponimod hemifumarate.
Drying crystalline Form SHF3 of Siponimod hemifumarate may be carried out under vacuum at about 30 °C to about 60 °C for a period of about 1 hour to about 10 hours.
In another aspect, the present application provides process for the preparation of crystalline Form SHF4 of Siponimod hemifumarate, comprising drying crystalline Form SHF3 of Siponimod hemifumarate of the present invention at about 45 °C using a vacuum tray dryer for a period of about 2 hours to obtain crystalline Form SHF4 of Siponimod hemifumarate.
In another embodiment, the crystalline Form SHF4 of Siponimod hemifumarate is further characterized by a PXRD pattern comprising the peaks at about 7.25, 12.95, and 17.50 ± 0.2° 2?.
In another aspect, the crystalline Form SHF4 of Siponimod hemifumarate is characterized by the PXRD pattern of Figure 2.
In another aspect, the crystalline Form SHF4 of Siponimod hemifumarate of the present application can also exist as Siponimod fumaric acid (2:1) co-crystal.
In another aspect, the present application provides a process for the preparation of crystalline Form SHF3 of Siponimod hemifumarate, comprising humidifying the amorphous Siponimod hemifumarate at a relative humidity of about 65 to 95 %.
Amorphous siponimod hemifumarate is humidified at about 20 °C to about 45 °C and at a relative humidity of about 65 to 95 % for a period of about 2 hours to 50 hours to obtain crystalline Form SHF3 of Siponimod hemifumarate.
In another aspect, the present application provides use of any of crystalline forms of Siponimod hemifumarate 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 hemifumarate 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 hemifumarate of the present application, or a pharmaceutical composition comprising any of crystalline forms of Siponimod hemifumarate 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 SHF3 of Siponimod hemifumarate
Siponimod hemifumarate (1.5 g) and cold n-hexane (75 mL of n-hexane pre cooled to 5 °C) were added to a 250 mL crystallization flask and the mixture was stirred for 6 hours at 5 °C. The resulted suspension was filtered under vacuum to obtain 1.5 g of crystalline Form SHF3 of Siponimod hemifumarate. PXRD as shown in Figure 1.

Example-2: Preparation of crystalline Form SHF4 of Siponimod hemifumarate
The crystalline Form SHF3 of Siponimod hemifumarate prepared in example-1 was dried using a vacuum tray dryer (VTD) at 45 °C for 2 hours to obtain crystalline Form-SHF4 of Siponimod hemifumarate. PXRD as shown in Figure 2.

Example-3: Preparation of crystalline Form SHF3 of Siponimod hemifumarate
Amorphous Siponimod hemifumarate (1.5 g) was added to petri plate. This was placed in a desiccator containing saturated potassium sulphate mixture in water (94 % RH). Maintained the same in desiccator for 1 day to obtain crystalline Form SHF3 of Siponimod hemifumarate. PXRD as shown in Figure 1.

Example-4: Preparation of crystalline Form SHF4 of Siponimod hemifumarate
The crystalline Form SHF3 of Siponimod hemifumarate prepared in example-3 was dehumidified in desiccator with silica gel for 4-5 days to obtain crystalline Form SHF4 of Siponimod hemifumarate. PXRD as shown in Figure 2.
,CLAIMS:We claim
1. Crystalline Form SHF3 of Siponimod hemifumarate characterized by an X-ray powder diffraction pattern comprising the peaks at about 11.85, 15.64, and 23.74 ± 0.2° 2?.
2. The crystalline Form SHF3 of Siponimod hemifumarate of claim 1 is further characterized by an X-ray powder diffraction pattern comprising the peak at about 12.7, 14.22, 18.80, 21.60 and 25.87 ± 0.2° 2?.
3. The crystalline Form SHF3 of Siponimod hemifumarate of claim 1 is characterized by a PXRD pattern as depicted in Figure 1.
4. A process for preparation of crystalline Form SHF3 of Siponimod hemifumarate comprising
(a) suspending Siponimod hemifumarate in an alkane solvent at below 20 °C,
(b) optionally stirring the suspension of step (a) at below 20 °C, and
(c) isolating the crystalline Form SHF3 of Siponimod hemifumarate..
5. The process according to claim 3, the alkane solvent used in step (a) is n-hexane.
6. Crystalline Form SHF4 of Siponimod hemifumarate, characterized by an X-ray powder diffraction pattern comprising the peaks at about 11.60 and 19.10 ± 0.2° 2?.
7. The crystalline Form SHF4 of Siponimod hemifumarate of claim 6 is further characterized by an X-ray powder diffraction pattern comprising the peak at about 7.25, 12.95, and 17.50 ± 0.2° 2?.
8. The crystalline Form SHF4 of Siponimod hemifumarate of claim 6 is characterized by a PXRD pattern as depicted in Figure 2.
9. A pharmaceutical composition comprising crystalline form SHF3 of Siponimod hemifumarate characterized by an X-ray powder diffraction pattern comprising the peaks at about 11.85, 15.64, and 23.74 ± 0.2° 2? and at least one pharmaceutically acceptable carrier.
10. A pharmaceutical composition comprising crystalline form SHF4 characterized by an X-ray powder diffraction pattern comprising the peaks at about 11.60 and 19.10 ± 0.2° 2? of Siponimod hemifumarate and at least one pharmaceutically acceptable carrier.