DESC:CRYSTALLINE POLYMORPHIC FORMS OF SIPONIMOD FUMARATE

FIELD OF THE INVENTION
The present application relates to crystalline polymorphic forms of Siponimod monofumarate, 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.
International patent application, WO 2019/064184 A1, published on 4 April 2019 describes crystalline solid state forms of Siponimod hemifumarate and siponimod monofumarate.
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 fumarate.

SUMMARY OF THE INVENTION
Aspects of the present application relate to novel crystalline forms of Siponimod monofumarate, its preparative processes and pharmaceutical compositions thereof.
In one aspect, the present application provides a process for the preparation of crystalline Form SF1 of Siponimod monofumarate, comprising,
(a) suspending Siponimod hemifumarate in methanol or a mixture of methanol and water,
(b) heating the suspension of step (a), and
(c) isolating the crystalline Form SF1 of Siponimod monofumarate.
In another aspect, the present application provides a process for the preparation of crystalline Form SF1 of Siponimod monofumarate, comprising,
(a) providing a mixture of Siponimod base, water and fumaric acid,
(b) cooling the suspension of step (a),
(c) adding a solution of fumaric acid into the suspension, and
(d) isolating the crystalline Form SF1 of Siponimod monofumarate.
In another aspect, the present application provides a crystalline Form SF2 of Siponimod fumarate, characterized by a PXRD pattern comprising the peaks at about 5.99, 11.21, 16.79, 17.08, 18.87, 19.69 and 23.91 ± 0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline Form SF2 of Siponimod fumarate, comprising,
(a) providing a mixture of Siponimod hemifumarate, DMSO and fumaric acid,
(b) heating the mixture of step (a), and
(c) isolating the crystalline Form SF2 of Siponimod fumarate
In another aspect, the present application provides use of the crystalline forms of 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 fumarate and at least one pharmaceutically acceptable carrier.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is powder X-ray diffraction ("PXRD") pattern of crystalline form SF1 of Siponimod monofumarate prepared according to Example 1.
Figure 2 is powder X-ray diffraction pattern of crystalline form SF2 of Siponimod fumarate prepared according to Example 5.

DETAILED DESCRITPION
Aspects of the present application relate to novel crystalline forms of Siponimod monofumarate, their preparative processes and pharmaceutical compositions thereof. The present application also encompasses the use of novel crystalline forms of Siponimod monofumarate 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 process for the preparation of crystalline Form SF1 of Siponimod monofumarate, comprising,
(a) suspending Siponimod hemifumarate in methanol or a mixture of methanol and water,
(b) heating the suspension of step (a), and
(c) isolating the crystalline Form SF1 of Siponimod monofumarate.
The step (a) involves mixing of Siponimod hemifumarate with methanol or a mixture of methanol and water. Any physical form of Siponimod hemifumarate may be used as starting material. The mixture of methanol and water may in the ratio of 1:9 to 9:1. In step (b) the mixture of step (a) is heated to about 45 °C to about 75 °C and the mixture may be filtered to remove undissolved particles and the resultant solution may be transferred into a fresh crystallization flask. The solution may be seeded with Form SF1 of Siponimod monofumarate and stirred for about 10 minutes to about 2 hours. The step (c) involves isolation of crystalline Form SF1 of Siponimod monofumarate.
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 slow evaporation and filtration by gravity or suction. In step (d) the isolated solid is dried under vacuum at about 50 ° C to about 80 °C to obtain crystalline Form SHF1 of Siponimod hemifumarate.
In another aspect, the crystalline Form SF1 of Siponimod monofumarate is characterized by a PXRD pattern comprising the peaks at about 11.62, 12.24, 13.52, and 16.7 ± 0.2° 2?.
In another aspect, the crystalline Form SF1 of Siponimod monofumarate is characterized by the PXRD pattern of Figure 1.
In another aspect, the present application provides a process for the preparation of crystalline Form SF1 of Siponimod monofumarate, comprising,
(a) providing a mixture of Siponimod base, water and fumaric acid,
(b) cooling the suspension of step (a),
(c) adding a solution of fumaric acid into the suspension, and
(d) isolating the crystalline Form SF1 of Siponimod monofumarate.
The step (a) involves mixing of Siponimod base with water and fumaric acid. Any physical form of Siponimod base may be used as starting material. The fumaric acid and water may be used as a saturated aqueous solution of fumaric acid. In step (b) the mixture obtained step (a) is cooled to about 5 °C and the mixture may be stirred for about 30 minutes to about 6 hours at 5 °C. The step (c) involves addition of fumaric acid solution into the suspension. The fumaric acid solution may be prepared by dissolving fumaric acid in DMSO. The resultant mixture may be stirred for about 30 minutes to about 5 hours. The suspension may be kept idle for about 10 hours to about 5 days. The step (d) involves isolation of crystalline Form SF1 of Siponimod monofumarate.
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 suck dried under vacuum to obtain crystalline Form SF1 of Siponimod hemifumarate.
The crystalline Form SF1 of Siponimod monofumarate is characterized by a PXRD pattern comprising the peaks at about 11.62, 12.24, 13.52, and 16.7 ± 0.2° 2?.
The crystalline Form SF1 of Siponimod monofumarate is characterized by the PXRD pattern of Figure 1.
In another aspect, the present application provides a crystalline Form SF2 of Siponimod fumarate, characterized by a PXRD pattern comprising the peaks at about 5.99, 11.21, 16.79, 17.08, 18.87, 19.69 and 23.91 ± 0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline Form SF2 of Siponimod fumarate, comprising,
(a) providing a mixture of Siponimod hemifumarate, DMSO and fumaric acid,
(b) heating the mixture of step (a), and
(c) isolating the crystalline Form SF2 of Siponimod fumarate
The step (a) involves mixing of Siponimod hemifumarate with DMSO and fumaric acid solution. Any physical form of Siponimod hemifumarate may be used for the preparation of the mixture. In step (b) the mixture is heated to about 70 °C to about 100 °C and the resultant solution may be seeded with crystals of Form SF1 of Siponimod monofumarate. The solution may be stirred for about 1 hour to about 15 hours at room temperature. The step (c) involves isolation of the crystalline Form SF2 of Siponimod fumarate.
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. The isolated solid may be washed with ethylacetate and dried under vacuum at about 30 °C to about 50 °C to obtain crystalline Form SF2 of Siponimod fumarate.
In another embodiment, the crystalline Form SF2 of Siponimod fumarate is further characterized by a PXRD pattern comprising the peaks at about 12.06, 15.12, 15.64, and 21.26 ± 0.2° 2?.
In another aspect, the crystalline Form SF2 of Siponimod fumarate is characterized by the PXRD pattern of Figure 2.
In another aspect, the present application provides use of any of crystalline forms of 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 monofumarate 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 monofumarate 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 SF1 of Siponimod monofumarate
Siponimod (0.75 g) was added to water (50 ml) saturated with fumaric acid and maintained at 5 °C in a crystallization flask. The resultant suspension was stirred for about 5 hours. To the resultant suspension, added DMSO-fumaric acid solution (0.2 g in 0.5 mL) and continued stirring for about 4 hours. The suspension obtained was maintained at 25 °C without stirring for about 3 days. The suspension obtained was filtered under vacuum and suck dried for about 2 hours to obtain Form-SF1 of Siponimod monofumarate. PXRD as shown in Figure 1.
Example-2: Preparation of crystalline Form SF1 of Siponimod monofumarate
Siponimod hemifumarate (2 g) and fumaric acid (0.808 g) were added to methanol-water (50 ml in 9:1 ratio respectively) and heated to 65 °C in a crystallization flask. The resultant mixture filtered under vacuum. The resultant solution was transferred into a fresh crystallization vessel and seeded with Form-SF1 of Siponimod monofumarate (0.05 g). The mixture was left for slow evaporation overnight. The resultant suspension was filtered under vacuum to obtain Form-SF1 of Siponimod monofumarate. PXRD as shown in Figure 1.
Example-3: Preparation of crystalline Form SF1 of Siponimod monofumarate
Siponimod (3.2 g) was added to water (200 ml) saturated with fumaric acid in a crystallization flask. The resultant suspension was stirred for about 5 hours. To the resultant suspension, added DMSO-fumaric acid solution (0.8 g in 2 mL) and continued stirring for about 4 hours. The suspension obtained was maintained at 25 °C without stirring for about 36 hrs. The suspension obtained was filtered under vacuum to obtain Form-SF1 of Siponimod monofumarate. PXRD as shown in Figure 1.
Example-4: Preparation of crystalline Form SF1 of Siponimod monofumarate
Siponimod hemifumarate (7.2 g) and fumaric acid (2.8 g) were added to methanol (180 ml) and heated to 65 °C in a crystallization flask. The resultant mixture was filtered under vacuum. The resultant solution was transferred into a fresh crystallization vessel and seeded with Form-SF1 (0.2 g). The mixture was left for slow evaporation overnight. The resultant suspension was filtered under vacuum to obtain Form-SF1 of Siponimod monofumarate. PXRD as shown in Figure 1.
Example-5: Preparation of crystalline Form SF2 of Siponimod fumarate
Siponimod hemifumarate (0.5 g) was added to DMSO (2.5 ml) and fumaric acid solution (1.25 g) maintained at 75 °C in a crystallization flask. To the resultant solution added Form-SF1 seed and left for recrystallization overnight. The resultant crystals were filtered under vacuum to obtain Form-SF2 of Siponimod fumarate. PXRD as shown in Figure 2.
Example-6: Preparation of crystalline Form SF2 of Siponimod fumarate
Siponimod hemifumarate (2 g) was added to DMSO (10 ml) and fumaric acid solution (5 g) maintained at 80 °C in a crystallization flask. To the resultant solution was left overnight. The resultant suspension was filtered under vacuum. The solid obtained was washed with ethylacetate (50 mL × 3) and suck dried for 1 hour to obtain Form-SF2 of Siponimod fumarate. PXRD as shown in Figure 2.
Example-7: Preparation of crystalline Form SF2 of Siponimod fumarate
Siponimod hemifumarate (5 g) was added to DMSO (15 ml) and fumaric acid solution (7.5 g) maintained at 90 °C in a crystallization flask. The resultant solution was cooled to 30 °C and stirred for about 2 hours. The resultant suspension was filtered under vacuum. The solid obtained was washed with ethylacetate (25 mL × 2) and suck dried for 30 minutes to obtain Form-SF2 of Siponimod fumarate. PXRD as shown in Figure 2.
,CLAIMS:We claim
1. A crystalline Form SF2 of Siponimod fumarate, characterized by a PXRD pattern comprising the peaks at about 5.99, 11.21, 16.79, 17.08, 18.87, 19.69 and 23.91 ± 0.2° 2?.
2. The crystalline Form SF2 of Siponimod fumarate of claim 1 is is further characterized by a PXRD pattern comprising the peaks at about 12.06, 15.12, 15.64, and 21.26 ± 0.2° 2?.
3. The crystalline Form SF2 of Siponimod fumarate of claim 1 is characterized by a PXRD pattern as depicted in Figure 2.
4. A process for preparation of crystalline Form SF2 of Siponimod fumarate of claim 1, comprising,
(d) providing a mixture of Siponimod hemifumarate, DMSO and fumaric acid,
(e) heating the mixture of step (a), and
(f) isolating the crystalline Form SF2 of Siponimod fumarate.
5. A process for preparation of crystalline Form SF1 of Siponimod fumarate characterized by a PXRD pattern comprising the peaks at about 11.62, 12.24, 13.52, and 16.7 ± 0.2° 2?, comprising
(d) suspending Siponimod hemifumarate in methanol or a mixture of methanol and water,
(e) heating the suspension of step (a), and
(f) isolating the crystalline Form SF1 of Siponimod fumarate.
6. A process for the preparation of crystalline Form SF1 of Siponimod fumarate characterized by a PXRD pattern comprising the peaks at about 11.62, 12.24, 13.52, and 16.7 ± 0.2° 2?., comprising,
(e) providing a mixture of Siponimod base, water and fumaric acid,
(f) cooling the suspension of step (a),
(g) adding a solution of fumaric acid into the suspension, and
(h) isolating the crystalline Form SF1 of Siponimod fumarate.
7. A pharmaceutical composition comprising crystalline form SF1 of Siponimod fumarate prepared by the process of claim 5 or claim 6, and at least one pharmaceutically acceptable carrier.
8. A pharmaceutical composition comprising crystalline form SF2 characterized by a PXRD pattern comprising the peaks at about 5.99, 11.21, 16.79, 17.08, 18.87, 19.69 and 23.91 ± 0.2° 2?, and at least one pharmaceutically acceptable carrier.