DESC:The following specification particularly describes the invention and the manner in which it is to be performed:
FIELD OF THE INVENTION
The present application relates to crystalline polymorphic forms of Siponimod hemifumarate, and 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 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 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 forms of Siponimod hemifumarate, its preparative processes and pharmaceutical compositions thereof.
In one aspect, the present application provides a crystalline Form SHF1 of Siponimod hemifumarate, characterized by a PXRD pattern comprising the peak at about 7.52 ± 0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline Form SHF1 of Siponimod hemifumarate, comprising,
(a) suspending Siponimod hemifumarate in water,
(b) heating the suspension of step (a),
(c) isolating the solid, and
(d) drying the solid to obtain crystalline Form SHF1 of Siponimod hemifumarate.
In another aspect, the present application provides a process for the preparation of crystalline Form SHF1 of Siponimod hemifumarate, characterized by a PXRD pattern comprising the peak at about 7.52 ± 0.2° 2?, comprising:
(a) providing a mixture of Siponimod hemifumarate and water,
(b) heating the mixture of step (a),
(c) adding an organic solvent to the mixture, and
(d) isolating and drying the solid to obtain crystalline Form SHF1 of Siponimod hemifumarate.
In another aspect, the present application provides a crystalline Form SHF2 of Siponimod hemifumarate, characterized by a PXRD pattern comprising the peaks at about 5.38 and 8.13 ± 0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline Form SHF2 of Siponimod hemifumarate, comprising,
(a) providing a mixture of Siponimod hemifumarate and 1,4-dioxane,
(b) stirring the mixture of step (a), and
(c) isolating the crystalline Form SHF2 of Siponimod hemifumarate.
In another aspect, the present application provides a crystalline Form SF1 of Siponimod monofumarate, characterized by a PXRD pattern comprising the peaks at about 11.62, 12.24, 13.52 and 16.70 ± 0.2° 2?.
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 and an organic solvent,
(b) adding fumaric acid to the mixture of step (a), and
(c) isolating the crystalline Form SF1 of Siponimod monofumarate.
In another aspect, the present application provides crystalline form S of siponimod base, characterized by a PXRD pattern comprising the peaks at about 6.95, 10.44, 12.12, 12.30, 17.09 and 22.11 ± 0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline Form S of Siponimod, comprising,
(a) adding Siponimod hemifumarate to hot glycerine,
(b) adding an alcohol solvent to the mixture of step (a), and
(c) isolating the crystalline Form S of Siponimod
In another aspect, the present application provides Siponimod L-proline co-crystal.
In another aspect, the present application provides a process for preparation of Siponimod hemifumarate L-proline co-crystal, comprising,
(a) providing a mixture of Siponimod base, fumaric acid and L-proline in a solvent or solvent mixture thereof,
(b) stirring and heating the mixture of step (a), and
(c) isolating the Siponimod hemifumarate L-proline co-crystal.
In another aspect, the present application provides use of the crystalline forms of Siponimod hemifumarate to improve the purity of Siponimod and other salts thereof.
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 SHF1 of Siponimod hemifumarate prepared according to Example 1.
Figure 2 is powder X-ray diffraction pattern of crystalline form SHF2 of Siponimod hemifumarate prepared according to Example 3.
Figure 3 is powder X-ray diffraction pattern of crystalline form SF1 of Siponimod monofumarate prepared according to Example 5.
Figure 4 is powder X-ray diffraction pattern of crystalline form of Siponimod hemifumarate L-proline co-crystal (SLP) prepared according to Example 6.
Figure 5 is powder X-ray diffraction pattern of crystalline form S of Siponimod base prepared according to Example 7.

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 hemifumarate and 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 crystalline Form SHF1 of Siponimod hemifumarate, characterized by a PXRD pattern comprising the peak at about 7.52 ± 0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline Form SHF1 of Siponimod hemifumarate, comprising,
(a) suspending Siponimod hemifumarate in water,
(b) heating the suspension of step (a),
(c) isolating the solid, and
(d) drying the solid to obtain crystalline Form SHF1 of Siponimod hemifumarate.
The step (a) involves mixing of Siponimod hemifumarate with water. Any physical form of Siponimod hemifumarate may be used as starting material. In step (b) the suspension is heated to about 50 °C and the suspension may be stirred for about 10 minutes to about 10 hours. The step (c) involves isolation of crystalline Form SHF1 of Siponimod hemifumarate.
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 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 SHF1 of Siponimod hemifumarate is further characterized by a PXRD pattern comprising the peaks at about 11.39, 12.51, 13.28, 14.31, 15.62, and 17.43 ± 0.2° 2?.
In another aspect, the crystalline Form SHF1 of Siponimod hemifumarate is characterized by the PXRD pattern of Figure 1.
In another aspect, the present application provides a process for the preparation of crystalline Form SHF1 of Siponimod hemifumarate, characterized by a PXRD pattern comprising the peak at about 7.52 ± 0.2° 2?, comprising:
(e) providing a mixture of Siponimod hemifumarate and water,
(f) heating the mixture of step (a),
(g) adding an organic solvent to the mixture, and
(h) isolating and drying the solid to obtain crystalline Form SHF1 of Siponimod hemifumarate.
The step (a) involves mixing of Siponimod hemifumarate with water. Water mau be 1:1 to 1:50 to the weight of Siponimod hemifumarate. Any physical form of Siponimod hemifumarate may be used as starting material. In step (b) the suspension is heated to about 40 °C to about 100 °C and the suspension may be stirred for about 10 minutes to about 10 hours. The step (c) involves addition of an organic solvent such as acetonitrile, acetone, THF, ethylacetate and the like to the hot mixture and the resulted mixture may be stirred for about 10 minutes to about 5 hours. The step (d) involves isolation of crystalline Form SHF1 of Siponimod hemifumarate.
Isolation of the solid may be carried out at about 0 °C to about 30 °C 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 is dried under vacuum at about 50 ° C to about 80 °C to obtain crystalline Form SHF1 of Siponimod hemifumarate characterized by a PXRD pattern comprising the peak at about 7.52 ± 0.2° 2?.
In another aspect, the present application provides a pharmaceutical composition comprising crystalline Form SHF1 of Siponimod hemifumarate of the present application and a pharmaceutically acceptable carrier.
In another aspect, the present application provides a crystalline Form SHF2 of Siponimod hemifumarate, characterized by a PXRD pattern comprising the peaks at about 5.38 and 8.13 ± 0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline Form SHF2 of Siponimod hemifumarate, comprising,
(a) providing a mixture of Siponimod hemifumarate and 1,4-dioxane,
(b) stirring the mixture of step (a), and
(c) isolating the crystalline Form SHF2 of Siponimod hemifumarate
The step (a) involves mixing of Siponimod hemifumarate with 1,4-dioxane. Any physical form of Siponimod hemifumarate may be used for the preparation of the mixture. In step (b) the mixture is stirred for about 10 minutes to about 10 hours at a temperature 0 °C to about 50 °C. The step (c) involves isolation of the crystalline Form SHF2 of Siponimod hemifumarate.
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 dried under vacuum at about 30 °C to about 50 °C to obtain crystalline Form SHF2 of Siponimod hemifumarate.
In another embodiment, the crystalline Form SHF2 of Siponimod hemifumarate is further characterized by a PXRD pattern comprising the peaks at about 10.89, 13.67, 14.98, 16.45, 19.23, 20.65, 22.13 and 23.19 ± 0.2° 2?.
In another aspect, the crystalline Form SHF2 of Siponimod hemifumarate is characterized by the PXRD pattern of Figure 2.
In another aspect, the present application provides a pharmaceutical composition comprising crystalline Form SHF2 of Siponimod hemifumarate of the present application and a pharmaceutically acceptable carrier.
In another aspect, the present application provides a crystalline Form SF1 of Siponimod monofumarate, 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 present application provides a process for the preparation of crystalline Form SF1 of Siponimod monofumarate, comprising,
(a) providing a mixture of Siponimod base and an organic solvent,
(b) adding fumaric acid to the mixture of step (a), and
(c) isolating the crystalline Form SF1 of Siponimod monofumarate
Providing a mixture in step (a) includes:
(i) direct use of a reaction mixture containing Siponimod monofumarate that is obtained in the course of its synthesis; or
(ii) direct use of reaction mixture containing Siponimod monofumarate that is obtained by treating Siponimod with fumaric acid; or
(iii) dissolving Siponimod monofumarate in a solvent.
The step (a) involves mixing of Siponimod base with a suitable organic solvent such as 2-propanol, 1-butanol, 2-butanol and ethylformate. Any form of Siponimod base may be used for the preparation of the mixture. The step (b) involves addition of fumaric acid to the mixture of step (a). The fumaric acid may be added as solid or as a solution by dissolving in in any suitable solvent. Preferably the solvent is same as the solvent used in step (a).
The resulted mixture is stirred for about 10 minutes to about 10 hours at a temperature 0 °C to about 50 °C. The step (c) involves isolation of the crystalline Form SF1 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. The isolated solid may be dried under vacuum at about 30 °C to about 50 °C to obtain crystalline Form SF1 of Siponimod monofumarate.
In another aspect, the crystalline Form SF1 of Siponimod monofumarate is further characterized by a PXRD pattern comprising the peaks at about 7.0, 10.56, 13.52, 14.11, 17.82, and 21.35 ± 0.2° 2?.
In another aspect, the crystalline Form SF1 of Siponimod monofumarate is characterized by the PXRD pattern of Figure 3.
In another aspect, the present application provides a pharmaceutical composition comprising crystalline Form SF1 of Siponimod monofumarate of the present application and a pharmaceutically acceptable carrier.
In one aspect, the present application provides a crystalline Form S of Siponimod, characterized by a PXRD pattern comprising the peaks at about 6.95, 10.44, 12.12, 12.30, 17.09 and 22.11 ± 0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline Form S of Siponimod, comprising,
(a) adding Siponimod hemifumarate to hot glycerin,
(b) adding an alcohol solvent to the mixture of step (a), and
(c) isolating the crystalline Form S of Siponimod.
The step (a) involves addition of Siponimod hemifumarate into hot glycerin. Any physical form of Siponimod hemifumarate may be used as starting material. Glycerin may be heated to about 60 °C to about 100 °C. After adding the Siponimod hemifumarate into hot glycerin the mixture may be stirred for about 10 minutes to about 5 hours at about 60 °C to about 100 °C. The step (b) involves adding an alcohol solvent to the mixture of step (a). The alcohol solvent may selected form the comprising methanol, ethanol, isopropyl alcohol, tert-butyl alcohol and amyl alcohol. Preferably, the alcohol solvent is methanol. The resulted mixture may be stirred at 60 °C to get complete dissolution. After complete dissolution the mixture may be filtered to get rid of particulate matter.
The step (c) involves isolation of solid from the mixture. 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 is isolated by slow evaporation of the solvent. The isolated solid may be washed with a suitable solvent like methyl tert-butyl ether to obtain the crystalline Form S of Siponimod.
In another aspect, the crystalline Form S of Siponimod is further characterized by a PXRD pattern comprising the peaks at about 13.68, 13.93, 20.54, 23.59, 26.20 and 31.66 ± 0.2° 2?.
In another aspect, the crystalline Form S of Siponimod is characterized by the PXRD pattern of Figure 5.
In another aspect, the present application provides use of crystalline forms of S Siponimod base of the present invention in the preparation of pure Siponimod hemifumarate.
In another aspect, the present application provides pharmaceutical composition comprising crystalline Form S of Siponimod base 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 crystalline Form S of Siponimod base of the present application.
In another aspect, the present application provides Siponimod hemifumarate L-proline co-crystal
In another aspect, the present application provides a process for preparation of Siponimod hemifumarate L-proline co-crystal, comprising,
(a) providing a mixture of Siponimod base, fumaric acid and L-proline in a solvent or a mixture thereof,
(b) stirring and heating the mixture of step (a), and
(c) isolating the Siponimod hemifumarate L-proline co-crystal.
The step (a) involves mixing of Siponimod base, fumaric acid and L-proline with one or more solvents. Suitable solvent that can be used for mixing the Siponimod base, fumaric acid and L-proline include but are not limited to: alcohol solvents such as methanol, ethanol, isopropyl alcohol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; ethers such as diethyl ether, dimethyl ether, di-isopropyl ether, 1 ,4-dioxane and the like; and any mixtures of two or more thereof .In one aspect, the solvent is ethanol. Any physical form of Siponimod base may be used as starting material.
In step (b) the mixture is heated to about 60 °C and the mixture may be stirred for about 10 minutes to about 10 hours. The step (c) involves isolation of Siponimod hemifumarate L-proline co-crystal.
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 step (d) the isolated solid is dried under vacuum at about 25 ° C to about 40 °C to obtain Siponimod hemifumarate L-proline co-crystal.
In another aspect, the Siponimod hemifumarate L-proline co-crystal exhibits a crystalline character. The characteristic diffraction peaks of the crystalline Form of Siponimod hemifumarate L-proline co-crystal (Form SLP) are 8.48, 17.89, 19.00, 21.29 and 24.60 ± 0.2° 2?.
In another aspect, the crystalline Form of Siponimod hemifumarate L-proline co-crystal (Form SLP) is further characterized by a PXRD pattern comprising the peaks at about 6.91, 9.48, 11.25, 12.42 and 15.11 ± 0.2° 2?.
In another aspect, the crystalline Form of Siponimod hemifumarate L-proline co-crystal (Form SLP) is characterized by the PXRD pattern of Figure 4.
In another aspect, the present application provides use of the Siponimod hemifumarate L-proline co-crystal in the preparation of pure Siponimod hemifumarate.
In another aspect, the present application provides use of any of crystalline forms of Siponimod hemifumarate and Siponimod monofumarate of the present invention in the preparation of pure 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 and 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 hemifumarate or 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 SHF1 of Siponimod hemifumarate
Amorphous siponimod hemifumarate (2.0 g) and water (6 mL) were charged into a 25 mL vial. The mixture was heated to 50 °C and stirred for 7 hours. The suspension was filtered and the wet solid was suction dried for 2 hours to yield 2 g of crystalline Form SHF1 of Siponimod hemifumarate. PXRD as shown in Figure 1.
Example-2: Preparation of crystalline Form SHF1 of Siponimod hemifumarate
Siponimod hemifumarate (3.0 g) and water (120 mL) were charged into a 500 mL crystallization flask. The mixture was heated to 50 °C and stirred for 30 minutes. Acetonitrile (40 mL) was added to the mixture and heated to 75 °C and stirred for 30 minutes. The resulted solution was gradually cooled to 5 °C and stirred for 1 hour at 5 °C. The suspension was filtered and the wet solid was suction dried for 2 hours to yield 2 g of crystalline solid. The wet solid was divided into two portions as Part-A and part-B. The part-A portion was dried under ATD at 45 °C for 1 hour. The part-B portion was dried under VTD at 45 °C for 1 hour. PXRD of both the portions is same and is shown in Figure 1.
Example-3: Preparation of crystalline Form SHF2 of Siponimod hemifumarate
Amorphous siponimod hemifumarate (1.0 g) and 1,4-Dioxane (2 mL) were charged into a 10 mL vial and stirred for 10 hours. The suspension was filtered and the wet solid was dried under vacuum at 40 ° C to yield 0.75 g of crystalline Form SHF2 of Siponimod hemifumarate. PXRD as shown in Figure 2.
Example-4: Preparation of crystalline Form SHF2 of Siponimod hemifumarate
Siponimod hemifumarate (7.5 g) and 1,4-Dioxane (130 mL) were charged into a 500 mL crystallization flask and the mixture was heated to 75 °C and stirred for 15 minutes. The clear solution was filtered at 50 °C and quickly transferred into another crystallization flask. The solution was stirred for 15 minutes at 75 °C and gradually cooled to 25 °C over a period of 3 hours. The suspension was filtered and the wet solid was suction dried for 1 hour to yield 6.5 g of crystalline Form SHF2 of Siponimod hemifumarate. PXRD as shown in Figure 2.

Example-5: Preparation of crystalline Form SF1 of Siponimod monofumarate
Siponimod base (100 mg), fumaric acid (22 mg) and ethylformate (1 mL) were charged into a 5 mL vial and stirred for 10 hours. The suspension was filtered and the wet solid was dried under vacuum at 40 ° C to yield crystalline Form SF1 of Siponimod monofumarate. PXRD as shown in Figure 3.
Example-6: Preparation of Siponimod hemifumarate L-proline (1:1) co-crystal
Siponimod base (100 mg), fumaric acid (11 mg), L-proline (22.2 mg) and methanol (5 mL) were charged into a 25 mL vial and stirred for 30 minutes. The mixture was heated to 60 °C and stirred for 7 hours. The mixture was cooled to 25 °C and stirred for 8 hours. The suspension was filtered and the wet cake was washed with n-heptane (5 mL). The wet solid was dried under vacuum at 40 ° C to yield crystalline Siponimod hemifumarate L-proline complex (Form SLP). PXRD as shown in Figure 19.
Example-7: Preparation of crystalline Siponimod base Form S
Glycerin (20 mL) was added to a crystallization vessel and heated to 75 °C. Siponimod hemifumarate (500 mg) was added to the hot glycerin and stirred for 5 hours at 75 °C. Glycerin (10 mL) was added to the mixture and cooled to 65 °C and methanol (25 mL) was added and the mixture was stirred for 2 hours at 65 °C to get clear solution. The solution was cooled to 0 °C and stirred for 10 hours. The mixture was left two days for slow evaporation at 27 °C. The suspension was filtered under vacuum and sucked to dry at 27 °C. PXRD as shown in Figure 5.
Example-8: Preparation of crystalline Siponimod base Form S
Glycerin (225 mL) was added to a crystallization vessel and heated to 85 °C. Siponimod hemifumarate (5 g) was added to the hot glycerin and stirred for 1 hour at 85 °C. The mixture was cooled to 65 °C and methanol (150 mL) was added and the mixture was stirred for 2 hours at 65 °C. Glycerin (15 mL) and methanol (10 mL) were added to the mixture and stirred for 1 hour at 65 °C to get clear solution. The solution was cooled to 30 °C and transferred to another crystallization vessel. The mixture was left four days for slow evaporation at 27 °C. The suspension was filtered under vacuum and the wet material was washed with MTBE (150 mL) and sucked to dry at 27 °C. The wet material was washed again with MTBE (150 mL) and sucked to dry at 27 °C. The material was dried in VTD at 40 °C. PXRD matches with Figure 5.
,CLAIMS:CLAIMS
We claim
1. Crystalline Form SHF1 of Siponimod hemifumarate characterized by an X-ray powder diffraction pattern comprising the peak at about 7.52 ± 0.2° 2?.
2. The crystalline Form SHF1 of Siponimod hemifumarate of claim 1 is further characterized by an X-ray powder diffraction pattern comprising the peak at about 11.39, 12.51, 13.28, 14.31, 15.62 and 17.43 ± 0.2° 2?.
3. A process for the preparation of crystalline Form SHF1 of Siponimod hemifumarate, comprising,
(e) suspending Siponimod hemifumarate in water,
(f) heating the suspension of step (a),
(g) isolating the solid, and
(h) drying the solid to obtain crystalline Form SHF1 of Siponimod hemifumarate.
4. A process for the preparation of crystalline Form SHF1 of Siponimod hemifumarate, characterized by a PXRD pattern comprising the peak at about 7.52 ± 0.2° 2?, comprising:
(a) providing a mixture of Siponimod hemifumarate and water,
(b) heating the mixture of step (a),
(c) adding an organic solvent to the mixture, and
(d) isolating and drying the solid to obtain crystalline Form SHF1 of Siponimod hemifumarate.
5. The process according to claim 4, the organic solvent used in step (c) is selected from the group comprising acetonitrile acetone, THF, ethylacetate.
6. Crystalline Form SHF2 of Siponimod hemifumarate, characterized by an X-ray powder diffraction pattern comprising the peaks at about 5.38 and 8.13 ± 0.2° 2?.
7. The crystalline Form SHF2 of Siponimod hemifumarate of claim 6 is further characterized by an X-ray powder diffraction pattern comprising the peak at about 10.89, 13.67, 14.98, 16.45, 19.23, 20.65, 22.13 and 23.19 ± 0.2° 2?.
8. A process for the preparation of crystalline Form SHF2 of Siponimod hemifumarate, comprising,
(d) providing a mixture of Siponimod hemifumarate and 1,4-dioxane,
(e) stirring the mixture of step (a), and
(f) isolating the crystalline Form SHF2 of Siponimod hemifumarate.
9. A pharmaceutical composition comprising crystalline form SHF1 of Siponimod hemifumarate characterized by an X-ray powder diffraction pattern comprising the peak at about 7.52 ± 0.2° 2? and at least one pharmaceutically acceptable carrier.
10. A pharmaceutical composition comprising crystalline form SHF2 characterized by an X-ray powder diffraction pattern comprising the peaks at about 5.38 and 8.13 ± 0.2° 2? of Siponimod hemifumarate and at least one pharmaceutically acceptable carrier.
11. Crystalline Form SF1 of Siponimod monofumarate, characterized by a PXRD pattern comprising the peaks at about 11.62, 12.24, 13.52 and 16.70 ± 0.2° 2?.
12. A process for the preparation of crystalline Form SF1 of Siponimod monofumarate, comprising,
(d) providing a mixture of Siponimod base and an organic solvent,
(e) adding fumaric acid to the mixture of step (a), and
(f) isolating the crystalline Form SF1 of Siponimod monofumarate.
13. Crystalline Form S of siponimod base, characterized by a PXRD pattern comprising the peaks at about 6.95, 10.44, 12.12, 12.30, 17.09 and 22.11 ± 0.2° 2?.
14. The crystalline Form S of Siponimod base of claim 13 is further characterized by a PXRD pattern comprising the peaks at about 13.68, 13.93, 20.54, 23.59, 26.20 and 31.66 ± 0.2° 2?.
15. A process for the preparation of crystalline Form S of Siponimod, comprising,
(d) adding Siponimod hemifumarate to hot glycerin,
(e) adding an alcohol solvent to the mixture of step (a), and
(f) isolating the crystalline Form S of Siponimod.
16. A pharmaceutical composition comprising crystalline Form S of Siponimod base characterized by a PXRD pattern comprising the peaks at about 13.68, 13.93, 20.54, 23.59, 26.20 and 31.66 ± 0.2° 2? and one or more pharmaceutically acceptable excipients.