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 and amorphous solid forms of Siponimod, 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, 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.

SUMMARY OF THE INVENTION
Aspects of the present application relate to novel solid state forms of Siponimod, their preparative processes and pharmaceutical compositions thereof.
In one aspect, the present application provides a crystalline Form SMA1 of Siponimod, characterized by a PXRD pattern comprising a peak at 17.85 ± 0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline Form SMA1 of Siponimod, comprising,
(a) providing a mixture of Siponimod, malic acid and a solvent,
(b) stirring the mixture of step (a), and
(c) isolating the crystalline Form SMA1 of Siponimod.
In another aspect, the present application provides a crystalline Form SME1 of Siponimod, characterized by a PXRD pattern comprising the peaks at about 3.64, 15.56, 16.57, 19.44 and 22.00 ± 0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline Form SME1 of Siponimod, comprising,
(a) providing a mixture of Siponimod, maleic acid and a solvent,
(b) stirring the mixture of step (a), and
(c) isolating the crystalline Form SME1 of Siponimod.
In another aspect, the present application provides amorphous form of Siponimod.
In another aspect, the present application provides a process for preparing amorphous form of Siponimod, which comprises;
a) providing a solution of a pharmaceutically acceptable salt or a co-crystal of Siponimod in a solvent;
b) adding a base to the solution obtained in step (a); and
c) isolating amorphous form of Siponimod.
In another aspect, the present application provides a process for preparing amorphous form of Siponimod, comprising,
a) providing a solution of Siponimod in a solvent or a mixture of solvents;
b) removing solvent from the solution of Siponimod obtained in step a); and
c) recovering amorphous form of Siponimod.
In another aspect, the present application provides use of the crystalline forms of Siponimod to improve the purity of Siponimod and its salts.
In another aspect, the present application provides a pharmaceutical composition comprising any of the crystalline forms of Siponimod of the present application and at least one pharmaceutically acceptable carrier.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is powder X-ray diffraction ("PXRD") pattern of crystalline form SMA1 of Siponimod prepared according to Example 1.
Figure 2 is powder X-ray diffraction pattern of crystalline form SME1 of Siponimod prepared according to Example 2.
Figure 3 is powder X-ray diffraction pattern of amorphous form of Siponimod prepared according to Example 3.
Figure 4 is powder X-ray diffraction pattern of amorphous form of Siponimod prepared according to Example 5.

DETAILED DESCRITPION
Aspects of the present application relate to novel crystalline solid forms of Siponimod, their preparative processes and pharmaceutical compositions thereof. The present application also encompasses the use of novel crystalline solid forms of Siponimod provided herein, for the preparation of other solid forms of Siponimod and its salts, for the purification of Siponimod fumaric acid co-crystal and for the preparation of pharmaceutical dosage forms.
In one aspect, the present application provides a crystalline Form SMA1 of Siponimod, characterized by a PXRD pattern comprising the peak at about 17.85 ± 0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline Form SMA1 of Siponimod, comprising,
(a) providing a mixture of Siponimod, malic acid and a solvent,
(b) stirring the mixture of step (a), and
(c) isolating the crystalline Form SMA1 of Siponimod.
The step (a) involves providing a mixture of Siponimod, malic acid and a suitable solvent. Siponimod may be prepared by the process described in the art or may be prepared by the process described in this application. The malic acid is D,L-malic acid and is used in 1:1 mole ratio with respect to Siponimod. The solvent may be taken in the ratio of 1:10 to 1:50 w/v with respect to Siponimod. The step (b) involves stirring the mixture of step (a) for about an hour to about 50 hours at above 30 °C.
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 filtration. The isolated solid may be washed with a suitable solvent to obtain the crystalline Form SMA1 of Siponimod.
In another aspect, the crystalline Form SMA1 of Siponimod is further characterized by a PXRD pattern comprising the peaks at about 6.72, 11.49, 16.04, 20.27, 21.77 and 24.10 ± 0.2° 2?.
In another aspect, the crystalline Form SMA1 of Siponimod is characterized by the PXRD pattern of Figure 1.
The crystalline Form SMA1 of Siponimod is a complex of Siponimod and Malic acid in 1:1 w/w. The crystalline Form SMA1 of Siponimod may exist as a co-crystal of Siponimod and Malic acid in 1:1 w/w.
In another aspect, the present application provides a crystalline Form SME1 of Siponimod, characterized by a PXRD pattern comprising the peaks at about 3.64, 15.56, 16.57, 19.44 and 22.00 ± 0.2° 2?.
In another aspect, the present application provides a process for the preparation of crystalline Form SME1 of Siponimod, comprising,
(a) providing a mixture of Siponimod, maleic acid and a solvent,
(b) stirring the mixture of step (a), and
(c) isolating the crystalline Form SME1 of Siponimod.
The step (a) involves providing a mixture of Siponimod, maleic acid and a suitable solvent. Siponimod may be prepared by the process described in the art or may be prepared by the process described in this application. The maleic acid is used in 1:1 mole ratio with respect to Siponimod. The solvent may be taken in the ratio of 1:10 to 1:50 w/v with respect to Siponimod. The step (b) involves stirring the mixture of step (a) for about an hour to about 50 hours at above 30 °C.
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 filtration. The isolated solid may be washed with a suitable solvent to obtain the crystalline Form SME1 of Siponimod.
In another embodiment, the crystalline Form SME1 of Siponimod is further characterized by a PXRD pattern comprising the peaks at about 7.29, 8.28 and 24.27 ± 0.2° 2?.
In another aspect, the crystalline Form SME1 of Siponimod is characterized by the PXRD pattern of Figure 2.
In another aspect, the present application provides amorphous form of Siponimod.
In another aspect, the present application provides a process for preparing amorphous form of Siponimod, which comprises;
(a) providing a solution of pharmaceutically acceptable salt or a co-crystal of Siponimod in a solvent;
(b) adding a base to the solution obtained in step (a); and
(c) isolating amorphous form of Siponimod.
The Siponimod salt or the co-crystal used as the input in the process for preparation of amorphous form of Siponimod of the present application can be prepared by any process known in the art or the process described in this application.
Providing a solution of Siponimod salt in step a) includes direct use of a reaction mixture containing Siponimod salt or siponimod co-crystal that is obtained in the course of its synthesis; or dissolving Siponimod salt or siponimod co-crystal in a suitable solvent.
In one aspect the siponimod salt or the co-crystal is formed with the acid or co-former selected from the group comprising fumaric acid, maleic acid, malic acid, tartaric acid, oxalic acid, acetic acid and hydrochloric acid.
Suitable solvents which can be used for dissolving Siponimod salt or co-crystal include but are not limited to ethyl acetate, dichloromethane, water and the like; and any mixtures of two or more thereof.
After dissolution in step (a), the obtained solution may optionally be filtered to remove any insoluble particles. Suitable techniques to remove insoluble particles are filtration, centrifugation, decantation, and any other known techniques in the art. The solution can be filtered by passing through paper, glass fiber, or other membrane material, or a clarifying agent such as Celite. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature precipitation of solid.
Step (b) involves adding a suitable base to the solution obtained in step (a). The base is selected form the group comprising lithium hydroxide, sodium hydroxide, sodium carbonate, sodium bicarbonate and ammonia.
Step (c) involves isolating the amorphous form of Siponimod. The isolation of amorphous form of Siponimod may be carried out by employing any of the techniques known to a person skilled in art. Techniques for the isolation of amorphous form of Siponimod include, but not limited to: decantation, filtration by gravity or suction, centrifugation, and the like, and optionally washing with a solvent.
The resulting compound in step (c) may optionally be further dried. Drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the Siponimod is not degraded in its quality. The drying can be carried out for any desired times until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours.
In another aspect, the present application provides a process for preparing amorphous form of Siponimod, which comprises;
(a) providing a solution of Siponimod in a solvent or a mixture of solvents;
(b) removing the solvent from the solution of Siponimod obtained in step a); and
(c) recovering amorphous form of Siponimod.
Siponimod used as the input in the process for preparation of amorphous form of siponimod of the present application can be prepared by any process known in the art or the process described in this application.
Providing a solution of Siponimod in step a) includes direct use of a reaction mixture containing Siponimod that is obtained in the course of its synthesis; or dissolving Siponimod in a suitable solvent.
Any physical form of Siponimod may be utilized for providing the solution of step a).
Suitable solvents which can be used for dissolving Siponimod include but are not limited to methanol, ethanol, isopropanol, ethyl acetate, dichloromethane and any mixtures of two or more thereof.
After dissolution in step (a), the obtained solution may optionally be filtered to remove any insoluble particles. Suitable techniques to remove insoluble particles are filtration, centrifugation, decantation, and any other known techniques in the art. The solution can be filtered by passing through paper, glass fiber, or other membrane material, or a clarifying agent such as Celite. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature precipitation of solid.
Step (b) involves removal of the solvent form the solution obtained in step (a). Suitable techniques which can be used for the removal of solvent include but not limited to evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, agitated thin-film drying, Rotary vacuum paddle dryer, agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying or any other suitable technique known in the art. The drying may be carried at normal pressure or under reduced pressure.
Step (c) involves recovering an amorphous form of Siponimod. The said recovery can be done by using the processes known in the art.
In an embodiment, the isolation of amorphous form of Siponimod may be carried out by employing any of the techniques known to a person skilled in art. Techniques for the isolation of amorphous form of Siponimod include, but not limited to: decantation, filtration by gravity or suction, centrifugation, and the like, and optionally washing with a solvent.
The resulting compound in step (c) may optionally be further dried. Drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the Siponimod is not degraded in its quality. The drying can be carried out for any desired times until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours.
In another aspect, the present application provides amorphous form of Siponimod characterized by powder X-ray diffraction (PXRD) substantially as illustrated in Figure 3.
In another aspect, the present application provides stable amorphous Siponimod. The amorphous Siponimod of the present application is stable for at least one year. The amorphous Siponimod prepared by the process of the present application is kept in a freezer at about 5 °C. After one year the solid was analyzed using PXRD. The solid remains in amorphous form and the PXRD pattern is shown in Figure 4.
In another aspect, the present application provides pharmaceutical composition comprising amorphous Siponimod and one or more pharmaceutically acceptable excipients.
In another aspect, the present application provides use of any of crystalline forms of Siponimod of the present invention in the purification of Siponimod or its salts and in the preparation of other crystalline forms of Siponimod.
In another aspect, the present application provides pharmaceutical composition comprising any of crystalline forms of Siponimod 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 of the present application, or a pharmaceutical composition comprising any of crystalline forms of Siponimod 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 SMA1 of Siponimod
Siponimod crystalline Form S2 (415 mg), D,L-Malic acid (106 mg) and acetonitrile (6 mL) were charged into a crystallization vial. The mixture was stirred for 44 hours at 30 °C. The slurry was filtered under vacuum and the solid material was characterized using PXRD.
PXRD as shown in Figure 1.
Example-2: Preparation of crystalline Form SME1 of Siponimod
Siponimod crystalline Form S2 (415 mg), Maleic acid (92 mg) and acetonitrile (6 mL) were charged into a crystallization vial. The mixture was stirred for 44 hours at 30 °C. The slurry was filtered under vacuum and the solid material was characterized using PXRD.
PXRD as shown in Figure 2.

Example-3: Preparation of amorphous form of Siponimod
Siponimod hemifumarate (88 g), ethylacetate (880 mL) and water (880 mL) were charged into a round bottom flask. The mixture was stirred for 10 minutes at 28 °C and pH of the mixture was adjusted to 6.5 using aqueous sodium bicarbonate. The resulted mixture was stirred for 20 minutes and layers separated. The aqueous layer was extracted with ethylacetate (2 × 440 mL). Organic layers were combined and washed with water (520 mL). The organic layer was dried over sodium sulphate and concentrated under vacuum at 50 °C. Dichloromethane (520 mL) was added to the residue and stirred for 10 minutes. The DCM layer was concentrated under vacuum at 40 °C to yield 57.2 g of off-white foamy solid. Purity: 98.75%.
PXRD as shown in Figure 3.

Example-4: Preparation of amorphous form of Siponimod
Siponimod (50 g) and Dichloromethane (400 mL) were charged into round bottom flask and stirred for 10 minutes. The clear solution was filtered through a celite bed and the bed was washed with Dichloromethane (50 mL). The filtrate was concentrated under vacuum at 40 °C to yield 43.5 g of off-white solid. Purity: 98.85%.
PXRD as shown in Figure 3.

Example-5: Stability of amorphous form of Siponimod
The amorphous form of siponimod prepared in example-3 was kept in an amber colored glass bottle at 2-8 °C for one year and the solid was analyzed using PXRD.
PXRD as shown in Figure 7.
,CLAIMS:We claim
1. Crystalline Form SMA1 of Siponimod characterized by a PXRD pattern comprising the peak at about 17.85 ± 0.2° 2?.
2. The crystalline Form SMA1 of Siponimod of claim 1 is characterized by the PXRD pattern of Figure 1.
3. A process for preparation of crystalline Form SMA1 of Siponimod, comprising,
(a) providing a mixture of Siponimod, malic acid and a solvent,
(b) stirring the mixture of step (a), and
(c) isolating the crystalline Form SMA1 of Siponimod.
4. The process according to claim 3, the malic acid used in step (a) is D,L-malic acid.
5. Amorphous form of Siponimod.
6. The amorphous form of Siponimod of claim 5 is characterized by the PXRD pattern of Figure 3.
7. A process for preparation of amorphous form of Siponimod, which comprises;
(a) providing a solution of pharmaceutically acceptable salt or a co-crystal of Siponimod in a solvent;
(b) adding a base to the solution obtained in step (a); and
(c) isolating amorphous form of Siponimod.
8. A process for preparing amorphous form of Siponimod, comprising,
(a) providing a solution of Siponimod in a solvent or a mixture of solvents;
(b) removing solvent from the solution of Siponimod obtained in step a); and
(c) recovering amorphous form of Siponimod.
9. A pharmaceutical composition comprising crystalline Form SMA1 of Siponimod characterized by a PXRD pattern comprising the peak at about 17.85 ± 0.2° 2?, and one or more pharmaceutically acceptable excipients.
10. A pharmaceutical composition comprising amorphous form of Siponimod and one or more pharmaceutically acceptable excipients.