DESC:
FIELD OF THE INVENTION
The present application relates to novel salts of Siponimod, crystalline forms thereof, pharmaceutical compositions comprising them, and methods of preparing said Siponimod salts and said crystalline forms 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.
US patent No. 8,486,930 B2 (US ‘930) describes Siponimod hydrochloride, Siponimod malate, Siponimod oxalate, and Siponimod tartrate salts and pharmaceutical compositions containing them.
New salts, new polymorphic forms and solvates of a pharmaceutical product can provide materials having better pharmacological activity, 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 salts or polymorphic forms. For at least theses reasons there remains a need to provide commercially viable and advantageous salts and polymorphic forms of siponimod and pharmaceutical compositions thereof.

SUMMARY OF THE INVENTION
The present application generally relates to novel salts of Siponimod, their crystalline forms, and pharmaceutical compositions containing them.
In one aspect, the present application provides, Siponimod di p-Toluolyl-L-tartrate, Siponimod dibenzoyl-D-tartrate, and Siponimod isethionate.
The present application further provides crystalline forms of Siponimod di p-Toluolyl-L-tartrate, Siponimod dibenzoyl-D-tartrate, and Siponimod isethionate, processes for preparing them, and pharmaceutical compositions containing them.
The present application further provides use of these salts and their crystalline forms for the preparation of Siponimod free base, Siponimod hemifumarate, other slats of Siponimod and solid state forms thereof.
The present application further provides pharmaceutical compositions comprising any one, or a combination thereof , the above described Siponimod salts and crystalline forms, and at least one pharmaceutically acceptable excipient.
The present application further provides the use of any one of the above described salts and crystalline forms for the treatment of multiple sclerosis, polymyositis, and dermatomyositis.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is powder X-ray diffraction ("PXRD") pattern of Siponimod di-p-Toluolyl-L-tartrate prepared according to Example 1.
Figure 2 is powder X-ray diffraction pattern of Siponimod di-benzoyl-D-tartrate prepared according to Example 2.
Figure 3 is powder X-ray diffraction pattern of Siponimod isethionate prepared according to Example 3.

DETAILED DESCRIPTION
The present application relates to novel salts of Siponimod, their crystalline forms, and pharmaceutical compositions containing them.
In a first aspect, the present application provides di-p-Toluolyl-L-tartaric acid salt of Siponimod. The di-p-Toluolyl-L-tartaric acid salt of Siponimod may exist in a crystalline form.
In a further aspect, the present application provides crystalline Form A of di-p-Toluolyl-L-tartaric acid salt of Siponimod. The crystalline Form A of di p-Toluolyl-L-tartaric acid salt of Siponimod is characterized in that it provides an X-ray powder diffraction pattern substantially as shown in FIG. 1.
In a further aspect, the present application provides crystalline Form A of di-p-Toluolyl-L-tartaric acid salt of Siponimod, wherein said crystalline Form A is characterized by X-ray powder diffraction pattern comprising the peaks at about 16.76°, 17.80°, 18.21° and 19.88° ± 0.2° 2?.
In a further aspect, the present application provides di-benzoyl-D-tartaric acid salt of Siponimod. The di-benzoyl-D-tartaric acid salt of Siponimod may exist in a crystalline form.
In a further aspect, the present application provides crystalline Form A of di-benzoyl-D-tartaric acid salt of Siponimod. The crystalline Form A of di-benzoyl-D-tartaric acid salt of Siponimod is characterized in that it provides an X-ray powder diffraction pattern substantially as shown in FIG. 2.
In a further aspect, the present application provides crystalline Form A of di-benzoyl-D-tartaric acid salt of Siponimod, wherein said crystalline Form A is characterized by X-ray powder diffraction pattern comprising the peaks at about 12.77°, 14.01°, 17.57°, 19.84° and 20.31° ± 0.2° 2?.
In a further aspect, the present application provides isethionic acid salt of Siponimod. The isethionic acid salt of Siponimod may exist in a crystalline form.
In a further aspect, the present application provides crystalline Form A of isethionic acid salt of Siponimod. The crystalline Form A of isethionic acid salt of Siponimod is characterized in that it provides an X-ray powder diffraction pattern substantially as shown in FIG. 3.
In a further aspect, the present application provides crystalline Form A of isethionic acid salt of Siponimod, wherein said crystalline Form A is characterized by X-ray powder diffraction pattern comprising the peaks at about 13.32°, 16.33°, 16.75°, 17.84°, 20.06° and 22.30° ± 0.2° 2?.
The crystalline forms of the salts of Siponimod described herein possess beneficial pharmaceutical properties that make them possible candidates for pharmaceutical development.
According to a further aspect of the application, there is provided a method of preparing a salt of Siponimod, including a crystalline form thereof, as defined herein, said method comprising the step of reacting the Siponimod free base with the corresponding acid in the presence of a suitable solvent or mixture of solvents.
In a specific aspect, the present application provides a method of preparing di-p-Toluolyl-L-tartaric acid salt of Siponimod, including crystalline Form A thereof, as defined herein, said method comprising the step of reacting Siponimod free base with di-p-Toluolyl-L-tartaric acid in the presence of a suitable solvent.
In a further aspect, the present application provides a method of preparing di-benzoyl-D-tartaric acid salt of Siponimod, including crystalline Form A thereof, as defined herein, said method comprising the step of reacting Siponimod free base with di-benzoyl-D-tartaric acid in the presence of a suitable solvent.
In a further aspect, the present application provides a method of preparing isethionic acid salt of Siponimod, including crystalline Form A thereof, as defined herein, said method comprising the step of reacting Siponimod free base with isethionic acid in the presence of a suitable solvent.
Any suitable solvent or mixture of solvents may be used to form the salts of Siponimod and their crystalline forms thereof defined herein.
A person skilled in the art will be able to select appropriate reaction times and conditions for carrying out the salt formation reaction.
Suitably, the Siponimod free base is dissolved together with the corresponding acid in a suitable solvent (such as those described in the accompanying examples). Alternatively, a solution of Siponimod free base may be dissolved in a suitable solvent and mixed with a solution of the corresponding acid (which is dissolved in either the same or a compatible solvent). Suitably, the solution is stirred to facilitate mixing of the Siponimod free base and the corresponding acid. The solution may be mixed at ambient temperature although the procedure may also be performed at higher temperatures.
The salts of Siponimod and their crystalline forms defined herein may be isolated by concentrating the reaction mixture and stirring the residue in a suitable solvent and isolating the salts by a known method such as filtration.
Alternatively, the salts of Siponimod and their crystalline forms defined herein may be isolated using techniques which are well known to those skilled in the art, for example decanting, filtering or centrifuging. Suitably, the salt is collected by filtration.
The method may additionally comprise the further step of washing the salt of Siponimod with a suitable solvent; and drying the salt. Preferably the washed salt is dried under vacuum.
The Siponimod salts of the present application can also be isolated as amorphous solids by known methods such as concentration of the reaction mixture, spray drying of the reaction mixture and lyophilization of the reaction mixture.
In a further aspect, the present application provides a pharmaceutical composition, comprising a salt of Siponimod or a crystalline form thereof, optionally with one or more pharmaceutically acceptable excipients.
In a further aspect, the present application provides the use of salts of Siponimod and crystalline forms thereof described herein for the preparation of Siponimod free base, other Siponimod salts and solid state forms thereof by converting the salt of Siponimod or a crystalline form of the present application into another salt of Siponimod or a solid state form thereof.
In a further aspect, the present application provides the use of salts of Siponimod and crystalline forms thereof described herein for the preparation of Siponimod hemifumarate by converting the salt of Siponimod or a crystalline form of the present application into Siponimod hemifumarate or a solid state form thereof.
The present application further provides the use of any one of the above described salts and crystalline forms for the treatment of multiple sclerosis, polymyositis, and dermatomyositis.
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 Siponimod hemifumarate solid dispersion of the present invention, or a pharmaceutical composition comprising the Siponimod hemifumarate solid dispersion 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.
Celite is flux-calcined diatomaceous earth. Hyflo is flux-calcined diatomaceous earth treated with sodium carbonate.
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 Di-p-toluolyl-L-tartaric acid salt of Siponimod
Siponimod (2.0 g) and ethanol (20 mL) were charged into a 250 mL round bottom flask at 25 °C. Di-p-toluolyl-L-tartaric acid (1.497 g) was added at 25 °C and the mixture was stirred for 20 minutes. The reaction mixture was concentrated under reduced pressure at 45 °C. To the residue acetonitrile (40 mL) was charged and the mixture was stirred at 25 °C for 6 hours. The precipitation was filtered and the solid was washed with acetonitrile (10 mL). The solid was dried in a hot air oven at 50 °C to yield 2.80 g of crystalline Siponimod Di-p-toluolyl-L-tartrate.
PXRD pattern: Figure 1. Purity: 98.8% by HPLC.
Example-2: Preparation of Di-benzoyl-D-tartaric acid salt of Siponimod
Siponimod (2.0 g) and ethanol (20 mL) were charged into a 250 mL round bottom flask at 25 °C. Di-Benzoyl-D-tartaric acid (1.388 g) was added at 25 °C and the mixture was stirred for 20 minutes. The reaction mixture was concentrated under reduced pressure at 45 °C. To the residue acetonitrile (40 mL) was charged and the mixture was stirred at 25 °C for 6 hours. The precipitation was filtered and the solid was washed with acetonitrile (10 mL). The solid was dried in a hot air oven at 40 °C to yield 2.70 g of crystalline Siponimod Di-Benzoyl-D-tartrate.
PXRD pattern: Figure 2. Purity: 97.0% by HPLC.
Example-3: Preparation of Isethionic acid salt of Siponimod
Siponimod (2.0 g) and ethanol (20 mL) were charged into a 250 mL round bottom flask at 25 °C. Isethionic acid (0.488 g) was added at 25 °C and the mixture was stirred for 20 minutes. The reaction mixture was concentrated under reduced pressure at 45 °C. To the residue acetonitrile (40 mL) was charged and the mixture was stirred for at 25 °C for 6 hours. The mixture was concentrated under reduced pressure at 45 °C. To the residue ethylacetate (40 mL) was charged and the mixture was stirred at 25 °C for 6 hours. The precipitation was filtered and the solid was dried under vacuum at 25 °C to yield 1.50 g of crystalline Siponimod isethionate. PXRD pattern: Figure 3. Purity: 98.2% by HPLC.
,CLAIMS:CLAIMS
We claim
1. Siponimod di p-Toluolyl-L-tartrate.
2. Crystalline Form A of Siponimod di p-Toluolyl-L-tartrate, characterized by an X-ray powder diffraction pattern comprising the peaks at about 16.76, 17.80, 18.21 and 19.88 ± 0.2° 2?.
3. A pharmaceutical composition comprising Siponimod di p-Toluolyl-L-tartrate and at least one pharmaceutically acceptable excipient.
4. Siponimod dibenzoyl-D-tartrate.
5. Crystalline Form A of Siponimod dibenzoyl-D-tartrate, characterized by an X-ray powder diffraction pattern comprising the peaks at about 12.77, 14.01, 17.57, 19.84 and 20.31 ± 0.2° 2?.
6. A pharmaceutical composition comprising Siponimod dibenzoyl-D-tartrate and at least one pharmaceutically acceptable excipient.
7. Siponimod isethionate.
8. Crystalline Form A of Siponimod isethionate, characterized by an X-ray powder diffraction pattern comprising the peaks at about 13.32, 16.33, 16.75, 17.84, 20.06 and 22.30 ± 0.2° 2?.
9. A pharmaceutical composition comprising Siponimod isethionate and at least one pharmaceutically acceptable excipient.