DESC:RELATED APPLICATION
This application claims the benefit of the earlier filing date of Indian Provisional Patent Application number 201821040743 filed on Oct. 29, 2018.
FIELD OF THE INVENTION
The present invention relates to solid forms of Siponimod or its hemifumarate and its process of preparation thereof.
BACKGROUND OF THE INVENTION
Siponimod hemifumarate, has a chemical name 1-{4-[(1E)-N-{[4-cyclohexyl-3-(trifluoromethyl)benzyl]oxy}]-2-ethylbenzyl}-3-azetidinecarboxylic acid, (E)-but-2-enedioic acid. Siponimod hemifumarate is represented by the following chemical structure according to Formula (I).

Formula I
Siponimod hemifumarate is a selective modulator of S1P1 and S1P5 receptors, allowing S1P1 receptor-dependent modulation of lymphocyte traffic without producing S1P3 receptor-mediated effects.
US7,939,519 discloses Siponimod and a process for the preparation thereof. US2018/0118678 discloses a process of preparation of Siponimod and the hemifumarate salt thereof; further US’678 patent discloses A, B, C, D and E solid forms of Siponimod hemifumarate.
In pharmaceutical dosage forms such as tablets, the conversion of one polymorphic form into another polymorphic form can be unfavourable, and results in different dissolution, hygroscopicity, and pharmacokinetic properties. Thereby, the bioavailability of the active agent might be undesirably unpredictable due to polymorphic conversion. Therefore, active agents having different interchangeable polymorphs may lead to regulatory and commercial disadvantages. Consequently, there is a need to develop a solid form of Siponimod and its hemifumarate having better stability, desired solubility, less hygroscopicity and preparation thereof, which is commercially viable.
SUMMARY OF THE INVENTION
An aspect of the present invention is to provide novel crystalline solid forms such as Form AL-1 and Form AL-2 of Siponimod hemifumarate and process of preparation thereof.
Another aspect of the present invention is to provide amorphous form of Siponimod hemifumarate and process of preparation thereof.
Another aspect of the present invention is to provide novel crystalline solid form such as Form B of Siponimod and process of preparation thereof.
Still another aspect of the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a solid form of Siponimod hemifumarate obtained according to present invention, and at least one pharmaceutically acceptable excipient thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig 1 shows the X-ray powder diffractogram ("PXRD") pattern of Form AL-1 of Siponimod hemifumarate.
Fig 2 shows the X-ray powder diffractogram ("PXRD") pattern of Form AL-2 of Siponimod hemifumarate.
Fig 3 shows the X-ray powder diffractogram ("PXRD") pattern of amorphous form of Siponimod hemifumarate.
Fig 4 shows the X-ray powder diffractogram ("PXRD") pattern of Form B of Siponimod.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect the present invention relates to novel crystalline solid forms of Siponimod hemifumarate.
The present invention relates to novel solid form AL-1 of Siponimod hemifumarate.
In an embodiment of the invention, crystalline solid form AL-1 of Siponimod hemifumarate is characterized by having at least one or more 2-theta peak(s) (XRPD) selected from the 11.42, 17.57, 19.53, 21.08 and 23.29.
In another embodiment of the invention, crystalline solid form AL-1 of Siponimod hemifumarate is characterized by having at least one or more 2-theta peak(s) (XRPD) selected from the 3.7, 7.62, 11.42, 11.51, 12.58, 13.33, 14.49, 15.61, 17.08, 17.57, 19.53, 21.08, 21.98, 23.29, 25.22 and 26.95.
In an embodiment of the invention, a novel crystalline form AL-1 of Siponimod hemifumarate having PXRD peaks as shown in Fig-1.
In yet another embodiment of the invention, the invention relates to a process of preparation of novel crystalline form AL-1 of Siponimod hemifumarate comprising;
a. providing solution of Siponimod hemifumarate in a one or more solvent;
b. optionally adding antisolvent and
c. isolating crystalline solid form AL-1 of Siponimod hemifumarate; and
d. drying the solid of step (b).
In yet another embodiment of the invention, suitable solvent used in step (a) of Form AL-1 preparation is selected from solvent consisting of N,N-dimethyl formamide, N,N-dimethyl sulfoxide, N,N-dimethyl acetamide and N-methyl pyrolidone and the anti-solvent used in step (b) selected from a solvent in which the solid form AL-1 is poorly soluble and preferably selected from water.
The present invention relates to novel solid form AL-2 of Siponimod hemifumarate.
In an embodiment of the invention, crystalline solid form AL-2 of Siponimod hemifumarate is characterized by having at least one or more 2-theta peak(s) (XRPD) selected from the 10.68, 17.22, 18.86, 21.46 and 23.76.
In an embodiment of the invention, crystalline solid form AL-2 of Siponimod hemifumarate is characterized by having at least one or more 2-theta peak(s) (XRPD) selected from the 5.6, 7.10, 8.60, 10.68, 11.51, 11.80, 12.59, 12.84, 13.50, 14.25, 15.57, 16.14, 16.55, 17.22, 18.86, 18.98, 19.26, 19.78, 20.60, 21.46, 22.24, 23.05, 23.76, 24.31, 25.09, 25.83, 26.81, 28.80, 29.72, 32.02 and 33.35
In an embodiment of the invention, a novel crystalline form AL-2 of Siponimod hemifumarate having PXRD peaks as shown in Fig-2.
In another embodiment of the invention, the invention relates to a process of preparation of novel crystalline form AL-2 of Siponimod hemifumarate comprising;
a. providing solution of Siponimod hemifumarate in a one or more solvent;
b. optionally adding antisolvent and
c. isolating crystalline solid form AL-2 of Siponimod hemifumarate.
In yet another embodiment of the invention, suitable solvent used in step (a) of Form AL-2 preparation is selected from solvent consisting of N,N-dimethyl formamide, N,N-dimethyl sulfoxide, N,N-dimethyl acetamide and N-methyl pyrolidone and the anti-solvent used in step (b) selected from a solvent in which the solid form AL-2 is poorly soluble and preferably selected from water.
In some embodiments of the present invention, the Siponimod hemifumarate used in step (a) for the preparation Form AL-1 or Form AL-2, can be obtained by the known methods that include direct use of a reaction mixture containing Siponimod and fumaric acid or Siponimod hemifumarate that is obtained in the course of its synthesis, or a solid form obtained by following any of the known process.
In some embodiments of the present invention, the step (a) for preparing Form AL-1 or Form AL-2, involves dissolving Siponimod hemifumarate in suitable solvent or dissolving Siponimod base in suitable solvent, and then adding fumaric acid solution prepared by dissolving in suitable solvent, if required involves stirring, heating and the combination thereof.
In some embodiments of the present invention, clear solution obtained in step (a) may be optionally seeded with required crystalline form to promote nucleation.
In some embodiment of the present invention, the isolation step (b) is performed by removing the solvent from the solution. Removal of solvent is accomplished by, for example, filtering the solid, substantially complete evaporation of the solvent, concentrating the solution and filtering the solid.
In some embodiments of the invention, Form AL-1 can be obtained by drying Form AL-2.
The present invention relates to the novel solid form of Siponimod hemifumarate is amorphous form.
In another embodiment of the invention, amorphous form is substantially pure without any crystalline peak.
In an embodiment of the invention, amorphous form of Siponimod hemifumarate having PXRD peaks as shown in Fig-3.
In another embodiment of the invention, invention relates to a process of preparation of amorphous Siponimod hemifumarate comprising the steps of:
a. heating Siponimod hemifumarate to melt optionally under vacuum; and
b. cooling the melted Siponimod hemifumarate obtained in step (a), so as to provide amorphous Siponimod hemifumarate..
In another embodiment of the invention, invention relates to a process of preparation of amorphous Siponimod hemifumarate comprising:
a. providing solution of Siponimod hemifumarate in a one or more solvent; and
b. isolating pure amorphous form of Siponimod hemifumarate.
In yet another embodiment of the invention, the solvent used in step (a) is selected from any solvent that can dissolve Siponimod hemifumarate in room temperature or at high temperature and the isolation of amorphous may be effected by removal of the solvent, the removal of solvent comprises is effected by distillation, distillation under vacuum, spray drying, agitated thin film dyring ("ATFD"), fluid bed drying, tray drying and the like or by freeze drying (lyophilization).
Alternatively, the isolation of amorphous form can be effected by addition of an anti-solvent to the solution obtain in step a).
In an embodiment of the invention, the present invention provides solid dispersion comprising amorphous form of Siponimod hemifumarate and at least one pharmaceutically acceptable excipient or carriers or polymers.
In another embodiment of the invention, the invention relates to a process for preparation of a composition comprising Siponimod hemifumarate which process comprises melting Siponimod hemifumarate together with at least one suitable excipient. A process according to above wherein the composition comprises amorphous Siponimod hemifumarate.
In another embodiment of the invention, the invention relates to a process for preparation of Siponimod hemifumarate solid dispersion comprising the steps of
a. providing a solution of Siponimod hemifumarate in a suitable solvent;
b. adding suitable excipients or carriers or polymers; and
c. removing the solvents.
In yet another embodiment of the invention, the solvent used in step (a) is selected from any solvent that can dissolve Siponimod hemifumarate in room temperature or at high temperature and the isolation of amorphous solid dispersion may be effected by removal of the solvent, the removal of solvent comprises is effected by distillation, distillation under vacuum, spray drying, agitated thin film dyring ("ATFD"), fluid bed drying, tray drying and the like or by freeze drying (lyophilization).
In some embodiments of the invention, non-limiting examples of suitable carriers or polymers or excipients are celluloses (e.g., carboxymethylcelluloses, methylcelluloses, hydroxypropylcelluloses, hydroxypropylmethylcelluloses); polysaccharides, hetero-polysaccharides (pectins); poloxamers; poloxamines; ethylene vinyl acetates; polyethylene glycols; dextrans; polyvinylpyrrolidones; chitosans; polyvinylalcohols; propylene glycols; polyvinylacetates; phosphatidylcholines (lecithins); miglyols; polylactic acid; polyhydroxybutyric acid; mixtures of two or more thereof, copolymers thereof, derivatives thereof, and the like. Further examples of carriers include copolymer systems such as polyethylene glycol-polylactic acid (PEG-PLA), polyethylene glycol-polyhydroxy butyric acid (PEG-PHB), polyvinylpyrrolidone polyvinylalcohol (PVP-PVA), carbopol, and derivatized copolymers such as copolymers of N-vinyl purine (or pyrimidine) derivatives and N-vinylpyrrolidone.
An enteric coating polymer can also be used according to the present
invention. Specific examples of the enteric coating polymers include cellulose
acetate phthalate, cellulose acetate trimellitate, cellulose acetate succinate,
hydroxymethylcellulose ethyl phthalate, hydroxypropylmethylcellulose phthalate,
eudragit, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethyl
acetate maleate, hydroxypropylmethyl trimellitate, carboxymethylethylcellulose,
polyvinyl butyrate phthalate, polyvinyl alcohol acetate phthalate, methacrylic
acid/ethyl acrylate copolymer, and methacrylic acid/methyl methacrylate copolymer, hydroxypropyl methylcellulose phthalate, hydroxypropylmethyl celluloseacetate succinate, hydroxypropylmethyl acetate maleate and hydroxypropylmethyl trimellitate.
Suitable pharmaceutically acceptable carriers or polymers or excipients that are dispersing agents which can be used in step (b) include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starches and the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc
stearate and the like; glidants such as colloidal silicon dioxide (Syloid, Aerosil, Cabo-sil etc.) and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but are not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, and the like.
Alternatively, the isolation of amorphous form can be effected by addition of an anti-solvent to the solution obtain in step c).
In some embodiments of the present invention, the anti-solvents described herein comprises one or more of hydrocarbons selected from hexanes, n-heptane, n-pentane, cyclohexane, and methylcyclohexane; aromatic hydrocarbons selected from toluene, xylene, and ethylbenzene; ethers selected diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,4-dioxane, and 2-methoxy ethanol.
In some embodiments of the invention, the excipients or pharmaceutically acceptable excipients includes but not limited to diluents, lubricants, disintegrants, glidants, stabilizers & surface active agents or mixtures thereof.
The present invention relates to novel solid form B of Siponimod.
In an embodiment of the invention, crystalline solid form B of Siponimod is characterized by having at least one or more 2-theta peak(s) (XRPD) selected from the 12.07, 17.69, 20.16, 21.45 and 23.73.
In another embodiment of the invention, crystalline solid form B of Siponimod is characterized by having at least one or more 2-theta peak(s) (XRPD) selected from the 4.01, 8.04, 9.57, 10.31, 11.60, 12.07, 13.53, 13.75, 14.01, 14.61, 15.46, 15.85, 16.21, 16.98, 17.69, 18.29, 19.23, 19.55, 20.16, 20.78, 21.45, 22.67, 23.22, 23.73, 24.05, 24.78, 25.76, 26.63, 27.22, 27.75, 28.20, 29.51, 32.23, 32.54, 35.45 and 37.36.
In an embodiment of the invention, a novel crystalline form B of Siponimod hemifumarate having PXRD peaks as shown in Fig-4.
In another embodiment of the invention, the invention relates to an improved process of preparation of crystalline Form B of Siponimod.
Another aspect of the invention relates to a process of preparation of form B of Siponimod comprising
a. providing Siponimod in a suitable solvent; and
b. isolating crystalline solid form B of Siponimod.
In an embodiment of the invention, providing a solution 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 suitable solvent. Any physical form of Siponimod may be utilized for providing the solution of Siponimod in step (i); if required involves stirring, heating and the combination thereof.
In an embodiment of the present invention, the step (a) involves dissolving Siponimod in a suitable solvent, if needed involves stirring, heating and the combination thereof.
In an embodiment of the present invention, clear solution obtained in step (a) may be optionally seeded with required crystalline form to promote nucleation.
In some embodiments of the present invention, the suitable solvent used in present invention, is/are selected from but not limited to water, propylene carbonate, paracymin, toluene and xylene or mixtures thereof.
In an embodiment of the present invention, the isolation step (b) is performed by any methods such as cooling, filtration or combination thereof.
In an embodiment of the present invention, the isolation step (b) further comprises optionally washing with a suitable solvent and drying.
The X-ray powder diffraction (XRPD) spectrum according to the present invention was measured on a PANalytical X'Pert PRO X- Ray Diffractometer. The parameters of the X-ray powder diffraction method of the present invention were as follows:
X-ray Reflection: Cu, Ka
Ka1 (Å): 1.54060; Ka2 (Å): 1.54443
Ka2 / Ka1 intensity ratio: 0.50
Voltage: 45 (kV), Current: 40 (mA)
Scan range: from 2.5084 degree to 40.0 degree.
In an embodiment of the invention, the novel solid forms of Siponimod hemifumarate according to the present invention includes pure crystalline forms, amorphous form, mixture of crystalline forms, or mixture of crystalline and amorphous forms.
In an embodiment of the invention, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a solid form of Siponimod hemifumarate obtained according to present invention, and at least one pharmaceutically acceptable carrier, diluent, vehicle or excipient thereof.
The “at least one pharmaceutically acceptable carrier, diluent, vehicle or excipient” can readily be selected by one of ordinary skill in the art and will be determined by the desired mode of administration.
In an embodiment of the invention, the present invention relates to a pharmaceutical composition according to present invention can be used for preparing drugs for treating a disease which responds to inhibition of S1P1 and S1P5 receptors.
The invention is further exemplified by the following non-limiting examples, which are illustrative representing the preferred modes of carrying out the invention. The invention's scope is not limited to these specific embodiments only but should be read in conjunction with what is disclosed anywhere else in the specification together with those information and knowledge which are within the general understanding of the person skilled in the art.

Examples
Example 1: Process of preparation of form AL-2 of Siponimod hemifumarate
To N,N-Dimethylsulfoxide (14 mL) , Siponimod hemifumarate (2 g) was added and heated to 50°C to get clear solution. Solution was cooled to 25±3°C followed by addition of water (50 mL) at 25±3°C and was stirred it for 20 hours, the obtained solid was filtered. Wet cake was washed with water (10 mL) followed by drying the material at 50°C in ATD to get 1.54 g of Siponimod hemifumarate.
Example 2: Process of preparation of form AL-2 of Siponimod hemifumarate
To N,N-Dimethylsulfoxide (3.5mL) , Siponimod hemifumarate (0.5 g) was added and heated to 80-85°C followed by addition of water (12.5 mL) at 80-85°C. The reaction mass was stirred at 80-85°C for 1 hour. Gradually cooled to 25±3°C and stirred for 15 hours, the obtained solid was filtered. Wet cake was dried in ATD to get Siponimod hemifumarate.
Example 3: Process of preparation of form AL-1 of Siponimod hemifumarate
To N,N-Dimethylsulfoxide (1.5mL) , Siponimod hemifumarate (0.5 g) was added and heated to 60-65°C followed by addition of water (7.5 mL) at 60-65°C and was stirred it for 15 hours, the obtained solid was filtered. Wet cake was dried in ATD for 5 hours followed by drying at 60°C under vacuum for 14 hours to get Siponimod hemifumarate
Example 4: Process of preparation of form AL-1 of Siponimod hemifumarate
Form AL-2 dried at 65°C under vacuum for 12 hours to get the Siponimod hemifumarate Form AL-2.
Example 5: Process of preparation of form B of Siponimod
Mixture of Siponimod free base and water (10 mL) heated to 50°C for 1 hour and cooled to 25±3°C. Stirred the material for 1 hour followed by filtration and drying to get Siponimod Form B.

Example 6: Process of preparation of amorphous form of Siponimod hemifumarate
Siponimod hemifumarate (5.0gm) was heated at 150oC till it melts. Cooled to obtain amorphous form of Siponimod hemifumarate
,CLAIMS:1. A crystalline Form B of Siponimod.
2. The crystalline Form B of Siponimod as claimed claim 1, having an X-ray
powder diffractogram comprising peak at diffraction of 2-theta angle selected
from 12.07± 0.2°, 17.69± 0.2°, 20.16± 0.2°, 21.45 ± 0.2°, and 23.73± 0.2°.
3. A process for preparing crystalline Form B of Siponimod comprising step of:
a. providing Siponimod in a suitable solvent; and
b. isolating crystalline solid form B of Siponimod.
4. The process claimed in claim 3, the suitable solvent in step (a) is selected
from the group comprising of water, propylene carbonate, paracymin, toluene
and xylene or mixtures thereof.
5. A process for preparing crystalline Form B of Siponimod comprising step of:
a. mixing Siponimod with water; and
b. isolating crystalline solid form B of Siponimod