DESC:RELATED APPLICATION:
This application claims the benefit of the earlier filing date of Indian Provisional Patent Application No. 201921016502 filed on Apr. 25, 2019
FIELD OF THE INVENTION
The present application provides solid forms of Siponimod and 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.
US 7,939,519 discloses Siponimod and a process for the preparation thereof. US 8,173,634 discloses Siponimod polymorph form A. US2018/0118678 discloses a process of preparation of Siponimod and the hemifumarate 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 having better stability, desired solubility, less hygroscopicity and preparation thereof, which is commercially viable.
SUMMARY OF THE INVENTION
Provided herein is an amorphous form of Siponimod and process of preparation thereof.
Also, provided herein is a solid dispersion of Siponimod, comprising Siponimod and one or more pharmaceutically acceptable carrier and process of preparation thereof.
Further provided herein is a pharmaceutical composition, comprising a therapeutically effective amount of a solid form of Siponimod obtained according to present application, and at least one pharmaceutically acceptable excipient thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig 1 shows the X-ray powder diffractogram ("PXRD") pattern of amorphous form of Siponimod.
Fig 2 shows the X-ray powder diffractogram ("PXRD") pattern of solid dispersion of Siponimod and hydroxy propyl cellulose.
DETAILED DESCRIPTION OF THE INVENTION
Provided herein is an amorphous form of Siponimod.
The amorphous form of Siponimod is characterized by powder X-ray diffraction (PXRD) substantially as illustrated in fig 1.
Provided herein is a process for preparing amorphous form of Siponimod, comprising the steps of:
a) providing a solution of Siponimod in a solvent or a mixture of two or more solvents;
b) removing solvent from the solution of Siponimod obtained in step a); and
c) isolating amorphous form of Siponimod.
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 a suitable solvent or a mixture of solvents.
The suitable techniques in step b) 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.
The isolation of amorphous form of Siponimod can be carried out by employing any of the techniques known in the art. Techniques for the isolation of amorphous form of Siponimod include, but not limited to: decantation, filtration by gravity or suction, evaporation of the solvent, concentrating the solution centrifugation, and the like, and optionally washing with a solvent.
Also, provided herein is a process for preparing amorphous form of Siponimod, by dissolving the Siponimod in a suitable solvent in which it is soluble followed by adding the solution containing Siponimod in to an anti-solvent in which Siponimod is insoluble or vice-versa.
Further, provided herein is a process for preparing amorphous form of Siponimod, the process comprising steps of
a) dissolving Siponimod in a solvent either acidic or basic condition;
b) adjusting pH of the solution of step a); and
c) isolating amorphous form of Siphonimod
The base used for dissolution or pH adjustment is selected from organic or inorganic base like alkali carbonates, alkali hydroxides or alkali bicarbonates, triethyl amine, pyridine or like and acid used for dissolution or pH adjustment is selected from inorganic acid such as HCl, HBr, formic acid, phosphoric acid. The pH can be adjusted using acid or base or buffer solution.
The pH of the solution is adjusted to 4.5 to 7.5 to isolate the amorphous form of Siponimod.
Further, provided herein is a solid dispersion of Siponimod comprising Siponimod and one or more pharmaceutically acceptable carrier.
Provided herein a process for preparing an solid dispersion comprising Siponimod and one or more pharmaceutically acceptable carriers, the process comprising
a) providing a solution comprising Siponimod and one or more pharmaceutically acceptable excipients;
b) removing solvent from the solution obtained in step (a); and
c) isolating an solid dispersion comprising Siponimod and one or more pharmaceutically acceptable excipient.
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 and pharmaceutically acceptable carrier in a suitable solvent or a mixture of solvents.
The pharmaceutically acceptable excipient in step (a) include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, Polyethylene glycol, copovidone, soluplus, silicified microcrystalline cellulose mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones such as polyvinylpyrrolidone K-30 (PVP K-30), hydroxypropyl celluloses, Klucel-LF, hydroxypropyl methylcelluloses such as HPMC, HPMC-Phthalate, HPMC-AS, HPMC-15 CPS; Kollidon-VA64 (vinylpyrrolidone-vinyl acetate copolymer); pregelatinized starches and the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, syloid and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide 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.
Suitable techniques which can be used for the removal of solvent include but not limited to evaporation, flash evaporation, simple evaporation, rotational drying such as drying using a rotavapor, spray drying, agitated thin-film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze drying, filtration or any other technique known in the art. The solid dispersion can also prepared by technique like hot-melt extrusion, the hot-melt extrusion is preferably carried out in the absence of solvent.
Also, provided herein is a complex of siponimod and a co-former.
The co-former can be any pharmaceutically acceptable coformer known in the art. In one embodiment, the coformer is oxalic acid, glycolic acid, propionic acid, carbonic acid, succinic acid, maleic acid, benzoic acid or resorcinol. Further the coformer is selected from acetylsalicylic acid, D-glucose, nicotinic acid, aconitic acid, L-glutamic acid, adipic acid, glutaric acid, L-proline, 4-aminosalicylic acid, glycine, propyl gallate, L-pyroglutamic acid, hippuric acid, saccharin, (+)-camphoric acid, 1-hydroxy-2-naphthoic acid, salicylic acid, capric acid, ketoglutaric acid, sebacic acid, cinnamic acid, L-lysine, sodium lauryl sulfate, magnesium bromide, sorbic acid, cyclamic acid, ethyl maltol, L-malic acid, L-tartaric acid, malonic acid, urea, D-fructose, maltol, vanillic acid, fumaric acid, D,L-mandelic acid, vanillin, gallic acid, gentisic acid.
The ratio of API to coformer may be stoichiometric or non-stoichiometric. In one embodiment, the ratio of API to coformer is about 5:1, 4:1, 3:1, 2.5:1, 2:1, 1.5:1, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:4, or 1:5.
Provided herein is a process of preparation of complex comprising Siponimod and a co-former; the process involves:
a. contacting Siponimod with co-former in suitable solvent; or milling or
grinding an Siponimod and a co-former with or without solvent; and
b. isolating complex.
The complex may be isolated by employing one or more techniques selected from the group consisting of filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization. The recovered solid may optionally be dried. Drying may 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 may be carried out at temperatures less than about 100° C., less than about 80° C., less than about 60° C., less than about 50° C., less than about 30° C., or any other suitable temperatures, at atmospheric pressure or under a reduced pressure, as long as the compound is not degraded in quality. The drying may be carried out for any desired times until the required product quality is achieved. The dried product may optionally be subjected to a size reduction procedure to produce desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller and hammer milling, and jet milling.
The suitable solvent and anti-solvent that can be used include but are not limited to: alcohol solvents such as methanol, ethanol, isopropyl alcohol, n-propanol, 2-butanol and the like; halogenated hydrocarbons such as dichloromethane, 1 ,2-dichloroethane, 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; hydrocarbons such as toluene, xylene and the like; nitriles such as acetonitrile, propionitrile and the like; water, dimethyl formamide, dimethylacetamide and dimethylsulfoxide, and any mixtures of two or more thereof.
Still further, provided herein is a pharmaceutical composition, comprising a therapeutically effective amount of a solid form of Siponimod obtained according to present application, 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.
Provided herein a method of treating multiple sclerosis comprising administering a pharmaceutical composition comprising, Siponimod or polymorphic forms thereof prepared by the processes of the present application and one or more pharmaceutically acceptable excipient.
The D10, D50, and D90 values are useful ways for indicating a particle size distribution. D90 refers to the value for the particle size for which at least 90 volume percent of the particles have a size smaller than the value. Likewise D50 and D10 refer to the values for the particle size for which 50 volume percent, and 10 volume percent, of the particles have a size smaller than the value. Methods for determining D10, D50 and D90 include laser diffraction, such as using Malvern Instruments Ltd. (of Malvern) equipment.
Siponimod obtained according to the process described herein or after performing size reduction operations such as milling or micronization, has a particle size distribution pattern of D10 less than or equal to about 150 µm, D50 less than or equal to about 300 µm, and D90 less than or equal to about 500 µm. There is no specific lower limit for any of the D values.
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.
Wherever applicable in the example of the present invention, the reaction solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure. The solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
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: Preparation of amorphous Siponimod
Siponimod (1.0 g) dissolved in methanol (10 mL) and stirred for 10 minutes at 25°C. The methanol was evaporated under vacuum at 55°C to obtain the amorphous Siponimod (1.0 g).
Example 2: Preparation of solid dispersion of Siponimod and Syloid
Siponimod (0.5 g), Syloid (0.25 g) in methanol (33 mL) was heated to 65°C for 20 minutes. The resulting clear solution was distilled under vacuum at 60-65°C to obtain the solid dispersion of Siponimod and Syloid (0.50 g).
Example 3: Preparation of solid dispersion of Siponimod and PVP K-30
Siponimod (0.5 g), PVP K-30 (0.5 g) in methanol (33 mL) was heated to 65°C for 20 minutes. The resulting clear solution was distilled under vacuum at 60-65°C to obtain the solid dispersion of Siponimod and PVP K-30 (0.71 g).
Example 4: Preparation of solid dispersion of Siponimod and Klucel LF
Siponimod (0.5 g), Klucel LF (0.5 g), acetone (50 mL) in methanol (50 mL) was heated to 65°C for 20 minutes. The resulting clear solution was spray dried in a lab spary drier model to obtain the solid dispersion of Siponimod and Klucel LF (0.72 g).
Example 5: Preparation of solid dispersion of Siponimod and hydroxy propyl cellulose
Siponimod (0.5 g), hydroxy propyl cellulose (L-HPC) (0.5 g) in a mixture of acetone (100 mL) and methanol (10 mL) was heated to 55°C for 20 minutes followed by distillation of solvent under vacuum at 55-60°C to obtain the Siponimod and hydroxy propyl cellulose (0.75 g).
Example 6: Preparation of amorphous Siponimod
To Siponimod (0.5 g) in water (25 mL) 10% aqueous solution of sodium hydroxide (25 mL) was added to adjust pH of the mixture to 11-12 and stirred. Then pH was adjusted to 6-7 using 10% aqueous hydrochloric acid (20 mL) and stirred, filtered and dried to obtain the amorphous Siponimod.
Example 7: Preparation of amorphous Siponimod
To Siponimod (1 g) in water (5 mL), 10% aqueous solution of sodium hydroxide (5 mL) was added to adjust pH to more than 10 and stirred for 30 minutes. Then pH was adjsuted to 6-8 using 20% aqueous hydrochloric acid solution (15.2 mL) and stirred, filtered and dried to obtain the amorphous Siponimod.
Example 8: Preparation of amorphous Siponimod
To Siponimod (1 g) and water (5 mL), 10% aqueous solution of ammonium hydroxide (5 mL) was added to adjust pH to more than 10 and stirred. Then pH was adjusted to 6-8 using 20% aqueous hydrochloric acid solution (7.5 mL) and stirred, filtered and dried the wet material to obtain the amorphous Siponimod.
Example 9: Preparation of amorphous Siponimod
To Siponimod (1 g) in water (5 mL), 10% aqueous solution of sodium carbonate (5 mL) was added to adjust pH to more than 10 and stirred. Then pH was adjusted to 6-8 using 20% aqueous hydrochloric acid solution (5 mL) and stirred, filtered and dried the wet material to obtain the amorphous Siponimod.
Example 10: Preparation of amorphous Siponimod
To Siponimod (1 g) in water (5 mL), 10% aqueous solution of potassium carbonate (5 ml) was added to adjust pH to more than 10 and stirred. Then pH was adjusted to 6-8 using 20% aqueous hydrochloric acid solution (4 mL) and stirred. Filtered and dried the wet material to obtain the amorphous Siponimod.
,CLAIMS:Claims:
We claim
1. A process for preparing amorphous form of Siponimod, comprising the steps of:
a) providing a solution of Siponimod in a solvent or a mixture of two or more solvents;
b) removing solvent from the solution of Siponimod obtained in step a); and
c) isolating amorphous form of Siponimod.
2. The process as claimed in claim 1, wherein the solvent is selected from the group of methanol, ethanol, isopropyl alcohol, n-propanol, dichloromethane, 1 ,2-dichloroethane, acetone, ethyl methyl ketone, methyl isobutyl ketone, ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate, diethyl ether, dimethyl ether, di-isopropyl ether, 1 ,4-dioxane, toluene, acetonitrile, propionitrile, water, dimethyl formamide, dimethylacetamide and dimethylsulfoxide, and any mixtures of two or more thereof.
3. A process for preparing amorphous form of Siponimod, the process comprising steps of:
a) dissolving Siponimod in a solvent either acidic or basic condition;
b) adjusting pH of the solution of step a); and
c) isolating amorphous form of Siponimod
4. The process as claimed in claim 3, wherein the solvent is water.
5. The process as claimed in claim 3, wherein in step a) or b) the base used for dissolution or pH adjustment is selected from the group of sodium carbonate, ammonium hydroxide, sodium hydroxide, triethyl amine, pyridine: and the acid used for dissolution or pH adjustment is selected from group of HCl, HBr, formic acid and phosphoric acid.
6. The process as claimed in claim 3, wherein in step b) the pH is adjusted using acid or base or buffer solution and the pH of the solution is adjusted to 4.5 to 7.5 to isolate the amorphous form of Siponimod.
7. A process for preparing an solid dispersion comprising Siponimod and one or more pharmaceutically acceptable carriers, the process comprising
a) providing a solution comprising Siponimod and one or more pharmaceutically acceptable excipients;
b) removing solvent from the solution obtained in step (a); and
c) isolating an solid dispersion comprising Siponimod and one or more pharmaceutically acceptable excipient.
8. The process as claimed in claim 7, wherein the pharmaceutically acceptable excipient is one or more selected form the group of lactose, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, Polyethylene glycol, copovidone, soluplus, mannitol, sorbitol, acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidone K-30 (PVP K-30), hydroxypropyl celluloses, Klucel-LF, HPMC, HPMC-Phthalate, HPMC-AS, HPMC-15 CPS; Kollidon-VA64, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, syloid, stearic acid, magnesium stearate, zinc stearate, colloidal silicon dioxide, cyclodextrins, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses or methyl methacrylates.