WO2020161632A1 - Crystalline solid forms of siponimod - Google Patents
Crystalline solid forms of siponimod Download PDFInfo
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- WO2020161632A1 WO2020161632A1 PCT/IB2020/050909 IB2020050909W WO2020161632A1 WO 2020161632 A1 WO2020161632 A1 WO 2020161632A1 IB 2020050909 W IB2020050909 W IB 2020050909W WO 2020161632 A1 WO2020161632 A1 WO 2020161632A1
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- WIPO (PCT)
- Prior art keywords
- siponimod
- crystalline form
- sfm2
- sfm1
- crystalline
- Prior art date
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
Definitions
- 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 present application provides a crystalline Form SFM1 of Siponimod, characterized by a PXRD pattern comprising the peaks at about 3.31, 6.57, 13.14, 19.78, 23.10 and 26.46 ⁇ 0.2° 2Q.
- 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 hemifumarate and for the preparation of pharmaceutical dosage forms.
- the present application provides a crystalline Form SFM1 of Siponimod, characterized by a PXRD pattern comprising the peaks at about 3.31, 6.57, 13.14, 19.78, 23.10 and 26.46 ⁇ 0.2° 2Q.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present application provides novel polymorphic forms of siponimod, their processes, their use in purification of other crystalline polymorphic forms of siponimod, and pharmaceutical compositions containing them. The present application specifically provides crystalline Form SFM1 and Form SFM2 of siponimod, their preparative methods, their use in purification of other crystalline forms of siponimod and pharmaceutical compositions containing novel polymorphic forms of siponimod.
Description
CRYSTALLINE SOLID FORMS OF SIPONIMOD
FIELD OF THE INVENTION
The present application relates to crystalline solid forms of Siponimod, their preparative methods and pharmaceutical compositions thereof.
BACKGROUND OF THE INVENTION
The dmg compound having the adopted name Siponimod, has a chemical name (E)-l-(4- (l-(((4-cyclohexyl-3-(trifluoromethyl)benzyl)oxy)-imino)ethyl)-2-ethylbenzyl)-azetidine-3- carboxylic acid, and is represented by the stmcture of formula I.
Siponimod is a selective sphingo sine -1 -phosphate receptor modulator dmg approved in USA for the treatment 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.
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 hemifumarate.
SUMMARY OF THE INVENTION
Aspects of the present application relate to novel crystalline forms of Siponimod, its preparative processes and pharmaceutical compositions thereof.
In one aspect, the present application provides a crystalline Form SFM1 of Siponimod, characterized by a PXRD pattern comprising the peaks at about 3.31, 6.57, 13.14, 19.78, 23.10 and 26.46 ± 0.2° 2Q.
In another aspect, the present application provides a process for the preparation of crystalline Form SFM1 of Siponimod, comprising,
(a) providing a mixture of Siponimod hemifumarate, maleic acid in methanol,
(b) heating the mixture of step (a) at above 50 °C, and
(c) isolating the crystalline Form SFM1 of Siponimod.
In another aspect, the present application provides a crystalline Form SFM2 of Siponimod, characterized by a PXRD pattern comprising the peaks at about 13.12, 18.76, 22.69 and 24.63 ± 0.2° 20.
In another aspect, the present application provides a process for the preparation of crystalline Form SFM2 of Siponimod, comprising,
(a) providing a mixture of Siponimod hemifumarate, maleic acid and acetonitrile,
(b) heating the mixture of step (a) to above 50 °C, and
(c) isolating the crystalline Form SFM2 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 and at least one pharmaceutically acceptable carrier.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is powder X-ray diffraction ("PXRD") pattern of crystalline form SFM1 of Siponimod prepared according to Example 1.
Figure 2 is powder X-ray diffraction pattern of crystalline form SFM2 of Siponimod prepared according to Example 2.
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 hemifumarate and for the preparation of pharmaceutical dosage forms.
In one aspect, the present application provides a crystalline Form SFM1 of Siponimod, characterized by a PXRD pattern comprising the peaks at about 3.31, 6.57, 13.14, 19.78, 23.10 and 26.46 ± 0.2° 2Q.
In another aspect, the present application provides a process for the preparation of crystalline Form SFM1 of Siponimod, comprising,
(a) providing a mixture of Siponimod hemifumarate, maleic acid in methanol,
(b) heating the mixture of step (a) at above 50 °C, and
(c) isolating the crystalline Form SFM1 of Siponimod.
The step (a) involves providing a mixture of Siponimod hemifumarate maleic acid and methanol. Methanol may be taken in the ratio of 1 :10 to 1 :50 w/v with respect to siponimod hemifumarate. Any physical form of Siponimod hemifumarate may be used as starting material. The step (b) involves heating the mixture of step (a) to above 50 °C. The mixture is heated to
get complete dissolution. After complete dissolution the mixture may be filtered to get rid of particulate matter. The clear solution may be stirred for about 10 minutes to about 20 hours.
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 methanol to obtain the crystalline Form SFM1 of Siponimod.
In another aspect, the crystalline Form SFM1 of Siponimod is a complex of Siponimod, fumaric acid and maleic acid.
In another aspect, the crystalline Form SFM1 of Siponimod is a complex of Siponimod, fumaric acid and maleic acid in the ratio of 1 :0.5 :0.5 w/w. The fumaric acid content in the crystalline Form SFM1 of Siponimod is 1 :0.5 w/w with respect to siponimod, and the maleic acid content in the crystalline Form SFM1 of Siponimod is 1 :0.5 w/w with respect to siponimod.
In another aspect, the crystalline Form SFM1 of Siponimod is a complex of Siponimod, fumaric acid and maleic acid in the ratio of 1 : 1 : 1 w/w. The fumaric acid content in the crystalline Form SFM1 of Siponimod is 1 :1 w/w with respect to siponimod, and the maleic acid content in the crystalline Form SFM1 of Siponimod is 1 : 1 w/w with respect to siponimod.
In another aspect, the crystalline Form SFM1 of Siponimod is further characterized by a PXRD pattern comprising the peaks at about 9.86, 10.37, 16.50, 17.95 and 20.82 ± 0.2° 20.
In another aspect, the crystalline Form SFM1 of Siponimod is characterized by the PXRD pattern of Figure 1.
In another aspect, the present application provides a crystalline Form SFM2 of Siponimod, characterized by a PXRD pattern comprising the peaks at about 13.12, 18.76, 22.69 and 24.63 ± 0.2° 20.
In another aspect, the present application provides a process for the preparation of crystalline Form SFM2 of Siponimod, comprising,
(a) providing a mixture of Siponimod hemifumarate, maleic acid and acetonitrile,
(b) heating the mixture of step (a) to above 50 °C, and
(c) isolating the crystalline Form SFM2 of Siponimod.
The step (a) involves providing a mixture of Siponimod hemifumarate, maleic acid and acetonitrile. The Acetonitrile solvent may be taken in the ratio of 1 : 10 to 1 : 100 w/v with respect to siponimod hemifumarate. Any physical form of Siponimod hemifumarate may be used as
starting material. The step (b) involves heating the mixture of step (a) to above 50 °C. The mixture is heated to get complete dissolution. After complete dissolution the mixture may be filtered to get rid of particulate matter. The clear solution may be stirred for about 10 minutes to about 20 hours.
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 acetonitrile to obtain the crystalline Form SFM2 of Siponimod.
In another aspect, the crystalline Form SFM2 of Siponimod is a complex of Siponimod, fumaric acid and maleic acid.
In another aspect, the crystalline Form SFM2 of Siponimod is a complex of Siponimod, fumaric acid and maleic acid in the ratio of 1 :0.5 :0.5 w/w. The fumaric acid content in the crystalline Form SFM2 of Siponimod is 1 :0.5 w/w with respect to siponimod, and the maleic acid content in the crystalline Form SFM2 of Siponimod is 1 :0.5 w/w with respect to siponimod.
In another aspect, the crystalline Form SFM2 of Siponimod is a complex of Siponimod, fumaric acid and maleic acid in the ratio of 1 : 1 : 1 w/w. The fumaric acid content in the crystalline Form SFM2 of Siponimod is 1 :1 w/w with respect to siponimod, and the maleic acid content in the crystalline Form SFM2 of Siponimod is 1 : 1 w/w with respect to siponimod.
In another embodiment, the crystalline Form SFM2 of Siponimod is further characterized by a PXRD pattern comprising the peaks at about 7.31, 17.09, 17.35, 17.65 and 22.09 ± 0.2° 20.
In another aspect, the crystalline Form SFM2 of Siponimod is characterized by the PXRD pattern of Figure 2.
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 constmed 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 constmed 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 instmment 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 constmed 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 SFM1 of Siponimod
Siponimod hemifumarate (2 g), Maleic acid (0.4 g) and methanol (80 mL) were charged into a rotavapor flask. The mixture was heated to 60-65 °C and stirred for 15 minutes. The clear solution was then filtered through a whatman filter paper. The solution was then kept at room temperature for slow evaporation of the solvent. After 6 days the solid formed was filtered to obtain 1.9 g of crystalline Form SFM1 of Siponimod. PXRD as shown in Figure 1.
The crystalline Form SFM1 is found to be a complex of Siponimod, fumaric acid and maleic acid in the ratio of 1 :0.5:0.5 w/w/w.
Example-2: Preparation of crystalline Form SFM2 of Siponimod
Siponimod hemifumarate (0.5 g), Maleic acid (0.1 g) and Acetonitrile (50 mL) were charged into a test tube flask. The mixture was heated to 90 °C, a hazy solution was obtained. The solution was then kept at room temperature for slow evaporation of the solvent. After 17 days the solid formed was filtered to obtain 0.35 g of crystalline Form SFM2 of Siponimod. PXRD as shown in Figure 2.
Claims
1. A crystalline Form SFM1 of siponimod, characterized by a PXRD pattern comprising the peaks at about 3.31, 6.57, 13.14, 19.78, 23.10, and 26.46 ± 0.2° 2Q.
2. The crystalline Form SFM1 of siponimod of claim 1 is a complex of Siponimod, fumaric acid and maleic acid.
3. The crystalline Form SFM1 of siponimod of claim 1 or claim 2 is a complex of Siponimod, fumaric acid and maleic acid in the ratio of 1 :0.5:0.5 w/w/w.
4. The crystalline Form SFM1 of siponimod of claim 1 is further characterized by a PXRD pattern comprising the peaks at about 9.86, 10.37, 16.50, 17.95 and 20.82 ± 0.2° 2Q.
5. The crystalline Form SFM1 of siponimod of claim 1 is characterized by a PXRD pattern substantially as depicted in Figure 1.
6. A process for preparation of crystalline Form SFM1 of siponimod of claim 1 , comprising:
(a) providing a mixture of siponimod hemifumarate, maleic acid in methanol,
(b) heating the mixture of step (a) at above 50 °C, and
(c) isolating the crystalline Form SFM1 of siponimod.
7. A pharmaceutical composition comprising crystalline Form SFM 1 of siponimod of claim 1, and at least one pharmaceutically acceptable carrier.
8. A crystalline Form SFM2 of siponimod, characterized by a PXRD pattern comprising the peaks at about 13.12, 18.76, 22.69 and 24.63 ± 0.2° 2Q.
9. The crystalline Form SFM2 of siponimod of claim 8 is a complex of Siponimod, fumaric acid and maleic acid.
10. The crystalline Form SFM2 of siponimod of claim 8 or claim 9 is a complex of Siponimod, fumaric acid and maleic acid in the ration of 1 :0.5:0.5 w/w/w.
11. The crystalline Form SFM2 of siponimod of claim 8 or claim 9 is a complex of Siponimod, fumaric acid and maleic acid in the ration of 1 : 1 : 1 w/w/w.
12. The crystalline Form SFM2 of siponimod of claim 8 is further characterized by a PXRD pattern comprising the peaks at about 7.31, 17.09, 17.35, 17.65 and 22.09 ± 0.2° 20.
13. The crystalline Form SFM2 of siponimod of claim 8 is characterized by a PXRD pattern substantially as depicted in Figure 2.
14. A process for preparation of crystalline Form SFM2 of siponimod of claim 6, comprising:
(a) providing a mixture of siponimod hemifumarate, maleic acid in acetonitrile,
(b) heating the mixture of step (a) at above 50 °C, and
(c) isolating the crystalline Form SFM2 of siponimod.
15. A pharmaceutical composition comprising crystalline Form SFM 2 of siponimod of claim 6, and at least one pharmaceutically acceptable carrier.
16. Use of crystalline Form SFM1 of siponimod of claims 1 to 5 in the purification of siponimod and its crystalline forms thereof.
17. Use of crystalline Form SFM2 of siponimod of claims 8 to 13 in the purification of siponimod and its crystalline forms thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN201941004818 | 2019-02-07 | ||
| IN201941004818 | 2019-02-07 |
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| WO2020161632A1 true WO2020161632A1 (en) | 2020-08-13 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11673860B2 (en) | 2018-01-22 | 2023-06-13 | Teva Pharmaceuticals International Gmbh | Crystalline siponimod fumaric acid and polymorphs thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010080409A1 (en) * | 2008-12-18 | 2010-07-15 | Novartis Ag | Hemifumarate salt of 1- [4- [1- ( 4 -cyclohexyl-3 -trifluoromethyl-benzyloxyimino ) -ethyl] -2 -ethyl-benzyl] -a zetidine-3-carboxylic acid |
| WO2013113915A1 (en) * | 2012-02-03 | 2013-08-08 | Novartis Ag | Process for preparing n-(4-cyclohexyl-3-trifluoromethyl-benzyloxy)-acetimidic acid ethyl ester |
-
2020
- 2020-02-05 WO PCT/IB2020/050909 patent/WO2020161632A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010080409A1 (en) * | 2008-12-18 | 2010-07-15 | Novartis Ag | Hemifumarate salt of 1- [4- [1- ( 4 -cyclohexyl-3 -trifluoromethyl-benzyloxyimino ) -ethyl] -2 -ethyl-benzyl] -a zetidine-3-carboxylic acid |
| WO2013113915A1 (en) * | 2012-02-03 | 2013-08-08 | Novartis Ag | Process for preparing n-(4-cyclohexyl-3-trifluoromethyl-benzyloxy)-acetimidic acid ethyl ester |
Non-Patent Citations (1)
| Title |
|---|
| MINO R. CAIRA: "CRYSTALLINE POLYMORPHISM OF ORGANIC COMPOUNDS", TOPICS IN CURRENT CHEMISTRY, vol. 198, 1998, pages 163 - 208, XP008166276, DOI: 10.1007/3-540-69178-2_5 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11673860B2 (en) | 2018-01-22 | 2023-06-13 | Teva Pharmaceuticals International Gmbh | Crystalline siponimod fumaric acid and polymorphs thereof |
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