WO2020234423A1 - Siponimod maleic acid and fumaric acid salt - Google Patents

Siponimod maleic acid and fumaric acid salt Download PDF

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Publication number
WO2020234423A1
WO2020234423A1 PCT/EP2020/064211 EP2020064211W WO2020234423A1 WO 2020234423 A1 WO2020234423 A1 WO 2020234423A1 EP 2020064211 W EP2020064211 W EP 2020064211W WO 2020234423 A1 WO2020234423 A1 WO 2020234423A1
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Prior art keywords
siponimod
maleic acid
solid form
salt
solid
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PCT/EP2020/064211
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French (fr)
Inventor
Bohumil Dymacek
Jiri PARTL
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Synthon B.V.
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Publication date
Application filed by Synthon B.V. filed Critical Synthon B.V.
Priority to EP20726476.3A priority Critical patent/EP3972954A1/en
Publication of WO2020234423A1 publication Critical patent/WO2020234423A1/en

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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/145—Maleic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/15—Fumaric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to salts of the compound Siponimod.
  • S1P1 lysophosphobpid EDG1 receptor ligand that is useful for treatment of immunological disorders. Fumaric acid salt of siponimod is now ongoing pre-registration for use in the treatment secondary progressive multiple sclerosis.
  • Siponimod was first disclosed in W02004/103306 by Novartis.
  • Hemifumarate salt of Siponimod i.e. ratio Siponimod: Fumaric acid is 1 :0.5
  • solid forms A, B, C, D and E of the hemifurate salt are disclosed in WO2010/080409 by Novartis.
  • HC1 salt, malate salt, oxalate salt, tartrate salt and their crystalline forms are disclosed in W02010/080455 by Novartis.
  • the presented invention relates to solid forms of Siponimod fumaric acid (1 : 1) salt.
  • the presented invention relates to a solid form of Siponimod fumaric acid (1: 1) salt, Form 1, characterized by XRPD pattern having 2Q values 7.1°, 12.1°, 16.4° and 17.9° 2Q (+ 0.2 degrees 2Q).
  • the presented invention also relates to a process for preparation of Siponimod fumaric acid (1 :1) salt, Form 1, comprising:
  • the presented invention further relates to Siponimod maleic acid (1 : 1) salt and solid forms thereof.
  • the presented invention relates to a solid form of Siponimod maleic acid (1 : 1) salt,
  • Form 1 characterized by XRPD pattern having 2Q values 3.6°, 15.6° and 16.7° 2Q (+ 0.2 degrees 2Q).
  • the presented invention also relates to a process for preparation of Siponimod maleic acid (1 :1) salt, Form 1, comprising:
  • the presented invention also relates to a solid form of Siponimod maleic acid (1 : 1) salt, Form 3, characterized by XRPD pattern having 2Q values 12.9°, 18.0° and 19.2° 2Q (+ 0.2 degrees 2Q).
  • the presented invention also relates to a process for preparation of Siponimod maleic acid (1 :1) salt, Form 3, comprising:
  • the presented invention further relates to a solid form of Siponimod maleic acid (1 : 1) salt, Form 4, characterized by XRPD pattern having 2Q values 12.7°, 17.6° and 20.4° 2Q (+ 0.2 degrees 2Q).
  • the presented invention also relates to a process for preparation of Siponimod maleic acid (1 :1) salt, Form 4, comprising:
  • the presented invention further relates to a solid form of Siponimod maleic acid (1 : 1) salt, Form 8, characterized by XRPD pattern having 2Q values 6.0°, 7.1°, 16.6° and 21.2° 2Q (+ 0.2 degrees 2Q).
  • the presented invention also relates to a process for preparation of Siponimod maleic acid (1 :1) salt, Form 8, comprising contacting Siponimod maleic acid salt with water.
  • the solid salts of Siponimod have lower water activity and therefore improved stability in comparison with prior art Siponimod salts.
  • the solid salts of Siponimod have also better flowability in comparison with prior art salts.
  • Figure 1 XRPD pattern of solid Form 1 of Siponimod Fumaric acid (1: 1) salt
  • Figure 2 DSC pattern of solid Form 1 of Siponimod Fumaric acid (1: 1) salt
  • Figure 8 DSC pattern of solid Form 3 of Siponimod Maleic acid (1: 1) salt
  • Figure 9 XRPD pattern of solid Form 4 of Siponimod Maleic acid (1 : 1) salt
  • Figure 10 DSC pattern of solid Form 4 of Siponimod Maleic acid (1 : 1) salt
  • Figure 11 XRPD pattern of solid Form 5 of Siponimod Maleic acid (1 : 1) salt
  • Figure 12 DSC pattern of solid Form 5 of Siponimod Maleic acid (1 : 1) salt
  • Figure 15 XRPD pattern of solid Form 7 of Siponimod Maleic acid (1 : 1) salt
  • Figure 16 XRPD pattern of solid Form 2 of Siponimod Maleic acid (1 : 1) salt
  • Figure 17 DSC pattern of solid Form 2 of Siponimod Maleic acid (1 : 1) salt
  • Figure 20 XRPD pattern of solid Form 9 of Siponimod Maleic acid (1 : 1) salt
  • Figure 21 DSC pattern of solid Form 9 of Siponimod Maleic acid (1 : 1) salt DETAILED DESCRIPTION OF THE INVENTION
  • the presented invention relates to Siponimod Fumaric acid salts (1 : 1) and solid form thereof.
  • the invention relates to a solid form of Siponimod fumaric acid (1 : 1) salt, Form 1, characterized by XRPD pattern having 2Q values 7.1°, 12.1°, 16.4° and 17.9° 2Q (+ 0.2 degrees 2Q).
  • the solid form of Siponimod fumaric acid (1: 1) salt, Form 1 can be also characterized by XRPD pattern having 2Q values 7.1°, 10.7°, 12.1°, 13.6°, 15.5°, 16.4° and 17.9° 2Q (+ 0.2 degrees 2Q).
  • the Form 1 can be further characterized by XRPD 2Q values (+ 0.2 degrees 2Q) stated in following table:
  • the Form 1 can be also characterized by XRPD pattern depicted in Figure 1 and DSC pattern depicted in Figure 2.
  • the Form 1 can be prepared by a process comprising:
  • Siponimod used in step a. is preferably amorphous.
  • the alcohol in step a. can be selected from methanol or ethanol or 1 -propanol or 2-propanol or butanol or tert-butanol, preferably it is ethanol.
  • the concentration of Siponimod in ethanol can be between 0.08 g/ml and 0.8 g/ml, preferably it is between 0.1 and 0.5 g/ml.
  • the molar ratio between Siponimod and Fumaric acid can be between 1 :0.5 and 1 : 1.5, preferably it is between 1: 1 and 1 : 1.1.
  • the mixture can be heated to dissolve both Siponimod and Fumaric acid in step a.
  • the mixture is either cooled in step b. to a temperature higher than 15°C and the solid is isolated or the solvent can be distilled off in the step b to isolate the solid.
  • the mixture is preferably heated to a temperature between 40°C and 80°C in step a. and stirred at this temperature for between 10 and 120 minutes, preferably for between 20 and 60 minutes.
  • the mixture can be then either cooled to a temperature between 15°C and 30°C, preferably to a temperature between 20°C and 30°C and stirred at this temperature for between 10 and 120 minutes, preferably for between 20 and 60 minutes to precipitate the solid Form 1.
  • the solid Form 1 can be prepared by a process where the isolating step b. comprises concentrating of the mixture of step a., preferably at an elevated temperature, for example between 40°C and 80°C.
  • the solid Form 1 of Siponimod fumaric acid (1 : 1) salt can be isolated by any suitable technique, for example by filtration and dried.
  • Siponimod preferably amorphous
  • Fumaric acid in molar ratio between 1 : 1 and 1: 1.5, preferably it is between 1 : 1 and 1: 1.1 in 2-propanol
  • concentration of Siponimod in 2-propanol can be between 0.08 g/ml and 0.8 g/ml, preferably it is between 0.1 and 0.5 g/ml, at an elevated temperature, preferably between 50°C and 90°C and stirred at this temperature for between 10 and 120 minutes, preferably for between 20 and 60 minutes and the solution is subsequently cooled to between -30°C and 10°C, preferably between 0°C and 10°C and stirred at this temperature for between 3 and 48 hours, solid Form 2 of Siponimod fumaric acid (1 : 1) salt is obtained.
  • the solid Form 2 can be characterized by XRPD 2Q values (+ 0.2 degrees 2Q) stated in following table:
  • the solid Form 2 can be also characterized by XRPD pattern depicted in Figure 3 and DSC pattern depicted in Figure 4.
  • the invention further relates to Siponimod maleic acid (1: 1) salt and solid forms thereof.
  • Solid Siponimod maleic acid (1: 1) salt, Form 1 can be characterized by XRPD pattern having 2Q values 3.6°, 15.6° and 16.7° 2Q (+ 0.2 degrees 2Q).
  • the solid Siponimod maleic acid (1: 1) salt Form 1 can be also characterized by XRPD pattern having 2Q values 3.6°, 8.3°, 14.8°, 15.6° and 16.7° 2Q (+ 0.2 degrees 2Q).
  • the solid Siponimod maleic acid (1: 1) salt Form 1 can be also characterized by XRPD pattern depicted in Figure 5 and DSC pattern depicted in Figure 6.
  • the solid Siponimod maleic acid (1: 1) salt Form 1 can be prepared by a process comprising: a. Contacting Siponimod and Maleic acid with a solvent selected from
  • Siponimod used in step a. is preferably amorphous.
  • the solvent used in step a. is preferably isopropylacetate that not only provide the solid Form 1 but also excellently increases the purity of obtained solid form after isolation.
  • the concentration of Siponimod in the solvent can be between 0.04 g/ml and 0.8 g/ml, preferably it is between 0.2 g/ml and 0.6 g/ml.
  • the molar ration between Siponimod and Maleic acid can be between 1 :0.5 and 1 : 1.5, preferably it is between 1 : 1 and 1 :1.1.
  • Siponimod and Maleic acid can be contacted with the solvent at a temperature between 20°C and 50°C, preferably at a temperature between 20°C and 30°C.
  • the isolating step b. can be performed by mixing the mixture for between 10 and 120 minutes, preferably for between 15 and 45 minutes or by an addition of for example an ether, such as diethyl ether or methyl tert-butyl ether and stirring the suspension for between 10 and 120 minutes, preferably for between 15 and 45 minutes.
  • the precipitated solid can be separated by any suitable technique, for example by filtration and dried.
  • the solid Siponimod maleic acid (1: 1) salt Form 1 can be also prepared by a process comprising:
  • the ratio (w/w) of ethanol or methanol and water can be between 1.1 : 1 and 1.6: 1, preferably it is between 1.2: 1 and 1 :4:1.
  • the concentration of Siponimod in the mixture can be between 0.015 g/ml and 0.05 g/ml.
  • the molar ration between Siponimod and Maleic acid can be between 1 :0.5 and 1 : 1.5, preferably it is between 1 : 1 and 1 : 1.5.
  • Siponimod can be dissolved in the mixture at an elevated temperature, for example between 40°C and 55°C. The mixture can be then cooled to a temperature between 20°C and 30°C.
  • Maleic acid is added either as solid or can be added as a mixture with methanol or ethanol.
  • the mixture is seeded with Form 1 of Siponimod Maleic acid (1 : 1) salt.
  • the amount of seed can be about 2-5% (weight) w.r.t. Siponimod.
  • the isolating step b. can be performed by slowly (in the course for example 2-3 hours) cooling the mixture to a temperature between 0°C and 20°C, preferably to a temperature between 10°C and 15°C and mixing the mixture for between 10 and 120 minutes, preferably for between 15 and 45 minutes.
  • the precipitated solid can be separated by any suitable technique, for example by filtration and dried.
  • the presented invention also relates to solid Siponimod maleic acid (1: 1) salt, Form 2, that can be characterized by XRPD pattern having 2Q values 8.4°, 13.1° and 17.7° 2Q (+ 0.2 degrees 2Q).
  • the solid Siponimod maleic acid (1 : 1) salt Form 2 can be also characterized by XRPD pattern having 2Q values 4.2°, 8.4°, 13.1°, 14.8° and 17.7° 2Q (+ 0.2 degrees 2Q).
  • the solid Siponimod maleic acid (1 : 1) salt Form 2 can be also characterized by XRPD 2Q values
  • the solid Siponimod maleic acid (1: 1) salt Form 2 can be also characterized by XRPD pattern depicted in Figure 16 and DSC pattern depicted in Figure 17.
  • the solid Form 2 can be prepared by a process comprising:
  • the concentration of Siponimod in the alcohol can be between 0.08 g/ml and 1 g/ml, preferably between 0.1 and 0.5 g/ml.
  • the molar ratio between Siponimod and Maleic acid can be between 1 :0.5 and 1 : 1.5, preferably it is between 1 : 1 and 1 : 1.1.
  • the mixture at step b. can be concentrated for example under vacuum at a temperature between 20°C and 50°C.
  • the concentration of the rest in the ether solvent can be between 0.025 g/ml and 1 mg/ml.
  • the mixture can be optionally left without stirring to crystallize or can be stirred to crystallize.
  • the crystallized solid can be separated by any suitable technique, for example by filtration and dried.
  • the presented invention further relates to solid Siponimod maleic acid (1: 1) salt, Form 3, that can be characterized by XRPD pattern having 2Q values 12.9°, 18.0° and 19.2° 2Q (+ 0.2 degrees 2Q).
  • the solid Siponimod maleic acid (1 : 1) salt Form 3 can be also characterized by XRPD pattern having 2Q values 7.5°, 8.1°, 12.9°, 18.0° and 19.2° 2Q (+ 0.2 degrees 2Q).
  • the solid Siponimod maleic acid (1: 1) salt Form 3 can be also characterized by XRPD 2Q values (+ 0.2 degrees 2Q) stated in following table:
  • the solid Siponimod maleic acid (1: 1) salt Form 3 can be also characterized by XRPD pattern depicted in Figure 7 and DSC pattern depicted in Figure 8.
  • the solid Form 3 can be prepared by a process comprising:
  • Siponimod used in step a. is preferably amorphous.
  • the concentration of Siponimod in methyl tert-butyl ether can be between 0.01 g/ml and 0.1 g/ml, preferably between 0.02 g/ml and 0.08 g/ml.
  • the molar ration between Siponimod and Maleic acid can be between 1 :0.5 and 1 : 1.5, preferably it is between 1 : 1 and 1 : 1.1.
  • Siponimod and Maleic acid can be contacted with the solvent at a temperature between 20°C and 50°C, preferably at a temperature between 20°C and 30°C. The mixture is then stirred at this temperature for between 1 and 50 hours, preferably for between 24 and 48 hours to precipitate the solid Form 3.
  • the precipitated solid can be separated by any suitable technique, for example by filtration and dried.
  • the invention also relates to solid Siponimod maleic acid (1: 1) salt, Form 4, that can be characterized by XRPD pattern having 2Q values 12.7°, 17.6° and 20.4° 2Q (+ 0.2 degrees 2Q).
  • the solid Siponimod maleic acid (1: 1) salt Form 4 can be also characterized by XRPD pattern having 2Q values 7.2°, 12.7°, 13.1°, 16.8°, 17.6° and 20.4° 2Q ( ⁇ 0.2 degrees 2Q).
  • the solid Siponimod maleic acid (1 : 1) salt Form 4 can be also characterized by XRPD 2Q values (+ 0.2 degrees 2Q) stated in following table:
  • the solid Siponimod maleic acid (1: 1) salt Form 4 can be also characterized by XRPD pattern depicted in Figure 9 and DSC pattern depicted in Figure 10.
  • the solid Form 4 can be prepared by a process comprising:
  • Siponimod used in step a. is preferably amorphous.
  • the concentration of Siponimod in cyclohexane can be between 0.01 g/ml and 0.1 g/ml, preferably between 0.02 g/ml and 0.08 g/ml.
  • the molar ration between Siponimod and Maleic acid can be between 1 :0.5 and 1 : 1.5, preferably it is between 1 : 1 and 1 :1.1.
  • Siponimod and Maleic acid can be contacted with the solvent at a temperature between 20°C and 50°C, preferably at a temperature between 20°C and 30°C. The mixture is then stirred at this temperature for between 1 and 50 hours, preferably for between 24 and 48 hours to precipitate the solid Form 4.
  • the precipitated solid can be separated by any suitable technique, for example by filtration and dried.
  • the solid Form 4 can be also prepared by a process comprising:
  • the acetate can be selected from methylacetate or ethylacetate or propylacetate or isopropylacetate or butylacetate or isobutylacetate or a mixture thereof, preferably it is isopropylacetate.
  • concentration of Siponimod in the acetate can be between 0. lg/ml and 0.3 g/ml.
  • the molar ration between Siponimod and Maleic acid can be between 1 :0.5 and
  • Siponimod is mixed with the acetate preferably at a temperature between 20°C and 25°C.
  • Maleic acid is added either in solid form or in form of a solution.
  • the mixture can be warmed to a temperature between 60°C and 90°C to obtain a solution.
  • the solution is then cooled to a temperature between -10°C and 30°C, preferably between 20°C and 25°C and stirred at this temperature for between 2 and 20 hours.
  • the mixture can be then optionally cooled to a temperature between -10°C and 10°C and stirred at this temperature for between 1 and 10 hours to obtain a suspension.
  • the precipitated solid can be separated by any suitable technique, for example by filtration and dried.
  • the presented invention further related to solid Siponimod maleic acid (1: 1) salt, Form 5.
  • Siponimod preferably amorphous, and Maleic acid are dissolved in methanol (step a.)
  • the mixture is concentrated to dryness (step b.)
  • an acetate is added to the rest (step c.)
  • the solid is isolated (step d.) and dried, Form 5 of Siponimod maleic acid (1: 1) salt is obtained.
  • the concentration of Siponimod in methanol can be between 0.1 g/ml and 1 g/ml, preferably between 0.2 g/ml and 0.8 g/ml.
  • the molar ration between Siponimod and Maleic acid can be between 1 :0.5 and 1 : 1.5, preferably it is between 1: 1 and 1 : 1.1.
  • Siponimod and Maleic acid can be dissolved at a temperature between 20°C and 50°C, preferably at a temperature between 20°C and 30°C.
  • the mixture is concentrated (step b.) preferably as a temperature between 20°C and 40°C and under vacuum.
  • an acetate such as ethyl acetate or methyl acetate or butyl acetate or tert-butyl acetate, preferably ethylacetate, is added to the rest.
  • Volume ratio between added acetate and methanol used in step a. can be between 1 : 1 and 2: 1, preferably it is between 1.4: 1 and 1.7: 1.
  • the mixture was left without stirring to crystallize for between 1 and 10 hours.
  • the crystallized solid can be separated by any suitable technique, for example by filtration
  • Form 5 of Siponimod maleic acid (1 : 1) salt can be characterized XRPD 2Q values (+ 0.2 degrees 2Q) stated in following table:
  • the solid Siponimod maleic acid (1: 1) salt Form 5 can be also characterized by XRPD pattern depicted in Figure 11 and DSC pattern depicted in Figure 12.
  • Siponimod preferably amorphous, and Maleic acid are dissolved in methanol (step a.)
  • the mixture is concentrated to dryness (step b.)
  • water is added to the rest (step c.)
  • the solid is isolated (step d.) and dried, Form 6 of Siponimod maleic acid (1: 1) salt is obtained.
  • concentration of Siponimod in methanol can be between 0.1 g/ml and 1 g/ml, preferably between 0.2 g/ml and 0.8 g/ml.
  • the molar ration between Siponimod and Maleic acid can be between 1 :0.5 and 1 : 1.5, preferably it is between 1: 1 and 1 : 1.1.
  • Siponimod and Maleic acid can be dissolved at a temperature between 20°C and 50°C, preferably at a temperature between 20°C and 30°C.
  • the mixture is concentrated (step b.) preferably as a temperature between 20°C and 40 °C and under vacuum.
  • step c. water is added to the rest.
  • the concentration of the rest in water can be between 0.08 g/ml and 1 g/ml, preferably between 0.1 g/ml and 1 g/ml.
  • the mixture was left without stirring to crystallize for between 1 and 10 hours.
  • the crystallized solid can be separated by any suitable technique, for example by filtration and dried.
  • Form 6 of Siponimod maleic acid (1 : 1) salt can be characterized XRPD 2Q values (+ 0.2 degrees 2Q) stated in following table:
  • the solid Siponimod maleic acid (1: 1) salt Form 6 can be also characterized by XRPD pattern depicted in Figure 13 and DSC pattern depicted in Figure 14.
  • Form 7 of Siponimod maleic acid (1 : 1) is obtained.
  • Form 7 of Siponimod maleic acid (1 :1) salt can be characterized XRPD 2Q values (+ 0.2 degrees 2Q) stated in following table:
  • the solid Siponimod maleic acid (1: 1) salt Form 7 can be also characterized by XRPD pattern depicted in Figure 15.
  • the invention further relates to solid Siponimod maleic acid (1: 1) salt, Form 8, that can be characterized by XRPD pattern having 2Q values 6.0°, 7.1°, 16.6° and 21.2° 2Q (+ 0.2 degrees 2Q).
  • the solid Siponimod maleic acid (1 : 1) salt Form 8 can be also characterized by XRPD pattern having 2Q values 6.0°, 7.1°, 13.1°, 15.8°, 16.6° and 21.2° 2Q (+ 0.2 degrees 2Q).
  • the solid Siponimod maleic acid (1: 1) salt Form 8 can be also characterized by XRPD
  • the solid Siponimod maleic acid (1: 1) salt Form 8 can be also characterized by XRPD pattern depicted in Figure 18 and DSC pattern depicted in Figure 19.
  • the solid Form 8 of Siponimod maleic acid (1: 1) salt can be prepared by a process comprising contacting Siponimod maleic acid salt with water.
  • the Siponimod maleic acid salt, Form 8 is monohydrate, i.e. it contains 2.7% of water according to TGA.
  • the invention also relates to solid Siponimod maleic acid (1: 1) salt, Form 9, that can be characterized by XRPD pattern having 2Q values 7.3°, 9.5°, 17.7° and 18.8° 2Q (+ 0.2 degrees 2Q).
  • the solid Siponimod maleic acid (1: 1) salt Form 9 can be also characterized by XRPD pattern having 2Q values 7.3°, 9.5°, 12.2°, 17.7°, 18.8° and 22.0° 2Q (+ 0.2 degrees 2Q).
  • the solid Siponimod maleic acid (1 : 1) salt Form 9 can be also characterized by XRPD 2Q values (+ 0.2 degrees 2Q) stated in following table:
  • the solid Siponimod maleic acid (1: 1) salt Form 9 can be also characterized by XRPD pattern depicted in Figure 20 and DSC pattern depicted in Figure 21.
  • the solid Form 9 can be prepared by a process comprising:
  • the ratio (w/w) of ethanol or methanol and water can be between 1.1 : 1 and 1.6: 1, preferably it is between 1.2: 1 and 1 :4:1.
  • the concentration of Siponimod in the mixture can be between 0.02 g/ml and 0.05 g/ml.
  • the molar ration between Siponimod and Maleic acid can be between 1 :0.5 and 1 : 1.5, preferably it is between 1 : 1 and 1 : 1.5.
  • Siponimod can be dissolved in the mixture at an elevated temperature, for example between 40°C and 55°C. The mixture can be then cooled to a temperature between 20°C and 30°C. To the mixture Maleic acid is added either as solid or can be added as a mixture with methanol or ethanol.
  • the isolating step b. can be performed by cooling the mixture to a temperature between 0°C and 20°C, preferably to a temperature between 10°C and 15°C and mixing the mixture for between 10 and 120 minutes, preferably for between 15 and 45 minutes.
  • the precipitated solid can be separated by any suitable technique, for example by filtration and dried.
  • the solid Form 9 of Siponimod maleic acid (1: 1) salt can be also prepared by a process comprising contacting Siponimod maleic acid salt with water for a long term, for example 1/2 year.
  • the solid Forms 1 or 2 of Siponimod Fumaric acid (1: 1) salt or solid Forms 1 or 2 or 3 or 4 or 5 or 6 or 8 or 9 of Siponimod maleic acid (1: 1) salt can be processed into a suitable pharmaceutical formulation.
  • the solid forms can be mixed with pharmaceutically acceptable adjuvants, diluents or carriers.
  • the amount of solid Forms 1 or 2 of Siponimod Fumaric acid (1 : 1) salt or solid Forms 1 or 2 or 3 or 4 or 5 or 6 or 8 or 9, in the formulation depends on the condition and a patient to be treated.
  • the pharmaceutical formulation can be if form of a solid oral formulation, for example a capsule, a pill, a powder or a granule.
  • the Siponimod salts according to presented invention can be mixed with one or more additives such as fillers or extenders or binders or wetting agents or disintegrating agents or absorbents or lubricants or buffering agents.
  • the formulation in a form of a tablet or a dragee or a capsule or a pill or a granule can be coated with a coating or shell such as enteric or other coating.
  • the oral formulation can be in a form of an oral emulsion or a solution or a suspension or a syrup.
  • the formulation can contain suitable additives such as diluent(s) or wetting agent(s) or emulsifying agent(s) or suspending agent(s) or sweetening agent(s) or flavoring agent(s).
  • suitable additive(s) are known to those skilled in the art.
  • the suitable pharmaceutical formulation can be in a parenteral form such as an injection or an infusion or an injectable depot or in a liposomal form comprising
  • the pharmaceutical formulation can be also in a form of a powder for reconstitution into an injection or infusion.
  • the formulation can further comprise additives such as preservative(s) or wetting agent(s) or emulsifying agent(s) or dispersing agent(s) or antibacterial or antifungal agents.
  • suitable additive(s) are known to those skilled in the art.
  • the suitable pharmaceutical formulation can be in a form suitable for rectal or vaginal administration further comprising suitable additive(s).
  • suitable additive(s) are known to those skilled in the art.
  • the solid forms 1 or 2 of Siponimod Fumaric acid (1 : 1) salt or solid forms 1 or 2 or 3 or 4 or 5 or 6 or 8 or 9 of Siponimod maleic acid (1 : 1) salt or a pharmaceutical formulation comprising the forms can be used for the treatment of conditions treatable with Siponimod or a salt thereof.
  • the compound of formula (I) can be prepared by a process disclosed in
  • the amorphous form of compound of formula (I) can be prepared by a process known from the prior art or by a procedure described in Example 1.
  • XRPD spectrum of solid compounds was obtained using the following measurement conditions: Panalytical Empyrean diffractometer with Q/2Q geometry (transmition mode), equipped with a PixCell 3D detector
  • DCS patterns were obtained using the following conditions: 10°C/min -> 250°C
  • Example 1 Preparation of Sinonimod Fumaric acid (1 : 1) salt.
  • amorphous Siponimod 0.4 g was mixed with 2 ml of ethanol. The reaction mixture was heated to 60°C to obtain a solution. 0.09 g of Fumaric acid was added to the mixture.
  • amorphous Siponimod was mixed with 0.09 g of Fumaric acid and 2 ml of ethanol. The reaction mixture was heated to 40°C to obtain a solution. The mixture was concentrated at 40°C to dryness by vacuum to obtain 0.32 g of Siponimod Fumaric acid (1 : 1) salt, Form 1.
  • XRPD pattern of obtained solid corresponds to XRPD pattern depicted in Figure 1.
  • DSC pattern of obtained solid corresponds to DSC pattern depicted in Figure 2.
  • amorphous Siponimod was mixed with 8 ml of 2-propanol. 0.09 g of Fumaric acid was added to the mixture. The reaction mixture was heated to 75 °C to obtain a solution. The mixture was cooled to 0°C and stirred at this temperature over weekend. Precipitated solid was filtered and dried in dryer (25°C, 3 hours, vacuum) to obtain 0.34 g of Siponimod Fumaric acid (1: 1) salt, Form 2.
  • XRPD pattern of obtained solid corresponds to XRPD pattern depicted in Figure 3.
  • DSC pattern of obtained solid corresponds to DSC pattern depicted in Figure 4.
  • amorphous Siponimod was mixed with 5 ml of isopropyl acetate. The mixture was stirred at 25°C for 15 minutes to obtain a solution. 0.09 g of Maleic acid was added to the mixture. The reaction mixture stirred at 25 °C for 45 minutes to obtain a suspension. The suspension was filtered and dried in dried in dryer (25°C, 1 hours, vacuum) to obtain 0.37 g of Siponimod Maleic acid (1: 1) salt, Form 1.
  • XRPD pattern of obtained solid corresponds to XRPD pattern depicted in Figure 5.
  • DSC pattern of obtained solid corresponds to DSC pattern depicted in Figure 6.
  • amorphous Siponimod was mixed 0.09 g of Maleic acid and 7 ml of methyl tert-butyl ether. The mixture was stirred at 25°C for 30 minutes. The suspension was filtered and dried in dried on filter (25°C, 1 hours, vacuum) to obtain 0.38 g of Siponimod Maleic acid (1 :1) salt, Form 1.
  • XRPD pattern of obtained solid corresponds to XRPD pattern depicted in Figure 5.
  • DSC pattern of obtained solid corresponds to DSC pattern depicted in Figure 6.
  • XRPD pattern of obtained solid corresponds to XRPD pattern depicted in Figure 5.
  • DSC pattern of obtained solid corresponds to DSC pattern depicted in Figure 6.
  • Example 9 Preparation of Siponimod Maleic acid (1 : 1) salt.
  • amorphous Siponimod was mixed with 8 ml of methyl tert-butyl ether. The mixture was stirred for 15 minutes at 25°C. 0.09 g of Maleic acid was added. The mixture was stirred at 25°C over weekend. The suspension was filtered and dried in dried in dryer (25°C, 1 hour, vacuum) to obtain 0.38 g of Siponimod Maleic acid (1 :1) salt, Form 3.
  • XRPD pattern of obtained solid corresponds to XRPD pattern depicted in Figure 7.
  • DSC pattern of obtained solid corresponds to DSC pattern depicted in Figure 8.
  • amorphous Siponimod was mixed with 8 ml of cyclohexane. The mixture was stirred for 15 minutes at 25°C. 0.09 g of Maleic acid was added. The mixture was stirred at 25°C over weekend. The suspension was filtered and dried in dried in dryer (25°C, 1 hour, vacuum) to obtain 0.37 g of Siponimod Maleic acid (1 : 1) salt, Form 4.
  • XRPD pattern of obtained solid corresponds to XRPD pattern depicted in Figure 9.
  • DSC pattern of obtained solid corresponds to DSC pattern depicted in Figure 10.
  • amorphous Siponimod was mixed with 2.5 ml of methanol. The mixture was stirred for 15 minutes at 25°C. 0.112 g of Maleic acid was added and stirred for 15 minutes. The solution was concentrated to dryness in dryer (25°C/12 h/vacuum). The rest was mixed with 4 ml of ethylacetate and left without stirring to crystallize (25°C, 1 hour). The suspension was decanted and the rest was dried on XRPD holder (25°C/30 min/vacuum) to obtain 0.35 g of Siponimod Maleic acid (1: 1) salt, Form 5.
  • XRPD pattern of obtained solid corresponds to XRPD pattern depicted in Figure 11.
  • DSC pattern of obtained solid corresponds to DSC pattern depicted in Figure 12.
  • Example 13 Preparation of Siponimod Maleic acid (1 : 1) salt.
  • Form 6 and Form 7 0.5 g of amorphous Siponimod was mixed with 2.5 ml of methanol. The mixture was stirred for 15 minutes at 25°C. 0.112 g of Maleic acid was added and stirred for 15 minutes. The solution was concentrated to dryness in dryer (25°C/12 h/vacuum). The rest was mixed with 2 ml of water and left without stirring to crystallize (25°C, 1 hour). The wet solid was analyzed and it corresponds to Form 7 of Siponimod Maleic acid (1: 1) salt. XRPD pattern of obtained solid corresponds to XRPD pattern depicted in Figure 15.
  • Siponimod maleic acid salt prepared according to Example 4 was mixed with 10 ml of water. The mixture was heated at 60°C for 2 hours, then cooled to 25 °C and filtered. The product was dried under vacuum over the night. Siponimod maleic acid salt, Form 8 was obtained in quantitative yield.
  • XRPD pattern of obtained solid corresponds to XRPD pattern depicted in Figure 18.
  • DSC pattern of obtained solid corresponds to DSC pattern depicted in Figure 19.
  • Siponimod maleic acid salt prepared according to Example 13 2 g was mixed with 10 ml of water and left standing for 1/2 year. Obtained solid was filtered off and dried on air overnight. Siponimod maleic acid salt, Form 9 was obtained in quantitative yield.
  • XRPD pattern of obtained solid corresponds to XRPD pattern depicted in Figure 20.
  • DSC pattern of obtained solid corresponds to DSC pattern depicted in Figure 21.
  • Prior art Siponimod Fumarate (1 :0.5), Form A was prepared according to a procedure disclosed in WO2010/080409. Water activity of the prior art form and solid forms of presented invention was measured: DVS machine ProUmid SPX-Im Advance, 25°C, 0-90-0 % relative humidity, step 10%, maximal time per step 10 hours. Equilibrium bandwidth 0.05%/60 minutes.
  • Water activity a difference between the weights of the sample in 0 and 90% of relative humidity at a constant temperature. It corresponds to the amount of water taken by
  • Siponimod salt when the humidity changes from 0 to 90% at a constant temperature.
  • the higher water activity the more water can be taken by the compound and that might result in lower purity of the compound because hydrolysis impurities can be formed. It can also result in mechanical stress in final products (for example tablets) because the compound taking water increases its volume and the volume of the final product (for example tablet) is also increased and that results in cracking of the product.

Abstract

The presented invention relates to salts of Siponimod with Fumaric acid (1:1) and solid Forms 1 and 2 thereof. The presented invention further relates to salts of Siponimod with Maleic acid (1:1) and solid Forms 1, 2, 3, 4, 5, 6, 7, 8 and 9 thereof.

Description

SIPONIMOD MALEIC ACID AND FUMARIC ACID SALT
BACKGROUND OF THE PRESENT INVENTION
The present invention relates to salts of the compound Siponimod.
Siponimod, l-{4-[l-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl- benzyl}-azetidine-3 -carboxylic acid of formula (I),
Figure imgf000002_0001
is a lysophosphobpid EDG1 (S1P1) receptor ligand that is useful for treatment of immunological disorders. Fumaric acid salt of siponimod is now ongoing pre-registration for use in the treatment secondary progressive multiple sclerosis.
Siponimod was first disclosed in W02004/103306 by Novartis. Hemifumarate salt of Siponimod (i.e. ratio Siponimod: Fumaric acid is 1 :0.5) and solid forms A, B, C, D and E of the hemifurate salt are disclosed in WO2010/080409 by Novartis. HC1 salt, malate salt, oxalate salt, tartrate salt and their crystalline forms are disclosed in W02010/080455 by Novartis.
It is important to prepare a salt of the Siponimod that shows good both chemical and polymorphic stability and that provides reproducible and reliable plasma concentration when it is used as a medicament.
SUMMARY OF THE INVENTION
The presented invention relates to solid forms of Siponimod fumaric acid (1 : 1) salt. The presented invention relates to a solid form of Siponimod fumaric acid (1: 1) salt, Form 1, characterized by XRPD pattern having 2Q values 7.1°, 12.1°, 16.4° and 17.9° 2Q (+ 0.2 degrees 2Q).
The presented invention also relates to a process for preparation of Siponimod fumaric acid (1 :1) salt, Form 1, comprising:
a. Dissolving Siponimod and Fumaric acid in an alcohol;
b. Isolating the solid form.
The presented invention further relates to Siponimod maleic acid (1 : 1) salt and solid forms thereof.
The presented invention relates to a solid form of Siponimod maleic acid (1 : 1) salt,
Form 1, characterized by XRPD pattern having 2Q values 3.6°, 15.6° and 16.7° 2Q (+ 0.2 degrees 2Q).
The presented invention also relates to a process for preparation of Siponimod maleic acid (1 :1) salt, Form 1, comprising:
a. Contacting Siponimod and Maleic acid with a solvent selected from
isopropylacetate or diethylether or methyl tert-butylether;
b. Isolating the solid form.
The presented invention also relates to a solid form of Siponimod maleic acid (1 : 1) salt, Form 3, characterized by XRPD pattern having 2Q values 12.9°, 18.0° and 19.2° 2Q (+ 0.2 degrees 2Q).
The presented invention also relates to a process for preparation of Siponimod maleic acid (1 :1) salt, Form 3, comprising:
a. Contacting Siponimod and Maleic acid with methyl tert-butyl ether;
b. Isolating the solid form. The presented invention further relates to a solid form of Siponimod maleic acid (1 : 1) salt, Form 4, characterized by XRPD pattern having 2Q values 12.7°, 17.6° and 20.4° 2Q (+ 0.2 degrees 2Q).
The presented invention also relates to a process for preparation of Siponimod maleic acid (1 :1) salt, Form 4, comprising:
a. Suspending Siponimod and Maleic acid in cyclohexane;
b. Isolating the solid form.
The presented invention further relates to a solid form of Siponimod maleic acid (1 : 1) salt, Form 8, characterized by XRPD pattern having 2Q values 6.0°, 7.1°, 16.6° and 21.2° 2Q (+ 0.2 degrees 2Q).
The presented invention also relates to a process for preparation of Siponimod maleic acid (1 :1) salt, Form 8, comprising contacting Siponimod maleic acid salt with water.
The solid salts of Siponimod have lower water activity and therefore improved stability in comparison with prior art Siponimod salts. The solid salts of Siponimod have also better flowability in comparison with prior art salts.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 : XRPD pattern of solid Form 1 of Siponimod Fumaric acid (1: 1) salt Figure 2: DSC pattern of solid Form 1 of Siponimod Fumaric acid (1: 1) salt
Figure 3: XRPD pattern of solid Form 2 of Siponimod Fumaric acid (1: 1) salt
Figure 4: DSC pattern of solid Form 2 of Siponimod Fumaric acid (1: 1) salt
Figure 5: XRPD pattern of solid Form 1 of Siponimod Maleic acid (1 : 1) salt
Figure 6: DSC pattern of solid Form 1 of Siponimod Maleic acid (1: 1) salt
Figure 7 : XRPD pattern of solid Form 3 of Siponimod Maleic acid (1 : 1) salt
Figure 8: DSC pattern of solid Form 3 of Siponimod Maleic acid (1: 1) salt Figure 9: XRPD pattern of solid Form 4 of Siponimod Maleic acid (1 : 1) salt Figure 10: DSC pattern of solid Form 4 of Siponimod Maleic acid (1 : 1) salt
Figure 11 : XRPD pattern of solid Form 5 of Siponimod Maleic acid (1 : 1) salt Figure 12: DSC pattern of solid Form 5 of Siponimod Maleic acid (1 : 1) salt
Figure 13: XRPD pattern of solid Form 6 of Siponimod Maleic acid (1 : 1) salt
Figure 14: DSC pattern of solid Form 6 of Siponimod Maleic acid (1 : 1) salt
Figure 15: XRPD pattern of solid Form 7 of Siponimod Maleic acid (1 : 1) salt Figure 16: XRPD pattern of solid Form 2 of Siponimod Maleic acid (1 : 1) salt Figure 17: DSC pattern of solid Form 2 of Siponimod Maleic acid (1 : 1) salt
Figure 18: XRPD pattern of solid Form 8 of Siponimod Maleic acid (1 : 1) salt
Figure 19: DSC pattern of solid Form 8 of Siponimod Maleic acid (1 : 1) salt
Figure 20: XRPD pattern of solid Form 9 of Siponimod Maleic acid (1 : 1) salt Figure 21: DSC pattern of solid Form 9 of Siponimod Maleic acid (1 : 1) salt DETAILED DESCRIPTION OF THE INVENTION
The presented invention relates to Siponimod Fumaric acid salts (1 : 1) and solid form thereof. The invention relates to a solid form of Siponimod fumaric acid (1 : 1) salt, Form 1, characterized by XRPD pattern having 2Q values 7.1°, 12.1°, 16.4° and 17.9° 2Q (+ 0.2 degrees 2Q). The solid form of Siponimod fumaric acid (1: 1) salt, Form 1, can be also characterized by XRPD pattern having 2Q values 7.1°, 10.7°, 12.1°, 13.6°, 15.5°, 16.4° and 17.9° 2Q (+ 0.2 degrees 2Q). The Form 1 can be further characterized by XRPD 2Q values (+ 0.2 degrees 2Q) stated in following table:
Figure imgf000006_0001
The Form 1 can be also characterized by XRPD pattern depicted in Figure 1 and DSC pattern depicted in Figure 2.
The Form 1 can be prepared by a process comprising:
a. Dissolving Siponimod and Fumaric acid in an alcohol;
b. Isolating the solid form. Siponimod used in step a. is preferably amorphous. The alcohol in step a. can be selected from methanol or ethanol or 1 -propanol or 2-propanol or butanol or tert-butanol, preferably it is ethanol. The concentration of Siponimod in ethanol can be between 0.08 g/ml and 0.8 g/ml, preferably it is between 0.1 and 0.5 g/ml. The molar ratio between Siponimod and Fumaric acid can be between 1 :0.5 and 1 : 1.5, preferably it is between 1: 1 and 1 : 1.1. The mixture can be heated to dissolve both Siponimod and Fumaric acid in step a. The mixture is either cooled in step b. to a temperature higher than 15°C and the solid is isolated or the solvent can be distilled off in the step b to isolate the solid.
The mixture is preferably heated to a temperature between 40°C and 80°C in step a. and stirred at this temperature for between 10 and 120 minutes, preferably for between 20 and 60 minutes. The mixture can be then either cooled to a temperature between 15°C and 30°C, preferably to a temperature between 20°C and 30°C and stirred at this temperature for between 10 and 120 minutes, preferably for between 20 and 60 minutes to precipitate the solid Form 1. Or the solid Form 1 can be prepared by a process where the isolating step b. comprises concentrating of the mixture of step a., preferably at an elevated temperature, for example between 40°C and 80°C. The solid Form 1 of Siponimod fumaric acid (1 : 1) salt can be isolated by any suitable technique, for example by filtration and dried.
When Siponimod, preferably amorphous, is mixed with Fumaric acid in molar ratio between 1 : 1 and 1: 1.5, preferably it is between 1 : 1 and 1: 1.1 in 2-propanol, the concentration of Siponimod in 2-propanol can be between 0.08 g/ml and 0.8 g/ml, preferably it is between 0.1 and 0.5 g/ml, at an elevated temperature, preferably between 50°C and 90°C and stirred at this temperature for between 10 and 120 minutes, preferably for between 20 and 60 minutes and the solution is subsequently cooled to between -30°C and 10°C, preferably between 0°C and 10°C and stirred at this temperature for between 3 and 48 hours, solid Form 2 of Siponimod fumaric acid (1 : 1) salt is obtained. The solid Form 2 can be characterized by XRPD 2Q values (+ 0.2 degrees 2Q) stated in following table:
Figure imgf000008_0001
The solid Form 2 can be also characterized by XRPD pattern depicted in Figure 3 and DSC pattern depicted in Figure 4.
The invention further relates to Siponimod maleic acid (1: 1) salt and solid forms thereof. Solid Siponimod maleic acid (1: 1) salt, Form 1, can be characterized by XRPD pattern having 2Q values 3.6°, 15.6° and 16.7° 2Q (+ 0.2 degrees 2Q). The solid Siponimod maleic acid (1: 1) salt Form 1 can be also characterized by XRPD pattern having 2Q values 3.6°, 8.3°, 14.8°, 15.6° and 16.7° 2Q (+ 0.2 degrees 2Q). The solid Siponimod maleic acid
(1 : 1) salt Form 1 can be also characterized by XRPD 2Q values (+ 0.2 degrees 2Q) stated in following table:
Figure imgf000009_0001
The solid Siponimod maleic acid (1: 1) salt Form 1 can be also characterized by XRPD pattern depicted in Figure 5 and DSC pattern depicted in Figure 6.
The solid Siponimod maleic acid (1: 1) salt Form 1 can be prepared by a process comprising: a. Contacting Siponimod and Maleic acid with a solvent selected from
isopropylacetate or diethylether or methyl tert-butylether;
b. Isolating the solid form.
Siponimod used in step a. is preferably amorphous. The solvent used in step a. is preferably isopropylacetate that not only provide the solid Form 1 but also excellently increases the purity of obtained solid form after isolation. The concentration of Siponimod in the solvent can be between 0.04 g/ml and 0.8 g/ml, preferably it is between 0.2 g/ml and 0.6 g/ml. The molar ration between Siponimod and Maleic acid can be between 1 :0.5 and 1 : 1.5, preferably it is between 1 : 1 and 1 :1.1. Siponimod and Maleic acid can be contacted with the solvent at a temperature between 20°C and 50°C, preferably at a temperature between 20°C and 30°C. The isolating step b. can be performed by mixing the mixture for between 10 and 120 minutes, preferably for between 15 and 45 minutes or by an addition of for example an ether, such as diethyl ether or methyl tert-butyl ether and stirring the suspension for between 10 and 120 minutes, preferably for between 15 and 45 minutes. The precipitated solid can be separated by any suitable technique, for example by filtration and dried.
The solid Siponimod maleic acid (1: 1) salt Form 1 can be also prepared by a process comprising:
a. Contacting Siponimod and Maleic acid with a solvent mixture of methanol or ethanol with water;
b. Seeding the mixture with solid Form 1 of Siponimod maleic acid (1: 1) salt;
c. Isolating the solid form.
The ratio (w/w) of ethanol or methanol and water can be between 1.1 : 1 and 1.6: 1, preferably it is between 1.2: 1 and 1 :4:1. The concentration of Siponimod in the mixture can be between 0.015 g/ml and 0.05 g/ml. The molar ration between Siponimod and Maleic acid can be between 1 :0.5 and 1 : 1.5, preferably it is between 1 : 1 and 1 : 1.5. Siponimod can be dissolved in the mixture at an elevated temperature, for example between 40°C and 55°C. The mixture can be then cooled to a temperature between 20°C and 30°C. To the mixture Maleic acid is added either as solid or can be added as a mixture with methanol or ethanol. The mixture is seeded with Form 1 of Siponimod Maleic acid (1 : 1) salt. The amount of seed can be about 2-5% (weight) w.r.t. Siponimod.
The isolating step b. can be performed by slowly (in the course for example 2-3 hours) cooling the mixture to a temperature between 0°C and 20°C, preferably to a temperature between 10°C and 15°C and mixing the mixture for between 10 and 120 minutes, preferably for between 15 and 45 minutes. The precipitated solid can be separated by any suitable technique, for example by filtration and dried.
The presented invention also relates to solid Siponimod maleic acid (1: 1) salt, Form 2, that can be characterized by XRPD pattern having 2Q values 8.4°, 13.1° and 17.7° 2Q (+ 0.2 degrees 2Q). The solid Siponimod maleic acid (1 : 1) salt Form 2 can be also characterized by XRPD pattern having 2Q values 4.2°, 8.4°, 13.1°, 14.8° and 17.7° 2Q (+ 0.2 degrees 2Q). The solid Siponimod maleic acid (1 : 1) salt Form 2 can be also characterized by XRPD 2Q values
(+ 0.2 degrees 2Q) stated in following table:
Figure imgf000011_0001
Figure imgf000012_0001
The solid Siponimod maleic acid (1: 1) salt Form 2 can be also characterized by XRPD pattern depicted in Figure 16 and DSC pattern depicted in Figure 17.
The solid Form 2 can be prepared by a process comprising:
a. Dissolving Siponimod and Maleic acid in an alcohol such as methanol or ethanol or 1 -propanol or isopropanol or butanol or tert-butanol, preferably in methanol; b. Concentrating of the mixture;
c. Contacting of the rest with an ether such as methyl ether or ethyl ether or methyl tert-butyl ether, preferably in methyl tert-butyl ether;
d. Isolating the solid form.
The concentration of Siponimod in the alcohol can be between 0.08 g/ml and 1 g/ml, preferably between 0.1 and 0.5 g/ml. The molar ratio between Siponimod and Maleic acid can be between 1 :0.5 and 1 : 1.5, preferably it is between 1 : 1 and 1 : 1.1. The mixture at step b. can be concentrated for example under vacuum at a temperature between 20°C and 50°C. The concentration of the rest in the ether solvent can be between 0.025 g/ml and 1 mg/ml. The mixture can be optionally left without stirring to crystallize or can be stirred to crystallize.
The crystallized solid can be separated by any suitable technique, for example by filtration and dried.
The presented invention further relates to solid Siponimod maleic acid (1: 1) salt, Form 3, that can be characterized by XRPD pattern having 2Q values 12.9°, 18.0° and 19.2° 2Q (+ 0.2 degrees 2Q). The solid Siponimod maleic acid (1 : 1) salt Form 3 can be also characterized by XRPD pattern having 2Q values 7.5°, 8.1°, 12.9°, 18.0° and 19.2° 2Q (+ 0.2 degrees 2Q). The solid Siponimod maleic acid (1: 1) salt Form 3 can be also characterized by XRPD 2Q values (+ 0.2 degrees 2Q) stated in following table:
Figure imgf000013_0001
The solid Siponimod maleic acid (1: 1) salt Form 3 can be also characterized by XRPD pattern depicted in Figure 7 and DSC pattern depicted in Figure 8.
The solid Form 3 can be prepared by a process comprising:
a. Contacting Siponimod and Maleic acid with methyl tert-butyl ether and optionally seeding the mixture with solid Form 3 of Siponimod maleic acid (1 : 1) salt;
b. Isolating the solid form.
Siponimod used in step a. is preferably amorphous. The concentration of Siponimod in methyl tert-butyl ether can be between 0.01 g/ml and 0.1 g/ml, preferably between 0.02 g/ml and 0.08 g/ml. The molar ration between Siponimod and Maleic acid can be between 1 :0.5 and 1 : 1.5, preferably it is between 1 : 1 and 1 : 1.1. Siponimod and Maleic acid can be contacted with the solvent at a temperature between 20°C and 50°C, preferably at a temperature between 20°C and 30°C. The mixture is then stirred at this temperature for between 1 and 50 hours, preferably for between 24 and 48 hours to precipitate the solid Form 3. The precipitated solid can be separated by any suitable technique, for example by filtration and dried.
The invention also relates to solid Siponimod maleic acid (1: 1) salt, Form 4, that can be characterized by XRPD pattern having 2Q values 12.7°, 17.6° and 20.4° 2Q (+ 0.2 degrees 2Q). The solid Siponimod maleic acid (1: 1) salt Form 4 can be also characterized by XRPD pattern having 2Q values 7.2°, 12.7°, 13.1°, 16.8°, 17.6° and 20.4° 2Q (± 0.2 degrees 2Q). The solid Siponimod maleic acid (1 : 1) salt Form 4 can be also characterized by XRPD 2Q values (+ 0.2 degrees 2Q) stated in following table:
Figure imgf000015_0001
The solid Siponimod maleic acid (1: 1) salt Form 4 can be also characterized by XRPD pattern depicted in Figure 9 and DSC pattern depicted in Figure 10.
The solid Form 4 can be prepared by a process comprising:
a. Suspending Siponimod and Maleic acid in cyclohexane;
b. Isolating the solid form.
Siponimod used in step a. is preferably amorphous. The concentration of Siponimod in cyclohexane can be between 0.01 g/ml and 0.1 g/ml, preferably between 0.02 g/ml and 0.08 g/ml. The molar ration between Siponimod and Maleic acid can be between 1 :0.5 and 1 : 1.5, preferably it is between 1 : 1 and 1 :1.1. Siponimod and Maleic acid can be contacted with the solvent at a temperature between 20°C and 50°C, preferably at a temperature between 20°C and 30°C. The mixture is then stirred at this temperature for between 1 and 50 hours, preferably for between 24 and 48 hours to precipitate the solid Form 4. The precipitated solid can be separated by any suitable technique, for example by filtration and dried.
The solid Form 4 can be also prepared by a process comprising:
a. Dissolving Siponimod and Maleic acid in an acetate
b. Isolating the solid form.
The acetate can be selected from methylacetate or ethylacetate or propylacetate or isopropylacetate or butylacetate or isobutylacetate or a mixture thereof, preferably it is isopropylacetate. The concentration of Siponimod in the acetate can be between 0. lg/ml and 0.3 g/ml. The molar ration between Siponimod and Maleic acid can be between 1 :0.5 and
1: 1.5, preferably it is between 1 : 1 and 1: 1.1. Siponimod is mixed with the acetate preferably at a temperature between 20°C and 25°C. Maleic acid is added either in solid form or in form of a solution. The mixture can be warmed to a temperature between 60°C and 90°C to obtain a solution. The solution is then cooled to a temperature between -10°C and 30°C, preferably between 20°C and 25°C and stirred at this temperature for between 2 and 20 hours. The mixture can be then optionally cooled to a temperature between -10°C and 10°C and stirred at this temperature for between 1 and 10 hours to obtain a suspension. The precipitated solid can be separated by any suitable technique, for example by filtration and dried.
The presented invention further related to solid Siponimod maleic acid (1: 1) salt, Form 5. When Siponimod, preferably amorphous, and Maleic acid are dissolved in methanol (step a.), the mixture is concentrated to dryness (step b.), an acetate is added to the rest (step c.), the solid is isolated (step d.) and dried, Form 5 of Siponimod maleic acid (1: 1) salt is obtained. The concentration of Siponimod in methanol can be between 0.1 g/ml and 1 g/ml, preferably between 0.2 g/ml and 0.8 g/ml. The molar ration between Siponimod and Maleic acid can be between 1 :0.5 and 1 : 1.5, preferably it is between 1: 1 and 1 : 1.1. Siponimod and Maleic acid can be dissolved at a temperature between 20°C and 50°C, preferably at a temperature between 20°C and 30°C. The mixture is concentrated (step b.) preferably as a temperature between 20°C and 40°C and under vacuum. In the step c. an acetate, such as ethyl acetate or methyl acetate or butyl acetate or tert-butyl acetate, preferably ethylacetate, is added to the rest. Volume ratio between added acetate and methanol used in step a. can be between 1 : 1 and 2: 1, preferably it is between 1.4: 1 and 1.7: 1. The mixture was left without stirring to crystallize for between 1 and 10 hours. The crystallized solid can be separated by any suitable technique, for example by filtration and dried.
Form 5 of Siponimod maleic acid (1 : 1) salt can be characterized XRPD 2Q values (+ 0.2 degrees 2Q) stated in following table:
Figure imgf000017_0001
The solid Siponimod maleic acid (1: 1) salt Form 5 can be also characterized by XRPD pattern depicted in Figure 11 and DSC pattern depicted in Figure 12.
When Siponimod, preferably amorphous, and Maleic acid are dissolved in methanol (step a.), the mixture is concentrated to dryness (step b.), water is added to the rest (step c.), the solid is isolated (step d.) and dried, Form 6 of Siponimod maleic acid (1: 1) salt is obtained. The concentration of Siponimod in methanol can be between 0.1 g/ml and 1 g/ml, preferably between 0.2 g/ml and 0.8 g/ml. The molar ration between Siponimod and Maleic acid can be between 1 :0.5 and 1 : 1.5, preferably it is between 1: 1 and 1 : 1.1. Siponimod and Maleic acid can be dissolved at a temperature between 20°C and 50°C, preferably at a temperature between 20°C and 30°C. The mixture is concentrated (step b.) preferably as a temperature between 20°C and 40 °C and under vacuum. In the step c. water is added to the rest. The concentration of the rest in water can be between 0.08 g/ml and 1 g/ml, preferably between 0.1 g/ml and 1 g/ml. The mixture was left without stirring to crystallize for between 1 and 10 hours. The crystallized solid can be separated by any suitable technique, for example by filtration and dried.
Form 6 of Siponimod maleic acid (1 : 1) salt can be characterized XRPD 2Q values (+ 0.2 degrees 2Q) stated in following table:
Figure imgf000018_0001
Figure imgf000019_0001
The solid Siponimod maleic acid (1: 1) salt Form 6 can be also characterized by XRPD pattern depicted in Figure 13 and DSC pattern depicted in Figure 14.
In case the solid obtained in step c. in the process for preparation of Form 6, is analysed, Form 7 of Siponimod maleic acid (1 : 1) is obtained. Form 7 of Siponimod maleic acid (1 :1) salt can be characterized XRPD 2Q values (+ 0.2 degrees 2Q) stated in following table:
Figure imgf000019_0002
The solid Siponimod maleic acid (1: 1) salt Form 7 can be also characterized by XRPD pattern depicted in Figure 15.
The invention further relates to solid Siponimod maleic acid (1: 1) salt, Form 8, that can be characterized by XRPD pattern having 2Q values 6.0°, 7.1°, 16.6° and 21.2° 2Q (+ 0.2 degrees 2Q). The solid Siponimod maleic acid (1 : 1) salt Form 8 can be also characterized by XRPD pattern having 2Q values 6.0°, 7.1°, 13.1°, 15.8°, 16.6° and 21.2° 2Q (+ 0.2 degrees 2Q). The solid Siponimod maleic acid (1: 1) salt Form 8 can be also characterized by XRPD
2Q values (+ 0.2 degrees 2Q) stated in following table:
Figure imgf000020_0001
The solid Siponimod maleic acid (1: 1) salt Form 8 can be also characterized by XRPD pattern depicted in Figure 18 and DSC pattern depicted in Figure 19.
The solid Form 8 of Siponimod maleic acid (1: 1) salt can be prepared by a process comprising contacting Siponimod maleic acid salt with water.
The Siponimod maleic acid salt, Form 8, is monohydrate, i.e. it contains 2.7% of water according to TGA.
The invention also relates to solid Siponimod maleic acid (1: 1) salt, Form 9, that can be characterized by XRPD pattern having 2Q values 7.3°, 9.5°, 17.7° and 18.8° 2Q (+ 0.2 degrees 2Q). The solid Siponimod maleic acid (1: 1) salt Form 9 can be also characterized by XRPD pattern having 2Q values 7.3°, 9.5°, 12.2°, 17.7°, 18.8° and 22.0° 2Q (+ 0.2 degrees 2Q). The solid Siponimod maleic acid (1 : 1) salt Form 9 can be also characterized by XRPD 2Q values (+ 0.2 degrees 2Q) stated in following table:
Figure imgf000021_0001
The solid Siponimod maleic acid (1: 1) salt Form 9 can be also characterized by XRPD pattern depicted in Figure 20 and DSC pattern depicted in Figure 21.
The solid Form 9 can be prepared by a process comprising:
a. Dissolving Siponimod in a mixture of methanol or ethanol with water b. Isolating the solid form
The ratio (w/w) of ethanol or methanol and water can be between 1.1 : 1 and 1.6: 1, preferably it is between 1.2: 1 and 1 :4:1. The concentration of Siponimod in the mixture can be between 0.02 g/ml and 0.05 g/ml. The molar ration between Siponimod and Maleic acid can be between 1 :0.5 and 1 : 1.5, preferably it is between 1 : 1 and 1 : 1.5. Siponimod can be dissolved in the mixture at an elevated temperature, for example between 40°C and 55°C. The mixture can be then cooled to a temperature between 20°C and 30°C. To the mixture Maleic acid is added either as solid or can be added as a mixture with methanol or ethanol. The isolating step b. can be performed by cooling the mixture to a temperature between 0°C and 20°C, preferably to a temperature between 10°C and 15°C and mixing the mixture for between 10 and 120 minutes, preferably for between 15 and 45 minutes. The precipitated solid can be separated by any suitable technique, for example by filtration and dried.
The solid Form 9 of Siponimod maleic acid (1: 1) salt can be also prepared by a process comprising contacting Siponimod maleic acid salt with water for a long term, for example 1/2 year.
The solid Forms 1 or 2 of Siponimod Fumaric acid (1: 1) salt or solid Forms 1 or 2 or 3 or 4 or 5 or 6 or 8 or 9 of Siponimod maleic acid (1: 1) salt can be processed into a suitable pharmaceutical formulation. In the pharmaceutical formulation the solid forms can be mixed with pharmaceutically acceptable adjuvants, diluents or carriers. The amount of solid Forms 1 or 2 of Siponimod Fumaric acid (1 : 1) salt or solid Forms 1 or 2 or 3 or 4 or 5 or 6 or 8 or 9, in the formulation depends on the condition and a patient to be treated. The pharmaceutical formulation can be if form of a solid oral formulation, for example a capsule, a pill, a powder or a granule. In the formulation the Siponimod salts according to presented invention can be mixed with one or more additives such as fillers or extenders or binders or wetting agents or disintegrating agents or absorbents or lubricants or buffering agents. The formulation in a form of a tablet or a dragee or a capsule or a pill or a granule can be coated with a coating or shell such as enteric or other coating. The oral formulation can be in a form of an oral emulsion or a solution or a suspension or a syrup. The formulation can contain suitable additives such as diluent(s) or wetting agent(s) or emulsifying agent(s) or suspending agent(s) or sweetening agent(s) or flavoring agent(s). The examples of suitable additive(s) are known to those skilled in the art. The suitable pharmaceutical formulation can be in a parenteral form such as an injection or an infusion or an injectable depot or in a liposomal form comprising
pharmaceutically acceptable aqueous or non-aqueous solution(s) or dispersion(s) or emulsions. The pharmaceutical formulation can be also in a form of a powder for reconstitution into an injection or infusion. The formulation can further comprise additives such as preservative(s) or wetting agent(s) or emulsifying agent(s) or dispersing agent(s) or antibacterial or antifungal agents. The examples of suitable additive(s) are known to those skilled in the art.
The suitable pharmaceutical formulation can be in a form suitable for rectal or vaginal administration further comprising suitable additive(s). The examples of suitable additive(s) are known to those skilled in the art.
The solid forms 1 or 2 of Siponimod Fumaric acid (1 : 1) salt or solid forms 1 or 2 or 3 or 4 or 5 or 6 or 8 or 9 of Siponimod maleic acid (1 : 1) salt or a pharmaceutical formulation comprising the forms can be used for the treatment of conditions treatable with Siponimod or a salt thereof.
The compound of formula (I) can be prepared by a process disclosed in
W02004/103306.
The amorphous form of compound of formula (I) can be prepared by a process known from the prior art or by a procedure described in Example 1.
The invention will be further illustrated by the following examples.
EXAMPLES
XRPD spectrum of solid compounds was obtained using the following measurement conditions: Panalytical Empyrean diffractometer with Q/2Q geometry (transmition mode), equipped with a PixCell 3D detector
Figure imgf000024_0001
DCS patterns were obtained using the following conditions: 10°C/min -> 250°C Example 1: Preparation of Sinonimod Fumaric acid (1 : 1) salt. Form 1
0.4 g of amorphous Siponimod was mixed with 2 ml of ethanol. The reaction mixture was heated to 60°C to obtain a solution. 0.09 g of Fumaric acid was added to the mixture.
The mixture was heated to 60°C. It was cooled to 25°C, filtered, dried (25°C/1 hour) on filter to obtain 0.3 g of Siponimod Fumaric acid (1 : 1) salt, Form 1. XRPD pattern of obtained solid corresponds to XRPD pattern depicted in Figure 1. DSC pattern of obtained solid corresponds to DSC pattern depicted in Figure 2.
Example 2: Preparation of Siponimod Fumaric acid (1 : 1) salt. Form 1
0.4 g of amorphous Siponimod was mixed with 0.09 g of Fumaric acid and 2 ml of ethanol. The reaction mixture was heated to 40°C to obtain a solution. The mixture was concentrated at 40°C to dryness by vacuum to obtain 0.32 g of Siponimod Fumaric acid (1 : 1) salt, Form 1. XRPD pattern of obtained solid corresponds to XRPD pattern depicted in Figure 1. DSC pattern of obtained solid corresponds to DSC pattern depicted in Figure 2.
Example 3: Preparation of Siponimod Fumaric acid (1 : 1) salt. Form 2
0.4 g of amorphous Siponimod was mixed with 8 ml of 2-propanol. 0.09 g of Fumaric acid was added to the mixture. The reaction mixture was heated to 75 °C to obtain a solution. The mixture was cooled to 0°C and stirred at this temperature over weekend. Precipitated solid was filtered and dried in dryer (25°C, 3 hours, vacuum) to obtain 0.34 g of Siponimod Fumaric acid (1: 1) salt, Form 2. XRPD pattern of obtained solid corresponds to XRPD pattern depicted in Figure 3. DSC pattern of obtained solid corresponds to DSC pattern depicted in Figure 4.
Example 4: Preparation of Siponimod Maleic acid (1 : 1) salt. Form 1
0.4 g of amorphous Siponimod was mixed with 5 ml of isopropyl acetate. The mixture was stirred at 25°C for 15 minutes to obtain a solution. 0.09 g of Maleic acid was added to the mixture. The reaction mixture stirred at 25 °C for 45 minutes to obtain a suspension. The suspension was filtered and dried in dried in dryer (25°C, 1 hours, vacuum) to obtain 0.37 g of Siponimod Maleic acid (1: 1) salt, Form 1. XRPD pattern of obtained solid corresponds to XRPD pattern depicted in Figure 5. DSC pattern of obtained solid corresponds to DSC pattern depicted in Figure 6.
Example 5: Preparation of Siponimod Maleic acid (1: 1) salt. Form 1
0.4 g of amorphous Siponimod was mixed 0.09 g of Maleic acid and 7 ml of diethyl ether. The mixture was stirred at 25°C for 30 minutes The suspension was filtered and dried in dried on filter (25°C, 1 hours, vacuum) to obtain 0.38 g of Siponimod Maleic acid (1: 1) salt, Form 1. XRPD pattern of obtained solid corresponds to XRPD pattern depicted in Figure 5. DSC pattern of obtained solid corresponds to DSC pattern depicted in Figure 6. Example 6: Preparation of Siponimod Maleic acid (1 : 1) salt. Form 1
8.4 g of Siponimod was mixed with 50 ml of isopropyl acetate. 1.8 g of Maleic acid was added to the mixture. The reaction mixture stirred at 25°C over weekend to obtain a suspension. To the suspension 20 ml of isopropyl acetate was added. The suspension was filtered, washed with 50 ml of isopropyl acetate and dried in dried on filter (25°C, 30 minutes, vacuum) to obtain 6.3 g of Siponimod Maleic acid (1: 1) salt, Form 1. XRPD pattern of obtained solid corresponds to XRPD pattern depicted in Figure 5. DSC pattern of obtained solid corresponds to DSC pattern depicted in Figure 6.
Example 7: Preparation of Siponimod Maleic acid (1 : 1) salt. Form 1
0.4 g of amorphous Siponimod was mixed 0.09 g of Maleic acid and 7 ml of methyl tert-butyl ether. The mixture was stirred at 25°C for 30 minutes. The suspension was filtered and dried in dried on filter (25°C, 1 hours, vacuum) to obtain 0.38 g of Siponimod Maleic acid (1 :1) salt, Form 1. XRPD pattern of obtained solid corresponds to XRPD pattern depicted in Figure 5. DSC pattern of obtained solid corresponds to DSC pattern depicted in Figure 6.
Example 8: Preparation of Siponimod Maleic acid (1 : 1) salt. Form 1
7.18 g of Siponimod was dissolved in 120 g of methanol and 90 g of water at 50 °C. The reaction mixture was cooled down to 25 °C and previously prepared solution from 6 g MeOH and 2.34 g maleic acid was added. The clear reaction mixture was seeded with 0.2 g of solid Form 1 of Siponimod Maleic acid (1: 1) salt prepared according to Example 7. The mixture was cooled down to 10-15 °C in the course of 2.5 hour and stirred for 20 minutes. The suspension was filtered and dried on filter for 2 h to obtain yield 6.9 g of solid Form 1 of Siponimod Maleic acid (1: 1) salt.
XRPD pattern of obtained solid corresponds to XRPD pattern depicted in Figure 5. DSC pattern of obtained solid corresponds to DSC pattern depicted in Figure 6. Example 9: Preparation of Siponimod Maleic acid (1 : 1) salt. Form 3
0.4 g of amorphous Siponimod was mixed with 8 ml of methyl tert-butyl ether. The mixture was stirred for 15 minutes at 25°C. 0.09 g of Maleic acid was added. The mixture was stirred at 25°C over weekend. The suspension was filtered and dried in dried in dryer (25°C, 1 hour, vacuum) to obtain 0.38 g of Siponimod Maleic acid (1 :1) salt, Form 3. XRPD pattern of obtained solid corresponds to XRPD pattern depicted in Figure 7. DSC pattern of obtained solid corresponds to DSC pattern depicted in Figure 8.
Example 10: Preparation of Siponimod Maleic acid (1 : 1) salt. Form 4
0.4 g of amorphous Siponimod was mixed with 8 ml of cyclohexane. The mixture was stirred for 15 minutes at 25°C. 0.09 g of Maleic acid was added. The mixture was stirred at 25°C over weekend. The suspension was filtered and dried in dried in dryer (25°C, 1 hour, vacuum) to obtain 0.37 g of Siponimod Maleic acid (1 : 1) salt, Form 4. XRPD pattern of obtained solid corresponds to XRPD pattern depicted in Figure 9. DSC pattern of obtained solid corresponds to DSC pattern depicted in Figure 10.
Example 11 : Preparation of Siponimod Maleic acid (1 : 1) salt. Form 4
4 g of Siponimod was dissolved in 25 ml of isopropyl acetate at 20-25°C. 0.9 g of Maleic acid was added and the mixture was heated at 80°C for 30 minutes. Final solution was cooled to 20-25°C and stirred overnight and then to 0°C in ice bath and stirred for lhour. White precipitate was filtered and dried under vacuum over the night to obtain 2.9 g of Siponimod Maleic acid (1: 1) salt, Form 4. XRPD pattern of obtained solid corresponds to XRPD pattern depicted in Figure 9. DSC pattern of obtained solid corresponds to DSC pattern depicted in Figure 10.
Example 12: Preparation of Siponimod Maleic acid (1 : 1) salt. Form 5
0.5 g of amorphous Siponimod was mixed with 2.5 ml of methanol. The mixture was stirred for 15 minutes at 25°C. 0.112 g of Maleic acid was added and stirred for 15 minutes. The solution was concentrated to dryness in dryer (25°C/12 h/vacuum). The rest was mixed with 4 ml of ethylacetate and left without stirring to crystallize (25°C, 1 hour). The suspension was decanted and the rest was dried on XRPD holder (25°C/30 min/vacuum) to obtain 0.35 g of Siponimod Maleic acid (1: 1) salt, Form 5. XRPD pattern of obtained solid corresponds to XRPD pattern depicted in Figure 11. DSC pattern of obtained solid corresponds to DSC pattern depicted in Figure 12.
Example 13: Preparation of Siponimod Maleic acid (1 : 1) salt. Form 6 and Form 7 0.5 g of amorphous Siponimod was mixed with 2.5 ml of methanol. The mixture was stirred for 15 minutes at 25°C. 0.112 g of Maleic acid was added and stirred for 15 minutes. The solution was concentrated to dryness in dryer (25°C/12 h/vacuum). The rest was mixed with 2 ml of water and left without stirring to crystallize (25°C, 1 hour). The wet solid was analyzed and it corresponds to Form 7 of Siponimod Maleic acid (1: 1) salt. XRPD pattern of obtained solid corresponds to XRPD pattern depicted in Figure 15.
The suspension was decanted and the rest was dried on XRPD holder (25°C/30 min/vacuum) to obtain 0.35 g of Siponimod Maleic acid (1 : 1) salt, Form 6. XRPD pattern of obtained solid corresponds to XRPD pattern depicted in Figure 13. DSC pattern of obtained solid corresponds to DSC pattern depicted in Figure 14.
Example 14: Preparation of Siponimod Maleic acid (1 : 1) salt. Form 2
0.5 g of amorphous Siponimod and 0.112 g of Maleic acid were dissolved in 2.5 ml of methanol. The mixture was concentrated to dryness in dryer (25°C/12 h/vacuum). The rest was contacted with 20 ml of diethyl ether and left without stirring to crystalize. The suspension was filtered, dried on filter to provide 0.45 g of Siponimod Maleic acid (1: 1) salt, Form 2. XRPD pattern of obtained solid corresponds to XRPD pattern depicted in Figure 16. DSC pattern of obtained solid corresponds to DSC pattern depicted in Figure 17. Example 15: Preparation of Siponimod Maleic acid (1 : 1) salt. Form 8
0.8 g of Siponimod maleic acid salt prepared according to Example 4 was mixed with 10 ml of water. The mixture was heated at 60°C for 2 hours, then cooled to 25 °C and filtered. The product was dried under vacuum over the night. Siponimod maleic acid salt, Form 8 was obtained in quantitative yield. XRPD pattern of obtained solid corresponds to XRPD pattern depicted in Figure 18. DSC pattern of obtained solid corresponds to DSC pattern depicted in Figure 19.
Example 16: Preparation of Siponimod Maleic acid (1 : 1) salt. Form 9
2 g of Siponimod maleic acid salt prepared according to Example 13 was mixed with 10 ml of water and left standing for 1/2 year. Obtained solid was filtered off and dried on air overnight. Siponimod maleic acid salt, Form 9 was obtained in quantitative yield. XRPD pattern of obtained solid corresponds to XRPD pattern depicted in Figure 20. DSC pattern of obtained solid corresponds to DSC pattern depicted in Figure 21.
Example 17: Preparation of Siponimod Maleic acid (1 : 11 salt. Form 9
2.93 g of Siponimod was dissolved in 40 g of methanol and 30 g of water at 50 °C. The mixture was cooled down to 25 °C. Previously prepared solution from 5 g MeOH and 0.9 g maleic acid was added. The clear reaction mixture was cooled down to 10-15 °C (without seeding). The suspension was filtered and dried on filter 2 h and subsequent in dryer at 60 °C for 3 h to obtain 2.5 g of Siponimod maleic acid salt, Form 9. XRPD pattern of obtained solid corresponds to XRPD pattern depicted in Figure 20. DSC pattern of obtained solid corresponds to DSC pattern depicted in Figure 21.
Comparison example 18: Comparison of stability
Prior art Siponimod Fumarate (1 :0.5), Form A, was prepared according to a procedure disclosed in WO2010/080409. Water activity of the prior art form and solid forms of presented invention was measured: DVS machine ProUmid SPX-Im Advance, 25°C, 0-90-0 % relative humidity, step 10%, maximal time per step 10 hours. Equilibrium bandwidth 0.05%/60 minutes.
Following table summarizes water activity of tested solid forms:
Figure imgf000030_0001
Water activity: a difference between the weights of the sample in 0 and 90% of relative humidity at a constant temperature. It corresponds to the amount of water taken by
Siponimod salt when the humidity changes from 0 to 90% at a constant temperature. The higher water activity the more water can be taken by the compound and that might result in lower purity of the compound because hydrolysis impurities can be formed. It can also result in mechanical stress in final products (for example tablets) because the compound taking water increases its volume and the volume of the final product (for example tablet) is also increased and that results in cracking of the product.
It can be concluded that lower water activity of the salts of the presented invention results in better stabilities and better mechanical properties of the final product in comparison with the prior art salt.

Claims

1. Siponimod maleic acid (1: 1) salt.
2. A solid form of Siponimod maleic acid (1: 1) salt.
3. The solid form according to claim 2, Form 1, characterized by XRPD pattern having 2Q values 3.6°, 15.6° and 16.7° 2Q (+ 0.2 degrees 2Q).
4. The solid form according to claim 3 characterized by XRPD pattern having 2Q values 3.6°, 8.3°, 14.8°, 15.6° and 16.7° 2Q (+ 0.2 degrees 2Q).
5. The solid form according to anyone of claims 3 or 4 characterized by DSC pattern depicted in Figure 6.
6. A process for preparation of the solid form according to anyone of claims 3 to 5
comprising:
a. Contacting Siponimod and Maleic acid in a solvent selected from
isopropylacetate or diethylether or methyl tert-butyl ether;
b. Isolating the solid form.
7. A process for preparation of the solid form according to anyone of claims 3 to 5
comprising:
a. Contacting Siponimod and Maleic acid with a solvent mixture of methanol or ethanol with water;
b. Seeding the mixture with solid Form lof Siponimod maleic acid (1 : 1) salt;
c. Isolating the solid form.
8. The solid form according to claim 2, Form 3, characterized by XRPD pattern having 2Q values 12.9°, 18.0° and 19.2° 2Q (+ 0.2 degrees 2Q).
9. The solid form according to claim 7, characterized by XRPD pattern having 2Q values 7.5°, 8.1°, 12.9°, 18.0° and 19.2° 2Q (+ 0.2 degrees 2Q).
10. The solid form according to anyone of claims 7 or 8 characterized by DSC pattern depicted in Figure 8.
11. A process for preparation of the solid form according to anyone of claims 7 to 10
comprising:
a. Contacting Siponimod and Maleic acid in methyl tert-butyl ether;
b. Isolating the solid form.
12. The process according to claim 11 wherein the mixture prepared in step a. is seeded with solid Form 3 of Siponimod maleic acid (1: 1) salt.
13. The solid form according to claim 2, Form 4, characterized by XRPD pattern having 2Q values 12.7°, 17.6° and 20.4° 2Q (+ 0.2 degrees 2Q).
14. The solid form according to claim 13, characterized by XRPD pattern having 2Q values
7.2°, 12.7°, 13.1°, 16.8°, 17.6° and 20.4° 2Q (± 0.2 degrees 2Q).
15. The solid form according to anyone of claims 13 or 14 characterized by DSC pattern depicted in Figure 10.
16. A process for preparation of the solid form according to anyone of claims 13 to 15 comprising:
a. Suspending Siponimod and Maleic acid in cyclohexane;
b. Isolating the solid form.
17. A process for preparation of the solid form according to anyone of claims 13 to 15 comprising:
a. Dissolving Siponimod and Maleic acid in an acetate;
b. Isolating the solid form.
18. The solid form according to claim 2, Form 8, characterized by XRPD pattern having 2Q values 6.0°, 7.1°, 16.6° and 21.2° 2Q (+ 0.2 degrees 2Q).
19. The solid form according to claim 18 characterized by XRPD pattern having 2Q values
6.0°, 7.1°, 13.1°, 15.8°, 16.6° and 21.2° 2Q (+ 0.2 degrees 2Q).
20. The solid form according to anyone of claims 18 or 19 characterized by DSC pattern depicted in Figure 19.
21. A process for preparation of the solid form according to anyone of claims 18 to 20 comprising contacting Siponimod maleic acid salt with water.
22. A solid form of Siponimod fumaric acid (1: 1) salt.
23. The solid form according to claim 22, Form 1, characterized by XRPD pattern having 2Q values 7.1°, 12.1°, 16.4° and 17.9° 2Q (+ 0.2 degrees 2Q).
24. The solid form according to claim 23 characterized by XRPD pattern having 2Q values
7.1°, 10.7°, 12.1°, 13.6°, 15.5°, 16.4° and 17.9° 2Q (+ 0.2 degrees 2Q).
25. The solid form according to anyone of claims 23 or 24 characterized by DSC pattern depicted in Figure 2.
26. A process for preparation of the solid form according to anyone of claims 23 to 25 comprising:
a. Dissolving Siponimod and Fumaric acid in an alcohol;
b. Isolating the solid form.
27. The process according to claim 26 wherein the alcohol is selected form methanol or ethanol or propanol or isopropanol or butanol or tert-butanol.
28. The process according to claim 27 wherein the alcohol is ethanol.
29. The process according to any one of claims 26 to 28 wherein the isolating step b. is done at a temperature higher than 15°C.
30. The process according to any one of claims 26 to 29 wherein the step a. comprises heating the solution to a temperature between 40°C and 80°C and the step c. comprises cooling the mixture to a temperature higher than 15°C.
1. The process according to any one of claims 26 to 29 wherein the step a. comprises heating the solution to a temperature between 40°C and 80°C and the step c. comprises concentrating of the mixture.
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WO2010080455A1 (en) 2008-12-18 2010-07-15 Novartis Ag New salts
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