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WO2020208167A1 - Formes solide de siponimod - Google Patents

Formes solide de siponimod Download PDF

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Publication number
WO2020208167A1
WO2020208167A1 PCT/EP2020/060213 EP2020060213W WO2020208167A1 WO 2020208167 A1 WO2020208167 A1 WO 2020208167A1 EP 2020060213 W EP2020060213 W EP 2020060213W WO 2020208167 A1 WO2020208167 A1 WO 2020208167A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
solid form
solid
xrpd pattern
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2020/060213
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English (en)
Inventor
Bohumil Dymacek
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Synthon BV
Original Assignee
Synthon BV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Synthon BV filed Critical Synthon BV
Priority to EP20716504.4A priority Critical patent/EP3953326A1/fr
Publication of WO2020208167A1 publication Critical patent/WO2020208167A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to solid forms 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.
  • a solid form of Siponiomod, form A, is disclosed in WO 2010/071794 application.
  • the presented invention relates to solid forms of Siponimod, compound of formula (I),
  • the presented invention relates to a solid form of compound of formula (I), Form 1 characterized by XRPD pattern having 2Q values 3.3°, 9.7°, 9.9° and 15.5° 2Q (+ 0.2 degrees 2Q).
  • the presented invention also relates to a process for preparation of solid Form 1 of compound of formula (I) comprising:
  • the presented invention further relates to a process for preparation of solid Form 2 of compound of formula (I) comprising:
  • the presented invention further relates to a solid form of compound of formula (I), Form 3 characterized by XRPD pattern having 2Q values 3.5°, 7.2°, 8.6°, 9.0°, 9.6 and 10.9° 2Q (+ 0.2 degrees 2Q).
  • the presented invention further relates to a process for preparation of solid Form 3 of compound of formula (I) comprising:
  • the presented invention also relates to a solid form of compound of formula (I), Form 6, characterized by XRPD pattern having 2Q values 2.4° 2Q (+ 0.2 degrees 2Q).
  • the presented invention further relates to a process for preparation the solid Form 6 comprising exposing a solid form of compound of formula (I) to relative humidity higher than 50%.
  • the presented invention also relates to a process for preparation of solid Form A of the compound of formula (I), characterized by XRPD pattern having 2Q values 18.2°C or 20.9° 2Q (+ 0.2 degrees 2Q), comprising:
  • the presented invention further relates to a process for preparation of solid Form A of the compound of formula (I), characterized by XRPD pattern having 2Q values 18.2°C or 20.9° 2Q (+ 0.2 degrees 2Q), comprising drying the solid Form 4 of the compound of formula (I).
  • the presented solid Forms 1, 2, 3 and 6 show good crystallinity and improved stability in comparison with solid Form A disclosed in the prior art.
  • the presented process for preparation of solid form A uses acetonitrile as a single solvent for crystallization of the compound of formula (I). Contrary to that the process disclosed in the prior art uses a solvent mixture.
  • Figure 8 XRPD pattern of solid Form 5 of compound of formula (I)
  • Figure 9 XRPD pattern of solid Form 6 of compound of formula (I)
  • the solid Form 1 can be further characterized by XRPD pattern having 2Q values 3.3°, 9.7°, 9.9°, 14.3°, 15.5°, 17.4° 2Q (+ 0.2 degrees 2Q).
  • the solid Form 1 can be also characterized by XRPD 2Q values (+ 0.2 degrees 2Q) stated in following table:
  • the solid Form 1 can be also characterized by XRPD pattern depicted in Figure 1.
  • the solid Form 1 can be further characterized by DSC pattern depicted in Figure 2.
  • the Form 1 of the compound of formula (I) can be prepared by a process comprising: 1. Dissolving compound of formula (I), preferably in amorphous form, in toluene;
  • an antisolvent such as an alkane (for example pentane or heptane or hexane or octane), preferably heptane;
  • the concentration of compound of formula (I) in toluene can be between 0.2 g/ml and 1 g/ml, preferably it is between 0.3 g/ml and 0.7 g/ml.
  • the mixture is stirred for between 20 and 120 minutes, preferably for between 30 and 60 minutes.
  • an antisolvent such as an alkane (for example pentane or heptane or hexane or octane), preferably heptane is added.
  • the volume ratio between toluene and used antisolvent can be between 1:2 and 1:5, preferably it is between 1:2.5 and 1:4, more preferably it is 1:3.
  • the mixture is stirred at a temperature between 20°C and 25°C for between 60 and 180 minutes, preferably for between 75 and 120 minutes to obtain solid Form 1 of compound of formula (I).
  • the obtained solid can be isolated by any suitable technique, for example by filtration and dried.
  • the solid can be dried either after filtration on the filter using blowing the air or at an elevated temperature, for example between 40°C and 90°C in a dryer.
  • the presented invention further relates to a solid Form 2 of compound of formula (I) characterized by XRPD pattern having 2Q values 3.7°, 11.1°, 12.1°, 13.5° and 17.3° 2Q (+ 0.2 degrees 2Q).
  • the solid Form 2 can be further characterized by XRPD pattern having 2Q values 3.1°, 10.1°, 11.1°, 12.1°, 13.5°, 14.8°, 15.4° and 17.3° 2Q ( ⁇ 0.2 degrees 2Q).
  • the solid Form 2 can be also 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.
  • the solid Form 2 can be further characterized by DSC pattern depicted in Figure 4.
  • the solid Form 2 of compound of formula (I) can be prepared by a process comprising:
  • the concentration of compound of formula (I) in diethylether can be between 0.04 and 0.08 g/ml, preferably it is between 0.05 and 0.07 g/ml.
  • the mixture is stirred to obtain a solution, preferably at a temperature between 20°C and 30°C for between 10 and 60 minutes.
  • the mixture is then stirred at a temperature between 20°C and 25°C to obtain a suspension.
  • the solid Form 2 of compound of formula (I) is isolated by any suitable technique, for example by filtration and dried. The solid can be dried either after filtration on the filter using blowing the air or at an elevated temperature, for example between 40°C and 90°C in a dryer.
  • the presented invention also relates to a solid Form 3 of compound of formula (I) characterized by XRPD pattern having 2Q values 3.5°, 7.2°, 8.5°, 9.0°, 9.6° and 10.9° 2Q (+ 0.2 degrees 2Q).
  • the solid Form 3 can be further characterized by XRPD pattern having 2Q values 3.5°, 7.2°, 8.5°, 9.0°, 9.6°, 10.9°, 15.4° and 15.7° 2Q (+ 0.2 degrees 2Q).
  • the solid Form 3 can be also characterized by XRPD 2Q values (+ 0.2 degrees 2Q) stated in following table:
  • the solid Form 3 can be also characterized by XRPD pattern depicted in Figure 5.
  • the solid Form 3 can be further characterized by DSC pattern depicted in Figure 6.
  • the solid Form 3 of compound of formula (I) can be prepared by a process comprising: 1. Contacting the compound of formula (I), preferably in amorphous form, with cyclohexane;
  • the concentration of compound of formula (I) in cyclohexane can be between 0.03 g/ml and 0.08 g/ml, preferably it is between 0.04 g/ml and 0.06 g/ml. After dissolution the mixture is stirred to obtain a suspension, for example for between 10 and 72 hours, preferably for between 10 and 20 hours.
  • the solid Form 3 of compound of formula (I) is isolated by any suitable technique, for example by filtration and dried. The solid can be dried either after filtration on the filter using blowing the air or at an elevated temperature, for example between 40°C and 90°C in a dryer.
  • the presented invention also relates to a solid Form 4 of compound of formula (I).
  • the solid form can be characterized by XRPD patern depicted in Figure 7.
  • the Form 4 can be further characterized by XRPD 2Q values (+ 0.2 degrees 2Q) stated in following table:
  • the solid Form 4 can be prepared by a process comprising:
  • the concentration of compound of formula (I) in diisopropylether can be between 0.03 g/ml and 0.08 g/ml, preferably it is between 0.04 g/ml and 0.06 g/ml.
  • solid Form 5 of compound of formula (I) is obtained.
  • the solid Form 5 can be characterized by XRPD patern depicted in Figure 8.
  • the solid Form 5 can be further characterized by XRPD 2Q values (+ 0.2 degrees 2Q) stated in following table:
  • the presented invention provides a process for preparation of solid Form A of the compound of formula (I), the process comprising drying the solid Form 4 of the compound of formula (I), preferably at a temperature between 20°C and 30°C.
  • the solid Form 4 can be dried at this temperature for between 20 and 120 minutes, preferably for between 30 and 60 minutes.
  • the Form 6 can be characterized by XRPD pattern having 2Q value 2.4° 2Q (+ 0.2 degrees 2Q).
  • the Form 6 can be characterized by XRPD pattern depicted in Figure 9.
  • the reflexion at approximately 6.4° 2Q originates from Kapton® Polyimide that is used for sealing the humidity chamber.
  • Kapton® Polyimide foil has reflection at this angle.
  • the Form 7 can be characterized by XRPD pattern depicted in Figure 10.
  • the Form 7 can be further characterized by XRPD 2Q values (+ 0.2 degrees 2Q) stated in following table:
  • the presented invention also provides a process for preparation of Form A of the compound of formula (I), the process comprising:
  • the concentration of the compound of formula (I) can be between 0.05 and 0.2 g/ml, preferably it is between 0.08 and 0.15 g/ml.
  • the compound of formula (I) is dissolved in acetonitrile at a temperature between 20°C and the reflux temperature of acetonitrile, the mixture is then cooled to a temperature between 20°C and 30°C, preferably to a temperature between 20°C and 25°C and stirred at this temperature for between 12 and 96 hours, preferably between 12 and 48 hours, to obtain a suspension.
  • the solid Form A of compound of formula (I) can be isolated by any suitable technique, for example by filtration and dried.
  • the solid can be dried either after filtration on the filter using blowing the air or at an elevated temperature, for example between 40°C and 90°C in a dryer.
  • the XRPD pattern of obtained solid Form A corresponds to XRPD patern of form A disclosed in WO
  • the XPRD patern of obtained solid Form A corresponds to XRPD patern depicted in Figure 11.
  • DSC patern of obtained solid Form A corresponds to DSC patern depicted in Figure 12.
  • the solid forms 1 or 2 or 3 or 4 or 5 or 6 or 7 of the compound of formula (I) 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 compound of formula (I), Form 1 or 2 or 3 or 4 or 5 or 6 or 7, 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 compound of formula (I) can be mixed with one or more additives such as fillers or extenders or binders or weting 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 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.
  • solid Forms 1 or 2 or 3 or 4 or 5 or 6 or 7 of the compound of formula (I) or a pharmaceutical formulation comprising the forms can be used for the treatment of conditions treatable with compound of formula (I).
  • 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.
  • DCS patterns were obtained using the following conditions: 10°C/min -> 250°C.
  • the solvent was removed by evaporation and the residue was diluted with 156 ml of water and 312 ml of ethyl acetate. pH of the mixture was adjusted by addition of 75 ml of 2M aqueous NaOH to approx 6 at 20°C-25°C. The phases were separated and the organic phase was washed with 60 ml of water, dried using MgS04 and filtered. To the filtrate was added 170 ml of absolute EtOH , the solution was concentrated to the 1 ⁇ 2 of the original volume. The mixture was again dried using MgSCH, filtered and concentrated to amount of 140 g. 170 ml of absolute EtOH absolute was added and the mixture was concentrated to amount of 140 g.
  • the XRPD pattern of obtained Form 6 corresponds to XRPD pattern depicted in Figure 9.
  • Form 7 of the compound of formula (I) was obtained by exposing Form 6 of the compound of formula (I) to a relative humidity 30% for 1 hour.
  • the XRPD pattern of obtained form 7 corresponds to XRPD pattern depicted in Figure 10.
  • Comparison example 8 Comparison of stability of solid Form A Form 1. Form 2
  • Form A of the compound of formula (I) can be prepared according to a process disclosed in WO 2010/071794 or by a process described in Example 8.
  • the stability of tested polymorph was measured at temperature 25°C in the humidity chamber in the relative humidity range 10-90% with 10% step.
  • the XRPD pattern of obtained solid Form A corresponds to XRPD pattern of form A disclosed in WO 2010/071794.
  • the XPRD pattern of obtained solid Form A corresponds to XRPD pattern depicted in Figure 11.
  • DSC pattern of obtained solid Form A corresponds to DSC pattern depicted in Figure 12.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (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

La présente invention concerne la forme solide 1, la forme solide 2, la forme solide 3 et la forme solide 6 du composé de siponimod et leurs procédés de préparation. La présente invention concerne en outre des procédés de préparation de la forme solide A du composé de siponimod.
PCT/EP2020/060213 2019-04-11 2020-04-09 Formes solide de siponimod Ceased WO2020208167A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP20716504.4A EP3953326A1 (fr) 2019-04-11 2020-04-09 Formes solide de siponimod

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP19168791 2019-04-11
EP19168791.2 2019-04-11

Publications (1)

Publication Number Publication Date
WO2020208167A1 true WO2020208167A1 (fr) 2020-10-15

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PCT/EP2020/060213 Ceased WO2020208167A1 (fr) 2019-04-11 2020-04-09 Formes solide de siponimod

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EP (1) EP3953326A1 (fr)
WO (1) WO2020208167A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004103306A2 (fr) 2003-05-19 2004-12-02 Irm Llc Composes immunosuppresseurs et compositions
WO2010071794A1 (fr) 2008-12-18 2010-06-24 Novartis Ag Nouvelle forme polymorphe de 1-(4-{l-[(e)-4-cyclohexyl-3-trifluorométhyl-benzyloxyimino]-éthyl}-2-éthyl-benzyl)-azétidine-s-carboxylique
WO2010103306A1 (fr) * 2009-03-10 2010-09-16 Astrazeneca Uk Limited Dérivés de benzimidazole et leur utilisation comme agents antiviraux
WO2019064184A1 (fr) * 2017-09-27 2019-04-04 Dr. Reddy's Laboratories Limited Procédé de préparation de siponimod, de ses sels et de formes à l'état solide associées

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004103306A2 (fr) 2003-05-19 2004-12-02 Irm Llc Composes immunosuppresseurs et compositions
WO2010071794A1 (fr) 2008-12-18 2010-06-24 Novartis Ag Nouvelle forme polymorphe de 1-(4-{l-[(e)-4-cyclohexyl-3-trifluorométhyl-benzyloxyimino]-éthyl}-2-éthyl-benzyl)-azétidine-s-carboxylique
WO2010103306A1 (fr) * 2009-03-10 2010-09-16 Astrazeneca Uk Limited Dérivés de benzimidazole et leur utilisation comme agents antiviraux
WO2019064184A1 (fr) * 2017-09-27 2019-04-04 Dr. Reddy's Laboratories Limited Procédé de préparation de siponimod, de ses sels et de formes à l'état solide associées

Also Published As

Publication number Publication date
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