EP3953326A1 - Solid forms of siponimod - Google Patents

Solid forms of siponimod

Info

Publication number
EP3953326A1
EP3953326A1 EP20716504.4A EP20716504A EP3953326A1 EP 3953326 A1 EP3953326 A1 EP 3953326A1 EP 20716504 A EP20716504 A EP 20716504A EP 3953326 A1 EP3953326 A1 EP 3953326A1
Authority
EP
European Patent Office
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.)
Withdrawn
Application number
EP20716504.4A
Other languages
German (de)
French (fr)
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
Publication of EP3953326A1 publication Critical patent/EP3953326A1/en
Withdrawn legal-status Critical Current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.

Abstract

The present invention relates to solid Form 1, Form 2, Form 3 and Form 6 of the compound Siponimod and processes for preparation thereof. The present invention further relates to processes for preparation of solid Form A of the compound Siponimod.

Description

SOLID FORMS OF SIPONIMOD
BACKGROUND OF THE PRESENT INVENTION
The present invention relates to solid forms of the compound Siponimod.
Siponimod, l-{4-[l-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl- benzyl}-azetidine-3 -carboxylic acid of formula (I),
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. A solid form of Siponiomod, form A, is disclosed in WO 2010/071794 application. SUMMARY OF THE INVENTION
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:
1. Dissolving compound of formula (I) in toluene;
2. Adding of an alkane;
3. Isolating of the solid Form 1.
It also relates to a solid form of compound of formula (I), Form 2 characterized by XRPD pattern having 2Q values 3.7°, 11.1°, 12.1°, 13.5° and 17.3° 2Q (+ 0.2 degrees 2Q).
The presented invention further relates to a process for preparation of solid Form 2 of compound of formula (I) comprising:
1. Dissolving compound of formula (I) in diethylether;
2. Stirring to obtain a suspension;
3. Isolating of the solid Form 2.
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:
1. Dissolving compound of formula (I) in cyclohexane;
1. Stirring to obtain a suspension;
2. Isolating of the solid Form 3.
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:
1. Dissolving the compound of formula (I) in acetonitrile;
2. Stirring the mixture to obtain suspension;
3. Isolating of the solid Form A.
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.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 : XRPD pattern of solid Form 1 of compound of formula (I)
Figure 2: DSC pattern of solid Form 1 of compound of formula (I)
Figure 3: XRPD pattern of solid Form 2 of compound of formula (I)
Figure 4: DSC pattern of solid Form 2 of compound of formula (I)
Figure 5: XRPD pattern of solid Form 3 of compound of formula (I)
Figure 6: DSC pattern of solid Form 3 of compound of formula (I)
Figure 7: XRPD pattern of solid Form 4 of compound of formula (I)
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)
Figure 10: XRPD pattern of solid Form 7 of compound of formula (I)
Figure 11: XRPD pattern of solid Form A of compound of formula (I)
Figure 12: DSC pattern of solid Form A of compound of formula (I)
DETAILED DESCRIPTION OF THE INVENTION
The presented invention to a solid Form 1 of compound of formula (I) characterized by XRPD pattern having 2Q values 3.3°, 9.7°, 9.9° and 15.5° 2Q (+ 0.2 degrees 2Q).
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;
2. Adding of an antisolvent such as an alkane (for example pentane or heptane or hexane or octane), preferably heptane;
3. Isolating of the solid Form 1.
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. To the mixture 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:
1. Dissolving compound of formula (I), preferably in amorphous form, in
diethylether;
2. Stirring to obtain a suspension;
3. Isolating of the solid Form 2.
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;
2 Stirring to obtain a suspension; 3. Isolating of the solid Form 3.
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:
1. Contacting the compound of formula (I), preferably in amorphous form, with diisopropylether;
2. Stirring to obtain a suspension; 3. Isolating the solid Form 4.
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.
The mixture is stirred at a temperature between 20°C and 30°C for between 60 and 180 minutes, a solid Form 4 is obtained.
When a suspension of solid Form 4 in a solvent, for example diisopropylether, is dried at a temperature between 20°C and 30°C for between 20 and 30 hours 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:
When a solid Form 4 of the compound of formula (I) is dried at a temperature between
20°C and 30°C for between 10 and 60 minutes Form A of compound of formula (I) is obtained.
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.
When a solid Form 2 or Form 3 of compound of formula (I) is exposed in a humidity chamber to humidity higher than 50%, preferably higher than 60 or 70% or 80% or 90%, for between 30 to 90 minutes, Form 6 of compound of formula (I) is obtained.
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.
When the Form 6 is exposed to humidity lower than 45% it converts to Form 7 of compound of formula (I).
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:
1. Dissolving the compound of formula (I) in acetonitrile;
2. Stirring the mixture to obtain suspension; 3. Isolating the Form A.
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
2010/071794. 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. In the 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. In the solid oral formulation 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). 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 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
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, non-limiting, 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;
DCS patterns were obtained using the following conditions: 10°C/min -> 250°C.
Example 1 : Preparation of amorphous form of compound of formula (I)
26 g of (E)-4-(l-(((4-cyclohexyl-3-(trifluoromethyl)benzyl)oxy)imino)ethyl)-2- ethylbenzaldehyde and 8.53 g of azetidine-3 -carboxylic acid were suspended in 400 ml of MeOH at 20°C-25°C. The suspension was stirred at 20°C-25°C for 30 minutes. 24.3 g of Sodium triacetoxyborohydride was added in 8 equal portions in 10-15 min intervals. The reaction was finished right after the final portion of the reducing agent was added. 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 ½ 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. 170 ml of absolute EtOH and 2.4 g of activated charcoal were added and the suspension was agitated for 30 min. The suspension was filtered and the filtrate was concentrated to amount 50 g. To this oily residue, 100 ml of n-heptane was added and the solution was again concentrated to amount 50 g. 100 ml of n-heptane was added and the solution was concentrated to dryness. The formed foam was dried to provide foam that can be crushed to white solid amorphous compound of formula (I), 28.22 g (89% of theoretical yield), 98.5% purity (HPLC in).
Example 2: Solid Form 1 of compound of formula (I)
0.4 g of compound of formula (I) were mixed with 0.8 ml of toluene. The mixture was stirred 0.5 hour at 20°C - 25°C to obtain solution. To the mixture 2.4 ml of n-heptane were added and the mixture was stirred for 1.5 hour at 20-25 °C. The obtained suspension was filtered and the obtained solid was dried on filter for 1 hour to provide 235 mg of Form 1 of compound of formula (I). XRPD pattern of obtained solid is depicted in Figure 1 and DSC pattern of obtained solid is depicted in Figure 2.
Example 3: Solid Form 1 of compound of formula (II
3.00 g of compound of formula (I) were dissolved in 10 ml of toluene 10 ml at 20- 25°C. 20 ml of n-heptane was added. The mixture was stirred for 20 hours. The mixture was filtrated and dried at 70 °C, 100 torr, N2 strip, for 6 hours. 1.85g of solid Form 1 was obtained. XRPD pattern of obtained solid is depicted in Figure 1 and DSC pattern of obtained solid is depicted in Figure 2.
Example 4: Solid Form 2 of compound of formula (II
0.4 g of compound of formula (I) were mixed with 7 ml of diethylether and the mixture was stirred at 25 °C for 10 minutes to obtain a solution. The mixture was stirred for 20 min to obtain suspension. The suspension was filtered, obtained solid was dried on filter to provide 280 mg of compound of formula (I), Form 2. XRPD pattern of obtained solid is depicted in Figure 3 and DSC pattern of obtained solid is depicted in Figure 4.
Example 5: Solid Form 3 of compound of formula (II
0.4 g of compound of formula (I) were mixed with 8 ml of cyclohexane. The mixture was stirred for 48 hours at 25 °C to obtain a suspension. The suspension was filtered.
Obtained solid dried on filter to provide 285 mg of compound of formula (I), Form 3. XRPD pattern of obtained solid is depicted in Figure 5 and DSC pattern of obtained solid is depicted in Figure 6.
Example 6: Solid Forms 4 or 5 of compound of formula (II
0.4 g of compound of formula (I) were mixed with 8 ml of diisopropylether. The mixture was stirred at 25°C for 1 hour to obtain a suspension. The obtained solid in the suspension is Form 4 of compound of formula (I). XRPD pattern of obtained solid is depicted in Figure 7. The obtained suspension was dried at 20 - 25°C for 24 hours to obtain Form 5 of compound of formula (I). XRPD pattern of obtained solid is depicted in Figure 8.
Example 7: Solid Forms 6 or 7 of compound of formula (II
Form 6 of the compound of formula (I) was obtained by either:
· Exposing the solid Form 2 to relative humidity 70% and 25°C for 45 minutes; or
• Exposing the solid Form 3 to relative humidity 90% and 25°C for 45 minutes.
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 3
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 result of the experiment is summarized in the following table.
It can be concluded that solid Forms 1 or 2 or 3 of the compound of formula (I) are more stable than solid Form A. Example 8: Compound of formula (I). Form A
0.4 g of compound of formula (I) were mixed with 4 ml of acetonitrile. The mixture was stirred at 20°C-25°C for two days to obtain a suspension. The suspension was filtered, the filtrated mass was dried on filter to provide 249 mg of the compound of formula (I), Form A. 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.
Example 9: Compound of formula (IT Form A
0.4 g of solid Form 4 of compound of formula (I) was dried at 20 - 25 °C for 30 minutes to obtain solid Form A of compound of formula (I). 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.

Claims

1. 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).
2. The solid form according to claim 1 wherein the solid form is characterized by DSC pattern depicted in Figure 2.
3. A process for preparation the solid form according to claims 1 or 2 comprising: a. Dissolving compound of formula (I) in toluene;
b. Adding of an alkane;
c. Isolating of the solid Form 1.
4. The process according to claim 3 wherein the alkane is selected from pentane or heptane or hexane or octane.
5. A solid form of compound of formula (I), Form 2, characterized by XRPD pattern having 2Q values 3.7°, 11.1°, 12.1°, 13.5° and 17.3° 2Q (+ 0.2 degrees 2Q).
6. The solid form according to claim 5 wherein the solid form is characterized by DSC pattern depicted in Figure 4.
7. A process for preparation the solid form according to claims 5 or 6 comprising: a. Dissolving compound of formula (I) in diethylether;
b. Stirring to obtain a suspension;
c. Isolating of the solid Form 2.
8. 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).
9. The solid form according to claim 8 wherein the solid form is characterized by DSC pattern depicted in Figure 6.
10. A process for preparation the solid form according to claims 8 or 9 comprising:
a. Contacting the compound of formula (I) with cyclohexane;
b. Stirring to obtain a suspension;
c. Isolating of the solid Form 3.
11. The process according to claims 3 or 7 or 10 wherein the compound of formula (I) is in an amorphous form.
12. A solid form of compound of formula (I), Form 6, characterized by XRPD pattern
having 2Q values 2.4° 2Q (+ 0.2 degrees 2Q).
13. A process for preparation the solid form according to claim 12 comprising exposing a solid form of compound of formula (I) to relative humidity higher than 50%.
14. The process according to claim 13 wherein the solid form of compound of formula (I) is the Form 2 or Form 3 of the compound of formula (I).
15. The process according to claims 13 or 14 wherein the relative humidity is higher than 60% or 70% or 80% or 90%.
16. 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:
a. Dissolving the compound of formula (I) in acetonitrile;
b. Stirring the mixture to obtain suspension;
c. Isolating of the solid Form A.
17. 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).
18. The process according to claim 17 wherein the Form 4 is dried at a temperature between 20°C and 30°C.
EP20716504.4A 2019-04-11 2020-04-09 Solid forms of siponimod Withdrawn EP3953326A1 (en)

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