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WO2025125383A1 - Formes cristallines d'hydrogénomaléate d'acalabrutinib - Google Patents

Formes cristallines d'hydrogénomaléate d'acalabrutinib Download PDF

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Publication number
WO2025125383A1
WO2025125383A1 PCT/EP2024/085803 EP2024085803W WO2025125383A1 WO 2025125383 A1 WO2025125383 A1 WO 2025125383A1 EP 2024085803 W EP2024085803 W EP 2024085803W WO 2025125383 A1 WO2025125383 A1 WO 2025125383A1
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WIPO (PCT)
Prior art keywords
acalabrutinib
ethanol
water
mixture
solid form
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.)
Pending
Application number
PCT/EP2024/085803
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English (en)
Inventor
Bohumil Dymacek
Michal HEGEDUS
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Synthon BV
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Synthon BV
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Publication of WO2025125383A1 publication Critical patent/WO2025125383A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to mixed ethanol-water solvate and methanol solvate of
  • Acalabrutinib hydrogen maleate compound of formula (1), solid forms thereof and processes for preparation thereof:
  • the invention relates to methanol solvate of Acalabrutinib hydrogen maleate (molar ratio between Acalabrutinib and maleic acid is 1: 1), compound of formula (1), solid form thereof and processes for preparation thereof:
  • Figure 1 depicts the X-Ray Powder Diffractogram (XRPD) pattern of crystalline Form
  • FIG. 2 depicts the Thermogravimetric (TGA) pattern of crystalline Form 1 of methanol solvate of Acalabrutinib hydrogen maleate, prepared according to Example 1.
  • Figure 3 depicts the DSC pattern of crystalline Form 1 of methanol solvate of Acalabrutinib hydrogen maleate, prepared according to Example 1.
  • Figure 5 depicts the X-Ray Powder Diffractogram (XRPD) pattern of crystalline Form
  • FIG. 6 depicts the Thermogravimetric (TGA) pattern of crystalline Form 2 of mixed ethanol water solvate of Acalabrutinib hydrogen maleate, prepared according to Example 2 or
  • Figure 7 depicts the DSC pattern of crystalline Form 2 of mixed ethanol water solvate of Acalabrutinib hydrogen maleate, prepared according to Example 2 or 3 or 4 or 5.
  • Figure 8 depicts SEM picture of crystalline Form 2 of mixed ethanol water solvate of Acalabrutinib hydrogen maleate, prepared according to Example 2 or 3 or 4 or 5.
  • Figure 9 depicts the X-Ray Powder Diffractogram (XRPD) pattern of crystalline Form A of Acalabrutinib hydrogen maleate, prepared according to process disclosed in WO2017002095.
  • XRPD X-Ray Powder Diffractogram
  • Figure 10 depicts the DSC pattern of crystalline Form A of Acalabrutinib hydrogen maleate, prepared according to process disclosed in W02017002095.
  • Figure 11 depicts SEM picture of crystalline Form A of Acalabrutinib hydrogen maleate, prepared according to process disclosed in W02017002095.
  • Figure 12 depicts the X-Ray Powder Diffractogram (XRPD) pattern of crystalline Form P2 of Acalabrutinib hydrogen maleate, prepared according to Example 2 or 3.
  • XRPD X-Ray Powder Diffractogram
  • Figure 13 depicts the X-Ray Powder Diffractogram (XRPD) pattern of crystalline Form
  • Figure 14 depicts the DSC pattern of crystalline Form 3 of Acalabrutinib hydrogen maleate, prepared according to Example 6.
  • XRPD X-Ray Powder Diffractogram
  • Figure 15 depicts the TGA pattern of crystalline Form 3 of Acalabrutinib hydrogen maleate, prepared according to Example 6.
  • Figure 16 depicts SEM picture of crystalline Form 2 of mixed ethanol water solvate of Acalabrutinib hydrogen maleate, prepared according to Example 2 or 3 or 4 or 5.
  • the present invention relates to methanol solvate of Acalabutinib hydrogen maleate, solid form thereof and a process for preparation thereof.
  • the solid form can be further characterized by XRPD patern described in the following table:
  • the Form 1 can be also characterized by XRPD patern depicted in Figure 1 or TGA patern depicted in Figure 2 or DSC patern depicted in Figure 3.
  • the solid Form 1 can be prepared by a process comprising: a. Dissolving free base of Acalabrutinib in methanol; b. Adding maleic acid; c. Isolating the solid form.
  • concentration of Acalabrutinib free base in methanol can be between 0.04 g/ml and 0.1 g/ml.
  • the molar ratio between Acalabrutinib free base and maleic acid can be between 1:2 and 1:2.5.
  • Acalabrutinib free base was mixed with methanol, the mixture was dissolved preferably at a temperature between 40°C and 60°C. To the mixture maleic acid was added.
  • Maleic acid can be added to the mixture in 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 portions.
  • the invention also relates to mixed ethanol water solvate of Acalabrutinib hydrogen maleate (molar ratio between Acalabrutinib and maleic acid is 1: 1), compound of formula (1), solid forms thereof and processes for preparation thereof.
  • the invention relates to a solid form, Form 2, wherein the molar ratio between Acalabrutinib: ethanol: water can be l:(0.49- 0.69):(0.27-0.51), preferably the molar ratio between Acalabrutinib: ethanol: water can be 1:0.5:0.5.
  • the solid form can be further characterized by XRPD pattern described in the following table:
  • the Form 2 can be also characterized by XRPD pattern depicted in Figure 5 or TGA pattern depicted in Figure 6 or DSC pattern depicted in Figure 7.
  • the solid Form 2 can be prepared by a process comprising: a. Suspending free base of Acalabrutinib in ethanol; b. Adding of maleic acid; c. Cooling the mixture to a temperature between 0°C and 30°C; d. Isolating solid form P2 of Acalabrutinib hydrogen maleate; e. Contacting the solid form P2 with humidity between 15% and 60% to obtain solid Form 2 of Acalabrutinib hydrogen maleate mixed ethanol water solvate.
  • the concentration of Acalabrutinib free base in ethanol can be between 0.01 g/ml and 0.2 g/ml.
  • the molar ratio between Acalabrutinib free base and maleic acid can be between 1:1 and 1:2.
  • Acalabrutinib free base is suspended in ethanol preferably at a temperature between 20°C and 78°C, more preferably between 50°C and 60°C.
  • Maleic acid is added to the mixture.
  • Maleic acid can be added to the mixture in 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 portions.
  • Maleic acid can be also added as a solution of maleic acid in ethanol.
  • the concentration of maleic acid in ethanol can be between 0.1 g/ml and 0.2 g/ml.
  • the mixture of Acalabrutinib with maleic acid and ethanol can be either a solution or a suspension. Crystallization of the Form P2 of Acalabutinib hydrogen maleate starts quickly.
  • Form P2 is ethanol solvate of Acalabutinib hydrogen maleate (molar ratio between Acalabrutinib and ethanol is 1:0.5).
  • Form P2 can optionally contained up to 0.1 mol of water per 1 mol of Acalabrutinib hydrogen maleate.
  • the mixture can be optionally cooled for example to a temperature between 0°C and 25°C, preferably to a temperature between 10°C and 15°C. Obtained suspension is filtered off and obtained Form P2 of Acalabutinib hydrogen maleate can be optionally washed with ethanol.
  • Form P2 is contacted with humidity between 15% and 60% for between 1.5 and 48 hours, for example between 2 and 24 hours or between 5 and 15 hours to obtain solid Form 2 of Acalabrutinib hydrogen maleate mixed ethanol water solvate.
  • the solid Form 2 can be also prepared by a process comprising: a. Mixing free base of Acalabrutinib with ethanol; b. Adding a solution of maleic acid in ethanol and water at a temperature between 50°C and 60°C, the molar ratio between free base of Acalabrutinib and added maleic acid can be between 1 :0.5 and 1 :0.55 and the molar ratio between free base of Acalabrutinib and water can be between 1 :2 and 1:7; c.
  • the molar ratio between Acalabrutinib and added maleic acid can be between 1:0.5 and 1:0.55 and the molar ratio between Acalabrutinib base and added water can be between 1:2 and 1:7; d. Cooling the mixture to a temperature between 0°C and 35°C, preferably between 10°C and 25°C; e. Isolating the solid Form 2 of Acalabrutinib hydrogen maleate mixed ethanol water solvate.
  • a solution of maleic acid in a mixture of ethanol and water at a temperature between 50°C and 60°C is added.
  • the molar ratio between Acalabrutinib and added maleic acid can be between 1:0.5 and 1:0.55.
  • the molar ratio between Acalabrutinib base and added water can be between 1:2 and 1:7.
  • the concentration of maleic acid in the ethanol water mixture can be between 0.15 g/ml and 0.25 g/ml.
  • the solution of maleic acid in ethanol-water mixture can be added in the course of between 10 minutes and 60 minutes, preferably in a course between 20 and 35 minutes.
  • the mixture is stirred for between 20 and 180 minutes.
  • the mixture is cooled to a temperature between 0°C and 35°C.
  • the mixture is then stirred for between 15 and 120 minutes to obtain a suspension.
  • the suspension is filtered off and obtained solid Form 2 can be optionally washed for example with ethanol and dried on air.
  • the concentration of Acalabrutinib free base in ethanol can be between 0.08 g/ml and 0.15 g/ml.
  • Acalabrutinib free base is preferably mixed with ethanol heated to a temperature between 50°C and 80°C, preferably between 60°C and 75°C or the mixture of Acalabrutinib in ethanol can be heated to a temperature between 50°C and 80°C, preferably between 60°C and 75°C after preparation of the mixture.
  • Maleic acid is dissolved in the mixture of ethanol and water.
  • the concentration of maleic acid in a mixture of ethanol and water can be between 0.2 g/ml and 0.3 g/ml.
  • the mixture is added to a mixture of Acalabrutinib free base in ethanol at a temperature between 50°C and 80°C, preferably between 60°C and 75°C in the course of between 15 and 60 minutes.
  • the mixture is stirred for between 20 and 60 minutes.
  • the mixture is cooled to a temperature between 0°C and 35°C preferably during between 30 and 180 minutes.
  • the mixture is stirred at this temperature for between 15 and 180 minutes to obtain a suspension.
  • the suspension is filtered off and obtained solid can be optionally washed with for example with ethanol and dried on air.
  • the solid form can be further characterized by XRPD pattern described in the following table:
  • the Form 3 can be also characterized by XRPD pattern depicted in Figure 13 or TGA pattern depicted in Figure 15 or DSC pattern depicted in Figure 14.
  • the solid Form 3 can be prepared by a process comprising:
  • molar ratio between free base of Acalabrutinib and maleic acid is between 1 : 1 and 1:1.2;
  • Acalabrutinib hydrogen maleate mixed ethanol water solvate The preparation can be done under protective atmosphere, for example under nitrogen or argon atmosphere.
  • the concentration of free base of Acalabrutinib in the mixture of ethanol and water can be between 0.08 g/ml and 0.2 g/ml.
  • Molar ratio between Acalabrutinib free base and water can be between 1:35 and 1:45, preferably it is 1:40.
  • the volume ratio between ethanol and water in the mixture of ethanol and water can be between 0.6:1 and 0.7:1.
  • the mixture is heated to a temperature between 50°C and 60°C. To the mixture a solution of maleic acid in ethanol is added.
  • Molar ratio between free base of Acalabrutinib and maleic acid is between 1:1 and 1:1.2.
  • concentration of maleic acid in ethanol can be between 0.1 g/ml and 0.25 g/ml.
  • the volume ratio of the total ethanol and water in the mixture can be between 0.9:1 and 1.1:1.
  • the solution can be added during between 45 and 180 minutes.
  • the mixture can be optionally stirred for between 30 and 120 minutes.
  • the mixture is cooled to a temperature between 10°C and 30°C and stirred at this temperature for between 1 and 24 hours to obtain a suspension.
  • the suspension was filtered off and obtained solid can be optionally washed and dried on air.
  • the crystalline Form 2 or Form 3 of mixed ethanol water solvate of Acalabutinib hydrogen maleate can be processed into a suitable pharmaceutical formulation.
  • the solid forms can be mixed with pharmaceutically acceptable adjuvants, diluents or carriers.
  • the amount of crystalline Form 2 or Form 3 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 oral formulation can be in a form of an oral emulsion or a solution or a suspension or a syrup
  • Acalabrutinib was prepared according to a process disclosed in W02013010868 application.
  • Solid Form A of Acalabrutinib maleate (1:1 or Acalabrutinib hydrogenmaleate) was prepared according to the process described in WO2017002095 application.
  • XRPD pattern of prepared solid form A is depicted in Figure 7
  • DSC pattern is depicted in Figure 8.
  • Example 1 Preparation of crystalline Form 1 of methanol solvate of Acalabrutinib hydrogen maleate
  • Example 2 Preparation of crystalline Form 2 of Acalabrutinib hydrogen maleate
  • Form P2 was contacted with humidized air for 7 h at 25°C/40% RH to provide solid Form 2 of Acalabrutinib hydrogen maleate.
  • XRPD pattern or prepared solid is depicted in Figure 5
  • TGA pattern is depicted in Figure 6
  • DSC pattern is depicted in Figure 7.
  • Example 4 Preparation of crystalline Form 2 of Acalabrutinib hydrogen maleate The reaction is performed under argon atmosphere.
  • the reaction is performed under argon atmosphere.
  • Acalabrutinib free base 20 g was mixed with 180 ml of ethanol, the mixture was heated to 74°C and stirred for 15 minutes.
  • 4.9 g of maleic acid was dissolved in a mixture of 3.8 ml of water and 15.5 ml of ethanol and the solution was dosed to reaction mixture of Acalabrutinib in ethanol over 25 minutes at temperature 70 - 74 °C. Mixture was stirred for 30 minutes at 70°C then cooled to 20°C over 1 hour.
  • the reaction was performed under argon atmosphere.
  • Crystalline structure was confirmed by Single crystal analysis. Crystal data collection of Form 3 is summarized in following table:
  • Example 7 Comparison between Form A, Form 2 and Form 3 of Acalabrutinib hydrogen maleate
  • Form 2 ( Figure 16) crystals form bigger aggregates.
  • the flowability properties of Form 2 are expected to be beter in comparison with flowability properties of Form A;
  • the material was poured through a funnel to form a cone.
  • the tip of the funnel should be held close to the growing cone and slowly raised as the pile grows, to minimize the impact of falling particles. If material block the output, the funnel was softly tapped.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un solvate de méthanol et solvate éthanol-eau mixte d'hydrogénomaléate d'acalabrutinib, un composé de formule (1), des formes solides de celui-ci et des procédés de préparation de celui-ci.
PCT/EP2024/085803 2023-12-11 2024-12-11 Formes cristallines d'hydrogénomaléate d'acalabrutinib Pending WO2025125383A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP23215619 2023-12-11
EP23215619.0 2023-12-11
EP24193618 2024-08-08
EP24193618.6 2024-08-08

Publications (1)

Publication Number Publication Date
WO2025125383A1 true WO2025125383A1 (fr) 2025-06-19

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013010868A1 (fr) 2011-07-19 2013-01-24 Msd Oss B.V. 4-imidazopyridazin-1-yl-benzamides et 4-imidazotriazin-1-yl-benzamides en tant qu'inhibiteurs de btk
WO2017002095A1 (fr) 2015-07-02 2017-01-05 Acerta Pharma B.V. Formes solides et formulations de (s)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-n-(pyridin-2-yl)benzamide
WO2018148961A1 (fr) * 2017-02-20 2018-08-23 杭州领业医药科技有限公司 Forme cristalline du sel acp-196, procédé de préparation, composition pharmaceutique et utilisation associés

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013010868A1 (fr) 2011-07-19 2013-01-24 Msd Oss B.V. 4-imidazopyridazin-1-yl-benzamides et 4-imidazotriazin-1-yl-benzamides en tant qu'inhibiteurs de btk
WO2017002095A1 (fr) 2015-07-02 2017-01-05 Acerta Pharma B.V. Formes solides et formulations de (s)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-n-(pyridin-2-yl)benzamide
WO2018148961A1 (fr) * 2017-02-20 2018-08-23 杭州领业医药科技有限公司 Forme cristalline du sel acp-196, procédé de préparation, composition pharmaceutique et utilisation associés

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MINO R CAIRA ED - MONTCHAMP JEAN-LUC: "CRYSTALLINE POLYMORPHISM OF ORGANIC COMPOUNDS", TOPICS IN CURRENT CHEMISTRY; [TOPICS IN CURRENT CHEMISTRY], SPRINGER, BERLIN, DE, vol. 198, 1 January 1998 (1998-01-01), pages 163 - 208, XP001156954, ISSN: 0340-1022, [retrieved on 19990226], DOI: 10.1007/3-540-69178-2_5 *

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