[go: up one dir, main page]

WO2025125383A1 - Crystalline forms of acalabrutinib hydrogen maleate - Google Patents

Crystalline forms of acalabrutinib hydrogen maleate Download PDF

Info

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
Authority
WO
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
Other languages
French (fr)
Inventor
Bohumil Dymacek
Michal HEGEDUS
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 WO2025125383A1 publication Critical patent/WO2025125383A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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.

Landscapes

  • 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)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

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.

Description

CRYSTALLINE FORMS OF ACALABRUTINIB HYDROGEN MALEATE
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:
Figure imgf000002_0001
BACKGROUND OF THE PRESENT INVENTION
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:
Figure imgf000002_0002
Acalabrutinib maleate (1: 1 or Acalabrutinib hydrogen maleate), 4-[8-Amino-3-[(2S)-l- (but-2-ynoyl)pyrrolidin-2-yl]imidazo[ 1 ,5-a]pyrazin- 1 -yl] -N-(pyri din-2 -yl)benzamide hydrogen maleate, is an oral Bruton tyrosine kinase (BTK) inhibitor used for the treatment of adults with mantle cell lymphoma who have received at least one prior therapy. Marketed product contains solid Form A of Acalabrutinib hydrogen maleate hydrate (molar ratio Acalabrutinib: maleic acid:water is 1:1: 1). Acalabrutinib and its maleate salt was disclosed in W02013010868 application. Solid form A of Acalabrutinib maleate (1:1 or Acalabrutinib hydrogen maleate) is disclosed in WO2017002095 application.
It is advantageous to develop a crystalline form of Acalabrutinib hydrogen maleate that shows improved flow properties, crystallinity and stability.
BRIEF DESCRIPTION OF THE INVENTION
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 imgf000003_0001
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.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 depicts the X-Ray Powder Diffractogram (XRPD) pattern of crystalline Form
1 of methanol solvate of Acalabrutinib hydrogen maleate, prepared according to Example 1.
Figure 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 4 depicts SEM picture 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
2 of mixed ethanol water solvate of Acalabrutinib hydrogen maleate, prepared according to Example 2 or 3 or 4 or 5.
Figure 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
3 or 4 or 5.
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.
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.
Figure 13 depicts the X-Ray Powder Diffractogram (XRPD) pattern of crystalline Form
Figure imgf000004_0001
Figure 14 depicts the DSC pattern of crystalline Form 3 of Acalabrutinib hydrogen maleate, prepared according to Example 6.
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.
DETAILED DESCRIPTION OF THE INVENTION
The invention relates to methanol solvate of Acalabrutinib hydrogen maleate, compound of formula (1), solid forms thereof and processes for preparation thereof:
Figure imgf000005_0001
The present invention relates to methanol solvate of Acalabutinib hydrogen maleate, solid form thereof and a process for preparation thereof. The solid Form 1 of methanol solvate of Acalabrutinib hydrogen maleate can be characterized by XRPD pattern having 20 values 5.3°, 10.6° and 11.6° degrees 2 theta (± 0.2 degrees 2 theta), when measured with CuKal radiation (X = 1.54060 A). The solid Form 1 can be also characterized by a XRPD pattern having 20 values at 5.3°, 10.6°, 11.6°, 24.3° and 24.7° degrees 2 theta (± 0.2 degrees 2 theta), when measured with CuKal radiation (X = 1.54060 A). The solid Form 1 can be further characterized by a XRPD pattern having 20 values at 5.3°, 10.6°, 11.6°, 15.1°, 16.2°, 21.8°, 23.1°, 24.3° and 24.7° degrees 2 theta (± 0.2 degrees 2 theta), when measured with CuKal radiation (X = 1.54060 A). The solid form can be further characterized by XRPD patern described in the following table:
Figure imgf000006_0001
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. The 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 mixture was cooled for example to a temperature between 0°C and 25°C, preferably to a temperature between 10°C and 15°C in the course of between 2 and 12 hours. The mixture is then stirred at this temperature for between 10 and 30 hours to obtain a suspension. Obtained suspension is filtered off and obtained methanol solvate of Acalabutinib hydrogen maleate can be optionally washed for example by methanol and dried.
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, Form 2, of Acalabutinib hydrogen maleate (molar ratio between Acalabrutinib and maleic acid is 1:1) mixed ethanol water solvate (the molar ratio between Acalabrutinib: ethanol: water can be l:(0.49-0.69):(0.27-0.51)), can be characterized by XRPD pattern having 20 values 5.3°, 10.5° and 11.6° degrees 2 theta (± 0.2 degrees 2 theta), when measured with CuKal radiation (X = 1.54060 A). The solid Form 2 can be also characterized by aXRPD pattern having 20 values at 5.3°, 9.6°, 10.5°, 11.6°, 19.3°, 22.6° and 24.1° degrees 2 theta (± 0.2 degrees 2 theta), when measured with CuKal radiation (X = 1.54060 A). The solid Form 2 can be further characterized by a XRPD pattern having 20 values at 5.3°, 9.6°, 10.5°, 11.4°, 11.6°, 14.9°, 19.3°, 22.6°, 24.1° and 27.1° degrees 2 theta (± 0.2 degrees 2 theta), when measured with CuKal radiation (X = 1.54060 A). The solid form can be further characterized by XRPD pattern described in the following table:
Figure imgf000008_0001
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. Depending on the temperature of the mixture and concentration of Acalabrutinib free base in the mixture, 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.
The Form P2 can be characterized by XRPD pattern described in following table:
Figure imgf000010_0001
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. Adding a solution of maleic acid in a mixture of ethanol and water, 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.
The concentration of Acalabrutinib in ethanol can be between 0.1 g/ml and 0.2 g/ml. Obtained mixture can be optionally a suspension. The mixture is heated to a temperature between 50°C and 60°C. To the mixture a solution of maleic acid in 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 free base of Acalabrutinib and water can be between 1:2 and 1:7. The concentration of maleic acid in ethanol-water mixture can be between 0.15 g/ml and 0.25 g/ml. The solution of maleic acid in ethanol can be added during between 30 seconds and 10 minutes, preferably during between 30 and 60 seconds. The mixture is stirred for between 20 and 60 minutes.
To the mixture 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 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 80°C, preferably at a temperature between 60°C and 75°C, the molar ratio between Acalabrutinib and added maleic acid can be between 1 : 1 and 1:1.2 and the volume ratio between Acalabrutinib base and added water 1:4 and 1:6; c. Cooling the mixture to a temperature between 0°C and 35°C, preferably between 10°C and 25°C; d. Isolating the solid Form 2 of Acalabrutinib hydrogen maleate mixed ethanol water solvate.
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 presented invention further relates to a solid Form 3 of mixed ethanol water solvate of Acalabrutinib hydrogen maleate and a process for preparation thereof. The solid form, Form 3, of Acalabutinib hydrogen maleate (molar ratio between Acalabrutinib and maleic acid is 1 : 1) mixed ethanol water solvate (the molar ratio between
Acalabrutinib: ethanol: water can be 1:0.28:0.35), can be characterized by XRPD pattern having 20 values 5.3°, 10.6°, 11.5° and 21.9° degrees 2 theta (± 0.2 degrees 2 theta), when measured with CuKal radiation (X = 1.54060 A). The solid Form 3 can be also characterized by a XRPD pattern having 20 values at 5.3°, 9.7°, 10.6°, 11.5°, 19.3°, 21.9°, 22.6°, 23.9° and 25.6° degrees 2 theta (± 0.2 degrees 2 theta), when measured with CuKal radiation (X = 1.54060 A). The solid Form 3 can be further characterized by a XRPD pattern having 20 values at 5.3°, 9.7°, 10.6°, 11.5°, 19.3°, 21.9°, 22.6°, 23.9°, 25.6° and 29.5° degrees 2 theta (± 0.2 degrees 2 theta), when measured with CuKal radiation (X = 1.54060 A). The solid form can be further characterized by XRPD pattern described in the following table:
Figure imgf000013_0001
Figure imgf000014_0001
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:
1. Mixing free base of Acalabrutinib with a mixture of ethanol and water, molar ratio between Acalabrutinib free base and water can be between 1:35 and 1:45;
2. Heating the mixture to a temperature between 50°C and 60°C;
3. Adding a solution of maleic acid in ethanol, molar ratio between free base of Acalabrutinib and maleic acid is between 1 : 1 and 1:1.2;
4. Cooling the mixture to a temperature between 0°C and 35°C, preferably between 10°C and 25°C;
5. Isolating the solid Form 3 of 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. The 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. In the 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
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. The pharmaceutical formulation can be also in a form of a powder for reconstitution into an injection or infusion. The suitable pharmaceutical formulation can be in a form suitable for rectal or vaginal administration.
The crystalline Form 2 or Form 3 of mixed ethanol water solvate of Acalabrutinib hydrogen maleate or a pharmaceutical formulation comprising the form can be used for the treatment of conditions treatable with Acalabutinib.
EXAMPLES
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.
XRPD spectrum was obtained using the following measurement conditions: Panalytical Empyrean diffractometer with 0/20 geometry (transmition mode), equipped with a PixCell 3D detector:
Figure imgf000016_0001
Figure imgf000017_0001
DCS patterns were obtained using the following conditions: 10°C/min -> 300°C. TGA patterns were obtained using the following conditions: 10°C/min -> 300°C. Pictures of crystals were obtained by Tescan VEGA LMu.
Example 1: Preparation of crystalline Form 1 of methanol solvate of Acalabrutinib hydrogen maleate
1 g of Acalabrutinib free base was dissolved in 15 ml of methanol at 50-52°C. 0.25 g of Maleic acid was added to the reaction mixture to obtain a solution. The mixture was stirred for 30 hours at 20°C - 25°C, Obtained suspension was filtered. The filter cake was washed with 5 ml MeOH and was dried for 5 hours at 40°C at vacuum drier to provide 1.086 g of Form 1.
XRPD pattern or prepared solid is depicted in Figure 1, TGA pattern is depicted in Figure 2 and DSC pattern is depicted in Figure 3. Crystalline structure was confirmed by Single crystal analysis. Ratio Acalabrutinib hydrogenmaleate:methanol: water was confirmed to be 4:2:1. Crystal data collection is summarized in following table:
Figure imgf000018_0001
Example 2: Preparation of crystalline Form 2 of Acalabrutinib hydrogen maleate
20 g of Acalabutinib free base was suspended in 200 ml of Ethanol at 50-55°C. To the mixture 4.99 g of Maleic acid was added in one portion. The mixture was cooled to 10-15°C, stirred at this temperature for one hour and filtered to provide form P2 of Acalabrutinib hydrogen maleate. The filter cake was washed with 70 ml of Ethanol and dried for 12 hours at 25°C on air (humidity of air 40% RH) to provide 25.9 g (99.9% yield) of Form 2 of Acalabutinib hydrogen maleate. XRPD pattern or prepared solid is depicted in Figure 5, TGA pattern is depicted in Figure 6 and DSC pattern is depicted in Figure 7. Crystalline structure was confirmed by Single crystal analysis. Crystal data collection of forms Form P2, Form 2 and Form A is summarized in following table:
Figure imgf000019_0001
Example 3: Preparation of crystalline Form 2 of Acalabrutinib hydrogen maleate 2.003 g of Acalabrutinib was mixed with 15 ml of ethanol under argon to give a suspension. The mixture was heated to 55°C. To the mixture a solution of 0.502 g of maleic acid in 3 ml of ethanol was added at 55-60°C during 1 hour. Then the mixture was left spontaneously to cool down during 30 minutes to 25°C and was stirred for additional next 30 minutes. The suspension was filtered, the filter cake was dried for 15 hours in a vacuum drier to provide 2.260 g of Form P2 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 and 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.
10 g of Acalabrutinib free base were mixed with 75 ml of ethanol (EtOH). The mixture was heated to 55°C. A solution of 1.312 g of maleic acid in 7.5 ml ethanol and 923 pl of water was added to the mixture at 55-60°C during 20 seconds. The mixture was stirred at 55-60°C for 30 minutes. A solution of 1.312 g of maleic acid in 7.5 ml ethanol and 926 pl of water was added to the mixture during 30 minutes at 55-60°C. The mixture was stirred for 1 hour at 55-60°C. The mixture was cooled during 45 minutes to 25°C and was stirred for next 30 minutes. The mixture was filtered, the filter cake was washed with 5 ml ethanol to obtain 12.7 g of solid Form 2 of Acalabrutinib hydrogen maleate ethanol water solvate in yield 96.4%. XRPD pattern or prepared solid is depicted in Figure 5, TGA pattern is depicted in Figure 6 and DSC pattern is depicted in Figure 7.
Example 5: Preparation of crystalline Form 2 of Acalabrutinib hydrogen maleate
The reaction is performed under argon atmosphere.
20 g of Acalabrutinib free base 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 suspension was stirred at 20°C for 1.5 hour and then filtered, washed with 15 ml of Ethanol, left dried on air overnight to provide 24.6 g of solid Form 2 of Acalabrutinib hydrogen maleate ethanol water solvate (yield 88%, purity 99.6%). XRPD pattern or prepared solid is depicted in Figure 5, TGA pattern is depicted in Figure 6 and DSC pattern is depicted in Figure 7.
Example 6: Preparation of crystalline Form 3 of Acalabrutinib hydrogen maleate
The reaction was performed under argon atmosphere.
2 g of free base of Acalabrutinib was mixed with a mixture of 6 ml of ethanol and 9 ml of water. The mixture was heated to 55°C. The solution of 0.5 g of maleic acid in 3 ml of ethanol was added at 55-60°C during 1 hour to the mixture of free base of Acalabrutinib in a mixture of ethanol and water. The mixture was cooled during 30 minutes to 25°C and stirred for next 12 hours. The mixture was filtered , the filter cake was dried for 2 hours on air, to provide 2.3 g of solid Form 3 of Acalabutinib hydrogen maleate. XRPD pattern or prepared solid is depicted in Figure 13, TGA patern is depicted in Figure 15 and DSC patern is depicted in Figure 14.
Crystalline structure was confirmed by Single crystal analysis. Crystal data collection of Form 3 is summarized in following table:
Figure imgf000021_0001
Example 7: Comparison between Form A, Form 2 and Form 3 of Acalabrutinib hydrogen maleate
There are following advantages of Form 2, Form 3 in comparison with Form A:
1. By comparing DSC paterns of Form A (Figure 10) with DSC paterns of Form 2 (Figure 7) or Form 3 (Figure 14), it can be concluded, that the chemical and thermodynamical stability Form 2 and Form 3 is higher than the chemical and thermodynamical stability of Form A;
2. Contrary to Form A (Figure 11), 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;
3. Beter flowability properties of Form 2 in comparison with Form A was confirmed by measurement of Angle of repose of the Forms by Fixed funnel method using 5 mm and 20 mm (funnel diameter) funnels.
In case of 5 mm funnel, 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.
In case of 20 mm funnel, the material was softly poured into the funnel and then the plate bellow the funnel was very slowly moved down. This method was used, because it better simulates real flowability problems during production, better indicate high angles of repose and detect ability stick particles. Angle of repose was calculated from the resulting cone (Arctangent of ratio the height divided by half the width of the base of the cone).
In the following Table average values of obtained Angle of repose of the samples are summarized:
Figure imgf000022_0001
Lower Angle of response corresponds to improved flow properties of the solid and flow properties of Form 2 are therefore better than flow properties of Form A.

Claims

1. A mixed ethanol water solvate of Acalabrutinib hydrogen maleate.
2. A solid form of compound of claim 1.
3. The solid form according to claim 2, Form 2, wherein the molar ratio between Acalabrutinib: ethanol: water is l:(0.49-0.69):(0.27-0.51).
4. The solid form according to claim 3 wherein the molar ratio between Acalabrutinib: ethanol: water is l:0.5:0.5.
5. The solid Form 2 according to claims 3 or 4 characterized by a XRPD pattern having 20 values at about 5.3°, 10.5° and 11.6° degrees 2 theta (± 0.2 degrees 2 theta), when measured with CuKal radiation (X = 1.54060 A).
6. The solid form according to claim 5 characterized by a XRPD pattern having 20 values at 5.3°, 9.6°, 10.5°, 11.6°, 19.3°, 22.6°and 24.1° degrees 2 theta (± 0.2 degrees 2 theta), when measured with CuKal radiation (X = 1.54060 A).
7. The solid form according to claim 6 characterized by a XRPD pattern having 20 values at 5.3°, 9.6°, 10.5°, 11.4°, 11.6°, 14.9°, 19.3°, 22.6°, 24.1° and 27.1° degrees 2 theta (± 0.2 degrees 2 theta), when measured with CuKal radiation (X = 1.54060 A).
8. A process for preparation of the solid form according to any one of claims 3 to 7 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 Alectinib hydrogen maleate; e. Contacting the solid form P2 with humidity between 15% and 60%.
9. A process for preparation of the solid form according to any one of claims 3 to 7 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 is between 1:0.5 and 1:0.55 and the molar ratio between free base of Acalabrutinib and water is between 1 :2 and 1:7; c. Adding a solution of maleic acid in a mixture of ethanol and water, the molar ratio between Acalabrutinib and added maleic acid is between 1:0.5 and 1:0.55 and the molar ratio between Acalabrutinib base and added water is between 1:2 and 1:7; d. Cooling the mixture to a temperature between 0°C and 35°C; e. Isolating the solid Form 2 of Acalabrutinib hydrogen maleate mixed ethanol water solvate.
10. A process for preparation of the solid form according to any one of claims 3 to 7 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 80°C, the molar ratio between Acalabrutinib and added maleic acid is between 1 : 1 and 1:1.2 and the volume ratio between Acalabrutinib base and added water is between 1:4 and 1:6; c. Cooling the mixture to a temperature between 0°C and 35°C; d. Isolating the solid Form 2 of Acalabrutinib hydrogen maleate mixed ethanol water solvate.
11. The solid form according to claim 2, Form 3, wherein the molar ratio between Acalabrutinib: ethanol: water is 1:0.28:0.35.
12. The solid form according to claims 11 characterized by a XRPD pattern having 20 values at about 5.3°, 10.6°, 11.5° and 21.9° degrees 2 theta (± 0.2 degrees 2 theta), when measured with CuKal radiation (X = 1.54060 A).
13. The solid form according to claim 12 characterized by a XRPD pattern having 20 values at 5.3°, 9.7°, 10.6°, 11.5°, 19.3°, 21.9°, 22.6°, 23.9° and 25.6° degrees 2 theta (± 0.2 degrees 2 theta), when measured with CuKal radiation (X = 1.54060 A).
14. The solid form according to claim 13 characterized by a XRPD pattern having 20 values at 5.3°, 9.7°, 10.6°, 11.5°, 19.3°, 21.9°, 22.6°, 23.9°, 25.6° and 29.5° degrees 2 theta (± 0.2 degrees 2 theta), when measured with CuKal radiation (X = 1.54060 A).
15. A process for preparation of the solid form according to any one of claims 11 to 14 comprising: a. Mixing free base of Acalabrutinib with a mixture of ethanol and water, molar ratio between Acalabrutinib free base and water can be between 1:35 and 1:45; b. Heating the mixture to a temperature between 50°C and 60°C; c. Adding a solution of maleic acid in ethanol, molar ratio between free base of Acalabrutinib and maleic acid is between 1 : 1 and 1:1.2; d. Cooling the mixture to a temperature between 0°C and 35°C; e. Isolating the solid Form 3 of Acalabrutinib hydrogen maleate mixed ethanol water solvate.
PCT/EP2024/085803 2023-12-11 2024-12-11 Crystalline forms of acalabrutinib hydrogen maleate Pending WO2025125383A1 (en)

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 (en) 2025-06-19

Family

ID=93841971

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2024/085803 Pending WO2025125383A1 (en) 2023-12-11 2024-12-11 Crystalline forms of acalabrutinib hydrogen maleate

Country Status (1)

Country Link
WO (1) WO2025125383A1 (en)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013010868A1 (en) 2011-07-19 2013-01-24 Msd Oss B.V. 4 - imidazopyridazin- 1 -yl-benzamides and 4 - imidazotriazin- 1 - yl - benzamides as btk- inhibitors
WO2017002095A1 (en) 2015-07-02 2017-01-05 Acerta Pharma B.V. Solid forms and formulations of (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 (en) * 2017-02-20 2018-08-23 杭州领业医药科技有限公司 Crystal form of acp-196 salt and preparation method, pharmaceutical composition, and use thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013010868A1 (en) 2011-07-19 2013-01-24 Msd Oss B.V. 4 - imidazopyridazin- 1 -yl-benzamides and 4 - imidazotriazin- 1 - yl - benzamides as btk- inhibitors
WO2017002095A1 (en) 2015-07-02 2017-01-05 Acerta Pharma B.V. Solid forms and formulations of (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 (en) * 2017-02-20 2018-08-23 杭州领业医药科技有限公司 Crystal form of acp-196 salt and preparation method, pharmaceutical composition, and use thereof

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 *

Similar Documents

Publication Publication Date Title
CA2537054C (en) 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester-methanesulphonate and use thereof as a medicament
CN114437084B (en) Heterocyclic compound and preparation method and application thereof
CN110312723B (en) Crystal form of ACP-196 salt, preparation method, pharmaceutical composition and application thereof
CN106661015B (en) Dasatinib salt
CN108137605A (en) Crystal form of ACP-196 and its preparation method and pharmaceutical composition
CN112390812A (en) Crystalline and amorphous solids of Ruogeli compounds and methods of making the same
CN113966332B (en) Polymorphs of a CDK9 inhibitor, methods of making and using the same
WO2025125383A1 (en) Crystalline forms of acalabrutinib hydrogen maleate
US20020107275A1 (en) Novel crystal and solvate forms of ondansetron hydrochloride and processes for their preparation
US9988398B2 (en) Crystalline form of rifaximin and process for its preparation
US20240287090A1 (en) Solid state forms of relugolix
CN110372635B (en) Preparation method of vortioxetine hydrobromide alpha crystal form
EP0307767A1 (en) Novel form of riboflavin
CN115368358A (en) Sotorasib novel crystal form and preparation method and application thereof
CN109400539A (en) A kind of methylpyrazine derivative semihydrate
US20250179037A1 (en) Crystalline form of leucogen and method for preparation thereof and use thereof
CN111087365A (en) Crystal form of vortioxetine hydrobromide and preparation method thereof
CN110964017A (en) Polymorph of Ribociclib monosuccinate and preparation method and application thereof
AU2020276695B2 (en) New crystalline forms of N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methvlphenyl)-2 (trifluoromethyl)isonicotinamide as RAF inhibitors for the treatment of cancer
EP4615831A1 (en) Crystalline form of asciminib hydrochloride
WO2002060441A1 (en) Novel forms of 2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo (1,2-a)pyridine-6-carboxamide
WO2025134057A1 (en) Solid state forms of trilaciclib citrate salt
TW202328132A (en) HEMI-FUMARATE CRYSTALS OF PI3Kδ/γ DUAL INHIBITOR COMPOUND AND PREPARATION METHOD THEREOF
CN121194965A (en) Amorphous form and crystal form of ozamado hydrochloride
EP4504705A1 (en) Solid forms of vismodegib

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24820775

Country of ref document: EP

Kind code of ref document: A1