EP4504705A1 - Solid forms of vismodegib - Google Patents

Solid forms of vismodegib

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Publication number
EP4504705A1
EP4504705A1 EP23717459.4A EP23717459A EP4504705A1 EP 4504705 A1 EP4504705 A1 EP 4504705A1 EP 23717459 A EP23717459 A EP 23717459A EP 4504705 A1 EP4504705 A1 EP 4504705A1
Authority
EP
European Patent Office
Prior art keywords
vismodegib
solid form
ppm
theta
degrees
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
EP23717459.4A
Other languages
German (de)
French (fr)
Inventor
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 EP4504705A1 publication Critical patent/EP4504705A1/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom

Definitions

  • the invention relates to solid forms of Vismodegib and to processes for preparation thereof.
  • This invention relates to solid forms of Vismodegib, compound of formula (1) and processes for preparation thereof,
  • Vismodegib 2-Chloro-N-[4-chloro-3-(pyridin-2-yl)phenyl]-4-(methanesulfonyl) benzamide, is a small molecule systemic hedgehog antagonist. Vismodegib was approved for the treatment of patients with advanced basal cell carcinoma for whom surgery is considered inappropriate.
  • Vismodegib was disclosed in W02006028958 application. Solid form of Vismodegib is described in WO2014147504 or WO2014195977 application.
  • An article published as Org. Process Res. Dev. 2016, 20, 1509-1519 described a process for preparation of Vismodegib and a solid form thereof, Form B.
  • the solid Form B prepared according to the process described in the article contains methyl isobutyl ketone, solvent used for preparation of the solid form, on levels 2000 ppm. Such high level might be inacceptable for the product used for a treatment.
  • Prior art there describes no process for preparation of solid Form B containing less than 550 ppm of methyl isobutyl ketone.
  • Solid form of a salt can have improved properties such as solubility, purity or stability that is requested when they are incorporated into a final formulation such as tablets or capsules. There is therefore still a need for solid forms of Vismodegib having improved properties such as a low content of solvent(s).
  • the presented invention relates to a process for preparation of solid form B of Vismodegib.
  • the presented invention also relates to solid form S of Vismodegib and to a process for preparation thereof.
  • the presented invention further relates to solid form M of Vismodegib and to a process for preparation thereof.
  • Solid forms of Vismodegib of the presented invention show excellent crystallinity, purity and stability.
  • Solid forms of Vismodegib of the presented invention preferably the solid Form B of Vismodegib, more preferably the solid Form B prepared according to the presented invention, contain less than 550 ppm, preferably less than 500 ppm or 450 ppm or 400 ppm or 350 ppm or 300 ppm or 250 ppm or 200 ppm of methyl isobutyl ketone.
  • Figure 1 depicts the X-Ray Powder Diffractogram (XRPD) of solid form of Vismodegib, Form S, prepared according to Example 1
  • Figure 2 depicts the DSC pattern of solid form of Vismodegib, Form S, prepared according to Example 1
  • Figure 3 depicts the TGA pattern of solid form of Vismodegib, Form S, prepared according to Example 1
  • Figure 4 depicts the X-Ray Powder Diffractogram (XRPD) of solid form of Vismodegib, Form M, prepared according to Example 2
  • Figure 1 depicts the X-Ray Powder Diffractogram (XRPD) of solid form of Vismodegib, Form B, prepared according to Example 3 or 4 or 5
  • the presented invention relates to a solid form of Vismodegib, Form S and to a process for preparation thereof.
  • the presented invention relates to a process for preparation of solid Form B of Vismodegib comprising subjecting solid Form S of Vismodegib to a temperature between 45°C and 65°C and relative humidity between 80% and 100% for between 2 and 21 days to provide solid Form B of Vismodegib.
  • the solid Form B of the presented invention preferably prepared by the process of the presented invention contains less than 550 ppm, preferably less than 500 ppm or 450 ppm or 400 ppm or 350 ppm or 300 ppm or 250 ppm or 200 ppm of methyl tert-butyl ether.
  • the presented invention further relates to a process for preparation of solid Form B of Vismodegib comprising: a. Mixing the solid Form S of Vismodegib with water; b. Stirring the mixture at a temperature between 85°C and 100°C for between 1.5 and 5 hours.
  • the concentration of solid Form S in water can be between 0.08 g/ml and 0.12 g/ml.
  • the mixture is stirred at temperature between 85°C and 100°C for between 1.5 and 5 hours.
  • the mixture is cooled to a temperature between 20°C and 25°C, obtained suspension is filtered off and obtained solid can be optionally dried.
  • the presented invention further relates to a process for preparation of solid Form B of Vismodegib comprising: a. Mixing the solid Form S of Vismodegib with water; b. Stirring the mixture at a temperature between 15°C and 35°C for between 1.5 and 5 hours.
  • the process can be optionally performed under a protective atmosphere for example under nitrogen or argon.
  • concentration of solid Form S in water can be between 8 g/ml and 16 g/ml.
  • the mixture is stirred at temperature between 15°C and 35°C for between 1.5 and 5 hours. Obtained suspension is filtered off and obtained solid can be optionally dried for example at a temperature between 40°C and 60°C for between 2 and 10 hours.
  • the solid Form B obtained by the process contains less than 550 ppm, preferably less than 500 ppm or 450 ppm or 400 ppm or 350 ppm or 300 ppm or 250 ppm or 200 ppm of methyl tert-butyl ether.
  • the solid Form S can be characterized by XRPD pattern having 20 values 17.3°, 20.7° and 21.8° degrees 2 theta ( ⁇ 0.2 degrees 2 theta).
  • the solid Form S can be also characterized by XRPD pattern having 20 values 10.0°, 11.6°, 17.3°, 19.0°, 20.7° and 21.8° degrees 2 theta ( ⁇ 0.2 degrees 2 theta).
  • the solid form can be further characterized by XRPD pattern described in the following table:
  • the solid Form S can be also characterized by XRPD pattern depicted in Figure 1.
  • the solid form can be further characterized by DSC pattern depicted in Figure 2.
  • the solid form can be further characterized by TGA pattern depicted in Figure 3.
  • the solid form S can be prepared by a process comprising: a. Dissolving Vismodegib in methyl isobutyl ketone to obtain a mixture; b. Cooling the mixture to a temperature between -5°C and 5°C at the rate of 2-4 °C/min; c. Isolating the solid form.
  • the concentration of Vismodegib in methyl isobutyl ketone can be between 0.03 g/ml and 0.07 g/ml.
  • Vismodegib is dissolved in methyl isobutyl ketone preferably at a temperature between 90°C and 120°C.
  • the mixture is rapidly (at the rate of 2-4 °C/min) cooled to a temperature between -5°C and 5°C.
  • the mixture is then stirred at a temperature between -5°C and 5 °C for between 1 and 5 hours. Obtained suspension was filtered off and obtained solid can be optionally dried in vacuum to provide solid Form S of Vismodegib.
  • the presented invention also relates to a solid form of Vismodegib, Form M and to a process for preparation thereof.
  • the solid Form M can be characterized by XRPD pattern having 20 values 7.5°, 11.3°and 15.1° degrees 2 theta ( ⁇ 0.2 degrees 2 theta).
  • the solid Form M can be also characterized by XRPD pattern having 20 values 7.5°, 11.3°, 15.1°, 18.2°, 19.1° and 23.3° degrees 2 theta ( ⁇ 0.2 degrees 2 theta).
  • the solid form can be further characterized by XRPD pattern described in the following table:
  • the solid form can be also characterized by XRPD pattern depicted in Figure 4.
  • the solid form M can be prepared by a process comprising: a. Heating the solid Form B of Vismodegib at a rate of 10°C/min to a temperature between 185°C and 187°C; b. Keep at this temperature for between 5 and 10 minutes.
  • the solid forms of presented invention can be used in a pharmaceutical composition for the treatment of conditions treatable by Vismodegib or a salt thereof.
  • Nuclear magnetic resonance spectroscopy was performed using Avance III 400 MHz NMR spectrometer.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Presented invention relates to solid forms of Vismodegib, compound of formula (1) and processes for preparation thereof.

Description

SOLID FORMS OF VISMODEGIB
The invention relates to solid forms of Vismodegib and to processes for preparation thereof.
BACKGROUND OF THE PRESENT INVENTION
This invention relates to solid forms of Vismodegib, compound of formula (1) and processes for preparation thereof,
Vismodegib, 2-Chloro-N-[4-chloro-3-(pyridin-2-yl)phenyl]-4-(methanesulfonyl) benzamide, is a small molecule systemic hedgehog antagonist. Vismodegib was approved for the treatment of patients with advanced basal cell carcinoma for whom surgery is considered inappropriate.
Vismodegib was disclosed in W02006028958 application. Solid form of Vismodegib is described in WO2014147504 or WO2014195977 application. An article published as Org. Process Res. Dev. 2016, 20, 1509-1519 described a process for preparation of Vismodegib and a solid form thereof, Form B. The solid Form B prepared according to the process described in the article contains methyl isobutyl ketone, solvent used for preparation of the solid form, on levels 2000 ppm. Such high level might be inacceptable for the product used for a treatment. Prior art there describes no process for preparation of solid Form B containing less than 550 ppm of methyl isobutyl ketone.
Solid form of a salt can have improved properties such as solubility, purity or stability that is requested when they are incorporated into a final formulation such as tablets or capsules. There is therefore still a need for solid forms of Vismodegib having improved properties such as a low content of solvent(s).
BRIEF DESCRIPTION OF THE INVENTION
The presented invention relates to a process for preparation of solid form B of Vismodegib.
The presented invention also relates to solid form S of Vismodegib and to a process for preparation thereof.
The presented invention further relates to solid form M of Vismodegib and to a process for preparation thereof.
Solid forms of Vismodegib of the presented invention show excellent crystallinity, purity and stability. Solid forms of Vismodegib of the presented invention, preferably the solid Form B of Vismodegib, more preferably the solid Form B prepared according to the presented invention, contain less than 550 ppm, preferably less than 500 ppm or 450 ppm or 400 ppm or 350 ppm or 300 ppm or 250 ppm or 200 ppm of methyl isobutyl ketone.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 depicts the X-Ray Powder Diffractogram (XRPD) of solid form of Vismodegib, Form S, prepared according to Example 1
Figure 2 depicts the DSC pattern of solid form of Vismodegib, Form S, prepared according to Example 1
Figure 3 depicts the TGA pattern of solid form of Vismodegib, Form S, prepared according to Example 1
Figure 4 depicts the X-Ray Powder Diffractogram (XRPD) of solid form of Vismodegib, Form M, prepared according to Example 2 Figure 1 depicts the X-Ray Powder Diffractogram (XRPD) of solid form of Vismodegib, Form B, prepared according to Example 3 or 4 or 5
DETAILED DESCRIPTION OF THE INVENTION
The presented invention relates to a solid form of Vismodegib, Form S and to a process for preparation thereof.
The presented invention relates to a process for preparation of solid Form B of Vismodegib comprising subjecting solid Form S of Vismodegib to a temperature between 45°C and 65°C and relative humidity between 80% and 100% for between 2 and 21 days to provide solid Form B of Vismodegib.
The solid Form B of the presented invention preferably prepared by the process of the presented invention contains less than 550 ppm, preferably less than 500 ppm or 450 ppm or 400 ppm or 350 ppm or 300 ppm or 250 ppm or 200 ppm of methyl tert-butyl ether.
The presented invention further relates to a process for preparation of solid Form B of Vismodegib comprising: a. Mixing the solid Form S of Vismodegib with water; b. Stirring the mixture at a temperature between 85°C and 100°C for between 1.5 and 5 hours.
The concentration of solid Form S in water can be between 0.08 g/ml and 0.12 g/ml. The mixture is stirred at temperature between 85°C and 100°C for between 1.5 and 5 hours. The mixture is cooled to a temperature between 20°C and 25°C, obtained suspension is filtered off and obtained solid can be optionally dried.
The presented invention further relates to a process for preparation of solid Form B of Vismodegib comprising: a. Mixing the solid Form S of Vismodegib with water; b. Stirring the mixture at a temperature between 15°C and 35°C for between 1.5 and 5 hours.
The process can be optionally performed under a protective atmosphere for example under nitrogen or argon. The concentration of solid Form S in water can be between 8 g/ml and 16 g/ml. The mixture is stirred at temperature between 15°C and 35°C for between 1.5 and 5 hours. Obtained suspension is filtered off and obtained solid can be optionally dried for example at a temperature between 40°C and 60°C for between 2 and 10 hours.
The solid Form B obtained by the process contains less than 550 ppm, preferably less than 500 ppm or 450 ppm or 400 ppm or 350 ppm or 300 ppm or 250 ppm or 200 ppm of methyl tert-butyl ether.
The solid Form S can be characterized by XRPD pattern having 20 values 17.3°, 20.7° and 21.8° degrees 2 theta (± 0.2 degrees 2 theta). The solid Form S can be also characterized by XRPD pattern having 20 values 10.0°, 11.6°, 17.3°, 19.0°, 20.7° and 21.8° degrees 2 theta (± 0.2 degrees 2 theta). The solid form can be further characterized by XRPD pattern described in the following table:
The solid Form S can be also characterized by XRPD pattern depicted in Figure 1. The solid form can be further characterized by DSC pattern depicted in Figure 2. The solid form can be further characterized by TGA pattern depicted in Figure 3. The solid form S can be prepared by a process comprising: a. Dissolving Vismodegib in methyl isobutyl ketone to obtain a mixture; b. Cooling the mixture to a temperature between -5°C and 5°C at the rate of 2-4 °C/min; c. Isolating the solid form. The concentration of Vismodegib in methyl isobutyl ketone can be between 0.03 g/ml and 0.07 g/ml. Vismodegib is dissolved in methyl isobutyl ketone preferably at a temperature between 90°C and 120°C. The mixture is rapidly (at the rate of 2-4 °C/min) cooled to a temperature between -5°C and 5°C. The mixture is then stirred at a temperature between -5°C and 5 °C for between 1 and 5 hours. Obtained suspension was filtered off and obtained solid can be optionally dried in vacuum to provide solid Form S of Vismodegib.
The presented invention also relates to a solid form of Vismodegib, Form M and to a process for preparation thereof. The solid Form M can be characterized by XRPD pattern having 20 values 7.5°, 11.3°and 15.1° degrees 2 theta (± 0.2 degrees 2 theta). The solid Form M can be also characterized by XRPD pattern having 20 values 7.5°, 11.3°, 15.1°, 18.2°, 19.1° and 23.3° degrees 2 theta (± 0.2 degrees 2 theta). The solid form can be further characterized by XRPD pattern described in the following table:
The solid form can be also characterized by XRPD pattern depicted in Figure 4.
The solid form M can be prepared by a process comprising: a. Heating the solid Form B of Vismodegib at a rate of 10°C/min to a temperature between 185°C and 187°C; b. Keep at this temperature for between 5 and 10 minutes.
The solid forms of presented invention can be used in a pharmaceutical composition for the treatment of conditions treatable by Vismodegib or a salt thereof.
The invention will be further described with reference to the following examples.
EXAMPLES
Nuclear magnetic resonance spectroscopy (NMR) was performed using Avance III 400 MHz NMR spectrometer.
XRPD spectrum was obtained using the following measurement conditions:
Panalytical Empyrean diffractometer with 0/20 geometry (transmition mode), equipped with a PixCell 3D detector;
Example 1: Solid Form S of Vismodegib
2 g of Vismodegib was dissolved in 10 ml of methyl tert-butyl ether at 105°C. The mixture was filtered off to remove solid impurities. The mixture cooled to 0°C in the course of 50 minutes. Obtained mixture was stirred at 0°C for 120 minutes. Obtained suspension was filtered off and obtained solid was suck dried in air for 1 hour and then at 30°C under vacuum (0.1 kPa) for 2 hours to provide solid Form S of Vismodegib in 75% yield.
Example 2: Solid Form S of Vismodegib
10 g of Vismodegib was dissolved in 200 ml of methyl tert-butyl ether at 105°C. The mixture was filtered off to remove solid impurities. The mixture was cooled to 0°C in the course of 50 minutes. Obtained mixture was stirred at 0°C for 180 minutes. Obtained suspension was filtered off and obtained solid was suck dried in air for 1 hour and then at 30°C under vacuum (0.1 kPa) for 2 hours to provide solid Form S of Vismodegib in 79% yield. Example 3: Preparation of Form B of Vismodegib
8.6 g of solid Form S of Vismodegib was subjected to 90% of relative humidity and 55°C on open Petri dish for two weeks to provide solid Form B of Vismodegib in quantitative yield. Obtained solid Form B of Vismodegib comprised 484 ppm of methyl isobutyl ketone. Example 4: Preparation of Form B of Vismodegib
1 g of solid Form S of Vismodegib was mixed with 10 ml of water. The mixture was stirred at 100°C for 2 hours. Obtained suspension was cooled to room temperature and filtered off. Obtained solid was dried for 1 hour in air to provide solid Form B of Vismodegib in quantitative yield. Obtained solid Form B of Vismodegib comprised 529 ppm of methyl isobutyl ketone.
Example 5: Preparation of Form B of Vismodegib
Under nitrogen protecting atmosphere 1 kg of solid Form S of Vismodegib was mixed with 0.076 kg of water. The mixture was stirred at 25°C for 2 hours. Obtained suspension was filtered off. Obtained solid was dried for 2 hour at 40°C and then for 4 hours at 60°C under vacuum to provide solid Form B of Vismodegib in quantitative yield. Obtained solid Form B of Vismodegib comprised 485 ppm of methyl isobutyl ketone.

Claims

CLAIMS A process for preparation of solid Form B of Vismodegib, characterized by XRPD patern having 20 values 10.3°, 14.0° and 18.1° degrees 2 theta ( ± 0.2 degrees 2 theta), the process comprising subjecting solid Form S of Vismodegib, characterized by XRPD patern having 20 values 17.3°, 20.7° and 21.8° degrees 2 theta (± 0.2 degrees 2 theta), to a temperature between 45°C and 65°C and relative humidity between 80% and 100%. A process for preparation of solid Form B of Vismodegib, characterized by XRPD patern having 20 values 10.3°, 14.0° and 18.1° degrees 2 theta ( ± 0.2 degrees 2 theta), the process comprising: a. Mixing the solid Form S of Vismodegib with water; b. Stirring the mixture at a temperature between 15°C and 100°C for between 1.5 and 5 hours. A solid Form B of Vismodegib, characterized by XRPD patern having 20 values 10.3°, 14.0° and 18.1° degrees 2 theta (± 0.2 degrees 2 theta), containing less than 550 ppm of methyl isobutyl ketone. The solid form according to claim 3 containing less than 500 ppm or 450 ppm or 400 ppm or 350 ppm or 300 ppm or 250 ppm or 200 ppm of methyl isobutyl ketone. The solid form according to claim 3 or 4 wherein the solid form is prepared according to claim 1 or 2. A solid form of Vismodegib, Form S, wherein the form is characterized by XRPD patern having 20 values 17.3°, 20.7° and 21.8° degrees 2 theta (± 0.2 degrees 2 theta). A process for preparation of the solid form according to claim 6 comprising: a. Dissolving Vismodegib in methyl isobutyl ketone to obtain a mixture; b. Cooling the mixture to a temperature between -5°C and 5°C at the rate of 2-4 °C/min; c. Isolating the solid form. A solid form of Vismodegib, Form M, wherein the form is characterized by XRPD pattern having 20 values 7.5°, 11 ,3°and 15.1° degrees 2 theta (± 0.2 degrees 2 theta). A process for preparation of the solid form according to claim 8 comprising: a. Heating solid Form B of Vismodegib at a rate of 10°C/min to a temperature between 185°C and 187°C; b. Keep at this temperature for between 5 and 10 minutes.
EP23717459.4A 2022-04-05 2023-04-03 Solid forms of vismodegib Pending EP4504705A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP22166755 2022-04-05
PCT/EP2023/058668 WO2023194300A1 (en) 2022-04-05 2023-04-03 Solid forms of vismodegib

Publications (1)

Publication Number Publication Date
EP4504705A1 true EP4504705A1 (en) 2025-02-12

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ID=81328350

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Application Number Title Priority Date Filing Date
EP23717459.4A Pending EP4504705A1 (en) 2022-04-05 2023-04-03 Solid forms of vismodegib

Country Status (2)

Country Link
EP (1) EP4504705A1 (en)
WO (1) WO2023194300A1 (en)

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2377430T3 (en) 2004-09-02 2012-03-27 Genentech, Inc. Hedgehog signaling pyridyl inhibitors
US9278932B1 (en) 2013-03-22 2016-03-08 Shilpa Medicare Limited Process for preparation of 2-chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide solid forms
WO2014195977A2 (en) 2013-06-05 2014-12-11 Hetero Research Foundation Novel polymorphs of vismodegib
WO2015169269A1 (en) * 2014-05-05 2015-11-12 Zentiva, K.S. Salts of 2-chloro-n-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide

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