WO2015078424A1 - Crystalline forms of vemurafenib - Google Patents
Crystalline forms of vemurafenib Download PDFInfo
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- WO2015078424A1 WO2015078424A1 PCT/CZ2014/000140 CZ2014000140W WO2015078424A1 WO 2015078424 A1 WO2015078424 A1 WO 2015078424A1 CZ 2014000140 W CZ2014000140 W CZ 2014000140W WO 2015078424 A1 WO2015078424 A1 WO 2015078424A1
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- vemurafenib
- preparation
- dioxane
- crystalline form
- solvent
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- 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 new crystalline forms of vemurafenib, i.e. N-(3- ⁇ [5-(4-chlorophenyl)- 1 H-pyrrolo [2,3 -b]pyridin-3 -yl]carbonyl ⁇ -2,4-difluorophenyl)propane- 1 -sulfonamide of formula (I) and a method of their preparation.
- Vemurafenib a B-Raf enzyme inhibitor is used to treat metastatic melanoma. Preparation of vemurafenib is described in WO2007002433. A number of solid forms of vemurafenib, including selected salts, solvates and solid solutions or dispersions are characterized in WO2010114928, WO2010129570 and WO2012/161776. However, available literature does not describe a crystallization procedure leading to chemically highly pure vemurafenib.
- the invention provides new crystalline forms of vemurafenib.
- Form A is characterized by the following characteristic reflections in the X-ray powder pattern:
- Another object of the invention is a preparation method of forms A and B and their use for the preparation of a medicament or for the preparation of highly pure vemurafenib, or its pharmaceutically acceptable salts, solvates, cocrystals, or solid solutions.
- the invention relates to new crystalline forms of vemurafenib, referred to as A and B. These forms have been characterized with the use of the X-ray Powder Diffraction, M , Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA).
- M X-ray Powder Diffraction
- DSC Differential Scanning Calorimetry
- TGA Thermogravimetric Analysis
- Form A of vemurafenib in accordance with this invention is characterized by the reflections presented in Table 1.
- Form B of vemurafenib in accordance with this invention is characterized by the reflections presented in Table 2.
- the crystalline forms A and B of vemurafenib in accordance with this invention have also been characterized by Differential Scanning Calorimetry DSC and Thermogravimetry TGA. The results of the DSC and TGA analysis of both the forms are shown in Table 3.
- the graphic appendix includes the respective DSC and TGA records of forms A and B.
- Form A of vemurafenib with an HPLC purity of at least 98.0 % can be obtained by crystallization of crude vemurafenib from dioxane, or a mixture of dioxane and another solvent from the group comprising CI - C4 alk l alcohols and water.
- dioxane or a mixture of dioxane and water or a mixture of dioxane and methanol is used.
- the ratio of the amounts of the solvent and crude vemurafenib is selected in the range of 20:1 to 1 :2 (weight ratio).
- Form A can be prepared both under reflux, wherein vemurafenib gets completely dissolved in the crystallization solvent, and at the room temperature (20 to 25 °C), wherein vemurafenib is only dissolved partly in the crystallization solvent.
- Form B of vemurafenib can be prepared by drying of form A at 40°C for one week.
- Forms A and B of vemurafenib are suitable to be used for preparation of medicaments thanks to their good physical-chemical characteristics. They can also be used in the preparation process of vemurafenib, or any other pharmaceutically acceptable form of vemurafenib from the group of solvates, salts and cocrystals, or solid solutions, with regard to the high purification capability during crystallization of crude vemurafenib from dioxane or a mixture of dioxane and/or another solvent and/or water.
- a flat powder sample was used that was placed on a Si plate.
- 0.02 rad SoUer slits and a 1 ⁇ 4 anti-diffusion slit were used.
- For the setting of the secondary optical equipment an X'Celerator detector with maximum opening of the detection slot, 0.02 rad Soller slits and a 5.0 mm anti-diffusion slit were used.
- the records of the differential scanning calorimetry were measured using a DSC Pyris 1 device from Perkin Elmer.
- the sample charge in a standard Al pot was between 3 and 4 mg and the heating rate was 10°C/min.
- the temperature program that was used consists of 1 min of stabilization at the temperature of 50°C and then of heating up to 250°C at the heating rate of 10°C/min.
- As the carrier gas 4.0 N 2 was used at the flow rate of 20 ml/min.
- the 1H NMR records were measured using a Bruker Avance 250 device at 250.013 MHz in the solvent DMSO-d6.
- Tested solution 10.0 mg of the API was dissolved in 10.0 ml of 50% acetonitrile R.
- Phosphate buffer (0.02 M hydrogen ammonium phosphate; adjusted to pH 9.8 ⁇ 0.05)
- Vemurafenib (5 g, HPLC 93.3%) was dissolved in 1,4 dioxane (20 ml) under reflux. The solution was then slowly crystallized by cooling to the room temperature. The obtained solid 5 was isolated by filtration and dried at 40°C overnight (for ca. 12 hours). The result was white powder (4.3 g, 86%), HPLC 98.3 %, Form A.
- Vemurafenib (5 g, HPLC 93,3%) was dissolved in a mixture of 1,4- dioxane/water (30/10 ml) under reflux. The solution was then slowly crystallized by cooling to the room temperature. The obtained solid was isolated by filtration and dried at 40°C overnight (for ca. 12 hours). The result was white powder (4.1 g, 82%), HPLC 94.8 %, Form A.
- Vemurafenib (5 g, HPLC 93.3%) was partly dissolved in 1,4-dioxane (10 ml) and stirred at 25°C. The obtained solid was isolated by filtration and dried at 40°C overnight (for ca. 12 hours). The result was white powder (4.5g, 90 %), HPLC 98.5%, Form A.
- Vemurafenib (5 g, HPLC 93.3%) was dissolved in a mixture of 1,4- dioxane/methanol (30/10 ml) under reflux. The solution was then slowly crystallized by cooling to the room !5 temperature. The obtained solid was isolated by filtration and dried at 40°C overnight (for ca.
- JO Form B was obtained by drying of Form A at 40°C for one week.
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Abstract
The invention relates to new crystalline forms of vemurafenib, i.e. N-(3-{[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl}-2,4-difluorophenyl)propane-1-sulfonamide of formula (I), exhibiting the following characteristic reflections in the X-ray powder pattern, measured with the use of CuKa radiation at the wavelength λ = 0.1542 nm: 6.5; 9.7; 18.0; 19.5 and 23,7 ± 0.2° 2-theta, and a method for the preparation thereof.
Description
Crystalline forms of vemurafenib
Technical Field The invention relates to new crystalline forms of vemurafenib, i.e. N-(3-{[5-(4-chlorophenyl)- 1 H-pyrrolo [2,3 -b]pyridin-3 -yl]carbonyl} -2,4-difluorophenyl)propane- 1 -sulfonamide of formula (I) and a method of their preparation.
Background Art
Vemurafenib, a B-Raf enzyme inhibitor is used to treat metastatic melanoma. Preparation of vemurafenib is described in WO2007002433. A number of solid forms of vemurafenib, including selected salts, solvates and solid solutions or dispersions are characterized in WO2010114928, WO2010129570 and WO2012/161776. However, available literature does not describe a crystallization procedure leading to chemically highly pure vemurafenib.
Disclosure of Invention
The invention provides new crystalline forms of vemurafenib. Form A is characterized by the following characteristic reflections in the X-ray powder pattern:
6.5; 9.7; 18.0; 19.5 and 23.7 ± 0.2° 2-theta.
Form B is characterized by the following characteristic reflections in the X-ray powder pattern:
5.9; 9.1; 14.2; 18.3; 19.7 and 23.7.
Another object of the invention is a preparation method of forms A and B and their use for the preparation of a medicament or for the preparation of highly pure vemurafenib, or its pharmaceutically acceptable salts, solvates, cocrystals, or solid solutions. Detailed description of the invention
The invention relates to new crystalline forms of vemurafenib, referred to as A and B. These forms have been characterized with the use of the X-ray Powder Diffraction, M , Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA).
Form A of vemurafenib in accordance with this invention is characterized by the reflections presented in Table 1.
Table 1: Diffraction peaks of Form A (b.n. VE-DW2)
The diffraction pattern of Form A is shown in Figure 1.
Form B of vemurafenib in accordance with this invention is characterized by the reflections presented in Table 2.
Table 2; Diffraction peaks of Form B (b.n. VE-DW2/1)
The diffraction pattern of Form B is shown in Figure 7.
The crystalline forms A and B of vemurafenib in accordance with this invention have also been characterized by Differential Scanning Calorimetry DSC and Thermogravimetry TGA. The results of the DSC and TGA analysis of both the forms are shown in Table 3.
Table 3: DSC and TGA analyses of crystalline forms A and B of vemurafenib
The graphic appendix includes the respective DSC and TGA records of forms A and B.
Form A of vemurafenib with an HPLC purity of at least 98.0 % can be obtained by crystallization of crude vemurafenib from dioxane, or a mixture of dioxane and another
solvent from the group comprising CI - C4 alk l alcohols and water. In a preferred embodiment dioxane or a mixture of dioxane and water or a mixture of dioxane and methanol is used. The ratio of the amounts of the solvent and crude vemurafenib is selected in the range of 20:1 to 1 :2 (weight ratio).
Form A can be prepared both under reflux, wherein vemurafenib gets completely dissolved in the crystallization solvent, and at the room temperature (20 to 25 °C), wherein vemurafenib is only dissolved partly in the crystallization solvent.
Form B of vemurafenib can be prepared by drying of form A at 40°C for one week.
Forms A and B of vemurafenib are suitable to be used for preparation of medicaments thanks to their good physical-chemical characteristics. They can also be used in the preparation process of vemurafenib, or any other pharmaceutically acceptable form of vemurafenib from the group of solvates, salts and cocrystals, or solid solutions, with regard to the high purification capability during crystallization of crude vemurafenib from dioxane or a mixture of dioxane and/or another solvent and/or water.
Brief Description of Drawings
Fig. l X-ray powder pattern of Form A
Fig. 2 1H NMR spectrum of Form A
Fig. 3 DSC record of Form A
Fig. 4 TGA record of Form A
Fig. 5 X-ray powder pattern of Form B
Fig. 6 1H NMR spectrum of Form B
Fig. 7 DSC record of Form B
Fig. 8 TGA record of Form B
Description of analytic methods
Measurement parameters of XRPD: The diffraction patterns were measured using an X'PERT PRO MPD PANalytical diffractometer with a graphite monochromator, radiation used: CuKa (λ=1,542 A = 0.15 nm), excitation voltage: 45 kV, anode current: 40 mA, measured range: 2 - 40° 2Θ, increment: 0.01° 2Θ. For the measurement a flat powder sample
was used that was placed on a Si plate. For the setting of the primary optical equipment programmable divergence slits with the irradiated area of the sample of 10 mm, 0.02 rad SoUer slits and a ¼ anti-diffusion slit were used. For the setting of the secondary optical equipment an X'Celerator detector with maximum opening of the detection slot, 0.02 rad Soller slits and a 5.0 mm anti-diffusion slit were used.
The records of the differential scanning calorimetry (DSC) were measured using a DSC Pyris 1 device from Perkin Elmer. The sample charge in a standard Al pot was between 3 and 4 mg and the heating rate was 10°C/min. The temperature program that was used consists of 1 min of stabilization at the temperature of 50°C and then of heating up to 250°C at the heating rate of 10°C/min. As the carrier gas 4.0 N2 was used at the flow rate of 20 ml/min.
The 1H NMR records were measured using a Bruker Avance 250 device at 250.013 MHz in the solvent DMSO-d6.
HPLC purity determination:
Tested solution: 10.0 mg of the API was dissolved in 10.0 ml of 50% acetonitrile R.
Column:
- size: 1 = 0.10 m, 0 = 4.6 mm
- stationary phase: Gemini NX C 18
- temperature: 30°C
Mobile phase:
A: Phosphate buffer (0.02 M hydrogen ammonium phosphate; adjusted to pH 9.8 ± 0.05)
B: acetonitrile R
Gradient program:
Time (min.) Flow rate % A % B
0 1.2 60 40
5 1.2 30 70
8 1.2 20 80
9 1.2 60 40
11 1.2 60 40
Detection: spectrophotometer at 230 nm
Injection: 2 μΐ
Sample temperature: 20°C
Examples
Example 1
Preparation of crude vemurafenib (N-{254-difluoro-3-[[5-(4-chlorophenyl)-lH-pynOlo[2,3- 63pyridin-3-yl]carbonyl] } propane- 1 -sulfonamide (I))
7.00 g (30.60 mmol) of 5-(4-cWorophenyl)-lH-pyrrolo[2,3- yridine of formula (VIII) was suspended in 140 ml 1,2-dichloroethane. After cooling of the suspension to 0°C, 28.57 g (214.23 mmol) of aluminium chloride was added during 10 minutes and the mixture was agitated for 30 minutes being continuously cooled. Then, a solution of the chloride of formula (TV) (45.91 mmol) in 1,2-dichloroethane (160 ml) was added dropwise during 40 minutes. The reaction mixture was agitated overnight while the temperature gradually rose from 0°C to 20°C. The resulting dark mixture was then poured on 300 g of ice and subsequently 320 ml of brine was added. The product was extracted with a mixture of 1 x 500 ml of ethyl acetate with 120 ml of ethanol and 1 x 400 ml of ethyl acetate with 100 ml of ethanol. The combined extracts were washed with 300 ml of brine, dried with sodium sulphate and evaporated. The residue was subjected to column chromatography; 220 g of silica gel, elution: 30% THF/hexane, 40% THF hexane, 50% THF hexane. The fractions containing the product were evaporated and the crude product was recrystallized from a THF/hexane mixture. After the 1st crystallization, of 9.00 g of yellowish vemurafenib crystals was obtained (60% yield).
Example 2
Preparation of crystalline form A of vemurafenib
Vemurafenib (5 g, HPLC 93.3%) was dissolved in 1,4 dioxane (20 ml) under reflux. The solution was then slowly crystallized by cooling to the room temperature. The obtained solid 5 was isolated by filtration and dried at 40°C overnight (for ca. 12 hours). The result was white powder (4.3 g, 86%), HPLC 98.3 %, Form A.
Example 3
Preparation of crystalline form A of vemurafenib
0 Vemurafenib (5 g, HPLC 93,3%) was dissolved in a mixture of 1,4- dioxane/water (30/10 ml) under reflux. The solution was then slowly crystallized by cooling to the room temperature. The obtained solid was isolated by filtration and dried at 40°C overnight (for ca. 12 hours). The result was white powder (4.1 g, 82%), HPLC 94.8 %, Form A.
5 Example 4
Preparation of crystalline form A of vemurafenib
Vemurafenib (5 g, HPLC 93.3%) was partly dissolved in 1,4-dioxane (10 ml) and stirred at 25°C. The obtained solid was isolated by filtration and dried at 40°C overnight (for ca. 12 hours). The result was white powder (4.5g, 90 %), HPLC 98.5%, Form A.
:0
Example 5
Preparation of crystalline form A of vemurafenib
Vemurafenib (5 g, HPLC 93.3%) was dissolved in a mixture of 1,4- dioxane/methanol (30/10 ml) under reflux. The solution was then slowly crystallized by cooling to the room !5 temperature. The obtained solid was isolated by filtration and dried at 40°C overnight (for ca.
12 hours). The result was white powder, (4.4g, 88 %), HPLC 97.6%, Form A.
Example 6
Preparation of crystalline form B of vemurafenib
JO Form B was obtained by drying of Form A at 40°C for one week.
Claims
1. Crystalline form A of vemurafenib, exhibiting the following characteristic reflections in the X-ray powder pattern, measured with the use of CuKa radiation at the wavelength λ = 0.1542 nm: 6.5; 9.7; 18.0; 19.5 and 23.7 ± 0.2° 2-theta.
2. Crystalline form B of vemurafenib, exhibiting the following characteristic reflections in the X-ray powder pattern, measured with the use of CuKa radiation at the wavelength λ = 0.1542 nm: 5.9; 9.1; 14.2; 18.3; 19.7 and 23.7 + 0.2° 2-theta.
3. A preparation method for crystalline form A of vemurafenib as defined in claim 1, characterized in that it comprises dissolution of vemurafenib in the solvent dioxane, or a mixture of dioxane and another solvent from the group of CI - C4 alkyl alcohols, or in a mixture of dioxane and water, and crystallization of form A of vemurafenib from the solution.
4. The preparation method in accordance with claim 3, characterized in that the solvent is dioxane.
5. The preparation method in accordance with claim 3, characterized in that the solvent is a mixture of dioxane and water.
6. The preparation method in accordance with claim 3, characterized in that the solvent is a mixture of dioxane and methanol.
7. The preparation method in accordance with claims 3 to 6, characterized in that vemurafenib is dissolved in the solvent under reflux and vemurafenib of form A is isolated after slow cooling to the room temperature.
8. The preparation method in accordance with claims 3 to 6, characterized in that vemurafenib is partly dissolved in the solvent at the room temperature, 20 to 25°C, and vemurafenib of form A is isolated after stirring the mixture for at least 1 hour.
9. A preparation method of crystalline form B of vemurafenib as defined in claim 2, characterized in that crystalline form A as defined in claim 1 is dried at 40°C for one week.
10. Use of crystalline form A of vemurafenib for the preparation of a medicament.
11. Use of crystalline form B of vemurafenib for the preparation of a medicament.
12. Use of crystalline form A or B for the preparation of any derived pharmaceutically acceptable forms of vemurafenib such as solvates, salts, cocrystals or solid solutions.
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CZPV2013-943 | 2013-11-27 | ||
CZ2013-943A CZ2013943A3 (en) | 2013-11-27 | 2013-11-27 | Vemurafenib crystalline forms |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017098336A1 (en) * | 2015-12-11 | 2017-06-15 | Laurus Labs Private Limited | Novel polymorphs of vemurafenib, process for its preparation and pharmaceutical composition thereof |
US10407427B2 (en) | 2016-07-01 | 2019-09-10 | Fermion Oy | Processes for the preparation of Vemurafenib |
US11040027B2 (en) | 2017-01-17 | 2021-06-22 | Heparegenix Gmbh | Protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death |
Citations (5)
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WO2007002433A1 (en) | 2005-06-22 | 2007-01-04 | Plexxikon, Inc. | Pyrrolo [2, 3-b] pyridine derivatives as protein kinase inhibitors |
WO2010114928A2 (en) | 2009-04-03 | 2010-10-07 | F.Hoffmann-La Roche Ag | Compositions and uses thereof |
WO2010129570A1 (en) | 2009-05-06 | 2010-11-11 | Plexxikon, Inc. | Solid forms of sulfonamides and amino acids |
WO2012161776A1 (en) | 2011-02-21 | 2012-11-29 | Plexxikon Inc. | Solid forms of a pharmaceutically active substance |
WO2014008270A1 (en) * | 2012-07-03 | 2014-01-09 | Ratiopharm Gmbh | Solid state form of vemurafenib choline salt |
-
2013
- 2013-11-27 CZ CZ2013-943A patent/CZ2013943A3/en unknown
-
2014
- 2014-11-26 WO PCT/CZ2014/000140 patent/WO2015078424A1/en active Application Filing
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007002433A1 (en) | 2005-06-22 | 2007-01-04 | Plexxikon, Inc. | Pyrrolo [2, 3-b] pyridine derivatives as protein kinase inhibitors |
WO2010114928A2 (en) | 2009-04-03 | 2010-10-07 | F.Hoffmann-La Roche Ag | Compositions and uses thereof |
WO2010129570A1 (en) | 2009-05-06 | 2010-11-11 | Plexxikon, Inc. | Solid forms of sulfonamides and amino acids |
WO2012161776A1 (en) | 2011-02-21 | 2012-11-29 | Plexxikon Inc. | Solid forms of a pharmaceutically active substance |
WO2014008270A1 (en) * | 2012-07-03 | 2014-01-09 | Ratiopharm Gmbh | Solid state form of vemurafenib choline salt |
Non-Patent Citations (1)
Title |
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CAIRA M R: "CRYSTALLINE POLYMORPHISM OF ORGANIC COMPOUNDS", TOPICS IN CURRENT CHEMISTRY, SPRINGER, BERLIN, DE, vol. 198, 1 January 1998 (1998-01-01), pages 163 - 208, XP001156954, ISSN: 0340-1022, DOI: 10.1007/3-540-69178-2_5 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017098336A1 (en) * | 2015-12-11 | 2017-06-15 | Laurus Labs Private Limited | Novel polymorphs of vemurafenib, process for its preparation and pharmaceutical composition thereof |
US10407427B2 (en) | 2016-07-01 | 2019-09-10 | Fermion Oy | Processes for the preparation of Vemurafenib |
US11040027B2 (en) | 2017-01-17 | 2021-06-22 | Heparegenix Gmbh | Protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death |
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