WO2016169532A1 - Crystalline forms of trametinib - Google Patents

Crystalline forms of trametinib Download PDF

Info

Publication number
WO2016169532A1
WO2016169532A1 PCT/CZ2016/000047 CZ2016000047W WO2016169532A1 WO 2016169532 A1 WO2016169532 A1 WO 2016169532A1 CZ 2016000047 W CZ2016000047 W CZ 2016000047W WO 2016169532 A1 WO2016169532 A1 WO 2016169532A1
Authority
WO
WIPO (PCT)
Prior art keywords
trametinib
solvate
crystalline form
dmso
endotherm
Prior art date
Application number
PCT/CZ2016/000047
Other languages
French (fr)
Inventor
Lukas KREJCIK
Violetta Kiss
Ondrej Dammer
Hana TOZICKOVA
Petr LEHNERT
Original Assignee
Zentiva, K.S.
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 Zentiva, K.S. filed Critical Zentiva, K.S.
Publication of WO2016169532A1 publication Critical patent/WO2016169532A1/en

Links

Classifications

    • 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

Definitions

  • the invention relates to a crystalline form of the DMSO solvate of Trametinib of formula I, chemically N- ⁇ 3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylammo)-6,8-dimethyl-2 5 4J-trioxo- 3,4,6, 7-tetrahydro-2H-pyrido[4,3-D]pyrimidin-l-yl]-phenyl ⁇ -acetamide dimethyl sulfoxide solvate, and a method of its preparation.
  • the invention further relates to another crystalline form of Trametinib (Form A) and a preparation method of this form.
  • acetamide (CAS: 871700-17-3), is found in medicinal products (original product Mekinist 0.5 mg; 1 mg and 2 mg) in the dimethyl sulfoxide form.
  • Trametinib is indicated for the treatment of adult patients with a non-resectable or metastatic melanoma with V600 mutation in the BRAF gene.
  • Trametinib is a reversible, highly selective, allosteric inhibitor of mitogen activated, extracellular signal-regulated kinase 1 (MEK1) and activation of MEK2 and kinase activity.
  • MEK1 extracellular signal-regulated kinase 1
  • the invention provides a crystalline form of the DMSO solvate of Trametinib and a method of its preparation.
  • the invention further relates to another crystalline form of Trametinib (Form A) and its preparation method.
  • These crystalline forms were characterized by means of X-ray powder diffraction, differential scanning calorimetry DSC and the thermogravimetric method TGA.
  • the starting material was crystalline Trametinib, characterized by the following reflections in the X-ray powder pattern: 3.6; 9.0; 14.5; 18.2 and 19.3 ⁇ 0.2° 2-theta (Table 1). The difrractograrn is shown in Figure 1.
  • Table 1 Diffraction peaks of Trametinib.
  • the process for preparing the crystalline form of the DMSO solvate comprises stirring up of Trametinib in dimethyl sulfoxide at 80°C in an oil bath. This solution is stirred at 80°C for the following 5 hours, during which the product is precipitated. The obtained suspension is subsequently cooled down to the room temperature while being continuously stirred. The precipitated product is finally filtered, washed with dimethyl sulfoxide and dried in a vacuum drier (60°C, 20 kPa).
  • the diffractogram of this solvate is shown in Figure 2 and is characterized by the following characteristic reflections in the X-ray powder pattern: 8.1; 11.6; 18.6; 21.4 and 23.5 ⁇ 0.2° 2- theta.
  • the DMSO solvate is characterized by the reflections presented in Table 2. a l 2 D ffrac io eaks of the DMSO s lvate.
  • a further aspect of the invention provides crystalline Form A of Trametinib.
  • This form is obtained by dissolution of Trametinib in chloroform at the room temperature. The solution is subsequently filtered through filtering paper and evaporated until dry by means of a pre-heated water bath at 40°C and a 5kPa vacuum.
  • Crystalline form A of Trametinib is characterized by the reflections presented in Table 3.
  • the characteristic reflections in the X-ray powder patterns are: 5.1; 11.2; 17.3; 18.1 and 20.3 ⁇ 0.2° 2-theta.
  • the diffractogram of this form is shown in Figure 5.
  • Table 3 Diffraction peaks of crystalline form A of Trametinib.
  • the TGA record of crystalline form A of Trametinib shows that the sample contains 2.1% of water and 4.9% of the solvate by weight.
  • Trametinib can be used for the preparation of a drug, or they can be used as an intermediate for the preparation of the active ingredient with a high chemical purity (Table 4).
  • Fig. 1 XRPD pattern of Trametinib
  • Fig. 2 XRPD pattern of Trametinib DMSO solvate
  • Fig.5 XRPD pattern of crystallme Form A of Trametinib.
  • Fig. 6 DSC record of crystalline Form A of Trametinib.
  • Fig. 7 TGA record of crystalline Form A of Trametinib.
  • 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 Soller slits and a 1 ⁇ 4° anti-diffusion slit were used.
  • For the setting of the secondary optical equipment an X ' Celerator detector (active length 2.122°), 5.0 mm anti-diffusion slit, Ni filter 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 1.5- 3 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 35°C and then of heating up to 350° 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.
  • thermogravimetric analysis TGA 6 device from Perkin Elmer.
  • the sample charge in a corundum pot was 13-20 mg and the heating rate was 10°C/min.
  • the temperature program that was used consists of 1 minute's stabilization at the temperature of 20°C and then of heating up to 250°C at the heating rate of 10°C/mm.
  • As the carrier gas 4.0 N 2 was used at the flow rate of 20 ml/min.
  • pH of the solution is adjusted to the value of 7.0 ⁇ 0.05 with the use of 25% ammonium hydroxide.
  • sample solvent DMSO/ACN, 10/90 (V/V)

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a crystalline form of the DMSO solvate of Trametinib of formula I, chemically N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl- 2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-D]pyrimidin-1-yl]-phenyl}-acetamide dimethyl sulfoxide solvate, and a method of its preparation. Another aspect of the invention relates to a crystalline form of Trametinib (Form A) and a preparation method of this form.

Description

Crystalline forms of trametinib
Technical Field
The invention relates to a crystalline form of the DMSO solvate of Trametinib of formula I, chemically N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylammo)-6,8-dimethyl-254J-trioxo- 3,4,6, 7-tetrahydro-2H-pyrido[4,3-D]pyrimidin-l-yl]-phenyl}-acetamide dimethyl sulfoxide solvate, and a method of its preparation.
Figure imgf000002_0001
The invention further relates to another crystalline form of Trametinib (Form A) and a preparation method of this form.
Background Art
Trametinib of formula I, chemically N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylami 6,8-dimemyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-D]pyrM
acetamide (CAS: 871700-17-3), is found in medicinal products (original product Mekinist 0.5 mg; 1 mg and 2 mg) in the dimethyl sulfoxide form. Trametinib is indicated for the treatment of adult patients with a non-resectable or metastatic melanoma with V600 mutation in the BRAF gene. Trametinib is a reversible, highly selective, allosteric inhibitor of mitogen activated, extracellular signal-regulated kinase 1 (MEK1) and activation of MEK2 and kinase activity.
Preparation of Trametinib was already described in the basic patent application WO2005121142 (EP1761528B), it consisted of 8 steps and is described in Example 4-1. The example mentions that a colourless crystalline substance was isolated, but this statement was not evidenced by any melting point, or XRPD spectra or DSC analyses. The product is only characterized by 1H NMR spectroscopy. The basic patent application WO2005121142 also described some solid forms of Trametinib: sodium salt, hydrate, acetic acid solvate, dimethyl sulfoxide solvate, ethanol solvate, nitromethane solvate, chlorobenzene solvate, 1-pentanol solvate, isopropyl alcohol solvate, ethylene glycol solvate and 3 -methyl butanol solvate. These forms of Trametinib were mentioned in Examples 4 to 149 and only characterized by means of 1H NMR spectroscopy again.
Disclosure of Invention
The invention provides a crystalline form of the DMSO solvate of Trametinib and a method of its preparation. The invention further relates to another crystalline form of Trametinib (Form A) and its preparation method. These crystalline forms were characterized by means of X-ray powder diffraction, differential scanning calorimetry DSC and the thermogravimetric method TGA.
The starting material was crystalline Trametinib, characterized by the following reflections in the X-ray powder pattern: 3.6; 9.0; 14.5; 18.2 and 19.3 ± 0.2° 2-theta (Table 1). The difrractograrn is shown in Figure 1.
Table 1: Diffraction peaks of Trametinib.
Figure imgf000003_0001
Figure imgf000004_0001
The process for preparing the crystalline form of the DMSO solvate comprises stirring up of Trametinib in dimethyl sulfoxide at 80°C in an oil bath. This solution is stirred at 80°C for the following 5 hours, during which the product is precipitated. The obtained suspension is subsequently cooled down to the room temperature while being continuously stirred. The precipitated product is finally filtered, washed with dimethyl sulfoxide and dried in a vacuum drier (60°C, 20 kPa).
The diffractogram of this solvate is shown in Figure 2 and is characterized by the following characteristic reflections in the X-ray powder pattern: 8.1; 11.6; 18.6; 21.4 and 23.5 ± 0.2° 2- theta. The DMSO solvate is characterized by the reflections presented in Table 2. a l 2 D ffrac io eaks of the DMSO s lvate.
Figure imgf000004_0002
Figure imgf000005_0001
The DSC record of the DMSO solvate (Figure 3) shows a minority endotherm that corresponds to the solvate Tonsetl = 168.8°C and Tpeakl = 186.2°C and a majority endotherm that corresponds to the melting point of Trametinib Tonset2 = 299.5°C and Tpeak2 = 302.6°C.
The TGA record of the DMSO solvate (Figure 4) shows that the sample contains 7.5% of the solvate.
A further aspect of the invention provides crystalline Form A of Trametinib. This form is obtained by dissolution of Trametinib in chloroform at the room temperature. The solution is subsequently filtered through filtering paper and evaporated until dry by means of a pre-heated water bath at 40°C and a 5kPa vacuum.
Crystalline form A of Trametinib is characterized by the reflections presented in Table 3. The characteristic reflections in the X-ray powder patterns are: 5.1; 11.2; 17.3; 18.1 and 20.3 ± 0.2° 2-theta. The diffractogram of this form is shown in Figure 5.
Table 3: Diffraction peaks of crystalline form A of Trametinib.
Figure imgf000006_0001
The DSC record of crystalline form A of Trametinib (Figure 6) shows a minority endotherm that corresponds to the solvate Tonsetl = 155.3°C and Tpeakl = 161.4°C and a majority endotherm that corresponds to the melting point of Trametinib Tonset2 = 292.5°C and Tpeak2 = 297.7°C.
The TGA record of crystalline form A of Trametinib (Figure 7) shows that the sample contains 2.1% of water and 4.9% of the solvate by weight.
The above mentioned crystalline forms of Trametinib can be used for the preparation of a drug, or they can be used as an intermediate for the preparation of the active ingredient with a high chemical purity (Table 4).
Table 4: HPLC purity of the forms of Trametinib
Figure imgf000007_0001
Brief Description of Drawings
Fig. 1: XRPD pattern of Trametinib
Fig. 2: XRPD pattern of Trametinib DMSO solvate
Fig. 3: DSC record of Trametinib DMSO solvate
Fig. 4: TGA record of Trametinib DMSO solvate
Fig.5: XRPD pattern of crystallme Form A of Trametinib.
Fig. 6: DSC record of crystalline Form A of Trametinib.
Fig. 7: TGA record of crystalline Form A of Trametinib. Examples
Example 1
Preparation of N-[3-[3-cyclopropyl-5-[(2-fluoro-4-iodo-phenyl)amino]-6,8-dimethyl- 2, 4,7-trioxo-pyrido[4,3-d]pyrimidin-l-yl] phenyl] acetamide (Trametinib) DMSO solvate
500 mg (0.812 mmol) of N-[3-[3-cyclopropyl-5-[(2-fluoro-4-iodo-phenyl)
dmiemyl-2,4,7-trioxo-pyrido[4,3-d]pyrimidm-l-yl]phenyl]ace (Trametinib) was stirred up in 2.5 ml of dimethyl sulfoxide at 80°C in an oil bath.
This solution was stirred at 80°C for the following 5 hours, during which the product precipitated. The obtained suspension was subsequently cooled down to the room temperature while being continuously stirred. The suspension was put' in a refrigerator for the night. The precipitated product was filtered, washed with dimethyl sulfoxide (3x0.2 ml) and dried overnight in a vacuum drier (60°C, 20 kPa).
Yield: 84%
Example 2
Preparation of N-[3-[3-cyclopropyl-5-[(2-fluoro-4-iodo-phenyl)amino5-6,8-dimethyl- 2,4,7-trioxo-pyrido[4,3-d]pyrimidin-l-yl] phenyl] acetamide (Trametinib) (crystalline form A of Trametinib)
100 mg (0.162 mmol) of N-[3-[3-cyclopropyl-5-[(2-fluoro-4-iodo-phenyl)amino]-6,8- dimethyl-2)4,7-trioxo-pyrido[4,3-d]pyrimidin-l -yl] phenyl] acetamide (Trametinib) was dissolved in 50 ml of chloroform at the room temperature. The prepared solution was filtered through filtering paper and evaporated until dry by means of a pre-heated water bath to 40°C and 5kPa vacuum.
Yield: 80%
Outline of analytic methods
Measurement parameters of XRPD: The diffractograms were measured using an X'PERT PRO MPD PANalytical diffractometer, used radiation CuKa (λ=01542 nm), excitation voltage: 45 kV, anode current: 40 mA, measured range: 2 - 40° 2Θ, increment: 0,01° 2Θ, 50s per increment. 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 Soller slits and a ¼° anti-diffusion slit were used. For the setting of the secondary optical equipment an X ' Celerator detector (active length 2.122°), 5.0 mm anti-diffusion slit, Ni filter 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 1.5- 3 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 35°C and then of heating up to 350° 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 records of the thermogravimetric analysis (TGA) were measured using a TGA 6 device from Perkin Elmer. The sample charge in a corundum pot was 13-20 mg and the heating rate was 10°C/min. The temperature program that was used consists of 1 minute's stabilization at the temperature of 20°C and then of heating up to 250°C at the heating rate of 10°C/mm. As the carrier gas 4.0 N2 was used at the flow rate of 20 ml/min.
HPLC purity determination:
mobile phase: A: 0.010M phosphate buffer (1.15 g) NH4H2PO4 is dissolved in 1 1 of
MQ water, pH of the solution is adjusted to the value of 7.0 ± 0.05 with the use of 25% ammonium hydroxide.
B: acetonitrile
elution: gradient
Figure imgf000009_0001
column: Ascentis Express CI 8, 2.7 μπι, 4.6 x 100 mm
sample solvent: DMSO/ACN, 10/90 (V/V)
detection: spectrophotometry 249 nm
injected amount: 1 μl
autosampler temperature: 15°C
column temperature: 35°C

Claims

Claims
1. A crystalline form of the solvate of Trametinib with dimethyl sulfoxide - DMSO, exhibiting the following characteristic reflections hi the X-ray powder pattern with the use of CuKa radiation: 8.1; 11.6; 18.6; 21.4 and 23.5 and 26.5 ± 0.2° 2-theta.
2. The crystalline form of the DMSO solvate of Trametinib according to claim 1, showing a minority endotherm in the DSC record, corresponding to the solvate, at the temperature
Figure imgf000010_0001
and a majority endotherm, corresponding to the melting point of Trametinib,
Figure imgf000010_0002
Figure imgf000010_0003
3. The crystalline form of the DMSO solvate of Trametinib according to claims 1 to 2, showing the content of 7.5% by weight of the solvate in the TG A record
4. A process for preparing the crystalline form of the DMSO solvate of Trametinib as defined in any one of claims 1 to 3, characterized in that it comprises stirring up of Trametinib in the solvent DMSO at the temperature of 80°C5 stirring of the solution at the same temperature for 5 hours, cooling of the solution to the room temperature and isolation of the product by filtration and drying in vacuum.
5. Crystalline Form A of Trametinib, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation 5.1; 11.2; 17.3; 18.1 and 20.3 ± 0.2° 2-theta.
6. Crystalline Form A of Trametinib according to claim 5, showing a minority endotherm in the DSC record, corresponding to the solvate, at the temperature
Figure imgf000010_0004
and a majority endotherm, corresponding to the melting point of Trametinib,
Figure imgf000010_0005
and
Figure imgf000010_0006
7. Crystalline Form A of Trametinib according to claims 5 to 6, showing the content of 2.1% by weight of water and 4.9% by weight of the solvate in the TGA record.
8. A process for preparing crystalline Form A of Trametinib as defined in claims 5 to 7, characterized in that it comprises dissolution of Trametinib in the solvent chloroform at the room temperature and evaporation of the solvent until dry by means of a pre-heated water bath at 40°C and a 5 kPa vacuum.
PCT/CZ2016/000047 2015-04-24 2016-04-19 Crystalline forms of trametinib WO2016169532A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CZ2015-278A CZ2015278A3 (en) 2015-04-24 2015-04-24 Trametinib crystalline forms
CZPV2015-278 2015-04-24

Publications (1)

Publication Number Publication Date
WO2016169532A1 true WO2016169532A1 (en) 2016-10-27

Family

ID=55948766

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CZ2016/000047 WO2016169532A1 (en) 2015-04-24 2016-04-19 Crystalline forms of trametinib

Country Status (2)

Country Link
CZ (1) CZ2015278A3 (en)
WO (1) WO2016169532A1 (en)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005121142A1 (en) 2004-06-11 2005-12-22 Japan Tobacco Inc. 5-amino-2,4,7-trioxo-3,4,7,8-tetrahydro-2h-pyrido’2,3-d! pyrimidine derivatives and related compounds for the treatment of cancer
WO2015081566A1 (en) * 2013-12-06 2015-06-11 杭州普晒医药科技有限公司 Crystalline forms of trametinib and solvate thereof, preparation method therefor, pharmaceutical composition comprising same and use thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005121142A1 (en) 2004-06-11 2005-12-22 Japan Tobacco Inc. 5-amino-2,4,7-trioxo-3,4,7,8-tetrahydro-2h-pyrido’2,3-d! pyrimidine derivatives and related compounds for the treatment of cancer
EP1761528B1 (en) 2004-06-11 2008-01-09 Japan Tobacco, Inc. 5-amino-2,4,7-trioxo-3,4,7,8-tetrahydro-2h-pyrido[2,3-d]pyrimidine derivatives and related compounds for the treatment of cancer
WO2015081566A1 (en) * 2013-12-06 2015-06-11 杭州普晒医药科技有限公司 Crystalline forms of trametinib and solvate thereof, preparation method therefor, pharmaceutical composition comprising same and use thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
COMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN USE (CHMP): "CHMP assessment report for EMA/CHMP/258608/2014", 25 April 2014 (2014-04-25), XP055275278, Retrieved from the Internet <URL:http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002643/WC500169708.pdf> [retrieved on 20160525] *
D.P. COSGROVE: "Trametinib dimethyl sulfoxide", DRUGS OF THE FUTURE, vol. 37, no. 12, 1 January 2012 (2012-01-01), ES, pages 847, XP055275361, ISSN: 0377-8282, DOI: 10.1358/dof.2012.037.012.1879452 *

Also Published As

Publication number Publication date
CZ2015278A3 (en) 2016-11-02

Similar Documents

Publication Publication Date Title
WO2017008773A1 (en) Crystalline forms of obeticholic acid
US9895377B2 (en) Solid forms of tyrosine kinase inhibitors, process for the preparation and their pharmaceutical composition thereof
EP3287444A1 (en) New crystal form of lenvatinib methanesulfonate salt and preparation method thereof
AU2018259089B2 (en) Polymorphs and solid forms of (s)-2-((2-((s)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo(ƒ)imidazo(1,2-d)(1,4)oxazepin-9-yl)amino)propanamide, and methods of production
WO2017174044A1 (en) Solid forms of ibrutinib
WO2017140283A1 (en) Crystalline olaparib solvates with acetone, 2-propanol and/or methyl ethyl ketone
WO2016090257A1 (en) Salts and crystalline forms of 6-acetyl-8-cyclopentyl-5-methyl-2((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d] pyrimidin-7(8h)-one (palbociclib)
WO2016127963A1 (en) Solid forms of palbociclib salts
WO2018046028A1 (en) Solid forms of eluxadoline
WO2016051380A1 (en) Crystalline form of afatinib dimaleate
WO2011108953A1 (en) PROCESS FOR PREPARATION OF POLYMORPHIC FORM α AND NEW POLYMORPHIC FORM OF IMATINIB MESYLATE ISOLATED IN THAT PROCESS
KR20160021077A (en) Base addition salts of nitroxoline and uses thereof
EP3272751A1 (en) Crystal form of ipi-145 and preparation method thereof
WO2015068055A1 (en) Crystalline dasatinib process
WO2018113801A1 (en) Crystalline forms of2-[1-ethylsulfonyl-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]azetidin-3-yl]acetonitrile with phosphoric acid and a method of their preparation
WO2016169532A1 (en) Crystalline forms of trametinib
EP3322709A1 (en) Crystalline forms of (3r)-3-cyclopentyl-3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propanenitrile salts and preparation thereof
WO2012090221A1 (en) Novel salts of imatinib
WO2015078424A1 (en) Crystalline forms of vemurafenib
WO2017028802A1 (en) Crystal form of 5-[2,6-di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine dihydrochloride and preparation method thereof
WO2017186197A1 (en) Salts of lenvatinib
AU2012204839A1 (en) Method for resolution of 4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-1,2,2-trimethyl-piperazine and 1-((1R,3S)-6-chloro-3-phenyl-indan- 1-yl)-3,3-dimethyl-piperazine
WO2016155560A1 (en) P-toluenesulfonic acid salt of lenvatinib, crystalline form and preparation method thereof
CN104788435A (en) I-type crystal of dibenzenesulfonate of inhibitor of protein tyrosine kinase
CN110526914B (en) Polymorphic substance of ALK inhibitor and preparation method thereof

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: 16721062

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16721062

Country of ref document: EP

Kind code of ref document: A1