WO2016001844A1 - Forme amorphe de dimaléate d'afatinib - Google Patents

Forme amorphe de dimaléate d'afatinib Download PDF

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Publication number
WO2016001844A1
WO2016001844A1 PCT/IB2015/054919 IB2015054919W WO2016001844A1 WO 2016001844 A1 WO2016001844 A1 WO 2016001844A1 IB 2015054919 W IB2015054919 W IB 2015054919W WO 2016001844 A1 WO2016001844 A1 WO 2016001844A1
Authority
WO
WIPO (PCT)
Prior art keywords
amorphous form
reaction mixture
afatinib dimaleate
afatinib
dimaleate
Prior art date
Application number
PCT/IB2015/054919
Other languages
English (en)
Inventor
Shyam Sunder Verma
Shravan Kumar Singh
Kaptan Singh
Mohan Prasad
Original Assignee
Sun Pharmaceutical Industries Limited
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 Sun Pharmaceutical Industries Limited filed Critical Sun Pharmaceutical Industries Limited
Publication of WO2016001844A1 publication Critical patent/WO2016001844A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention provides an amorphous form of afatinib dimaleate, processes for its preparation, a pharmaceutical composition comprising it, and its use for the treatment of metastatic non-small cell lung cancer.
  • Afatinib dimaleate is a tyrosine kinase inhibitor, chemically designated as 2- butenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(35)-tetrahydro-3-furanyl]oxy]-6- quinazolinyl]-4-(dimethylamino)-,(2£)-, (2Z)-2-butenedioate (1:2) having the structure depicted by Formula I.
  • 2013/052157 provide processes for the preparation of crystalline forms of afatinib and their salts.
  • the present invention provides an amorphous form of afatinib dimaleate, processes for its preparation, a pharmaceutical composition comprising it, and its use for the treatment of metastatic non-small cell lung cancer.
  • the amorphous form of afatinib dimaleate is a highly pure, easy to filter, free-flowing solid, and is stable towards polymorphic conversion.
  • a first aspect of the present invention provides an amorphous form of afatinib dimaleate.
  • a second aspect of the present invention provides a process for the preparation of an amorphous form of afatinib dimaleate comprising:
  • a third aspect of the present invention provides a process for the preparation of an amorphous form of afatinib dimaleate comprising:
  • a fourth aspect of the present invention provides a process for the preparation of an amorphous form of afatinib dimaleate comprising subjecting a solution of afatinib dimaleate to spray drying, agitated thin film drying, lyophilization, or concentrating a reaction mixture containing afatinib dimaleate in a solvent under reduced pressure.
  • a fifth aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an amorphous afatinib dimaleate and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • a sixth aspect of the present invention provides the use of an amorphous form of afatinib dimaleate for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have an epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations.
  • NSCLC metastatic non-small cell lung cancer
  • EGFR epidermal growth factor receptor
  • Figure 1 X-ray powder diffraction (XRPD) pattern of an amorphous form of afatinib dimaleate.
  • ambient temperature refers to a temperature in the range of about 20°C to about 35°C.
  • scanning refers to the act of getting solid material (for example, seed crystals) out of a reaction mixture by rubbing or crushing the reaction vessel by any means, for example, through glass rod, spatula, etc.
  • Afatinib can be obtained by following the processes disclosed in U.S. Patent No. RE43,431.
  • the preparation of the amorphous form of afatinib dimaleate is carried out by reacting afatinib with maleic acid in the presence of one or more solvents and heating the reaction mixture at about 40°C to about 80°C for about 2 hours followed by cooling the reaction mixture to ambient temperature, then scratching the material obtained with a spatula.
  • the solvent may be selected from the group comprising alcohols, ketones, alkyl acetates, and mixtures thereof.
  • alcohols include methanol, ethanol, n- propanol, isopropanol, «-butanol, and 2-methyl-l-pentanol.
  • ketones include acetone, methyl ethyl ketone, and i-butyl ketone.
  • alkyl acetates include ethyl acetate, propyl acetate, and /-butyl acetate.
  • Isolation of the amorphous form of afatinib dimaleate from its reaction mixture is carried out by concentration, precipitation, cooling, filtration, centrifugation, or a combination thereof, followed by drying. Drying can be carried out using any suitable method, such as drying under reduced pressure, air drying, vacuum tray drying or heating.
  • the isolation of the amorphous form of afatinib dimaleate is carried out by filtration, followed by drying at a temperature of about 40°C to about 55°C.
  • the amorphous form of afatinib dimaleate can be prepared by subjecting a solution of afatinib dimaleate to spray drying, agitated thin film drying, lyophilization, or concentrating a reaction mixture containing afatinib dimaleate in a solvent under reduced pressure
  • amorphous form of afatinib dimaleate of the present invention exhibits an X- ray powder diffraction (XRPD) pattern substantially as depicted in Figure 1.
  • the amorphous form of afatinib dimaleate is a highly pure, easy to filter, free- flowing solid, and is stable towards polymorphic conversion.
  • X-ray diffraction patterns were recorded using a PANalytical ® X'pert PRO with X'celerator ® as the detector, 0.02 as step size, and 3-40° 2 ⁇ as range, using CuKa radiation.
  • the sticky material was scratched with a spatula, and then the reaction mixture was further stirred at about 20°C to about 25°C for about 1 hour.
  • the material obtained was filtered, and then washed with ethyl acetate (20 mL).
  • the solid obtained was dried under vacuum at about 45°C to about 50°C for about 15 hours to obtain the amorphous form of afatinib dimaleate.

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

Abstract

La présente invention porte sur une forme amorphe de dimaléate d'afatinib, sur des procédés pour le préparer, sur une composition pharmaceutique le contenant, et sur son utilisation pour le traitement du cancer métastatique du poumon non à petites cellules. La présente invention porte sur une forme amorphe de dimaléate d'afatinib, sur des procédés pour le préparer, sur une composition pharmaceutique le contenant, et sur son utilisation pour le traitement du cancer métastatique du poumon non à petites cellules. Ladite forme amorphe de dimaléate d'afatinib se présente sous la forme d'un solide à écoulement fluide, hautement pur, facile à filtrer, et stable par rapport à une transformation polymorphique .
PCT/IB2015/054919 2014-06-30 2015-06-30 Forme amorphe de dimaléate d'afatinib WO2016001844A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1738DE2014 2014-06-30
IN1738/DEL/2014 2014-06-30

Publications (1)

Publication Number Publication Date
WO2016001844A1 true WO2016001844A1 (fr) 2016-01-07

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Application Number Title Priority Date Filing Date
PCT/IB2015/054919 WO2016001844A1 (fr) 2014-06-30 2015-06-30 Forme amorphe de dimaléate d'afatinib

Country Status (1)

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WO (1) WO2016001844A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105717226A (zh) * 2016-02-02 2016-06-29 北京科莱博医药开发有限责任公司 一种运用高效液相色谱检测马来酸阿法替尼异构体及主要降解杂质的方法
WO2018187643A1 (fr) 2017-04-06 2018-10-11 Johnson Matthey Public Limited Company Nouvelles formes de dimaléate d'afatinib
US10329281B2 (en) * 2015-04-17 2019-06-25 Hetero Labs Ltd Polymorphs and process for the preparation of quinazolinyl derivatives
WO2020016191A1 (fr) * 2018-07-16 2020-01-23 Universitat Autònoma De Barcelona Utilisation thérapeutique d'afatinib dans le cancer

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040242661A1 (en) * 2003-03-17 2004-12-02 Igor Rukhman Polymorphs of valsartan
US20070027170A1 (en) * 2003-10-17 2007-02-01 Rainer Soyka Process for preparing amino crotonyl compounds
WO2012121764A1 (fr) * 2010-11-25 2012-09-13 Ratiopharm Gmbh Nouveaux sels et formes polymorphes d'afatinib

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040242661A1 (en) * 2003-03-17 2004-12-02 Igor Rukhman Polymorphs of valsartan
US20070027170A1 (en) * 2003-10-17 2007-02-01 Rainer Soyka Process for preparing amino crotonyl compounds
WO2012121764A1 (fr) * 2010-11-25 2012-09-13 Ratiopharm Gmbh Nouveaux sels et formes polymorphes d'afatinib

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10329281B2 (en) * 2015-04-17 2019-06-25 Hetero Labs Ltd Polymorphs and process for the preparation of quinazolinyl derivatives
CN105717226A (zh) * 2016-02-02 2016-06-29 北京科莱博医药开发有限责任公司 一种运用高效液相色谱检测马来酸阿法替尼异构体及主要降解杂质的方法
WO2018187643A1 (fr) 2017-04-06 2018-10-11 Johnson Matthey Public Limited Company Nouvelles formes de dimaléate d'afatinib
US11136314B2 (en) 2017-04-06 2021-10-05 Johnson Matthey Public Limited Company Forms of afatinib dimaleate
WO2020016191A1 (fr) * 2018-07-16 2020-01-23 Universitat Autònoma De Barcelona Utilisation thérapeutique d'afatinib dans le cancer

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