EP2542548A1 - Procédé pour la préparation de forme polymorphe et nouvelle forme polymorphe d'imatinib mésylate isolée dans ce procédé - Google Patents

Procédé pour la préparation de forme polymorphe et nouvelle forme polymorphe d'imatinib mésylate isolée dans ce procédé

Info

Publication number
EP2542548A1
EP2542548A1 EP11715079A EP11715079A EP2542548A1 EP 2542548 A1 EP2542548 A1 EP 2542548A1 EP 11715079 A EP11715079 A EP 11715079A EP 11715079 A EP11715079 A EP 11715079A EP 2542548 A1 EP2542548 A1 EP 2542548A1
Authority
EP
European Patent Office
Prior art keywords
polymorphic form
imatinib mesylate
temperature
imatinib
mixture
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.)
Withdrawn
Application number
EP11715079A
Other languages
German (de)
English (en)
Inventor
Tomasz Kozluk
Robert Wozniak
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.)
Individual
Original Assignee
Individual
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 Individual filed Critical Individual
Publication of EP2542548A1 publication Critical patent/EP2542548A1/fr
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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 present invention relates to the process for preparation of polymorphic form a of imatinib mesylate.
  • the present invention relates to preparation of polymorphic form a of imatinib mesylate characterized by high bulk density.
  • the present invention also relates to the new polymorphic form of imatinib mesylate isolated in that process and its use for preparation of polymorphic form a.
  • Imatinib is indicated for the treatment of patients with Philadelphia chromosome positive (PH+) chronic myeloid leukemia (CML) and with Kit-positive gastrointestinal stromal tumours (GIST) including unresectable and/or metastatic malignant disease and resected disease post-surgery, for use in adult patients with newly diagnosed PH+ acute lymphoblastic leukemia (ALL) in combination with chemotherapy, and as single agent for patients with relapsed or refractory Ph+ALL.
  • PH+ Philadelphia chromosome positive
  • CML chronic myeloid leukemia
  • GIST Kit-positive gastrointestinal stromal tumours
  • ALL PH+ acute lymphoblastic leukemia
  • WO 99/03854 discloses two polymorphic forms, a and ⁇ , of imatinib mesylate that significantly differ in physico-chemical properties.
  • the polymorphic form ⁇ crystallizing in ethanol is thermodynamically stable and its plate-like crystals have relatively good processing parameters.
  • Polymorphic form a crystallizes as elongated needle-like crystals, which are fragile and very hygroscopic. Unfavorable flow properties of polymorphic form a crystals and as well as its mixtures with pharmaceutical excipients is the main disadvantage encountered in technology. It seems obvious, the hygroscopic polymorphic form a is not suitable active substance for the output of tablets in wet granulation process.
  • imatinib mesylate is obtained in the reaction of imatinib base and methanesulfonic acid in methyl or ethyl alcohol.
  • esters of methanesulfonic acid are likely to be formed. These toxic by-products may contaminate the active substance, thus causing the danger to human health.
  • Preclinical studies proved high biological activity of methyl and ethyl esters of methanesulfonic acids as DNA alkylating agents. These compounds even at trace amounts ( ⁇ 5 ppm) may cause mutagenic, cancerogenic and teratogenic changes.
  • European Medicines Agency advises the pharmaceutical manufacturers to take particular precautions to produce the pharmaceutically active substances deprived of alkyl sulfonates impurities.
  • the present inventors have focused on developing the process resulting in stable polymorphic form of imatinib mesylate.
  • the process is expected not only to eliminate the possibility of contamination with toxic, lower alkyl esters of methanesulfonic acid, but also to enable removal of solvent under relatively mild conditions. Obtained this method imatinib mesylate is expected to meet the ICH requirements (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use), which regard pharmaceutically accepted level of impurities and residual solvents assay of pharmaceuticals for human use.
  • the present invention relates to the preparation of polymorphic form a of imatinib mesylate in the reaction of equimolar amount of imatinib base and methanesulfonic acid, in the mixture of isopropyl alcohol and diisopropyl ether or in methylene dichloride.
  • step (g) optionally, when the process of imatinib mesylate preparation was carried out in methylene di chloride, after step (f) crystalline product is heated at temperature above 160°C or it is subject to maceration in isopropyl alcohol, yielding polymorphic form a.
  • Fig. 1 represents XRPD pattern of imatinib mesylate polymorphic form a obtained according to the present invention
  • Fig. 2 represents IR spectra of imatinib mesylate polymorphic form a obtained according to the present invention
  • Fig. 3 presents DSC curve of imatinib mesylate polymorphic form a obtained according to the present invention
  • Fig. 4 presents 1 H-NMR spectra of imatinib mesylate polymorphic form a, obtained according to the present invention
  • Fig. 5 represents XRPD pattern of imatinib mesylate polymorphic form N
  • Fig. 6 represents IR spectra of imatinib mesylate polymorphic form N
  • Fig. 7 represents DSC curve of imatinib mesylate polymorphic form N
  • Fig. 8 represents TGA curve of imatinib mesylate reproduced according to WO 2005/077933
  • Fig. 9 represent the microscopic view of polymorphic form a of imatinib mesylate in macrocrystalline form
  • Fig. 10 represents the microscopic view of polymorphic form a of imatinib mesylate in granulated form
  • Fig. 1 1 represents the microscopic view of polymorphic form N of imatinib mesylate. Detailed description of the invention
  • the process is performed in the mixture of isopropyl alcohol and diisopropyl ether at temperature range from +10°C to reflux.
  • the process is carried out in the mixture containing from 10 to 90% of diisopropyl ether volume, more preferably about 30% of diisopropyl ether volume.
  • the process according to the present invention enables preparation of reproducible, pure, homogenous polymorphic form a of imatinib mesylate characterized by HPLC purity higher than 99,5 % and content of residual solvent lower than 0,5 %.
  • the term “machine polymorphic form a of imatinib mesylate” defines the compound, which is deprived of other crystalline impurities such as imatinib free base, polymorphic form ⁇ of imatinib mesylate, imatinib dimesylate, at quantities detectable by DSC, IR or XRPD techniques.
  • X-Ray powder diffraction pattern (XRPD) is depicted on Fig. 1.
  • the IR spectrum (in KBr) of polymorphic form of imatinib mesylate, obtained according to the invention is depicted on Fig. 2. This IR spectrum differs from IR spectrum of polymorphic form ⁇ within the whole spectral range.
  • the DSC curve of imatinib mesylate, obtained according to the present invention is depicted on Fig. 3.
  • Melting point was determined as extrapolated value 226.4°C and repetonset" 225.0°C, which remains in accordance with published analytical data regarding imatinib mesylate polymorphic form a.
  • Melting point of polymorph a is about 10°C higher than melting point of polymorph ⁇ (about 217°C).
  • Polymorphic form a of imatinib mesylate can be isolated from the crystallization mixture, consisting of isopropyl alcohol and diisopropyl ether, either as microcrystalline form or granulate, depending on the method of drying.
  • Microcrystalline form of imatinib mesylate polymorph a which is characterized by particle size below 20 ⁇ , is obtained when drying the crystals under vacuum in a tray drier, at temperature 120-140°C, preferably about 130°C, for about 24 h. Shape and size of obtained that method crystals is illustrated by the microscopic view depicted on Fig. 9.
  • Granulate of imatinib mesylate polymorphic form a is obtained, when crystals are dried under similar conditions in a rotary drier; it is characterized by about 200 ⁇ ⁇ particle size. Shape and size of granulate is illustrated by microscopic view depicted on Fig. 10.
  • Granulated form of polymorphic form a of imatinib mesylate is mainly used in pharmaceutical technology to manufacture solid dosage forms, especially capsules. Due to significantly higher bulk density of granulate in comparison with that of microcrystalline form, capsules of smaller size can be filled with the same amount of imatinib mesylate. Hard gelatin capsules can be filled with granulate of imatinib mesylate itself or its mixture with pharmaceutically accepted excipients.
  • the process of preparation of imatinib mesylate polymorphic form a is carried out in methylene dichloride.
  • methanesulfonic acid or its solution in methylene dichloride is added, the reaction mixture is stirred at temperature from -10°C to reflux, preferably at temperature about 20°C, crystallization mixture is cooled down, if necessary, to room temperature, the crystalline product is isolated from the mixture and it is dried under vacuum at temperature from 60 to 160°C.
  • Polymorphic form N of imatinib mesylate, obtained according to the present invention is characterized by crystalline homogeneity, HPLC purity higher than 99.5%, contents of residual solvent below 0.05 % and particle size below 20 ⁇ ⁇ (Fig. 11).
  • X-Ray powder diffraction pattern (XRPD) is depicted on Fig. 5.
  • the IR spectrum (in KBr) of polymorphic form N of imatinib mesylate obtained according to the invention is depicted on Fig. 2. This IR spectrum differs from IR spectrum of polymorph ⁇ within the whole spectral range.
  • the DSC curve of imatinib mesylate obtained according to the present invention is depicted on Fig. 6.
  • Main absorption bands are presented in the table below. They are compared with data collected for polymorphic form a, which were obtained according to the first embodiment of the invention and the absorption bands of polymorphic form ⁇ , obtained according to the description revealed in WO 2005/095379:
  • Polymorphic form N of imatinib mesylate is stable at temperature up to 160°C, but upon heating at temperature from 160°C to 200°C it transforms into polymorph a. Maceration in isopropyl alcohol also results in transformation of polymorph N into polymorphic form a .
  • Polymorphic form N as well as polymorphic form a of imatinib mesylate, obtained according to the present invention show advantageous physico-chemical properties. Both polymorphic forms crystallize as non needle-like crystals (Fig. 9 and 11), therefore they are useful in the process of solid dosage forms manufacture.
  • polymorphic form a of imatinib mesylate as granulate, characterized by particle size of about 200 ⁇ (Fig. 10). Theses properties enable direct capsules filling with granulate. The content of residual solvent is detected significantly below the level of pharmacopoeian requirements.
  • Polymorphic form N and polymorphic form a of imatinib mesylate are thermodynamically stable under storage conditions and also under long-term and accelerated stability measurements conditions.
  • XRPD X-ray powder diffraction patterns
  • DSC data were obtained using differential scanning calorimeter Du Pont Thermal Analyst System 2100, within temperature range 30-260°C, with heat flow 5°C/min. Melting point was determined as extrapolated value and repeatonset" value.
  • Example 1 DSC data were obtained using differential scanning calorimeter Du Pont Thermal Analyst System 2100, within temperature range 30-260°C, with heat flow 5°C/min. Melting point was determined as extrapolated value and repeatonset" value. Example 1.
  • the product was characterized by XRPD (Fig. 1), IR (Fig. 2) and DSC (Fig. 3) as polymorphic form a. Residual solvents - below 3000 ppm.
  • Example 2 To the mixture of isopropyl alcohol and diisopropyl ether (100 ml) at volume ration 6:4 imatinib base (5 g) was added. To the resulting suspension the solution of methanesulfonic acid (0.660 ml) in diisopropyl ether (3 ml) was added dropwise at room temperature within 10 min. The mixture was refluxed for 6 h. The solution was gradually cooled down within 5 h. The solid was filtered off and washed with diisopropyl ether. The product was dried under vacuum at 130°C for 24 h in a tray drier. Form a of imatinib mesylate was obtained in 5.73 g (96%) yield. The identity of the product was confirmed by ⁇ -NMR and its polymorphic form was proved by IR, XRPD and DSC methods.
  • Imatinib base 50 g was added to methylene dichloride (1500 ml). To the resulting suspension the solution of methanesulfonic acid (6.60 ml) in methylene dichloride (30 ml) was added at room temperature within 10 min. The solution was stirred at room temperature for 22 h. The solid was filtered off and washed with methylene dichloride. The product was dried under vacuum at 110°C for 24 h. Polymorphic form N of imatinib mesylate was obtained in 50.83 g (84%) yield. The identity of the product was confirmed by 1 H-NMR and polymorphic form was proved by IR (Fig. 5), XRPD (Fig. 6) and DSC (Fig. 7). The content of residual methylene dichloride was below 30 ppm.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé de préparation de forme polymorphe α d'imatinib mésylate, dans la réaction de quantités équimolaires d'imatinib base et d'acide méthanesulfonique dans un mélange d'alcool isopropylique et d'éther diisopropylique ou dans du dichlorométhane. Selon la présente invention, la forme polymorphe α d'imatinib mésylate est obtenue sous forme microcristalline ou forme granulée caractérisée par une densité apparente élevée. La présente invention concerne en outre la nouvelle forme polymorphe N d'imatinib mésylate et son utilisation dans le procédé de préparation de forme polymorphe α.
EP11715079A 2010-03-04 2011-03-04 Procédé pour la préparation de forme polymorphe et nouvelle forme polymorphe d'imatinib mésylate isolée dans ce procédé Withdrawn EP2542548A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PL390611A PL390611A1 (pl) 2010-03-04 2010-03-04 Sposób otrzymywania polimorficznej formy alfa i nowa forma polimorficzna mesylanu imatinibu
PCT/PL2011/000028 WO2011108953A1 (fr) 2010-03-04 2011-03-04 Procédé pour la préparation de forme polymorphe α et nouvelle forme polymorphe d'imatinib mésylate isolée dans ce procédé

Publications (1)

Publication Number Publication Date
EP2542548A1 true EP2542548A1 (fr) 2013-01-09

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP11715079A Withdrawn EP2542548A1 (fr) 2010-03-04 2011-03-04 Procédé pour la préparation de forme polymorphe et nouvelle forme polymorphe d'imatinib mésylate isolée dans ce procédé

Country Status (3)

Country Link
EP (1) EP2542548A1 (fr)
PL (1) PL390611A1 (fr)
WO (1) WO2011108953A1 (fr)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2013110058A (ru) * 2010-08-11 2014-09-20 Синтон Б.В. Фармацевтический гранулят, содержащий иматиниба мезилат
ITMI20111309A1 (it) * 2011-07-14 2013-01-15 Italiana Sint Spa Procedimento di preparazione di imatinib mesilato
EP2604596A1 (fr) * 2011-12-16 2013-06-19 Deva Holding Anonim Sirketi Polymorphes d'imatinib
WO2013136141A1 (fr) 2012-03-13 2013-09-19 Fresenius Kabi Oncology Ltd. Procédé amélioré pour la préparation de la forme alpha de mésylate d'imatinib
CN103044396A (zh) * 2012-12-14 2013-04-17 浙江华海药业股份有限公司 一种甲磺酸伊马替尼α晶型晶体的制备方法
US20160122315A1 (en) * 2013-06-12 2016-05-05 Shilpa Medicare Limited Crystalline imatinib mesylate process

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Publication number Priority date Publication date Assignee Title
TW225528B (fr) 1992-04-03 1994-06-21 Ciba Geigy Ag
CO4940418A1 (es) 1997-07-18 2000-07-24 Novartis Ag Modificacion de cristal de un derivado de n-fenil-2- pirimidinamina, procesos para su fabricacion y su uso
GB0209265D0 (en) 2002-04-23 2002-06-05 Novartis Ag Organic compounds
TR200504337T1 (tr) 2003-06-02 2006-12-21 Hetero Drugs Limited Imatinib mezilat'ın yeni polimorfları
DK1720853T3 (en) 2004-02-11 2016-03-29 Natco Pharma Ltd HIS UNKNOWN POLYMORPH FORM OF IMATINIBMYLYLATE AND PROCEDURE FOR PREPARING IT
UA84462C2 (ru) 2004-04-02 2008-10-27 Институт Фармацевтични Полиморфные модификации кислотно-аддитивных солей иматиниба с метансульфоновой кислотой
WO2006048890A1 (fr) 2004-11-04 2006-05-11 Sun Pharmaceutical Industries Limited Forme cristalline d'imatinib mesylate et procede d'elaboration
WO2006054314A1 (fr) 2004-11-17 2006-05-26 Natco Pharma Limited Formes polymorphes de mesylate d'imatinibe
ATE445392T1 (de) 2005-08-15 2009-10-15 Siegfried Generics Int Ag Filmtablette oder granulat enthaltend ein pyridylpyrimidin
AU2006283842B2 (en) 2005-08-26 2011-03-17 Novartis Ag Delta and epsilon crystal forms of imatinib mesylate
BRPI0618993A2 (pt) 2005-11-25 2011-09-20 Novartis Ag formas de cristais f, g, h, i e k de mesilato de imatinib
US7977348B2 (en) * 2006-04-27 2011-07-12 Sicor Inc. Polymorphic forms of imatinib mesylate and processes for preparation of novel crystalline forms as well as amorphous and form α
EP2291366A4 (fr) * 2008-05-26 2012-06-06 Reddys Lab Ltd Dr Préparation de mésylate d imatinib

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Publication number Publication date
PL390611A1 (pl) 2011-09-12
WO2011108953A1 (fr) 2011-09-09

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