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WO2008111092A1 - Forme cristalline de monohydrate de témozolomide et procédé de préparation de cette dernière - Google Patents

Forme cristalline de monohydrate de témozolomide et procédé de préparation de cette dernière Download PDF

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Publication number
WO2008111092A1
WO2008111092A1 PCT/IN2008/000134 IN2008000134W WO2008111092A1 WO 2008111092 A1 WO2008111092 A1 WO 2008111092A1 IN 2008000134 W IN2008000134 W IN 2008000134W WO 2008111092 A1 WO2008111092 A1 WO 2008111092A1
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WO
WIPO (PCT)
Prior art keywords
temozolomide
crystalline
monohydrate
mixture
activated carbon
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.)
Ceased
Application number
PCT/IN2008/000134
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English (en)
Inventor
Bijan Panda
Golak Chandra Maikap
Shiv Kumar Agarwal
Manoj Kumar Singh
Manu Jaggi
Ashwini Nangia
Nanubolu Jagadeesh BABU
Srinivasulu AITIPAMULA
Lingireddy Sreenivas REDDY
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.)
Fresenius Kabi Oncology Ltd
Original Assignee
Fresenius Kabi Oncology Ltd
Dabur Pharma Ltd
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 Fresenius Kabi Oncology Ltd, Dabur Pharma Ltd filed Critical Fresenius Kabi Oncology Ltd
Publication of WO2008111092A1 publication Critical patent/WO2008111092A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel crystalline Temozolomide Monohydrate and a process for preparation thereof.
  • the present invention further relates to pharmaceutical compositions comprising the novel crystalline Temozolomide Monohydrate, useful for treatment of cancers of various origins.
  • Temozolomide which is chemically known as 3,4-dihydro-3-methyl-4-oxoimidazo[5,l-d]- as-tetrazine-8-carboxamide and represented by formula (I),
  • Temozolomide is marketed under the brand name TEMOD AR ® , which is available as a Capsule in strengths of 5mg, 20 mg, 100 mg, 140 mg, 180 mg, and 250 mg for treatment of adult patients with newly diagnosed Glioblastoma Multiforme, concomitantly with radiotherapy and then as maintenance treatment. It is also indicated for the treatment of adult patients with Refractory Anaplastic Astrocytoma i.e. patients who have experienced disease progression on a drug regimen containing Nitrosourea and Procarbazine.
  • Temozomide per se was first disclosed by Lunt et. al in US 5,260,291, which apart from claiming the molecule i.e. Temozolomide also discloses a process for preparation thereof as well as pharmaceutical compositions comprising the same for treatment of malignant neoplasms, e.g. carcinomas, melanomas, sarcomas, lymphomas and leukaemias, and in the treatment of glioma and mycosis fungoides at doses which are generally between 0.1 and 200, preferably between 1 and 20, mg/kg body weight per day.
  • malignant neoplasms e.g. carcinomas, melanomas, sarcomas, lymphomas and leukaemias
  • glioma and mycosis fungoides at doses which are generally between 0.1 and 200, preferably between 1 and 20, mg/kg body weight per day.
  • Example 4 of US 5,260,291 similarly states that Temozolomide obtained after reaction of 5- diazo-lH-imidazole-4-carboxamide of formula (II) with methyl isocyanate is isolated from ethyl acetate to give a cream colored solid having a melting point of 212 0 C (with effervescence). It is further stated that the material thus obtained can be recrystallised from three different solvent systems to give three different polymorphic forms having different IR spectra. For e.g.
  • Example 9 of US 5,260,291 similarly states that Temozolomide obtained after reaction of 5- diazo-lH-imidazole-4-carboxamide of formula (II) with methyl isocyanate in a mixture of dichloromethane and n-methylpyrrolid-2-one and on isolation from diethyl ether gives a pale purple solid having a melting point 202-203 0 C (with decomposition). Further, an additional polymorphic form was also disclosed, which was obtained by dissolving Temozolomide in acetonitrile, filtering, concentration of the filtrate to dryness, and trituration of the resulting residue with diethyl ether. Temozolomide thus obtained is stated to be an orange-tinged solid, having a melting point of about 200 0 C (with decomposition).
  • Temozolomide very specifically, various crystalline forms of Temozolomide have been disclosed in US 2005/0187206 Al, which provides nine crystalline forms referred to as Form I, Form II, Form III, Form IV, Form V, From VI, Form VII, Form VIII and Form IX, which posses distinct X-ray (Powder) diffraction pattern and Infrared spectrum.
  • the present inventors have found that a novel crystalline form of Temozolomide, especially a novel crystalline Temozolomide Monohydrate could be prepared by a selective method which forms the subject matter of the present invention.
  • Fig-1 represents a characteristic X-ray (Powder) Diffraction Pattern of the crystalline Temozolomide Monohydrate of the present invention.
  • Fig-2 represents a characteristic Differential Scanning Calorimetry Thermogram of the crystalline Temozolomide Monohydrate of the present invention.
  • Fig-3 represents a characteristic Infra Red Spectrum of the crystalline Temozolomide Monohydrate of the present invention.
  • Fig-4 represents the intrinsic dissolution profile of the crystalline Temozolomide Monohydrate of the present invention.
  • Fig-5 represents the intrinsic dissolution profile of the known crystalline form IH of Temozolomide, as disclosed in US2005/0187206.
  • Fig-6 represents the Plasma concentration profile of the crystalline Temozolomide Monohydrate of the present invention and the known crystalline form III of Temozolomide, as disclosed in US2005/0187206 in Wistar rat upto 8 hours.
  • Fig-7 represents the Plasma concentration profile of the active metabolite (MTIC) of the crystalline Temozolomide Monohydrate of the present invention and the known crystalline form III of Temozolomide, as disclosed in US2005/0187206 in Wistar rat upto 8 hours.
  • Fig-8 represents the Plasma concentration profile of a Capsule Blend of Temozolomide prepared from the crystalline Temozolomide Monohydrate of the present invention and the Reference Listed Drug (TEMOD AR ® ) in Wistar rat upto 24 hours.
  • MTIC active metabolite
  • Fig-8 represents the Plasma concentration profile of a Capsule Blend of Temozolomide prepared from the crystalline Temozolomide Monohydrate of the present invention and the Reference Listed Drug (TEMOD AR ® ) in Wistar rat upto 24 hours.
  • Fig-9 represents the Plasma concentration profile of a Capsule Blend of Temozolomide prepared from crystalline Temozolomide Monohydrate of the present invention and the Reference Listed Drug (TEMODAR ® ) in Wistar rat upto 8 hours.
  • the novel crystalline Temozolomide Monohydrate has water content in range of 8 to 9% and exhibits a Differential Scanning Calorimetry Thermogram having a characteristic endotherm and exotherm at about 74 0 C to about 78 0 C and about 198 0 C to about 214 0 C respectively, which is as depicted in Fig-2.
  • the Infra Red spectrum of the crystalline Temozolomide Monohydrate has characteristic peaks at ⁇ max 3414, 3285, 3171, 3131, 3026, 2908, 2777, 2361, 1743 and 1673 cm “1 , which is as essentially depicted in Fig-3.
  • the novel crystalline Temozolomide Monohydrate exhibits characteristic 2 ⁇ and ⁇ /-spacing values in its X-Ray (Powder) Diffraction Pattern as summarized in Table-I and as depicted in Fig-1.
  • Table -I X-ray (Powder) Diffraction Reflections In 2 ⁇ Values And Interplanar Distance (d) Of The Crystalline Temozolomide Monohydrate Of The Present Invention
  • the novel crystalline Temozolomide Monohydrate is prepared by crystallization of Temozolomide from a mixture of water and water-miscible organic solvents, which are selected from aliphatic nitriles such as acetonitrile and propionitrile; ketones such as acetone, methyl isobutyl ketone and methyl ethyl ketone; and cyclic ethers such as tetrahydrofuran and dioxane etc.
  • the water-miscible organic solvent and water are typically employed in a proportion of between 1 : 1 v/v to 4:1 v/v. Amongst the water-miscible organic solvents, acetone is most preferred.
  • the novel crystalline Temozolomide monohydrate could be conveniently obtained by crystallization of Temozolomide from a mixture of acetone and water in a definite ratio of 3:lv/v under certain specific conditions. More particularly, it was found that the crystalline Temozolomide monohydrate could be obtained by dissolving Temozolomide in a mixture of acetone and water in a ratio of 3:1 v/v at a temperature of about 50-55 0 C followed by cooling the mixture to 0-5 0 C and collecting the crystals of Temozolomide monohydrate.
  • Temozolomide was largely dependent on the ratio of the individual solvents in the mixture with a proportion of acetone and water in a v/v ratio of 3:1 specifically forming the crystalline Temozolomide monohydrate whereas, other proportions were found to give a crystalline product different from the monohydrate form of the present invention.
  • the crystalline Temozolomide monohydrate prepared by the abovementioned process has water content in the range of 8-9 % w/w and is found to be stable for upto 3 months under accelerated stability conditions.
  • a new crystalline Monohydrate form of Temozolomide having a characteristic X-ray (Powder) Diffraction Pattern, Differential Scanning Calorimetry Thermogram and a characteristic Infra Red Spectrum as depicted in Fig-1, Fig-2 and Fig-3 respectively.
  • a process for the preparation of the abovementioned novel crystalline Temozolomide monohydrate comprising the steps of: i) dissolving Temozolomide, having a purity of 50-70% in acetone at a temperature of about 50-55 0 C; ii) optionally adding activated carbon to the solution of step i); iii) filtering the activated carbon from the mixture of step ii); iv) evaporating the filtrate of step iii) to obtain a solid substance; v) dissolving the solid substance obtained in step iv) in a mixture of acetone and water in the ratio of 3:1 v/v at a temperature from about 50 0 C to reflux temperature; vi) optionally adding activated carbon to the solution of step v); vii) cooling the mixture of step vi) to ambient temperature; viii) filtering the activated carbon from the mixture of step vii); ix) cooling the filtrate of step viii) to a temperature of 0-5
  • compositions comprising the novel crystalline Temozolomide monohydrate and pharmaceutically acceptable excipients.
  • pharmaceutically acceptable excipients include diluents, fillers, binding agents, disintegrants, preservatives, lubricants, colouring and flavoring agents and the like.
  • the oral route is the preferred route for administration.
  • the composition according to the present invention, for oral administration also include capsules of absorbable materials such as gelatin containing one or more of the active substances with or without the addition of diluents or excipients.
  • the pharmaceutical compositions prepared with the novel crystalline monohydrate form are used in the treatment of various forms of cancer and solid tumors. Pharmacokinetic Studies On The Crystalline Temozolomide Monohydrate Prepared As
  • the intrinsic dissolution rate is defined as the dissolution rate of pure substances under the condition of area constant surface.
  • the measurement of intrinsic dissolution rate is a tool that is used to characterize the bulk drug substances and excipients.
  • the dissolution rate and bioavailibility of a drug substance are influenced by its solid-state properties i.e. crystallinity, amorphism, polymorphism, hydration, solvation, particle size, and particle surface area.
  • the measured intrinsic dissolution rate is dependent on these solid-state properties.
  • the intrinsic dissolution rate of Temozolomide monohydrate of the present invention was found to be 0.73124 mg/min/cm 2 and that of the known form III, as disclosed in US 2005/0187206 was found to be 0.7125 mg/min/cm 2 thereby showing that the intrinsic dissolution properties of the two forms are comparable.
  • the non-clinical studies carried out also included the determination of the pharmacokinetics of the crystalline Temozolomide monohydrate of the present invention, and its comparison with the pharmacokinetics of the known form III of Temozolomide, as disclosed in US 2005/0187206 and the Reference Listed Drug (RLD).
  • the marketed composition of Temozolomide actually conforms to the polymorphic Form III as disclosed in US 2005/0187206.
  • the pharmacokinetics of the crystalline Temozolomide monohydrate was compared with that of Form III and the marketed composition.
  • the Pharmacokinetic study was conducted in male Wistar rats under fasting conditions. Care and handling of animals were in accordance with Institutional Animal Ethics Committee (IAEC). Each composition was orally administered as a 0.4% suspension in methylcellulose to the group of seven animals separately at a dose of 30 mg/kg.
  • IAEC Institutional Animal Ethics Committee
  • Temozolomide is an alkylating agent of the imidazotetrazine derivative that exhibits broad spectrum antitumor activity against murine tumors. It exerts its antitumor activity through linear triazine MTIC. Temozolomide is chemically converted to MTIC both in vitro and in vivo. It is believed that Temozolomide exerts its antitumor activity via its biologically active degradation product MTIC; hence, it was imperative to determine plasma concentration of both Temozolomide and MTIC in plasma when its PK profile was studied.
  • Table-IV Pharmacokinetic Parameters of Crystalline Temozolomide Monohydrate of the Present Invention and Form III Of Temozolomide, as disclosed in US2005/018206 and their metabolites
  • Temozolomide (5gm) was added to a mixture of acetone and water (700ml) in the ratio of 3:1
  • Temozolomide Monohydrate having the characteristic X-ray (Powder) diffraction pattern as depicted in Table-I and Fig-1; the characteristic Differential Scanning Calorimetry Thermogram as depicted in Fig-2; and Infra Red spectrum as depicted in Fig-3.
  • Temozolomide (lgm) was added to a mixture of acetonitrile and water (26ml) in the ratio of 3:1 (v/v) and stirred at 55 0 C for about 30 minutes to dissolve the material.
  • Activated carbon (lgm) was added to the solution and the mixture agitated at 20-25 0 C for another 1 hour. The mixture was then filtered and the filtrate stirred at 0-5 0 C for 2-3 hours. The solid material crystallizing out was then filtered and dried at 25-3O 0 C under vacuum to give crystalline Temozolomide form III as disclosed in US2005/0187206.
  • Temozolomide (lgm) was added to a mixture of tetrahydrofuran and water (90ml) in the ratio of 3:1 (v/v) and stirred at 55 0 C to for about 30 minutes to dissolve the material.
  • Activated carbon (lgm) was added to the solution and the mixture agitated at 20-25 0 C for another 1 hour. The mixture was then filtered and the filtrate stirred at 0-5 0 C for 2-3 hours. The solid material crystallizing out was then filtered and dried at 25-3O 0 C under vacuum to give crystalline Temozolomide form III as disclosed in US2005/0187206.
  • Temozolomide (lgm) was added to a mixture of N,N dimethylformamide and water (40ml) in the ratio of 3:1 (v/v) and stirred at 55 0 C for about 30 minutes to dissolve the material.
  • Activated carbon (lgm) was added to the solution and the mixture agitated at 20-25 0 C for another 1 hour. The mixture was then filtered and the filtrate stirred at 0-5 0 C for 2-3 hours. The solid material crystallizing out was then filtered and dried at 25-3O 0 C under vacuum to give crystalline Temozolomide form III as disclosed in US2005/0187206.
  • Temozolomide (lgm) was added to a mixture of acetone and water (140ml) in the ratio of 3:1 (v/v) and stirred at room temperature for about 30 minutes to dissolve the material.
  • Activated carbon (lgm) was added to the solution and the mixture agitated at 20-25 0 C for another 1 hour. The mixture was then filtered and the filtrate stirred at 0-5 0 C for 2-3 hours. The solid material crystallizing out was then filtered and dried at 25-3O 0 C under vacuum to give crystalline Temozolomide form IX as disclosed in US2005/0187206.

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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 un monohydrate de témozolomide cristallin. Un procédé de préparation de ce dernier consiste: à dissoudre du témozolomide d'une pureté comprise entre 50 et 70% dans de l'acétone à une température de l'ordre de 50-55°C; ii) à ajouter éventuellement du charbon actif dans la solution de l'étape i); iii) à filtrer le charbon actif ajouté dans le mélange de l'étape ii); iv) à laisser s'évaporer le filtrat de l'étape iii) pour obtenir une substance solide; v) à dissoudre la substance solide obtenue dans l'étape iv) dans un mélange d'acétone et d'eau suivant un rapport de 3:1 v/v à une température comprise entre environ 50°C et la température de reflux; vi) à ajouter éventuellement du charbon actif à la solution de l'étape v); vii) à refroidir le mélange de l'étape vi) à la température ambiante; viii) à filtrer le charbon actif provenant de l'étape vii); ix) à refroidir le filtrat de l'étape viii) jusqu'à une température de 0-5 °C et à collecter les cristaux et à déshydrater le filtrat de l'étape viii) pour obtenir le monohydrate de témozolomide cristallin.
PCT/IN2008/000134 2007-03-09 2008-03-10 Forme cristalline de monohydrate de témozolomide et procédé de préparation de cette dernière Ceased WO2008111092A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102285991A (zh) * 2011-07-20 2011-12-21 江苏奥赛康药业股份有限公司 一种替莫唑胺的精制方法
WO2015062481A1 (fr) 2013-10-29 2015-05-07 天士力控股集团有限公司 Formes cristallines de témozolomide et leur procédé de préparation
EP2965757A1 (fr) * 2011-02-04 2016-01-13 Actelion Pharmaceuticals Ltd. Combinaisons contenant du macitentan destinées au traitement du glioblastoma multiforme
EP3613436A1 (fr) 2018-12-13 2020-02-26 Orphelia Pharma Suspension orale de témozolomide
CN116655640A (zh) * 2023-05-31 2023-08-29 南通大学 替莫唑胺晶体及其制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5260291A (en) * 1981-08-24 1993-11-09 Cancer Research Campaign Technology Limited Tetrazine derivatives
US20050187206A1 (en) * 2003-12-30 2005-08-25 Itai Adin Novel crystalline forms of temozolomide

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5260291A (en) * 1981-08-24 1993-11-09 Cancer Research Campaign Technology Limited Tetrazine derivatives
US20050187206A1 (en) * 2003-12-30 2005-08-25 Itai Adin Novel crystalline forms of temozolomide

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2965757A1 (fr) * 2011-02-04 2016-01-13 Actelion Pharmaceuticals Ltd. Combinaisons contenant du macitentan destinées au traitement du glioblastoma multiforme
CN102285991A (zh) * 2011-07-20 2011-12-21 江苏奥赛康药业股份有限公司 一种替莫唑胺的精制方法
WO2015062481A1 (fr) 2013-10-29 2015-05-07 天士力控股集团有限公司 Formes cristallines de témozolomide et leur procédé de préparation
EP3613436A1 (fr) 2018-12-13 2020-02-26 Orphelia Pharma Suspension orale de témozolomide
US11730732B2 (en) 2018-12-13 2023-08-22 Orphelia Pharma Oral suspension of temozolomide
CN116655640A (zh) * 2023-05-31 2023-08-29 南通大学 替莫唑胺晶体及其制备方法

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