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WO2012007952A1 - Nouveau composé polymorphe du chlorhydrate d'irinotécan - Google Patents

Nouveau composé polymorphe du chlorhydrate d'irinotécan Download PDF

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Publication number
WO2012007952A1
WO2012007952A1 PCT/IN2010/000466 IN2010000466W WO2012007952A1 WO 2012007952 A1 WO2012007952 A1 WO 2012007952A1 IN 2010000466 W IN2010000466 W IN 2010000466W WO 2012007952 A1 WO2012007952 A1 WO 2012007952A1
Authority
WO
WIPO (PCT)
Prior art keywords
irinotecan hydrochloride
solvent
crystalline form
hydrochloride crystalline
irinotecan
Prior art date
Application number
PCT/IN2010/000466
Other languages
English (en)
Inventor
Bandi Parthasaradhi Reddy
Kura Rathnakar Reddy
Dasari Muralidhara Reddy
Rapolu Raji Reddy
Puranik Ramachandra
Bandi Vamsi Krishna
Original Assignee
Hetero Research Foundation
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 Hetero Research Foundation filed Critical Hetero Research Foundation
Priority to PCT/IN2010/000466 priority Critical patent/WO2012007952A1/fr
Publication of WO2012007952A1 publication Critical patent/WO2012007952A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings

Definitions

  • the present invention provides a novel crystalline form of irinotecan hydrochloride, process for its preparation and pharmaceutical compositions comprising it.
  • Irinotecan hydrochloride is chemically, (S)-4,l l-diethyl-3,4,12,14-tetrahydro-4- hydroxy-3,14-dioxo-lH-pyrano[3',4':6,7]-indolizino[l,2-6]quinolin-9-yl[l ,4'- bipiperidine]-l-carboxylate hydrochloride and has the structural formula:
  • Irinotecan hydrochloride is an antineoplastic agent of the topoisomerase I inhibitor class.
  • Irinotecan hydrochloride is a semisynthetic derivative of camptothecin, and alkaloid extract from plants such as Camptotheca acuminata.
  • Irinotecan hydrochloride is approved by the Food and Drug Administration as a component of first- line therapy in combination with 5-fluorouracil and leucovorin for patients with metastatic carcinoma of the colon or rectum. It is also approved for treating patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil-based therapy.
  • Irinotecan hydrochloride is commercially available in injection form under the trade name Camptosar ® .
  • Polymorphism is defined as "the ability of a substance to exist as two or more crystalline phases that have different arrangement and/or conformations of the molecules in the crystal Lattice. Thus, in the strict sense, polymorphs are different crystalline forms of the same pure substance in which the molecules have different arrangements and/or different configurations of the molecules". Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability.
  • Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC) and Infrared spectrometry (IR).
  • XRD X-ray diffraction
  • DSC Differential Scanning Calorimetry
  • IR Infrared spectrometry
  • Solvent medium and mode of crystallization play very important role in obtaining a crystalline form over the other.
  • Irinotecan hydrochloride can exist in different polymorphic forms, which may differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
  • Irinotecan hydrochloride was disclosed in U.S. patent no. 4,604,463. According to the patent, irinotecan hydrochloride (example 37) was obtained as an amorphous solid (form A).
  • irinotecan hydrochloride form C can be prepared by stirring a suspension of irinotecan hydrochloride form A or irinotecan hydrochloride form B in acetonitrile or acetone.
  • U.S. patent no. 7,435,818 (herein after referred to as the '818 patent) disclosed crystalline form I, form II, form III and form IV of irinotecan hydrochloride trihydrate.
  • crystalline form I of irinotecan hydrochloride trihydrate can be prepared by crystallization of irinotecan acetate from ethanol, n-heptane and hydrochloric acid.
  • crystalline form II of irinotecan hydrochloride trihydrate can be prepared by crystallization of irinotecan acetate from ethanol and hydrochloric acid.
  • crystalline form III of irinotecan hydrochloride trihydrate can be prepared by crystallization of irinotecan acetate from methanol, ethyl acetate and hydrochloric acid.
  • crystalline form IV of irinotecan hydrochloride trihydrate can be prepared by crystallization of irinotecan acetate from ethanol, ethyl acetate and hydrochloric acid.
  • irinotecan hydrochloride crystalline form H can be prepared by crystallization of irinotecan hydrochloride from dichloromethane.
  • an object of the present invention is to provide a novel crystalline form of irinotecan hydrochloride, process for its preparation and pharmaceutical compositions comprising it.
  • the present invention provided a crystalline form of irinotecan hydrochloride designated as form HI characterized by peaks in the powder x-ray diffraction spectrum having 2 ⁇ angle positions at about 5.3, 6.2, 8.3, 8.5, 10.1, 1 1.3, 14.8, 15.9, 19.7 and 23.8 ⁇ 0.2 degrees.
  • the present invention provided a process for the preparation of irinotecan hydrochloride crystalline form HI, which comprises crystallizing irinotecan hydrochloride from a solvent system comprising alcohol solvent, chlorinated solvent and ketonic solvent and isolating irinotecan hydrochloride crystalline form HI .
  • the present invention provided a pharmaceutical composition
  • a pharmaceutical composition comprising irinotecan hydrochloride crystalline form HI and a pharmaceutically acceptable excipient.
  • Figure 1 is X-ray powder diffraction spectrum of irinotecan hydrochloride crystalline form HI .
  • X-ray powder diffraction spectrum was measured on a bruker axs D8 advance X- ray powder diffractometer having a copper- ⁇ radiation. Approximately 1 gm of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees two-theta, at 0.02 degrees to theta per step and a step of 10.4 seconds. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 V and current 35 mA.
  • a crystalline form of irinotecan hydrochloride designated as form HI characterized by peaks in the powder x-ray diffraction spectrum having 2 ⁇ angle positions at about 5.3, 6.2, 8.3, 8.5, 10.1 , 1 1.3, 14.8, 15.9, 19.7 and 23.8 ⁇ 0.2 degrees.
  • the powdered x-ray diffractogram (PXRD) of irinotecan hydrochloride crystalline form HI is shown in figure 1.
  • Irinotecan hydrochloride crystalline form HI may contain water content.
  • the water content of the irinotecan hydrochloride crystalline form HI may be in between 3.0 to 13.0% by weight and typically may be in between 4.0 to 8.0% by weight.
  • a process for the preparation of irinotecan hydrochloride crystalline form HI which comprises crystallizing irinotecan hydrochloride from a solvent system comprising alcohol solvent, chlorinated solvent and ketonic solvent and isolating irinotecan hydrochloride crystalline form H 1 .
  • Irinotecan hydrochloride used in the process may preferably be irinotecan . hydrochloride obtained by the known process.
  • the alcohol solvent used in the process may preferably be a solvent or mixture of solvents selected from methanol, ethanol and isopropyl alcohol, and more preferable alcohol solvent is methanol.
  • the chlorinated solvent used in the process may preferably be a solvent or mixture of solvents selected from methylene chloride, chloroform, carbontetrachloride and ethylene dichloride, and more preferable chlorinated solvent is methylene dichloride.
  • the ketonic solvent used in the process may preferably be a solvent or mixture of solvents selected from acetone, methyl ethyl ketone, methyl isobutyl ketone and diethyl ketone, and more preferable ketonic solvent is acetone.
  • Isolation of irinotecan hydrochloride crystalline form HI in the process may preferably be performed by conventional techniques such as centrifugation and filtration.
  • a pharmaceutical composition that comprises irinotecan hydrochloride crystalline form HI and pharmaceutically acceptable carriers, diluents or excipients and optionally other therapeutic ingredients.
  • the irinotecan hydrochloride crystalline form HI may preferable be formulated into tablets, capsules, suspensions, dispersions, injectables and other pharmaceutical forms.
  • Triphosgene (45 gm) was added to methylene dichloride (500 ml) at room temperature and then cooled to 0 to 10°C.
  • a solution of 4-piperidinopiperidine (50 gm) in methylene dichloride (500 ml) was added to the reaction mass for 2 hours 30 minutes at 0 to 10°C.
  • the temperature of the reaction mass was raised to room temperature, stirred for 1 hour and then added sodium bicarbonate (50 gm).
  • the reaction mass was stirred for 1 hour at room temperature and the mass was filtered through hi-flow bed.
  • To the mixture of 7-ethyl- 10-hydroxy camptothecin (50 gm) in pyridine (1250 ml) was added filtrate obtained above slowly for 2 hours at room temperature.
  • the reaction mass was stirred for 20 hours at 35 to 40°C and the solvent was distilled off completely under reduced pressure at 45°C to obtained residue.
  • To the residue was added methylene dichloride at room temperature. The organic layer was separated and dried over sodium sulfate. The solvent was distilled off completely under reduced pressure at 45°C and co- distilled with hexane.
  • the reaction mass was cooled to room temperature and then added hexane (1000 ml).
  • the reaction mass was stirred for 30 minutes at room temperature and filtered.
  • To the wet solid obtained was added acetonitrile (1000 ml) and stirred for 30 minutes at room temperature.
  • the solid obtained was collected by filtration and dried at room temperature for 8 hours to obtain 63 gm of irinotecan.
  • Irinotecan (50 gm) as obtained in reference example 1 was dissolved in water (550 ml) at room temperature and then added concentrated hydrochloric acid (10 gm). The contents were heated to 40 to 45°C and stirred for 1 hour at 40 to 45°C. The reaction mass was treated with charcoal at 40 to 45°C. The reaction mass was cooled to room temperature and the mass was filtered through hi-flow bed. The hi-flow bed washed with water and again washed with ethyl acetate. 50 percent of the solvent was distilled off under reduced pressure at 45°C and filtered. To the filtrate was added concentrated hydrochloric acid (1.65 gm) and water (3.3 ml) at room temperature.
  • reaction mass was stirred for 18 hours at room temperature and then added acetone (500 ml).
  • the reaction mass was stirred for 2 hours at room temperature and filtered.
  • the solid obtained was dried under reduced pressure at 35 to 40°C for 16 hours to obtain 34 gm of irinotecan hydrochloride trihydrate.
  • Irinotecan hydrochloride trihydrate (10 gm) as obtained in reference example 2 was dissolved in a mixture of methanol (50 ml) and methylene dichloride (50 ml) under stirring at room temperature. About 80 percent of the solvent was distilled off under vacuum at below 40°C to obtain a residual mass. The residual mass was stirred for 18 hours at room temperature to form solid. To the solid was added acetone (60 ml) and stirred for 2 hour at room temperature. The solid obtained was collected by filtration and dried under vacuum at below 40°C for 15 hours to obtain 7.5 gm of irinotecan hydrochloride crystalline form HI .
  • Irinotecan hydrochloride trihydrate (10 gm) was dissolved in a mixture of methanol (30 ml) and methylene dichloride (30 ml) under stirring at room temperature. About 80 percent of the solvent was distilled off under vacuum at below 40°C to obtain a residual mass. The residual mass was stirred for 18 hours at room temperature to form solid. To the solid was added acetone (50 ml) and stirred for 2 hour at room temperature. The solid obtained was collected by filtration and dried under vacuum at below 40°C for 17 hours to obtain 7.2 gm of irinotecan hydrochloride crystalline form HI .
  • Irinotecan hydrochloride trihydrate (10 gm) was dissolved in a mixture of methanol (60 ml) and methylene dichloride (40 ml) under stirring at room temperature. About 80 percent of the solvent was distilled off under vacuum at below 40°C to obtain a residual mass. The residual mass was stirred for 18 hours at room temperature to form solid. To the solid was added acetone (50 ml) and stirred for 2 hour at room temperature. The solid obtained was collected by filtration and dried under vacuum at below 40°C for 16 hours to obtain 7 gm of irinotecan hydrochloride crystalline form HI .
  • Irinotecan hydrochloride trihydrate (10 gm) was dissolved in a mixture of methanol (50 ml) and methylene dichloride (50 ml) under stirring at room temperature. About 80 percent of the solvent was distilled off under vacuum at below 40°C to obtain a residual mass. The residual mass was added acetone (60 ml) and stirred for 18 hour at room temperature, filtered. The solid obtained dried under vacuum at below 40°C for 15 hours to obtain 7.2 gm of irinotecan hydrochloride crystalline form HI .
  • Irinotecan hydrochloride trihydrate (5 gm) was dissolved in a mixture of methanol (25 ml) and methylene dichloride (25 ml) under stirring at room temperature. To the solution was added (30 ml) and the mass was stirred for 18 hour at room temperature. The separated solid was filtered and dried under vacuum at below 40°C for 14 hours to obtain 3.5 gm of irinotecan hydrochloride crystalline form HI .
  • Irinotecan hydrochloride trihydrate crystalline form I (10 gm) was dissolved in a mixture of methanol (50 ml) and methylene dichloride (50 ml) under stirring at room temperature. About 80 percent of the solvent was distilled off under vacuum at below 40°C to obtain a residual mass. The residual mass was stirred for 18 hours at room temperature to form solid. To the solid was added acetone (60 ml) and stirred for 2 hour at room temperature. The solid obtained was collected by filtration and dried under vacuum at below 40°C for 16 hours to obtain 7 gm of irinotecan hydrochloride crystalline form HI .
  • Example 7 Example 7:
  • Example 6 was repeated using irinotecan hydrochloride trihydrate crystalline form II instead of irinotecan hydrochloride crystalline trihydrate form I to obtain irinotecan hydrochloride crystalline form HI .
  • Example 6 was repeated using irinotecan hydrochloride trihydrate crystalline form III instead of irinotecan hydrochloride crystalline trihydrate form I to obtain irinotecan hydrochloride crystalline form HI .
  • Example 6 was repeated using irinotecan hydrochloride trihydrate crystalline form IV instead of irinotecan hydrochloride crystalline trihydrate form I to obtain irinotecan hydrochloride crystalline form HI .

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

Abstract

La présente invention concerne une nouvelle forme cristalline du chlorhydrate d'irinotécan, son procédé de préparation et des compositions pharmaceutiques la comprenant. Ainsi, par exemple, du chlorhydrate d'irinotécan trihydraté a été dissous dans un mélange de méthanol et de dichlorure de méthylène, le solvant a été distillé et de l'acétone a été ajoutée, et le mélange a été agité pendant 18 heures à température ambiante, filtré et séché pour obtenir la forme cristalline H1 du chlorhydrate d'irinotécan.
PCT/IN2010/000466 2010-07-12 2010-07-12 Nouveau composé polymorphe du chlorhydrate d'irinotécan WO2012007952A1 (fr)

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PCT/IN2010/000466 WO2012007952A1 (fr) 2010-07-12 2010-07-12 Nouveau composé polymorphe du chlorhydrate d'irinotécan

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Application Number Priority Date Filing Date Title
PCT/IN2010/000466 WO2012007952A1 (fr) 2010-07-12 2010-07-12 Nouveau composé polymorphe du chlorhydrate d'irinotécan

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102850363A (zh) * 2012-09-18 2013-01-02 山东罗欣药业股份有限公司 盐酸伊立替康化合物及其药物组合物

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060046993A1 (en) * 2004-09-01 2006-03-02 Pharmacia Italia S.P.A. Crystalline polymorphic form of irinotecan hydrochloride
US20070072890A1 (en) * 2005-09-20 2007-03-29 Scinopharm Pte, Ltd. Novel crystal forms of irinotecan hydrochloride
US20070105885A1 (en) * 2005-10-10 2007-05-10 Cipla Limited Novel crystalline polymorphic form of a camptothecin analogue
US20070208050A1 (en) * 2006-02-24 2007-09-06 Palle Venkata Raghavendra Acha Process for preparing irinotecan
WO2008148261A1 (fr) * 2007-06-08 2008-12-11 Qihong Lin Procédé de production de revêtement en magnésium et en verre avec des grains de bois

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060046993A1 (en) * 2004-09-01 2006-03-02 Pharmacia Italia S.P.A. Crystalline polymorphic form of irinotecan hydrochloride
US20070072890A1 (en) * 2005-09-20 2007-03-29 Scinopharm Pte, Ltd. Novel crystal forms of irinotecan hydrochloride
US20070105885A1 (en) * 2005-10-10 2007-05-10 Cipla Limited Novel crystalline polymorphic form of a camptothecin analogue
US20070208050A1 (en) * 2006-02-24 2007-09-06 Palle Venkata Raghavendra Acha Process for preparing irinotecan
WO2008148261A1 (fr) * 2007-06-08 2008-12-11 Qihong Lin Procédé de production de revêtement en magnésium et en verre avec des grains de bois

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102850363A (zh) * 2012-09-18 2013-01-02 山东罗欣药业股份有限公司 盐酸伊立替康化合物及其药物组合物
CN102850363B (zh) * 2012-09-18 2013-07-10 山东罗欣药业股份有限公司 盐酸伊立替康化合物及其药物组合物

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