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WO2011099018A1 - Polymorphes de bortézomib - Google Patents

Polymorphes de bortézomib Download PDF

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Publication number
WO2011099018A1
WO2011099018A1 PCT/IN2010/000084 IN2010000084W WO2011099018A1 WO 2011099018 A1 WO2011099018 A1 WO 2011099018A1 IN 2010000084 W IN2010000084 W IN 2010000084W WO 2011099018 A1 WO2011099018 A1 WO 2011099018A1
Authority
WO
WIPO (PCT)
Prior art keywords
bortezomib
crystalline form
process according
preparation
amorphous
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/IN2010/000084
Other languages
English (en)
Inventor
Bandi Parthasaradhi Reddy
Kura Rathnakar Reddy
Dasari Muralidhara Reddy
Rapolu Raji Reddy
Puranik Ramachandra
Bandi Vamsi Krishna
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.)
Hetero Research Foundation
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/IN2010/000084 priority Critical patent/WO2011099018A1/fr
Publication of WO2011099018A1 publication Critical patent/WO2011099018A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds

Definitions

  • the present invention provides novel crystalline form of bortezomib, process for its preparation and pharmaceutical composition comprising it.
  • the present invention also provides novel processes for the preparation of bortezomib amorphous form.
  • Bortezomib is an anti-neoplastic agent and was therapeutic proteosome inhibitor available in the market under the brand name "VELCADE®" in the form of injection.
  • U.S. Patent No. 5,780,454 disclosed bortezomib and its pharmaceutically acceptable salts, pharmaceutical composition and use to inhibit the proteosome function in a mammal. Further, it disclosed a process for the preparation of bortezomib and its analogues.
  • 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.
  • 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. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph.
  • 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.
  • Bortezomib can exist in different polymorphic forms, which differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
  • U.S. Patent no. 6,713,446 disclosed lyophilized formulation of bortezomib esters. According to the patent, bortezomib prepared by the process as described in U.S. patent no. 5,780,454 was white amorphous powder.
  • crystalline form I of bortezomib (characterized by an X-ray powder diffraction pattern having peaks expressed as 2 ⁇ at about 5.643, 9.785, 1 1 .435, 12.952, 15.275, 20.467, 20.762, 21.486, 22.079, 23.632 and 26.264 ⁇ 0.2 degrees) can be prepared by dissolving bortezomib in solvent such as acetone, chloroform, dichloromethane or acetonitrile, adding anti solvent such as diisopropyl ether, tert-butylmethyl ether, n-hexane or n-heptane stirring of the resulting solution and filtering.
  • solvent such as acetone, chloroform, dichloromethane or acetonitrile
  • crystalline form II of bortezomib (characterized by an X-ray powder diffraction pattern having peaks expressed as 20 at about 4.532, 6.066, 8.497, 9.374, 1 1 .869, 12.270, 14.539, 16.355, 22.585 and 23.420 ⁇ 0.2 degrees; and differential scanning calorimetric peaks from 1 37.50 to 1 53.57°C (onset 140.41 °C) and from 172.32 to 1 82.14°C (onset 1 77.08°C) can be prepared by dissolving bortezomib in solvent such as ethyl acetate or isopropyl acetate at 70°C, cooling and filtering.
  • solvent such as ethyl acetate or isopropyl acetate
  • bortezomib crystalline form A can be prepared by crystallizing a solution containing bortezomib in methanol.
  • bortezomib crystalline form B can be prepared by crystallizing a solution of bortezomib in dichloromethane and adding toluene.
  • One object of the present invention is to provide a novel crystalline form of bortezomib, process for their preparation and pharmaceutical composition comprising it.
  • Another object of the present invention is to provide a novel processes for the preparation of amorphous form.
  • the present invention is to provide a novel crystalline form of bortezomib designated as form H I characterized by peaks in the powder x-ray diffraction spectrum having 2 ⁇ angle positions at about 6.8, 13.2, 1 8.2, 19. 1 and 19.5 ⁇ 0.2 degrees.
  • the present invention is to provide a process for preparing bortezomib crystalline from H I , which comprises:
  • step (b) distilling off the solvent from a solution obtained in step (a) until at least precipitation of bortezomib is started;
  • the present invention is to provide a process for preparing bortezomib amorphous from, which comprises:
  • step (b) maintaing the solution obtained in step (a) at below 20°C and adding water;
  • the present invention is to provide a process for preparing bortezomib amorphous from, which comprises:
  • step (a) adding an aliphatic hydrocarbon solvent to the solution obtained in step (a);
  • the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a novel crystalline form H I of bortezomib and a pharmaceutically acceptable excipient.
  • Figure 1 is X-ray powder diffraction spectrum of bortezomib crystalline form HI .
  • Figure 2 is X-ray powder diffraction spectrum of bortezomib amorphous form.
  • X-ray powder diffraction spectrum was measured on a bruker axs D8 advance X-ray powder diffractometer having a copper- ⁇ radiation. Approximately l 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 1 0.4 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 bortezomib designated as form H I characterized by peaks in the powder x-ray diffraction spectrum having 2 ⁇ angle positions at about 6.8, 1 3.2, 1 8.2, 19.1 and 19.5 ⁇ 0.2 degrees.
  • the powdered x-ray diffractogram (PXRD) of bortezomib crystalline form H I is shown in figure 1.
  • a process for the preparation of bortezomib crystalline form H I which comprises: a) providing a solution of bortezomib in a hot acetonitrile;
  • step (b) distilling off the solvent from a solution obtained in step (a) until at least precipitation of bortezomib is started;
  • Bortezomib used in step (a) may preferably be any other polymorphic forms.
  • bortezomib crystalline form II, bortezomib amorphous form or bortezomib crystalline form I may be used.
  • acetonitrile refers to acetonitrile at a temperature of 40°C to boiling temperature of acetonitrile.
  • acetonitrile used in step (a) is at about 50 to 70°C.
  • bortezomib crystalline form H I may be performed by conventional techniques such as centrifugation and filtration.
  • a process for the preparation of bortezomib amorphous form which comprises: a) dissolving bortezomib in dimethylformamide;
  • step (b) maintaing the solution obtained in step (a) at below 20°C and adding water;
  • Bortezomib used in step (a) may preferably be any other polymorphic forms.
  • the preferable temperature in step (b) is at below 10°C and more preferably temperature is at about 0 to 5°C.
  • the isolation of bortezomib amorphous form may be performed by conventional techniques such as centrifugation and filtration.
  • a process for the preparation of bortezomib amorphous form which comprises: a) dissolving bortezomib in ethyl acetate;
  • step (a) adding an aliphatic hydrocarbon solvent to the solution obtained in step (a);
  • Bortezomib used in step (a) may preferably be any other polymorphic forms.
  • bortezomib crystalline form II, bortezomib crystalline form H I of the invention or bortezomib crystalline form I may preferably be any other polymorphic forms.
  • the preferable aliphatic hydrocarbon solvent used in step (b) is a solvent or mixture of solvents selected from cyclohexane, hepatane and hexane. More preferable aliphatic hydrocarbon solvent is cyclohexane.
  • the isolation of bortezomib amorphous form may be performed by conventional techniques such as centrifugation and filtration.
  • a pharmaceutical composition comprising a novel crystalline form H I of bortezomib and a pharmaceutically acceptable excipient.
  • Novel crystalline form H I of bortezomib is suitable for the preparation of pharmaceutical compositions such as tablets, capsules, injections, creams and gels.
  • Acetonitrile 60 ml was heated to 60°C and maintained for 15 minutes at 60°C.
  • Bortezomib crystalline form 11 1 gm was added to the above acetonitrile at 60°C and stirred for 1 0 minutes at 60°C.
  • the solution was filtered to remove5 undissolved particles to obtain clear solution.
  • the solution was partially distilled off at 40 to 45°C under vacuum.
  • the separated solid was filtrate, washed with acetonitrile and then dried at 40 to 45°C under vacuum to obtain 0.75 gm of bortezomib crystalline form H I (High performance liquid chromatography (HPLC) Purity: 99.75%).
  • Acetonitrile 60 ml was heated to 60°C and maintained for 1 5 minutes at 60°C.
  • bortezomib amorphous form 1 gm
  • the solution was filtered to remove undissolved particles to obtain clear solution.
  • the solution was partially distilled off at 40 to 45°C under vacuum, filtered.
  • the solid obtained was washed with acetonitrile and dried at 40 to 45°C under vacuum to obtain 0.55 gm of bortezomib crystalline form H I .
  • Example 5 Example 5 :
  • Example 3 was repeated using bortezomib crystalline form I instead of bortezomib crystalline form II to obtain bortezomib crystalline form H I .
  • Example 6 was repeated using bortezomib crystalline form I instead of bortezomib crystalline form II to obtain bortezomib crystalline form H I .
  • Example 7 was repeated using bortezomib crystalline form I instead of bortezomib crystalline form H I to obtain bortezomib amorphous form.
  • Example 9 was repeated using bortezomib crystalline form I instead of bortezomib crystalline form H I to obtain bortezomib amorphous form.
  • Example 1 1
  • Example 9 was repeated using bortezomib crystalline form II instead of bortezomib crystalline form H I to obtain bortezomib amorphous form.
  • Example 12 was repeated using bortezomib crystalline form II instead of bortezomib crystalline form H I to obtain bortezomib amorphous form.
  • Example 12 was repeated using bortezomib crystalline form I instead of bortezomib crystalline form H I to obtain bortezomib amorphous form.
  • Example 12 was repeated using bortezomib crystalline form II instead of bortezomib crystalline form H I to obtain bortezomib amorphous form.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (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

Cette invention concerne une nouvelle forme cristalline de bortézomib, son procédé de préparation et une composition pharmaceutique la contenant. Cette invention concerne également de nouveaux procédés de préparation d'une forme amorphe de bortézomib. Ces procédés comprennent : chauffage de l'acétonitrile à 60°C et maintien pendant 15 minutes, ajout de la forme cristalline II du bortézomib à 60°C et agitation pendant 10 minutes, séparation partielle de la solution par distillation à 40-45°C sous vide, filtration, lavage à l'acétonitrile, puis séchage pour obtenir la nouvelle forme cristalline, Hl, de bortézomib.
PCT/IN2010/000084 2010-02-15 2010-02-15 Polymorphes de bortézomib Ceased WO2011099018A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/IN2010/000084 WO2011099018A1 (fr) 2010-02-15 2010-02-15 Polymorphes de bortézomib

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2010/000084 WO2011099018A1 (fr) 2010-02-15 2010-02-15 Polymorphes de bortézomib

Publications (1)

Publication Number Publication Date
WO2011099018A1 true WO2011099018A1 (fr) 2011-08-18

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PCT/IN2010/000084 Ceased WO2011099018A1 (fr) 2010-02-15 2010-02-15 Polymorphes de bortézomib

Country Status (1)

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WO (1) WO2011099018A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012131707A3 (fr) * 2011-03-28 2012-11-29 Laurus Labs Private Limited Nouvelle forme cristalline de bortezomib, son procédé de préparation et composition pharmaceutique l'utilisant
WO2014076713A2 (fr) 2012-11-16 2014-05-22 Shilpa Medicare Limited Procédé de préparation de bortézomib cristallin
WO2014097306A1 (fr) 2012-12-21 2014-06-26 Natco Pharma Limited Forme polymorphe stable et pure du bortézomib
WO2015122702A1 (fr) * 2014-02-14 2015-08-20 Kyongbo Pharm. Co., Ltd. Nouvelle forme cristalline de bortézomib et procédé de préparation associé
AU2018221670B2 (en) * 2017-02-17 2021-02-04 Fresenius Kabi Oncology Ltd. An improved process for the preparation of boronic acid esters
US11964993B2 (en) 2021-07-03 2024-04-23 Shilpa Pharma Lifesciences Limited Crystalline bortezomib process

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006117616A1 (fr) * 2005-05-03 2006-11-09 Ranbaxy Laboratories Limited Forme polymorphe de lumefantrine et procedes de preparation
WO2008075376A1 (fr) * 2006-12-18 2008-06-26 Natco Pharma Limited Formes polymorphes du bortézomibe et leur procédé de préparation
WO2009036281A2 (fr) * 2007-09-12 2009-03-19 Dr. Reddy's Laboratories Ltd. Bortézomib et procédé de production de celui-ci
WO2009091967A2 (fr) * 2008-01-18 2009-07-23 Mutual Pharmaceutical Company Polymorphes d'acide fénofibrique; procédés de fabrication; et procédés d'utilisation de ceux-ci

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006117616A1 (fr) * 2005-05-03 2006-11-09 Ranbaxy Laboratories Limited Forme polymorphe de lumefantrine et procedes de preparation
WO2008075376A1 (fr) * 2006-12-18 2008-06-26 Natco Pharma Limited Formes polymorphes du bortézomibe et leur procédé de préparation
WO2009036281A2 (fr) * 2007-09-12 2009-03-19 Dr. Reddy's Laboratories Ltd. Bortézomib et procédé de production de celui-ci
WO2009091967A2 (fr) * 2008-01-18 2009-07-23 Mutual Pharmaceutical Company Polymorphes d'acide fénofibrique; procédés de fabrication; et procédés d'utilisation de ceux-ci

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012131707A3 (fr) * 2011-03-28 2012-11-29 Laurus Labs Private Limited Nouvelle forme cristalline de bortezomib, son procédé de préparation et composition pharmaceutique l'utilisant
WO2014076713A2 (fr) 2012-11-16 2014-05-22 Shilpa Medicare Limited Procédé de préparation de bortézomib cristallin
JP2015536342A (ja) * 2012-11-16 2015-12-21 シルパ・メディケア・リミテッドＳｈｉｌｐａ Ｍｅｄｉｃａｒｅ Ｌｉｍｉｔｅｄ 結晶ボルテゾミブの方法
EP2919786A4 (fr) * 2012-11-16 2016-06-01 Shilpa Medicare Ltd Procédé de préparation de bortézomib cristallin
WO2014097306A1 (fr) 2012-12-21 2014-06-26 Natco Pharma Limited Forme polymorphe stable et pure du bortézomib
WO2015122702A1 (fr) * 2014-02-14 2015-08-20 Kyongbo Pharm. Co., Ltd. Nouvelle forme cristalline de bortézomib et procédé de préparation associé
KR101763106B1 (ko) 2014-02-14 2017-08-01 주식회사 경보제약 보르테조밉(Bortezomib)의 신규한 결정형 및 그의 제조방법
AU2018221670B2 (en) * 2017-02-17 2021-02-04 Fresenius Kabi Oncology Ltd. An improved process for the preparation of boronic acid esters
US11667654B2 (en) 2017-02-17 2023-06-06 Fresenius Kabi Oncology Ltd. Process for the preparation of boronic acid esters
US11964993B2 (en) 2021-07-03 2024-04-23 Shilpa Pharma Lifesciences Limited Crystalline bortezomib process

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