WO2015122702A1 - Nouvelle forme cristalline de bortézomib et procédé de préparation associé - Google Patents

Nouvelle forme cristalline de bortézomib et procédé de préparation associé Download PDF

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Publication number
WO2015122702A1
WO2015122702A1 PCT/KR2015/001424 KR2015001424W WO2015122702A1 WO 2015122702 A1 WO2015122702 A1 WO 2015122702A1 KR 2015001424 W KR2015001424 W KR 2015001424W WO 2015122702 A1 WO2015122702 A1 WO 2015122702A1
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WO
WIPO (PCT)
Prior art keywords
bortezomib
crystalline form
prepared
peaks
novel crystalline
Prior art date
Application number
PCT/KR2015/001424
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English (en)
Inventor
Hoe Joo Son
Yong Kyu Park
Young-Min Kim
Jae-Min Hwang
Jung Hee Kim
Original Assignee
Kyongbo Pharm. Co., 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 Kyongbo Pharm. Co., Ltd. filed Critical Kyongbo Pharm. Co., Ltd.
Publication of WO2015122702A1 publication Critical patent/WO2015122702A1/fr

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    • 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 System
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds
    • 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
    • A61K31/69—Boron compounds

Definitions

  • the present invention relates to a novel crystalline form of bortezomib, which has improved stability, and a preparation method thereof.
  • Bortezomib (CAS No. 179324-69-7) is an anticancer compound having a chemical name of [(lR)-3-methyl-l [[(2S)-l-oxo-3-phenyl-2-
  • Velcade ® is a proteasome inhibitor approved for use in the treatment of multiple myeloma or mantle cell lymphoma and contains 3.5 mg of sterilized and lyophilized bortezomib per vial for intravenous injection.
  • US Patent No. 5,780,454 discloses bortezomib, a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the same, and the use thereof for inhibiting proteasome function in a mammal.
  • it discloses methods for preparing bortezomib (referred to as MG-341 compound in the patent document) and its derivatives.
  • Polymorphism is the occurrence of different crystalline forms of a single compound, and crystalline polymorphs are regarded as different solids having the same molecular formula and have unique physical and chemical properties such as solubility, melting point, X-ray diffraction peaks or IR absorption spectra. Such physiological and chemical properties offer an opportunity to increase the stability, solubility and flowability of an active pharmaceutical ingredient (API) to thereby increase the safety and efficacy of the pharmaceutical drug.
  • API active pharmaceutical ingredient
  • crystalline form I and crystalline form II of bortezomib discloses crystalline form I and crystalline form II of bortezomib and a preparation process thereof.
  • crystalline form I of bortezomib is prepared using a acetone or a mixture of chloroform and isopropyl ether or a mixture of acetonitrile and isopropyl ether, has 2 ⁇ values of 5.643, 9.785, 11.435, 12.952, 15.275, 20.467, 20.762, 21.486, 22.079, 23.632 and 26.264 ⁇ 0.2°, and has a melting point of 160.44 to 180.75°C as measured by differential scanning calorimetry (DSC).
  • DSC differential scanning calorimetry
  • Crystalline form II of bortezomib is prepared using ethyl acetate, has 2 ⁇ values of 4.532, 6.066, 8.497, 9.374, 11.869, 12.270, 14.539, 16.355, 22.585 and 23.420 ⁇ 0.2°, and has melting points of 137.50 to 153.57 °C and 172.32 to 182.14 °C as measured by differential scanning calorimetry (DSC).
  • DSC differential scanning calorimetry
  • crystalline form A of bortezomib is prepared using a mixture of methanol and purified water, was identified as a monomer in mass spectral analysis, and has a moisture content of 5% or less. Also, it was identified to have the melting point at 75.2°C and 179.73°C in differential scanning calorimetry (DSC). Crystalline form A of bortezomib is characterized in that the purity thereof is maintained for 90 days during storage at 2-8°C. Crystalline form B of bortezomib is prepared using a mixture of ethyl acetate or dichloromethane and toluene.
  • bortezomib crystalline form HI discloses bortezomib crystalline form HI, bortezomib amorphous form, and preparation processes thereof.
  • bortezomib crystalline form HI is prepared using acetonitrile, and has 2 ⁇ values of 6.8, 13.2, 18.2, 19.1 and 19.5 ⁇ 0.2°.
  • WO 2011/107912 discloses crystalline form Al of bortezomib, crystalline form A2 of bortezomib, and preparation processes thereof.
  • crystalline form Al of bortezomib is prepared using acetonitrile, has 2 ⁇ values of 3.52, 4.16, 4.55, 4.69, 4.83, 5.31, 5.59, 6.08, 6.69, 7.25, 8.72, 10.39 and 12.37 ⁇ 0.2°, and exhibits a melting point between 195 and 205°C in differential scanning calorimetry (DSC).
  • Crystalline form A2 of bortezomib is prepared using a mixture of dioxane and purified water, has 2 ⁇ values of 3.37, 3.50, 4.15, 4.54, 4.66, 4.84, 5.36, 5.54, 6.05, 6.67, 7.26, 8.30, 8.79, 10.38, 12.27 and 12.86 ⁇ 0.2°, and exhibits melting points between 170 and 185 °C and between 195 and 210 °C in differential scanning calorimetry (DSC).
  • DSC differential scanning calorimetry
  • Bortezomib an active pharmaceutical ingredient, is generally freeze-stored (about - 20°C). If it is cold-stored (about 5°C), problems can arise during the storage and distribution thereof, because the appearance thereof changes, related compounds increase, and the content thereof decreases (see the bortezomib interview form of the Japanese Pharmaceutical Prescription). Accordingly, there is an urgent need for the development of a technology for preparing a novel crystalline form of bortezomib which is stable even at room temperature.
  • the present invention provides a crystalline form of bortezomib, characterized by X-ray powder diffraction with peaks at 2 ⁇ of 5.7, 7.5, 9.9, 11.5, 18.0, 20.8 and 23.7 ⁇ 0.2°.
  • a crystalline form of bortezomib characterized by X-ray powder diffraction with peaks at 2 ⁇ of 5.7, 7.5, 9.9, 11.5, 15.2, 17.2, 18.0, 20.4, 20.8, 23.7, 25.2, 26.6 and 27.9 ⁇ 0.2°.
  • bortezomib which characterized by X-ray powder diffraction with peaks at 2 ⁇ of 5.7, 7.5, 9.9, 11.5, 18.0, 20.8 and 23.7 ⁇ 0.2°, and shows endothermic peaks at 69°C and 180°C in differential scanning calorimetry (DSC; heating from 30°C to 200°C at a rate of 10°C/min).
  • a crystalline form of bortezomib which characterized by X-ray powder diffraction with peaks at 2 ⁇ of 5.7, 7.5, 9.9, 11.5, 15.2, 17.2, 18.0, 20.4, 20.8, 23.7, 25.2, 26.6 and 27.9 ⁇ 0.2°, and shows endothermic peaks at 69°C and 180°C in differential scanning calorimetry (DSC; heating from 30°C to 200°C at a rate of 10°C/min). More specifically, the crystalline form of bortezomib has a moisture content of 6-9%.
  • the novel crystalline form of bortezomib according to the present invention has excellent physical and chemical stability, and thus has high storage stability and can be advantageously used in pharmaceutical compositions.
  • FIG. 1 shows the powder X-ray diffraction (PXRD) peaks of a crystalline form of bortezomib prepared in Example 1.
  • FIG. 2 shows a differential scanning calorimetry (DSC) thermogram of a crystalline form of bortezomib prepared in Example 1.
  • FIG. 3 shows the Fourier transform infrared (FT-IR) spectrum of a crystalline form of bortezomib prepared in Example 1.
  • a novel crystalline form of bortezomib according to the present invention is prepared by crystallizing bortezomib from a mixed solvent of methanol and acetonitrile and filtering the formed crystal. Specifically, bortezomib is dissolved in methanol and concentrated in a vacuum, after which acetonitrile is added thereto, followed by stirring at 15 ⁇ 30°C. After about 30 minutes to 2 hours of stirring, a crystal is formed. The crystal is completely precipitated when the suspension is maintained at 0 ⁇ 20°C for 2 hours or more. The obtained crystal is filtered and washed with acetonitrile.
  • bortezomib is characterized by a moisture content of 6.0-9.0% as measured by the Karl Fischer water content determination method. Also, it has melting points of about 69°C and 180°C as measured by differential scanning calorimetry (DSC).
  • DSC differential scanning calorimetry
  • the present invention provides a crystalline form of bortezomib characterized by having peaks at 2 ⁇ of 5.7, 7.5, 9.9, 11.5, 15.2, 17.2, 18.0, 20.4, 20.8, 23.7, 25.2, 26.6 and 27.9 ⁇ 0.2°, as shown in Table 1 below.
  • Table 1 Table 1.
  • DSC Differential scanning calorimetry
  • Powder X-ray diffraction (PXRD) analysis was performed on a Bruker D8
  • FT-IR Fourier transform infrared
  • This analysis was performed using a JASCO FT/IR-4100 type A spectrometer.
  • Example 1 Preparation of crystalline form of bortezomib
  • bortezomib purity: 99.686% was dissolved completely in 200 mL of methanol, and then concentrated in a vacuum at 40 ⁇ 45°C. 4 L of acetonitrile was added to the oily material and stirred at 20 ⁇ 25°C. After 1 hour, a crystal started to precipitate, and the solution was stirred at an internal temperature of 10-15°C for 10 hours. The crystal was filtered, washed with 300 mL of acetonitrile, and then dried in a vacuum at 50°C for 2 hours, thereby obtaining 77 g of the desired compound as a white solid.
  • Residual solvents 173 ppm of acetonitrile, and 109 ppm of methanol.
  • FIG. 1 shows me powder X-ray diffraction peaks of a crystalline form of bortezomib prepared in Example 1.
  • FIG. 2 shows a differential scanning calorimetry (DSC) thermogram of a crystalline form of bortezomib prepared in Example 1.
  • FIG. 3 shows the Fourier transform infrared (FT-IR) spectrum of a crystalline form of bortezomib prepared in Example 1.
  • Example 2 Stability test (temperature: 25 ⁇ 2°C, and relative humidity: 60 ⁇ 5%
  • Example 1 The crystalline form of bortezomib prepared in Example 1 was subjected to a stability test in a sealed state at a temperature of 25 ⁇ 2°C and a relative humidity of 60 ⁇ 5% for 12 months. As a result, it was shown that the crystalline form of bortezomib was maintained in a stable state without any change in the HPLC purity, content, moisture content and crystalline form (PXRD) thereof.
  • Example 3 Stability test (temperature: 25 ⁇ 2°C, and relative humidity: 60 ⁇ 5%) Crystalline form II of bortezomib as disclosed in International Patent Publication No. WO 08/075376, and crystalline form A of bortezomib as disclosed in International Patent Publication No. WO 09/036281, were prepared according to the methods described in the patent documents. For comparison, the prepared crystalline forms together with the novel crystalline form of bortezomib according to the present invention were subjected to a moisture content test in a stability chamber at a temperature of 25 ⁇ 2°C and a relative humidity of 60 ⁇ 5% for 20 days in a state in which the cap was open.
  • Example 4 Stability test (60 ⁇ 2°C)
  • the prepared crystalline forms together with the novel crystalline form of bortezomib according to the present invention were subjected to a moisture content test in a stability chamber at a temperature of 60 ⁇ 2°C for 20 days in a sealed state.
  • Table 4 Table 4.

Abstract

La présente invention concerne une nouvelle forme cristalline de bortézomib et un procédé de préparation associé. La nouvelle forme cristalline de bortézomib est préparée par la cristallisation du bortézomib à partir d'un solvant mixte de méthanol et d'acétonitrile et la filtration du cristal formé. La nouvelle forme cristalline de bortézomib selon la présente invention présente une stabilité sensiblement améliorée par rapport aux formes cristallines connues.
PCT/KR2015/001424 2014-02-14 2015-02-12 Nouvelle forme cristalline de bortézomib et procédé de préparation associé WO2015122702A1 (fr)

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KR10-2014-0017476 2014-02-14

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018150386A1 (fr) * 2017-02-17 2018-08-23 Fresenius Kabi Oncology Ltd. Procédé amélioré pour la préparation d'esters d'acide boronique
CN109134601A (zh) * 2017-06-15 2019-01-04 重庆医药工业研究院有限责任公司 一种硼替佐米的杂质及其制备方法
CN110642881A (zh) * 2019-10-18 2020-01-03 扬子江药业集团上海海尼药业有限公司 一种硼替佐米晶型m及其制备方法和用途

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008075376A1 (fr) * 2006-12-18 2008-06-26 Natco Pharma Limited Formes polymorphes du bortézomibe et leur procédé de préparation
KR20100051828A (ko) * 2007-09-12 2010-05-18 닥터 레디스 레보러터리즈 리미티드 보르테조밉 및 그의 제조방법
WO2011099018A1 (fr) * 2010-02-15 2011-08-18 Hetero Research Foundation Polymorphes de bortézomib
WO2012131707A2 (fr) * 2011-03-28 2012-10-04 Laurus Labs Private Limited Nouvelle forme cristalline de bortezomib, son procédé de préparation et composition pharmaceutique l'utilisant
US20120289699A1 (en) * 2011-05-12 2012-11-15 Scino Pharm Taiwan, Ltd. Process for Preparing and Purifying Bortezomib

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008075376A1 (fr) * 2006-12-18 2008-06-26 Natco Pharma Limited Formes polymorphes du bortézomibe et leur procédé de préparation
KR20100051828A (ko) * 2007-09-12 2010-05-18 닥터 레디스 레보러터리즈 리미티드 보르테조밉 및 그의 제조방법
WO2011099018A1 (fr) * 2010-02-15 2011-08-18 Hetero Research Foundation Polymorphes de bortézomib
WO2012131707A2 (fr) * 2011-03-28 2012-10-04 Laurus Labs Private Limited Nouvelle forme cristalline de bortezomib, son procédé de préparation et composition pharmaceutique l'utilisant
US20120289699A1 (en) * 2011-05-12 2012-11-15 Scino Pharm Taiwan, Ltd. Process for Preparing and Purifying Bortezomib

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018150386A1 (fr) * 2017-02-17 2018-08-23 Fresenius Kabi Oncology Ltd. Procédé amélioré pour la préparation d'esters d'acide boronique
CN110312727A (zh) * 2017-02-17 2019-10-08 费森尤斯卡比肿瘤学有限公司 一种改进的制备硼酸酯的方法
JP2020507615A (ja) * 2017-02-17 2020-03-12 フレゼニウス・カビ・オンコロジー・リミテッド ボロン酸エステルの調製のための改良プロセス
US11667654B2 (en) 2017-02-17 2023-06-06 Fresenius Kabi Oncology Ltd. Process for the preparation of boronic acid esters
CN109134601A (zh) * 2017-06-15 2019-01-04 重庆医药工业研究院有限责任公司 一种硼替佐米的杂质及其制备方法
CN110642881A (zh) * 2019-10-18 2020-01-03 扬子江药业集团上海海尼药业有限公司 一种硼替佐米晶型m及其制备方法和用途

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