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Bortezomib crystal form, preparation method, pharmaceutical composition and application thereof

A technology of bortezomib and its composition, which is applied in the field of medicinal chemistry, can solve the problems of weak antioxidant capacity, unfavorable preparation of liquid preparations, poor solubility of bortezomib crystal forms, etc., and achieve fast dissolution, good clarity and visible foreign matter , cheap effect

Active Publication Date: 2015-06-10
HANGZHOU HUADONG MEDICINE GRP PHARMA RES INST +1
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  • Application Information

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Problems solved by technology

[0021] The object of the present invention is exactly in order to overcome the deficiency of the physical property of existing bortezomib crystal form, provides a kind of bortezomib new crystal form, is called crystal form F, solves the poor solubility of existing bortezomib crystal form, resistance Weak oxidizing ability, which is not conducive to the preparation of liquid preparations

Method used

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  • Bortezomib crystal form, preparation method, pharmaceutical composition and application thereof
  • Bortezomib crystal form, preparation method, pharmaceutical composition and application thereof
  • Bortezomib crystal form, preparation method, pharmaceutical composition and application thereof

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preparation example Construction

[0068] The preparation of the crude bortezomib compound used in the present invention can refer to Chinese invention patent CN1960996.

[0069] Among them, amorphous bortezomib, bortezomib FormI and FormII can be purchased from the market, or can be prepared by existing methods, for example, refer to WO2008075376A1 to prepare FormI and FormII, and refer to US5780454 to prepare amorphous bortezomib.

Embodiment 1

[0072] Put 100mg of bortezomib Form I in a 5ml glass vial, add 2ml of ethyl acetate, stir the crystal slurry at room temperature for 6 hours, centrifuge, and vacuum dry at 40°C for 4 hours to obtain bortezomib Form F, the purity of which was 99.6% by HPLC. The X-ray powder diffraction (XRD) pattern of this crystal form is shown in figure 1 ; IR spectrum see figure 2 ; TGA spectrum see image 3 , the weight loss of Form F is about 3.8% before 150°C, and the decomposition temperature is about 248°C; see the PLM spectrum Figure 4 ; DVS map see Figure 5 , see 6 for the before and after comparison of oxidation stability XRD.

Embodiment 2

[0074] Put 50mg of bortezomib Form I in a 5ml glass vial, add 2ml of ethyl acetate, stir the crystal slurry at room temperature for 4 hours, centrifuge, and vacuum dry at 40°C for 6 hours to obtain bortezomib Form F, the purity of which was 99.5% by HPLC. The X-ray powder diffraction (XRD) collection of patterns and figure 1 Basically the same, other spectrograms are consistent with those of Example 1.

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Abstract

The invention relates to the field of medicinal chemistry and particularly relates to a new crystal form of the bortezomib. The invention additionally discloses a preparation of the crystal form and an application in the antineoplastic medicine. The crystal form disclosed by the invention solves the technical problems that the current bortezomib crystal form has bad solubility and weak antioxidant ability and is not good for liquid formulation preparation, and has the advantages of good solubility, high stability and strong antioxidant ability; simultaneously the crystal form prepared by the method disclosed by the invention is high in crystal form purity and safe in medicine use.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to bortezomib crystal form F and a preparation method thereof, a pharmaceutical composition containing the crystal form and its use in preparing medicines for treating or preventing tumor-related diseases. Background technique [0002] Bortezomib (Bortezomib, CAS: 179324-69-7), trade name Velcade, white or off-white block or powder, chemical name: [(1R)-3-methyl-1-[[ (2S)-1-Oxo-3-phenyl-2-[(pyrazinecarboxy)amino]propyl]amino]butyl]boronic acid, the molecular formula is C 19 h 25 BN 4 o 4 , the structural formula is as formula I: [0003] [0004] Bortezomib is a new type of anti-tumor drug developed by Millennium Pharmaceutical Company of the United States. It is a synthetic reversible inhibitor of 26S proteasome chymotrypsin-like activity in mammals, which can induce apoptosis in various tumor cell lines and cancerous cells. It can significantly enhance the efficacy of ce...

Claims

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Application Information

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IPC IPC(8): C07K5/078C07K1/30A61K38/05A61P35/00A61P35/02
Inventor 谢厅徐仲军周汉君陈辅辰
Owner HANGZHOU HUADONG MEDICINE GRP PHARMA RES INST
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