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Midostaurin new crystal forms and preparation method and application thereof

A technology of midostaurin and crystal form, which is applied in the field of chemical pharmacy and can solve problems such as difficulty in promotion, difficulty in spontaneous crystallization, and difficulty in realizing industrialized operation and the like

Pending Publication Date: 2021-05-18
ZHEJIANG HISUN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] At present, the crystal form of midostaurin preparations sold on the market is crystal form II. According to its patent description, seeds must be added during the preparation process to trigger crystallization, indicating that it is difficult to spontaneously crystallize, and its preparation technology has limitations. Difficult to promote
The preparation method of crystal form III and crystal form IV is a supercritical fluid method, which is suitable for laboratory research and difficult to realize industrial operation
The crystal forms V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, etc. are all solvates, which are difficult to apply in preparations

Method used

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  • Midostaurin new crystal forms and preparation method and application thereof
  • Midostaurin new crystal forms and preparation method and application thereof
  • Midostaurin new crystal forms and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0086] Example 1 Preparation of Midostaurin Form A

[0087] Dissolve 1.0 g of midostaurin crude product in 4 mL of benzyl alcohol, heat up to 80 ° C, dissolve, filter, add 50 ml of poor solvent (volume ratio of ethanol to water: 1:1) while stirring, finish adding within 10 min, and then cool down to Stir and crystallize at 0°C for 16 hours, filter, and vacuum-dry at 40°C to obtain 0.95 g of crystals, which are easy to filter and have a purity of 99.72% by HPLC.

[0088] The X-ray powder diffraction pattern of this crystal is detailed in figure 1 , see the TGA spectrum figure 2 , which is named midostaurin crystal form A in the present invention.

Embodiment 2

[0089] Example 2 Preparation of Midostaurin Form A

[0090] Dissolve 0.5 g of midostaurin crude product in 1 mL of benzyl alcohol, heat up to 80 ° C, dissolve, filter, add 6 ml of poor solvent (volume ratio of ethanol to water: 1:1) while stirring, finish adding within 5 min, and then cool down to Stir and crystallize at 0°C for 48 hours, filter, and vacuum-dry at 40°C to obtain 0.47 g of crystals, which are easy to filter and have a purity of 99.71% by HPLC. After measuring the X-ray powder diffraction pattern (XRD), it was confirmed to be midostaurin crystal form A.

Embodiment 3

[0091] Example 3 Preparation of Midostaurin Form A

[0092] Dissolve 0.5 g of midostaurin crude product in 5 mL of benzyl alcohol, heat up to 40 ° C, dissolve, filter, add 250 ml of poor solvent (volume ratio of ethanol to water: 1:1) while stirring, finish adding within 30 min, and then cool down to Stir and crystallize at 20°C for 24 hours, filter, and vacuum-dry at 40°C to obtain 0.47 g of crystals, which are easy to filter and have a purity of 99.71% by HPLC. After measuring the X-ray powder diffraction pattern (XRD), it was confirmed to be midostaurin crystal form A.

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Abstract

The invention relates to midostaurin novel crystal forms A, B and C as well as a preparation method and application of the novel crystal forms A, B and C. The crystal forms have excellent properties in the aspects of physical and chemical stability and processing adaptability. The crystallization process is simple and convenient to operate, and industrial production can be realized.

Description

technical field [0001] The invention relates to the field of chemical pharmacy. More specifically, the present invention relates to a new crystal form of midostaurin, a preparation method of the new crystal form and their medical application. [0002] technical background [0003] Protein kinase C (PKC is an abbreviation), is one of the key enzymes in the cell signal transduction pathway, and it plays a key role in the control of cell proliferation and differentiation. PKC is a family of serine / threonine kinases. [0004] Midostaurin shows high anti-proliferative and anti-tumor activity, and its highly selective and effective PKC inhibition brings better clinical effect to patients, that is, delays or inhibits disease, compared with similarly tolerated treatment regimens It is extremely useful for cancer treatment, especially for breast cancer, colon cancer, ovarian cancer and leukemia. [0005] The drug midostaurin is used as an antineoplastic agent and the preparation of...

Claims

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Application Information

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IPC IPC(8): C07D498/22A61K31/553A61P35/00A61P35/02
CPCC07D498/22A61P35/00A61P35/02C07B2200/13C07B2200/07
Inventor 郑剑锋施珍娟李娜苏笛陈连蔚赵美玉
Owner ZHEJIANG HISUN PHARMA CO LTD
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