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Ribociclib monosuccinate crystal form and its preparation method and use

A technology of succinate and succinic acid, which is applied in the field of drug crystals, can solve the problems of reducing tablet and filling production efficiency in preparations, poor physical stability, and difficult drug quality.

Active Publication Date: 2022-06-17
CRYSTAL PHARMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The inventor found through research that the solubility of the hydrate form is lower, less than 0.5mg / mL, and the solubility of the non-hydrate form is better. Therefore, we choose the non-hydrate form as the comparison crystal form, but the non-hydrate form is at 80±3°C It is obtained by reaction crystallization in isopropanol under certain conditions, and high temperature increases the risk of esterification reaction between succinic acid and isopropanol, and also increases the risk of degradation
In addition, the non-hydrated form is easy to crystallize. Under 90% RH, up to 7.35% of the non-hydrated form will be converted into a hydrated form. The transformation of the crystal form of the drug will bring problems such as efficacy and safety to the drug.
In addition, the non-hydrated powder has poor physical properties. These unfavorable properties may reduce the production efficiency of tableting and filling in the preparation, and at the same time bring greater difficulties to the quality control of the drug.
Although crystal form I overcomes the problems of side reactions and easy degradation at high temperature in the preparation process of non-hydrate form, it still has some unsatisfactory properties, such as low chemical stability, poor physical stability under high humidity conditions, powder Unsatisfactory academic nature, etc.

Method used

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  • Ribociclib monosuccinate crystal form and its preparation method and use
  • Ribociclib monosuccinate crystal form and its preparation method and use
  • Ribociclib monosuccinate crystal form and its preparation method and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0205] Example 1: Preparation of seed crystals of Form X

[0206] 100.8 mg of compound (I) and 32.5 mg of succinic acid were added to 5.5 mL of a mixed solvent of acetonitrile and methanol (V:V=10:1), suspended and stirred for crystallization at 50°C for 24 hours, and then seed crystals (CN105085533B) were added thereto. Form I), suspended and stirred for crystallization at 50°C for 72 hours, centrifuged to separate the solid, and vacuum-dried at room temperature to obtain white solid crystals.

[0207] After testing, the obtained crystalline solid is the crystal form X of the present invention, and its X-ray powder diffraction data are as follows: figure 1 , as shown in Table 1.

[0208] Table 1

[0209]

[0210]

[0211]

Embodiment 2

[0212] Example 2: Preparation of Form X

[0213] 401.4 mg of compound (I) and 129.3 mg of succinic acid were added to 19.8 mL of a mixed solvent of acetonitrile and methanol (V:V=10:1), suspended and stirred for crystallization at 50°C for 24 hours, and 9 mL of the suspension was taken in another Into a glass bottle, the seed crystal of crystal form X was added, suspended and stirred for crystallization at 50° C. for 68 hours, the solid was separated by centrifugation, and vacuum-dried at room temperature to obtain a white crystalline solid.

[0214] After testing, the obtained crystalline solid is the crystal form X of the present invention, and its X-ray powder diffraction data are as follows: figure 2 , as shown in Table 2.

[0215] Compound (I) monosuccinate crystal form X prepared by the above method, which 1 H NMR spectrum as Figure 5 As shown, the identification data is as follows:

[0216] 1 H NMR (400MHz, D 2 O)δ8.63(s, 1H), 7.83(d, J=1.2Hz, 1H), 7.65-7.53(m...

Embodiment 3

[0222] Example 3 Hygroscopicity of Form X

[0223] About 10 mg of the crystal form X of the present invention was taken for dynamic moisture adsorption (DVS) test. The results are shown in Table 3, and the DVS diagram of Form X is attached Image 6 , the XRPD overlays of Form X before and after the DVS test are shown in the attached Figure 7 .

[0224] table 3

[0225]

[0226] Note: The hygroscopicity data for the non-hydrated form is from CN103201275A [Page 16 / 17, Table 1, Cycle 1]

[0227] About the description of hygroscopicity characteristics and the definition of hygroscopicity weight gain (Chinese Pharmacopoeia 2015 edition general rule 9103 Drug hygroscopicity test guidelines, experimental conditions: 25℃±1℃, 80% relative humidity):

[0228] Deliquescence: Absorbs sufficient water to form a liquid

[0229] Extremely hygroscopic: wet weight gain is not less than 15.0%

[0230] Moisture: Moisture gain is less than 15.0% but not less than 2.0%

[0231] Slight...

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Abstract

Crystal forms X, III and V of the monosuccinate salt of Ribociclib represented by the formula (1), and a preparation method thereof. A pharmaceutical composition containing the crystal form. Use of the crystal form in preparing cyclin-dependent kinase 4 / 6 inhibitors and pharmaceutical preparations for treating breast cancer.

Description

technical field [0001] The present invention relates to the technical field of pharmaceutical crystals, in particular, to a crystal form of monosuccinate of Ribociclib and a preparation method and application thereof. Background technique [0002] Cyclin-dependent kinase 4 / 6 (CDK4 / 6) is a serine / threonine kinase that binds to cyclin D (Cyclin D) and regulates the transition of cells from G1 phase to S phase . In many tumors, there are abnormalities in the "Cyclin D-CDK4 / 6-INK4-Rb pathway". The alteration of this pathway accelerates the G1 phase process and accelerates the proliferation of tumor cells to gain a survival advantage. Therefore, its intervention has become a therapeutic strategy, and CDK4 / 6 has thus become one of the anti-tumor targets. [0003] Ribociclib (also known as Ribociclib, LEE011), a cyclin-dependent kinase 4 / 6 inhibitor, was approved by the U.S. FDA on March 13, 2017, and is available in the form of monosuccinate. Ribociclib is a drug developed by N...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04A61K31/519A61P35/00
CPCA61K31/519A61P35/00C07D487/04
Inventor 陈敏华张炎锋刘远刘凯张晓宇钱佳乐陈宇浩
Owner CRYSTAL PHARMATECH CO LTD
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