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Hemi-succinate crystal form CSI of Ribociclib as well as preparation method and application thereof

A crystal form and application technology, applied in the hemisuccinate crystal form of ribociclib and its preparation, can solve problems affecting the clinical efficacy and safety of drugs

Inactive Publication Date: 2021-05-14
CRYSTAL PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to different physical and chemical properties, different crystal forms of drugs may have different dissolution and absorption in vivo, which in turn affects the clinical efficacy and safety of drugs to a certain extent.

Method used

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  • Hemi-succinate crystal form CSI of Ribociclib as well as preparation method and application thereof
  • Hemi-succinate crystal form CSI of Ribociclib as well as preparation method and application thereof
  • Hemi-succinate crystal form CSI of Ribociclib as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Example 1: Preparation method of crystal form CSI

[0055] Add 1.0095g of compound (I) and 0.055g of succinic acid into 30mL of n-butanol / anisole (1:1, v / v) solvent, dissolve at 80°C, let stand at room temperature until the solid precipitates, centrifuge at 25°C Drying under vacuum for 13 hours, and vacuum drying at 40°C for 10 hours gave white solid crystals. After testing, the obtained crystalline solid is the crystal form CSI described in the present invention, and its XRPD pattern is as follows figure 1 , XRPD data are shown in Table 1.

[0056] TGA as figure 2 As shown, when it is heated to 100°C, it has a mass loss of 0.9%, and from 100°C to 175°C, there is about 9.9% of the mass loss due to the removal of the solvent in the solvate.

[0057] DSC such as image 3 As shown, it has two endothermic peaks, the endothermic peak around 151°C is the desolvation endothermic peak, and the endothermic peak around 203°C is the melting endothermic peak.

[0058] Table...

Embodiment 2

[0061] Example 2: Dynamic solubility of crystalline form CSI

[0062] Simulated gastrointestinal fluids such as SGF (simulated gastric fluid), FaSSIF (simulated fasting state intestinal fluid), FeSSIF (simulated fed state intestinal fluid) are biologically relevant media, which can better reflect the effect of gastrointestinal physiological environment on drug release. The solubility tested in such media is closer to the solubility in the human environment.

[0063] Take about 20 mg of the crystal form CSI of the present invention and suspend in 1.5 mL of SGF, 1.5 mL of FaSSIF, 1.5 mL of FeSSIF and 1.5 mL of water to prepare a suspension, and equilibrate for 1 hour, 4 hours and 24 hours respectively with high-efficiency liquid The content (mg / mL) of the sample in the solution was tested by phase chromatography.

Embodiment 3

[0064] Example 3: Intrinsic dissolution rate of crystalline form CSI

[0065] Weigh about 100mg of crystal form CSI, pour it into the inherent dissolution mold, and keep it under 5kN pressure for 1min to make a surface area of ​​0.5cm 2 For the flakes, the mold with the flakes was transferred to the dissolution apparatus to test the intrinsic dissolution rate.

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PUM

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Abstract

The invention relates to a crystal form of hemisuccinic acid Ribociclib, a preparation method and application thereof, a pharmaceutical composition containing the crystal form, and application of the crystal form in preparation of a cyclin-dependent kinase 4 / 6 inhibitor and a pharmaceutical preparation for treating breast cancer. Compared with the prior art, the Ribociclib crystal form CSI provided by the invention has one or more improved properties, and has important value for optimization and development of the medicine in the future.

Description

technical field [0001] The invention relates to the field of chemistry and medicine, in particular to the hemisuccinate crystal form of ribociclib and its preparation method and application. Background technique [0002] Cyclin-dependent kinase 4 / 6 (Cyclin-dependent kinase4 / 6, CDK4 / 6) is a kind of serine / threonine kinase that binds to cyclin D (CyclinD) and regulates the transition of cells from G1 phase to S phase. In many tumors, there are abnormalities in the "CyclinD-CDK4 / 6-INK4-Rb pathway". The change of this pathway accelerates the process of G1 phase, which accelerates the proliferation of tumor cells and obtains a survival advantage. Therefore, its intervention has become a therapeutic strategy, and CDK4 / 6 has therefore become one of the anti-tumor targets. [0003] Ribociclib (also known as LEE011) is a small molecule inhibitor of cyclin-dependent kinase 4 / 6, which was approved by the US FDA on March 13, 2017, and is marketed in the form of succinate. Ribociclib ...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61P35/00A61K31/519
CPCA61P35/00C07B2200/13C07D487/04
Inventor 陈敏华李英杰钱佳乐
Owner CRYSTAL PHARMA CO LTD
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