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New crystal form of acalabrutinib and its preparation method and use

A cu-ka and material crystal technology, applied in the direction of organic chemical methods, medical preparations containing active ingredients, pharmaceutical formulas, etc., can solve the problems affecting and affecting the clinical efficacy and safety of drugs, and achieve good physical stability, Good purification effect, good acceleration and stability effect

Active Publication Date: 2021-03-12
CRYSTAL PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Because different crystal forms of drugs may affect their dissolution and absorption in the body, which may affect the clinical efficacy and safety of the drug to a certain extent; especially for poorly soluble oral drugs, the crystal form will have a greater impact

Method used

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  • New crystal form of acalabrutinib and its preparation method and use
  • New crystal form of acalabrutinib and its preparation method and use
  • New crystal form of acalabrutinib and its preparation method and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0208] Example 1 The preparation method of L-ethyl lactate solvate crystal form A

[0209] Weigh 2.50g of Acalabrutinib free base into a 100mL crystallization kettle, add 25mL of L-ethyl lactate, raise the temperature to 40°C, stir for 8 hours, cool down to 20°C, stir overnight, and separate to obtain a solid. After testing, the solid obtained in this example is L-lactate ethyl solvate crystal form A. Its XRPD is attached figure 1 , and its XRPD data sheet is shown in Table 1. Its DSC diagram is attached figure 2 , when heated to 137°C, the first endothermic peak appears, which is the desolvation endothermic peak. Its TGA diagram is attached image 3 , has a mass loss of about 20.1% when heated to 180°C. liquid hydrogen NMR Figure 4 , according to NMR data, it can be seen that L-ethyl lactate solvate crystal form A contains about 1 mole of L-ethyl lactate, and the NMR peaks around 1.25, 4.09 and 5.34 are the characteristic peaks of L-ethyl lactate.

[0210] Table 1 ...

Embodiment 2

[0212] Example 2 The preparation method of L-ethyl lactate solvate crystal form A

[0213] Weigh 1.23g of Acalabrutinib free base sample into a 20mL glass bottle, add 12.0mL L-ethyl lactate / ethyl acetate (1:1, v / v). After magnetic stirring at 50° C. for 3 days, 1.34 g of solid was obtained by separation and drying. After detection, the obtained solid is the crystal form A of the present invention, and its XRPD data is shown in Table 2. The crystal form A obtained in this example has the same or similar XRPD pattern as the crystal form A in Example 1, is the same crystal form, and has the same properties.

[0214] Table 2

[0215]

[0216]

Embodiment 3

[0217] Example 3 Purification of L-ethyl lactate solvate crystal form A

[0218] The purity of the free base solid and the L-lactate ethyl lactate solvate crystal form A of the present invention was measured by HPLC, and the purity change was calculated.

[0219] The HPLC purity test results show that the L-lactate ethyl lactate solvate crystal form A of the present invention has a remarkable purification effect. The purity of the free base solid is 98.93%, and the purity of the L-lactate ethyl lactate solvate crystal form A of the present invention is 99.63%, with a purity increase of 0.70%.

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Abstract

The invention relates to a new crystal form of Acalabrutinib and a preparation method thereof, a pharmaceutical composition containing the crystal form, and an application of the crystal form in preparing Bruton's tyrosine kinase inhibitors and pharmaceutical preparations for treating mantle cell lymphoma. The crystal form of Acalabrutinib provided by the present invention has one or more improved properties compared with the prior art, and is of great value to the optimization and development of the drug in the future.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry. Specifically, it relates to a crystal form of Acalabrutinib and its preparation method and use. Background technique [0002] Mantle Cell Lymphoma (Mantle Cell Lymphoma) is a type of non-Hodgkin's lymphoma, which is an incurable lymphoma. BTK is a member of the Tec family of tyrosine kinases and has been shown to be a key regulator of early B cell development as well as mature B cell activation and survival. BTK has been reported to play a role in apoptosis, therefore BTK inhibitors may be useful in the treatment of certain B-cell lymphomas and leukemias. [0003] Acalabrutinib is a second-generation BTK inhibitor. Compared with the first-generation BTK inhibitor Ibrutinib, it has higher drug selectivity and lower side effects. The listing of Acalabrutinib provides a new treatment option for patients with relapsed and drug-resistant mantle cell lymphoma. Acalabrutinib was developed ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04A61K31/4985A61P35/00A61P35/02
CPCA61K31/4985A61P35/00A61P35/02C07D487/04C07B2200/13
Inventor 陈敏华张炎锋刘远汪建明
Owner CRYSTAL PHARMA CO LTD
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