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Crystal forms of camostat mesilate and solvate thereof as well as preparation method and application of crystal forms of camostat mesylate and solvate thereof

A technology of ester mesylate and crystal form, applied in the preparation of organic compounds, preparation of sulfonates, chemical instruments and methods, etc., can solve problems such as unfavorable drug stability

Pending Publication Date: 2021-11-23
TIANJIN INSTITUTE OF PHARMA RESEARCH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It can be seen that the camostat mesylate prepared according to the existing literature is a mixed crystal form, which is unfavorable for the stability of the drug

Method used

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  • Crystal forms of camostat mesilate and solvate thereof as well as preparation method and application of crystal forms of camostat mesylate and solvate thereof
  • Crystal forms of camostat mesilate and solvate thereof as well as preparation method and application of crystal forms of camostat mesylate and solvate thereof
  • Crystal forms of camostat mesilate and solvate thereof as well as preparation method and application of crystal forms of camostat mesylate and solvate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] The preparation of embodiment 1 acetone solvate crystal form D

[0065] 5 g of the free base was added to 50 ml of acetone, and stirred to obtain a suspension. Cool down to 15-25°C, add dropwise a methanesulfonic acid solution prepared by 1.2g methanesulfonic acid and 2.4g acetone, and keep the temperature not exceeding 25°C during the dropping process. After dropping, the system was insoluble and clear. Keep stirring at 15-25°C for 1 hour to fully form a salt. Filter, rinse the filter cake with acetone, and blow dry at 50° C. for 4 hours to obtain 4.4 g of the compound of formula (I) 4-(4-guanidinobenzoyloxy)phenylacetic acid [2-(dimethylamino)-2 Acetonide form D of -oxoethyl] ester mesylate.

Embodiment 2

[0066] Embodiment 2 prepares crystal form B with acetonate crystal form D

[0067] Add 5 g of the acetone solvate crystal form D prepared in Example 1 into 50 ml of acetone, and heat up while stirring. During the heating process, the solid in the system was dissolved first, and then precipitated when it was not yet dissolved. The temperature was raised to 30-40 ° C, and the temperature was kept and stirred for 4 hours. Lower the temperature to 10-15°C and continue stirring for 2h. After filtration, the filter cake was rinsed with acetone to obtain a white crystalline solid. Air drying at 50° C. for 5 hours to obtain 4-(4-guanidinobenzoyloxy)phenylacetic acid [2-(dimethylamino)-2-oxoethyl group represented by formula (I) in the form of crystal form B ] Ester mesylate 4.2 g.

Embodiment 3

[0068] Embodiment 3 prepares the pharmaceutical composition of camostat mesylate crystal form B

[0069] Prepare 1,000 tablets, each containing 100 mg of camostat mesylate in crystal form B, adding 10 mg of hydroxypropyl cellulose, 5 mg of carboxymethyl cellulose calcium, 1 mg of magnesium stearate, and 5 mg of polyoxyethylene , 3 mg of polyoxypropylene, 3 mg of ethylene glycol, and 10 mg of lactose hydrate were directly compressed and coated to prepare camostat mesylate crystal form B tablets.

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Abstract

The invention provides a crystal form of camostat mesylate, a crystal form of an acetone solvate of the camostat mesylate, and preparation methods and applications of the crystal forms of the camostat mesylate and the solvate thereof. The invention provides application of the crystal form and the crystal form of the acetone solvate in preparation of medicines for treating pancreatitis, reflux esophagitis and diseases caused by coronavirus infection. Compared with the mixed crystal form of the camostat mesylate, the crystal form of the camostat mesylate and the crystal form of the acetone solvate of the camostat mesylate provided by the invention have better stability, and the physicochemical properties of the camostat mesylate and the acetone solvate of the camostat mesylate are more stable than those of the existing crystal form in the preparation process.

Description

technical field [0001] The present invention relates to the crystal forms of camostat mesylate and solvates thereof, their preparation methods, their pharmaceutical preparations and their application in the treatment of acute pancreatitis, reflux esophagitis and diseases caused by coronavirus infection. Background technique [0002] Camostat Mesilate (Camostat Mesilate) chemical name: 4-(4-guanidinobenzoyloxy) phenylacetic acid [2-(dimethylamino)-2-oxoethyl] ester methanesulfonic acid Salt, the structural formula is as follows: [0003] [0004] Molecular formula: C 20 h 22 N 4 o 5 ·CH 4 o 3 S, molecular weight: 494.52, CAS accession number: 57921-29-8. [0005] Camostat mesylate is an orally administered non-peptide proteolytic enzyme inhibitor, which can effectively inhibit the activities of trypsin, plasma kallikrein, plasmin, thrombin, C1r and C1 esterase, etc., and the The compound has no significant inhibitory effect on α-chymotrypsin, pepsin and pancreatic ...

Claims

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Application Information

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IPC IPC(8): C07C279/18C07C277/08C07C303/32C07C309/04C07C49/08C07C45/81A61K31/245A61P1/18A61P29/00A61P1/04A61P31/14
CPCC07C279/18C07C277/08C07C303/32C07C309/04C07C49/08C07C45/81A61P1/18A61P29/00A61P1/04A61P31/14C07B2200/13
Inventor 李树军穆帅张慕军陈蔚闫少杰王浩雷永胜周学福潘毅陈华刘福景孙靖汤立达
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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