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Dapagliflozin hemihydrate and its crystal form, its preparation method and pharmaceutical composition

A hemihydrate and composition technology, which is applied in the field of dapagliflozin hemihydrate and its crystal form, can solve the problems of long preparation time, expensive propylene glycol, failure to maintain the original crystal form, etc., and achieve simple preparation method, The effect of cheap solvents

Active Publication Date: 2019-11-08
SOLIPHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The present inventors have disclosed the dapagliflozin amorphous substance and the dapagliflozin hydrate crystal form A, the dapagliflozin hydrate crystal form B, and the dapagliflozin (S)-propylene glycol monohydrate disclosed in the above documents. Repeated tests and property tests were carried out, and the results showed that: the known amorphous form of dapagliflozin is easy to absorb moisture into oil or transform into other hydrate crystal states; the known crystal form of dapagliflozin hydrate The crystalline form B of the hydrate of dapagliflozin needs to add polyhydric alcohols during preparation, and the preparation time is relatively long. The known (S)-propylene glycol monohydrate of dapagliflozin is expensive for the use of (S)-propylene glycol; the known The Dapagliflozin Hydrate Form A, Dapagliflozin Hydrate Form B and Dapagliflozin (S)-propylene glycol monohydrate could not maintain their original crystal form in the water stability competition test ;

Method used

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  • Dapagliflozin hemihydrate and its crystal form, its preparation method and pharmaceutical composition
  • Dapagliflozin hemihydrate and its crystal form, its preparation method and pharmaceutical composition
  • Dapagliflozin hemihydrate and its crystal form, its preparation method and pharmaceutical composition

Examples

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preparation example 1

[0074] Preparation Example 1 (preparation of known dapagliflozin amorphous substance)

[0075] The known amorphous dapagliflozin can be prepared according to the method described in the patent document US6515117B2 or according to the following method.

[0076] Take 40 mg of dapagliflozin oil, add 400 microliters of dichloromethane to dissolve, spin dry at room temperature, and obtain white foamy dapagliflozin amorphous.

preparation example 2

[0077] Preparation example 2 (preparation of known dapagliflozin amorphous substance)

[0078] Take 500 mg of dapagliflozin oil, add 5 ml of dichloromethane to dissolve, and spin dry at room temperature to obtain part of oil and part of foamy solid mixed. Add 5 ml of n-heptane, stir at room temperature for 4 hours, filter under reduced pressure, and dry the filter cake in vacuum at room temperature for 24 hours to obtain the amorphous dapagliflozin.

[0079] XRPD chart see figure 1 , appearing as amorphous.

preparation example 3

[0080] Preparation example 3 (preparation of known dapagliflozin dihydrate crystal form A)

[0081] The known crystal form A of dapagliflozin dihydrate can be prepared according to the method described in Example 3 of patent document CN103958491A or according to the following method.

[0082] The specific preparation method is as follows: suspend 50 mg of the amorphous dapagliflozin prepared in Preparation Example 2 in 3 ml of water, and heat to 80°C. A solution of 20 mg of xylitol in 0.5 ml of water was added to the mixture to form an emulsion which was cooled to 5°C at a rate of 2°C per hour. At this temperature, the mixture was stirred for approximately 20 hours or until crystals could be detected by light microscopy. After crystallization, the suspension was filtered, and the solid product was dried in air at room temperature at a relative humidity of about 50% for about 1 hour to obtain crystalline form A of dapagliflozin dihydrate.

[0083] XRPD chart see figure 2 ...

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Abstract

The invention relates to a dapagliflozin hemihydrate and a crystal form C thereof. Compared with the prior art, the dapagliflozin hemihydrate and the crystal form C thereof have high stability in water or a water-containing system and are more suitable for being treated with the wet granulation technology or being prepared into suspension. The invention further relates to a preparation method of the crystal form C of the dapagliflozin hemihydrate.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical crystals. Specifically, it relates to dapagliflozin hemihydrate, its crystal form, and a preparation method. Background technique [0002] Dapagliflozin (trade name: Farxiga) is a sodium-glucose cotransporter-2 (SGLT2) inhibitor, which can reduce the glucose in the renal tubules by making it unable to reabsorb smoothly into the blood and excreted with the urine. Blood glucose concentration, indicated in adults with type 2 diabetes as an adjunct to diet and exercise to improve glycemic control. Daxigliflozin was jointly developed by AstraZeneca and Bristol-Myers Squibb. The drug was approved by the European Commission for the treatment of type 2 diabetes in adults on November 12, 2012. It is also the world's first SGLT2 drug. an approved drug. The U.S. Food and Drug Administration (FDA) refused approval in January 2012 on the grounds that it may cause breast and bladder cancer safety issu...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D309/10A61K31/351A61P3/10A61P3/06A61P25/00A61P27/02A61P13/12A61P17/02A61P5/50A61P3/04A61P3/00A61P9/10A61P9/12
Inventor 汪晶盛晓霞
Owner SOLIPHARMA
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