Isavuconazole sulfate crystal and preparation method thereof

A technology of isavuconazole sulfate and crystals, which is applied in the field of antifungal drug isavuconazole sulfate crystal form and its preparation, and can solve the problems of stability, water-soluble dissolution rate, storage stability, preparation easiness, Affect drug activity and other issues, to achieve the effect of stability, small change in purity, and high purity

Active Publication Date: 2017-04-19
JIANGSU CHIA TAI FENGHAI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The same drug has different crystal forms, and there are large differences in the stability, water solubility, dissolution rate, storage stability, and ease of preparation of the preparation, which also seriously affect the activity of the drug.

Method used

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  • Isavuconazole sulfate crystal and preparation method thereof
  • Isavuconazole sulfate crystal and preparation method thereof
  • Isavuconazole sulfate crystal and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Embodiment 1 Preparation of isavuconazole sulfate crystal form

[0039]Dissolve 0.9 g (1 mmol) of isavuconazole hydrochloride in 9 mL of water, lower the temperature to 0 ° C, adjust the pH to 7 with aqueous sodium bicarbonate solution, add 9 mL of dichloromethane for extraction, dry and concentrate after liquid separation, and then add 10 mL of methanol Dissolve, cool down to -5°C, add 0.09g (1mmol) of concentrated sulfuric acid and 0.11g (1mmol) of 30% hydrogen peroxide dropwise, stir for 30min, concentrate, add 5mL of 95% ethanol and 5mL of ethyl acetate for recrystallization, and heat to 40 ℃ dissolved, stirred and cooled to 20 ℃, crystallized, suction filtered, and vacuum dried to obtain 0.62g white solid with a yield of 76% and a purity of 97.6%. The XRPD pattern was as follows: figure 1 shown.

Embodiment 2

[0040] Embodiment 2 Preparation of isavuconazole sulfate crystal form

[0041] Dissolve isavuconazole hydrochloride 0.9g (1mmol) in 9mL of water, cool down to -5°C, adjust the pH to 7 with ammonia solution, add 9mL of dichloromethane for extraction, dry and concentrate after liquid separation, add 10mL of methanol to dissolve , cooled to -5°C, added dropwise 0.12g (1.2mmol) of concentrated sulfuric acid and 0.15g (1.3mmol) of 30% hydrogen peroxide, stirred for 30min, concentrated, added 5mL of 95% ethanol and 10mL of ethyl acetate for recrystallization, and heated to Dissolve at 40°C, stir and cool to 10°C, crystallize, filter with suction, and dry in vacuo to obtain 0.55 g of white solid with a yield of 67% and a purity of 97.4%.

Embodiment 3

[0042] Embodiment 3 Preparation of isavuconazole sulfate crystal form

[0043] Dissolve 0.9 g (1 mmol) of isavuconazole hydrochloride in 9 mL of water, cool down to -3 °C, adjust the pH to 7 with aqueous sodium carbonate solution, add 9 mL of dichloromethane for extraction, dry and concentrate after liquid separation, then add 10 mL of ethanol Dissolve, cool down to -5°C, add 0.13g (1.3mmol) of concentrated sulfuric acid and 0.12g (1.1mmol) of 30% hydrogen peroxide dropwise, stir for 30min, concentrate, add 5mL of 95% ethanol and 20mL of ethyl acetate for recrystallization, and heat Dissolve at 40°C, stir and cool to 20°C, crystallize, filter with suction, and dry in vacuo to obtain 0.50 g of white solid with a yield of 62% and a purity of 97.7%.

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PUM

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Abstract

The invention relates to an isavuconazole sulfate crystal form, and a preparation method and a medicinal composition thereof. The crystal form has the advantages of good stability, high purity, good reappearance and suitableness for preparing medicinal preparations. The preparation method comprises the following steps: dissociating isavuconazole hydrochloride by using an alkali, carrying out salt exchange by using concentrated sulfuric acid and hydrogen peroxide, and carrying out re-crystallization. The method has the advantages of mild reaction conditions, simple post-treatment and high purity of the above product, and meets basic requirements of industrial amplified production.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemical crystallization, and in particular, the invention relates to an antifungal drug isavuconazole sulfate crystal form and a preparation method thereof. Background technique [0002] Isavuconazole (Isavuconazole, CAS No. 241479-67-4) is an antifungal drug jointly developed by Switzerland Baselia Pharmaceutical Co., Ltd. and Japan Astellas. Its water-soluble prodrug is sulfate, and its chemical The structural formula is as follows: [0003] [0004] Isavuconazole, as a new type of broad-spectrum triazole drug, has the following characteristics compared with other similar drugs: (1) The finished drug component is a water-soluble prodrug, which can be developed into oral and intravenous administration, and there is no Containing cyclodextrin, there is no potential risk of nephrotoxicity of excipients; (2) High bioavailability, and the two routes of administration can be easily switched. I...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/14C07D417/06
CPCA61K9/0019A61K9/08A61K47/10C07B2200/13C07D417/06C07D417/14
Inventor 朱永强杨杨侯可辉关众于钦策张兵兵
Owner JIANGSU CHIA TAI FENGHAI PHARMA
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