The Transformation Relationship between Two Hydrates of Calcium Dobesilate and its Application in Crystallization Process,Crystal Research and Technology

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The Transformation Relationship between Two Hydrates of Calcium Dobesilate and its Application in Crystallization Process
Crystal Research and Technology ( IF 1.5 ) Pub Date : 2020-10-12 , DOI: 10.1002/crat.202000139
Xuan Yao ₁ , Yan‐Fang Wu ₁ , Shu‐Jia Sun ₁ , Fu‐Zheng Ren ₁ , Shun‐Ping Yang ₁ , Yan Liu ₁

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As a classic drug with several hydrate forms, Calcium Dobesilate is widely used in the treatment of diabetic retinopathy and chronic venous insufficiency, and Monohydrate is the medicinal form. The key impurity, hydroquinone, is an important synthetic raw material of Calcium Dobesilate, but has a potential genotoxicity, so the content of hydroquinone in the final product should be lower. In this paper, based on characterization results of different hydrates, the Dihydrate is found as the beneficial form for purification, thus a novel crystallization process for purification has been carried out. The Dihydrate is obtained by a recrystallization and then transformed into the Monohydrate. From the results of solid‐state characterization and process analysis of phase transformation, the transformation relationship between the two hydrates is determined, and it is found out that the transformation from Dihydrate to Monohydrate could only happen via solution‐mediated transformation in Ethanol or Isopropanol. The impurity content of the Monohydrate product prepared by the new crystallization process is far below the current standard in the Pharmacopoeia.

中文翻译：

两种水合铍硅酸钙的转化关系及其在结晶过程中的应用

作为几种水合物形式的经典药物，苯磺酸硅酸钙被广泛用于糖尿病性视网膜病变和慢性静脉功能不全的治疗，而一水合物是药用形式。关键杂质对苯二酚是苯磺酸硅酸钙的重要合成原料，但具有潜在的遗传毒性，因此最终产品中对苯二酚的含量应降低。在本文中，根据不同水合物的表征结果，发现二水合物是纯化的有益形式，因此进行了新的纯化结晶过程。通过重结晶获得二水合物，然后转化为一水合物。从固态表征的结果和相变的过程分析，确定了两种水合物之间的转化关系，发现从二水合物到一水合物的转化只能通过在乙醇或异丙醇中进行溶液介导的转化来实现。通过新的结晶工艺制备的一水合物产品的杂质含量远低于药典中的现行标准。

更新日期：2020-12-10

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