The Transformation Relationship between Two Hydrates of Calcium Dobesilate and its Application in Crystallization Process

Abstract

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.