Investigation of the Polymorphic Transformation of the Active Pharmaceutical Ingredient Clopidogrel Bisulfate Using the Ionic Liquid AEImBF4

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• 作者：Ji-Hun An ; Feng Jin ; Hak Sung Kim ; Hyung Chul Ryu ; Jae Sun Kim ; Hyuk Min Kim ; Ki Hyun Kim ; Alice Nguvoko Kiyonga ; Kiwon Jung
• 刊名：Crystal Growth & Design
• 出版年：2016
• 出版时间：April 6, 2016
• 年：2016
• 卷：16
• 期：4
• 页码：1829-1836
• 全文大小：472K
• ISSN：1528-7505

文摘

Since ionic liquids (ILs), salts with a melting point below 100 °C, have unique physicochemical properties, they have been spotlighted as novel alternatives to organic solvents. However, studies relating to polymorph control using IL as solvent have not yet been performed due to the numerous (10¹⁸) available IL types with unknown effects on the control of polymorphic transformation, and the extremely high unit price compared with conventional organic solvents. Presently, the pharmaceutical industry highly prefers the high soluble form-I polymorph among several polymorphs of the active pharmaceutical ingredients (APIs), clopidogrel bisulfate (CLP). However, as form-I polymorphs are metastable crystals, their phase transformation to stable form-II crystals occurs only within 5 min in the organic solvent. Therefore, the present study was performed in order to control the phenomenon that induces the rapid phase transformation from form-I to form-II. Ethanol was used as solvent, ILs including 1-allyl-3-ethylimidazolium tetrafluoroborate (AEImBF₄), 1-butyl-2,3-dimethylimidazolium tetrafluoroborate (BDMImBF₄), and 1,3-diallylimidazolium tetrafluoroborate (AAImBF₄) were used as antisolvents, and drowning-out crystallization was the method applied. Among three ILs used in this experiment, only AEImBF₄ could induce crystals precipitation. Therefore, AEImBF₄ was used as antisolvent for further studies. The thermodynamic factor, the temperature, was set in the range of 25 to 50 °C; then the phase transformation phenomenon from form-I to form-II under temperature variation was studied. In order to illustrate the quantitative analysis of the polymorphic transformation under the new IL solvent, the nucleation and mass transfer equations were used.