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Crystals 2019, 9(1), 53;

Simple and Efficient Spherical Crystallization of Clopidogrel Bisulfate Form-I via Anti-Solvent Crystallization Method

College of Pharmacy, CHA University, Sungnam 13844, Korea
College of Pharmacy, Korea University, Sejong City 30019, Korea
Authors to whom correspondence should be addressed.
Both authors equally contributed to this work.
Received: 24 December 2018 / Revised: 11 January 2019 / Accepted: 15 January 2019 / Published: 17 January 2019
(This article belongs to the Special Issue Anti-Solvent Crystallization)
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Clopidogrel bisulfate (CLP) form-I crystals are irregular, rectangular-shaped crystals. Because of their poor compressibility, flowability and their strong surface tension, manufacturers apply spherical crystallization methods to produce CLP form-I spherical agglomerates with a uniform particle size distribution. Consequently, manufacturers primarily synthesize CLP form-I crystal salts utilizing very complex methods, which produces form-I spherical agglomerates by means of spherical crystallization. In this study, spherical crystals of CLP Form-I were directly prepared from CLP Form-II, the most stable polymorph at room temperature, by using ethanol as solvent and a mixture of isopropyl alcohol (IPA)/n-Hexane (Hex) as an anti-solvent. To provide systematic inputs for the development of spherical agglomerates of optimal morphology, size, particle size distribution (PSD), and polymorphic form, processing parameters such as anti-solvent type, a mixture of IPA/Hex, pure Hex, or pure acetone; stirring speeds of 500, 600, 700, or 800 rpm; and temperatures ranging from 25 to 40 °C were explored. The effects of these parameters on spherical crystallization and polymorphic form were studied in terms of supersaturation, a driving force for polymorphic transformation, and the crystallization solution. Notably, our method does not require a large volume of anti-solvent which is the main complication of conventional anti-solvent crystallization methods. View Full-Text
Keywords: polymorphs; clopidogrel bisulfate; anti-solvent crystallization; spherical agglomerate polymorphs; clopidogrel bisulfate; anti-solvent crystallization; spherical agglomerate

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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An, J.-H.; Kiyonga, A.N.; Lee, E.H.; Jung, K. Simple and Efficient Spherical Crystallization of Clopidogrel Bisulfate Form-I via Anti-Solvent Crystallization Method. Crystals 2019, 9, 53.

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