The Crystallization of Active Pharmaceutical Ingredients with Low Melting Points in the Presence of Liquid–Liquid Phase Separation

Liquid–liquid phase separation (LLPS) during the crystallization of active pharmaceutical ingredients (APIs) often causes agglomeration and other quality issues in crystal products; thus, it should be avoided if possible. However, LLPS in the crystallization of APIs with low melting points cannot be...

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Autores principales:	Wei Han Lin, Zai-Qun Yu, Pui Shan Chow, Reginald Beng Hee Tan
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	liquid–liquid phase separation oiling out crystallization development phase diagram Crystallography QD901-999
Acceso en línea:	https://doaj.org/article/b5f1922001cf4335a8e0b4d7f2d4d12d
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spelling	oai:doaj.org-article:b5f1922001cf4335a8e0b4d7f2d4d12d2021-11-25T17:18:19ZThe Crystallization of Active Pharmaceutical Ingredients with Low Melting Points in the Presence of Liquid–Liquid Phase Separation10.3390/cryst111113262073-4352https://doaj.org/article/b5f1922001cf4335a8e0b4d7f2d4d12d2021-10-01T00:00:00Zhttps://www.mdpi.com/2073-4352/11/11/1326https://doaj.org/toc/2073-4352Liquid–liquid phase separation (LLPS) during the crystallization of active pharmaceutical ingredients (APIs) often causes agglomeration and other quality issues in crystal products; thus, it should be avoided if possible. However, LLPS in the crystallization of APIs with low melting points cannot be circumvented in some cases due to yield considerations. The crystallization of ibuprofen in an ethanol/water mixture was studied to explore methods to reduce agglomeration in the presence of LLPS. It was found that unseeded crystallization produced agglomerates when LLPS took place. The two liquid phases resulting from LLPS underwent LLPS again when they were cooled separately, indicating the dynamic nature of LLPS. Seeding and seed ageing at a low supersaturation were very effective in mitigating agglomeration. The effects of two widely used surfactants, i.e., Tween 80 and hydroxypropyl methylcellulose (HPMC), on LLPS and crystallization were confirmed preliminarily. More work needs to be conducted to explore their usefulness in LLPS handling. The findings and techniques presented in this study may be applicable to the crystallization of other APIs with low melting points.Wei Han LinZai-Qun YuPui Shan ChowReginald Beng Hee TanMDPI AGarticleliquid–liquid phase separationoiling outcrystallization developmentphase diagramCrystallographyQD901-999ENCrystals, Vol 11, Iss 1326, p 1326 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	liquid–liquid phase separation oiling out crystallization development phase diagram Crystallography QD901-999
spellingShingle	liquid–liquid phase separation oiling out crystallization development phase diagram Crystallography QD901-999 Wei Han Lin Zai-Qun Yu Pui Shan Chow Reginald Beng Hee Tan The Crystallization of Active Pharmaceutical Ingredients with Low Melting Points in the Presence of Liquid–Liquid Phase Separation
description	Liquid–liquid phase separation (LLPS) during the crystallization of active pharmaceutical ingredients (APIs) often causes agglomeration and other quality issues in crystal products; thus, it should be avoided if possible. However, LLPS in the crystallization of APIs with low melting points cannot be circumvented in some cases due to yield considerations. The crystallization of ibuprofen in an ethanol/water mixture was studied to explore methods to reduce agglomeration in the presence of LLPS. It was found that unseeded crystallization produced agglomerates when LLPS took place. The two liquid phases resulting from LLPS underwent LLPS again when they were cooled separately, indicating the dynamic nature of LLPS. Seeding and seed ageing at a low supersaturation were very effective in mitigating agglomeration. The effects of two widely used surfactants, i.e., Tween 80 and hydroxypropyl methylcellulose (HPMC), on LLPS and crystallization were confirmed preliminarily. More work needs to be conducted to explore their usefulness in LLPS handling. The findings and techniques presented in this study may be applicable to the crystallization of other APIs with low melting points.
format	article
author	Wei Han Lin Zai-Qun Yu Pui Shan Chow Reginald Beng Hee Tan
author_facet	Wei Han Lin Zai-Qun Yu Pui Shan Chow Reginald Beng Hee Tan
author_sort	Wei Han Lin
title	The Crystallization of Active Pharmaceutical Ingredients with Low Melting Points in the Presence of Liquid–Liquid Phase Separation
title_short	The Crystallization of Active Pharmaceutical Ingredients with Low Melting Points in the Presence of Liquid–Liquid Phase Separation
title_full	The Crystallization of Active Pharmaceutical Ingredients with Low Melting Points in the Presence of Liquid–Liquid Phase Separation
title_fullStr	The Crystallization of Active Pharmaceutical Ingredients with Low Melting Points in the Presence of Liquid–Liquid Phase Separation
title_full_unstemmed	The Crystallization of Active Pharmaceutical Ingredients with Low Melting Points in the Presence of Liquid–Liquid Phase Separation
title_sort	crystallization of active pharmaceutical ingredients with low melting points in the presence of liquid–liquid phase separation
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/b5f1922001cf4335a8e0b4d7f2d4d12d
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The Crystallization of Active Pharmaceutical Ingredients with Low Melting Points in the Presence of Liquid–Liquid Phase Separation

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