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Tuning morphology in active pharmaceutical ingredients: controlling the crystal habit of lovastatin through solvent choice and non-size-matched polymer additives

Hatcher, Lauren E., Li, Wei, Payne, Pollyanna, Benyahia, Brahim, Rielly, Chris D. and Wilson, Chick C. 2020. Tuning morphology in active pharmaceutical ingredients: controlling the crystal habit of lovastatin through solvent choice and non-size-matched polymer additives. Crystal Growth and Design 20 (9) , pp. 5854-5862. 10.1021/acs.cgd.0c00470

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Abstract

Additive crystallization routes to control the crystal habit of the active pharmaceutical ingredient (API) lovastatin are presented, at small scale up to 25 mL. Lovastatin is an archetypical example of an API that forms needle-like crystals via solution-based recrystallization, causing issues for downstream pharmaceutical processing stages. In this work, the size and shape of lovastatin needles are shown to be subtly influenced by the crystallization solvent, concentration, and crystallization procedure, with moderately hygroscopic ethyl acetate solvent producing needles with improved aspect ratios in comparison to the acetone/water mixtures primarily used for industrial recrystallization. Further, the inclusion of soluble, non-size-matched polymer additives, at very low concentrations (0.5 wt %/wt), into the solution has a pronounced impact on the crystal habit. While the inclusion of the hydrophilic polymer poly(ethylene glycol) promotes the formation of even longer, thinner needles than those formed by nonadditive routes, the use of hydrophobic poly(propylene glycol) improves the habit from needles toward plate-like crystals. The product materials are analyzed by a combination of microscopy, thermal analysis, and diffraction-based techniques, with the latter enabling rationalization of the habit control via identification of the prominent crystal faces and growth directions with respect to the underlying crystal structure.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Chemistry
Publisher: American Chemical Society
ISSN: 1528-7483
Date of First Compliant Deposit: 23 September 2020
Date of Acceptance: 4 August 2020
Last Modified: 04 Aug 2021 01:30
URI: http://orca.cardiff.ac.uk/id/eprint/135034

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