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Issue 32, 2017
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Compositional effect of complex biorelevant media on the crystallization kinetics of an active pharmaceutical ingredient

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Abstract

Bile salts are endogenous surfactants present in the human gastrointestinal tract in the form of mixed micelles that also contain phospholipids. Due to the inevitable encounter of oral drug formulations with bile salts, it is important to understand the impact of bile salts on the crystallization tendency of poorly soluble compounds that form supersaturated solutions in vivo in order to maximize oral drug absorption. Although there has been an increasing number of studies focusing on the role of individual bile salts on drug crystallization, the effects of mixed micelles and biorelevant media composition on crystallization kinetics have only been studied to a limited extent. In this study, we evaluated the ability of binary and ternary bile salt combinations to maintain supersaturated aqueous solutions of telaprevir. Crystallization kinetics were also compared in more complex media that also contained the phospholipid, lecithin. These included fasted state simulated intestinal fluid (FaSSIF) (a widely used medium for formulation testing which contains a single bile salt, sodium taurocholate), and media that contained several endogenous bile salts. Finally, the combined effects of a polymer, hydroxypropyl methyl cellulose acetate succinate, and the testing media on crystallization kinetics were evaluated to provide insights into supersaturation formulation design. Solution bile salt composition was found to significantly influence crystallization kinetics. However, the presence of the polymer increased induction times sufficiently that differences between media were minimized. This study suggests that when evaluating the crystallization kinetics of systems with a propensity to undergo supersaturation in vivo, attention should be paid to selecting biorelevant media.

Graphical abstract: Compositional effect of complex biorelevant media on the crystallization kinetics of an active pharmaceutical ingredient

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Publication details

The article was received on 16 Jun 2017, accepted on 21 Jul 2017 and first published on 21 Jul 2017


Article type: Paper
DOI: 10.1039/C7CE01128H
Citation: CrystEngComm, 2017,19, 4797-4806
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    Compositional effect of complex biorelevant media on the crystallization kinetics of an active pharmaceutical ingredient

    J. Lu, J. D. Ormes, M. Lowinger, A. K. P. Mann, W. Xu, S. Patel, J. D. Litster and L. S. Taylor, CrystEngComm, 2017, 19, 4797
    DOI: 10.1039/C7CE01128H

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