Lu, J., Ormes, J.D., Lowinger, M. et al. (5 more authors) (2017) Impact of Endogenous Bile Salts on the Thermodynamics of Supersaturated Active Pharmaceutical Ingredient Solutions. Crystal Growth & Design, 17 (3). pp. 1264-1275. ISSN 1528-7483
Abstract
A variety of formulation strategies have been developed to mitigate the inadequate aqueous solubility of certain therapeutic agents. Among these, achieving supersaturation in vivo is a promising approach to improve the extent of oral absorption. Because of the thermodynamic instability of supersaturated solutions, inhibitors are needed to kinetically hinder crystallization. In addition to commonly used polymeric additives, bile salts, naturally present in the gastrointestinal tract, have been shown to exhibit crystallization inhibition properties. However, the impact of bile salts on solution thermodynamics is not well understood, although this knowledge is essential in order to explore the mechanism of crystallization inhibition. To better describe solution thermodynamics in the presence of bile salts, a side-by-side diffusion cell was used to evaluate solute flux for solutions of telaprevir in the absence and presence of the six most abundant bile salts in human intestinal fluid at various solute concentrations; flux measurements provide information about the solute thermodynamic activity and hence can provide an improved measurement of supersaturation in complex solutions. Trihydroxy bile salts had minimal impact on solution phase boundaries as well as solute flux, while micellar dihydroxy bile salts solubilized telaprevir leading to reduced solute flux across the membrane. An inconsistency between the concentration-based supersaturation ratio and that based on solute thermodynamic activity (the fundamental driving force for crystallization) was noted, suggesting that the activity-based supersaturation should be determined to better interpret any modification in crystallization kinetics in the presence of these additives. These findings indicate that bile salts are not interchangeable from a thermodynamic perspective and provide a foundation for further studies evaluating the mechanism of crystallization inhibition.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | This document is the Accepted Manuscript version of a Published Work that appeared in final form in Crystal Growth and Design, © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.cgd.6b01664. |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Engineering (Sheffield) > Department of Chemical and Biological Engineering (Sheffield) |
Funding Information: | Funder Grant number ENGINEERING AND PHYSICAL SCIENCE RESEARCH COUNCIL (EPSRC) EP/P006965/1 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 17 May 2017 11:07 |
Last Modified: | 12 Jan 2018 01:39 |
Published Version: | https://doi.org/10.1021/acs.cgd.6b01664 |
Status: | Published |
Publisher: | American Chemical Society |
Refereed: | Yes |
Identification Number: | 10.1021/acs.cgd.6b01664 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:116570 |