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Effect of Excipients on Salt Disproportionation during Dissolution: A Novel Application of In Situ Raman Imaging

Abouselo, Amjad; Rance, Graham A.; Tres, Francesco; Taylor, Lynne S.; Kwokal, Ana; Renou, Ludovic; Scurr, David J.; Burley, Jonathan C.; Aylott, Jonathan W.

Effect of Excipients on Salt Disproportionation during Dissolution: A Novel Application of In Situ Raman Imaging Thumbnail


Authors

Amjad Abouselo

Francesco Tres

Lynne S. Taylor

Ana Kwokal

Ludovic Renou

DAVID SCURR DAVID.SCURR@NOTTINGHAM.AC.UK
Principal Research Fellow



Abstract

We have employed a bespoke setup combining confocal Raman microscopy and an ultraviolet–visible (UV–Vis) spectroscopy flow cell to investigate the effect of excipients on the disproportionation kinetics of Pioglitazone HCl (PioHCl) in tablets during dissolution. Three binary formulations of PioHCl, containing citric acid monohydrate (CA), lactose monohydrate (LM), or magnesium stearate (MgSt), respectively, were used as models to study the influence of excipients’ physicochemical properties on the rate of salt disproportionation kinetics and dissolution performance in different aqueous pH environments. It was found that formulation excipients can induce or prevent salt disproportionation by modulating the microenvironmental pH regardless of the pH of the dissolution media. Incorporating CA in PioHCl tablets preserves the salt form and enhances the dissolution performance of the salt in the acidic medium (pH = 1.2). In contrast, LM and MgSt had a detrimental effect on in vitro drug performance by inducing salt disproportionation in the tablet during dissolution in the same acidic medium. Dissolution in the neutral medium (pH = 6.8) showed rapid formation of the free base upon contact with the dissolution medium. The Raman maps of the cross-sectioned tablets revealed the formation of a shell consisting of the free base around the edge of the tablet. This shell decreased the rate of penetration of the dissolution medium into the tablet, which had significant implications on the release of the API into the surrounding solution, as shown by the UV–vis absorption spectroscopy drug release data. Our findings highlight the utility of the Raman/UV–vis flow cell analytical platform as an advanced analytical technique to investigate the effect of excipients and dissolution media on salt disproportionation in real time. This methodology will be used to enhance our understanding of salt stability studies that may pave the way for more stable multicomponent formulations.

Citation

Abouselo, A., Rance, G. A., Tres, F., Taylor, L. S., Kwokal, A., Renou, L., …Aylott, J. W. (2021). Effect of Excipients on Salt Disproportionation during Dissolution: A Novel Application of In Situ Raman Imaging. Molecular Pharmaceutics, 18(9), 3247-3259. https://doi.org/10.1021/acs.molpharmaceut.1c00119

Journal Article Type Article
Acceptance Date May 24, 2021
Online Publication Date Aug 16, 2021
Publication Date Sep 6, 2021
Deposit Date Jun 25, 2021
Publicly Available Date Aug 16, 2021
Journal Molecular Pharmaceutics
Print ISSN 1543-8384
Electronic ISSN 1543-8392
Publisher American Chemical Society
Peer Reviewed Peer Reviewed
Volume 18
Issue 9
Pages 3247-3259
DOI https://doi.org/10.1021/acs.molpharmaceut.1c00119
Keywords Drug Discovery; Pharmaceutical Science; Molecular Medicine
Public URL https://nottingham-repository.worktribe.com/output/5722686
Publisher URL https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.1c00119