posted on 2021-08-17, 00:03authored byAmjad Abouselo, Graham A. Rance, Francesco Tres, Lynne S. Taylor, Ana Kwokal, Ludovic Renou, David J. Scurr, Jonathan C. Burley, Jonathan W. Aylott
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.