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

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.

Theoretical Calculations of Organic Salts and Their Correlation with Proton Conductivity

“…This spectral difference can be explained using the protonation of the pyridine ring in PVPy that changes the vibrational modes of the pyridine ring and carbonyl group. 37 However, the peak at 1604 cm −1 was unshifted or shifted to the low wavenumber side in PVPySA−AA and PVPySA−DFA. The reaction between acid and PVPy was insufficient because the acidic constant (pK a ) values of AA and DFA are 4.8 and 1.33, respectively, which is not far from the pK a of pyridine (pK a = 5.25).…”

“…Two peaks were observed between 1596 and 1633 cm –1 ; the PVPy base shows a single peak at 1604 cm –1 . This spectral difference can be explained using the protonation of the pyridine ring in PVPy that changes the vibrational modes of the pyridine ring and carbonyl group . However, the peak at 1604 cm –1 was unshifted or shifted to the low wavenumber side in PVPySA–AA and PVPySA–DFA.…”

Innovative Approaches for Drug Discovery: Quantifying Drug Distribution and Response with Raman Imaging

“…For example, Fateixa et al used confocal RS imaging to investigate degradation mechanisms and tablet compositional changes under various storage conditions . Abouselo et al revealed a reliance on salt disproportionation reactions for excipient-influenced microenvironmental pH in situ . Excipients also influence API release, which can be determined by in vitro dissolution profiles.…”

Integrative Salt Selection and Formulation Optimization: Perspectives of Disproportionation and Microenvironmental pH Modulation

“…Among the pH-modulation approaches, adding a pH modifier as an excipient is the most common strategy to achieve pH-independent solubility. There are examples of using enteric polymer or carriers to optimize the release further; ,, however, most of the cases have been the addition of small-molecule acids or bases, particularly organic acids (e.g., citric, succinic, tartaric) − , or alkalizers (e.g., sodium carbonates, magnesium oxide). − ,,, A summary of the physical properties of these frequently used pH modifiers can be found in the literature . The pH modifiers’ effectiveness in controlling microenvironmental pH (pH M ) varies with their acid/base strength (p K a ) and aqueous solubility.…”

“…The selection of excipients is of paramount importance because disproportionation often takes place through an excipient-induced solution-mediated mechanism . Among the excipient properties, its acidity/basicity, ,, aqueous solubility, buffering capacity, ,, structural integrity (amorphous/crystalline, particle size/surface area), ,, and hygroscopicity/water activity , are all important parameters. Numerous studies have covered these aspects, including alternative approaches such as using polymer matrices to minimize API/excipient contacts .…”