Mechanistic mass transport analysis of dissolution of weak-base drugs considering the influence of surface pH in formulations with and without acidifying agents
- 1Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida , , ,
- 2Pharmaceutical Research & Development, Formulation & Process Development, F. Hoffmann—La Roche Ltd. , ,
- 3Pharmaceutical Research & Early Development, Roche Innovation Center Basel, F. Hoffmann—La Roche Ltd. , ,
Abstract
At the solid–liquid interface, the dissolution of weakly basic drugs, particularly those exhibiting poor solubility, is highly sensitive to local pH conditions. These compounds frequently show pH-dependent solubility and reduced bioavailability when co-administered with acid-reducing agents, which presents significant difficulties for formulation design and clinical efficacy. Despite advances in physiologically based biopharmaceutics modeling, most existing dissolution modeling frameworks fail to account for microenvironmental pH changes induced by functional excipients such as acidifying or basifying agents. To address this critical gap, we developed a mechanistic mass-transport-based dissolution framework that explicitly quantifies surface pH as a function of excipient diffusion and acid–base equilibria. The model integrates coupled diffusion–reaction kinetics within the diffusion boundary layer, enabling accurate prediction of interfacial pH under both buffered and unbuffered conditions. Building on the classical framework, we numerically captured the impact of monoprotic and diprotic acidifying agents on surface pH. Model validation was performed using entrectinib, a clinically relevant weak base, across formulations with and without acidifying agents, supported by experimental dissolution data generated under different media conditions. The results demonstrate that bulk pH-based modeling is insufficient to capture critical formulation-driven dissolution behavior and establish surface pH as a primary determinant of dissolution kinetics. Overall, this study establishes surface pH modeling as a key advancement for mechanistic dissolution prediction of oral drug products containing functional pH-modifying excipients.
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BibTeX
@article{kowthavarapu2026mechanistic,
title = {{Mechanistic mass transport analysis of dissolution of weak-base drugs considering the influence of surface pH in formulations with and without acidifying agents}},
author = {Venkata Krishna Kowthavarapu and Nitin Bharat Charbe and Tatiana Iakovleva and Cordula Stillhart and Neil John Parrott and Stephan Schmidt and Rodrigo Cristofoletti},
journal = {Frontiers in pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1924679},
url = {https://europepmc.org/article/PMC/PMC13670172},
note = {CC BY},
}
RIS
TY - JOUR
TI - Mechanistic mass transport analysis of dissolution of weak-base drugs considering the influence of surface pH in formulations with and without acidifying agents
AU - Venkata Krishna Kowthavarapu
AU - Nitin Bharat Charbe
AU - Tatiana Iakovleva
AU - Cordula Stillhart
AU - Neil John Parrott
AU - Stephan Schmidt
AU - Rodrigo Cristofoletti
PY - 2026
DA - 2026/10/01
JO - Frontiers in pharmacology
DO - 10.3389/fphar.2026.1924679
UR - https://europepmc.org/article/PMC/PMC13670172
AB - At the solid–liquid interface, the dissolution of weakly basic drugs, particularly those exhibiting poor solubility, is highly sensitive to local pH conditions. These compounds frequently show pH-dependent solubility and reduced bioavailability when co-administered with acid-reducing agents, which presents significant difficulties for formulation design and clinical efficacy. Despite advances in physiologically based biopharmaceutics modeling, most existing dissolution modeling frameworks fail to account for microenvironmental pH changes induced by functional excipients such as acidifying or basifying agents. To address this critical gap, we developed a mechanistic mass-transport-based dissolution framework that explicitly quantifies surface pH as a function of excipient diffusion and acid–base equilibria. The model integrates coupled diffusion–reaction kinetics within the diffusion boundary layer, enabling accurate prediction of interfacial pH under both buffered and unbuffered conditions. Building on the classical framework, we numerically captured the impact of monoprotic and diprotic acidifying agents on surface pH. Model validation was performed using entrectinib, a clinically relevant weak base, across formulations with and without acidifying agents, supported by experimental dissolution data generated under different media conditions. The results demonstrate that bulk pH-based modeling is insufficient to capture critical formulation-driven dissolution behavior and establish surface pH as a primary determinant of dissolution kinetics. Overall, this study establishes surface pH modeling as a key advancement for mechanistic dissolution prediction of oral drug products containing functional pH-modifying excipients.
SN - 1663-9812
ER -