| Autor: |
Repin IA; Departamento de Farmácia, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, São Paulo, 05508-000, Brazil., Loebenberg R; Faculty of Pharmacy & Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, T6G 2H7, Canada., DiBella J; Simulations Plus, Inc., 42505 10th Street West, Lancaster, California, 93534, USA., Conceição ACL; Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, 1049-001, Lisboa, Portugal., Minas da Piedade ME; Centro de Química Estrutural, Faculdade de Ciências, Universidade de Lisboa, 1749-016, Lisboa, Portugal. memp@fc.ul.pt., Ferraz HG; Departamento de Farmácia, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, São Paulo, 05508-000, Brazil., Issa MG; Departamento de Farmácia, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, São Paulo, 05508-000, Brazil., Bou-Chacra NA; Departamento de Farmácia, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, São Paulo, 05508-000, Brazil., Ermida CFM; Departamento de Farmácia, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, São Paulo, 05508-000, Brazil., de Araujo GLB; Departamento de Farmácia, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, São Paulo, 05508-000, Brazil. gabriel.araujo@usp.br. |
| Abstrakt: |
This work describes an exploratory experimental and in silico study of the influence of polymorphism, particle size, and physiology on the pharmacokinetics of lercanidipine hydrochloride (LHC). Equilibrium and kinetic solubility studies were performed on LHC forms I and II, as a function of pH and buffer composition. GastroPlus® was used to evaluate the potential effect of solubility differences due to polymorphism, particle size, and physiological conditions, on the drug pharmacokinetics. The results indicated that solubilities of LHC polymorphs are strongly dependent on the composition and pH of the buffer media. The concentration ratio (C I /C II ) is particularly large for chloride buffer (C I /C II = 3.3-3.9) and exhibits a slightly decreasing tendency with the pH increase for all other buffers. Based on solubility alone, a higher bioavailability of form I might be expected. However, exploratory PBPK simulations suggested that (i) under usual fasted (pH 1.3) and fed (pH 4.9) gastric conditions, the two polymorphs have similar bioavailability, regardless of the particle size; (ii) at high gastric pH in the fasted state (e.g., pH 3.0), the bioavailability of form II can be considerably lower than that of form I, unless the particle size is < 20 μm. This study demonstrates the importance of investigating the effect of the buffer nature when evaluating the solubility of ionizable polymorphic substances. It also showcases the benefits of using PBPK simulations, to assess the risk and pharmacokinetic relevance of different solubility and particle size between crystal forms, for diverse physiological conditions. |
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