Exploratory Study on Lercanidipine Hydrochloride Polymorphism: pH-Dependent Solubility Behavior and Simulation of its Impact on Pharmacokinetics

Author(s)

Repin, Ilia Alekseevich ^[1] ; Loebenberg, Raimar ^[2] ; DiBella, John ^[3] ; Conceicao, Antonio C. L. ^[4] ; Minas da Piedade, Manuel E. ^[5] ; Ferraz, Humberto G. ^[1] ; Issa, Michele G. ^[1] ; Bou-Chacra, Nadia A. ^[1] ; Ermida, Catharine F. M. ^[1] ; de Araujo, Gabriel L. B. ^[1]

Affiliation

^[1] Univ Sao Paulo, Fac Ciencias Farmaceut, Dept Farm, BR-05508000 Sao Paulo, SP - Brazil

^[2] Univ Alberta, Fac Pharm & Pharmaceut Sci, Edmonton, AB T6G 2H7 - Canada

^[3] Simulat Plus Inc, 42505 10th St West, Lancaster, CA 93534 - USA

^[4] Univ Lisbon, Inst Super Tecn, Ctr Quim Estrutural, P-1049001 Lisbon - Portugal

^[5] Univ Lisbon, Fac Ciencias, Ctr Quim Estrutural, P-1749016 Lisbon - Portugal

• Document type: Journal article
• Source: AAPS PHARMSCITECH; v. 22, n. 2 FEB 21 2021.
• Web of Science Citations: 0

Abstract

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 (R) 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 mu m. 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. (AU)

• FAPESP's process: 15/05685-7 - Crystallization and polymorphism of Flubendazole and other ill-characterized drugs
• Grantee: Gabriel Lima Barros de Araujo
• Support Opportunities: Regular Research Grants