Based on the recent publication from AAPS PharmSci Tech, this 60-minute webinar will showcase an example of the use of GastroPlus® to assess the risk and pharmacokinetic relevance of different solubility and particle size between crystal forms of a poorly water-soluble antihypertensive drug, for diverse physiological conditions.

The work in the publication 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 is particularly large for chloride buffer 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 1.) under usual fasted and fed gastric conditions, the two polymorphs have similar bioavailability, regardless of the particle size; 2.) at high gastric pH in the fasted state, the bioavailability of form II can be considerably lower than that of form I, unless the particle size is less than 20 micrometers.

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.

Speaker: Professor Gabriel L. B. de Araujo from the University of São Paulo on March 23rd, 2022.