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

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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® 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 (CI/CII) is particularly large for chloride buffer (CI/CII = 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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Abbreviations

API:

Active pharmaceutical ingredient

AUC0→t :

The area under the concentration-time curve from zero up to the last time point

BCS:

Biopharmaceutics Classification System

C l :

Drug concentration in the lumen compartment

C max :

The maximum (or peak) serum concentration

C p :

Plasma concentration

C s :

Solubility in the lumen compartment

D W :

Diffusion coefficient

h :

Diffusion layer thickness

I :

Ionic strength

IR:

Immediate-release

k 12 and k 21 :

Distribution rate constants

LHC:

Lercanidipine hydrochloride

M d :

Dissolved amount of drug

M u :

Undissolved amount of drug

ρ :

Density

P app :

apparent permeability

PBPK:

Physiologically based pharmacokinetic

PE:

Prediction error

P eff :

Effective permeability

PSA:

Particle sensitivity analysis

s :

Shape factor

SR:

Bile salt solubilization ratio

r t :

Spherical particle radius

t max :

The time to reach Cmax

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Acknowledgments

The authors gratefully acknowledge Simulation Plus, Inc. (Lancaster, CA, USA) for providing the software license and Conselho Nacional de Desenvolvimento Científico e Tecnológico-CNPq (scholarship # 132717/2017-4) and São Paulo Research Foundation (FAPESP; Grant #2015/05685-7).

Funding

MEMP received financial support from Fundação para a Ciência e a Tecnologia (FCT), Portugal, through Projects PTDC/QUI-OUT/28401/2017 (LISBOA-01-0145-FEDER-028401) and UID/MULTI/00612/2013.

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Authors and Affiliations

  1. Departamento de Farmácia, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, São Paulo, 05508-000, Brazil

    Ilia Alekseevich Repin, Humberto G. Ferraz, Michele G. Issa, Nadia A. Bou-Chacra, Catharine F. M. Ermida & Gabriel L. B. de Araujo

  2. Faculty of Pharmacy & Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, T6G 2H7, Canada

    Raimar Loebenberg

  3. Simulations Plus, Inc., 42505 10th Street West, Lancaster, California, 93534, USA

    John DiBella

  4. Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, 1049-001, Lisboa, Portugal

    António C. L. Conceição

  5. Centro de Química Estrutural, Faculdade de Ciências, Universidade de Lisboa, 1749-016, Lisboa, Portugal

    Manuel E. Minas da Piedade

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  1. Ilia Alekseevich Repin
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  2. Raimar Loebenberg
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  8. Nadia A. Bou-Chacra
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Correspondence to Manuel E. Minas da Piedade or Gabriel L. B. de Araujo.

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Repin, I.A., Loebenberg, R., DiBella, J. et al. Exploratory Study on Lercanidipine Hydrochloride Polymorphism: pH-Dependent Solubility Behavior and Simulation of its Impact on Pharmacokinetics. AAPS PharmSciTech 22, 54 (2021). https://doi.org/10.1208/s12249-021-01923-0

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