On the Usefulness of Two Small-Scale In Vitro Setups in the Evaluation of Luminal Precipitation of Lipophilic Weak Bases in Early Formulation Development.

Patrick J O’Dwyer,Christos Reppas,Georgios Imanidis,Karl J Box

doi:10.3390/pharmaceutics12030272

Abstract

A small-scale biphasic dissolution setup and a small-scale dissolution-permeation (D-P) setup were evaluated for their usefulness in simulating the luminal precipitation of three lipophilic weak bases—dipyridamole, ketoconazole and itraconazole. The transition from the gastric to intestinal environment was incorporated into both experimental procedures. Emulsification during the biphasic dissolution experiments had a minimal impact on the data, when appropriate risk mitigation steps were incorporated. Precipitation parameters estimated from the in vitro data were inputted into the Simcyp® physiologically based pharmacokinetic (PBPK) modelling software and simulated human plasma profiles were compared with previously published pharmacokinetic data. Average Cmax and AUC values estimated using experimentally derived precipitation parameters from the biphasic experiments deviated from corresponding published actual values less than values estimated using the default simulator parameters for precipitation. The slow rate of transport through the biomimetic membrane in the D-P setup limited its usefulness in forecasting the rates of in vivo precipitation used in the modelling of average plasma profiles.

Highlights

Basic drugs usually have no solubility issues in the acidic environment of the stomach
The surface tension changed from 47.61 ± 1.51 mN/m (n = 3, ± SD) prior to the addition estimated from the plasma profiles simulated using the default values for precipitation rate constant (PRC) and Critical Supersaturation Ratio (CSR) in Simcyp software (4 h−1 and 10, respectively) and using models in which no in vivo precipitation was simulated
After confirming that mixing of the organic layer with Level II FaSSIF components has minimal effect, if any, this study showed that biphasic experiments are useful for estimating PRC values of dipyridamole and ketoconazole

Summary

Introduction

Basic drugs usually have no solubility issues in the acidic environment of the stomach. Due to the increased pH in the small intestine, concentrations (especially of lipophilic weak bases) arriving in the small intestine could supersaturate and/or precipitate in the contents of the small intestine and impact (at least early) drug exposure. One limitation of many relevant methodologies, especially of the so-called small-scale in vitro methodologies which are used early in the drug development process when available amounts of the new active pharmaceutical ingredient (API) are limited, is their inadequate validation with human data. Another issue with many of the in vitro methodologies is the lack of simulation of drug disappearance from bulk luminal contents, due to the absorption process. In many situations, overestimation of precipitation has been reported [1]

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