Impact of Drug Physicochemical Properties on Lipolysis-Triggered Drug Supersaturation and Precipitation from Lipid-Based Formulations

Molecular Pharmaceutics
Linda C AlskärChristel A S Bergström

Abstract

In this study we investigated lipolysis-triggered supersaturation and precipitation of a set of model compounds formulated in lipid-based formulations (LBFs). The purpose was to explore the relationship between precipitated solid form and inherent physicochemical properties of the drug. Eight drugs were studied after formulation in three LBFs, representing lipid-rich (extensively digestible) to surfactant-rich (less digestible) formulations. In vitro lipolysis of drug-loaded LBFs were conducted, and the amount of dissolved and precipitated drug was quantified. Solid form of the precipitated drug was characterized with polarized light microscopy (PLM) and Raman spectroscopy. A significant solubility increase for the weak bases in the presence of digestion products was observed, in contrast to the neutral and acidic compounds for which the solubility decreased. The fold-increase in solubility was linked to the degree of ionization of the weak bases and thus their attraction to free fatty acids. A high level of supersaturation was needed to cause precipitation. For the weak bases, the dose number indicated that precipitation would not occur during lipolysis; hence, these compounds were not included in further studies. The solid st...Continue Reading

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Citations

May 22, 2020·Pharmaceutical Research·Oliver J Hedge, Christel A S Bergström
Oct 31, 2020·Drug Development and Industrial Pharmacy·Alexandra-Roxana IlieRené Holm
Jan 16, 2021·Journal of Controlled Release : Official Journal of the Controlled Release Society·Estelle J A SuysChristopher J H Porter
Oct 26, 2020·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Yusuke TanakaSatoshi Kasaoka
Dec 10, 2019·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Maria Terezinha FrançaHellen Karine Stulzer

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Methods Mentioned

BETA
differential scanning calorimetry
Precipitation
solubility studies
X-ray

Software Mentioned

ADMET Predictor
Simca
GraphPad Prism
PLS
Excel
DragonX

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