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

摘要

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. Forthe weak bases, the dose number indicated that precipitation wouldnot occur during lipolysis; hence, these compounds were not includedin further studies. The solid state analysis proved that danazol andgriseofulvin precipitated in a crystalline form, while niclosamideprecipitated as a hydrate. Felodipine and indomethacin crystals werevisible in the PLM, whereas the Raman spectra showed presenceof amorphous drug, indicating amorphous precipitation that quicklycrystallized. The solid state analysis was combined with literaturedata to allow analysis of the relationship between solid form andthe physicochemical properties of the drug. It was found that lowmolecular weight and high melting temperature increases the probabilityof crystalline precipitation, whereas precipitation in an amorphousform was favored by high molecular weight, low melting temperature,and positive charge.