Using a systematic and quantitative approach to generate new insights into drug loading of PLGA nanoparticles using nanoprecipitation

Abstract

The synthesis of drug-loaded PLGA nanoparticles through nanoprecipitation in solvent/antisolvent mixtures is well reported but lacks clarity in explaining drug loading mechanisms and the prediction of efficiency of drug entrapment. Various methods using physical parameters such as log P and solid-state drug-polymer solubility aim to predict the intensity of drug–polymer interactions but lack precision. In particular, the zero-enthalpy method for drug/polymer solubility may be intrinsically inaccurate, as we demonstrate. Conventional measurement of loading capacity (LC), expressed in weight ratios, can be misleading for comparing different drugs and we stress the importance of using molar units. This research aims to provide new insights and critically evaluate the established methodologies for drug loading of PLGA nanoparticles. The study employs four model drugs with varying solubilities in solvent/antisolvent mixtures, log P values, and solid-state solubility in PLGA: ketoprofen (KPN), indomethacin (IND), sorafenib (SFN), and clofazimine (CFZ). This study highlights that drug loading efficiency is primarily influenced by the drug's solubilities within the solvent system. We emphasise that both kinetic and thermodynamic factors play a role in the behaviour of the system by considering the changes in drug solubility during mixing. The study introduces a pseudo-constant K* to characterise drug–polymer interactions, with CFZ and SFN showing the highest K* values. Interestingly, while IND and KPN have lower K* values, they achieve higher loading capacities due to their greater solubilities, indicating the key role of solubility in determining LC.