Hot-melt Extrusion Promotes Dissolution, Extends “Spring-Parachute” Process and Inhibits Crystallization in Supersaturating Microparticle Systems

Despite the potential advantages of amorphism-induced supersaturation, the merit of new amorphization formation methods on the properties of the amorphous drug including the stability of the amorphous state, dissolution/solubility, supersaturation, and “spring-parachute” process is still poorly understood, particularly for certain amorphous supersaturating drug delivery systems (aSDDS). The present work aimed to explore the detailed merit of current attractive amorphization manufacturing methods (i. g., hot-melt extrusion (HME) technique) on the property improvement of aSDDS in form of amorphous solid dispersion microparticles by employing a model BCS II drug nitrendipine and a polyvinylpyrrolidone-based model polymer copovidone. Many aSDDS systems were developed by various methods, and their physicochemical properties were characterized by SEM, PXRD and DSC. HME-triggered amorphization induced superior supersaturation by the observation of the highest dissolution and solubility. HME induced the optimal supersaturation duration by the observed greatest extension of “spring-parachute” process (e. g., maximum AUCspring-parachute). HME technique is comparable with other techniques for the stabilization of amorphous state during storage. All aSDDS systems by HME and other methods showed improved long-term stability of the amorphous state in comparison to the pure amorphous drug. Fourier transformation infrared spectroscopy, Noyes-Whitney equation, nucleation theory and Gibbs free energy of transfer (ΔGto) were used to analyze the underlying mechanisms. Molecular mechanism studies indicated that HME caused a stronger crystallization inhibition effect in the aSDDS systems than other methods, but molecular interaction is not a dominant mechanism for property enhancement caused by HME. For the mechanism associated with the polymer itself (PVPVA64), it could inhibit the drug recrystallization, solubilize the drug spontaneously and cause the improved molecular interactions in all aSDDS systems. This study provided a deep insight into detailed advantage of HME-triggered supersaturation/amorphization and facilitated the applications of the technique both in the field of particuology and in pharmaceutical industry.