Optimization of Amorphization Kinetics during Hot Melt Extrusion by Particle Engineering: An Experimental and Computational Study

Abstract

Hot melt extrusion (HME) to prepare amorphous solid dispersions (ASDs) at temperatures below the drug's melting point requires the crystalline drug to dissolve into the molten polymer. This requires an understanding of the drug's solubility in the molten polymer as well as amorphization (crystal dissolution) kinetics. The goal of this study was to identify drug crystal attributes which contribute to rapid amorphization during hot melt extrusion processing to form ASDs. Particle engineering approaches were used to recrystallize bicalutamide with different particle size distributions and defect density. These lots were then used to prepare ASDs by HME to monitor the amorphization kinetics. Particle size had the expected effect on the amorphization rate, and defect density was also observed to accelerate amorphization. A population balance model using dissolution and breakage phenomena was developed to investigate the dynamic evolution of crystal size distribution during a hot melt extrusion process, and parameter estimation was utilized to simulate the experimental HME results. Breakage kinetics were found to dominate the crystal dissolution process, synergistically accelerated by particles with high defect density. The findings have implications for particle engineering of crystals to enable the hot melt extrusion process, as well as improved process modeling through incorporating particle attributes.

Impact of process stress on protein stability in highly-loaded solid protein/PEG formulations from small-scale melt extrusion

“…4 ). Moseson et al (2022) discus the dependence of the residence time during hot melt extrusion and the dissolution rate of drug crystals in the molten polymer. The crystal model drugs showed a significant residual crystallinity for short residence times (2 min.…”

“…The crystal model drugs showed a significant residual crystallinity for short residence times (2 min. ), indicating a low crystal dissolution rate ( Moseson et al, 2022 ). During our TSE experiments, the residence times were < 1 min assuming that the time for dissolving and dissolution rate of protein powder particles in molten PEG 20,000 was extremely small.…”

Impact of Gastric pH Variations on the Release of Amorphous Solid Dispersion Formulations Containing a Weakly Basic Drug and Enteric Polymers

“…Thus, matrix crystallization seems to be an important failure mechanism that occurs during suspension of the ASD in aqueous media, with the extent of surface crystallization varying with pH, polymer, and if the salt or free base form of the drug is present in the ASD. The mass fraction of crystals formed from ASDs during gastric immersion was low, given that crystallization was undetectable by PXRD (Figure ), which is typically considered to have detection limits of about 1–5% crystallinity. − Despite the low amount of crystals observed, they are potentially catastrophic to release performance, when the pH is increased to a value where the polymer becomes soluble.…”

Ultrafast Magic Angle Spinning Solid-State NMR Spectroscopy: Advances in Methodology and Applications

“…The remarkable 1 H and 19 F resolution and sensitivity have significantly facilitated the development of quantitative and multidimensional MAS NMR spectroscopy for molecular investigations of pharmaceuticals. Most recently, 1 H and 19 F spectra acquired under 60 kHz MAS have been utilized to examine potential form changes or crystalline defects of bicalutamide produced from different particle engineering processes . Polenova and co-workers have recently demonstrated the structural characterization of fluorinated drug substances in commercial formulations using UFMAS at 60 to 111 kHz.…”

“…Most recently, 1 H and 19 F spectra acquired under 60 kHz MAS have been utilized to examine potential form changes or crystalline defects of bicalutamide produced from different particle engineering processes. 533 Polenova and co-workers have recently demonstrated the structural characterization of fluorinated drug substances in commercial formulations using UFMAS at 60 to 111 kHz. They show exciting results by analyzing the fluorine moiety which can be acquired in minutes.…”