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High-resolution solid-state analysis of multicomponent molecular systems, e.g., pharmaceutical formulations, is a great challenge. Solid-state nuclear magnetic resonance (ssNMR) spectroscopy plays a critical role in the characterization of solid dosage forms due to its capabilities of chemical identification, quantification, and structural elucidation at a molecular level. However, the low NMR sensitivity as well as the high spectral complexity and low drug loading of multicomponent products hinder an in-depth investigation of the active pharmaceutical ingredient (API) at the natural isotopic abundance. Herein, we developed two new three-dimensional (3D) ssNMR methods, including 1H–19F–1H and 19F–19F–1H correlations and successfully applied them to characterize a fluorinated drug molecule, aprepitant, and its commercial nanoparticulate formulation EMEND (Merck & Co, Inc., Kenilworth, NJ, USA). These 1H-detection methods utilize the significantly enhanced sensitivity and resolution of 1H and 19F afforded by 60 kHz ultrafast magic angle spinning (MAS) and enable the analysis of milligram samples. The 3D techniques simultaneously provide homonuclear 1H–1H and 19F–19F, and heteronuclear 1H–19F correlations of the crystalline aprepitant without interferences from other pharmaceutical components in the drug product. Moreover, our results demonstrate that 19F is a highly sensitive spin for probing molecular details of fluorinated drug substances in solid formulations, due to its high isotopic abundance, large gyromagnetic ratio, and absence of signal interference from pharmaceutical excipients, as well as for characterizing structural properties of a broad range of fluorine-containing materials.
High-resolution solid-state analysis of multicomponent molecular systems, e.g., pharmaceutical formulations, is a great challenge. Solid-state nuclear magnetic resonance (ssNMR) spectroscopy plays a critical role in the characterization of solid dosage forms due to its capabilities of chemical identification, quantification, and structural elucidation at a molecular level. However, the low NMR sensitivity as well as the high spectral complexity and low drug loading of multicomponent products hinder an in-depth investigation of the active pharmaceutical ingredient (API) at the natural isotopic abundance. Herein, we developed two new three-dimensional (3D) ssNMR methods, including 1H–19F–1H and 19F–19F–1H correlations and successfully applied them to characterize a fluorinated drug molecule, aprepitant, and its commercial nanoparticulate formulation EMEND (Merck & Co, Inc., Kenilworth, NJ, USA). These 1H-detection methods utilize the significantly enhanced sensitivity and resolution of 1H and 19F afforded by 60 kHz ultrafast magic angle spinning (MAS) and enable the analysis of milligram samples. The 3D techniques simultaneously provide homonuclear 1H–1H and 19F–19F, and heteronuclear 1H–19F correlations of the crystalline aprepitant without interferences from other pharmaceutical components in the drug product. Moreover, our results demonstrate that 19F is a highly sensitive spin for probing molecular details of fluorinated drug substances in solid formulations, due to its high isotopic abundance, large gyromagnetic ratio, and absence of signal interference from pharmaceutical excipients, as well as for characterizing structural properties of a broad range of fluorine-containing materials.
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.
High-temperature exposure during hot melt extrusion processing of amorphous solid dispersions may result in thermal degradation of the drug. Polymer type may influence the extent of degradation, although the underlying mechanisms are poorly understood. In this study, the model compound, ritonavir (T m = 126 °C), undergoes thermal degradation upon high-temperature exposure. The extent of degradation of ritonavir in amorphous solid dispersions (ASDs) formulated with poly(vinylpyrrolidone) (PVP), poly(vinylpyrrolidone) vinyl acetate copolymer (PVP/VA), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and hydroxypropyl methylcellulose (HPMC) following isothermal heating and hot melt extrusion was evaluated, and mechanisms related to molecular mobility and intermolecular interactions were assessed. Liquid chromatography–mass spectrometry (LC–MS/MS) studies were used to determine the degradation products and pathways and ultimately the drug–polymer compatibility. The dominant degradation product of ritonavir was the result of a dehydration reaction, which then catalyzed a series of hydrolysis reactions to generate additional degradation products, some newly reported. This reaction series led to accelerated degradation rates with protic polymers, HPMCAS and HPMC, while ASDs with aprotic polymers, PVP and PVP/VA, had reduced degradation rates. This work has implications for understanding mechanisms of thermal degradation and drug–polymer compatibility with respect to the thermal stability of amorphous solid dispersions.
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