RESUMO
PURPOSE: The purpose of this work is to evaluate the interrelationship of microstructure, properties, and dissolution performance for amorphous solid dispersions (ASDs) prepared using different methods. METHODS: ASD of GDC-0810 (50% w/w) with HPMC-AS was prepared using methods of spray drying and co-precipitation via resonant acoustic mixing. Microstructure, particulate and bulk powder properties, and dissolution performance were characterized for GDC-0810 ASDs. In addition to application of typical physical characterization tools, we have applied X-Ray Microscopy (XRM) to assess the contribution of microstructure to the characteristics of ASDs and obtain additional quantification and understanding of the drug product intermediates and tablets. RESULTS: Both methods of spray drying and co-precipitation produced single-phase ASDs. Distinct differences in microstructure, particle size distribution, specific surface area, bulk and tapped density, were observed between GDC-0810 spray dried dispersion (SDD) and co-precipitated amorphous dispersion (cPAD) materials. The cPAD powders prepared by the resonant acoustic mixing process demonstrated superior compactibility compared to the SDD, while the compressibility of the ASDs were comparable. Both SDD powder and tablets showed higher in vitro dissolution than those of cPAD powders. XRM calculated total solid external surface area (SA) normalized by calculated total solid volume (SV) shows a strong correlation with micro dissolution data. CONCLUSION: Strong interrelationship of microstructure, physical properties, and dissolution performance was observed for GDC-0810 ASDs. XRM image-based analysis is a powerful tool to assess the contribution of microstructure to the characteristics of ASDs and provide mechanistic understanding of the interrelationship.
Assuntos
Liberação Controlada de Fármacos , Solubilidade , Pós , Composição de Medicamentos/métodos , Comprimidos/químicaRESUMO
The purpose of the study is introduce a two-phase flow model to simulate water penetration into pharmaceutical tablets. This model was built by integrating Darcy's law with the continuity principle, on the premise that water penetration was driven by capillary actions. Notably, this model concerned both the ingress of water (wetting phase) and simultaneous displacement of air (non-wetting phase). Due to the interference of the two fluids, the relative permeability and capillary pressure vary during water penetration. Evolution of these parameters was incorporated in the model. Calibration of the model by water penetration experiments of the microcrystalline cellulose (MCC) tablet yielded an average pore radius of 42 nm. This derived result was corroborated by FIB-SEM analysis revealing the presence of extensive microporosity within MCC particles with an average radius of â¼30 nm. Further validation was achieved through close resemblance between the simulated and experimental water penetration profiles of MCC tablets possessing different porosities. Overall, this study underscored the advantage of the two-phase flow model over single-phase flow models, by capturing the dependence of permeability and capillary pressure on water saturation. Therefore it holds promise for an enhanced description of water penetration into tablets.