Wei Jia1, Phillip D Yawman2, Keyur M Pandya1, Kellie Sluga1, Tania Ng1, Dawen Kou1, Karthik Nagapudi1, Paul E Luner2,3, Aiden Zhu2, Shawn Zhang2, Hao Helen Hou4. 1. Small Molecule Pharmaceutical Sciences, Genentech Inc., 1 DNA Way, South San Francisco, California, 94080, USA. 2. DigiM Solution LLC, 67 South Bedford Street, Suite 400 West, Burlington, Massachusetts, 01803, USA. 3. Triform Sciences LLC, Waterford, Connecticut, 06385, USA. 4. Small Molecule Pharmaceutical Sciences, Genentech Inc., 1 DNA Way, South San Francisco, California, 94080, USA. hou.hao@gene.com.
Abstract
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.
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.
Authors: James C DiNunzio; Chris Brough; Dave A Miller; Robert O Williams; James W McGinity Journal: Eur J Pharm Sci Date: 2010-03-15 Impact factor: 4.384