Amorphous solid (glassy) states are ubiquitous in pharmaceutical products, covering such diverse systems as solid molecular dispersions of drug molecules in a polymeric matrix, freeze-dried proteins imbedded into a sugar matrix, and viral vaccines and gene delivery vectors, which are commonly stored as frozen solutions.<br/>The first part of the presentation covers recent studies on low-temperature mobility and structure of concentrated solutions and glasses of polyhydroxy compounds (PHC) by an array of methods, including thermally stimulated (de)polarization current, terahertz and infrared spectroscopies, and small- and wide-angle neutron scattering (SANS and WANS).  In 70% sorbitol-water mixture, for example, a transition from a state with predominantly vibrational mobility modes to the one with rotational mobility has been observed at approx. 130 K, which is similar to the glass transition temperature (Tg) for low density amorphous ice.  WANS studies of the same system reveal the presence of nanoscaled water clusters surrounded by (and interacting with) sorbitol molecules, thereby relating the low-temperature mobility transition to water clusters.  Furthermore, on the mesoscopic (submicrometer) scale, a significant increase in the SANS signal, and therefore development of pronounced inhomogeneities, has been observed after cooling the amorphous sorbitol-water mixture below its calorimetric Tg (approx. 210 K).  The SANS data reveals the existence of domains with well-defined and sharp interfaces on the submicrometer length scale, probably as a result of the appearance and growth of microscopic voids in the glassy matrix.<br/>In the second part of the presentation, learning from the studies of the model PHC-water systems are applied to discuss practical aspects as related to manufacturing and stability of amorphous pharmaceuticals, as follows: (i) why water-to-ice transformation during freezing of typical pharmaceutical solutions is always incomplete: beyond glass transition; (ii) impact of water on amide hydrolysis in amorphous small molecular weight drugs; (iii) dual role of water in deamidation of proteins: water clusters as proton transfer enablers vs water as a stabilizer of higher-order structure; (iv) role of voids in interfacial destabilization of proteins during freeze-drying and reconstitution.

Local and mesoscopic-scale water structure and inhomogeneity: Implications for freezing and stability of amorphous pharmaceuticals

255th National Meeting (2018)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.