MIXING BEHAVIOR OF COLYOPHILIZED BINARY-SYSTEMS

The purpose of this study was to investigate the factors which govern the mixing of amorphous sucrose with trehalose, poly(vinylpyrrolidone) (PVP), dextran, and poly(vinylpyrrolidone-co-vinyl acetate) (PVP/VA). These materials were chosen as model systems to represent multicompon ent freeze-dried pharmaceutical preparations. Mixtures were prepared b y colyophilization of the components from aqueous solutions. The glass transition temperatures (T-g) of these mixtures were measured using d ifferential scanning calorimetry (DSC) and were compared to prediction s based on simple mixing rules. FT-Raman spectroscopy was used to prob e selected mixtures for evidence of molecular interactions between com ponents. Colyophilized mixtures were confirmed to be amorphous by X-ra y powder diffraction. The T-g values of the various mixtures generally were lower than values predicted from free volume and thermodynamic m odels, indicating that mixing is not ideal. The FT-Raman spectra of co lyophilized sucrose-PVP and sucrose-PVP/VA mixtures provided evidence for interaction between the components through hydrogen bonding. Hydro gen bonds formed between components in colyophilized sucrose-additive mixtures are formed at the expense of hydrogen bonds within sucrose an d in some cases within the additive. A thermodynamic analysis of these mixtures indicates that mixing is endothermic, which is consistent wi th a net loss in the degree of hydrogen bonding on mixing. There is al so a positive excess entropy of mixing which accompanies the net loss in hydrogen bonds. Despite this gain in excess entropy, the excess fre e energy of mixing is positive, consistent with the observed deviation s in T-g from values predicted using models which assume ideal mixing.