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  • Title: Mixing behavior of colyophilized binary systems.
    Author: Shamblin SL, Taylor LS, Zografi G.
    Journal: J Pharm Sci; 1998 Jun; 87(6):694-701. PubMed ID: 9607945.
    Abstract:
    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 multicomponent freeze-dried pharmaceutical preparations. Mixtures were prepared by colyophilization of the components from aqueous solutions. The glass transition temperatures (Tg) of these mixtures were measured using differential scanning calorimetry (DSC) and were compared to predictions based on simple mixing rules. FT-Raman spectroscopy was used to probe selected mixtures for evidence of molecular interactions between components. Colyophilized mixtures were confirmed to be amorphous by X-ray powder diffraction. The Tg values of the various mixtures generally were lower than values predicted from free volume and thermodynamic models, indicating that mixing is not ideal. The FT-Raman spectra of colyophilized sucrose-PVP and sucrose-PVP/VA mixtures provided evidence for interaction between the components through hydrogen bonding. Hydrogen bonds formed between components in colyophilized sucrose-additive mixtures are formed at the expense of hydrogen bonds within sucrose and in some cases within the additive. A thermodynamic analysis of these mixtures indicates that mixing is endothermic, which is consistent with a net loss in the degree of hydrogen bonding on mixing. There is also a positive excess entropy of mixing which accompanies the net loss in hydrogen bonds. Despite this gain in excess entropy, the excess free energy of mixing is positive, consistent with the observed deviations in Tg from values predicted using models which assume ideal mixing.
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