SepPhase Behavior of Amorphous Molecular Dispersions I: Determination of the Degree and Mechanism of Solid Solubility

Phase Behavior of Amorphous Molecular Dispersions I: Determination of the Degree and Mechanism of Solid Solubility
September 2004
Madhav Vasanthavada1; Wei-Qin Tong2; Yatindra Joshi2; M. Serpil Kislalioglu3
1: Department of Applied Pharmaceutical Sciences, The University of Rhode Island, Kingston, Rhode Island 02881, USA 2: Pharmaceutical & Analytical Development, Novartis Pharmaceutical Corporation, East Hanover, New Jersey 07936,
3: Department of Applied Pharmaceutical Sciences, The University of Rhode Island, Kingston, Rhode Island 02881, USA. Email: skis@uri.edu
Pharmaceutical Research, September 2004, vol. 21, no. 9, pp. 1598-1606(9)
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Abstract:
Purpose. To understand the phase behavior and the degree and mechanism of the solid solubility in amorphous molecular dispersions by the use of thermal analysis.
Methods. Amorphous molecular dispersions of trehalose-dextran and trehalose-PVP were prepared by co-lyophilization. The mixtures were exposed to 23?C, 40?C, and 50?C [75% relative humidity (RH)] and 23?C (69% RH) storage conditions, respectively. Thermal analysis was conducted by modulated differential scanning calorimeter (MDSC).
Results. Upon exposure to moisture, two glass transition temperatures (TgS), one for phase-separated amorphous trehalose (Tg1) and the other for polymer-trehalose mixture (Tg2), were observed. With time, Tg2 increased and reached to a plateau (Tgeq), whereas Tg1 disappeared. The disappearance of Tg1 was attributed to crystallization of the phase-separated amorphous trehalose. It was observed that Tgeq was always less than Tg of pure polymer. The lower Tgeq when compared to Tg of pure polymer may be the result of solubility of a fraction of trehalose in the polymers chosen. The miscible fraction of trehalose was estimated to be 12% and 18% wt/wt in dextran at 50?C/75% RH and 23?C/75% RH, respectively, and 10% wt/wt in PVP at 23?C/69% RH.
Conclusions. Mixing behavior of trehalose-dextran and trehalose-PVP dispersions were examined both experimentally and theoretically. A method determining the ?extent of molecular miscibility,? referred to as ?solid solubility,? was developed and mechanistically and thermodynamically analyzed. Solid dispersions prepared at trehalose concentrations below the ?solid solubility limit? were physically stable even under accelerated stability conditions.