Phase behavior of amorphous molecular dispersions I: Determination of the degree and mechanism of solid solubility.
OBJECTIVE
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 degrees C, 40 degrees C, and 50 degrees C [75% relative humidity (RH)] and 23 degrees 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 (Tg(eq)), whereas Tg1 disappeared. The disappearance of Tg1 was attributed to crystallization of the phase-separated amorphous trehalose. It was observed that Tg(eq) was always less than Tg of pure polymer. The lower Tg(eq) 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 degrees C/75% RH and 23 degrees C/75% RH, respectively, and 10% wt/wt in PVP at 23 degrees 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.
Vasanthavada
Madhav
M
Department of Applied Pharmaceutical Sciences, The University of Rhode Island, Kingston, Rhode Island 02881, USA.
Tong
Wei-Qin
WQ
Joshi
Yatindra
Y
Kislalioglu
M Serpil
MS
D002152:Calorimetry, Differential Scanning; D003460:Crystallization; D003911:Dextrans / Q000737:chemistry; D004355:Drug Stability; D005612:Freeze Drying; D008956:Models, Chemical; D015394:Molecular Structure; D011205:Povidone / Q000737:chemistry; D011208:Powders / Q000737:chemistry*; D013696:Temperature; D013816:Thermodynamics; D014199:Trehalose / Q000737:chemistry; D014867:Water
D003911:Dextrans; D011208:Powders; D014867:Water; D014199:Trehalose; D011205:Povidone