Prediction of the Synergistic Glass Transition Temperature of Coamorphous Molecular Glasses Using Activity Coefficient Models.

The glass transition temperature (Tg) of a binary miscible mixture of molecular glasses, termed a coamorphous glass, is often synergistically increased over that expected for an athermal mixture due to the strong interactions between the two components. This synergistic interaction is particularly important for the formulation of coamorphous pharmaceuticals since the molecular interactions and resulting Tg strongly impact stability against crystallization, dissolution kinetics, and bioavailability. Current models that describe the composition dependence of Tg for binary systems, including the Gordon-Taylor, Fox, Kwei, and Braun-Kovacs equations, fail to describe the behavior of coamorphous pharmaceuticals using parameters consistent with experimental ΔCP and Δα. Here, we develop a robust thermodynamic approach extending the Couchman and Karasz method through the use of activity coefficient models, including the two-parameter Margules, non-random-two-liquid (NRTL), and three-suffix Redlich-Kister models. We find that the models, using experimental values of ΔCP and fitting parameters related to the binary interactions, successfully describe observed synergistic elevations and inflections in the Tg versus composition response of coamorphous pharmaceuticals. Moreover, the predictions from the NRTL model are improved when the association-NRTL version of that model is used. Results are reported and discussed for four different coamorphous systems: indomethacin-glibenclamide, indomethacin-arginine, acetaminophen-indomethacin, and fenretinide-cholic acid.

The glass transition and enthalpy recovery of a single polystyrene ultrathin film using Flash DSC.

The kinetics of the glass transition are measured for a single polystyrene ultrathin film of 20 nm thickness using Flash differential scanning calorimetry (DSC). Tg is measured over a range of cooling rates from 0.1 to 1000 K/s and is depressed compared to the bulk. The depression decreases with increasing cooling rate, from 12 K lower than the bulk at 0.1 K/s to no significant change at 1000 K/s. Isothermal enthalpy recovery measurements are performed from 50 to 115 °C, and from these experiments, the temperature dependence of the induction time along the glass line is obtained, as well as the temperature dependence of the time scale required to reach equilibrium, providing a measure of the shortest effective glassy relaxation time and the longest effective equilibrium relaxation time, respectively. The induction time for the ultrathin film is found to be similar to the bulk at all temperatures presumably because the Tg values are the same due to the use of a cooling rate of 1000 K/s prior to the enthalpy recovery measurements. On the other hand, the times required to reach equilibrium for the ultrathin film and bulk are similar at 100 °C, and considerably shorter for the ultrathin film at 90 °C, consistent with faster dynamics under nanoconfinement at low temperatures. The magnitude of the "Tg depression" is smaller when using the equilibrium relaxation time from the structural recovery experiment as a measure of the dynamics than when measuring Tg after a cooling experiment. A relaxation map is developed to summarize the results.

Crystallization and vitrification of a cyanurate trimer in nanopores.

The effects of nanopore confinement on the crystallization and vitrification of a low molecular weight organic material, tris(4-cumylphenol)-1,3,5-triazine, are investigated using differential scanning calorimetry. The material shows cold crystallization and subsequent melting in the bulk state. Under the nanoconfinement of controlled pore glasses (CPG), cold crystallization and melting shift to lower temperatures. Crystallization kinetics are hindered in nanoconfinement, and no crystallization occurs in 13 nm diameter pores over the course of a week. Using a traditional Avrami analysis, the restricted crystallization under nanopore confinement is quantified; for crystallization at 80 °C, the Avrami exponent decreases with decreasing pore size and the overall crystallization rate is approximately 30 times slower for material confined in 50 nm diameter pores than the bulk. When compared at the temperature at which the crystallization rate is a maximum, the Avrami exponent is higher in nanoconfined samples and the crystallization rate is approximately 10 times slower for material confined in 50 nm diameter pores. Under CPG nanoconfinement, the glass transition temperature also decreases and shows two values; interestingly, the T(g) values further decrease with increasing crystallinity.

Kinetic study of trimerization of monocyanate ester in nanopores.

A kinetic study of the trimerization of monocyanate ester both in the bulk and in the nanoconfinement of controlled pore glass is performed using differential scanning calorimetry. Both isothermal and dynamic experiments are analyzed. Although the activation energy for the reaction is the same within experimental error for the bulk and nanoconfined samples (approximately 21-23 kcal/mol), the reaction is accelerated under nanoconfinement by approximately 50 times in 13 nm pores compared with bulk.

Trimerization of monocyanate ester in nanopores.

The effects of nanoconfinement on the reaction kinetics and properties of a monocyanate ester and the resulting cyanurate trimer are studied using differential scanning calorimetry (DSC). On the basis of both dynamic heating scans and isothermal reaction studies, the reaction rate is found to increase with decreasing nanopore size without a change in reaction mechanism. Both the monocyanate ester reactant and cyanurate product show reduced glass transition temperatures (T(g)s) as compared to the bulk; the T(g) depression increases with conversion and is more pronounced for the fully reacted product, suggesting that molecular stiffness influences the magnitude of nanoconfinement effects. Our results are consistent with the accelerated reaction and the T(g) depression found previously for the nanoconfined difunctional cyanate ester, supporting the supposition that intracyclization is not the origin of these effects.