(504e) Glass Transition Temperatures of CO2/Pharmaceutical Excipient Systems

Recently, up to 40% of new drug candidates and drugs currently on the market are poorly water-soluble drugs. Solid dispersion (SD) is a method to improve the drug solubility and is defined as the dispersion of one or more active pharmaceutical ingredients in inert carriers such as hydrosoluble polymers. Melting method is the most common procedure for the preparation of the SDs, in which the drug and carrier are mixed in a molten state. However, this method needs high temperature condition and there is possibility that the drug or carrier may be thermally degraded. To overcome this problem, application of compressed carbon dioxide (CO2) might be utilized. The compressed CO2 is quite soluble in polymers at moderate pressure, leading to the depression of the melting and glass transition temperatures (Tg). Therefore, by the use of the compressed CO2, melting method can be performed at lower temperatures. Thus, it is very important to comprehend the Tg depression behavior of pharmaceutical excipients.

In this study, Tg depression of CO2/poly(vinyl acetate) (PVAc), CO2/poly(vinyl pyrrolidone) K30 (PVP K30), and CO2/kollidon VA64 (VA64) were measured. VA64 is a copolymer of VAc and VP (PVP:PVAc=6:4) and used for the formulation of the SD as a hydrosoluble polymer. The Tg measurements were carried out visually at constant temperature with varying the CO2 pressure. The obtained results were correlated with the Sanchez-Lacombe equation of state (SL-EOS) with the Gibbs-DiMarzio criterion, which states that the entropy of a mixture is zero at the glass transition point. In addition, the prediction of Tg in the CO2/VA64 system were also examined in order to establish the prediction model of CO2/copolymer systems.

In the CO2/VA64, CO2/PVAc and CO2/PVP K30 systems, Tg of all polymers indicated retrograde vitrification phenomenon which shows maximum glass transition pressure with respect to the temperature. Therefore, it is useful for the SD preparation process in low temperature region because the pressure required for the glass transition is low.

The obtained results of CO2/PVAc and CO2/PVP K30 systems were correlated fairly well with using SL-EOS with Gibbs-DiMarzio criterion, and the binary interaction parameter kij for these systems were determined.

Tg of the CO2/VA64 system were estimated from the SL-EOS with the kij of CO2/PVAc and CO2/PVP K30, using the ternary mixing rule and the copolymer mixing rule. Estimated results were compared with the experimental results of the CO2/VA64 system. Copolymer mixing rule gave a good agreement with the experimental values. Ternary mixing rule could not predict Tg of the CO2/VA64 system.