Increasing the Ambient Pressure Solubility by Forming a Glass at High Pressure and Its Thermodynamics, a Much Sought-After Pharmaceutical Advantage.

With the objective of increasing the bioavailability of poorly soluble curative compounds, we describe a thermodynamics-based method for increasing their solubility, σ. It requires forming their pressure-densified glassy (PDG) state by supercooling the melt under a high pressure to form glass, depressurizing, and recovering the glass at a low temperature. First, we formally show that the excess free energy of PDG is higher at ambient pressure than that of a glass (normally) formed by supercooling the melt at ambient pressure (NG), and therefore its σ will be higher. For a given compound, σ would increase with the pressure under which the liquid is cooled to form PDG and also with increase in the cooling rate. Second, we propose that this increase may be determined by using differential scanning calorimetry heating scans and, more accurately and directly, by vapor pressure measurement. Analysis of calorimetry data of poly(styrene) shows that the magnitude of increase in σ is considerable and is expected to be much higher for curative compounds. Since σ is related to vapor pressure through the free energy change, and to the dissolution rate, Γ, the PDG state a compound would not only sublimate rapidly but also dissolve rapidly. We discuss the stability of PDG relative to NG against structural relaxation and crystallization and, hence, of their bioavailability with time.