Phase behavior of amorphous molecular dispersions - II: Role of hydrogen bonding in solid solubility and phase separation kinetics

Purpose. To determine the factors influencing "solid solubility" and phase separation kinetics of drugs from amorphous solid dispersions. Methods. Solid dispersions of griseofulvin-poly(vinyl pyrrolidone) (PVP) and indoprofen-PVP were prepared using solvent evaporation technique. Dispersions demonstrating single T-g were exposed to 40 degrees C/69% RH for 90 days. Drug solid solubility in the polymer and phase separation rates were determined from changes in T. of solid dispersions. FTIR spectroscopy and XRD were used to characterize drug-polymer interactions and drug crystallinity, respectively. Results. Freshly prepared solid dispersion of up to 30% w/w griseofulvin and indoprofen were molecularly miscible with PVP. Hydrogen bonding was evident in indoprofen-PVP, but not in griscofulvin-PVP dispersions. When exposed to 40 degrees C/69% RH, griseofulvin phase separated completely, whereas the solid solubility of indoprofen was determined as 13% w/w. The first-order rate constants of phase separation for 10%. 20%, and 30% w/w griseofulvin dispersions were estimated as 4.66, 5.19, and 12.50 (x10(2)) [day(-1)], and those of 20% and 30% w/w indoprofen dispersions were 0.62 and 1.25 (x10(2)) [day(-1)], respectively. Conclusions. Solid solubility of griseofulvin and indoprofen in PVP is -0% w/w and similar to 13% w/w, respectively. Drug-polymer hydrogen bonding in indoprofen-PVP dispersions favors solid solubility. Phase separation rate of drug from the solid dispersions depends on the initial drug content and the nature of drug-polymer interactions.