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

• Published in: Pharmaceutical research Vol. 22; no. 3; pp. 440 - 448
• Main Authors: Vasanthavada, Madhav, Tong, Wei-Qin, Joshi, Yatindra, Kislalioglu, M Serpil
• Format: Journal Article
• Language: English
• Published: United States Springer Nature B.V 01.03.2005
• Subjects: Hot Temperature; Hydrogen Bonding; Pharmaceutical Preparations - chemistry; Pharmaceutical Preparations - metabolism; Phase Transition; Solubility; X-Ray Diffraction - methods
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-004-1882-y

To determine the factors influencing "solid solubility" and phase separation kinetics of drugs from amorphous solid dispersions. Solid dispersions of griseofulvin-poly(vinyl pyrrolidone) (PVP) and indoprofen-PVP were prepared using solvent evaporation technique. Dispersions demonstrating single Tg 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 Tg of solid dispersions. FTIR spectroscopy and XRD were used to characterize drug-polymer interactions and drug crystallinity, respectively. 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 griseofulvin-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. Solid solubility of griseofulvin and indoprofen in PVP is approximately 0% w/w and approximately 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.