Rumondor A, Marsac P, Stanford L, Taylor LS
Phase Behavior of Poly(vinylpyrrolidone) Containing Amorphous Solid Dispersions in the Presence of Moisture. [JOURNAL ARTICLE]
Mol Pharm 2009 Jul 27.
The objective of this study was to investigate the phase behavior of amorphous solid dispersions comprised of a hydrophobic drug and a hydrophilic polymer (poly(vinylpyrrolidone) (PVP)) following exposure to elevated relative humidity. Infrared spectroscopy, differential scanning calorimetry (DSC) and moisture sorption analysis were performed on five model systems (nifedipine-PVP, indomethacin-PVP, ketoprofen-PVP, droperidol-PVP, and pimozide-PVP). Complete miscibility between the drug and the polymer immediately after solid dispersion formation was confirmed by the presence of specific drug-polymer interactions and a single glass transition (Tg) event. Following storage at elevated relative humidity (75-94% RH), nifedipine-PVP, pimozide-PVP, and droperidol-PVP dispersions formed drug-rich and polymer-rich amorphous phases prior to crystallization of the drug, while indomethacin-PVP and ketoprofen-PVP dispersions did not. Drug crystallization in systems exhibiting amorphous-amorphous phase separation commenced much faster (<6 days at 94% RH) as compared to the systems that remained miscible (>46 days at 94% RH). Evidence of moisture-induced amorphous-amorphous phase separation was observed following storage as low as 54% RH for the pimozide-PVP system. In conclusion, when an amorphous molecular level solid dispersion containing a hydrophobic drug and hydrophilic polymer is subjected to moisture, it appears that drug crystallization can occur via one of two routes: crystallization from the plasticized one phase solid dispersion, or crystallization from a plasticized drug-rich amorphous phase in a two-phase solid dispersion. In the former case, the polymer is still present in the same phase of the drug and can inhibit crystallization to greater extent than the latter scenario, where the polymer concentration in the drug phase is reduced as a result of the phase separation. The strength of drug-polymer interactions appear to be important in influencing the phase behavior.
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