A mechanistic study to identify physically stable amorphous solid dispersion

Madhav Vasanthavada, University of Rhode Island

Abstract

Amorphous solid dispersions are known to improve the oral bioavailability of poorly water-soluble drugs. However, the physical instability of solid dispersions leading to phase separation and subsequent crystallization is limiting their commercial use. Polymers used in solid dispersions have shown to inhibit drug crystallization by either increasing the glass transition temperature (Tg) of the mixture; and/or by interacting with the drug. To effectively inhibit drug crystallization, the polymer has to remain miscible with the drug. Drug crystallization could occur if drug-carrier miscibility is adversely affected by heat or humidity. It is therefore important to understand the drug-carrier miscibility to define strategies for ensuring the physical stability of amorphous solid dispersions. ^ In this study, an approach is presented with which one can determine the “solid solubility”, defined as the amount of drug that remains miscible with the carrier under specified heat and humidity condition. Modulated differential scanning calorimeter (MDSC) was used to determine the solid solubility of trehalose, griseofulvin, and indoprofen, in amorphous polymers like PVP and dextran. The solid dispersions of varying drug content were subjected to accelerated stability conditions and the extent of drug-carrier miscibility was analyzed by monitoring their Tgs. The mechanism of solid solubility and the influence of factors like storage temperature, moisture and the drug-carrier hydrogen bonding on the solid solubility have been examined. Also, the kinetic rate of drug phase separation from the polymer was estimated by fitting the Tg of miscible mixtures, to the first-order rate equation. ^ The effect of surfactants on the drug solid solubility in the polymer was also investigated. To probe into the factors responsible for physical instability of amorphous solid dispersions, the molecular mobility of a model drug-griseofulvin and the polymer-PVP was studied. Isothermal and non-isothermal crystallization studies were conducted on griseofulvin to determine the activation energy for crystallization. Molecular mobility of PVP was studied using thermally stimulated current spectroscopy and the factors influencing the molecular motions were studied. ^

Subject Area

Health Sciences, Pharmacy

Recommended Citation

Madhav Vasanthavada, "A mechanistic study to identify physically stable amorphous solid dispersion" (2004). Dissertations and Master's Theses (Campus Access). Paper AAI3147810.
http://digitalcommons.uri.edu/dissertations/AAI3147810

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