Date of Award

2004

Degree Type

Dissertation

Degree Name

Doctor of Pharmacy (PharmD)

First Advisor

Serpi' Kislalioglu

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 (T g) 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. Solid dispersions that exhibit single Tg, were exposed to accelerated storage conditions and their Tg(s) were monitored periodically. An increase in Tg or the fonnation of multiple Tgs indicated the phase separation of drug from the polymer. The Tg was monitored until a plateau was reached, indicating an equilibrium state and no further phase separation. The solid solubility of drug in the polymer was detennined from the calibration plot of Tg of freshly prepared solid dispersion vs. drug-polymer ratio. The mechanism of solid solubility was elucidated and hydrogen bonding was shown to play a critical role in enhancing the solid solubility. lndoprofen that hydrogen bonds to PVP had solid solubility of l 3%w/w, whereas griseofulvin which had no hydrogen bonding to the polymer crystallized completely from the solid dispersions when stored at accelerated conditions of 40°C and 69% relative humidity. In the case of trehalose and dextran miscible solid dispersions the solid solubility of trehalose seemed to decrease with increasing storage temperatures and moisture levels. The kinetic rate of indoprofen and griseofulvin phase separation from the polymer was estimated by fitting the Tg of miscible mixtures, to the first-order rate equation. The phase separation rate of indoprofen was found to be at least 10 times lower than that of griseofulvin. 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.

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