Incorporation of Lipophilic Drugs in Sugar Glasses by Lyophilization using a Mixture of Water and Tertiary Butyl Alcohol as Solvent

Abstract

In this study, a new and robust method was evaluated to prepare physically stable solid dispersions. Trehalose, sucrose, and two inulins having different chain lengths were used as carrier. Diazepam, nifedipine, Δ9-tetrahydrocannabinol, and cyclosporine A were used as model drugs. The sugar was dissolved in water and the drug in tertiary butyl alcohol (TBA). The two solutions were mixed in a 4/6 TBA/water volume ratio and subsequently freeze dried. Diazepam could be incorporated at drug loads up to 63% w/w. DSC measurements showed that, except in some sucrose dispersions, 97–100% of the diazepam was amorphous. In sucrose dispersions with high drug loads, about 10% of the diazepam had crystallised. After 60days of exposure at 20°C and 45% relative humidity (RH), diazepam remained fully amorphous in inulin dispersions, whereas in trehalose and sucrose crystallization of diazepam occurred. The excellent physical stability of inulin containing solid dispersions can be attributed to the high glass transition temperature (Tg) of inulin. For the other drugs similar results were obtained. The residual amount of the low toxic TBA was only 0.1–0.5% w/w after freeze drying and exposure to 45% RH and 20°C. Therefore, residual TBA will not cause any toxicity problems. This study provides a versatile technique, to produce solid dispersions. Inulin glasses are preferred because they provide an excellent physical stability of the incorporated amorphous lipophilic drugs. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association