Application of Melt Extrusion in the Development of a Physically and Chemically Stable High-Energy Amorphous Solid Dispersion of a Poorly Water-Soluble Drug

• Published in: Molecular pharmaceutics Vol. 5; no. 6; pp. 994 - 1002
• Main Authors: Lakshman, Jay P, Cao, Yu, Kowalski, James, Serajuddin, Abu T. M
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01.12.2008
• Subjects: Animals; Biological Availability; Capsules; Chemical Phenomena; Chemistry, Pharmaceutical - methods; Cross-Over Studies; Dogs; Drug Stability; Hot Temperature; Hydrogen-Ion Concentration; Molecular Structure; Molecular Weight; Pharmaceutical Preparations - blood; Pharmaceutical Preparations - chemistry; Pharmaceutical Solutions - chemistry; Pharmaceutical Solutions - pharmacokinetics; Solubility; Water - chemistry; high-energy solid; bioavailability; dissolution; melt extrusion; Amorphous solid; poorly soluble drug; stability
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/mp8001073

Formulation of active pharmaceutical ingredients (API) in high-energy amorphous forms is a common strategy to enhance solubility, dissolution rate and, consequently, oral bioavailability of poorly water-soluble drugs. Amorphous APIs are, however, susceptible to recrystallization and, therefore, there is a need to physically stabilize them as solid dispersions in polymeric carriers. Hot melt extrusion has in recent years gained wide acceptance as a method of choice for the preparation of solid dispersions. There is a potential that the API, the polymer or both may degrade if excessively high temperature is needed in the melt extrusion process, especially when the melting point of the API is high. This report details a novel method where the API was first converted to an amorphous form by solvent evaporation and then melt-extruded with a suitable polymer at a drug load of at least 20% w/w. By this means, melt extrusion could be performed much below the melting temperature of the drug substance. Since the glass transition temperature of the amorphous drug was lower than that of the polymer used, the drug substance itself served as the plasticizer for the polymer. The addition of surfactants in the matrix enhanced dispersion and subsequent dissolution of the drug in aqueous media. The amorphous melt extrusion formulations showed higher bioavailability than formulations containing the crystalline API. There was no conversion of amorphous solid to its crystalline form during accelerated stability testing of dosage forms.