Evaluation of Drug-Polymer and Drug-Drug Interaction in Cellulosic Multi-Drug Delivery Matrices.

Abstract

Multi-drug delivery systems have gained increasing interest from the pharmaceutical industry. Alongside this is the interest in amorphous solid dispersions as an approach to achieve effective oral delivery of compounds with solubility-limited bioavailability. Despite this, there is limited information regarding predicting the behavior of two or more drugs (in amorphous forms) in a polymeric carrier and whether molecular interactions between the compounds, between each compound, and if the polymer have any effect on the physical properties of the system. This work studies the interaction between model drug combinations (two of ibuprofen, malonic acid, flurbiprofen, or naproxen) dispersed in a polymeric matrix of hypromellose acetate succinate (HPMCAS) using a solvent evaporation technique. Hildebrand and Hansen calculations were used to predict the miscibility of compounds as long as the difference in their solubility parameter values was not greater than 7 MPa^1/2. It was observed that the selected APIs (malonic acid, ibuprofen, naproxen, and flurbiprofen) were miscible within the formed polymeric matrix. Adding the API caused depression in the Tg of the polymer to certain concentrations (17%, 23%, 13%) for polymeric matrices loaded with malonic acid, ibuprofen, and naproxen, respectively. Above this, large crystals started to form, and phase separation was seen. Adding two APIs to the same matrix resulted in reducing the saturation concentration of one of the APIs. A trend was observed and linked to Hildebrand and Hansen solubility parameters (HSP).