Rapid, practical and predictive excipient compatibility screening using isothermal microcalorimetry

Conditions for conducting excipient compatibility studies via isothermal mi crocalorimetry were explored using model reactions. The resulting recommend ed procedure for rapid and practical screening consisted of using binary mi xtures (100 mg of each component), the addition of 20% (w/w) water, and mon itoring the mixture at 50 degreesC for 3 days using an isothermal microcalo rimeter. The correlation between calorimetric excipient compatibility resul ts and formulation stability was investigated for two developmental drugs. A comparison of calorimetric results to actual formulation stability sugges ted that it was possible to predict relative stability within functional cl asses. However, caution should be exercised in such predictions, because ap parent reaction enthalpies were found to vary three-fold among excipients i n the same functional class. Based on these observations, a two-step proced ure is suggested for efficient development of stable formulations. First, e xcipient compatibility screening should be conducted using a rapid calorime tric technique. The calorimetric results are then used to evaluate relative risk of incompatibility for each excipient within a particular functional class. The calorimetric data and the functional requirements of the dosage form are then integrated in developing a limited number of model formulatio ns that are likely to succeed from both a performance and a stability persp ective. The second step of the process is to conduct traditional HPLC-based accelerated stability studies on the limited number of model formulations. (C) 2001 Elsevier Science B.V. All rights reserved.