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.