Physical characteristics and chemical degradation of amorphous quinapril hydrochloride

This study was designed to investigate the relationships between the solid- state chemical instability and physical characteristics of a model drug, qu inapril hydrochloride (QHCl), in the amorphous state. Amorphous QHCI sample s were prepared by rapid evaporation from dichloromethane solution and by g rinding and subsequent heating of the crystalline form. Physical characteri stics, including the glass transition temperature and molecular mobility, w ere determined using differential scanning calorimetry, thermogravimetric a nalysis, powder x-ray diffractometry, polarizing microscopy, scanning elect ron microscopy, and infrared spectroscopy. The amorphous form of QHCI, prod uced by both methods, has a T-g of 91 degrees C. Isothermal degradation stu dies showed that cyclization of QHCl occured at the same rate for amorphous samples prepared by the two methods. The activation energy was determined to be 30 to 35 kcal/mol. The rate of the reaction was shown to be affected by sample weight, dilution through mixing with another solid, and by alteri ng the pressure above the! sample. The temperature dependence for chemical reactivity below T-g correlated very closely with the temperature dependenc e of molecular mobility. Above T-g, however, the reaction was considerably slower than predicted from molecular mobility. From an analysis of all data , it appears that agglomeration and sintering of particles caused by soften ing of the solid, particularly above T-g and a resulting reduction of the p article surface/volume ratio play a major role in affecting the reaction ra te by decreasing the rate of removal of the gaseous HCl product. (C) 2000 W iley-Liss, Inc. and the American Pharmaceutical Association.