Physical characteristics and chemical degradation of amorphous quinapril hydrochloride

• Published in: Journal of pharmaceutical sciences Vol. 89; no. 1; p. 128
• Main Authors: Guo, Y, Byrn, S R, Zografi, G
• Format: Journal Article
• Language: English
• Published: United States 01-01-2000
• Subjects: Angiotensin-Converting Enzyme Inhibitors - chemistry; Antihypertensive Agents - chemistry; Calorimetry, Differential Scanning; Crystallization; Hot Temperature; Isoquinolines - chemistry; Spectroscopy, Fourier Transform Infrared; Tetrahydroisoquinolines; Thermogravimetry; X-Ray Diffraction
• ISSN: 0022-3549
• DOI: 10.1002/(SICI)1520-6017(200001)89:1<128::AID-JPS13>3.0.CO;2-Z

This study was designed to investigate the relationships between the solid-state chemical instability and physical characteristics of a model drug, quinapril hydrochloride (QHCl), in the amorphous state. Amorphous QHCl samples were prepared by rapid evaporation from dichloromethane solution and by grinding and subsequent heating of the crystalline form. Physical characteristics, including the glass transition temperature and molecular mobility, were determined using differential scanning calorimetry, thermogravimetric analysis, powder x-ray diffractometry, polarizing microscopy, scanning electron microscopy, and infrared spectroscopy. The amorphous form of QHCl, produced by both methods, has a T(g) of 91 degrees C. Isothermal degradation studies showed that cyclization of QHCl occurred 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 altering the pressure above the sample. The temperature dependence for chemical reactivity below T(g) correlated very closely with the temperature dependence 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 softening of the solid, particularly above T(g), and a resulting reduction of the particle surface/volume ratio play a major role in affecting the reaction rate by decreasing the rate of removal of the gaseous HCl product.