Triazolines. XXI: Preformulation degradation kinetics and chemical stability of a novel triazoline anticonvulsant.

The effect of pH, temperature, and two buffer species (citric acid-phosphate and bicarbonate-carbonate) on the stability of 1-(4-chlorophenyl)-5-(4-pyridyl)-delta 2-1,2,3-triazoline (ADD17014; 1), a novel triazoline anticonvulsant, was determined by HPLC. One of the main degradation products of 1 at pH 7.0 was isolated by TLC and identified as the aziridine derivative by MS. Investigations were carried out over a range of pH (2.2-10.7) and buffer concentration [ionic strength (mu), 0.25-4.18] at 23 degrees C. The degradation followed buffer-catalyzed, pseudo-first-order kinetics and was accelerated by a decrease in pH and an increase in temperature. The activation energy for the degradation in citric acid-phosphate buffer (pH 7.0 and constant ionic strength mu at 0.54) was 12.5 kcal/mol. General acid catalysis was observed at pH 7.0 in citric acid-phosphate buffer. The salt effect on the degradation obeyed the modified Debye-Hückel equation well; however, the observed charge product (ZAZB) value (2.69) deviated highly from the theoretical value (1.0), perhaps because of the high mu values (0.25-4.18) of the solutions used. The stability data will be useful in preformulation studies in the development of a stable, oral dosage form of 1.