Triazolines. XXI: Preformulation Degradation Kinetics and Chemical Stability of a Novel Triazoline Anticonvulsant

• Published in: Journal of pharmaceutical sciences 1992-04, Vol.81 (4), p.392-396
• Main Authors: Hamelijnck, M.A. Freeke, Stevenson, Paul J., Kadaba, Pankaja K., Damani, L.A.
• Format: Article
• Language: English
• Subjects: Analysis; Anticonvulsants - chemistry; Biological and medical sciences; Chemistry, Pharmaceutical; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; Drug Stability; General pharmacology; Kinetics; Mass Spectrometry; Medical sciences; Osmolar Concentration; Pharmacology. Drug treatments; Temperature; Triazoles - chemistry
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.2600810421

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)‐Δ2‐1,2,3‐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 (μ), 0.25–4.18] at 23°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 μ 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 μ 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.