Nefopam Hydrochloride Degradation Kinetics in Solution

A stability-indicating reversed-phase high performance liquid chromatographic method was developed for the detection of nefopam hydrochloride and its degradation products under accelerated degradation conditions. The degradation kinetics of nefopam hydrochloride in aqueous solutions over a pH range of 1.18 to 9.94 at 90 ± 0.2°C was studied. The degradation of nefopam hydrochloride was found to follow apparent first-order kinetics. The pH–rate profile shows that maximum stability of nefopam hydrochloride was obtained at pH 5.2–5.4. No general acid or base catalysis from acetate, phosphate, or borate buffer species was observed. The catalytic rate constants on the protonated nefopam imposed by hydrogen ion and water was determined to be 7.16 × 10−6 M−1 sec−1, and 4.54 × 10−9 sec−1, respectively. The pKa of nefopam hydrochloride in aqueous solution was determined to be 8.98 ± 0.33 (n = 3) at 25 ± 0.2°C by the spectrophotometric method. The catalytic rate constant of hydroxyl ion on the degradation of nefopam in either protonated or nonprotonated form was determined to be 6.63 × 10−6 M−1 sec−1 and 4.06 × 10−6 M−1 sec−1, respectively. A smaller effect of hydroxyl ion on the degradation of nonprotonated than on the degradation of protonated nefopam was observed. The salt effect on the degradation of nefopam hydrochloride in pH 3.11 and pH 7.26 solutions obeyed the modified Debye-Huckel equation well; however, the observed ZAZB values (1.54 for pH 3.11 and −1.21 for pH 7.26 solutions) deviated slightly from the theoretical values (1.0 for pH 3.11 and −1.0 for pH 7.26 solutions) due to the high ionic strength (μ = 0.05 to 0.9) of the solutions. The temperature effect study shows an activation energy of 19.04 kcal/mol of the degradation of nefopam hydrochloride in a pH 3.11 solution with a constant ionic strength of 0.5. No significant effect of UV irradiation (254 nm) at a distance of 30 cm and intensity of 150 μwatt/cm2 on the degradation of nefopam hydrochloride in pH 3.11 solution at 25 ± 0.2°C was found when compared with the light-protected controls. Incorporation of nonaqueous propylene glycol or polyethylene glycol 400 in the pH 3.11 nefopam hydrochloride solution shows an increase in its stability at 90 ± 0.2 °C.