Linear Degradation Programmed Humidifying Drug Stability Experiments

Conventionally, the stability of a solid drug that is unstable to both moisture and heat has been assessed by a set of experiments at constant humidity and temperature. The standard methods are generally accurate and reliable, however, they waste time, labor and materials, and its application is limited. Zhao et al. reported a programmed humidity and temperature controlled method, using a pocket computer. The kinetic parameters related to both moisture and temperature were obtained by a single pair of programmed experiments: one with humidity control and the other non-isothermal. In their experiments, the humidity was decreased linearly and the temperature was decreased reciprocally. The choice of humidifying and heating model was based on the simplification of the heating and humidifying control system and the convenience for computation. The deficiency of their experiments is the uncertainties in m, E_a, and A are all greater than those of the isothermal experiments at constant humidity.Both in the conventional isothermal stability experiments at constant humidity and in the programmed humidifying and heating experiments, the degradation rate at room temperature and moisture is predicted from the rate constant obtained in experiments conducted at elevated temperature and humidity. To reduce the experimental error, the ranges of temperature and humidity change should be as large as possible, and the degradation of drugs should be as uniform as possible for different temperature and humidity ranges to make full use of these ranges. The reason for the great uncertainties of parameters in Zhao's experiments is just because of the un-uniform degradation for different temperature and humidity ranges.Zhan et al. reported an exponential heating model in which the degradation of drug is more uniform for different temperature ranges and the experimental results are more precise than those in other non-isothermal experiments. In the light of this idea, a new programmed humidifying model (linear degradation humidifying) for drug stability experiment is now presented. In the new model, a linear relationship between the content function of drugs and the relative humidity is obtained, the degradation of drugs is most uniform for different humidity ranges, and therefore the experimental error can be improved significantly.The computer simulations, based on the degradation kinetics of penicillin potassium, were carried out in our study. By a theoretical investigation of simulated the programmed humidifying and heating experiments, the estimates for the kinetic parameters (E_a, m, A and t_0.9) obtained by the programmed humidifying and exponential heating models were statistically evaluated and were compared with those obtained by the isothermal measurements at constant humidity. The effects of the changes in experimental error, in extent of drug degradation, in humidity range, in temperature range, in mean humidity, in mean temperature, in sampling modes, and in sampling frequency on accuracy and precision of the estimates for the kinetic parameters were explored. The results indicated that under the same experimental conditions, the estimates obtained by our new model were significantly more accurate and precise than those obtained by models reported by Zhao. The estimates obtained by the isothermal method at constant humidity were somewhat more accurate and precise than those obtained by our new model. However, the experimental period needed by the isothermal method at constant humidity was longer than that needed by the programmed humidifying and heating models. The results also showed that in each of the heating models, the estimates are more accurate and precise by increasing the extent of drug degradation, changing humidity and temperature range or sampling frequency, or by having the mean temperature and mean humidity closer to room temperature and relative humidity of room temperature, respectively.The stability of penicillin potassium, as a solid state model, was investigated by our linear degradation programmed humidifying and exponential heating experiments. The kinetic parameters (E_a, m, A and t_0.9) obtained are significantly more precise than those obtained by the linear programmed humidifyingand the reciprocal heating models.