Abstract

Drug particle size distribution has a profound impact to the content uniformity in low-dose solid drug products. We derived theoretically the skewness of potency distribution as a function of particle size distribution and target dose. It was demonstrated that both skewness and coefficient of variation diverge simultaneously with inverse square root of the target dose. This scaling relation was observed in recent experiment and was verified by Monte Carlo (MC) simulation, which was employed for the first time to solve for the full potency distribution from a random retrieving model. When tested against the criteria from USP 905 uniformity of dosage units, MC simulation showed a striking anisotropic distribution of the data. This suggests a full-scale consideration of the potency distribution is necessary for evaluating the impacts from particle size distribution and the dose, as compared against the normality assumption used before. A nomograph of the median particle size and the dose that meets a 99% pass rate was constructed for the specification of particle size or the lowest dose limit. Furthermore, we showed quantitatively the lowest dose limit can be drastically reduced if a cut-off size is imposed by removing oversized particles.