RESUMEN
Accurate assessment of tablet content uniformity is critical for narrow therapeutic index drugs such as phenytoin sodium. This work presents a near-infrared (NIR)-based analytical method for rapid prediction of content uniformity based on a large number of phenytoin sodium formulation tablets. Calibration tablets were generated through an integrated experimental design by varying formulation and process parameters, and scale of manufacturing. A partial least squares model for individual tablet content was developed based on tablet NIR spectra. The tablet content was obtained from a modified United States Pharmacopeia phenytoin sodium high-performance liquid chromatography assay method. The partial least squares model with 4 latent variables explained 92% of the composition variability and yielded a root mean square error of prediction of 0.48% w/w. The resultant NIR model successfully assayed the composition of tablets manufactured at the pilot scale. For one such batch, bootstrapping was applied to calculate the confidence intervals on the mean, acceptance value, and relative SD for different sample sizes, n = 10, 30, and 100. As the bootstrap sample size increased, the confidence interval on the mean, acceptance value, and relative SD became narrower and symmetric. Such a 'large N' NIR-based process analytical technology method can increase reliability of quality assessments in solid dosage manufacturing.