Pharmaceutical analysis and process monitoring: Novel near-IR spectroscopic methods for intact dosage form characterization

Near-infrared (near-IR) spectroscopic methods intended to control pharmaceutical processes and to replace in-process and release testing are being widely investigated. However, the technique's application to pharmaceutical analysis is still in its infancy, with the practical limits for many samples still unknown. This work traces the development of near-IR spectroscopy in solid dosage form analysis from its inception to the present. This research investigates the application of near-IR spectroscopy and chemometric techniques to the analysis of tablet dosage forms for the determination of assay, hardness, and coating level, and explores the limits of the technique for such samples.; Near-IR spectroscopic analysis of intact tablets is used to measure and predict the dissolution rate, assay, and hardness of the dosage forms. A sampling device to permit on-line near-IR monitoring of a tablet film coating operation has been invented, patented, and tested. A new reference method based upon size exclusion chromatography (SEC) is developed for the quantification of ethylcellulose applied to tablets. This reference technique is superior to scanning electron microscopy (SEM) and average tablet weight gain for the development of near-IR calibrations. Tablet hardness changes affect spectral baseline slope. A spectral best-fit (SBF) algorithm is developed, and uses this property to advantage for the determination of tablet hardness. Performance comparable to multivariate techniques is demonstrated. A factorial experimental design is used to evaluate the practical limits of near-IR spectroscopy in the analysis of tablets for the prediction of hardness, coating level, and assay, and the influence of each of these variables on the prediction of the other variables. Prediction of tablet assay is the most challenging, and is most greatly affected by changes in coating level and hardness.; This work demonstrates feasibility of several near-IR applications not previously identified, develops a new coating quantification method and process monitoring technique, and explores the practical limits of the method for solid dosage form analysis.