Steady-state determination of continuous powder mixing by near infrared spectroscopy as process analytical technology

Abstract

Powder mixing is one of an important unit operation in pharmaceutical manufacturing of solid dosage forms. Continuous mixing was developed as an alternative method to reduce disadvantages of traditional batch mixing processes. This process was originally developed using horizontal cylindrical mixer equipped with Process Analytical Technology (PAT) tools for real-time monitoring. In the present study, a vertical cylindrical mixer was developed and evaluated. Near Infrared (NIR) spectra obtained by monitoring the mixing process were pretreated with Multiplicative Scatter Correction (MSC), second derivative treatment and Norris-William smoothing in the 6800 - 8700 cm-1 range before a calibration model using PLS was developed using X-ray powder diffractometry (XRPD) as a primary method. Concentrations of mixtures in steady-state and mixing phases were identified after changing impeller alignments (aligned and opposite) and distances between impellers (0.5 and 1.0 inch). Blend quality was found to be affected by both the impeller alignment and impeller distance. Steady-state phases, onset time, mixing performance, measurement robustness and accuracy of final mixture concentrations were evaluated. It was found that aligned impeller with 0.5-inch distance shows the best mixing set-up leading to higher mixture homogeneity. However, onset time to reach steady-state was compromised.