FT-NIR spectroscopy with a fiber optical reflection probe was applied as a process analytical technology tool for the continuous quantitative in-line monitoring of pharmaceutical powder mixing processes in a bladed mixer. Two powders, acetyl salicylic acid as an active pharmaceutical ingredient (API) and alpha-lactose monohydrate as an excipient were characterized in advance in terms of shear cell tests, flowability tests and particle-size determination to deduce flow properties of the powders. For the quantitative monitoring of the API content, two predictive models were developed with partial-least-squares calibration based on off-line calibration. On the basis of these predictive models, powder agitation and mixing times until blend uniformity were quantitatively monitored. Mixing experiments with systematically varied filling levels and filling protocols showed a strong variation in mixing, but eventually yielded uniform powder blend. Simulation results from the literature were linked to our experimental findings in order to identify and elucidate the effects of convective and diffusive mixing. In accordance to the international conference on harmonization acceptance level of 5% for the nominal API content, UV/Vis reference measurements were performed to verify the blend uniformity as predicted by the NIR measurements.

• Research Center Pharmaceutical Engineering GmbH (RCPE)
• U.S. Food and Drug Administration (US FDA)
• GL Pharma GmbH

• Oral solid dose
• PAT

1. blend uniformity
2. Multivariate analysis
3. Near-infrared spectroscopy
4. oral solid dose
5. pat
6. Powder mixing dynamics
7. Process analytic technology
8. Quantitative continuous monitoring
9. Research Article