Moisture Monitoring in Fluid-Bed Granulation by Multi-Resonance Microwave Sensor: Applicability on Crystal-Water Containing Donepezil Granules

Abstract

Multi-resonance microwave sensors have recently been introduced for moisture monitoring of pharmaceutical particulates up to > 20% residual moisture. The extended measuring range compared to previous systems as well as the microwave moisture values independent of other physical attributes make them promising process analytical technology (PAT) tools for various pharmaceutical production processes. However, so far, research focused on measurements on raw materials or drug-free model granulates and has neither evaluated the applicability for materials with crystal water containing excipients nor for active ingredients. In this study, possible influence of crystal water was evaluated using lactose monohydrate and donepezil hydrochloride, an active pharmaceutical ingredient (API) against dementia. The study clearly showed that the contained hydrate does not cause interferences and is not monitored by the applied frequencies. Material-related limits measuring lactose monohydrate were only observed above typical granulation moistures and could be explained using raw resonance curves. Furthermore, the inclusion of donepezil hydrochloride into the monitored formulations and varied process parameters demonstrated the versatility of the microwave resonance sensor system. Inlet air temperature, spraying rate, and air flow were varied according to a 2 3 full factorial experimental design. A predictive model (R 2  = 0.9699, RMSEC = 0.33%) could be established using samples produced with different process parameter settings adjusted according to the corner points of the full factorial design and validated on the center point granulation processes (RMSEV = 0.38%). Thereby, performance on actual formulations and conditions faced during process development could be thoroughly assessed, and hence, another key requirement for applicability in formulation development could be met.