In this paper, the design of a novel multi-resonance microwave resonance sensor for moisture monitoring of pharmaceutical granulations is reviewed. This sensor allows a reliable determination of residual moisture directly in the production container. The reliably determinable measuring range could be extended from below 10% to at least 20% independent of other physical attributes and thus covers the complete moisture range typically occurring in fluid bed granulations. For this purpose, experimental prototypes with a novel electronic structure were developed. In order to enable the installation in the various granulators, prototypes with different dimensions of the sensor heads were realized. Within this publication, the measurement principle will be reviewed and prospects for the multi-resonance sensor will be provided.

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 23 full factorial experimental design. A predictive model (R2 = 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.

The trend towards continuous manufacturing in the pharmaceutical industry is associated with an increasing demand for advanced control strategies. It is a mandatory requirement to obtain reliable real-time information on critical quality attributes (CQA) during every process step as the decision on diversion of material needs to be performed fast and automatically. Where possible, production equipment should provide redundant systems for in-process control (IPC) measurements to ensure continuous process monitoring even if one of the systems is not available. In this paper, two methods for real-time monitoring of granule moisture in a semi-continuous fluid-bed drying unit are compared. While near-infrared (NIR) spectroscopy has already proven to be a suitable process analytical technology (PAT) tool for moisture measurements in fluid-bed applications, microwave resonance technology (MRT) showed difficulties to monitor moistures above 8% until recently. The results indicate, that the newly developed MRT sensor operating at four resonances is capable to compete with NIR spectroscopy. While NIR spectra were preprocessed by mean centering and first derivative before application of partial least squares (PLS) regression to build predictive models (RMSEP = 0.20%), microwave moisture values of two resonances sufficed to build a statistically close multiple linear regression (MLR) model (RMSEP = 0.07%) for moisture prediction. Thereby, it could be verified that moisture monitoring by MRT sensor systems could be a valuable alternative to NIR spectroscopy or could be used as a redundant system providing great ease of application.

Recently, microwave resonance technology (MRT) sensor systems operating at four resonances instead of a single resonance frequency were established as a process analytical technology (PAT) tool for moisture monitoring. The additional resonance frequencies extend the technologies' possible application range in pharmaceutical production processes remarkably towards higher moisture contents. In the present study, a novel multi-resonance MRT sensor was installed in a bottom-tangential-spray fluidized bed granulator in order to provide a proof-of-concept of the recently introduced technology in industrial pilot-scale equipment. The mounting position within the granulator was optimized to allow faster measurements and thereby even tighter process control. As the amount of data provided by using novel MRT sensor systems has increased manifold by the additional resonance frequencies and the accelerated measurement rate, it permitted to investigate the benefit of more sophisticated evaluation methods instead of the simple linear regression which is used in established single-resonance systems. Therefore, models for moisture prediction based on multiple linear regression (MLR), principal component regression (PCR), and partial least squares regression (PLS) were built and assessed. Correlation was strong (all R-2 > 0.988) and predictive abilities were rather acceptable (all RMSE 0.5%) for all models over the whole granulation process up to 16% residual moisture. While PCR provided best predictive abilities, MLR proofed as a simple and valuable alternative without the need of chemometric data evaluation.

Microwave sensor systems using resonance technology at a single resonance in the range of 2-3 GHz have been shown to be a rapid and reliable tool for moisture determination in solid materials including pharmaceutical granules. So far, their application is limited to lower moisture ranges or limitations above certain moisture contents had to be accepted. Aim of the present study was to develop a novel multi resonance sensor system in order to expand the measurement range. Therefore, a novel sensor using additional resonances over a wide frequency band was designed and used to investigate inherent limitations of first generation sensor systems and material-related limits. Using granule samples with different moisture contents, an experimental protocol for calibration and validation of the method was established. Pursuant to this protocol, a multiple linear regression (MLR) prediction model built by correlating microwave moisture values to the moisture determined by Karl Fischer titration was chosen and rated using conventional criteria such as coefficient of determination (R-2) and root mean square error of calibration (RMSEC). Using different operators, different analysis dates and different ambient conditions the method was fully validated following the guidance of ICH Q2(R1).The study clearly showed explanations for measurement uncertainties of first generation sensor systems which confirmed the approach to overcome these by using additional resonances. The established prediction model could be validated in the range of 7.6-19.6%, demonstrating its fit for its future purpose, the moisture content determination during wet granulations. (C) 2017 Elsevier B.V. All rights reserved.

Microwave resonance technology (MRT) is known as a process analytical technology (PAT) tool for moisture measurements in fluid-bed granulation. It offers a great potential for wet granulation processes even where the suitability of near-infrared (NIR) spectroscopy is limited, e.g. colored granules, large variations in bulk density. However, previous sensor systems operating around a single resonance frequency showed limitations above approx. 7.5% granule moisture. This paper describes the application of a novel sensor working with four resonance frequencies. In-line data of all four resonance frequencies were collected and further processed. Based on calculation of density-independent microwave moisture values multiple linear regression (MLR) models using Karl-Fischer titration (KF) as well as loss on drying (LOD) as reference methods were build. Rapid, reliable in-process moisture control (RMSEP≤0.5%) even at higher moisture contents was achieved.

The paper first describes the design and construction of two different kinds of quasi-planar stray field ring resonators for microwave moisture and density measurements, which are typical for the state of the art, and then the practical performance of such sensors. The changes in resonant frequency and resonator bandwidth are utilized for the determination of the moisture content or the material's density. Nonlinear temperature behaviour is identified as a critical property of conventional stray field resonators, which restricts their measurement accuracy. A novel trough guide resonator is then presented which is entirely manufactured from a ring of alumina oxide ceramics and overcomes the temperature problems. The ring is metallized at its surface except at the front face, which permits a stray field to come into contact with the material under test. The described resonator is capable of withstanding considerable abrasive forces without having a protective cover. At the same time it shows excellent linear and predictive temperature behaviour, which allows precise compensation of the inherent temperature dependence of the resonator. Under constant environmental conditions, the sensibility and accuracy of the old and new resonator designs are exactly the same. However, at varying temperature, an error can be removed to a much higher extent for the new resonators, restricting deviations in the moisture content caused by temperature to typically less than 0.1%, as compared to errors of up to several per cent for the previous designs over a temperature range of similar to 20 - 50 degrees C.

This is the first report on in-line moisture measurement of pharmaceutical products by microwave resonance technology. In order to meet the FDA's PAT approach, a microwave resonance sensor appropriate for pharmaceutical use was developed and implemented into two different fluidized-bed dryers. The novel sensor enables a continuous moisture measurement independent from the product density. Hence, for the first time precise real time determination of the moisture in pharmaceutical granules becomes possible. The qualification of the newly developed sensor was performed by drying placebo granules under experimental conditions and the validation using drug loaded granules under real process conditions. The results of the investigations show good correlations between water content of the granules determined by the microwave resonance sensor and both reference methods, loss on drying by infrared light exposure and Karl Fischer titration. Furthermore, a considerable time saving in the drying process was achieved through monitoring the residual water content continuously by microwave resonance technology instead of the formerly used discontinuous methods.