ABSTRACT
High shear wet granulation (HSWG) is widely used in tablet manufacturing mainly because of its advantages in improving flowability, powder handling, process run time, size distribution, and preventing segregation. In line process analytical technology measurements are essential in capturing detailed particle dynamics and presenting real-time data to uncover the complexity of the HSWG process and ultimately for process control. This study presents an opportunity to predict the properties of the granules and tablets through torque measurement of the granulation bowl and the force exerted on a novel force probe within the powder bed. Inline force measurements are found to be more sensitive than torque measurements to the granulation process. The characteristic force profiles present the overall fingerprint of the high shear wet granulation, in which the evolution of the granule formation can improve our understanding of the granulation process. This provides rich information relating to the properties of the granules, identification of the even distribution of the binder liquid, and potential granulation end point. Data were obtained from an experimental high shear mixer across a range of key process parameters using a face-centred surface response design of experiment (DoE). A closed-form analytical model was developed from the DOE matrix using the discovery of evolutionary equations. The model is able to provide a strong predictive indication of the expected tablet tensile strength based only on the data in-line. The use of a closed form mathematical equation carries notable advantages over other AI methodologies such as artificial neural networks, notably improved interpretability/interrogability, and minimal inference costs, thus allowing the model to be used for real-time decision making and process control. The capability of accurately predicting, in real time, the required compaction force required to achieve the desired tablet tensile strength from upstream data carries the potential to ensure compression machine settings rapidly reach and are maintained at optimal values, thus maximising efficiency and minimising waste.
ABSTRACT
The pharmaceutical industry is undergoing a paradigm shift towards continuous processing from batch, where continuous direct compression (CDC) is considered to offer the most straightforward implementation amongst powder processes due to the relatively low number of unit operations or handling steps. Due to the nature of continuous processing, the bulk properties of the formulation will require sufficient flowability and tabletability in order to be processed and transported effectively to and from each unit operation. Powder cohesion presents one of the greatest obstacles to the CDC process as it inhibits powder flow. As a result, there have been many studies investigating potential manners in which to overcome the effects of cohesion with, to date, little consideration of how these controls may affect downstream unit operations. The aim of this literature review is to explore and consolidate this literature, considering the impact of powder cohesion and cohesion control measures on the three-unit operations of the CDC process (feeding, mixing, and tabletting). This review will also cover the consequences of implementing such control measures whilst highlighting subject matter which could be of value for future research to better understand how to manage cohesive powders for CDC manufacture.
ABSTRACT
Simulating the response of a radiation detector is a modelling challenge due to the stochastic nature of radiation, often complex geometries, and multi-stage signal processing. While sophisticated tools for Monte Carlo simulation have been developed for radiation transport, emulating signal processing and data loss must be accomplished using a simplified model of the electronics called the digitizer. Due to a large number of free parameters, calibrating a digitizer quickly becomes an optimisation problem. To address this, we propose a novel technique by which evolutionary algorithms calibrate a digitizer autonomously. We demonstrate this by calibrating six free parameters in a digitizer model for the ADAC Forte. The accuracy of solutions is quantified via a cost function measuring the absolute percent difference between simulated and experimental coincidence count rates across a robust characterisation data set, including three detector configurations and a range of source activities. Ultimately, this calibration produces a count rate response with 5.8% mean difference to the experiment, improving from 18.3% difference when manually calibrated. Using evolutionary algorithms for model calibration is a notable advancement because this method is novel, autonomous, fault-tolerant, and achieved through a direct comparison of simulation to reality. The software used in this work has been made freely available through a GitHub repository.
