The crystal growth kinetics of a proprietary active pharmaceutical ingredient (API) was investigated by isothermal seeded batch de-supersaturation experiments in solvent mixtures using the "true" thermodynamic representation of the supersaturation driving force, which considers the activities of the saturated and supersaturated states. Three approaches to approximate the experimentally inaccessible activity coefficients of the supersaturated state were assessed, as well as the most common approximation, which omits the activity coefficients altogether. Subsequently, the supersaturation data from the different expressions were fed into a population balance model to estimate kinetic parameters for the empirical, Burton− Cabrera−Frank, and birth-and-spread growth models. The results demonstrate that the approach used to compute the supersaturation alters the estimated kinetic parameters significantly, having potentially serious implications for their physical interpretation and for extracting the physical properties they represent in lumped form. Moreover, including the chemical activities in the supersaturation leads to kinetic parameters with a tighter joint confidence interval and weaker parameter correlation that can better explain the experimental observation of the API growing appreciably only under higher antisolvent amounts. Finally, the simultaneous occurrence of multiple crystal growth mechanisms is investigated, concluding that the additive contribution of B+S and BCF best explains the supersaturation decay observed in the experiments for this API.

This document contains the post-print pdf-version of the refereed paper: "Optimal experiment design under parametric uncertainty: a comparison of a sensitivities based approach versus a polynomial chaos based stochastic approach" by Philippe Nimmegeers, Satyajeet Bhonsale, Dries Telen, and Jan Van Impe which has been archived on the university repository Lirias (https://lirias.kuleuven.be/) of the KU Leuven.The content is identical to the content of the published paper, but without the final typesetting by the publisher.

Second-generation biomass is an underexploited resource, which can lead to valuable products in a circular economy. Available locally as food waste, gardening and pruning waste or agricultural waste, second-generation biomass can be processed into high-valued products through a flexi-feed small-scale biorefinery. The flexi-feed and the use of local biomass ensure the continuous availability of feedstock at low logistic costs. However, the viability and sustainability of the biorefinery must be ensured by the design and optimal operation. While the design depends on the available feedstock and the desired products, the optimisation requires the availability of a mathematical model of the biorefinery. This paper details the design and modelling of a small-scale biorefinery in view of its optimisation at a later stage. The proposed biorefinery comprises the following processes: steam refining, anaerobic digestion, ammonia stripping and composting. The models’ integration and the overall biorefinery operation are emphasised. The simulation results assess the potential of the real biowaste collected in a commune in Flanders (Belgium) to produce oligosaccharides, lignin, fibres, biogas, fertiliser and compost. This represents a baseline scenario, which can be subsequently employed in the evaluation of optimised solutions. The outlined approach leads to better feedstocks utilisation and product diversification, raising awareness on the impact and importance of small-scale biorefineries at a commune level.

In data-driven empirical or hybrid modeling, the experimental data influences the model parameters and thus also the model predictions. The experimental data has some variability due to measurement noise and due to the intrinsic stochastic nature of certain pharmaceutical processes such as aggregation or breakage. To use predictive models, it is imperative that the accuracy of the predictions is known. To this extent, various uncertainty propagation techniques applied to a predictive breakage population balance model are studied. Three uncertainty propagation techniques are studied: linearization, sigma point, and polynomial chaos. These are compared to the uncertainty obtained from Monte Carlo simulations. Linearization performs the worst in the given scenario, while sigma point and polynomial chaos methods have similar performance in terms of accuracy.

Spray drying is a key unit operation used to achieve particulate products of required properties. Despite its widespread use, the product and process design, as well as the process control remain highly empirical and depend on trial and error experiments. Studying the effect of operational parameters experimentally is tedious, time consuming, and expensive. In this paper, we carry out a model-based global sensitivity analysis (GSA) of the process. Such an exercise allows us to quantify the impact of different process parameters, many of which interact with each other, on the product properties and conditions that have an impact on the functionality of the final drug product. Moreover, classical sensitivity analysis using the Sobol-based sensitivity indices was supplemented by a polynomial chaos-based sensitivity analysis, which proved to be an efficient method to reduce the computational cost of the GSA. The results obtained demonstrate the different response dependencies of the studied variables, which helps to identify possible control strategies that can result in major robustness for the spray drying process.

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