Séverine Mortier

Mechanistic modelling of fluidized bed drying processes of wet porous granules: a review.

Fluidized bed dryers are frequently used in industrial applications and also in the pharmaceutical industry. The general incentives to develop mechanistic models for pharmaceutical processes are listed, and our vision on how this can particularly be done for fluidized bed drying processes of wet granules is given. This review provides a basis for future mechanistic model development for the drying process of wet granules in pharmaceutical processes. It is intended for a broad audience with a varying level of knowledge on pharmaceutical processes and mathematical modelling. Mathematical models are powerful tools to gain process insight and eventually develop well-controlled processes. The level of detail embedded in such a model depends on the goal of the model. Several models have therefore been proposed in the literature and are reviewed here. The drying behaviour of one single granule, a porous particle, can be described using the continuum approach, the pore network modelling method and the shrinkage of the diameter of the wet core approach. As several granules dry at a drying rate dependent on the gas temperature, gas velocity, porosity, etc., the moisture content of a batch of granules will reside in a certain interval. Population Balance Model (ling) (PBM) offers a tool to describe the distribution of particle properties which can be of interest for the application. PBM formulation and solution methods are therefore reviewed. In a fluidized bed, the granules show a fluidization pattern depending on the geometry of the gas inlet, the gas velocity, characteristics of the particles, the dryer design, etc. Computational Fluid Dynamics (CFD) allows to model this behaviour. Moreover, turbulence can be modelled using several approaches: Reynolds-averaged Navier-Stokes Equations (RANS) or Large Eddy Simulation (LES). Another important aspect of CFD is the choice between the Eulerian-Lagrangian and the Eulerian-Eulerian approach. Finally, the PBM and CFD frameworks can be integrated, to describe the evolution of the moisture content of granules during fluidized bed drying.

Mechanistic modelling of the drying behaviour of single pharmaceutical granules.

The trend to move towards continuous production processes in pharmaceutical applications enhances the necessity to develop mechanistic models to understand and control these processes. This work focuses on the drying behaviour of a single wet granule before tabletting, using a six-segmented fluidised bed drying system, which is part of a fully continuous from-powder-to-tablet manufacturing line. The drying model is based on a model described by Mezhericher et al. and consists of two submodels. In the first drying phase (submodel 1), the surface water evaporates, while in the second drying phase (submodel 2), the water inside the granule evaporates. The second submodel contains an empirical power coefficient, β. A sensitivity analysis was performed to study the influence of parameters on the moisture content of single pharmaceutical granules, which clearly points towards the importance of β on the drying behaviour. Experimental data with the six-segmented fluidised bed dryer were collected to calibrate β. An exponential dependence on the drying air temperature was found. Independent experiments were done for the validation of the drying model.

Moisture and drug solid-state monitoring during a continuous drying process using empirical and mass balance models

Classically, the end point detection during fluid bed drying has been performed using indirect parameters, such as the product temperature or the humidity of the outlet drying air. This paper aims at comparing those classic methods to both in-line moisture and solid-state determination by means of Process Analytical Technology (PAT) tools (Raman and NIR spectroscopy) and a mass balance approach. The six-segmented fluid bed drying system being part of a fully continuous from-powder-to-tablet production line (ConsiGma™-25) was used for this study. A theophylline:lactose:PVP (30:67.5:2.5) blend was chosen as model formulation. For the development of the NIR-based moisture determination model, 15 calibration experiments in the fluid bed dryer were performed. Six test experiments were conducted afterwards, and the product was monitored in-line with NIR and Raman spectroscopy during drying. The results (drying endpoint and residual moisture) obtained via the NIR-based moisture determination model, the classical approach by means of indirect parameters and the mass balance model were then compared. Our conclusion is that the PAT-based method is most suited for use in a production set-up. Secondly, the different size fractions of the dried granules obtained during different experiments (fines, yield and oversized granules) were compared separately, revealing differences in both solid state of theophylline and moisture content between the different granule size fractions.

Development of a Population Balance Model of a pharmaceutical drying process and testing of solution methods

Abstract Drying is frequently used in the production of pharmaceutical tablets. Simulation-based control strategy development for such a drying process requires a detailed model. First, the drying of wet granules is modelled using a Population Balance Model. A growth term based on a reduced model was used, which describes the decrease of the moisture content, to follow the moisture content distribution for a batch of granules. Secondly, different solution methods for solving the PBM are compared. The effect of grid size (discretization methods) is analyzed in terms of accuracy and calculation time. All tested methods are compared based on their ability to predict moment dynamics and the distribution, and their computational burden. The Method of Characteristics, a fast method, is able to calculate the distribution accurately with a coarse grid. The Quadrature Method of Moments requires even less calculation time, but results in a set of moments.

Model-based analysis of a twin-screw wet granulation system for continuous solid dosage manufacturing

Abstract Implementation of twin-screw granulation in a continuous from-powder-to-tablet manufacturing line requires process knowledge development. This is often pursued by application of mechanistic models incorporating the underlying mechanisms. In this study, granulation mechanisms considered to be dominant in the kneading element regions of the granulator i.e., aggregation and breakage, were included in a one-dimensional population balance model. The model was calibrated using the experimentally determined inflow granule size distribution, and the mean residence time was used as additional input to predict the outflow granule size distribution. After wetting, the first kneading block caused an increase in the aggregation rate which was reduced afterwards. The opposite was observed in case of the breakage rate. The successive kneading blocks lead to a granulation regime separation inside the granulator under certain process conditions. Such a physical separation between the granulation regimes is promising for future design and advanced control of the continuous granulation process.

Towards advanced aeration modelling: from blower to bubbles to bulk

Aeration is an essential component of aerobic biological wastewater treatment and is the largest energy consumer at most water resource recovery facilities. Most modelling studies neglect the inherent complexity of the aeration systems used. Typically, the blowers, air piping, and diffusers are not modelled in detail, completely mixed reactors in a series are used to represent plug-flow reactors, and empirical correlations are used to describe the impact of operating conditions on bubble formation and transport, and oxygen transfer from the bubbles to the bulk liquid. However, the mechanisms involved are very complex in nature and require significant research efforts. This contribution highlights why and where there is a need for more detail in the different aspects of the aeration system and compiles recent efforts to develop physical models of the entire aeration system (blower, valves, air piping and diffusers), as well as adding rigour to the oxygen transfer efficiency modelling (impact of viscosity, bubble size distribution, shear and hydrodynamics). As a result of these model extensions, more realistic predictions of dissolved oxygen profiles and energy consumption have been achieved. Finally, the current needs for further model development are highlighted.

Surrogate-Based Correlation Models in View of Real-Time Control of Ozonation of Secondary Treated Municipal Wastewater—Model Development and Dynamic Validation

New robust correlation models for real-time monitoring and control of trace organic contaminant (TrOC) removal by ozonation are presented, based on UVA254 and fluorescence surrogates, and developed considering kinetic information. The abatement patterns of TrOCs had inflected shapes, controlled by the reactivity of TrOCs toward ozone and HO• radicals. These novel and generic correlation models will be of importance for WRRF operators to reduce operational costs and minimize byproduct formation. Both UVA254 and fluorescence surrogates could be used to control ΔTrOC, although fluorescence measurements indicated a slightly better reproducibility and an enlarged control range. The generic framework was validated for several WRRFs and correlations for any compound with known kinetic information could be developed solely using the second order reaction rate constant with ozone (kO3). Two distinct reaction phases were defined for which separate linear correlations were obtained. The first was mainly ozone controlled, while the second phase was more related to HO• reactions. Furthermore, parallel factor analysis of the fluorescence spectra enabled monitoring of multiple types of organic matter with different O3 and HO• reactivity. This knowledge is of value for kinetic modeling frameworks and for achieving a better understanding of the occurring changes of organic matter during ozonation.

Analysing drying unit performance in a continuous pharmaceutical manufacturing line by means of mass--energy balances.

The current trend in the pharmaceutical industry to move from batch-wise to continuous production processes strengthens the need for monitoring and controlling the process in-line. The ConsiGma™ continuous tableting line collects data of the different subunits in real-time, but these are not really used. In this paper the data of the six-segmented fluidized bed dryer in the line are used for the development and evaluation of a mass and energy balance. The objectives are multiple: (1) prediction of the moisture content of the granules leaving the dryer solely based on the currently logged data and (2) prediction of the gas outlet temperature to check the mass balances. Once a validated system is established the gas temperature in different horizontal sections of the drying unit can be predicted. Calculations are also used to identify errors in the system and to propose alternative sensor locations. A calibration is performed in order to predict the evaporation rate. The balances were able to predict both the moisture content of the granules at the end of the drying process and the gas outlet temperature quite accurately. Combining the gathered information with the height of the bed in the fluidized bed can be used to predict the gas temperature in different horizontal sections of the dryer. An extra sensor measuring the gas temperature and the humidity at the wet transfer line would increase the accuracy of the calculations. An extra gas velocity sensor at the outlet would be useful to incorporate an extra supervision of the calculations.

In-depth experimental analysis of pharmaceutical twin-screw wet granulation in view of detailed process understanding

Twin-screw wet granulation is gaining increasing interest within the pharmaceutical industry for the continuous manufacturing of solid oral dosage forms. However, limited prior fundamental physical understanding has been generated relating to the granule formation mechanisms and kinetics along the internal compartmental length of a twin-screw granulator barrel, and about how process settings, barrel screw configuration and formulation properties such as particle size, density and surface properties influence these mechanisms. One of the main reasons for this limited understanding is that experimental data is generally only collected at the exit of the twin-screw granulator barrel although the granule formation occurs spatially along the internal length of the barrel. The purpose of this study is to analyze the twin-screw wet granulation process using both hydrophilic and hydrophobic formulations, manufactured under different process settings such as liquid-to-solid ratio, mass throughput and screw speed, in such a way that the mechanisms occurring in the individual granulator barrel compartments (i.e., the wetting and different conveying and kneading compartments) and their impact upon granule formation are understood. To achieve this, a unique experimental setup was developed allowing granule characteristic data-collection such as size, shape, liquid and porosity distribution at the different compartments along the length of the granulator barrel. Moreover, granule characteristic information per granule size class was determined. The experimental results indicated that liquid-to-solid ratio is the most important factor dictating the formation of the granules and their corresponding properties, by regulating the degree of aggregation and breakage in the different compartments along the internal length of the twin-screw granulator barrel. Collecting appropriate and detailed experimental data about granule formation along the internal length of the granulator barrel is thus crucial for gaining fundamental physical understanding of the twin-screw wet granulation process.

The use of Rheology Combined with Differential Scanning Calorimetry to Elucidate the Granulation Mechanism of an Immiscible Formulation During Continuous Twin-Screw Melt Granulation

PurposeTwin screw hot melt granulation (TS HMG) is a valuable, but still unexplored alternative to continuous granulation of moisture sensitive drugs. However, knowledge of the material behavior during TS HMG is crucial to optimize the formulation, process and resulting granule properties. The aim of this study was to evaluate the agglomeration mechanism during TS HMG using a rheometer in combination with differential scanning calorimetry (DSC).MethodsAn immiscible drug-binder formulation (caffeine-Soluplus®) was granulated via TS HMG in combination with thermal and rheological analysis (conventional and Rheoscope), granule characterization and Near Infrared chemical imaging (NIR-CI).ResultsA thin binder layer with restricted mobility was formed on the surface of the drug particles during granulation and is covered by a second layer with improved mobility when the Soluplus® concentration exceeded 15% (w/w). The formation of this second layer was facilitated at elevated granulation temperatures and resulted in smaller and more spherical granules.ConclusionThe combination of thermal and rheological analysis and NIR-CI images was advantageous to develop in-depth understanding of the agglomeration mechanism during continuous TS HMG and provided insight in the granule properties as function of process temperature and binder concentration.