Wet Granulation Process Research Articles

Challenges and opportunities in modelling wet granulation in pharmaceutical industry – A critical review

Wet granulation is a key step in the pharmaceutical manufacturing of solid-dosage forms. Wet granulation is used in pharmaceutical production to enhance formulation qualities such as flowability, compressibility, etc. Different methods are used for wet granulation, including fluidised bed, twin-screw extrusion, and high-shear method, leading to different mechanisms and granule properties. Modelling wet granulation is of great importance for the pharmaceutical industry, which is aspiring to shift from batch mode to a continuous one. Moreover, model-based understanding is critical for implementing the Quality-by-Design (QbD) approach in the pharmaceutical industry. The current critical review represents an overview of current approaches in modelling wet granulation. Three major models, including the population balance model (PBM), discrete element method (DEM), and data-driven models, are evaluated, and the advantages of each approach are outlined. The PBM is the primary approach for modelling granulation in which granule properties are tracked in the process. On the other hand, DEM provides a better understanding of granulation at the particle level. Recent DEM modelling studies have significantly advanced the knowledge for design and scale-up of DEM models, such as capturing the suitable wetting physics and particle scaling and thus mitigating the traditionally known challenges in the application of DEM for wet granulation processes. However, further research is required to include particle level effects, like breakage, attrition, into the DEM model through either built-in approaches or hybrid approaches. Data-driven models are fast and accurate but do not investigate the mechanisms involved in granulation. Data-driven models based on neural networks have been indicated to be adopted for application in continuous granulation with great accuracy compared to other approaches, which can also be implemented for process control. A great joint prospect for first-principles and data-driven modelling approaches is anticipated, which can play an important role in future process design, optimisation, and control of pharmaceutical wet granulation processes.

Industry 4.0 in Action: Digitalisation of a Continuous Process Manufacturing for Formulated Products

The pharmaceutical industry is going through a significant change to adopt smart manufacturing for more integrated supply chains and improved sustainability. Today's competitive market demands have put pressure on healthcare systems to take a comprehensive assessment of the drug life cycle, its environmental effect, industrial use of energy and resources, supply chain, and impact on end-users. The exploitation of emerging Industry 4.0 technologies will allow a sustainable process design and personalised health care system through the realisation of digital twins, which could transform the pharmaceutical sector to be more flexible, robust, adaptive, and smart. A significant level of research and development has been applied to pharmaceutical manufacturing especially in existing, outdated design and scale-up paradigms in isolated unit operations. However, addressing the key challenges in pharmaceutical manufacturing requires whole systems approaches to incorporate Industry 4.0 concepts.This paper aims to share the latest development of an advanced digital twin of a continuous wet granulation and tableting process at The University of Sheffield. These include the delivery of a digital platform consisting of an Advanced Process Control system (APC), mechanistic model platform and industrial IoT platform for data analytics and visualisation. The combined solution aligns with the concepts of Industry 4.0 by providing a digital twin, cloud integration, sophisticated statistical, as well as hybrid and mechanistic models. The models are in turn, used for soft-sensors, Model Predictive Control and Optimisation algorithms to predict and control product Quality Attributes. The potential application of digital twins in the pharmaceutical industry will also be explored.

Formulation and in vitro evaluation of inosine acedoben dimepranol tablets

The present work was carried out to formulate and evaluate immediate release tablets of Inosine Acedoben Dimepranol (IAD). Tablets were prepared by wet granulation process to overcome the poor compression properties of IAD powder and produce high-dose tablets. Various type of binders and disintegrants like Povidone K-30, K-25, wheat starch, mannitol were used to prepare some series of tablets. Granules were evaluated for pre-compression parameters and tablets were evaluated for post- compression parameters. The composition batch № IAD L03 was the best for producing IAD 500 mg tablets. The optimal lubricant is glycerol dibehenate at a concentration of 3.08%. Optimized formulation was evaluated for in-vitro dissolution test. Stability studies were performed for the selected composition.

Process validation and in vitro-in vivo evaluation of rosuvastatin calcium tablets

Establishing documented evidence that provides a high degree of assurance that a specific wet granulation process for manufacturing rosuvastatin calcium tablets 40 mg will consistently produce a product meeting its pre-determined specifications and quality attributes. It mainly involves the steps to be followed to evaluate and qualify the acceptability of the wet granulation manufacturing process of rosuvastatin calcium tablets 40 mg. The process is limited to the three batches manufactured of specific batch size with specified equipment and control parameters for rosuvastatin calcium tablets 40 mg. The results suggest providing documentary evidence that all the manufactured rosuvastatin calcium tablets were evaluated as per specifications. The steps involved such as Blend uniformity results between 90% and 110%, compression assay results between 90% and 110% were found within acceptable limits. Other tests related to compression such as hardness, thickness, disintegration, dissolution and for coatings such as weight gain, dissolution was found within acceptable limit. The design was chosen for fasting and fed study and showed bioequivalence with RLD (Codine®), with 90% CI values found to be between 80% and 125%.

A numerical tool to predict powder behaviour for pharmaceutical handling and processing

In this article, we discuss the potential of a numerical model to predict the behaviour of powders during pharmaceutical handling and processing. The model is based on the discrete element method (DEM) where simple experiments are required to calibrate the model used such as angle of repose tests. In a first step, the numerical calibration provided the coefficient of static friction and surface energy of the powders tested. This model has been validated with experimental data in different configurations: powder and granule settling by vibration, powder flow within a polydisperse system and mixing study in a rotary drum. Each comparison with the experimental data leads to a good accuracy of the model. In a second step, the method was used to predict numerically the granule formation during the wet granulation process and the manufacture of tablets during the compression process. Therefore, mixing (segregation), compression (mass uniformity and homogeneity of the components in the tablet) or cohesion problems can be modelled and predicted in order to limit some of the manufacturing problems during the industrialisation of pharmaceutical products such as granules or tablets, providing a scale-up of the process.

Theophylline extended-release monolithic matrix comprising natural rubber latex as binder

A major component of polymer in natural rubber latex (NRL) obtained from Hevea brasiliensis consists of poly-cis-1,4-isoprene. Poly-cis-1,4-isoprene exhibited interesting physical properties suitable for possible use as a binder in pharmaceutical solid dosage forms such as monolithic matrix tablet. The aim of this study was to study the feasibility of using NRL as the binder in theophylline anhydrous (THE)-incorporated monolithic matrix tablet in comparison with polyvinyl pyrrolidone K-30 (PVP-30). Physical properties of granules and tablets fabricated with wet granulation and tableting process, in vitro drug release test and release kinetic model were investigated and compared with those prepared using PVP-K30 as a binder. THE-incorporated monolithic matrix tablet was successfully fabricated with wet granulation and tableting process using NRL or PVP-K30 as binder. Granules and tablets of monolithic matrix tablet using NRL as a binder exhibited similar physical properties to those of tablet prepared using PVP-K30 as a binder. In addition, the controlled THE release with diffusion mechanism were presented in both formulations. Surprisingly, the addition of sodium bicarbonate in THE monolithic matrix tablets employing NRL as a binder could also prolong the drug release.

Numerical study of the dynamic behaviour of iron ore particles during wet granulation process using discrete element method

Iron ore granulation process is simulated by the discrete element method to understand the dynamic behaviour of iron ore particles. The results show that the macroscopic particle flow transits from rolling regime to cascading regime after water addition, with the angle of repose of particles increasing and the level of particle size segregation decreasing. The moisture distribution becomes more uniform through particle tumbling, which improves the granule growth. The microdynamic behaviours of the fines, intermediates and nuclei during the auto-layering process have been studied respectively. The variations in the average contact number, kinetic and rotational energy per particle with granulation time are analysed. The optimal moisture contents for Ores N, M and Y are estimated as 6.46 wt%, 9.12 wt% and 8.70 wt%, respectively. The numerical results are generally in accordance with the corresponding experimental ones, which basically validates the DEM modelling of iron ore granulation presented in this paper.

QbD Consideration for Developing a Double-Layered Tablet into a Single-Layered Tablet with Telmisartan and Amlodipine.

The aim of this study was to develop a single-layered version of commercially available Twynstar® (Telmisartan + Amlodipine) double-layered tablets to improve the dosing convenience. A quality-by-design approach was applied to develop the single-layered version. To evaluate the range and cause of risks for a single-layered tablet in the formulation design research, we used the tools of the risk assessment, initial risk assessment of preliminary hazard analysis and main risk assessment of failure mode and effect analysis to determine the parameters affecting formulation, drug dissolution, and impurities. The critical material attributes were the stabilizer and disintegrant, and the critical process parameters were the wet granulation and tableting process. The optimal range of the design space was determined using the central composite design in the wet granulation and tablet compression processes. The stabilizer, kneading time, and disintegrant of the wet granulation were identified as X values affecting Y values. The compression force and turret speed in the tablet compression were identified as X values affecting Y values. After deciding on the design space with the deduced Y values, the single-layered tablets were formulated, and their dissolution patterns were compared with that of the double-layered tablet. The selected quality-by-design (QbD) approach single-layered tablet formulated using design space were found to be bioequivalent to the Twynstar® double-layered tablets. Hence, the development of single-layered tablets with two API using the QbD approach could improve the medication compliance of patients and could be used as a platform to overcome time-consuming and excessive costs and the technical and commercial limitations related to various multi-layered tablets.

An edible erodible semi‐interpenetrating polymer network as a microcapsule shell to protect probiotic bacteria during reconstitution of powdered infant formula at elevated temperatures

AbstractProbiotic bacteria (PB) are added to some powdered infant formula (PIF) to fortify their composition and to make them more similar to human breast milk. However, the effectiveness of the probiotics may disappear when PIF is reconstituted at 70°C according to the WHO guidelines designated to destroy possible contaminants. We present a unique microencapsulation technique to effectively protect Bifidobacterium breve M‐16 V (B. breve) during the reconstitution process at 70°C, to enable their incorporation into PIF. The microcapsules were prepared by a wet granulation process to encompass the bacteria within a core matrix which was subsequently coated by two consecutive protective layers including an edible erodible semi‐interpenetrating polymer network (IPN) as the outer layer. The semi‐IPN sample films and the final microcapsules were characterized using different analytical methods. The survival of the microencapsulated bacteria during reconstitution in hot water (70°C) was evaluated and compared to that of the free bacteria. While the viability of the free bacteria was significantly reduced during the reconstitution process, the microencapsulated bacteria maintained high viability. The degree of PB protection was strongly influenced by the structure of the microcapsules, the composition and thickness of the semi‐IPN layer, and the content of the bacteria.

A review on key aspects of wet granulation process for continuous pharmaceutical manufacturing of solid dosage oral formulations

Wet granulation process is a major unit operation in production of pharmaceuticals as solid dosage oral formulation. Indeed, granulation is used to improve the formulation properties such as flowability, compressibility, and so on for pharmaceutical manufacturing. Different types of granulations can be used in pharmaceutical manufacturing in which the selection of proper process depends on the operational conditions as well as formulation properties. In current decades, twin-screw wet granulation has been of paramount interest owing to its superior properties. Pharmaceutical manufacturing industry are trying to move towards continuous mode by which the efficiency can be improved compared to the batch mode. Therefore, development of continuous granulation process is of great importance. In this review article, various processing units applicable for wet granulation of pharmaceutical formulations for solid dosage forms are reviewed and discussed. The advantages and disadvantages of the processes are discussed and listed along with modeling approaches for simulation of process. The governing models and numerical schemes applicable for design of wet granulation are also critically discussed. The main focus is on wet granulation as this method has attracted much attention in pharmaceutical processing.

FORMULATION AND DEVELOPMENT OF FIXED-DOSE COMBINATION OF BI-LAYER TABLETS OF EFAVIRENZ, LAMIVUDINE AND TENOFOVIR DISOPROXIL FUMARATE TABLETS 600 MG/300 MG/300 MG

Objective: This study is to formulate bi-layer tablet as a multidrug regimen against each reference listed drugs of Brand SUSTIVA® (efavirenz tablets 600 mg), EPIVER®(lamivudine tablets 300 mg), and VIREAD®(tenofovir disoproxil tablets 300 mg) to treat human immunodeficiency virus (HIV) infections. Which provides highly active antiretroviral therapy to provide effective treatment. Methods: Bilayer formulation was developed with each blend of layer-I (efavirenz) and layer-II (lamivudine and tenofovir disoproxil fumarate) through wet granulation process and roller compaction process, respectively. Further, both layers were compressed by using bi-layer compression followed by film coating. Layer-I and II formulations were developed by using various concentrations of diluents, surfactants, and disintegrants to improve the solubility of efavirenz and improve the flowability and uniformity of layer-II. Finally, the optimum formulation was developed to compare the in vitro dissolution with each branded formulation. Results: Drug-excipients interaction results revealed that the mixtures of three drug substances in 50 °C/75 % relative humidity (RH) resulted in an increase in tenofovir IMP-E and the highest unknown impurity was significantly increased and additionally decreased tenofovir assay in the presence of efavirenz. Sodium lauryl sulfate is very critical and it acts as a wetting agent and increases the solubility of efavirenz, and directly influences the dissolution of a drug product. Microcrystalline and croscarmellose sodium have a chance to affect the dissolution and friability of tenofovir. Powdered cellulose was acting as a diluent and flow property of the lamivudine part and it also affects the uniformity and dissolution. So, these ranges were optimized. X-ray diffraction (XRD) indicates there are no polymorphic changes for the optimized formulation and there is no interaction between the three active substances, and finally, in vitro dissolution results for the optimized formulation against the reference drugs. Conclusion: Optimum formulation yielded consistent drug release against each branded drug to treat human immunodeficiency virus (HIV1) infections. This formulation is robust and easily scale up for the next stage.

Development and Evaluation of Elementary Osmotic Pump Tablet of Tizanidine Hydrochloride

Aim The objective of present research work was to develop a sustained release osmotic tablet of Tizanidine HCl using suitable osmogens.Methodology Tizanidine HCl containing elementary osmotic tablets were prepared using a wet granulation process. Initially dried granules were screened for various pre compression evaluation parameters. Further dried granules were punched using 8 mm die cavity in a tablet punching machine. Thus developed tablets were evaluated for post compression parameters like tablet hardness thickness weight variation friability dissolution studies stability studies and scanning electron microscopy. Prior to dissolution studies an orifice was drilled on surface of tablet and the size of orifice was determined using SEM analysis.Results The pre compression evaluation for all the formulations had shown good results which in turn confirm excellent flow properties of granules. All formulations exhibited a weight gain of roughly 5-7. Dissolution studies confirm that the drug release pattern was controlled up to 24 hours formulation F9 had the maximum drug release around 97.27 at the end of 24 hours. The drug release was impacted by the amount of added osmogen microcrystalline cellulose and lactose concentrations. SEM studies were carried out to find the membrane surface diameter of the orifice and it was found to be 0.3 mm and revealed that the coat was intact devoid of pores after the dissolution. Kinetic study confirmed that all the formulations followed Zero order kinetics. Optimized formulation F9 was stable at room temperature and elevated temperature upto 30 days.Conclusion Developed Tizanidine HCl elementary osmotic pump tablets showed prolonged release of drug and found reproducible results for all the in vitro evaluation parameters.

Research progress on granulation process of iron and steel slag

Efficient utilization of iron and steel slag is one of the important measures to achieve peak carbon emissions and carbon neutrality in the iron and steel industry. Improving the recycling rate of iron and steel slag has become an urgent problem to be solved by scholars and enterprises at home and abroad. Therefore, it is of great significance to continuously optimize the recycling process of iron and steel slag and waste heat recovery technology. By comparing and analyzing the advantages and disadvantages of different granulation processes for iron and steel slag, the disadvantages of using dry or wet granulation processes alone for iron and steel slag are pointed out in this paper. Then, a combined granulation process mode combining dry and wet processes is proposed to improve the processing efficiency of molten slag. The increase in resource conversion rate and the quality of granulated slag after primary granulating of iron and steel slag contribute to reducing the amount of slag to be treated secondarily. Furthermore, the energy consumption and pollutant emissions of slag secondary treatment will be decreased as well. It is intended to provide a reference for slag treatment technology and slag utilization rate expansion in iron and steel enterprises.

Development of Novel Etodolac Matrix Tablet and their Pharmaceutical Characterization

The current work poses a difficulty in producing etodolac oral controlled release tablets using five of the most well-known hydrophilic release rate retardant polymers, including non-toxic materials like HPMC K4M, Carbopol 974, and Eudragit RS100. The batches were created using the wet granulation process. According to the prescribed methods, the pre-and post-compression properties were evaluated. To identify the likely drug release mechanism, the formulations were tested for their capacity to release the drug in the simulated gastric medium. The results were then fitted into several kinetic model(s). The investigation of short-term stability was also carried out. The bulk and tapped densities, which are in the range of 0.85 to 0.86 g/cm3 and 0.95 to 0.98 g/cm3, respectively, show an excellent pre-compression feature. The drug concentration was discovered to be between 98.26%-100.15%. The formulation F3 (102.95%) had the maximum in vitro drug release because it had the ideal concentration of polymer combination, which delayed the drug release and used the diffusion cum erosion process (s). When matrix formulations are carefully fabricated, the frequency of medication administration may be reduced to twice daily while also reducing blood level variations, which ultimately improves patient compliance and therapy regimens.

Assessment of Abrasion-Induced Visual Defects in Twin Screw Wet Granulation Using Wall Friction Measurements

Starting point of the presented study were abrasion effects occurring during a twin screw wet granulation (TSG) process of a new chemical entity (NCE) formulation, resulting in gray spots on the final tablets. Several actions and systematic changes of equipment and process parameter settings of TSG process were conducted which reduced the visual defect rate of the tablets, i.e., gray spots on the surface, below the specification limit. To understand the rationale and mechanism behind these improvements, correlations of defect rates and wall friction measurements using a Schulze ring shear tester were evaluated. To check the suitability of the method, a broad range of wall materials as well as powder formulations at various moisture levels were investigated with regard to their wall friction angle. As differences in wall friction angle could be detected, further experiments were conducted using wall material samples made out of different screw materials for TSG. Evaluation of these screw wall material samples gave first hints, which screw materials should be preferred in regard of friction for TSG process. In the finally presented case study, wall friction measurements were performed using the above mentioned NCE formulation with known abrasion issues at TSG processing. The results confirmed that changes which led to a reduced visual defect rate of tablets correlated with a decreased wall friction angle. The results suggest wall friction measurements as a potent tool for equipment selection and establishment of a suitable process window prior to conducting TSG experiments.Graphical abstract

The effect of screw configuration and formulation variables on liquid requirements and granule quality in a continuous twin screw wet granulation process

The effect of two screw configurations with varying stagger angle was evaluated on the liquid amount required to produce good quality granules for a highly (mannitol-based) and a poorly (DCP-based) soluble formulation containing different binders. It is generally known that the use of a higher liquid amount improves the granule quality in twin screw granulation. However, from an industrial point of view, lower liquid amounts for effective granulation are preferred, as this speeds up the production time as less time is required for drying. A screw configuration containing mixing elements with a higher stagger angle (90°) produced granules with a lower friability and a larger size at lower liquid-to-solid ratios compared to a screw configuration with all the mixing elements staggered at 60°. For each binder, incorporating a highly soluble filler into the formulation allowed granulation at lower liquid-to-solid ratios compared to a filler having a poorer aqueous solubility. The different binder types affected the granule quality and liquid requirements for granulation differently. Furthermore, similar granule quality between (partially) pregelatinized starches and in situ gelatinized starches was achieved.

Prediction of quality attributes (mechanical strength, disintegration behavior and drug release) of tablets on the basis of characteristics of granules prepared by high shear wet granulation.

High shear wet granulation is commonly applied technique for commercial manufacturing of tablets. Granulation process for tablets manufacturing is generally optimized by hit and trial which involves preparation of granules under different processing parameters, compression of granules and evaluation of the resultant tablets; and adjustment is made in granulation process on the basis of characteristics of tablets. Objective of the study was to optimize the process of high shear wet granulation and prediction of characteristics of tablets on the basis of properties of granules. Atenolol granules were prepared by high shear wet granulation method, using aqueous solution of polyvinyl pyrrolidone (PVP k-30) as binder. Concentration of binder solution and granulation time were taken as process variables, both studied at three levels. Different combinations of process variables were determined by Design Expert software. Granules were evaluated for different parameters on the basis of SeDeM-ODT (Sediment Delivery Model-Oro Dispersible Tablets) expert system. Granules from all the trials were compressed using round (10.5 mm) flat faced punches at compression weight of 250 mg/tablet. Tablets were evaluated of different quality control parameters as per USP. Results showed that both the process variables had positive effect on mechanical strength of tablets and negative effect on disintegration and dissolution rate. Granule prepared with highest level of binder concentration (15%) and highest granulation time (60 sec) resulted in tablets with highest crushing strength (11.8 kg), specific crushing strength (0.328 kg/mm2), tensile strength (0.208 kg/mm2), lowest value of friability (0.19%) and highest disintegration time (10.9 min), as predicted from granules characteristics on the basis of SeDeM-ODT expert system. Drug release from Trial-13 (processed under highest level of both process parameters) was also lower than rest of the trials. It is concluded from the study that quality characteristics of tablets can be predicted from granules characteristics using SeDeM-ODT expert system. Furthermore, SeDeM-ODT expert system can also be used for optimization of the process of high shear wet granulation.

FORMULATION, DEVELOPMENT AND EVALUATION OF IMMEDIATE RELEASE ROSUVASTATIN CALCIUM TABLET

Rosuvastatin belongs to the statin medication class, which is used to treat excessive cholesterol and prevent heart disease. The Biopharmaceutical Classification System classifies it as class II. The goal of this project is to create 10 mg Rosuvastatin instant release pills using several types of materials. To boost the drug's bioavailability, superdisintegrants were used to speed up the disintegration and dissolution of Rosuvastatin calcium. Cited research work aims to formulate an immediate release tablet of Rosuvastatin for the treatment of hypercholesterolemia, hypolipoproteinemia, and atherosclerosis. The present work used a cost-effective wet granulation process to create an immediate release formulation of Rosuvastatin calcium. All of the batches were manufactured, and the granules were evaluated for pre-compression properties such as loss on drying, bulk density, tapped density, and compressibility index. Disintegration time and assay were determined to be within acceptable parameters, as were weight fluctuation, thickness, hardness, and friability of tablets. The effect of several superdisintegrants on in vitro dissolutions in 6.8 PH phosphate buffer was investigated. The final formulation was chosen based on the dissolving profile; dissolution studies revealed that formulations F2 and F4 released 80 percent of the medication within 15 minutes. Two different formulations of Rosuvastatin Calcium 5.199 and 10.398 mg employing immediate-release tablets were successfully generated using Crospovidone, Meglumine, and Comprecel 112D+®. The tablets showed complete drug release in 60 minutes and fair flow characteristics when compared to the innovators' product.

FORMULATION, DEVELOPMENT AND EVALUATION OF IMMEDIATE RELEASE ROSUVASTATIN CALCIUM TABLET

Rosuvastatin belongs to the statin medication class, which is used to treat excessive cholesterol and prevent heart disease. The Biopharmaceutical Classification System classifies it as class II. The goal of this project is to create 10 mg Rosuvastatin instant release pills using several types of materials. To boost the drug's bioavailability, superdisintegrants were used to speed up the disintegration and dissolution of Rosuvastatin calcium. Cited research work aims to formulate an immediate release tablet of Rosuvastatin for the treatment of hypercholesterolemia, hypolipoproteinemia, and atherosclerosis. The present work used a cost-effective wet granulation process to create an immediate release formulation of Rosuvastatin calcium. All of the batches were manufactured, and the granules were evaluated for pre-compression properties such as loss on drying, bulk density, tapped density, and compressibility index. Disintegration time and assay were determined to be within acceptable parameters, as were weight fluctuation, thickness, hardness, and friability of tablets. The effect of several superdisintegrants on in vitro dissolutions in 6.8 PH phosphate buffer was investigated. The final formulation was chosen based on the dissolving profile; dissolution studies revealed that formulations F2 and F4 released 80 percent of the medication within 15 minutes. Two different formulations of Rosuvastatin Calcium 5.199 and 10.398 mg employing immediate-release tablets were successfully generated using Crospovidone, Meglumine, and Comprecel 112D+®. The tablets showed complete drug release in 60 minutes and fair flow characteristics when compared to the innovators' product.

Model-driven design using population balance modelling for high-shear wet granulation

Model-driven design approaches have great potential to improve current engineering workflows for wet granulation and other particulate processes. The key to model-driven design is a predictive process model. In this paper, a novel predictive model is proposed for high-shear wet granulation using a one-dimensional population balance modelling framework. The wet granulation mechanisms are represented by rate expressions which are based on mechanistic understanding. Material characterisation tests and granulation experiments are designed to verify critical modelling assumptions and determine the modelling parameters. Based on the Sobol’ indices results from a parameter sensitivity analysis, the impactful parameters to estimate are identified: critical pore saturation, and coefficients for consolidation, collision and breakage. Only impactful parameters that cannot be measured are estimated to reduce the experimental effort and improve the model's predictive power. Lab-scale experiments are designed to estimate parameters individually before fine-tuning the results. The model is assessed using a novel model validation workflow, which is based on predictions of experiments at four different scales from lab scale to pilot plant: 2 L to 70 L.