Spherical agglomeration, a process of in-suspension particle size enlargement, can substantially improve critical quality attributes of powders. In this work, a paracetamol-heptane-water system is used to investigate the kinetics of spherical agglomeration, demonstrating for the first time the influence of true bridging liquid to solid ratio (TBSR) and suspension loading on the evolving size, shape and density of agglomerates. A critical range of TBSR is identified where robust agglomerates are formed that are round, moderately dense, and have a controlled size distribution. Immersion nucleation, drop breakage, and agglomerate densification by impact are the controlling rate processes. Increasing mixing intensity reduces agglomerate size, porosity and agglomeration time. Increasing solids loading increases agglomeration time while yielding smaller agglomerates with lower porosity. A first order consolidation model quantitatively predicts the agglomeration kinetics as well as agglomerate properties with increasing TBSR, and is a powerful tool for design and scale up.

Roller compaction is a widely used continuous dry granulation process in the food and pharmaceutical industries. The flow and distribution of the powder across the rollers in the compaction area plays a crucial role in determining the quality of the final product. Non-uniform powder flow and distribution across the rollers can lead to variations in quality across the ribbon, resulting in uneven qualities in the granules. Hence, it is essential to enhance the powder flow and distribution across the rollers in the compaction area. Besides that, insufficient compaction stress on both sides of the roller edges can also contribute to presence of uncompacted fines during compaction process. This research aims to systematically study a whole range of customized guiders design (T-1 until T-14) that improves powder flow and distribution across the rollers and reduces the percentage of fines in the compaction zone. The 3D printed customized guiders with different grade (1 mm until 14 mm) were applied in roller compactor with horizontal feeding system to control the amount of powder passing through the roller width by guiding more powder to the sides between the rollers and less powder to the centre. The effectiveness of the design was validated by examining crystalline and spray dry lactose powders with varying flowabilities using online thermal imaging. The results demonstrate a significant trend, indicating improved uniformity of powder flow and distribution across the rollers and reduced production of fines. These findings have the potential to contribute to long-term sustainability and resource conservation in industrial applications by reducing the need for material recycling and lowering energy consumption in continuous processes.

Wet granulation, a particle size enlargement process, can significantly enhance the critical quality attributes of powders and improve the ability to form tablets in pharmaceutical manufacturing. In this study, a mechanistic-based population balance model is applied to twin screw wet granulation. This model incorporated a recently developed breakage kernel specifically designed for twin screw granulation, along with nucleation, layering, and consolidation. Calibration and validation were performed on Hydrochlorothiazide and Acetaminophen formulations, which exhibit different particle size and wettability characteristics. Utilizing a compartmental experimental dataset, a comprehensive global sensitivity analysis identified critical inputs impacting quality attributes. The study revealed that the nucleation rate process model, effectively represented particle size distributions for both formulations. Adjustments to nucleation and breakage rate parameters, influenced by material properties and screw configuration, improved the model’s accuracy. A model-driven workflow was proposed, offering step-by-step guidelines and facilitating PBM model usage, providing essential details for future active pharmaceutical ingredient (API) formulations.

Predicting the mechanical properties of powder mixtures without extensive experimentation is important for model driven design in solid dosage form manufacture. Here, a new binary interaction-based model is proposed for predicting the compressibility and compactability of directly compressed pharmaceutical powder mixtures based on the mixture composition. The model is validated using blends of MCC, lactose and paracetamol or ibuprofen. Both compressibility and compactability profiles are predicted well for a variety of blend compositions of ternary mixtures for the two formulations. The model performs well over a wide range of compositions for both blends and better than either an ideal mixing model or a ternary interaction model. A design of experiments which reduces the amount of API required for fitting the model parameters for a new formulation is proposed to reduce amount of API required. The design requires only three blends containing API. The model gives similar performance to the well-known Reynolds et al. model (2017) when trained using the same data sets. The binary interaction model approach is generalizable to other powder mixture properties. The model presented in this work is limited to curve-fitting of empirical compaction models for mixtures of common pharmaceutical powders and is not intended to provide guidance on the practical operating space (or design space) limits.

Purpose This work seeks to improve the particle processability of needle-like lovastatin crystals and develop a small-footprint continuous MicroFactory for its production. Methods General conditions for optimal spherical agglomeration of lovastatin crystals and subsequent product isolation are developed, first as batch processes, and then transferred to continuous MicroFactory operation. Results Methyl isobutyl ketone is a suitable bridging liquid for the spherical agglomeration of lovastatin. Practical challenges including coupling unit operations and solvent systems; mismatched flow rates and inconsistent suspension solid loading were resolved. The successful continuous production of lovastatin spherical agglomerates (D 50 = 336 µm) was achieved. Spherical agglomeration increased the density of the bulk lovastatin powder and improved product flowability from poor to good, whilst maintaining lovastatin tablet performance. Conclusion A continuous, integrated MicroFactory for the crystallisation, spherical agglomeration, and filtration of lovastatin is presented with improved product particle processability. Up to 16,800 doses of lovastatin (60 mg) can be produced per day using a footprint of 23 m 2 .

Many experimental and numerical studies have been performed on the impact breakage of particulate solids, leading to a variety of impact breakage models developed to predict breakage probability. Ideally, impact breakage models would be mechanistic in nature, mathematically simple and inclusive of critical breakage parameters. In this paper, a critical review of the most widely used impact breakage models is presented, with the conclusion that the majority of existing breakage models inadequately pre-dict breakage probability under oblique impact. In this work, a novel oblique impact model is proposed where the effect of impact angle is considered by the equivalent velocity. A breakage database compiled from the literature is deployed to interrogate the validity of the proposed model across a variety of obli-que impact circumstances. In this way, the new oblique impact model is shown to provide excellent pre-dictions of breakage probability, requiring only one set of fitting parameters under various impact angles. The unique feature of this oblique impact model is not necessarily required to be used with any specific normal impact breakage models, but can instead be universally applied with any of the assessed normal impact breakage models to establish unified breakage master curves for any oblique impact. (c) 2022 Published by Elsevier Ltd.

Spherical agglomeration of crystals via addition of an immiscible bridging liquid can improve active pharmaceutical ingredient handling and tabletability. Bridging liquid amount is quantified by the bridging liquid-solid ratio (BSR). However, the optimal range of the BSR for agglomerates to form is highly dependent on the bridging liquid/solvent/antisolvent system. Here, a new definition is introduced to account for bridging liquid-solvent miscibility; true bridging liquid-solid ratio (TBSR). A method for calculating TBSR from the system ternary phase diagram is demonstrated for five different common binder liquids with acetone/water as the solvent/ antisolvent system. Results show the value of BSR varies dramatically for a given TBSR as a function of both the system and the solids loading. Experimental salicylic acid agglomeration studies confirm optimal BSR varied widely with binder liquid and solids loading between 0.2 and 2, but the optimum TBSR for all experiments was in a narrow range between 0.05 and 0.15. Thus, TBSR is a robust dimensionless parameter for design and scale up of spherical agglomeration processes.

In the pharmaceutical industry, powder flowability is an essential manufacturability attribute to consider when selecting the suitable manufacturing route and formulation. The selection of the formulation is usually based on the physical and chemical properties of the Active Pharmaceutical Ingredient (API) under consideration. Current industrial practice heavily relies on experimental work, which often results in significant labor and API consumption that results in higher costs. In this study we describe the development of a mixing rule to predict powder blend flowability from the flow properties of the individual components for industrial formulations manufactured via Direct Compression (DC). The mixing rule assumes that the granular solids' interactions are dominated by cohesive forces but are pragmatic to calibrate from the perspective of the typical data collated in an industrial environment. The proposed model was validated using a range of different APIs and the results show that the model can effectively predict the flowability properties of any formulation across the space of DC-relevant formulation compositions. Finally, a connection between the model and APIs properties (shape and size) was investigated via a linear correlation between the API particle properties and interparticle forces.

Spherical agglomeration is emerging as an important unit process for pharmaceutical manufacturing. However, at present, quantitative process design to control agglomerate attributes is impossible. A new population balance model to predict agglomerate attributes is presented where for the first time, all of the key rate processes that control agglomerate properties are included. A parameter sensitivity analysis is undertaken to study the effect of process parameters on agglomerate attributes. Bridging liquid droplet size and bridging liquid to solids ratio (BSR) are critical controlling parameters. Good quality agglomerates are formed over a relatively narrow range of BSR. Within this range, bridging liquid droplet size can be used to tune agglomerate size. Primary crystal size and process mixing intensity have only a modest effect on equilibrium agglomerate attributes but do impact agglomerate formation kinetics. This new model provides the basis for improved process understanding and quantitative process design of spherical agglomeration.

The pharmaceutical field is currently moving towards continuous manufacturing pursuing reduced waste, consistency, and automation. During continuous manufacturing, it is important to understand how both operating conditions and material properties throughout the process affect the final properties of the product to optimise and control production. In this study of a continuous wet granulation line, the liquid to solid ratio (L/S) and drying times were varied to investigate the effect of the final granule moisture content and the liquid to solid ratio on the properties of the granules during tabletting and the final tensile strength of the tablets. Both variables (L/S and granule moisture) affected the tablet tensile strength with the moisture content having a larger impact. Further analysis using a compaction model, showed that the compactability of the granules was largely unaffected by both L/S and moisture content while the compressibility was influenced by these variables, leading to a difference in the final tablet strength and porosity. The granule porosity was linked to the L/S ratio and used instead for the model fitting. The effect of moisture content and granule porosity was added to the model using a 3d plane relationship between the compressibility constant, the moisture content and porosity of the granules. The tablet tensile strength model, considering the effect of moisture and granule porosity, performed well averaging a root mean squared error across the different conditions of 0.17 MPa.

Roller compaction is a continuous dry granulation process in which two counter-rotating rollers compress the powder. The feeding of powder to the compaction zone has a significant effect on product quality in the process. This work aims to improve ribbon property uniformity using new feeding guiders and develop a relationship map. The feeding guiders were designed in a range of grades considering the different powder properties and process parameters to achieve a uniform powder feeding to the compaction zone. An online thermal imaging camera was used as a process analytical technology to monitor the powder compaction and the uniformity of temperature across ribbon width, which was indirectly related to the powder distribution. The uniformity of the ribbon temperature of all powders increased from 20% using the original design to about 70% using the optimum design of the guiders, which indicated better powder distribution during the compaction. A relationship was also investigated for different materials with varying properties, grades of feeding guider and roller forces, which is useful for the design of experiments and predicting relative temperature uniformity of other materials.

This paper presents a flowsheet modelling of an integrated twin screw granulation (TSG) and fluid bed dryer (FBD) process using a Model Driven Design (MDD) approach. The MDD approach is featured by appropriate process models and efficient model calibration workflow to ensure the product quality. The design space exploration is driven by the physics of the process instead of extensive experimental trials. By means of MDD, the mechanistic-based process kernels are first defined for the TSG and FBD processes. With the awareness of the underlying physics, the complementary experiments are carried out with relevance to the kinetic parameters in the defined models. As a result, the experiments are specifically purposeful for model calibration and validation. The L/S ratio (liquid to solid ratio) and inlet air temperature are selected as the Critical Process Parameters (CPPs) in TSG and FBD for model validation, respectively. Global System Analysis (GSA) is further performed to assess the uncertainty of CPPs imposed on the Critical Quality Attributes (CQAs), which provides significant insights to the exploration of the design space considering both TSG and FBD process parameters.

The crystallization of calcium carbonate is shown to be dictated by the Ostwald rule of stages (ORS), for high relative initial supersaturations (SCaCO3=[Ca2+][CO32−]/KSP, Calcite>2500), under sweet (carbon dioxide saturated) and anoxic (oxygen depleted) solution conditions. Rhombohedral calcite crystals emerge after the sequential crystallization and dissolution of the metastable polymorphs: vaterite (snowflake-shaped) and aragonite (needle-shaped). However, the presence of certain cations, which can form trigonal carbonates (e.g. Fe2+ and Ni2+), in concentrations as low as 1.5 mM, triggers the emergence of calcite crystals, with a star-shaped crystal habit, first. These star-shaped crystals dissolve to yield needle-shaped aragonite crystals, which in turn dissolve to give the rhombohedral calcite crystals. The star-shaped crystals, formed at high SCaCO3, possess higher surface free energy (therefore higher apparent solubility) than their rhombohedral counterparts. This sequence of dissolution and recrystallization demonstrates that the ORS does not only drive the crystal towards its thermodynamically most stable polymorph but also towards its most stable crystal habit.

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. (c) 2021 Elsevier B.V. All rights reserved.

The interplay between polymorphism and facet-specific surface energy on the dissolution of crystals is examined in this work. It is shown that, using cationic additives, it is possible to produce star-shaped calcite crystals at very high supersaturations. In crystallization processes following the Ostwald rule of stages these star-shaped crystals appear to have higher solubility than both their rhombohedral counterparts and needle-shaped aragonite crystals. The vapour pressures of vaterite, aragonite, star-shaped calcite and rhombohedral calcite crystals are measured using thermogravimetric analysis and the corresponding enthalpies of melting are obtained. Using inverse gas chromatography, the surface energy of the aforementioned crystals is measured as well and the surface energy of the main crystal facets is calculated. Combining the effect of facet-specific surface energies and the enthalpies of melting on a modified version of the classical solubility equation for regular solutions, it is proved that the star-shaped calcite crystals can indeed have higher apparent solubility than aragonitecrystals.

Ibuprofen is a popular analgesic and is mostly marketed as tablet dosage form. It is helpful in tablet production to have feed crystals of regular shape and narrow size distribution. Controlled crystallization techniques can provide such a desired size and shape of ibuprofen crystal/powder. To design a controlled crystallizer for ibuprofen [((RS)-2-(4-(2-methylpropyl) phenyl) propanoic acid)] from ethanol and water - ethanol mixtures it is necessary to know the nucleation rate kinetics of its solutions. Secondary nucleation rates for the crystallization of racemic ibuprofen from aqueous ethanol have been measured by adding seeds to an ibuprofen solution supersaturated above the secondary nucleation threshold (SNT). After the onset of nucleation, crystal samples were taken over short time intervals and the numbers of crystals in the vessel determined. The rate of change in the number of crystals gave the nucleation rate B. It is assumed that the order of the nucleation rate dependence on supersaturation s and the order of dependence on the crystal content Mc are both first order, giving equation B = kB Mc s, where s is the supersaturation in Delta I/E (mass ratio ibuprofen to ethanol) units. For aqueous ethanolic solutions and for the nucleation rate B in number/min/(kg crystal/L slurry) units, kB = 2.4 x 109/T1.4 (independent of XW, the solution water content), where T is the solution temperature in oC. The estimated 95% probable uncertainty in the constant is +/- 6%, while that of the temperature exponent is +/- 30%. The correlation fits 95% of the experimental data within a factor of 6.

Continuous manufacturing in the pharmaceutical industry has been gaining traction in the past few years. To fully understand and optimise continuous manufacturing processes it is important not only to focus on the single units which act as building blocks but also to understand how the parameters in different units affect and interact each other and the final product. In this study, the drying behaviour of granules in a segmented fluidised bed dryer was studied. Granules were produced in a twin screw granulator, forming part of a continuous powder to table line (Consigma-25). The temperature readings and the moisture content were recorded during the drying process of granules produced with different amounts of liquid binder. From the temperature profiles, it was possible to create a method able to detect when the drying process loses efficiency (the drying rate drops) and therefore predict the optimal drying time at different conditions. The method was validated via online Near Infra Red (NIR) moisture measurements to detect the moisture content of the granules during the drying, and was compared to the available fixed drying time and temperature controlled end of drying methods. The method was successful in targeting a specific moisture content and could be used to locate the optimal drying temperature for a target moisture content in the future. The moisture content during the filling of the dryer was also recorded and provided further insight into the drying behaviour of the granules in the segmented dryer; this characteristic behaviour could later be used to detect problems during the filling time. The drying rate was also calculated making it possible to predict the optimal drying time at different operating conditions in the granulator and to assess the impact on drying of the different liquid to solid ratio used.

Granule breakage is an important rate process in wet granulation that promotes product uniformity and controls product size and strength. In this work, a model to predict granule breakage is proposed and experimentally validated. The model assumes exponential of the surviving granules, dependent on a probability of breakage; a function of powder and binder properties, as well as operating parameters. Validation experiments were performed with a breakage-only granulator, filled with cohesive, non granulating sand. Premade pellets made from lactose monohydrate and silicone oils were granulated at several impeller speeds, and the number of survivors was observed over time. The results revealed that the number of granules did indeed decay exponentially. It was found that the overall probability of breakage was inversely proportional to the capillary number. Moreover, the pore saturation played an important role in determining the probability of breakage, with higher pore saturations reducing breakage overall. A comparison with experimental data from literature revealed that the developed models agrees qualitatively with the experimental data, but is unable to fully capture the effect of powder properties and powder-binder interaction. ? 2021 The Society of Powder Technology Japan. Published by Elsevier B.V. and The Society of Powder Technology Japan. All rights reserved.

This paper presents a comprehensive assessment of the most widely used tablet compaction models in a continuous wet granulation tableting process. The porosity models, tensile strength models and lubricant models are reviewed from the literature and classified based on their formulations i.e. empirical or theoretical and applications, i.e. batch or continuous. The majority of these models are empirical and were initially developed for batch tabletting process. To ascertain their effectiveness and serviceability in the continuous tableting process, a continuous powder processing line of Diamond Pilot Plant (DiPP) installed at The University of Sheffield was used to provide the quantitative data for tablet model assessment. Magnesium stearate (MgSt) is used as a lubricant to investigate its influence on the tensile strength. Whilst satisfactory predictions from the tablet models can be produced, a compromise between the model fidelity and model simplicity needs to be made for a suitable model selection. The Sonnergaard model outperforms amongst the porosity models whilst the Reynolds model produces the best goodness of fitting for two parameters fitting porosity models. An improved tensile strength model is proposed to consider the influence of powder size and porosity in the continuous tableting process.