Continuous Twin Screw Wet Granulation Research Articles

Evaluation of Polyvinyl Alcohol as Binder during Continuous Twin Screw Wet Granulation.

Binder selection is a crucial step in continuous twin-screw wet granulation (TSWG), as the material experiences a much shorter residence time (2-40 s) in the granulator barrel compared to batch-wise granulation processes. Polyvinyl alcohol (PVA) 4-88 was identified as an effective binder during TSWG, but the potential of other PVA grades-differing in polymerization and hydrolysis degree-has not yet been studied. Therefore, the aim of the current study was to evaluate the potential of different PVA grades as a binder during TSWG. The breakage and drying behavior during the fluidized bed drying of drug-loaded granules containing the PVA grades was also studied. Three PVA grades (4-88, 18-88, and 40-88) were characterized and their attributes were compared to previously investigated binders by Vandevivere et al. through principal component analysis. Three binder clusters could be distinguished according to their attributes, whereby each cluster contained a PVA grade and a previously investigated binder. PVA 4-88 was the most effective binder of the PVA grades for both a good water-soluble and water-insoluble formulation. This could be attributed to its high total surface energy, low viscosity, good wettability of hydrophilic and hydrophobic surfaces, and good wettability by water of the binder. Compared to the previously investigated binders, all PVA grades were more effective in the water-insoluble formulation, as they yielded strong granules (friability below 30%) at lower L/S-ratios. This was linked to the high dispersive surface energy of the high-energy sites on the surface of PVA grades and their low surface tension. During fluidized bed drying, PVA grades proved suitable binders, as the acetaminophen (APAP) granules were dried within a short time due to the low L/S-ratio, at which high-quality granules could be produced. In addition, no attrition occurred, and strong tablets were obtained. Based on this study, PVA could be the preferred binder during twin screw granulation due to its high binder effectiveness at a low L/S-ratio, allowing efficient downstream processing. However, process robustness must be controlled by the included excipients, as PVA grades are operating in a narrow L/S-ratio range.

Studying the API Distribution of Controlled Release Formulations Produced via Continuous Twin-Screw Wet Granulation: Influence of Matrix Former, Filler and Process Parameters.

Hydroxypropyl methylcellulose (HPMC) is a preferred hydrophilic matrix former for controlled release formulations produced through continuous twin-screw wet granulation. However, a non-homogeneous API distribution over sieve fractions with underdosing in the fines fraction (<150 µm) was previously reported. This could result in content uniformity issues during downstream processing. Therefore, the current study investigated the root cause of the non-homogeneous theophylline distribution. The effect of process parameters (L/S-ratio and screw configuration) and formulation parameters (matrix former and filler type) on content uniformity was studied. Next, the influence of the formulation parameters on tableting and dissolution behavior was investigated. Altering the L/S-ratio or using a more aggressive screw configuration did not result in a homogeneous API distribution over the granule sieve fractions. Using microcrystalline cellulose (MCC) as filler improved the API distribution due to its similar behavior as HPMC. As excluding HPMC or including a hydrophobic matrix former (Kollidon SR) yielded granules with a homogeneous API distribution, HPMC was identified as the root cause of the non-homogeneous API distribution. This was linked to its fast hydration and swelling (irrespective of the HPMC grade) upon addition of the granulation liquid.

A Colourful Way to Unravel the Important Fluidization-Related Granule Size Effect on Semi-Continuous Drying.

Continuous twin screw wet granulation (TSWG) systems are possible pathways for oral solid dosage manufacturing in the pharmaceutical industry. TSWG requires a drying step after granulation before the tableting process. Typically, semi-continuous fluidized bed dryers (FBDs) are used for this purpose. At the same time, the pharmaceutical sector is interested in mathematical prediction models to save resources during the early drug product development (DPD) stage or to control manufacturing. Several authors have already developed prediction models for semi-continuous drying processes. However, these model structures reported systematic prediction offsets, which could be related to the incomplete implementation of fluidization and granule segregation phenomena. This study evaluates the complex fluidization behavior of wet granules in industrially relevant semi-continuous FBDs. A transparent perspex version of the dryer was used for the analysis of bed height, pressure drop, porosity, segregation, and spatial heating patterns at varying process settings. The investigated behaviors of the fluidizing bed will be helpful to derive phenomenological (sub)models for the detailed description of segregation in the semi-continuous fluidized bed system. In this study, it was found that semi-continuous FBDs are characterized by a change in fluidization regime from plug flow to a bubbling bed at the moment that the granule bed slumps. Secondly, the presence of size-based vertical segregation phenomena as well as spatial temperature differences were proven. The experimental results suggest that larger granules are dried under more intense drying conditions than smaller granules.

Validation of model-based design of experiments for continuous wet granulation and drying

This paper presents an application case of model-based design of experiments for the continuous twin-screw wet granulation and fluid-bed drying sequence. The proposed framework consists of three previously developed models. Here, we are testing the applicability of previously published unit operation models in this specific part of the production line to a new active pharmaceutical ingredient. Firstly, a T-shaped partial least squares regression model predicts d-values of granules after wet granulation with different process settings. Then, a high-resolution full granule size distribution is computed by a hybrid population balance and partial least squares regression model. Lastly, a mechanistic model of fluid-bed drying simulates drying time and energy efficiency, using the outputs of the first two models as a part of the inputs. In the application case, good operating conditions were calculated based on material and formulation properties as well as the developed process models. The framework was validated by comparing the simulation results with three experimental results. Overall, the proposed framework enables a process designer to find appropriate process settings with a less experimental workload. The framework combined with process knowledge reduced 73.2% of material consumption and 72.3% of time, especially in the early process development phase.

T-shaped partial least squares for high-dosed new active pharmaceutical ingredients in continuous twin-screw wet granulation: Granule size prediction with limited material information

This work presents a granule size prediction approach applicable to diverse formulations containing new active pharmaceutical ingredients (APIs) in continuous twin-screw wet granulation. The approach consists of a surrogate selection method to identify similar materials with new APIs and a T-shaped partial least squares (T-PLS) model for granule size prediction across varying formulations and process conditions. We devised a surrogate material selection method, employing a combination of linear pre-processing and nonlinear classification algorithms, which effectively identified suitable surrogates for new materials. Using only material properties obtained through four characterization methods, our approach demonstrated its predictive prowess. The selected surrogate methods were seamlessly integrated with our developed T-PLS model, which was meticulously validated for high-dose formulations involving three new APIs. When surrogating new APIs based on Gaussian process classification, we achieved the lowest prediction errors, signifying the method’s robustness. The predicted d-values were within the range of uncertainty bounds for all cases, except for d90 of API C. Notably, the approach offers a direct and efficient solution for early-phase formulation and process development, considerably reducing the need for extensive experimental work. By relying on just four material characterization methods, it streamlines the research process while maintaining a high degree of accuracy.

Exploring the effect of raw material properties on continuous twin-screw wet granulation manufacturability

Twin-screw wet granulation (TSWG) stands out as a promising continuous alternative to conventional batch fluid bed- and high shear wet granulation techniques. Despite its potential, the impact of raw material properties on TSWG processability remains inadequately explored. Furthermore, the absence of supportive models for TSWG process development with new active pharmaceutical ingredients (APIs) adds to the challenge. This study tackles these gaps by introducing four partial least squares (PLS) models that approximate both the applicable liquid-to-solid (L/S) ratio range and resulting granule attributes (i.e., granule size and friability) based on initial material properties. The first two PLS models link the lowest and highest applicable L/S ratio for TSWG, respectively, with the formulation blend properties. The third and fourth PLS models predict the granule size and friability, respectively, from the starting API properties and applied L/S ratio for twin-screw wet granulation. By analysing the developed PLS models, water-related material properties (e.g., solubility, wettability, dissolution rate), as well as density and flow-related properties (e.g., flow function coefficient), were found to be impacting the TSWG processability. In addition, the applicability of the developed PLS models was evaluated by using them to propose suitable L/S ratio ranges (i.e., resulting in granules with the desired properties) for three new APIs and related formulations followed by an experimental validation thereof. Overall, this study helped to better understand the effect of raw material properties upon TSWG processability. Moreover, the developed PLS models can be used to propose suitable TSWG process settings for new APIs and hence reduce the experimental effort during process development.

Application of I-Optimal Design for Modeling and Optimizing the Operational Parameters of Ibuprofen Granules in Continuous Twin-Screw Wet Granulation.

The continuous twin-screw wet granulation (TSWG) process was investigated and optimized with prediction-oriented I-optimal designs. The I-optimal designs can not only obtain a precise estimation of the parameters that describe the effect of five input process parameters, including the screw speed, liquid-to-solid (L/S) ratio, TSWG feed rate, and numbers of the 30° and 60° mixing elements, on the granule quality in a TSWG process, but it can also provide a prediction of the response to determine the optimum operating conditions. Based on the constraints of the desired granule properties, a design space for the TSWG was determined, and the ranges of the operating parameters were defined. An acceptable degree of prediction was confirmed through validation experiments, demonstrating the reliability and effectiveness of using the I-optimal design method to study the TSWG process. The I-optimal design method can accelerate the screening and optimization of the TSWG process.

Pharmaceutical Application of Process Understanding and Optimization Techniques: A Review on the Continuous Twin-Screw Wet Granulation.

Twin-screw wet granulation (TSWG) is a method of continuous pharmaceutical manufacturing and a potential alternative method to batch granulation processes. It has attracted more and more interest nowadays due to its high efficiency, robustness, and applications. To improve both the product quality and process efficiency, the process understanding is critical. This article reviews the recent work in process understanding and optimization for TSWG. Various aspects of the progress in TSWG like process model construction, process monitoring method development, and the strategy of process control for TSWG have been thoroughly analyzed and discussed. The process modeling technique including the empirical model, the mechanistic model, and the hybrid model in the TSWG process are presented to increase the knowledge of the granulation process, and the influence of process parameters involved in granulation process on granule properties by experimental study are highlighted. The study analyzed several process monitoring tools and the associated technologies used to monitor granule attributes. In addition, control strategies based on process analytical technology (PAT) are presented as a reference to enhance product quality and ensure the applicability and capability of continuous manufacturing (CM) processes. Furthermore, this article aims to review the current research progress in an effort to make recommendations for further research in process understanding and development of TSWG.

Partial least squares regression to calculate population balance model parameters from material properties in continuous twin-screw wet granulation

In the pharmaceutical industry, twin-screw wet granulation has become a realistic option for the continuous manufacturing of solid drug products. Towards the efficient design, population balance models (PBMs) have been recognized as a tool to compute granule size distribution and understand physical phenomena. However, the missing link between material properties and the model parameters limits the swift applicability and generalization of new active pharmaceutical ingredients (APIs). This paper proposes partial least squares (PLS) regression models to assess the impact of material properties on PBM parameters. The parameters of the compartmental one-dimensional PBMs were derived for ten formulations with varying liquid-to-solid ratios and connected with material properties and liquid-to-solid ratios by PLS models. As a result, key material properties were identified in order to calculate it with the necessary accuracy. Size- and moisture-related properties were influential in the wetting zone whereas density-related properties were more dominant in the kneading zones.

Evaluation of the influence of material properties and process parameters on granule porosity in twin-screw wet granulation

In recent years, continuous twin-screw wet granulation (TSWG) is gaining increasing interest from the pharmaceutical industry. Despite the many publications on TSWG, only a limited number of studies focused on granule porosity, which was found to be an important granule property affecting the final tablet quality attributes, e.g. dissolution. In current study, the granule porosity along the length of the twin-screw granulator (TSG) barrel was evaluated. An experimental set-up was used allowing the collection of granules at the different TSG compartments. The effect of active pharmaceutical ingredient (API) properties on granule porosity was evaluated by using six formulations with a fixed composition but containing APIs with different physical–chemical properties. Furthermore, the importance of TSWG process parameters liquid-to-solid (L/S) ratio, mass feed rate and screw speed for the granule porosity was evaluated. Several water-related properties as well as particle size, density and flow properties of the API were found to have an important effect on granule porosity. While the L/S ratio was confirmed to be the dictating TSWG process parameter, granulator screw speed was also found to be an important process variable affecting granule porosity. This study obtained crucial information on the effect of material properties and process parameters on granule porosity (and granule formation) which can be used to accelerate TSWG process and formulation development.

Model development and calibration of two-dimensional population balance model for twin-screw wet granulation based on particle size distribution and porosity

Population balance models (PBMs) have been widely studied for the simulation of continuous twin-screw wet granulation. Due to the limited data availability and computational efforts, one-dimensional PBM is the most popular application to the pharmaceutical industry. While multi-dimensional PBMs can predict multiple granule quality attributes, model development and calibration has been the big challenges. This paper presents a two-dimensional compartmental PBM which compute granule size and porosity. Granulation experiments were performed for two formulations and two process settings, followed by granule characterizations. In PBM development, consolidation was newly introduced, whereas the aggregation and breakage kernels were based on the previous model. Calibration results proved that the model can simulate granule size and porosity simultaneously for different formulations and process settings. Some cases show porosity increase that needs to be considered in the future. Further experiments and model development can increase the applicability of the two-dimensional PBM for the pharmaceutical industry.

Continuous Twin-Screw wet granulation process with In-Barrel drying and NIR setup for Real-Time Moisture Monitoring

The purpose of this study was to evaluate if wet granule formation and drying could take place in a single operation by utilizing in-barrel drying. The drying kinetics of the formulation were studied in order to select appropriate processing parameters and assess feasibility with short residence times in the extruder. The 18-mm extruder was operated in a 40:1 L:D ratio with 8 zones. The first two zones were used for material feeding and wet granule formation and the remaining zones were used for drying at elevated temperature. The impact of screw configuration as well as screw speed, feed rate, and residence time were all studied to optimize the drying process. Due to limitations of temperature and residence time, vacuum was added to enable sufficient drying. In-line NIR spectroscopy was incorporated into the twin-screw wet granulation (TSWG) process to monitor the moisture content of wet granules in real-time. The set-up was optimized and a predictive model was developed for future experiments.This study demonstrated the success of this technique on a pilot-scale (18-mm) extruder for the first time. Granules were formed and dried to a target loss on drying (LOD) of less than 2 % at moderate temperatures (100 °C – 110 °C) with one single operation. Streamlining wet granulation and drying into one unit operation can have a profound impact on pharmaceutical manufacturing reducing time, footprint, and environmental exposure due to reduced product transfers.

Control strategy definition for a drug product continuous wet granulation process: Industrial case study

This paper describes the specific control strategy of the commercial manufacturing process of an immediate release tablet formulation based on continuous twin-screw wet granulation. This control strategy has been defined by a multidisciplinary team using an enhanced approach, in alignment with the quality by design principles. During process development, experiments have been performed according to multivariate designs first to identify critical material attributes and critical process parameters and then, to define process conditions generating a product having the required quality. Hence, controls have been applied on critical quality attributes and on related critical process parameters and critical material attributes. Due to the specificity of the process that combines batch and continuous unit operations, a specific control strategy has been designed to ensure intermediate and end product quality. Therefore, controls including soft sensor model and in process controls have been developed to continuously monitor granules residual moisture content, assay and dissolution as granules and tablets critical attributes. In addition, process analytical technology implementation enabled increased process understanding and provided support for the development of the control strategy. This study is therefore considered as a real industrial case study of control strategy definition and implementation for an intended commercial continuous manufacturing process.

Faster to First-time-in-Human: Prediction of the liquid solid ratio for continuous wet granulation

In early development, when active pharmaceutical ingredient (API) is in short supply, it would be beneficial to reduce the number of experiments by predicting a suitable L/S ratio before starting the product development. The aim of the study was to decrease development time and the amount of API needed for the process development of high drug load formulations for continuous twin-screw wet granulation (TSWG). Mixer torque rheometry was used as a pre-formulation tool to predict the suitable L/S ratios for granulation experiments. Three different values that were based on the MTR curves, were determined and assessed for their ability to predict the suitable L/S ratio for TSWG. Three APIs (allopurinol, paracetamol and metformin HCl) were used as model substances in high drug load formulations containing 60% drug substance. The MCC-mannitol ratio was varied to assess the optimal composition for the high-dose formulations. The API solubility affected the mixer torque rheometer (MTR) curves and the optimum L/S ratio for TSWG. The highly soluble metformin needed a much lower L/S ratio compared with allopurinol and paracetamol. A design space was determined for each API based on granule flowability and tablet tensile strength. The flowability of the granules and tensile strength of the tablets improved with an increasing L/S ratio. The MCC-mannitol filler ratio had a significant effect on tabletability for paracetamol and metformin, and these APIs having poor compaction properties needed higher MCC ratios to achieve the 2 MPa limit. The MCC-mannitol ratio had no effect on the granule flow properties. Instead, API properties had the largest influence on both granule flow properties and tensile strength. Based on this study, both the L/S ratio and MCC-mannitol ratio are crucial in controlling the critical quality attributes in high drug load formulations processed by TSWG. The optimum flow and tablet mechanical properties were achieved when using 75:25 MCC-mannitol ratio. Both start of the slope and 2/3 of the L/S ratio at the maximum torque in MTR provided a solid guideline to aim for in a TSWG experiment.

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.

Indirect monitoring of ultralow dose API content in continuous wet granulation and tableting by machine vision

This paper presents new machine vision–based methods for indirect real-time quantification of ultralow drug content during continuous twin-screw wet granulation and tableting. Granulation was performed with a solution containing carvedilol (CAR) as API in the ultralow dose range (0.05w/w% in the granule) and the addition of riboflavin (RI) as a coloured tracer. An in-line calibration in the range of 0.047–0.058 w/w% was prepared for the measurement of CAR concentration using colour analysis (CA) and particle size analysis (PSA), and the validation with HPLC resulted in respective relative errors of 2.62% and 2.30% showing great accuracy. To improve the technique, a second in-line calibration was conducted in a broader CAR concentration range of 0.039–0.063 w/w% utilizing only half the amount of RI (0.045 w/w%), while doubling the output of the granulation line to 2 kg/h, producing a relative error of 4.51% and 4.29%, respectively. Finally, it was shown that the CA technique can also be carried on to monitor the CAR content of tablets in the 42–62 μg dose range with a relative error of 5.20%. Machine vision was proven to be a potent indirect method for the in-line, determination and monitoring of ultralow API content during continuous manufacturing.

Improvement of a 1D Population Balance Model for Twin-Screw Wet Granulation by Using Identifiability Analysis.

Recently, the pharmaceutical industry has undergone changes in the production of solid oral dosages from traditional inefficient and expensive batch production to continuous manufacturing. The latest advancements include increased use of continuous twin-screw wet granulation and application of advanced modeling tools such as Population Balance Models (PBMs). However, improved understanding of the physical process within the granulator and improvement of current population balance models are necessary for the continuous production process to be successful in practice. In this study, an existing compartmental one-dimensional PBM of a twin-screw granulation process was improved by altering the original aggregation kernel in the wetting zone as a result of an identifiability analysis. In addition, a strategy was successfully applied to reduce the number of model parameters to be calibrated in both the wetting zone and kneading zones. It was found that the new aggregation kernel in the wetting zone is capable of reproducing the particle size distribution that is experimentally observed at different process conditions as well as different types of formulations, varying in hydrophilicity and API concentration. Finally, it was observed that model parameters could be linked not only to the material properties but also to the liquid to solid ratio, paving the way to create a generic PBM to predict the particle size distribution of a new formulation.

Continuous Twin Screw Granulation: A Review of Recent Progress and Opportunities in Formulation and Equipment Design.

Continuous twin screw wet granulation is one of the key continuous manufacturing technologies that have gained significant interest in the pharmaceutical industry as well as in academia over the last ten years. Given its considerable advantages compared to wet granulation techniques operated in batch mode such as high shear granulation and fluid bed granulation, several equipment manufacturers have designed their own manufacturing setup. This has led to a steep increase in the research output in this field. However, most studies still focused on a single (often placebo) formulation, hence making it difficult to assess the general validity of the obtained results. Therefore, current review provides an overview of recent progress in the field of continuous twin screw wet granulation, with special focus on the importance of the formulation aspect and raw material properties. It gives practical guidance for novel and more experienced users of this technique and highlights some of the unmet needs that require further research.

Continuous twin screw granulation: Impact of microcrystalline cellulose batch-to-batch variability during granulation and drying – A QbD approach

Despite significant advances in the research domain of continuous twin screw granulation, limited information is currently available on the impact of raw material properties, especially considering batch-to-batch variability. The importance of raw material variability and subsequent mitigation of the impact of this variability on the manufacturing process and drug product was recently stressed in the Draft Guidance for Industry on Quality Considerations for Continuous Manufacturing by the U.S. Food and Drug Administration (FDA). Therefore, this study assessed the impact of microcrystalline cellulose (MCC) batch-to-batch variability and process settings in a continuous twin screw wet granulation and semi-continuous drying line. Based on extensive raw material characterization and subsequent principal component analysis, raw material variability was quantitatively introduced in the design of experiments approach by means of t1 and t2 scores. L/S ratio had a larger effect on critical granule attributes and processability than screw speed and drying time. A large impact of the t1 and t2 scores was found, indicating the importance of raw material attributes. For the studied formulation, it was concluded that MCC batches with a low water binding capacity, low moisture content and high bulk density generated granules with the most desirable quality attributes. Additionally, an innovative and quantitative approach towards mitigating batch-to-batch variability of raw materials was proposed, which is also applicable for additional excipients and APIs.

The Influence of Equipment Design and Process Parameters on Granule Breakage in a Semi-Continuous Fluid Bed Dryer after Continuous Twin-Screw Wet Granulation.

The drying unit of a continuous from-powder-to-tablet manufacturing line based on twin-screw granulation (TSG) is a crucial intermediate process step to achieve the desired tablet quality. Understanding the size reduction of pharmaceutical granules before, during, and after the fluid bed drying process is, however, still lacking. A first major goal was to investigate the breakage and attrition phenomena during transport of wet and dry granules, the filling phase, and drying phase on a ConsiGma-25 system (C25). Pneumatic transport of the wet granules after TSG towards the dryer induced extensive breakage, whereas the turbulent filling and drying phase of the drying cells caused rather moderate breakage and attrition. Subsequently, the dry transfer line was responsible for additional extensive breakage and attrition. The second major goal was to compare the influence of drying air temperature and drying time on granule size and moisture content for granules processed with a commercial-scale ConsiGma-25 system and with the R&D-scale ConsiGma-1 (C1) system. Generally, the granule quality obtained after drying with C1 was not predictive for the C25, making it challenging during process development with the C1 to obtain representative granules for the C25.