Twin Screw Wet Granulation Process Research Articles

A novel combination of machine learning models and metaheuristic algorithm to predict important parameters of twin screw wet granulation process

Twin screw granulation (TSG) has recently been emerged as a novel approach for the continuous wet granulation of fine particles (i.e., powders) in the pharmaceutical industry. The presence of brilliant advantages like the ability of operation at very low liquid concentrations and excellent product consistency has made this technique promising. Except positive points, the existence of major challenges like scalability and flexibility in the processing regimes has enhanced the importance of deeper investigations towards true recognition of this process. The central aim of this theoretical article is to develop the modeling process of TSG employing four machine learning models and one metaheuristic algorithms in a hybrid approach. Screw speeds, material throughputs, liquid binder (water)-to-solid ratios, and screw configurations are known as important parameters of TSG process, which were validated via their comparison with the obtained experimental data. GBR, SGD, and SVR were finally selected for 3 targets with their best combinations of hyper-parameters employing FA. The output is based on d-values (d10, d50, d90) for the granulate particle size distribution (PSD). Final models have R2 scores of 0.919, 0.960, and 0.877 for d10, d50, d90 outputs, respectively.

Characterizing a design space for a twin-screw wet granulation process: A case study of extended-release tablets

Twin-screw wet granulation is an emerging continuous manufacturing technology for solid oral dosage forms. This technology has been successfully employed for the commercial manufacture of immediate-released tablets. However, the higher polymer content in extended-release (ER) formulations may present challenges in developing and operating within a desired design space. The work described here used a systematic approach for defining the optimum design space by understanding the effects of the screw design, operating parameters, and their interactions on the critical characteristics of granules and ER tablets. The impacts of screw speed, powder feeding rate, and the number of kneading (KEs) and sizing elements on granules and tablets characteristics were investigated by employing a definitive screening design. A semi-mechanistic model was used to calculate the residence time distribution parameters and validated using the tracers. The results showed that an increase in screw speed decreased the mean residence time of the material within the barrel, while an increase in the powder feeding rate or number of KEs did the opposite and increased the barrel residence time. Screw design and operating parameters affected the flow and bulk characteristics of granules. The screw speed was the most significant factor impacting the tablet's breaking strength. The dissolution profiles revealed that granule characteristics mainly influenced the early phase of drug release. This study demonstrated that a simultaneous optimization of both operating and screw design parameters was beneficial in producing ER granules and tablets of desired performance characteristics while mitigating any failure risks, such as swelling during processing.

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.

Risk Assessment for a Twin-Screw Granulation Process Using a Supervised Physics-Constrained Auto-encoder and Support Vector Machine Framework.

Quality risk management is an important task when it pertains to the pharmaceutical industry, as this is directly related to product performance. With the ICH Q9 guidelines, several regulatory bodies have encouraged the pharmaceutical industry to implement risk management plans using scientific and systemic approaches such as quality-by-design to asses product quality. However, the implementation of such methods has been challenging as assessment of risks requires accurate quantitative models to predict changes in quality when variations occur. This study describes a framework that quantitatively assesses risk for a twin screw wet granulation process. This framework consists of a physics-constrained autoencoder system, whose outputs are constrained using physics-based boundary conditions. The latent variables obtained from the auto-encoder are used in a support vector machine-based classifier to understand the granule growth behavior occurring within the system. This framework is able to predict the process outcomes with 86% accuracy and classify the granule growth regimes with a true positive rate of 0.73. Based on the classification the risk associated with the process can be estimated.

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.

Particle-Scale Modeling to Understand Liquid Distribution in Twin-Screw Wet Granulation.

Experimental characterization of solid-liquid mixing for a high shear wet granulation process in a twin-screw granulator (TSG) is very challenging. This is due to the opacity of the multiphase system and high-speed processing. In this study, discrete element method (DEM) based simulations are performed for a short quasi-two-dimensional simulation domain, incorporating models for liquid bridge formation, rupture, and the effect of the bridges on inter-particular forces. Based on the knowledge gained from these simulations, the kneading section of a twin-screw wet granulation process was simulated. The time evolution of particle flow and liquid distribution between particles, leading to the formation of agglomerates, was analyzed. The study showed that agglomeration is a rather delayed process that takes place once the free liquid on the particle surface is well distributed.

TPLS as predictive platform for twin-screw wet granulation process and formulation development

In recent years, the interest in continuous manufacturing techniques, such as twin-screw wet granulation, has increased. However, the understanding of the influence of the combination of raw material properties and process settings upon the granule quality attributes is still limited. In this study, a T-shaped partial least squares (TPLS) model was developed to link raw material properties, the ratios in which these raw materials were combined and the applied process parameters for the twin-screw wet granulation process with the granule quality attributes. In addition, the predictive ability of the TPLS model was used to find a suitable combination of formulation composition and twin-screw granulation process settings for a new API leading to desired granule quality attributes. Overall, this study helped to better understand the link between raw material properties, formulation composition and process settings on granule quality attributes. Moreover, as TPLS can provide a reasonable starting point for formulation and process development for new APIs, it can reduce the experimental development efforts and consequently the consumption of expensive (and often limited available) new API.

Identifying Critical Binder Attributes to Facilitate Binder Selection for Efficient Formulation Development in a Continuous Twin Screw Wet Granulation Process.

The suitability of pharmaceutical binders for continuous twin-screw wet granulation was investigated as the pharmaceutical industry is undergoing a switch from batch to continuous manufacturing. Binder selection for twin-screw wet granulation should rely on a scientific approach to enable efficient formulation development. Therefore, the current study identified binder attributes affecting the binder effectiveness in a wet granulation process of a highly soluble model excipient (mannitol). For this formulation, higher binder effectiveness was linked to fast activation of the binder properties (i.e., fast binder dissolution kinetics combined with low viscosity attributes and good wetting properties by the binder). As the impact of binder attributes on the granulation process of a poorly soluble formulation (dicalcium phosphate) was previously investigated, this enabled a comprehensive comparison between both formulations in current research focusing on binder selection. This comparison revealed that binder attributes that are important to guide binder selection differ in function of the solubility of the formulation. The identification of critical binder attributes in the current study enables rational and efficient binder selection for twin-screw granulation of well soluble and poorly soluble formulations. Binder addition proved especially valuable for a poorly soluble formulation.

Continuous twin screw granulation and fluid bed drying: A mechanistic scaling approach focusing optimal tablet properties.

This study provides the results of investigation on scaling approaches for three differently-sized continuous granulation lines, each consisting of a twin screw wet granulation process and a continuous fluid bed drying process. To check the initial scaling approach with regard to granule and tablet properties, a process parameter Design of experiment (DoE) was performed on each of the three equipment scales. The processed formulation did not contain cellulose to allow a high overall flowrate through the directly connected granulation and drying sections. Enhanced scaling aspects showed the influence of Froude number [-] at different twin screw granulator scales and screw speeds on the overgranulated particle fraction [% (V/V] as well as on the scale-dependent drying performance of the continuous fluid bed dryers. Scale-independent, specification limits of the two granule material attributes particle fine fraction [%] and residual water content [%] could be defined, resulting in high tableting performance in terms of tabletability and compressibility. Based on these specification limits and the statistical evaluation of the process parameter DoE, a process design space for the continuous granulation and drying process for each scale was calculated. It came up, that this process design space was decreasing in range with increasing equipment scale. The applicability of the presented scaling approach in terms of granule and tablet properties could successfully be demonstrated by three control experiments performed on the different equipment scales. In sum, this work delivers a basis for a smooth transition of scales within process development on the investigated continuous twin screw granulation and drying lines.

Influence of binder attributes on binder effectiveness in a continuous twin screw wet granulation process via wet and dry binder addition.

The effect of a wide variety of binders on the quality of granules produced via continuous twin screw wet granulation was studied. Anhydrous dicalcium phosphate was used as poorly soluble filler and was granulated applying dry or wet addition of binders. Furthermore, dry and wet binder characteristics were determined and linked to the binder effectiveness. PVA 4-88 and starch octenyl succinate exhibited the lowest granule friability at low liquid-to-solid ratios, i.e. the highest binder effectiveness, which was attributed to fast binder activation based on the fast wetting kinetics of the binder, to efficient wetting of DCP particles, and to good spreading in the powder bed. The performance of wettability measurements in an early formulation development stage is therefore considered highly important. Additionally, an increased stickiness of the binder surface caused by high binder viscosity and slow dissolution kinetics also positively influenced the binder effectiveness. In conclusion, this study revealed which binder attributes have a critical impact on the granulation process of dicalcium phosphate. Additionally, dry binder addition proved successful for creation of high quality granules.

Native starch as in situ binder for continuous twin screw wet granulation.

The use of native starch as in situ binder in a continuous twin screw wet granulation process was studied. Gelatinization of pea starch occurred in the barrel of the granulator using a poorly soluble excipient (anhydrous dicalcium phosphate), but the degree of gelatinization depended on the liquid-to-solid ratio, the granule heating and the screw configuration. Furthermore, the degree of starch gelatinization was correlated with the granule quality: higher binder efficiency was observed in runs where starch was more gelatinized. SEM and PLOM images showed experimental runs which resulted in completely gelatinized starch. Other starch types (maize, potato and wheat starch) could also be gelatinized when processed above a critical barrel temperature for gelatinization. This barrel temperature was different for all starches. In situ starch gelatinization was also investigated in combination with a highly soluble excipient (mannitol). The lower granule friability observed using pure mannitol compared to a mannitol/starch mixture indicated that starch did not contribute to the binding, hence starch did not gelatinize during processing. The study showed that native starch can be considered as a promising in situ binder for continuous twin screw wet granulation of a poorly soluble formulation.

Design space determination and process optimization in at-scale continuous twin screw wet granulation

At-scale industrial continuous twin screw wet granulation process was analyzed and optimized via design of experiment (DoE). The Box-Behnken method was selected to investigate the influence of key process variables on granule properties and tablet properties. The effects of the key process variables were analyzed. The experimental results have demonstrated that both the granule properties and tablet properties are influenced by the throughput, the screw speed and the screw element. Particularly, the screw element type and the milling process were found having significant effects on tablet tensile strength and disintegration time. The design space (DS) based on volume average granule diameter (Y4 < 800 µm) and tablet disintegration time (Y8 < 4 min) was determined using Monte Carlo simulations. Validation experiments have shown the robustness of the DS. A case study of the DS application is presented. It was demonstrated how to select optimum working conditions of key process parameters based on the DS.

Managing API raw material variability during continuous twin-screw wet granulation

Very few studies have investigated the impact of raw material variability upon the granule critical quality attributes (CQAs) produced via twin-screw wet granulation (i.e., granule size distribution, density, flowability). In this study, the impact of the raw material variability of an active pharmaceutical ingredient (API) in a high dose formulation on the twin-screw wet granulation process and on the resulting granule quality attributes was investigated. In a previous study (Stauffer et al., 2018), eight API batches were characterized to determine the API batch-to-batch variability. Principal component analysis (PCA) was then used to analyse the raw material property differences between the API batches and to determine the causes of the batch-to-batch variability. In current study, the three principal components from that PCA model were used as factors together with twin-screw granulation process parameters (i.e., screw speed and liquid-to-solid ratio) in a D-optimal screening design of experiments to understand the influence of these factors upon the granule CQAs. It was found that the API particle size distribution and related properties (e.g., density, agglomeration profile) were critical for the granule CQAs. In a next step, the significant factors from the screening design results were used to determine the design space of the twin-screw granulation process for the studied formulation via a D-optimal optimisation design, herewith controlling the risk of failure for the potential API raw material variability. The possibility to obtain suitable granule CQAs with a risk of failure of 1% for all API batches was demonstrated. It was thus possible to identify a combination of process parameters that can manage the API batch-to-batch variability leading to granules with pre-defined suitable CQAs.

Simplified end-to-end continuous manufacturing by feeding API suspensions in twin-screw wet granulation

This study focussed on investigating the coupling of continuous manufacturing of drug substance and continuous manufacture of drug product. An important step in such an integrated end-to-end continuous manufacturing was envisioned by dosing the API as suspension into a twin-screw wet granulation process. To achieve this goal, a model drug substance (ibuprofen) was fed as a concentrated aqueous suspension (50% w/w) into a twin-screw granulator and compared against traditional solid feeding of the model drug substance to meet a target ibuprofen load of 60% w/w in the formulation. Granulation and compaction behaviour were evaluated to determine the impact of feeding API as suspension in twin-screw wet granulation on the critical quality attributes of the drug product. It was demonstrated that the ibuprofen suspension feed is comparable with the ibuprofen dry blend feed in twin-screw wet granulation. Next to enabling end-to-end continuous manufacturing, API suspension feed in twin-screw wet granulation could afford a number of additional advantages including manufacturing efficiency by removing the drying step for API, or overcoming processing issues linked to the bulk properties of the API powder (e.g. flowability).

Real-time feedback control of twin-screw wet granulation based on image analysis

The present paper reports the first dynamic image analysis-based feedback control of continuous twin-screw wet granulation process. Granulation of the blend of lactose and starch was selected as a model process. The size and size distribution of the obtained particles were successfully monitored by a process camera coupled with an image analysis software developed by the authors. The validation of the developed system showed that the particle size analysis tool can determine the size of the granules with an error of less than 5 µm. The next step was to implement real-time feedback control of the process by controlling the liquid feeding rate of the pump through a PC, based on the real-time determined particle size results. After the establishment of the feedback control, the system could correct different real-life disturbances, creating a Process Analytically Controlled Technology (PACT), which guarantees the real-time monitoring and controlling of the quality of the granules. In the event of changes or bad tendencies in the particle size, the system can automatically compensate the effect of disturbances, ensuring proper product quality. This kind of quality assurance approach is especially important in the case of continuous pharmaceutical technologies.

A novel approach to support formulation design on twin screw wet granulation technology: Understanding the impact of overarching excipient properties on drug product quality attributes

The overall objective of this work is to understand how excipient characteristics influence the drug product quality attributes and process performance of a continuous twin screw wet granulation process. The knowledge gained in this study is intended to be used for Quality by Design (QbD)-based formulation design and formulation optimization. Three principal components which represent the overarching properties of 8 selected pharmaceutical fillers were used as factors, whereas factors 4 and 5 represented binder type and binder concentration in a design of experiments (DoE). The majority of process parameters were kept constant to minimize their influence on the granule and drug product quality. 27 DoE batches consisting of binary filler/binder mixtures were processed via continuous twin screw wet granulation followed by tablet compression. Multiple linear regression models were built providing understanding of the impact of filler and binder properties on granule and tablet quality attributes (i.e. 16 DoE responses). The impact of fillers on the granule and tablet responses was more dominant compared to the impact of binder type and concentration. The filler properties had a relevant effect on granule characteristics, such as particle size, friability and specific surface area. Binder type and concentration revealed a relevant influence on granule flowability and friability as well as on the compactability (required compression force during tableting to obtain target hardness). In order to evaluate the DoE models’ validity, a verification of the DoE models was performed with new formulations (i.e. a new combination of filler, binder type and binder concentration) which were initially not included in the dataset used to build the DoE models. The combined PCA (principle component analysis)/DoE approach allowed to link the excipient properties with the drug product quality attributes.

Twin screw granulation: An evaluation of using micronized lactose as a solid binder

In twin screw wet granulation process, the binding excipients could be added in two ways: premixed with powder materials before granulation or dissolved in water as a solution. In this paper, the feasibility of using micronized lactose as a solid binder excipient in twin screw granulation process was examined. Different proportions of micronized lactose were mixed with lactose and microcrystalline cellulose (MCC) powder before granulation, respectively. As a comparison, hydroxypropyl cellulose (HPC) was prepared in solid and liquid phase (i.e. premixed with powder and dissolved as solution respectively). Granulation was carried out to investigate the binding potential by studying the effect of micronized lactose and HPC on the granules properties such as size, shape and surface structure. Due to its small size, micronized lactose was proven to be an ideal alternative as a solid binding excipient to provide strong bonds and produce granules with improved granule size distributions. Furthermore, the binding capacity of micronized lactose was also examined on the compact powder bed where the contact angle, nucleus hardness and surface structure were studied.

Assessment of spatial heterogeneity in continuous twin screw wet granulation process using three-compartmental population balance model

In this study, a novel three-compartmental population balance model (PBM) for a continuous twin screw wet granulation process is developed, combining the techniques of PBM and regression process modeling. The developed model links screw configuration, screw speed, and blend throughput with granule properties to predict the granule size distribution (GSD) and volume-average granule diameter. The granulator screw barrel was divided into three compartments along barrel length: wetting compartment, mixing compartment, and steady growth compartment. Different granulation mechanisms are assumed in each compartment. The proposed model therefore considers spatial heterogeneity, improving model prediction accuracy. An industrial data set containing 14 experiments is applied for model development. Three validation experiments show that the three-compartmental PBM can accurately predict granule diameter and size distribution at randomly selected operating conditions. Sixteen combinations of aggregation and breakage kernels are investigated in predicting the experimental GSD to best judge the granulation mechanism. The three-compartmental model is compared with a one-compartmental model in predicting granule diameter at different experimental conditions to demonstrate its advantage. The influence of the screw configuration, screw speed and blend throughput on the volume-average granule diameter is analyzed based on the developed model.

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.