Continuous Twin-screw Granulation Research Articles

Development of prediction model with machine learning in continuous twin screw granulation

Development of prediction model with machine learning in continuous twin screw granulation

Considering inelasticity in the real-time monitoring of particle size for twin-screw granulation via acoustic emissions

A recently developed process analytical technology (PAT) using artificial intelligence to form the framework of its model, combining frequency-domain acoustic emissions (AE) and elastic impact mechanics to accurately predict complex particle size distributions (PSD) in real-time. This model was modified in this study to give more accurate predictions for the more highly cohesive granules typical of pharmaceutical solid oral dosage formulations. AE spectra were collected from the granulated impacts of various formulations with ranging characteristics from largely elastic to highly inelastic collision responses. A viscoelastic (Hertzian spring-dashpot) and elastoplastic (Walton-Braun) contact force model were compared to understand how these different micro-mechanical approaches would affect the prediction accuracy of particle sizes relevant to granulation. Retraining the artificial intelligence model with the Walton-Braun transformation and a more comprehensive dataset of AE spectra spanning a broad range of granulated formulations showed the prediction error drop to as low as 2% compared to the original elastic version showing errors as large as 18.6% with representative formulations of the industry. The improved PAT shows good applicability to monitoring bimodal PSD that are typical of continuous twin-screw granulation.

Effect of fill level in continuous twin-screw granulator: A combined experimental and simulation study

• Fill level effect in twin-screw granulator on tablet hardness was investigated. • Fill level in twin screw granulator was directly measured in experiments. • Interparticle adhesion force increased with increase in fill level. • DEM simulations demonstrated high compressive force on particles at high fill level. • Combination of experiments and simulations revealed mechanism of fill level effect. Twin-screw granulators for continuous wet granulation have attracted interest in the pharmaceutical industry. The physical properties of granules and tablets prepared through the twin granulation process depend on several factors, such as screw and barrel geometries, operating conditions, and formulations of raw materials. The fill level has been reported to be one of the most important factors in determining granule properties. However, the mechanism of the fill level effect on granule properties has not yet been fully clarified. In this study, the effects of the fill level in the twin-screw granulator on granule and tablet properties were investigated through a combination of experimental and simulation studies. In the experiment, temporal changes in the fill level were directly measured. It was found that a high fill level increased granule strength, resulting in large tablet hardness. The discrete element method simulations demonstrated that the compressive force on the particles in the granulator strongly depends on the fill level. In addition, by combining the experimental and simulation results, it was quantitatively revealed that a high fill level increased the interparticle adhesion, leading to the high hardness of tablets prepared with the granules.

Continuous integrated production of glucose granules with enhanced flowability and tabletability

Glucose is widely used in both the food and pharmaceutical industry. However, the application of industrially crystallized glucose in solid dosage forms is challenged by its poor flowability and tabletability. To improve these characteristics continuous twin-screw granulation was tested, which has the potential to be integrated into the continuous production of solid glucose from corn starch. A completely continuous manufacturing line (including drying and milling) was developed and the different production steps were examined and synchronized. Our line was supplemented with an in-line applicable near-infrared spectroscopic probe to monitor the moisture content of the milled granules in real-time. The flowability and tabletability of the powder improved significantly, and tablets with acceptable breaking force (greater than 100 N) could be prepared from the granules. The developed continuous line can be easily installed into the industrial solid glucose production process resulting in pure glucose granules with adequate flow properties and tabletability in a simple, continuous and efficient way.

Mechanistic understanding of the effects of process and design parameters on the mixing dynamics in continuous twin-screw granulation

Wet granulation is a size enlargement process in which fine powders are agglomerated into larger granules via the presence of a liquid binder. Among various types and modes of granulation processes, twin-screw granulation is a popular continuous wet granulation technique. The typical residence time that powders spend in a twin-screw granulator are in the order of seconds, hence, the rigorous mixing of solid and liquid particles across particle sizes and equipment geometry becomes even more important. This study aims to improve the mechanistic understanding of the effect of process and screw parameters on the mixing dynamics inside a twin-screw granulator using dispersion coefficient as a key metric. The dispersion coefficient quantifies the dispersion and is directly proportional to the extent of mixing occurring inside the granulator. An analysis of the experimentally obtained dispersion coefficient is performed to understand the effect of key process and design parameters such as feed rate, screw speed, number of kneading elements and, stagger angle. A semi-mechanistic model that incorporates these parameters was developed to estimate and predict the dispersion coefficient. The model accurately predicts the dispersion coefficient values and the goodness-of-fit values (R2) for the test set and full data set were found to be equal to 0.920 and 0.932 respectively. This model was further tested by predicting the complete RTD curves using the predicted dispersion coefficients. The average goodness-of-fit value (R2) for the prediction of RTD curves for all the experimental runs was calculated to be equal to 0.698.

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.

Comparison between twin-screw and high-shear granulation - The effect of filler and active pharmaceutical ingredient on the granule and tablet properties

The aim of the study was to compare continuous twin-screw granulation (TSG) with batch-wise high-shear granulation (HSG). Two different formulations containing either microcrystalline cellulose (MCC) and mannitol or MCC and dibasic calcium phosphate (DCP) as fillers were used. Three different active pharmaceutical ingredients (APIs) (allopurinol, paracetamol and metformin HCl) were used as model substances. To find the suitable liquid-to-solid (L/S) ratio for the granulations, preliminary trials were carried out using a mixer torque rheometry (MTR). Both granule and tablet properties were studied. Granules were characterized with respect to particle size distribution and flowability, while tablets were analysed for tensile strength. Both granulation techniques produced granules with unimodal particle size distribution after milling with the selected L/S ratios. Continuous TSG was less sensitive for liquid amount than HSG when comparing the granule size and tensile strength of tablets. The tabletability of the MCC-DCP formulation was decreased after the wet granulation, whereas the tabletability of MCC-mannitol was increased after wet granulation. Tablets made of TSG granules had a higher tensile strength than HSG tablets for all formulations. Even the APIs with poor compaction properties produced tablets with sufficient tensile strength. All the model substances behaved in a same way independently of the particle size and solubility of the pure API. These findings confirmed that continuous twin-screw granulation is a good alternative to batch-wise high-shear granulation.

Continuous twin screw granulation: Robustness of lactose/MCC-based formulations.

In recent years, significant progress has been made in the field of continuous twin screw granulation. However, only limited knowledge is currently available on the impact of active pharmaceutical ingredient (API) properties on granule quality and processability. In this study, the response behavior of four formulations containing APIs (5-10% drug load) with diverse characteristics was compared to the behavior of the corresponding placebo formulation consisting of lactose, microcrystalline cellulose (MCC) and hydroxypropylmethylcellulose (HPMC). API selection was based on extensive material characterization, combining conventional testing with in silico descriptors. For each formulation, a design of experiments was set up, evaluating the impact of liquid to solid (L/S) ratio and screw speed. Response ranges, response behavior and processability of each of the four formulations proved very similar to the placebo formulation when an appropriate center point L/S ratio was chosen. Hence, this robust placebo formulation could prove useful by decreasing drug product development time and consequently providing patients with a faster access to innovative medicine. Additionally, APIs with similar properties exhibited highly comparable response behavior at similar L/S ratios, indicating the potential use of surrogate APIs in novel drug product development.

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.

Continuous twin screw granulation – An advanced alternative granulation technology for use in the pharmaceutical industry

Hot melt extrusion has been an exciting technology in the pharmaceutical field owing to its novel applicability. Twin-screw granulation presents a great potential and offers many advantages relative to conventional granulation processes. Different twin-screw granulation techniques, such as twin-screw dry granulation, twin-screw wet granulation, and twin-screw melt granulation, are currently being developed as robust and reproducible granulation processes. The competence of twin-screw granulation as a continuous manufacturing process has contributed to its suitability as an alternative granulation option within the pharmaceutical industry. In this article, different types of twin-screw granulation techniques were discussed. In addition, the screw elements, scale-up process, continuous twin-screw granulation which involves process analytical tools, and excipients were explored. This economical, industrially scalable process can be automated for continuous manufacturing to produce granules for the development of oral solid dosage forms. However, extensive research using process analytical tools is warranted to develop processes for the continuous manufacture of granules.

Continuous twin screw granulation: Impact of binder addition method and surfactants on granulation of a high-dosed, poorly soluble API.

Despite the recent commercialization of several drug products manufactured through continuous manufacturing techniques, knowledge on the formulation aspect of these techniques, such as twin screw wet granulation, is still rather limited. Previous research identified lactose/MCC/HPMC as a robust platform formulation for several model formulations, although granulation of the high-dosed, poorly soluble API mebendazole proved challenging. Therefore, current research evaluated the binder addition method (wet or dry) as well as surfactant (SLS) addition when using PVP, instead of HPMC. Compared to the previous formulation, using HPMC as binder, all four formulations with PVP yielded significantly stronger granules at similar to significantly lower liquid to solid (L/S) ratios. Through the combination of four replicate center composite circumscribed designs, each evaluating the impact of screw speed and L/S ratio on granule quality attributes, the effect of the formulation variables was assessed. Overall, L/S ratio had the most significant impact on granule characteristics whereas the effect of screw speed was negligible. Similar granule quality attributes were obtained for each formulation, although the addition of SLS and wet binder addition significantly reduced the required L/S ratio to achieve the desired characteristics. This significant reduction could prove useful for processing other formulations requiring high amounts of moisture, which could otherwise not be dried at a high throughput due to the limited drying capacity of the dryer unit of the Consigma system.

Continuous twin screw granulation: Influence of process and formulation variables on granule quality attributes of model formulations.

In recent years, continuous manufacturing techniques, such as twin screw wet granulation, have gained significant momentum. Due to the large diversity of the (model) formulations and equipment, it is often difficult to generalize conclusions about the importance of process settings. As only limited knowledge is available on the importance of formulation variables, this study focused on the systematic quantification of both process as formulation effects on critical quality attributes of granules from several model formulations. Apart from conventional process and formulation variables, also non-conventional process factors such as nozzle diameter, nozzle orientation and inclusion of a new type of size control elements were evaluated using a Plackett-Burman screening design. Although effects were often formulation-dependent, liquid-to-solid ratio proved the most influential variable for all formulations. Furthermore, binder concentration had a clear effect on granule characteristics, whereas barrel fill level and barrel temperature were less influential. The novel type of size control elements improved granule size distribution and density. The impact of nozzle diameter and wet binder addition proved negligible towards granule properties. Overall it was apparent that lactose/MCC-based formulations correlated better than lactose-based formulations, indicating the possible process robustness of the first filler combination to accommodate API and excipient variability and to handle APIs with different characteristics.

Continuous twin screw granulation: Impact of the starting material properties and various process parameters

The purpose of this study is to confirm the correlation between the formulation factors and the process parameters using multivariate analysis (MVA) during twin screw granulation. Various grades of lactose and MCC were used as starting materials and the characteristics of final granules were investigated by varying the L/S ratio and feed rate. The size distribution, friability, and various flow properties of granules using powder rheometer were evaluated. When the effect of formulation factors and process parameters were investigated, it was confirmed that the characteristics of granules change largely according to L/S ratio. MVA also showed that the influence of formulation factors on characteristics of granules was significant as L/S ratio. The feed rate had few effects on the characteristics of the granules. MVA is a useful tool to confirm the correlations of various factors. The properties of the starting materials are important in the continuous twin screw granulation process.

Heat Transfer Evaluation During Twin-Screw Wet Granulation in View of Detailed Process Understanding.

During the last decade, the pharmaceutical industry has shown a growing interest in continuous twin-screw granulation (TSG). Despite flourishing literature on TSG, limited studies focused on fundamental process understanding on its mechanisms. In current study, granule quality attributes along the length of the TSG barrel were evaluated together with heat transfer in order to achieve a more fundamental understanding of the granulation process. An experimental setup was developed allowing the collection of granules at the different TSG compartments. In addition to the determination of typical granule attributes, mechanical energy, barrel and granule temperature (measured using an in-line implemented infra-red camera) were measured to evaluate heat transfer occurring at the different compartments and to relate them to granulation mechanisms. Collected data identified wetting enthalpy and friction forces as the main sources of heat along the granulator length. Wetting occurred in the wetting zone and generated temperature increase depending on liquid-to-solid ratio and powder wettability. In the kneading zones, granule temperature increase was proportional to mechanical energy. While it is usually admitted that granule consolidation and reshaping are the consequence of the high shear experienced by the granules, it was highlighted that most of the mechanical energy is converted into thermal energy with no correlation between mechanical energy and granule size distribution. Combined mass and energy balance of the granulation process are therefore necessary to capture the interaction between granule properties and physico-chemical and mechanical phenomena occurring in each compartment.

Analysis of Microstructure of Granules Prepared by Continuous Twin Screw Granulator Using X-Ray Micro-computed Tomography.

Granules prepared by a continuous twin screw granulator (TSG) were analyzed by X-ray micro-computed tomography (X-ray μCT) and the relationships between porosity of granules and granule properties were investigated. A model formulation containing ibuprofen, lactose monohydrate, microcrystalline cellulose, and hydroxypropyl cellulose was used. The porosity of granules was measured by X-ray μCT and mercury porosimetry. The data sets obtained by both methods showed linear correlation despite different values, which were attributed to the resolution of X-ray μCT and a low-signal-to-noise ratio of the original cross-sectional images. The porosity of granules measured by X-ray μCT decreased from 11-14 to 6-7% as liquid-to-solid ratio (L/S) increased, while the standard deviation (S.D.) of the porosity of individual granules decreased from 4-5 to 2%. L/S affected the porosity of granules. By contrast, the effect of screw speed was not significant. Pressure transmission, G, which indicates the liquid dispersion in wet kneaded masses, increased as the porosity of granules and the S.D. decreased. The cross-sectional images showed that granules were densified as L/S increased. Based on these results, the effect of L/S on the porosity of granules can be explained by liquid dispersion and densification of the wet granules. The porosity of granules measured by X-ray μCT showed good linear correlation with friability and drug dissolution rate (R2 = 0.9107 and 0.8834, respectively). This study revealed that the drug dissolution rate was regulated by a disintegration step in which the porosity of granules plays an important role.

Assessing Particle Segregation Using Near-Infrared Chemical Imaging in Twin Screw Granulation.

In the present study the application of near-infrared chemical imaging (NIR-CI) for assessing particle segregation in granules from continuous twin screw granulation (TSG) granules, were the complex attributes of the machinery configuration in relation to particle segregation is not well understood was investigated. Experiments were performed along the compartmental length of the TSG barrel channel by varying the screw element type and liquid binder viscosity. Examination of the data showed a direct correlation between dispersion due to shear force and de-mixing of particles, which allowed for identification of fundamental granule segregation mechanisms affecting content uniformity in TSG. Particle segregation behavior was linked to dispersion due to shear force through a proposed regime mapping approach which links de-mixing potential to controlling granule formation mechanisms with a new dimensionless mixing number. This was carried out in order to provide a general guideline of how particles segregate along the length of the TSG barrel channel.

Managing API raw material variability in a continuous manufacturing line - Prediction of process robustness.

Many studies on continuous twin-screw granulation only focus on the granulator without linking this process step to the upstream and downstream unit operations. Product critical quality attributes (CQAs) are however not only determined by the granulation step. In this study, the possibility to manage the batch-to-batch variability of an active pharmaceutical ingredient (API) in a high drug loaded formulation on a continuous line was investigated to obtain consistent tablet CQAs. As the ultimate goal of continuous manufacturing is to produce 24/7, current study also aimed at guaranteeing long term stability of the process. To do so, previously identified API critical material attributes (CMAs) were varied together with granulation, drying and milling critical process parameters (CPPs) in a screening design of experiments to understand the influence of these factors upon product CQAs and process stability. To evaluate the factors affecting the process stability with a reduced amount of materials, process deviations recorded by process sensors were used. While product CQAs only depended on process CPPs, process stability was strongly affected by API CMAs. The effect of API batch-to-batch variability on process stability could nonetheless be managed by applying suitable granulation conditions. Therefore, appropriate ranges of CPPs were defined to ensure both product CQAs and process stability. By studying the fully integrated continuous manufacturing line, it was possible to highlight the interactions between the different unit operations and the API CMAs and to design a robust process.

Advanced process design and understanding of continuous twin-screw granulation via implementation of in-line process analytical technologies

Process analytical technologies (PAT) are identified as an essential element in the Quality by Design framework, providing the cornerstone to implement continuous pharmaceutical manufacturing. This study is concerned with employing three in-line PATs: Eyecon™ 3D imaging system, Near-infrared spectroscopy (NIRS) and Raman spectroscopy (RS), in a continuous twin-screw granulation process to enable real-time monitoring and prediction of critical quality attributes of granules. The Thermo Scientific™ Pharma 11 twin-screw granulator was used to manufacture granules from a low-dose formulation with caffeine anhydrous as the model drug. A 30-run full factorial design including three critical process parameters (liquid to solid ratio, barrel temperature and throughput) was conducted to evaluate the performance of each analytical tool. Eyecon™ successfully captured the granule size and shape variation from different experimental conditions and demonstrated sufficient sensitivity to the fluctuation of size parameter D10 in the presence of process perturbations. The partial least square regression (PLSR) models developed using NIRS showed small relative standard error of prediction values (less than 5%) for most granule physical properties. In contrast, the RS-based PLSR models revealed higher prediction errors towards granule drug concentration, potentially due to the inhomogeneous premixing of raw materials during calibration model development.

A comprehensive analysis and optimization of continuous twin-screw granulation processes via sequential experimentation strategy

Nowadays twin-screw granulation has been emerging as an attractive continuous wet granulation technique. This study was geared towards better process design and understanding with emphasis on bridging the knowledge gap between input and output variables by employing sequential experimentation strategy. A low-dose formulation for granulation experiments contained anhydrous caffeine as the model drug. In the first phase of parameter screening, D-optimal design and stepwise regression were leveraged to develop interaction models following the examination of various quantitative and qualitative factors of potential importance. To maximize the design space dictated by predefined quality target values, several variables were fixed at optimum levels: 700 rpm screw speed, 60° kneading element staggering angle, 5 kneading elements and distributive feed screw in the screw configuration. In the second phase of characterization, response surface design was utilized to investigate the dependence of critical quality attributes of granules and tablets on selected critical process parameters (L/S ratio, throughput and barrel temperature). The results indicated that the influence of throughput and barrel temperature was relatively inferior to L/S ratio. Higher degree of liquid saturation led to granules with narrower size distribution, smaller porosity and enhanced flowability and tablets with declining tensile strength yet slackened drug release.