Twin-screw Granulation Research Articles

Impact of Different Dry and Wet Granulation Techniques on Granule and Tablet Properties: A Comparative Study

Four granulation techniques were compared evaluating their impact on granule properties and the tablet tensile strength. A common formulation was chosen to be processed with both wet and dry granulation techniques: roll compaction/dry granulation, high-shear granulation, twin-screw granulation, and fluidized-bed granulation. The produced granules were characterized in terms of granule size distribution, X-ray powder diffraction, scanning electron microscopy, porosity, and strength. Granules were tableted, and the tablets were evaluated in terms of tensile strength and mass variation. A particular focus was given to granule strength measurements. Granule strength showed to be strongly affected by the used granulation technique. Moreover, a nonlinear inverse correlation was identified between granule strength and tablet tensile strength. High-shear granulation produced the densest and strongest granules, which presented the lowest tablet tensile strength. Granules manufactured by roll compaction/dry granulation showed no loss in tabletability with the used formulation even for the more compacted and strong granules. Tablets produced by the fluidized-bed granulation showed the best properties in terms of tensile strength and mass variation. However, twin-screw granulation presented comparable results for the specific formulation evaluated in the study, thus revealing a great potential of this technique.

Characteristics of multi-component formulation granules formed using distributive mixing elements in twin screw granulation

This work examines the influence of pharmaceutical powder formulation characteristics on granule properties formed using distributive mixing elements (DMEs) in twin screw granulation. High and low drug dose formulations with three different active pharmaceutical ingredients (APIs) were considered. The type and concentration of the API in the formulation significantly affected the dry blend particle size distribution and the wet blend dynamic yield strength. However, despite the differences in blend properties, the granule size distributions were not significantly affected by the type of API used. The granule size distributions were solely the functions of the liquid-to-solid ratio and screw element geometry. However, the granule porosities were observed to be dependent on both the liquid-to-solid ratio and the dynamic yield strength of the blends. This work is the first to study the influence of drug loading and API type on the granule attributes produced using distributive mixing elements.

In-Depth Evaluation of Data Collected During a Continuous Pharmaceutical Manufacturing Process: A Multivariate Statistical Process Monitoring Approach

The present work presents an in-depth evaluation of continuously collected data during a twin-screw granulation and drying process performed on a continuous manufacturing line. During operation, the continuous line logs 49 univariate process variables, hence generating a large amount of data. Three identical 5-h continuous manufacturing runs were performed. Multivariate data analysis tools, more specifically latent variable modeling tools such as principal component analysis, were used to extract information from the generated data sets unveiling process trends and drifts. Furthermore, a statistical process monitoring strategy is presented. The approach is based on the application of multivariate statistical process monitoring to model the variables that remain around a steady state.

Twin-screw granulation – a systematic analysis of process parameters

Twin-screw granulation has a significant advantage over traditional granulation methods leading to the possibility of continuous manufacturing. Although this technology has drawn attention in recent years, the general understanding of the process is limited. This study gives a brief overview of the most important process parameters and their influence on product quality. Experimental results from a benchtop granulator and an in-line particle size measurement have been analysed. From this basic study conclusions can be drawn how to tailor the particle size distribution in twin-screw granulation. The most crucial parameters are the liquid-to-solid ratio and the filling level of the screws.

Continuous Single-Step Wet Granulation with Integrated in-Barrel-Drying.

It was investigated if continuous wet granulation and drying could be combined in a twin-screw granulator with the aim to provide (pre-)dried granules in a single-step process, i.e. in-barrel-drying. To have a consistent and robust material propulsion mechanism, a twin-screw granulator was divided into two compartments. One compartment was operated at lower temperature to granulate and to pre-heat the material, while another compartment was operated at very high temperature to evaporate the granulation liquid as rapidly as possible. Design of experiments was used to investigate the in-barrel-drying process in detail. The process was further investigated for twin-screw wet granulation with API suspension feed, and compared against traditional fluidised-bed drying. Granule and compact properties were evaluated to study the process impact on the product quality. In-barrel-drying was demonstrated as feasible and yielded completely dried and granulated material at specific settings. The evaporation zone temperature and the processed mass of water were identified as key parameters to balance the evaporation capacity of the process and the material throughput. Granules and compacts showed an acceptable product quality. In-barrel-drying can be used to condense the wet granulation and drying process steps into one piece of equipment, thereby limiting or even omitting downstream drying process steps.

A high-dimensional, stochastic model for twin-screw granulation – Part 1: Model description

In this work we present a novel four-dimensional, stochastic population balance model for twin-screw granulation. The model uses a compartmental framework to reflect changes in mechanistic rates between different screw element geometries. This allows us to capture the evolution of the material along the barrel length. The predictive power of the model is assessed across a range of liquid-solid feed ratios through comparison with experimental particle size distributions. The model results show a qualitative agreement with experimental trends and a number of areas for model improvement are discussed. A sensitivity analysis is carried out to assess the effect of key operating variables and model parameters on the simulated product particle size distribution. The stochastic treatment of the model allows the particle description to be readily extended to track more complex particle properties and their transformations.

Twin Screw Granulation: Effects of Properties of Primary Powders.

Lactose and mannitol are some of the most commonly used powders in the pharmaceutical industry. The limited research published so far highlights the effects of process and formulation parameters on the properties of the granules and the tablets produced using these two types of powders separately. However, the comparison of the performance of these two types of powders during twin screw wet granulation has received no attention. The present research is focused on understanding the granulation mechanism of different grades of two pharmaceutical powders with varying properties (i.e., primary particle size, structure, and compressibility). Three grades each of lactose and mannitol were granulated at varying liquid to solid ratios (L/S) and screw speed. It was noticed that primary powder morphology plays an important role in determining the granule size and structure, and tablet tensile strength. It was indicated that the processed powders such as spray-dried and granulated lactose and mannitol can be used in formulation for wet granulation where flowability of active pharmaceutical ingredient (API) is poor.

Twin Screw Granulation: An Investigation of the Effect of Barrel Fill Level.

This paper focuses on investigating the influence of varying barrel fill levels on the mean residence time, granule properties (median size, size distribution, and shape), and tensile strength of tablets. Specific feed load (SFL) (powder feed rate divided by screw speed) and powder feed number (PFN) (i.e., powder mass flow rate divided by the product of screw speed, screw diameter, and the material density in the denominator) were considered as surrogates for the barrel fill level. Two type of powders (lactose and microcrystalline cellulose (MCC)) were granulated separately at varying fill levels at different liquid-to-solid ratios (L/S). It was observed that by controlling the barrel fill level, the granule size, shape, and tablet tensile strength can be maintained at specific L/S. It was also noticed that the mean residence time decreased with increasing fill levels in the case of both lactose and MCC powder. However, it was only found to be related to the change in granule size in case of granulating microcrystalline cellulose at varying fill levels. At very high fill levels, granule size decreased, owing to a limited interaction between MCC powder and liquid at high throughput force and short residence time.

On the modelling of granule size distributions in twin-screw wet granulation: Calibration of a novel compartmental population balance model

In recent years, novel developments in the continuous manufacturing of solid dosage forms using twin-screw wet granulation have grasped the attention of the pharmaceutical industry. In spite of this progress, there still exists a lack of fundamental knowledge on the physical processes occurring in the barrel of the twin-screw granulator. A major contributor to this knowledge gap has been the unavailability of measurements of granule properties (particle size, liquid content, porosity, etcetera) along the length of the barrel. Recently conducted tedious measurements at different barrel locations have been essential to build a hypothesis in terms of locally occurring mechanisms in twin-screw wet granulation. This paper proposes a novel kernel for modelling either the uni- or bimodal behaviour observed at different L/S ratios in the wetting zone, assuming pure aggregation only. Furthermore, a two stage (wetting and kneading zone) compartmental population balance model is constructed to successfully simulate granule sizes from preblend to the end of the granulator. This population balance model can simulate granule size distributions at a reasonable accuracy both in the case of single compartments as well as in the full two stage compartmental set-up. The proposed model in this paper is a first important step in knowledge build-up of twin-screw granulation and towards a general population balance model for twin-screw wet granulation.

Twin-screw granulation: Understanding the mechanical properties from powder to tablets

Granulation is a technique commonly used before tabletting because it solves powder handling problems and ensures uniform filling of the compression dies. However, granulation can have an adverse impact on powder transformation into a tablet; i.e. tabletability.The aim of this work is to examine the effect of continuous wet granulation using twin-screw granulator (TSG) on the tabletability of the granulated materials. Also, the study investigates the mechanisms that dictate the change in tabletability after wet granulation using TSG.Granules and tablet properties were characterised using a range of mechanical and X-ray analysis techniques. It was found that wet granulation using TSG has an impact on the tabletability of the granulated pharmaceutical excipients. The presented work suggests that there is a correlation between the yield pressure, plastic and elastic work of the primary powder and the percentage of change in tabletability after granulation. The study found that plastically deformable materials like microcrystalline cellulose (MCC) experience a significant reduction of tabletability (up to 67%) when granulated compared with the direct compression of its powder. On the other hand, brittle materials like crystalline mannitol C160 or calcium phosphate dibasic anhydrous maintain their tabletability after twin-screw granulation.The presented results show that the granule size of microcrystalline cellulose and mannitol 100 SD does not affect tabletability for the range studied. However increasing the strength of granules was found to cause reduction of the tabletability. On the other hand, the granule size of mannitol C160 and calcium phosphate dibasic anhydrous did affect its tabletability.

Effect of formulation and process variables on lipid based sustained release tablets via continuous twin screw granulation: A comparative study

The current study's aim is to prepare lipid based sustained release tablets via a twin-screw granulation technique and compare those dosage forms with conventional techniques, namely wet granulation and direct compression. The granules were successfully manufactured in a single-step, continuous twin-screw granulation process with a low proportion of binder (Klucel™ EF, HPC SSL) using Compritol® 888 ATO, Precirol® ATO 5 and Geleol™ as sustained release agents. The granules prepared showed good flow characteristics and compaction properties. DSC and XRD studies were conducted to characterize the granules prepared via a twin-screw granulation method and the results demonstrated the crystalline nature of lipids within the granules. FTIR data indicated that there were no interactions with the formulation components investigated. The formulations developed by all three methods were compressed into tablets with a mechanical strength of 14–16 KP. The tablets formulated were characterized for physicochemical properties, in vitro drug release studies, water uptake and erosion studies. These results showed that the drug was not completely released after 24 h for tablets developed by the wet granulation process using all three lipids. The tablets prepared by the direct compression method demonstrated a burst release within 8 to 10 h from Precirol ATO 5® and Geleol™ formulations compared to Compritol® 888 ATO. However, tablets prepared using twin-screw granulation exhibited sustained release of the drug over 24 h and the water uptake and erosion results were in accordance with dissolution data. Stability data for 45 days at accelerated conditions (40 °C/75% RH) showed similar release profiles with ƒ2 values above 50 for all of the twin screw granulation formulations, indicating the suitability of the process for formulating sustained release tablets. These findings of a single-step, continuous twin-screw granulation process are novel and demonstrate new opportunities for development of sustained release tablets.

A high-dimensional, stochastic model for twin-screw granulation Part 2: Numerical methodology

In the second part of this study, we present the stochastic weighted particle population balance framework used to solve the twin-screw granulation model detailed in the first part of this study. Each stochastic jump process is presented in detail, including a new nucleation jump event capable of capturing the immersion nucleation processes in twin-screw granulation. A variable weighted inception algorithm is presented and demonstrated to reduce the computational cost of simulations by up to two orders of magnitude over traditional approaches. The relationship between the performance of the simulation algorithm and key numerical parameters within the nucleation jump process are explored and optimum operating conditions are identified. Finally, convergence studies on the complete simulation algorithm demonstrate that the algorithm is very robust against changes in the number of stochastic particles used, provided that the number of particles exceeds a minimum required for numerical stability.

Process monitoring and evaluation of a continuous pharmaceutical twin-screw granulation and drying process using multivariate data analysis

The present study aims at acquiring an in-depth process knowledge about a twin-screw granulation and fluid bed drying process performed on the commercially available continuous line. Batch Statistical Process Monitoring (BSPM) principles are used to describe and monitor the variables with a relevant time-related trajectory. The continuous granulator operates in a truly continuous manner and variables logged by this unit do not present time-relevant features. On the other hand, the fluid bed dryer is divided in six identical cells, which are sequentially filled and discharged, ensuring a continuous flow of material. Multiple variables logged at the dryer and subsequent product control unit, present time-relevant features. A profound analysis of these variables logged during normal operation, as well as an in-depth description of the startup period of the different units, were achieved.The BSPM concepts allows to monitor the time relevant variables of this continuous manufacturing line, to detect and diagnose deviations from normal operation and assign possible causes for the disturbances.

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.

A fast multipole boundary element method implemented for wet single particle and wall interactions

The progress is described in developing a parallel computer code to study the dynamics of wet granular systems based on the Fast Multi-pole Boundary Element Method (FMBEM). Here, three examples are considered that have closed-form or numerical solutions and thus able to act as benchmarks. They involved capillary interactions, the formation of a solid-solid contact when a particle approaches a solid wall while immersed in a Newtonian fluid, and the isoviscous hydrodynamic and elastohyrodynamic sliding of a particle. While computationally more expensive than DEM, there are a number of advantages such as extending interactions from the pendular to more saturated states, the ease with which non-spherical particles can be modelled and the ability to model wet granular systems that may exhibit transitions from frictional to lubricated flow. Consequently, FMBEM is able to model wet agglomerates more realistically than DEM and this is important for improving the performance of twin screw granulation, which is the intended application of the current work.

Hydrophobic/hydrophilic powders: Practical implications of screw element type on the reduction of fines in twin screw granulation

This study focuses on the role that various screw elements play in the reduction of fines in twin screw wet granulation (TSG) when using increasing amounts of hydrophobic component in the formulation. The elements used are conveying-type elements (CE-type), kneading elements (KE-type) and tooth mixing-type elements (TME-type)). Fines are defined as <150 μm granules. Further, this work attempts to rationalize the positioning of the various screw elements along the barrel by studying the granule size, granule porosity, liquid binder distribution and residence time distribution results. The length of the screw elements was kept constant to ensure constant and comparable mixing quality.It was found that CE-type elements promoted poor mixing through concentration of activity in the intermeshing region of the twin screw, which resulted in large agglomerates being formed, together with large amounts of <150 μm granules. At increased formulation hydrophobicity, the distribution of the liquid binder droplets using the CE-type elements became unachievable, forming liquid marbles - ‘solid particles spreading around the liquid droplet’. The order of superior cross-sectional mixing behavior across the barrel channel width was observed to be CE < KE < TME, particularly with increase in formulation hydrophobicity. This was due to progressively improved liquid distribution with increase in material residence time, which resulted in less production of <150 μm granules and greater extent of granule formation with that order of elements. The axial cuttings through the flights of the CE-type elements are necessary to reduce the internal free volume of the intermeshing gap and cross-sectional area which promote material compression and higher degree of fill before the mixing zone in TSG. Whilst, the increase in internal free volume of the mixing elements provide more cross-sectional free volume for granules to be compacted.

Breakage and drying behaviour of granules in a continuous fluid bed dryer: Influence of process parameters and wet granule transfer

Although twin screw granulation has already been widely studied in recent years, only few studies addressed the subsequent continuous drying which is required after wet granulation and still suffers from a lack of detailed understanding. The latter is important for optimisation and control and, hence, a cost-effective practical implementation. Therefore, the aim of the current study is to increase understanding of the drying kinetics and the breakage and attrition phenomena during fluid bed drying after continuous twin screw granulation. Experiments were performed on a continuous manufacturing line consisting of a twin-screw granulator, a six-segmented fluid bed dryer, a mill, a lubricant blender and a tablet press. Granulation parameters were fixed in order to only examine the effect of drying parameters (filling time, drying time, air flow, drying air temperature) on the size distribution and moisture content of granules (both of the entire granulate and of size fractions). The wet granules were transferred either gravimetrically or pneumatically from the granulator exit to the fluid bed dryer. After a certain drying time, the moisture content reached an equilibrium. This drying time was found to depend on the applied airflow, drying air temperature and filling time. The moisture content of the granules decreased with an increasing drying time, airflow and drying temperature. Although smaller granules dried faster, the multimodal particle size distribution of the granules did not compromise uniform drying of the granules when the target moisture content was achieved. Extensive breakage of granules was observed during drying. Especially wet granules were prone to breakage and attrition during pneumatic transport, either in the wet transfer line or in the dry transfer line. Breakage and attrition of granules during transport and drying should be anticipated early on during process and formulation development by performing integrated experiments on the granulator, dryer and mill.

Development of an in-line Raman spectroscopic method for continuous API quantification during twin-screw wet granulation

Raman spectroscopy was evaluated as a process analytical technology (PAT) tool for continuous API quantification during twin-screw wet granulation. Therefore, a Raman probe was implemented in front of the granulator barrel. This setup enabled the collection of Raman spectra upon a constant granule flow.To develop an in-line PLS calibration model, eight binary mixtures of the API and lactose monohydrate with API contents between 5 and 50% were pre-blended and granulated in a twin-screw granulator with a screw speed of 150 rpm and a powder feed rate of 40 g/min. Water was used as a granulation liquid with different liquid to solid ratios depending on the API content. Ibuprofen and diclofenac sodium were chosen as model drugs and separated PLS models were built for each API.The predictive performance of the developed PLS models was determined by granulating and monitoring new test samples containing different API concentrations. This evaluation showed that the models were able to predict the API concentration with an RMSEP of 0.59% for ibuprofen and 1.5% for diclofenac sodium.In a second part, the developed in-line Raman spectroscopic method was used to determine the API concentration during a split feeding process. Therefore, the API and lactose monohydrate were added by two independently adjustable feeders into the twin-screw granulator barrel. The in-line spectroscopy analysis which was verified by UV-analysis indicated that the mixing ability of the twin-screw granulator was good for the used settings and all adjusted API concentrations.

Tailored granule properties using 3D printed screw geometries in twin screw granulation

Twin screw granulation is becoming increasingly relevant due to its compact size, continuous and robust mode of operation, customizable design, and flexible production capacity. This work describes the experimental study undertaken to understand the dependence of granule properties on the screw element design in a twin screw granulator. A CAD geometry analysis of the free volume in the granulator revealed that there is a direct quantitative correlation between the screw geometry and the maximum size and aspect ratio of the granules obtained using conveying elements. Conveying element geometries with different pitch lengths were 3D printed to generate cost-effective prototypes of the designs. Wet granulation experiments were performed using the 3D printed designs to test the hypothesis that the correlation between the granule shape and maximum granule size and the screw element geometry is predictable a priori. The feasibility of 3D printing method for fabricating new screw element designs is examined. Quality-by-Design strategies and scale-up criteria for twin screw granulation are discussed.

Transparent predictive modelling of the twin screw granulation process using a compensated interval type-2 fuzzy system

In this research, a new systematic modelling framework which uses machine learning for describing the granulation process is presented. First, an interval type-2 fuzzy model is elicited in order to predict the properties of the granules produced by twin screw granulation (TSG) in the pharmaceutical industry. Second, a Gaussian mixture model (GMM) is integrated in the framework in order to characterize the error residuals emanating from the fuzzy model. This is done to refine the model by taking into account uncertainties and/or any other unmodelled behaviour, stochastic or otherwise. All proposed modelling algorithms were validated via a series of Laboratory-scale experiments. The size of the granules produced by TSG was successfully predicted, where most of the predictions fit within a 95% confidence interval.