High-shear Granulation Research Articles

Towards a unified theory of wet agglomeration

Size control in granulation is of great importance yet is often difficult to achieve. While numerical and analytical models have previously been reported there is still no comprehensive model to describe wet agglomeration systems. In this paper the basis for a new analytical solution towards predict limiting granule size is suggested. The focus of the model is on bulk behaviour of the granules where the interactions in the granular bulk after the initial contact between agglomerating granules continues to affect the properties, such as in high-shear granulation as well as flow processes such as pan or drum agglomeration. The model as developed assumes that granule size is limited by both saturation and dynamic interactions, and matches the results in the literature regarding the final and continuous growth behaviour in those systems where the model is appropriate. Based on the factors that limit the size, granule growth behaviour can be predicted as a consequence of consolidation. The model matches the behaviour of systems captured by classical growth regime maps in a more quantitative manner, and should allow improved scaling as the model develops.

Preparation and Characterization of Hydrophilic Polymer Based Sustained-Release Matrix Tablets of a High Dose Hydrophobic Drug.

The objective of this study was the preparation and characterization of a sustained-release matrix tablet containing a high-dose hydrophobic drug and its comparison with marketed products. In the present study, HPMC was applied as the matrix-forming polymer for the sustained release of clarithromycin (500 mg). The compatibility of clarithromycin and excipients was studied using a binary mixture approach and compatible excipients were selected. Matrix tablets were prepared using the high-shear wet granulation technique. Tablets were compressed using oblong (19 mm), shallow concave punches, under a compression weight of 900 mg/tablet. The flow of granules was evaluated by determining their bulk density, tapped density, angle of repose, Hausner ratio, and Car’s index. Compressed tablets were tested for their physical parameters, mechanical characteristics, drug content, and in vitro drug release, as per United States Pharmacopeia (USP). Clarithromycin is a drug having poor water solubility and showed compatibility with all the excipients used in the formulation of polymeric matrix tablets. FTIR spectra of clarithromycin, before and after being subjected to the stress conditions, confirmed the compatibility of clarithromycin and other ingredients of the matrix tablets. All the formulations exhibited good rheological characteristics and all the parameters related to flow showed results in the acceptable range. Physically, matrix tablets were smooth and shiny, without any surface defects. Weight variation (±5%) and drug content of the tablets (95–102%) were within the pharmacopeial limits. HPMC successfully sustained the drug release for 24 h. It is concluded from the study that dissolution rate of clarithromycin can be sustained using hydrophilic polymer (HPMC) as a release-controlling agent.

Does Direct Transfer from A High Shear Granulator To a Fluidized Bed Dryer Improve Finished Tablet Quality Attributes?

Does Direct Transfer from A High Shear Granulator To a Fluidized Bed Dryer Improve Finished Tablet Quality Attributes?

Comparisons of iron ore granulation and sintering performance between horizontal high-shear granulators and drum granulators

Granulation is a key operation unit in preparation of iron ore raw materials. This work presented an experimental study on the iron ore granulation and sintering using a novel horizontal high-shear granulator and a traditional drum granulator. The mixing and granulation performance and the effect of granulation on sintering indicators were analyzed. The results showed that the optimal filling level of the shear granulator was about 9%, which was slightly lower than that of the drum granulator (12%). However, the uniformity, bed permeability and the fracture strength of the granules from the shear granulator were significantly better than those from the drum granulator. Compared with the drum granulator, the shear granulator had better mixing ability in the axial direction, more even distributions of water and calcium and less segregation. For the thick-bed sintering with a height of 900 mm, the sintering indicators in terms of sintering speed, sinter yield, strength and flue composition showed the shear granulator was significantly better than that of the drum granulator.

Switching from batch to continuous granulation: A case study of metoprolol succinate ER tablets

Continuous manufacturing (CM) has been used to produce several immediate release drug products. No extended-release (ER) product manufactured employing CM technology has been approved yet. This study investigated the critical aspects of switching from the batch mode of high shear granulation to the continuous operation of twin-screw granulation for extended-release tablets. Metoprolol succinate ER tablets was used as a model ER formulation for this purpose. A central composite design (CCD) was employed to determine the effects of high shear granulator (HSG) parameters, namely impeller speed, granulation time, and binder liquid feeding rate, on the critical granulation characteristics important for product performance. These critical granulation characteristics served as a guide for switching from the batch processing to the continuous operation for achieving the same breaking strength and dissolution for this ER metoprolol tablets.The granulation time was the most critical factor affecting the bulk properties of granules which contributed to tablet dissolution. The higher density and lower compressibility of granules were attained at the longest granulation time of 5.4 min with the fastest liquid feeding rate of 75 g/min. The granules’ density was the primary factor negatively affecting the dissolution of metoprolol tablets. However, the breaking strength of tablets confounded the effect of granules density on metoprolol dissolution. Switching the processing parameters of high shear granulation to twin-screw granulation achieved similar dissolution profiles (F2 greater than 50). The screw speed was not found to affect bulk properties of granules. The root cause of granulation failures in twin-screw granulation, such as premature consolidation, excessive swelling, poor cohesion, inconsistent shearing effects, and formation of deformed agglomerates, were identified. In conclusion, the use of critical granulation characteristics through a performance-based approach of ER tablets facilitated the switching of manufacturing of an ER formulation form batch to continuous operation.

Novel preparation approach with a 2-step process for spherical particles with high drug loading and controlled size distribution using melt granulation: MALCORE®

A novel approach for preparing drug-containing particles (DCPs) with controlled size distribution and high drug loading was developed using melt granulation. This approach comprises two steps. First, melting component adsorbed particles (MAs) were prepared by mixing and heating the melting components with a porous carrier using a high shear granulator. Second, DCPs were prepared by layering the drug on MAs using a fluidized bed rotor granulator. The time taken for both steps was within 30 min. Adding the polymer in the second step remarkably increased the viscosity of the mixture of melting components and the polymer. Therefore, DCPs could be successfully loaded with a high amount of drug (70% w/w). The particle size distribution of the DCPs was narrow, and it depended on that of the MAs. The flowability of the DCPs was excellent, and the sphericity was close to 1. A unique particle formulation mechanism was suggested based on the observation of DCPs using scanning electron microscopy. The manufacturing time and DCP characteristics were not affected by the manufacturing scale. In conclusion, we have successfully developed a highly efficient novel approach for preparing optimal DCPs through melt granulation, named “Melt Adsorption and Layering with Porosity Core” (MALCORE®).

The impacts of method selectivity and binders on the properties of carbamazepine granules and their applications: A case study

Background: Carbamazepine (CBZ) is a BCS II class drug, having many challenges in solubility, flowability, and compactibility. The study focused on the improvement of solubility, flow behavior, and drug release of carbamazepine. Methods: Low shear granulation (LSG), extrusion spheronization (ES), high shear granulation (HSG), fluid bed granulation (FBG), and hot melt granulation (HMG) methods were employed to prepare CBZ granules. Polyvinylpyrrolidone (PVP) K29/32, PVP K90, and Hydroxypropyl methylcellulose (HPMC) E5 were used as a binder. The drug to binder ratio was maintained in the proportion of 95:5. The nature of granules was analyzed by using X-ray Diffraction and Differential Scanning Calorimetry techniques. A powder flow tester was utilized to study the flow characteristics of the granules. Results: The HMG has successfully converted the crystalline structure of CBZ granules into an amorphous form. Dispersive and distributive mixing in the HMG has achieved better solid dispersion and fast drug release. The ES technique has reported the incompressible nature of the granules. PVP K90 and HPMC E5 were superior binders for imparting strength to the CBZ granules than PVP K29/32. The FBG has exhibited the free-flowing nature of granules due to their uniform and spherical shape. Conclusion: The HMG and FBG were the most effective methods that have remarkably improved drug release, flow properties, and compactibility of CBZ granules.

Investigation on the granulation behavior of iron ore fine in a horizontal high-shear granulator

High-shear granulation is widely used in many particulate industries for its good capability to improve the size, strength and composition uniformity of powder substances. This work conducted an experimental study to investigate the granulation behavior of iron ore fine in a horizontal high-shear granulator, such as granules size distribution, granules growth rate, and permeability of the granules bed. The results show that the granule size and permeability of packed granules bed increase gradually with increasing the granulation time, and the growth of granules can be divided into three stages: the rapid growth stage, the slow growth stage and the relatively stable stage. Both the higher rotational speed and larger number of impellers increase the kinetic energy and collision frequency of the particles, which causes the increase of average granule size, growth rate and permeability of granules packed bed. On the other hand, the shear damage effect of the impellers on the granules is also enhanced with the increase of rotational speed and impeller number, resulting in significant granule size segregation.

Systematic Study of the Effects of High Shear Granulation Parameters on Process Yield, Granule Size, and Shape by Dynamic Image Analysis.

The aim of the work was to analyze the influence of process parameters of high shear granulation on the process yield and on the morphology of granules on the basis of dynamic image analysis. The amount of added granulation liquid had a significant effect on all monitored granulometric parameters and caused significant changes in the yield of the process. In regard of the shape, the most spherical granules with the smoothest surface were formed at a liquid to solid ratio of ≈1. The smallest granules were formed at an impeller speed of 700 rpm, but the granules formed at 500 rpm showed both the most desirable shape and the highest process yield. Variation in the shape factors relied not only on the process parameters, but also on the area equivalent diameter of the individual granules in the batch. A linear relationship was found between the amount of granulation liquid and the compressibility of the granules. Using response surface methodology, models for predicting the size of granules and process yield related to the amount of added liquid and the impeller speed were generated, on the basis of which the size of granules and yield can be determined with great accuracy.

Applicability of image analysis to support QbD driven development of pellets

Objective The stages of preparing high drug loaded pellets were investigated using static and dynamic imaging techniques to provide a greater understanding and ease the scale up process. Significance An example of a real case laboratory and production scale quality by design (QbD) based development of pellets is demonstrated. Potential process analytical technology (PAT) approaches by dynamic image analysis (DIA) are presented in various process phases. Methods Pellets were prepared at laboratory and production scale (high shear granulation, extrusion/spheronization, drying, and coating). The influence of process parameters on pellet properties (aspect ratio (AR), yield, pellet size, and their distribution) was investigated using static and DIA. During coating, we focused on the coating thickness and identification of potential agglomeration. Results and conclusion The effects of kneading time, amount of water, extrusion screen plate (ESP) opening diameter and thickness on pellet properties were confirmed in accordance with literature. In terms of screw speed, spheronization speed and time, no considerable influence on pellet properties was observed in the range of studied process parameters, thereby confirming the design space. In addition to the ESP thickness and opening diameter, quality of the ESP impacts the pellet properties. Lastly, coating thickness measurements with dynamic and static image analysis were comparable and an exemplary case of in-line agglomeration detection was presented. Real-time evaluation with PATVIS APA is an effective PAT tool for the evaluation of spheronization (pellet size distribution, AR, and yield) and coating (coating thickness, agglomeration detection).

Effects of the controlled temperature in the production of high-shear granulated protein-containing granules

During wet granulation, the sample can be exposed to considerable mechanical effects, moisture content and elevated temperatures, and during high-shear granulation the impeller and chopper speeds can induce elevated temperatures and influence the parameters of the products. In our work, we therefore aimed to investigate the effect of cooling and process parameters on product parameters by factorial design in accordance with QbD guidelines. Our other goal was to study the effect of the type of granulation, therefore two series were used to prepare granules in a high-shear granulator, with water and binder solution as granulating fluid, at different chopper and impeller speeds with application of factorial design. The particle size was higher when cooling in the case of granules prepared with binder solution. The pepsin solution had a good granulating effect, the granules displayed a larger particle size, a higher breaking hardness and a favourable deformation process.

Systematic study of paracetamol powder mixtures and granules tabletability: Key role of rheological properties and dynamic image analysis

The aim of this systematic study was to analyze the granulometric and rheological behavior of tableting mixtures in relation to tabletability by single tablet and lab-scale batch compression with an eccentric tablet machine. Three mixtures containing 33, 50, and 66% of the cohesive drug paracetamol were prepared. The high compressibility of the powder mixtures caused problems with overcompaction or lamination in the single tablet compression method; due to jamming of the material during the filling of the die, the lab-scale batch compression was impossible. Using high shear granulation, the flow properties and tabletability were adjusted. A linear relationship between the span of granules and the specific energy measured by FT4 powder rheometer was detected. In parallel, a linear relationship between conditioned bulk density and the tensile strength of the tablets at lab-scale batch tableting was noted. The combination of dynamic image analysis and powder rheometry was useful for predicting the tabletability of pharmaceutical mixtures during the single tablet (design) compression and the lab-scale batch compression.

Investigation the iron ore fine granulation effects and particle adhesion behavior in a horizontal high-shear granulator

This work presents a study of the granulation of iron fines in a horizontal high shear granulator. Both experiments and DEM simulations were conducted to investigate the effect of water content, impeller rotational speed and particle sizes on granulation performance. The experimental results showed that the granule size increased with increasing water content, but the granules had the most uniform size at 8% of water content. The DEM model was developed to understand the inter-particle force, particle motion and adhesion during granulating. The results show that the liquid bridge force and the amount of bonded small particles increased with increasing water content, resulting in larger granules with wider granule size distributions. Increasing impeller speed also increased granulation efficiency due to increased collisions between particles. The simulation of the granulation of particles with different size ratios showed that granulation efficiency increased with increasing size ratios of nucleating and adhesive particles.

Effect of processing conditions and material attributes on the design space of lysozyme pellets prepared by extrusion/spheronization

The present work aimed to investigate the impact of the critical material attributes on the design space of the production of lysozyme pellets with suitable biological and physical properties for the subsequent coating process. The effect of two brands of both lysozyme and conformation stabilizing mannitol on the behavior of the composition in an extrusion/spheronization process was studied, while the experiments were designed according to 23 factorial design. The kneading of the mass was carried out in a high shear granulator equipped with a specially designed granulation chamber (Opulus Ltd, Hungary) constructed with seven built-in sensors for the measurement of temperature and relative humidity (RH). The special chamber is a novel tool for the identification of the critical points during processing a thermolabile drug by providing the online monitoring of critical environmental parameters and could be used to accurately determine the effect of critical process parameters and material attributes. The prepared samples were investigated for their biological and physical properties. It was found that the critical material attributes have a potential effect on the production process and product quality, and highly influence the size of the process design space. Therefore, the screening of the formulation materials is a key factor in macromolecular drug development.

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.

Identification of Granule Growth Regimes in High Shear Wet Granulation Processes Using a Physics-Constrained Neural Network

The digitization of manufacturing processes has led to an increase in the availability of process data, which has enabled the use of data-driven models to predict the outcomes of these manufacturing processes. Data-driven models are instantaneous in simulate and can provide real-time predictions but lack any governing physics within their framework. When process data deviates from original conditions, the predictions from these models may not agree with physical boundaries. In such cases, the use of first-principle-based models to predict process outcomes have proven to be effective but computationally inefficient and cannot be solved in real time. Thus, there remains a need to develop efficient data-driven models with a physical understanding about the process. In this work, we have demonstrate the addition of physics-based boundary conditions constraints to a neural network to improve its predictability for granule density and granule size distribution (GSD) for a high shear granulation process. The physics-constrained neural network (PCNN) was better at predicting granule growth regimes when compared to other neural networks with no physical constraints. When input data that violated physics-based boundaries was provided, the PCNN identified these points more accurately compared to other non-physics constrained neural networks, with an error of <1%. A sensitivity analysis of the PCNN to the input variables was also performed to understand individual effects on the final outputs.

High-shear granulation: An investigation into granule breakage rates

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

Integrated twin-screw wet granulation, continuous vibrational fluid drying and milling: A fully continuous powder to granule line

Highly homogeneous low-dose (50 μg) tablets were produced incorporating perfectly free-flowing granules prepared by a fully integrated Continuous Manufacturing (CM) line. The adopted CM equipment consisted of a Twin-Screw Wet Granulator (TSWG), a Continuous Fluid Bed Dryer (CFBD) and a Continuous Sieving (CS) unit. Throughout the experiments a pre-blend of lactose-monohydrate and corn starch was gravimetrically dosed with 1 kg/h into the TSWG, where they were successfully granulated with the drug containing water-based PVPK30 solution. The wet mass was subsequently dried in the CFBD on a vibratory conveyor belt and finally sieved in the milling unit. Granule production efficiency was maximized by determining the minimal Liquid-to-Solid (L/S) ratio (0.11). Design of Experiments (DoE) were carried out in order to evaluate the influence of the drying process parameters of the CFBD on the Loss-on-Drying (LOD) results. The manufactured granules were compressed into tablets by an industrial tablet rotary press with excellent API homogeneity (RSD < 3%). Significant scale-up was realized with the CM line by increasing the throughput rate to 10 kg/h. The manufactured granules yielded very similar results to the previous small-scale granulation runs. API homogeneity was demonstrated (RSD < 2%) with Blend Uniformity Analysis (BUA). The efficiency of TSWG granulation was compared to High-Shear Granulation (HSG) with the same L/S ratio. The final results have demonstrated that both the liquid distribution and more importantly API homogeneity was better in case of the TSWG granulation (RSD 1.3% vs. 4.5%).

Melt granulation: A comparison of granules produced via high-shear mixing and twin-screw granulation.

Melt granules of DI-CAFOS® A12 and 15% (w/w) Kolliphor® P407 were manufactured in a twin-screw granulator (TSG) at five different conditions (screw speed and throughput varied) and compared to granules manufactured in a high-shear granulator (HSG) (rotation speed of chopper/impeller and granulation time varied). Evaluated granules characteristics were process yield, particle-size distribution (PSD), particle morphology, flowability, porosity, specific surface area (SSA), tabletability, compressibility and binder distribution. Compared to TSG, granules produced from HSG were more spherical in shape with lower porosity, smaller mean particle size and a superior flowability. Granules made by TSG showed a more elongated structure, higher porosity and larger mean particle size with smaller SSA instead. Concerning the compression process of granules, tablets made of TSG granules exhibited a higher tabletability compared to HSG granules, whereas the compressibility remained similar. In the case of the TSG granules, energy-dispersive-X-ray (EDX) measurements of the tablet surface indicated an enhanced homogenous binder distribution. Additionally, the EDX-analyses determined that more binder was available between the individual particles, resulting in a stronger bonding.

Development and pharmaceutical performance of a novel co-processed excipient of alginic acid and microcrystalline cellulose

In this study, a co-processed excipient (Cop AA-MCC) was prepared from alginic acid (AA) and microcrystalline cellulose (MCC101) using a laboratory scale high-shear granulator. The obtained granules were compared to the primary materials (AA, MCC101), to the dry mixture and to wet granulated MCC. The effect of the two components ratio, the amount of added water or binder during granulation and the particle size, on the properties of the prepared co-processed excipient, was investigated. Results showed that optimal granule and tablet properties were obtained using a ratio of 10% of alginic acid, 90% of MCC101 and 70% of water. Moreover, the co-processed product has shown good tabletability, enhanced powder flowability and a considerable faster disintegration time in comparison to the primary materials and to a commercial co-processed excipient (Prosolv® ODT). Finally, the designed product was found to offer effective functionalities, which supports its exploitation as a valuable industrial pharmaceutical excipient.