High Shear Granulation Process Research Articles

High-Shear Granulation of Hygroscopic Probiotic-Encapsulated Skim Milk Powder: Effects of Moisture-Activation and Resistant Maltodextrin.

A fine, hygroscopic, and poorly flowable probiotic powder encapsulating Lactobacillus rhamnosus GG (LGG) was granulated using a high-shear granulation process, wherein a small amount of water (4%, w/w) was used for moisture-activation with or without 10% (w/w) resistant maltodextrin (RM). The process consisted of four steps; premixing, agglomeration, moisture absorption, and drying steps. The moisture content, water activity, and viable cell count were monitored during the granulation. The size, morphology, and flowability of the granules were determined. The powder was successfully converted to about 10-times-larger granules (mass mean diameter = 162-204 µm) by this process, and the granules had a 'snowball' morphology. The LGG cells were well preserved under the high-shear granulation conditions, and the viable cell count of the granules greatly exceeded the minimum therapeutic level recommended for probiotic powders. The addition of RM decreased the moisture content of the granules; improved cell resistance to drying stress; narrowed the particle size distribution, with reductions seen in both very fine and very large particles; and produced more flowable granules. Moisture sorption analysis and differential scanning calorimetry demonstrated that these positive effects of RM on granulation were primarily attributed to its water distribution ability rather than its glass transition-related binding ability.

Studies on the influence of high-shear granulation process on the compressibility of microcrystalline cellulose

Microcrystalline cellulose (MCC) is a diluent for oral solid dosage forms. The wet granulation process was selected to prepare losartan potassium tablets using MCC as a model for a predictive study. It was found that the hardness of the tablets could not satisfy the quality standards. In this study, the effect of the high-shear granulation process on the compressibility of MCC was characterized by plotting the compression characteristics curve, as well as the mechanism of the effect from the perspectives of mechanical properties, powder properties. The solid-state properties were also analyzed. Combined with the Heckel equation, the Ryshkewitch-Duckworth equation, the energy method, PXRD, SEM, and other evaluation methods, the results suggest that the high-shear granulation process reduced the compressibility of MCC, which may be caused by the reduced plastic deformation capacity of MCC and the change of the particle morphology structure. The method applied in this study can also be applied to other excipients, which is an important guideline for solving possible problems and process selections during the preparation stage of solid formulations.

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.

Converting a batch based high-shear granulation process to a continuous dry granulation process; a demonstration with ketoprofen tablets

When one wishes to convert a batch based manufacturing process of an existing tablet product to a continuous process, there are several available strategies which can be adopted. Theoretically, the most straightforward way would be to proceed with the corresponding processing principles, for example to change a wet granulation (WG) batch process into its continuous WG counterpart. However, in some cases, the choice of roller compaction (RC) could be very attractive due to the notably simpler and inherently continuous nature of the RC manufacturing principle. The aim of this study was to examine a process conversion from batch based high-shear wet granulation (HSWG) to continuous RC manufacturing, without any significant formulation changes. An optimization of the formulation is often needed during the process conversion. However, our primary goal was to demonstrate the possibilities to perform this kind of process adaptation with minimal formulation changes. Furthermore, the effect of three different locations of lubrication feeding with two production rate levels was studied. An additional target was to identify possible over-lubrication with these manufacturing configurations, and to clarify which of these three possibilities steps produced a final product that conformed to the same quality requirements as HSWG tablets. Previously, the effects of lubrication only on compacted ribbons (Miguelez-Moran A.M, 2008) and final product with CDC (continuous direct compression) (Taipale-Kovalainen, et al., 2017; 2019) have been investigated. Here, the effect of lubrication on both ribbon and on final product was examined. No signs of over-lubrication were observed, but there was a clear effect of the feeding location of lubricant on the final product. On the basis of these results, it is concluded that in the future, if a good product/process understanding of the alternative manufacturing process with different techniques can be obtained, it will be possible to devise more flexible and effective ways to allow the pharmaceutical industry to switch from batch manufacturing towards CM.

Switch of tablet manufacturing from high shear granulation to twin-screw granulation using quality by design approach.

This study aimed to transfer a high shear granulation (HSG) process to a twin-screw granulation (TSG) process while maintaining equivalent dissolution profiles. Ibuprofen (IBP) was used as poorly soluble model drug. Granules were obtained by HSG or TSG according to a full factorial design. The liquid-to-solid ratio and wet massing time (HSG) or powder throughput (TSG) were selected as factors. The granules were compressed to tablets with immediate release and a drug load of 50% (w/w). Quality attributes (QAs) of the granules, especially the granule strength (GS), and the resulting tablets were evaluated. The effect of process parameters on the QAs was statistically analyzed. The comparison of HSG tablets with TSG tablets revealed that TSG tablets showed higher tensile strength and lower ejection force than HSG tablets. The dissolution profiles of the tablets in different pH media were also evaluated. Equivalent dissolution profiles in all four media (e.g., f2 values≥54 in pH5.5) were obtained by adjusting process parameters. It was concluded that the GS was the most important QA for dissolution.

Dynamic Image Analysis to Determine Granule Size and Shape, for Selected High Shear Granulation Process Parameters

Abstract The aim of this study was to investigate the usage of Dynamic Image Analysis for determination of size, shape and distribution of granules of microcrystalline cellulose, created by high shear granulation. A series of experiments was carried out to analyse the effect of process parameters on a created granule morphology. The amount of the granulation liquid and speed of the impeller have a significant effect on the median size granule value, the sphericity, the granule distribution width, but also on the granulation process yield.

High share granulation process affecting the quality and stability of spine date seed oil (SDSO) tablets

The purpose of the present study was to prepare the solidified microcapsules and identify the effect of granulation and compression on the quality and stability of solidified spine date seed oil (SDSO). The fatty acid profile and the oxidative stabilities of the products were applied as indicators. The microencapsulation of SDSO–loaded granules were prepared using an electrostatic layer-by-layer deposition method and subsequently compressed as tablets. The study of granulation suggested that the impeller and chopper speed significantly affect retention efficiency of SDSO in granules (P < 0.05). However, the peroxide value was not affected by these parameters (P > 0.05). The overall study also suggested that the fatty acid composition was not changed significantly during the microencapsulation, granulation, and compressing process (P > 0.05). Moreover, the peroxide value of SDSO in the tablets (9.79 ± 0.62 mmol/kg) was lower than SDSO (47.57 ± 5.25 mmol/kg) and the microcapsules (23.16 ± 3.06 mmol/kg) (P < 0.05), after accelerated storage for 12 days, although the oxidative stability of the SDSO contained granules (84.23 ± 2.19 mmol/kg) was not satisfied in this study. The results of this work suggested that the microencapsulation of functional oils followed by the high shear granulation and tabletting process could be applied for oil products solidification due to the advantages of stability.

Stage-wise characterization of the high shear granulation process by impeller torque changing rate

Fine cornstarch powders are wet granulated in a lab-scale high shear granulator. The torque required for maintaining the impeller passing through the bed with a constant rotating speed is monitored during the continuous binder addition granulation process. A new method is proposed to identify 6 stages during the granulation process based on the fraction of the positive impeller torque changing rate in a characteristic period of time. The morphologies and the behavior of the bed are found intrinsically different in the identified 6 stages. The influence of the impeller blade inclined angle on the impeller torque in each stage is initially reported. The impeller with planner 45° blades requires higher torques in Stages I and II due to the overall powder bed mass loading. The impeller with steeper 60° blades requires higher torques in Stages III and IV due to the higher collision frequencies between the blade and granules. The suitable granulation liquid binder to solid powder mass ratio can be readily identified in Stages II and III, and its range is found to increase with the increasing of the impeller rotational speed and is independent to the blade inclined angle.

Dimensionless criteria as a tool for creation of a model for predicting the size of granules in high-shear granulation

This work deals with the creation of a mathematical model which will predict with sufficient accuracy the size of granules in the high-shear granulation process. The aim of the paper was to create a model created with dimensionless criteria to give the size of granules as a function of selected process parameters, equipment, and experimental material. Microcrystalline cellulose granules were manufactured in an experimental granulator of our own construction using a high amount of granulation liquid (absolute humidity >40%). The work also focuses on the study of granule size distribution and the yield of the process in achieving the target granule fraction (0.4–3 mm). Particle size and particle size measurement were performed using 3 D dynamic image analysis (PartAn 3 D, Microtrac). The granules were analyzed with respect to their shape and width of distribution. Using the created model, it is possible with high probability, 89.4%, to predict on our device the median value of the granule size of microcrystalline cellulose, with ±0.1 mm precision.

Determination of significant factors in high-shear granulation process of sucrose with aqueous solution of sodium lauryl sulphate using partial least square regression approach

Sucrose as one of the most commonly used raw materials in pediatric formulations is soluble and sticky excipient and its manipulation in high shear granulators may be very difficult. Therefore, to determine the correct amount of liquid binder is very important because it falls in a very narrow range and may vary due to small variations in the material properties or environmental conditions. The possibility of using the sugar as powder for granulation may be very challenging because of solubility and moisture adsorption properties of crystalline sugar, especially if the binder solution is water. The aim of this study was trying to solve these problems and produce sucrose granules using high share granulation and water as a binding liquid, with properties required for final product good performance. By reducing the sucrose particle size and improving the uniformity of the size distribution, the differences of the processes of nucleation and growth for small and large particles might be reduced. According to the variable importance or VIP scores from the developed partial least square (PLS) model, raw material particle size is as influential variable as the quantity and composition of the granulation liquid (Gra), granulation time (Grn) and impeller rate (Imp). Keywords: sucrose, particle size distribution, high-shear granulation, partial least square

High-shear granulation of high-molecular weight hypromellose: effects of scale-up and process parameters on flow and compaction properties

Context: Knowledge of the effects of high-shear granulation process parameters and scale-up on the properties of the produced granules is essential for formulators who face challenges regarding poor flow and compaction during development of modified release tablets based on high-molecular weight hypromellose (hydroxypropylmethylcellulose (HPMC)) polymers. Almost none of the existing studies deal with realistic industrial formulation.Objective: The aim was to investigate the effects of scale-up and critical process parameters (CPPs) of high-shear granulation on the quality attributes of the granules, particularly in terms of the flow and compaction, using a realistic industrial formulation based on HPMC K100M polymer.Methods: The flow properties were determined using flow time, Carr index, tablet mass, and crushing strength variations. The compaction properties were quantified using the ‘out-of-die’ Heckel and modified Walker models, as well as the tensile strength profile and elastic recovery. High-shear granulation was performed at different scales: 4 L, 300 L, and 600 L.Results and conclusion: The scale itself had larger effects on the granule properties than the CPPs, which demonstrated high robustness of formulation on the individual scale level. Nevertheless, to achieve the desired flow and compaction, the values of the CPPs need to be precisely selected to fine-tune the process conditions. The best flow was achieved at high volumes of water addition, where larger and more spherical granules were obtained. The CPPs showed negligible influence on the compaction with no practical implications, however, the volume of water addition volume was identified as having the largest effects on compaction.

Use of Mixer Torque Rheometer to Clarify the Relationship between the Kneading States of Wet Mass and the Dissolution of Final Product in High Shear Granulation

The properties of wet mass, which indicate the progress of high shear granulation processes, usually have an effect on final product properties, such as tablet dissolution. The mixer torque rheometer (MTR) is a useful tool for quantitatively measuring the 'kneading state' of wet mass and detecting differences in granules. However, there have been no studies of the relationship between the MTR torque and the final product properties to date. In this study, we measured the MTR torque of wet granules at different kneading states, which were prepared by changing the granulation conditions. We then evaluated the relationship between the MTR torque and the dissolution rate of the final product properties. The amperage of the high shear granulator is usually monitored during granulation, but we could not detect a difference in the kneading state through the amperage. However, using MTR torque we were able to quantify the difference of the wet mass. Moreover, MTR torque showed a high correlation with dissolution, compared with the correlations with other intermediate properties, such as granules particle size and tablet hardness. These other properties are affected by following processes and are not properties that directly relate to the kneading state. Thus, MTR torque is a property of wet mass after granulation, and it can be used to directly evaluate differences of the kneading state, and as a result, dissolution. These results indicate the importance of controlling the kneading state, i.e., the progress of granulation, and the utility of MTR for detecting differences in wet mass.

An investigation on the evolution of granule formation by in-process sampling of a high shear granulator

Understanding the growth mechanisms in granulation process is an important topic, providing valuable insights and supports control strategies. Typically, observations in high shear granulators are made after stopping the process. In this work, an in-process sampling technique is described and applied to a high shear wet granulation process. Different samples can be collected over the cause of the high shear granulation process. This allowed observation of the evolution of granules during addition of water at a constant flowrate. For a typical pharmaceutical formulation, we observed that granules nucleate in the first 2min after starting the water addition and then grow to an average size of 200–1200μm at 12.5min, corresponding to a sharp increase in torque. Longer water addition times lead to oversized granules and eventually a paste and highly fluctuating torque. Sampling was also continued after stopping water addition which showed with time larger formed granules smoothen, whilst the smaller ones disintegrate. The work shows the in-process sampling can facilitate the identification of the granule growth kinetics and required binder quantity in high shear granulation.

In-Line Monitoring of a High-Shear Granulation Process Using the Baseline Shift of Near Infrared Spectra.

Although near infrared (NIR) spectra are primarily influenced by undesired variations, i.e., baseline shifts and non-linearity, and many applications of NIR spectroscopy to the real-time monitoring of wet granulation processes have been reported, the granulation mechanisms behind these variations have not been fully discussed. These variations of NIR spectra can be canceled out using appropriate pre-processing techniques prior to spectral analysis. The present study assessed the feasibility of directly using baseline shifts in NIR spectra to monitor granulation processes, because such shifts can reflect changes in the physical properties of the granular material, including particle size, shape, density, and refractive index. Specifically, OPUSGRAN®, a novel granulation technology, was investigated by in-line NIR monitoring. NIR spectra were collected using a NIR diffuse reflectance fiber optic probe immersed in a high-shear granulator while simultaneously examining the morphology, particle size, density, strength, and Raman images of the mixture during granulation. The NIR baseline shift pattern was found to be characteristic of the OPUSGRAN® technology and was attributed to variations in the light transmittance, reflection, and scattering resulting from changes in the physicochemical properties of the samples during granulation. The baseline shift also exhibited an inflection point around the completion of granulation, and therefore may be used to determine the endpoint of the process. These results suggest that a specific pattern of NIR baseline shifts are associated with the unique OPUSGRAN® granulation mechanism and can be applied to monitor the manufacturing process and determine the endpoint.

Integrating the physics with data analytics for the hybrid modeling of the granulation process

A hybrid model based on physical and data interpretations to investigate the high shear granulation (HSG) process is proposed. This model integrates three separate component models, namely, a computational fluid dynamics model, a population balance model, and a radial basis function model, through an iterative procedure. The proposed hybrid model is shown to provide the required understanding of the HSG process, and to also accurately predict the properties of the granules. Furthermore, a new fusion model based on integrating fuzzy logic theory and the Dempster‐Shafer theory is also developed. The motivation for such a new modeling framework stems from the fact that integrating predictions from models which are elicited using different paradigms can lead to a more robust and accurate topology. As a result, significant improvements in prediction performance have been achieved by applying the proposed framework when compared to single models. © 2017 American Institute of Chemical Engineers AIChE J, 2017

Analysis of mesoscale effects in high-shear granulation through a computational fluid dynamics–population balance coupled compartment model

There is a need for mesoscale resolution and coupling between flow-field information and the evolution of particle properties in high-shear granulation. We have developed a modelling framework that compartmentalizes the high-shear granulation process based on relevant process parameters in time and space. The model comprises a coupled-flow-field and population-balance solver and is used to resolve and analyze the effects of mesoscales on the evolution of particle properties. A Diosna high-shear mixer was modelled with microcrystalline cellulose powder as the granulation material. An analysis of the flow-field solution and compartmentalization allows for a resolution of the stress and collision peak at the impeller blades. Different compartmentalizations showed the importance of resolving the impeller region, for aggregating systems and systems with breakage. An independent study investigated the time evolution of the flow field by changing the particle properties in three discrete steps that represent powder mixing, the initial granulation stage mixing and the late stage granular mixing. The results of the temporal resolution study show clear changes in collision behavior, especially from powder to granular mixing, which indicates the importance of resolving mesoscale phenomena in time and space.

Immobilization of photocatalytically active TiO2 nanopowder by high shear granulation

Nano-TiO2 powder is known to show high photocatalytic reactivity in the degradation of several organic pollutants. In this work, the powder was fixed on the surface of SiO2 granules with the size of several micrometers using a high shear granulation process. Nanozirconia sol was applied as an inorganic binder. When the samples were tempered at 300°C, they showed high stability in an aqueous solution for several hours. An energy dispersive x-ray spectroscopy (EDX) analysis confirmed that the cores and shells of the granules consisted solely of SiO2 and TiO2 respectively, and that ZrO2 was found throughout the whole granules. Methylene blue (MB) was employed as a model system to evaluate the photocatalytic activity of the TiO2 nanopowder and coated granules. It was shown that the TiO2-coated granules lead to the degradation of MB under UV irradiation, whereas no effect was observed in the dark. After the degradation experiments the granules could be recovered and they remained active for further applications.

Effects of Process and Design Parameters on Granule Size Distribution in a Continuous High Shear Granulation Process

Wet granulation is widely used in the pharmaceutical industry. This advantageous technology is capable of enhancing compression and powder handling, decreasing ingredient segregation, and promoting blend and content uniformity. Currently, a high level of interest exists in the continuous version of this technology, both by the US Food and Drug Administration (FDA), and by pharmaceutical manufacturers. In this paper, a continuous high shear wet granulation process was examined based on a placebo formulation comprising 70% ∂-lactose monohydrate and 30% microcrystalline cellulose (Avicel® PH101). Granulation was then carried out in a continuous high shear mixer granulator, Glatt GCG 70. The impact of two process variables (rotation speed and liquid/solid (L/S) ratio) and two design parameters (blade configuration and nozzle position) were evaluated via an I-optimal design. Multi-factor analysis of variance (ANOVA) indicated that rotation speed and L/S ratio dominated the granulation process and had the most significant effects on granule size distribution (GSD). The largest granule mass median diameter was obtained at the lowest rotation speed and highest L/S ratio. The granulation mechanism underlying this continuous process was examined using a wetting and nucleation regime map. For the cases studied here, the mechanical dispersion regime controlled the formation of granule nuclei, leading to a broad GSD and a limited growth ratio.

Predictive modelling of the granulation process using a systems-engineering approach

The granulation process is considered to be a crucial operation in many industrial applications. The modelling of the granulation process is, therefore, an important step towards controlling and optimizing the downstream processes, and ensuring optimal product quality. In this research paper, a new integrated network based on Artificial Intelligence (AI) is proposed to model a high shear granulation (HSG) process. Such a network consists of two phases: in the first phase the inputs and the target outputs are used to train a number of models, where the predicted outputs from this phase and the target are used to train another model in the second phase to lead to the final predicted output. Because of the complex nature of the granulation process, the error residual is exploited further in order to improve the model performance using a Gaussian mixture model (GMM). The overall proposed network successfully predicts the properties of the granules produced by HSG, and outperforms also other modelling frameworks in terms of modelling performance and generalization capability. In addition, the error modelling using the GMM leads to a significant improvement in prediction.

A compartmental CFD‐PBM model of high shear wet granulation

The conventional, geometrically lumped description of the physical processes inside a high shear granulator is not reliable for process design and scale‐up. In this study, a compartmental Population Balance Model (PBM) with spatial dependence is developed and validated in two lab‐scale high shear granulation processes using a 1.9L MiPro granulator and 4L DIOSNA granulator. The compartmental structure is built using a heuristic approach based on computational fluid dynamics (CFD) analysis, which includes the overall flow pattern, velocity and solids concentration. The constant volume Monte Carlo approach is implemented to solve the multi‐compartment population balance equations. Different spatial dependent mechanisms are included in the compartmental PBM to describe granule growth. It is concluded that for both cases (low and high liquid content), the adjustment of parameters (e.g. layering, coalescence and breakage rate) can provide a quantitative prediction of the granulation process. © 2016 American Institute of Chemical Engineers AIChE J, 63: 438–458, 2017