High Shear Wet Granulation Research Articles

Understanding of Wetting Mechanism Toward the Sticky Powder and Machine Learning in Predicting Granule Size Distribution Under High Shear Wet Granulation.

The granulation of traditional Chinese medicine (TCM) has attracted widespread attention, there is limited research on the high shear wet granulation (HSWG) and wetting mechanisms of sticky TCM powders, which profoundly impact the granule size distribution (GSD). Here we investigate the wetting mechanism of binders and the influence of various parameters on the GSD of HSWG and establish a GSD prediction model. Permeability and contact angle experiments combined with molecular dynamics (MD) simulations were used to explore the wetting mechanism of hydroalcoholic solutions with TCM powder. Machine learning (ML) was employed to build a GSD prediction model, feature importance explained the influence of features on the predictive performance of the model, and correlation analysis was used to assess the influence of various parameters on GSD. The results show that water increases powder viscosity, forming high-viscosity aggregates, while ethanol primarily acted as a wetting agent. The contact angle of water on the powder bed was the largest and decreased with an increase in ethanol concentration. Extreme Gradient Boosting (XGBoost) outperformed other models in overall prediction accuracy in GSD prediction, the binder had the greatest impact on the predictions and GSD, adjusting the amount and concentration of adhesive can control the adhesion and growth of granules while the impeller speed had the least influence on granulation. The study elucidates the wetting mechanism and provides a GSD prediction model, along with the impact of material properties, formulation, and process parameters obtained, aiding the intelligent manufacturing and formulation development of TMC.

Predicting tablet properties using In-Line measurements and evolutionary equation Discovery: A high shear wet granulation study

High shear wet granulation (HSWG) is widely used in tablet manufacturing mainly because of its advantages in improving flowability, powder handling, process run time, size distribution, and preventing segregation. In line process analytical technology measurements are essential in capturing detailed particle dynamics and presenting real-time data to uncover the complexity of the HSWG process and ultimately for process control.This study presents an opportunity to predict the properties of the granules and tablets through torque measurement of the granulation bowl and the force exerted on a novel force probe within the powder bed. Inline force measurements are found to be more sensitive than torque measurements to the granulation process. The characteristic force profiles present the overall fingerprint of the high shear wet granulation, in which the evolution of the granule formation can improve our understanding of the granulation process. This provides rich information relating to the properties of the granules, identification of the even distribution of the binder liquid, and potential granulation end point. Data were obtained from an experimental high shear mixer across a range of key process parameters using a face-centred surface response design of experiment (DoE). A closed-form analytical model was developed from the DOE matrix using the discovery of evolutionary equations. The model is able to provide a strong predictive indication of the expected tablet tensile strength based only on the data in-line. The use of a closed form mathematical equation carries notable advantages over other AI methodologies such as artificial neural networks, notably improved interpretability/interrogability, and minimal inference costs, thus allowing the model to be used for real-time decision making and process control. The capability of accurately predicting, in real time, the required compaction force required to achieve the desired tablet tensile strength from upstream data carries the potential to ensure compression machine settings rapidly reach and are maintained at optimal values, thus maximising efficiency and minimising waste.

Evaluation And Selection Of Optimal Deep Learning Architecture For Predicting The Endpoint In High Shear Wet Granulation For Antacid Tablet Production

Objective: The purpose of this research was to evaluate and select the best architecture among native convolutional neural network (CNN), MobileNetV2, ResNet50V2, and EfficientNetB0 for predicting the endpoint of the high shear wet granulation process, with accuracy as the main evaluation metric. Methods: The dataset was captured from an industrial camera using static image analysis and was manually labeled as “NOT READY” and “READY” according to the traditional endpoint method based on the mixer’s ampere point in the granulator. The dataset contained a total of 180 images, which were split between training and validation sets. Native CNN and TensorFlow Keras application programming interface (API) were utilized with MobileNetV2, EfficientNetB0, and ResNet50V2 as base feature encoders. Hyperparameters, such as final Fully Connected (FC) layer width, dropout rate, and learning rate, were optimized for binary classification using Keras hyper tuning. Results: The best was the native CNN, it was also the fastest among the three other models, taking only 20-30 ms per step for inference during runtime, though it requires 9000 ms time for training, the longest time among the models. It achieved an accuracy of 98%, and a validation accuracy of 97%. Conclusion: The system was able to determine when a wet granulation process has reached its endpoint based on live images from a camera after being trained on previously labeled data. The native CNN was the best model, offering the fastest runtime performance and the highest accuracy.

An Understanding of the Relationship Between Mixing Performance and Power Consumption in a High-Shear Wet Granulation Pre-mixing

An Understanding of the Relationship Between Mixing Performance and Power Consumption in a High-Shear Wet Granulation Pre-mixing

Pre-nucleation in high-shear wet granulation

Wet granulation is broken down into three rate processes that are often inseparable from each other, hindering characterization of the relationship between operating conditions and product properties. Single-drop granulation is a form of drop-controlled nucleation intended to isolate the Wetting & Nucleation rate process. In this work, single-dropped granules (pre-nucleated granules) were charged to a mixer granulator under varied conditions to observe how the individual rate processes and resulting granulated product were affected by various pre-nucleation conditions. Batches with larger fractions of pre-nucleated granules tended to produce a larger granule size than batches with few or no pre-nucleated granules. A clear and consistent trend of deviation from traditional granulation results is observed. Liquid to solid ratio is ruled out as a sole cause for the deviation, indicating that pre-nucleation may have applications in granular material production with respect to liquid dosing in granules, granule size control, and efficient material usage.

Effect of the drying type on the properties of granules and tablets produced by high shear wet granulation

Although high shear mixers can represent a single-pot process, separate drying equipment is commonly employed. Limited literature exists on the use of a heating jacket coupled with a vacuum pump typically used in a single-pot setup, so this study compares the drying effects of a single-pot setup (DSP) and ventilated oven (DVO) on the properties of granules and tablets. Granules containing three actives of varying water solubility were produced and characterised. The results showed that DSP reduced the drying time and produced smaller, irregular, and weaker granules with different compression mechanisms. The tablets were produced and characterised. All tablets passed the uniformity test. Compression differences had no impact on tablet properties for poorly water-soluble actives, but altered properties for highly soluble actives due to increased active migration and crystallization on the granule surface. In conclusion, while DSP offers advantages, careful consideration of the drying technique is essential during product development.

Exploring the effect of raw material properties on continuous twin-screw wet granulation manufacturability

Twin-screw wet granulation (TSWG) stands out as a promising continuous alternative to conventional batch fluid bed- and high shear wet granulation techniques. Despite its potential, the impact of raw material properties on TSWG processability remains inadequately explored. Furthermore, the absence of supportive models for TSWG process development with new active pharmaceutical ingredients (APIs) adds to the challenge. This study tackles these gaps by introducing four partial least squares (PLS) models that approximate both the applicable liquid-to-solid (L/S) ratio range and resulting granule attributes (i.e., granule size and friability) based on initial material properties. The first two PLS models link the lowest and highest applicable L/S ratio for TSWG, respectively, with the formulation blend properties. The third and fourth PLS models predict the granule size and friability, respectively, from the starting API properties and applied L/S ratio for twin-screw wet granulation. By analysing the developed PLS models, water-related material properties (e.g., solubility, wettability, dissolution rate), as well as density and flow-related properties (e.g., flow function coefficient), were found to be impacting the TSWG processability. In addition, the applicability of the developed PLS models was evaluated by using them to propose suitable L/S ratio ranges (i.e., resulting in granules with the desired properties) for three new APIs and related formulations followed by an experimental validation thereof. Overall, this study helped to better understand the effect of raw material properties upon TSWG processability. Moreover, the developed PLS models can be used to propose suitable TSWG process settings for new APIs and hence reduce the experimental effort during process development.

The Influence of Wet Granulation Parameters on the Compaction Behavior and Tablet Strength of a Hydralazine Powder Mixture.

The aim of this paper was to describe the influence of high-shear wet granulation process parameters on tablet tensile strength and compaction behavior of a powder mixture and granules containing hydralazine. The hydralazine powder mixture and eight types of granules were compacted into tablets and evaluated using the Heckel, Kawakita and Adams analyses. The granules were created using two types of granulation liquid (distilled water and aqueous solution of polyvinylpyrrolidone), at different impeller speeds (500 and 700 rpm) and with different wet massing times (without wet massing and for 2 min). Granulation resulted in improved compressibility, reduced dustiness and narrower particle-size distribution. A significant influence of wet massing time on parameters from the Kawakita and Adams analysis was found. Wet massing time had an equally significant effect on tablet tensile strength, regardless of the granulation liquid used. Granules formed with the same wet massing time showed the same trends in tabletability graphs. Tablets created using a single-tablet press (batch compaction) and an eccentric tablet press showed opposite values of tensile strength. Tablets from granules with a higher bulk density showed lower strength during batch compaction and, conversely, higher strength during eccentric tableting.

Intelligent co-design of material, process, and equipment for manufacturing high-quality traditional Chinese medicine preparations

In the context of Pharma 4.0, the design tools that support the pharmaceutical Quality by Design(QbD) are iterating fast toward intelligent or smart design. The conventional development methods for traditional Chinese medicine(TCM) preparations have the limitations such as over dependence on experience, low dimensions for the designed experiment parameters, poor compatibility between the process and equipment, and high trial-and-error cost during process scale-up. Therefore, this paper innovatively proposed the intelligent co-design involving material, process, and equipment for manufacturing high-quality TCM preparations, and introduced the design philosophy, targets, tools, and applications with TCM oral solid dosage(OSD) as an example. In terms of design philosophy, the pharmaceutical design tetrahedron composed of critical material attributes, critical process parameters, critical equipment attributes, and critical quality attributes was developed. The design targets were put forward based on the product performance classification system. The design tools involve a design platform that contains several modules, such a as the iTCM material database, the processing route classification system, the system modeling and simulation, and reliability-based optimization. The roles of different modules in obtaining essential and universal design knowledge of the key common manufacturing units were introduced. At last, the applications of the co-design methodology involving material, process, and equipment in the high shear wet granulation process development and the improvement of the dissolving or dispersion capability of TCM formula granules are illustrated. The research on advanced pharmaceutical design theory and methodology will help enhance the efficiency and reliability of drug development, improve the product quality, and promote the innovation of high-end TCM products across the industry.

Attribute transmission and effects of diluents and granulation liquids on granule properties and tablet quality for high shear wet granulation and tableting process

This study aims to examine (i) the effect of diluent types (lactose monohydrate, corn starch, and microcrystalline cellulose) and granulation liquids (20% polyvinylpyrrolidone K30, 65% alcohol, and dispersion containing 40% model drug– Pithecellobium clypearia Benth extracted powder) on granule properties and tablet quality for high shear wet granulation and tableting (HSWG-T) and, more importantly, (ii) the attribute transmission in the process. In general, the impact of diluents on granule properties and tablet quality was more dominant than that of granulation liquids. Attribute transmission patterns were revealed as follows. The granules’ ISO. Roundness and density correlated with raw material (i.e., model drug, diluent, and/or granulation liquid) properties such as density and viscosity. The granules’ compressibility parameter a correlated with the granules’ Span, and parameter y0 correlated with the granules’ flowability and friability. Compactibility parameters ka and kb correlated mainly with granules' flowability and density, and parameter b correlated significantly and positively with tablet tensile strength. The compressibility correlated negatively with tablet solid fraction (SF) and friability, while the compactibility correlated positively with tablet disintegration time. Moreover, the rearrangement and elasticity of granules correlated positively with SF and friability, respectively. Overall, this study provides some guides for achieving high-quality tablets via HSWG-T.

End-point determination of heterogeneous formulations using inline torque measurements for a high-shear wet granulation process

In this study, the torque profiles of heterogeneous granulation formulations with varying powder properties in terms of particle size, solubility, deformability, and wettability, were studied, and the feasibility of identifying the end-point of the granulation process for each formulation based on the torque profiles was evaluated. Dynamic median particle size (d50) and porosity were correlated to the torque measurements to understand the relationship between torque and granule properties, and to validate distinction between different granulation stages based on the torque profiles made in previous studies. Generally, the torque curves obtained from the different granulation runs in this experimental design could be categorized into two different types of torque profiles. The primary factor influencing the likelihood of producing each profile was the binder type used in the formulation. A lower viscosity, higher solubility binder resulted in a type 1 profile. Other contributing factors that affected the torque profiles include API type and impeller speed. Material properties such as the deformability and solubility of the blend formulation and the binder were identified as important factors affecting both granule growth and the type of torque profiles observed. By correlating dynamic granule properties with torque values, it was possible to determine the granulation end-point based on a pre-determined target median particle size (d50) range which corresponded to specific markers identified in the torque profiles. In type 1 torque profiles, the end-point markers corresponded to the plateau phase, whereas in type 2 torque profiles the markers were indicated by the inflection point where the slope gradient changes. Additionally, we proposed an alternative method of identification by using the first derivative of the torque values, which facilitates an easier identification of the system approaching the end-point. Overall, this study identified the effects of different variations in formulation parameters on torque profiles and granule properties and implemented an improved method of identification of granulation end-point that is not dependent on the different types of torque profiles observed.

Comparison of Two Manufacturing Processes of Daprodustat for Bioequivalence and Dissolution in Healthy Volunteers: A Randomized Crossover Study.

Daprodustat, an orally bioavailable hypoxia-inducible factor-prolyl hydroxylase enzyme inhibitor, has recently completed phase 3 clinical development for treating anemia of chronic kidney disease. Part A of this 2-part, randomized, double-blind, single-dose, cross-over study (NCT04640311) compared pharmacokinetic properties of a single oral dose of daprodustat 4 mg tablets manufactured via twin-screw wet granulation (process 1) to 2 sets of 4 mg tablets manufactured via high-shear wet granulation (process 2), to assess the impact of different dissolution profiles on pharmacokinetics. Part B assessed the bioequivalence of daprodustat tablets manufactured via process 1 with tablets manufactured via process 2 at 5 different dose strengths (1, 2, 4, 6, and 8mg). In part A, mean plasma concentrations of daprodustat were comparable over a 24-hour period despite differences in manufacturing processes and dissolution profiles. In part B, the 90% confidence intervals of the ratios of the least squared means for area under the concentration-time curve and maximum observed plasma concentration fell within the 0.8-1.25 bioequivalence range for all doses, except for maximum observed plasma concentration at 8mg. A prespecified sensitivity analysis jointly assessing all doses showed bioequivalence for all doses tested. No new safety concerns for daprodustat were identified.

A new methodology of understanding the mechanism of high shear wet granulation based on experiment and molecular dynamics simulation

In high shear wet granulation (HSWG), the interaction mechanism between binder and powder with different sugar content is still unclear. Herein, the law and mechanism of the interaction between binder and powder were studied on the molecular level by combining experiment analysis through the Kriging model and molecular dynamics (MD) simulation. For the sticky powder with high sugar content, the ethanol in the binder played a pivotal role in dispersing water into powders, and the amount of water determined the growth of granules. In the saturating stage, the reduction of sugar content facilitates the penetration of ethanol molecules. The concentration of ethanol determines whether the mixture is blended uniformly in the merging stage. The simulation results are consistent with the actual situation and explain the competition mechanism of interaction with binder and powder. Therefore, this research offers an efficient strategy for the in-depth understanding of the HSWG process where the powder is sticky, as well as providing guidelines for the practical application of preparation for Traditional Chinese Medicine (TCM) granules.

Multi-objective optimization of high-shear wet granulation process for better granule properties and fluidized bed drying characteristics

This study determines the effects of influential process parameters of high-shear wet granulation (HSWG) on the critical process and quality attributes of the granules. The wet granules from HSWG experiments were dried in a fluidized bed dryer wherein the granule drying characteristics were analyzed by introducing Page's equation, which fits well with R2 values of above 0.95 for all the batches. Response surface methodology (RSM) based nonlinear models predicting the drying time, flow angle of repose, and surface mean diameter of the granules effectively capture the granulation phenomena with high correlation coefficients of above 0.93. Multi-objective constrained grid-search (MOCGS) optimization is utilized to optimize the HSWG process. Selected optimization results include the minimum drying time of 23 min, the minimum flow angle of repose of granules as 21° and the maximum surface mean diameter of the granules as 0.62 mm for the batch size of 1.8 kg.

Using a Material Library to Understand the Change of Tabletability by High Shear Wet Granulation.

Understanding the tabletability change of materials after granulation is critical for the formulation and process design in tablet development. In this paper, a material library consisting of 30 pharmaceutical materials was used to summarize the pattern of change of tabletability during high shear wet granulation and tableting (HSWGT). Each powdered material and the corresponding granules were characterized by 19 physical properties and nine compression behavior classification system (CBCS) parameters. Principal component analysis (PCA) was used to compare the physical properties and compression behaviors of ungranulated powders and granules. A new index, namely the relative change of tabletability (CoTr), was proposed to quantify the tabletability change, and its advantages over the reworking potential were demonstrated. On the basis of CoTr values, the tabletability change classification system (TCCS) was established. It was found that approximately 40% of materials in the material library presented a loss of tabletability (i.e., Type I), 50% of materials had nearly unchanged tabletability (i.e., Type II), and 10% of materials suffered from increased tabletability (i.e., Type III). With the help of tensile strength (TS) vs. compression pressure curves implemented on both powders and granules, a data fusion method and the PLS2 algorithm were further applied to identify the differences in material properties requirements for direct compression (DC) and HSWGT. Results indicated that increasing the plasticity or porosity of the starting materials was beneficial to acquiring high TS of tablets made by HSWGT. In conclusion, the presented TCCS provided a means for the initial risk assessment of materials in tablet formulation design and the data modeling method helped to predict the impact of formulation ingredients on the strength of compacts.

Compression Density as an Alternative to Identify an Optimal Moisture Content for High Shear Wet Granulation as an Initial Step for Spheronisation.

Pellet production is a multi-step manufacturing process comprising granulation, extrusion and spheronisation. The first step represents a critical control point, since the quality of the granule mass highly influences subsequent process steps and, consequently, the quality of final pellets. The most important parameter of wet granulation is the liquid requirement, which can often only be quantitatively evaluated after further process steps. To identify an alternative for optimal liquid requirements, experiments were conducted with a formulation based on lactose and microcrystalline cellulose. Granules were analyzed with a Powder Vertical Shear Rig. We identified the compression density (ρpress) as the said alternative, linking information from the powder material and the moisture content (R2 = 0.995). We used ρpress to successfully predict liquid requirements for unknown formulation compositions. By means of this prediction, pellets with high quality, regarding shape and size distribution, were produced by carrying out a multi-step manufacturing process. Furthermore, the applicability of ρpress as an alternative quality parameter to other placebo formulations and to formulations containing active pharmaceutical ingredients (APIs) was demonstrated.

High-Shear Wet Granulation of SMEDDS Based on Mesoporous Carriers for Improved Carvedilol Solubility.

Mesoporous carriers are a convenient choice for the solidification of self-microemulsifying drug delivery systems (SMEDDS) designed to improve the solubility of poorly water-soluble drugs. They are known for high liquid load capacity and the ability to maintain characteristics of dry, free-flowing powders. Therefore, five different mesoporous carriers were used for the preparation of carvedilol-loaded SMEDDS granules by wet granulation methods—in paten (manually) and using a high-shear (HS) granulator. Granules with the highest SMEDDS content (63% and 66% of total granules mass, respectively) and suitable flow properties were obtained by Syloid® 244FP and Neusilin® US2. SMEDDS loaded granules produced by HS granulation showed superior flow characteristics compared to those obtained manually. All SMEDDS granules exhibited fast in vitro release, with 93% of carvedilol releasing from Syloid® 244FP-based granules in 5 min. Upon compaction into self-microemulsifying tablets, suitable tablet hardness and very fast disintegration time were achieved, thus producing orodispersible tablets. The compaction slightly slowed down the carvedilol release rate; nevertheless, upon 1 h (at pH 1.2) or 4 h (at pH 6.8) of in vitro dissolution testing, the amount of released drug was comparable with granules, confirming the suitability of orodispersible tablets for the production of the SMEDDS loaded single unit oral dosage form.

Real-Time Monitoring of Critical Quality Attributes during High-Shear Wet Granulation Process by Near-Infrared Spectroscopy Effect of Water Addition and Stirring Speed on Pharmaceutical Properties of the Granules.

To produce high-quality pharmaceuticals, a real-time monitoring method for the high-shear wet granulation process (HSWG) was developed based on near-infrared spectroscopy (NIRS). Samples consisting of lactose, potato starch, and hydroxypropyl cellulose were prepared using HSWG with varying amounts of purified water (80, 90, and 100 mL) and impeller speed (200, 400, and 600 rpm), which produces granules of different characteristics. Twelve batches of samples were used for the calibration and nine batches were used for validation. After drying, the median particle size (D50), tapped density (TD), and Hauser ratio (HR) were measured. The best calibration models to predict moisture content (MC), D50, TD, and HR were determined based on pretreated NIR spectra using partial least squares regression analysis (PLSR). The temporal changes in the pharmaceutical properties under different amounts of water added and stirring speed were monitored in real time using NIRS/PLSR. Because the most important critical quality attribute (CQA) in the process was MC, granule characteristics such as D50, TD, and HR were analyzed with respect to MC. They might be used as robust and simple monitoring methods based on MC to evaluate the pharmaceutical properties of HSWG granules.

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.

A wet granulation method to prepare graphite particles with a high tap density for high volumetric energy density lithium-ion storage

Graphite is the most widely used anode material for lithium ion batteries (LIBs). Increasing the sphericity and tap density of the graphite particles is important for improving their volumetric energy density. We report a simple approach to prepare high tap-density graphite granules by high-shear wet granulation. Graphitic onion-like carbon (GOC) and artificial graphite (AG) were densified into granules by wet-granulation to obtain WG-GOC and WG-AG, respectively. Results indicate that, compared with the original graphite before granulation, the tap densities of WG-GOC and WG-AG increased by 34% and 44%, respectively. The respective volumetric energy densities of WG-GOC and WG-AG increased by 35% and 55% at a current density of 50 mA g−1. The rate performance of WG-GOC was also significantly improved. The volumetric capacity of WG-GOC at a current density of 2000 mA g−1 was 169.1% of the original GOC. The significant improvement of electrochemical performance is ascribed to the increased tap density of the graphite granules.