Wet Granulation Process Research Articles

Effects of zirconium diboride addition on porosity reduction in laser metal deposition of tungsten carbide–cobalt cermet material

Laser metal deposition of tungsten carbide–cobalt (WC-Co) cermet material is a promising means of improving the wear resistance of metal products. However, laser metal deposition of WC-Co has constraints on its practical use because a clad bead of WC-Co often includes numerous gas pores. Earlier studies have found CO gas generation in a molten pool by reaction of carbon and oxygen to be the main cause of gas porosity in a WC-Co clad bead. Preventing the gas reaction is important to obtain clad beads with few pores. The addition of elements with strong affinity for oxygen, such as aluminum, was found to be effective for porosity reduction in a clad bead. However, the addition of highly reactive pure aluminum particles on WC-Co powder presents some difficulties for industrial use. For this study, zirconium diboride (ZrB2), a chemically stable compound, was used as an additive to WC-Co powder. After WC-Co powder with adhered ZrB2 particles was prepared using a wet granulation process, laser metal deposition was conducted. Zirconium stemming from the dissolution of ZrB2 in the molten pool was found to have the effect of trapping oxygen elements as solid zirconium oxides. Consequently, gas generation in the molten pool by the reaction of carbon and oxygen was restrained. Clad beads having few pores and fine microstructures were obtained. Observations of the molten pool behavior taken using a high-speed camera indicated that ZrB2 addition drastically improves process stability compared to processes using conventional WC-Co powder.

Population balance modelling and reconstruction by quadrature method of moments for wet granulation

Population balance methods utilised in multiphase flow simulations mark a significant advancement in computational fluid dynamics. However, existing approaches exhibit shortcomings, such as being prone to inaccuracies or being computationally prohibitive. Addressing these challenges, a recent innovation in closure for the method of moments is the introduction of quadrature based moments methods (QBMM). Discretising a distribution by a number of discrete elements, QBMM facilitate efficient and accurate tracking of density distributions, particularly for particle size distributions (PSD). However, obtaining the full particle size distribution information using these methods requires reconstructing the distribution from a finite set of moments, which is not a trivial step.This study introduces a novel combination of the maximum entropy reconstruction (MER) and QBMM, establishing a robust and rapid framework for the time evolution and reconstruction of PSDs. As proof of concept for this framework, we focus on the direct quadrature method of moments (DQMOM) with spatially homogeneous and monovariate distributions. We show that coupling of MER with DQMOM has numerous advantages. To verify the framework, special cases of constant growth, aggregation, and breakage are considered for which analytical solutions can be found. Furthermore, we show the advantage of using DQMOM with volume-based over length-based distributions, and address numerical as well as theoretical issues.Application of the framework is successfully conducted on the evolution of the PSD from a twin-screw wet granulation dataset, considering all active primary physical mechanisms in a wet granulation process, namely growth, aggregation, and breakage. This showcases the consistency of the proposed framework and underscores its applicability to real-world scenarios.

Formulation and Evaluation of Metformin Using Fenugreek Seed Mucilage Used as a Natural Polymer

The major goal of this study was to develop and test metformin sustained release tablets employing fenugreek seed mucilage (FSM) as a new binder, as opposed to standard polymers such as xanthan gum and HPMC. The study shows how FSM provides sustained medication release while keeping metformin physicochemical characteristics. The sustained-release matrix tablets were made on a laboratory scale utilizing the wet granulation process. 5 batches were created, each with varying quantities of fenugreek seed mucilage, xanthan gum, and HPMC. To examine the tablet's physical properties and consistency, different criteria such as thickness, hardness, weight variation, and content homogeneity were measured. FTIR tests were performed to determine the compatibility of metformin and the polymers employed. The results showed no incompatibility, indicating that the novel excipient, FSM was not affecting the drug's physicochemical qualities. The in-vitro drug dissolution investigation was conducted utilizing a USP type-II paddle apparatus to quantify the drug release rate from dosage forms and to assess thepolymers' efficacy in retarding drug release. The study discovered that raising the concentration ofthe matrix ingredient reduced the medication release rate. Among the formulations, the combination of FSM with HPMC (MS1) resulted in 95% drug release, FSM with xanthan gum achieved 96% drug release, and the MS4 formulation had the greatest drug release rate. Finally, the study showed that fenugreek seed mucilage and xanthan gum effectively develop metformin continuous-release matrix tablets. Lower concentrations of these polymers were more suited and effective, resulting in sustained drug release. This study demonstrates the potential of fenugreek seed mucilage as a novel and effective binder in sustained-release formulations.

Formulation Development and Evaluation of Atorvastatin Calcium Extended-Release Tablets

Atorvastatin calcium is an antihyperlipidemic agent that acts as HMG- COA reductase inhibitor. The objectives of the current research are to evaluate Atorvastatin calcium release from sustained-release tablets. FTIR analysis reveals that drug and polymer have no interaction. The tablets were created utilizing the wet granulation process by using various concentrations of polymer like HPMC. The prepared extended-release tablets have been assessed for friability, thickness, drug content, hardness, and in-vitro drug release studies. From the release analysis at high concentrations demonstrate better release than HPMC low concentration. The in-vitro release data findings indicate that HPMC polymer exhibits a better release rate at 18 hours showing 97.63.

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.

Development of novel portable NIR spectroscopy process analytical technology (PAT) tool for monitoring the transition of ibuprofen to ibuprofen sodium during wet granulation process

The aim of this research was to develop a process analytical technology (PAT) tool for monitoring the transformation of the active ingredient ibuprofen into the fast-dissolving salt ibuprofen sodium during the wet granulation process. Two near-infrared (NIR) spectrophotometers, portable and benchtop spectrophotometer, were compared. During the analysis with the built models, both demonstrated comparable accuracy and precision (R2X = 0.995, R2Y = 0.927, Q2 = 0.995, and R2X = 0.990, R2Y = 0.948, Q2 = 0.992, respectively). Considering the applicability, a model based on the portable NIR spectroscopic data was chosen for further development and application as a PAT tool for monitoring different steps during the wet granulation process. The evaluation of the model's predictive capability involved analyzing laboratory trial batches with varying amounts of sodium carbonate, resulting in different concentrations of ibuprofen sodium at the end of the wet granulation process. Subsequently, tablets were manufactured from each trial batch, followed by dissolution analysis. The dissolution rate assays were in good agreement with the NIR-predicted concentrations of ibuprofen sodium at the end of the wet granulation process. Based on the results, the proposed model provides an excellent tool to monitor the ibuprofen acid-salt transformation, to determine the end-point of the reaction, and to efficiently control the wet granulation process.

Effect of hydroxy propyl cellulose grade and foam quality on foam granulation of a high drug load formulation

Foam granulation is a relatively newer wet granulation process whereby foamed binder solutions are added to the powders in the mixer to reduce localized over-wetting encountered during the wet granulation. This study is the first to investigate the effect of binder grade and foam quality on foam granulation process and granule properties of a high drug load formulation. Two different HPC grades, HPC LF (two times more viscous) and HPC EXF at an equivalent 7.4%w/w solution concentration, and foam quality of 50%, 90% and binder solution dripped were added to a high drug load (81%w/w) formulation for wet granulation. The granules were evaluated for compactibility and resultant compact strengths. The 50% foam quality of either HPC LF and HPC EXF resulted in lowest impeller power reading and water activity compared to 90% foam quality or dripped HPC solution. Granules prepared with 50% foam quality also exhibited smaller granule size, wider size distribution and higher specific surface area, resulting in higher compactibility. Whilst the granules prepared with different foamed HPC grades were not significantly different in compression behavior, they were higher in compact strengths, suggesting that foam mixing was more efficient in binder distribution compared to binder liquid penetration and distribution.

Exploring the Potential of Momordica charantia Fruits Mucilage as a Novel Pharmaceutical Excipient

Background: The discovery and developments of new drug formulations are inspired by medicinal plants. Polysaccharides, such as mucilage or gum from medicinal plants, have a variety of physicochemical properties and are commonly used in pharmaceutical applications. Objectives: The current study's objectives are to construct and assess Metformin HCl tablets employing Momordica charantia (MC) natural mucilage as a binder and release modifier. Methods: The mucilage was isolated from the fruits of MC. The tablet was made using a wet granulation process, and the formulation included several mucilage ratios (1%, 2.5%, 5%, and 10%). Results: It was found that the granules and tablets had good flow qualities based on results of the pre- and post-compression parameters. The release kinetic study showed that F4 showed the first order release kinetics and F8 showed the zero and the higuchi’s release kinetics. In low concentration of mucilage tablets showed good binding properties with immediate release properties. As the concentration was increased, tablets showed good binding properties with sustained release properties. Conclusion: The isolated mucilage from Momordica charantias has the potential to be used as a tablet binder and as an intermediary in the development of a sustained-release drug

Investigating the Effects of Mixing Dynamics on Twin-Screw Granule Quality Attributes via the Development of a Physics-Based Process Map.

Twin-screw granulation (TSG) is an emerging continuous wet granulation technique that has not been widely applied in the industry due to a poor mechanistic understanding of the process. This study focuses on improving this mechanistic understanding by analyzing the effects of the mixing dynamics on the granule quality attributes (PSD, content uniformity, and microstructure). Mixing is an important dynamic process that simultaneously occurs along with the granulation rate mechanisms during the wet granulation process. An improved mechanistic understanding was achieved by identifying and quantifying the physically relevant intermediate parameters that affect the mixing dynamics in TSG, and then their effects on the granule attributes were analyzed by investigating their effects on the granulation rate mechanisms. The fill level, granule liquid saturation, extent of nucleation, and powder wettability were found to be the key physically relevant intermediate parameters that affect the mixing inside the twin-screw granulator. An improved geometrical model for the fill level was developed and validated against existing experimental data. Finally, a process map was developed to depict the effects of mixing on the temporal and spatial evolution of the materials inside the twin-screw granulator. This process map illustrates the mechanism of nucleation and the growth of the granules based on the fundamental material properties of the primary powders (solubility and wettability), liquid binders (viscosity), and mixing dynamics present in the system. Furthermore, it was shown that the process map can be used to predict the granule product quality based on the granule growth mechanism.

Analysis and simulation of wet-granulation processes

BackgroundSize enlargement by wet-granulation is one of the most important unit operation in several industrial fields: pharmaceutics, food processing, animal nutrition, agronomics, and so on. A lot of techniques have been used in order to measure the particle size distributions (PSD) and a few different approaches are available to model the PSD evolution during the process, mainly based on population balance equations (PBE). However, difficulties in both the activities (reliable measurement and robust modeling) have hindered their diffusion in industrial practice, keeping the granulation closer to an art than to a science. MethodsIn this work, a fast and reliable method to measure PSD, based on dynamic image analysis (DIA) is presented and used in two case histories, one on a batch process on lab scale, and the other on a continuous process on plant scale. Significant findingsThe evolution of PSD was successfully described by models based on PBE, confirming the validity and the usefulness of the two approaches (experimental/modeling). The resulting model could be used as a basis for the process analysis and – to some extent – to predict the system's behavior in different conditions.

Optimization of ticagrelor tablet for gastro-retentive drug delivery using full factorial design

Purpose: To identify the optimized region of formulation using quality by design for developing ticagrelor gastro-retentive (GR) tablets. 
 Methods: A 23 + 3 full factorial design of experiments study was used to identify three factors (polyethylene oxide (PEO), compression, and volume of granulating fluid) involved in the wet granulation and compression process of ticagrelor GR tablets. Hardness, friability, content, dosage unit uniformity, and pH 1.2 dissolution rate (at 4, 8, and 12 h) were evaluated as critical quality attributes via analysis of variance using Design Expert software. 
 Results: All seven models were significantly influenced based on analysis of variance results (p < 0.05). Hardness and friability were significantly affected by compression (p < 0.0001). Content uniformity was significantly affected by the interaction between compression and granulating water volume for wet granulation (p < 0.05), and dosage unit uniformity was significantly affected by the volume of granulating fluid for wet granulation (p < 0.05). However, all results were within acceptable ranges. Polyethylene oxide (PEO) (4 h, p < 0.05; 8 h, p < 0.05; 12 h, p < 0.05) and compression (4 h, p < 0.05; 8 h, p < 0.05; 12 h, p < 0.05) had negative effect on pH 1.2 dissolution rate. 
 Conclusion: Design of experiment (DoE) approach has been used to optimize region of PEO, compression, and volume of granulating fluid for formulation development. This outcome is expected to be a basis for further research to develop TCG GR tablets on a large production scale.

A novel combination of machine learning models and metaheuristic algorithm to predict important parameters of twin screw wet granulation process

Twin screw granulation (TSG) has recently been emerged as a novel approach for the continuous wet granulation of fine particles (i.e., powders) in the pharmaceutical industry. The presence of brilliant advantages like the ability of operation at very low liquid concentrations and excellent product consistency has made this technique promising. Except positive points, the existence of major challenges like scalability and flexibility in the processing regimes has enhanced the importance of deeper investigations towards true recognition of this process. The central aim of this theoretical article is to develop the modeling process of TSG employing four machine learning models and one metaheuristic algorithms in a hybrid approach. Screw speeds, material throughputs, liquid binder (water)-to-solid ratios, and screw configurations are known as important parameters of TSG process, which were validated via their comparison with the obtained experimental data. GBR, SGD, and SVR were finally selected for 3 targets with their best combinations of hyper-parameters employing FA. The output is based on d-values (d10, d50, d90) for the granulate particle size distribution (PSD). Final models have R2 scores of 0.919, 0.960, and 0.877 for d10, d50, d90 outputs, respectively.

An Evaluation of Wet Granulation Process Selection for API Prone to Polymorphic Form Conversion in the Presence of Moisture and Heat.

Wet granulation (WG) is one of the most versatile processes to improve blend properties for processing. However, due to its need for moisture and heat, it is often considered not amenable to active pharmaceutical ingredients (APIs) prone to forming hydrates. Despite this claim, little literature exists evaluating the extent to which polymorphic form conversions occur for such API when processed with WG. This work sets out to explore two common WG methods, high-shear (HSG) and fluid-bed (FBG), and two drying processes, tray-drying (TD) and fluid-bed drying (FBD), and evaluate the risk they pose to hydrate form conversion. The progression of anhydrous to hydrate form conversion of two model compounds with vastly different solubilities, fexofenadine hydrochloride and carbamazepine, was monitored throughout the various processes using powder X-ray diffraction. The resultant granules were characterized using thermogravimetric analysis, differential scanning calorimetry, BET adsorption, and sieve analysis. FBG and FBD processing resulted in the preservation of the original form of both APIs, while HSG+TD resulted in the complete conversion of the API. The FBD of fexofenadine and carbamazepine granules prepared with HSG resulted in partial and complete re-conversion back to the original anhydrous forms, respectively. The drying process is a critical factor in anhydrous form conservation. FBG and FBD yielded better preservation of the initial anhydrous forms. HSG could be an acceptable granulation method for API susceptible to hydrate formation if the API solubility is low. Selecting an FBG+FBD process minimizes API hydrate formation and preserves the original anhydrous form.

Formulation and characterization: Metoprolol succinate controlled release matrix tablets

Metoprolol succinate-controlled release matrix tablets were made utilizing the wet granulation process with various ratio of Hydroxypropyl methyl cellulose (HPMC K4M). Isopropyl alcohol is used as a granulating agent in the Povidone (PVP K30) solution. In addition to being utilised as diluents to raise the weight of the tablets, magnesium stearate and talc were added to enhance the granules' flow ability during tablet compression. The crushed tablets underwent physicochemical characteristics, in-vitro and kinetic tests, and the micromeritic properties of the generated granules were evaluated. In every formulation, results were nearly satisfactory, with M4 being the best among the others. All of the formulations showed good correlation. The drug diffusion kinetics from matrix tablets appeared to be zero order, and the release mechanism was diffusion regulated.

Characterizations of Swelling Granule of Clove Leaf (Syzygium aromaticum L.) Ethanol Extract

Cloves, scientifically known as Syzygium aromaticum L., hold promise as a potential antiulcer remedy due to their rich composition of compounds, including high levels of phenolic compounds such as eugenol, eugenol acetate, and gallic acid. To improve bioavailability in the gastric environment, this study focuses on optimizing and evaluating a swelling granule system derived from clove leaf extract. The granules were produced using wet granulation with Carbopol, HPMC, and their combination as polymer matrices. Results indicated favorable properties in the swelling granules, with the optimal composition of 210 mg Carbopol, 36 mg PVP, and 404 mg Avicel pH 101. These granules exhibited a uniform particle size distribution, with 90.1% below 149 µm and 9.9% distributed across mesh numbers 100, 80, and 40. The formula with Carbopol polymer showed superior flow rate, compressibility, and swelling capacity compared to other formulations. The interaction between Carbopol's C=O groups and HPMC's hydroxyl groups significantly influenced parameters, especially swelling capacity. Thus, when combining polymers, potential chemical or physical reactions should be considered. The wet granulation process effectively preserved secondary metabolite levels from clove leaf. Further tests are recommended to evaluate the granulation's effectiveness as a delivery system for clove leaf extract.

The role of adding nanoparticles and surfactant to the enzyme liquid binder in fluidized bed granulation process

The influence of enzyme liquid binder properties on wet granulation process was evaluated at both micro- and macro-scales. The micro-scale phenomena, including binder droplet spreading on and penetration into the powder bed, as well as liquid bridge shape and force, were analyzed by introducing SiO2 nanoparticles and SDS surfactant into the liquid binder containing a protease enzyme and 1 wt% of NaCMC. Moreover, the simultaneous effect of formulation variables, including NPs and SDS concentrations, and process conditions, such as binder spray rate and air temperature, was investigated using design of experiments. The average size and the span were considered as the responses. Nanofluid binder without SDS exhibited lower spreading and penetration times and a stronger bridge force. All formulation and process factors significantly influenced granule size distribution. Notably, increasing nanoparticle concentration and binder flow rate, while decreasing SDS concentration and air temperature, resulted in larger granules and a narrower size distribution.

Quantitative analysis of the effects of multi-component formulation parameters on granule and tablet properties via a combined population balance and statistical predictive model

In pharmaceutical drug product manufacturing, the use of multi-component mixtures in the formulation is a common practice. However, the introduction of each material alters the powder blend properties and affects the granule growth mechanisms in a wet granulation process. In this study, we quantified the effects of varying formulation parameters on granule growth rate, expressed by the liquid amount required for granulation to reach completion, and on granule and tablet quality attributes. Process models, including population balance and statistical models, were developed to represent the granulation, milling, and tableting process, and predict relevant granule and tablet properties. Overall, prediction of granule properties had an accuracy of above 80% and the prediction of different tablet properties ranged from an R2 of 0.68 to 0.9. These models are computationally efficient and can be simulated serially to predict the performance of different multi-component formulations by using the pre-blend properties as model inputs.

Optimization of wet granulation process for manufacturing Rivaroxban generic immediate-release tablets using PBPK modeling and simulations.

The online version contains supplementary material available at 10.1007/s40203-024-00249-6.

Flexible Manufacturing with Starch-based Excipient Blends for Early-Stage Drug Product Development

INTRODUCTIONStarch-based excipients have gained attention in early-stage drug product development due to their unique properties and process flexibility. Studies have demonstrated their use in various manufacturing techniques, such as roller compaction, wet granulation, direct compression, and fluid bed granulation (Svačinová, P et al., 2021). These excipients have been shown to improve the compressibility, tabletability, and strength of the final drug product. By conducting laboratory-based compaction analysis early within the formulation and process development may de-risk tablet development (Stewart, S et al, 2021).MATERIALS AND METHODSStarch 1500®  and StarTab® were supplied by Colorcon Ltd, mannitol was obtained from Roquette microcrystalline cellulose (MCC) was provided by IMCD Ltd,and magnesium carbonate (surrogate API) was procured from Scora S.A.S. Blends for direct compression and roller compaction were prepared by mixing the ingredients in a Turbula blender for 10 minutes. The granulation process utilized both fluid bed and high shear granulation techniques, involving the application of water and subsequent drying. The resulting granules/blends were lubricated with 0.5% w/w magnesium stearate and analysed for compaction using a Gamlen™ D-Series compaction analyser.RESULTS AND DISCUSSIONTable 1 shows the formulations of multifunctional excipients like Starch 1500® and StarTab®, combined with plastically deforming MCC and brittle deforming mannitol. These excipient blends were selected to strike the right balance between tablet strength and disintegration, making them suitable for immediate-release drug products.Figure 1 displays tabletability profiles of different formulations from Table 1, produced using various manufacturing processes. The results show that fluidized bed granulation generated the strongest tablets (tensile strength ≥ 1.8 MPa) at all compaction pressures.Roller compaction produced weaker, yet acceptable tablets. Surprisingly, the wet-granulation process, intended to enhance tablet hardness, showed similar tabletability to the DC StarTab® blend. This suggests that high tensile strength tablets can be achieved using the direct compression grade of Starch(StarTab®).Figure 2 presents compressibility profiles(compaction pressure vs solid fraction) of the different processes. The data shows that all combinations have a solid fraction of ≤0.9 at a nominal compression pressure of 200 MPa, indicating minimal risk of over compression.This finding is crucial as over compression can cause undesirable outcomes like capping and lamination. Figure 3 illustrates compactability profiles (solid fraction vs tensile strength) of the blends. The results indicate that the fluid bed granulation process generates the highest tensile strength at similar solid fraction levels. This is likely due to starch activation with water,which acts as a binder and increases compact hardness. Additionally, the fluid bed granulation process promotes granule formation and uniform mixing of excipients, resulting in a more homogenous blend and higher tensile strength.CONCLUSIONSThe study concludes that starch-based powder blends offer process flexibility and compatibility with different manufacturing techniques in the pharmaceutical industry. The results suggest that fluid bed granulation is a more suitable technique for achieving strong tablet blends compared to roller compaction.REFERENCESSvačinová, P., Mužíková, J., & Ondrejček, P.(2021). Comparison of compressibility, compactability, and lubricant sensitivity of two partially pregelatinized starches. Starch/Stärke, 73(1-2),2000166. Stewart, S., Dean, I. L., Lawlor, M. &Lawrence, S., (2022) The Use of Compaction Simulation as a Tool to Aid Successful Tablet Formulation, British Journal of Pharmacy 7(2).

Design, Development and Physicochemical Evaluation of Effervescent Tablets of Antihistamine Drug

Purpose: Effervescent bilastine tablets were the focus of this investigation because of their ease of administration and the fact that some patients, especially younger ones or those with impaired swallowing abilities, have trouble ingesting oral dosage forms. Methods: Using the wet granulation process, 20 mg of effervescent bilastine tablets were produced. Pre-compression properties assessed for powder blend and granule combination. Here are some post-compression properties of the tablets that were examined: friability, hardness, drug content, pH, dissolution time, content uniformity, water content, X-ray, and Differential scanning calorimetry (DSC). We also measured carbon dioxide content and effervescence duration. To get the greatest results, we looked for effervescent systems that dissolved quickly in water and had the right properties before and after compression. Results: Based on their physicochemical properties, F2 formulations were determined to be best formulations, and the results demonstrated that the wet granulation process had greater flowability. Conclusion: Sweeteners such as mannitol, sodium saccharine, methylparaben, and citric acid were chosen for this investigation, along with sodium bicarbonate. If you want to hide the bitter flavor of bilastine, sodium saccharine is your best bet. From a physicochemical and physical property standpoint, the wet granulation process outshines the alternatives.