High-shear Granulation Research Articles

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.

Multivariate statistical process control of a continuous pharmaceutical twin-screw granulation and fluid bed drying process

A multivariate statistical process control (MSPC) strategy was developed for the monitoring of the ConsiGma™-25 continuous tablet manufacturing line. Thirty-five logged variables encompassing three major units, being a twin screw high shear granulator, a fluid bed dryer and a product control unit, were used to monitor the process. The MSPC strategy was based on principal component analysis of data acquired under normal operating conditions using a series of four process runs. Runs with imposed disturbances in the dryer air flow and temperature, in the granulator barrel temperature, speed and liquid mass flow and in the powder dosing unit mass flow were utilized to evaluate the model’s monitoring performance. The impact of the imposed deviations to the process continuity was also evaluated using Hotelling’s T2 and Q residuals statistics control charts. The influence of the individual process variables was assessed by analyzing contribution plots at specific time points. Results show that the imposed disturbances were all detected in both control charts. Overall, the MSPC strategy was successfully developed and applied. Additionally, deviations not associated with the imposed changes were detected, mainly in the granulator barrel temperature control.

New gentle-wing high-shear granulator: impact of processing variables on granules and tablets characteristics of high-drug loading formulation using design of experiment approach

The aim of this work was to study the application of design of experiment (DoE) approach in defining design space for granulation and tableting processes using a novel gentle-wing high-shear granulator. According to quality-by-design (QbD) prospective, critical attributes of granules, and tablets should be ensured by manufacturing process design. A face-centered central composite design has been employed in order to investigate the effect of water amount (X1), impeller speed (X2), wet massing time (X3), and water addition rate (X4) as independent process variables on granules and tablets characteristics. Acetaminophen was used as a model drug and granulation experiments were carried out using dry addition of povidone k30. The dried granules have been analyzed for their size distribution, density, and flow pattern. Additionally, the produced tablets have been investigated for; weight uniformity, breaking force, friability and percent capping, disintegration time, and drug dissolution. Results of regression analysis showed that water amount, impeller speed and wet massing time have significant (p < .05) effect on granules and tablets characteristics. However, the water amount had the most pronounced effect as indicated by its higher parameter estimate. On the other hand, water addition rate showed a minimal impact on granules and tablets properties. In conclusion, water amount, impeller speed, and wet massing time could be considered as critical process variables. Thus, understanding the relationship between these variables and quality attributes of granules and corresponding tablets provides the basis for adjusting granulation variables in order to optimize product performance.

Sugars with different thickening power in high shear granulation

Sugars and sweeteners are common ingredients in foods and also in pharmaceutical industries. They are soluble and sticky ingredients and their processing in granulators may be difficult since they can easily adhere to mixer walls or lead to uncontrolled granule growth. The purpose of this research was to evaluate the feasibility of the high shear wet granulation process and to find the optimal amount of binder by studying the granulation performances of four sugars: mannitol, sorbitol, xylitol and sucrose in different amounts. Sugar interactions with the liquid binder and solid carrier were carefully characterized. The increased viscosity of the liquid bridges, due to the partial solubilization of the sugars, was found to play a major role in the agglomeration process since it controls the liquid mobility and its distribution. Experiments demonstrate the feasibility of the process and the ability of mixer torque rheometer to predict the optimal binder amount.

Key physical parameters of hawthorn leaf granules by stepwise regression analysis method

The purpose of this study was to investigate the effect of key physical properties of hawthorn leaf granule on its dissolution behavior. Hawthorn leaves extract was utilized as a model drug. The extract was mixed with microcrystalline cellulose or starch with the same ratio by using different methods. Appropriate amount of lubricant and disintegrating agent was added into part of the mixed powder, and then the granules were prepared by using extrusion granulation and high shear granulation. The granules dissolution behavior was evaluated by using equilibrium dissolution quantity and dissolution rate constant of the hypericin as the indicators. Then the effect of physical properties on dissolution behavior was analyzed through the stepwise regression analysis method. The equilibrium dissolution quantity of hypericin and adsorption heat constant in hawthorn leaves were positively correlated with the monolayer adsorption capacity and negatively correlated with the moisture absorption rate constant. The dissolution rate constants were decreased with the increase of Hausner rate, monolayer adsorption capacity and adsorption heat constant, and were increased with the increase of Carr index and specific surface area. Adsorption heat constant, monolayer adsorption capacity, moisture absorption rate constant, Carr index and specific surface area were the key physical properties of hawthorn leaf granule to affect its dissolution behavior.

Non-destructive Determination of Disintegration Time and Dissolution in Immediate Release Tablets by Terahertz Transmission Measurements

ABSTRACTPurposeThe aim of this study was to establish the suitability of terahertz (THz) transmission measurements to accurately measure and predict the critical quality attributes of disintegration time and the amount of active pharmaceutical ingredient (API) dissolved after 15, 20 and 25 min for commercial tablets processed at production scale.MethodsSamples of 18 batches of biconvex tablets from a production-scale design of experiments study into exploring the design space of a commercial tablet manufacturing process were used. The tablet production involved the process steps of high-shear wet granulation, fluid-bed drying and subsequent compaction. The 18 batches were produced using a 4 factor split plot design to study the effects of process changes on the disintegration time. Non-destructive and contactless terahertz transmission measurements of the whole tablets without prior sample preparation were performed to measure the effective refractive index and absorption coefficient of 6 tablets per batch.ResultsThe disintegration time (R2 = 0.86) and API dissolved after 15 min (R2 = 0.96) linearly correlates with the effective refractive index, neff, measured at terahertz frequencies. In contrast, no such correlation could be established from conventional hardness measurements. The magnitude of neff represents the optical density of the sample and thus it reflects both changes in tablet porosity as well as granule density. For the absorption coefficient, αeff, we observed a better correlation with dissolution after 20 min (R2 = 0.96) and a weaker correlation with disintegration (R2 = 0.83) compared to neff.ConclusionThe measurements of neff and αeff provide promising predictors for the disintegration and dissolution time of tablets. The high penetration power of terahertz radiation makes it possible to sample a significant volume proportion of a tablet without any prior sample preparation. Together with the short measurement time (seconds), the potential to measure content uniformity and the fact that the method requires no chemometric models this technology shows clear promise to be established as a process analyser to non-destructively predict critical quality attributes of tablets.

Development of Extended-Release Oral Flexible Tablet (ER-OFT) Formulation for Pediatric and Geriatric Compliance: an Age-Appropriate Formulation.

Development of age-appropriate formulation suitable for pediatric and geriatric patients involves various challenges. The objective of this research was to develop extended-release oral flexible tablet (ER-OFT) formulation using carbamazepine (CBZ) as model drug for pediatric and geriatric compliance. ER-microparticles of carbamazepine, a BCS class 2, and narrow therapeutic index (NTI) drug, were prepared using ethyl cellulose as matrixing polymer and hypromellose as hydrophilic pore former. Microparticles were prepared using high-shear granulator fitted with an atomizing spray system. Granulation of carbamazepine and ethyl cellulose (EC-FP) with ethanolic binder solution resulted in ER-microparticles with extended-release >16h. Release kinetics of ER microparticles showed Higuchi model by drug diffusion and erosion. Korsemeyer-peppas release exponent "n" value 0.42 suggested Fickian diffusion. ER-OFT was prepared by blending of ER-microparticles with water-insoluble compressible aid and disintegrating agent. ER-OFT was characterized for performance characteristics and elemental impurities. As the polymer content in formulation was <10%, the size of ER-OFT was smaller compared to marketed ER-formulations. ER-OFT showed in vitro disintegration time of <30s as per USP and dispersion time of ∼60 to 180s in 5 to 10mL of water. Drug release profiles of ER-microparticles and ER-OFT were comparable as f2 values were >50. In vitro dissolution of ER-OFT was comparable to the marketed ER formulation in the pH range of GIT. ER-OFT can be orally swallowed, orally disintegrating, and used as dispersible tablets. Compared to non-disintegrating type ER-formulations, ER-OFT would provide uniform drug release in GIT with low within-subject variability an essential criterion for NTI drug.

Effects of moisture content and compression pressure of various deforming granules on the physical properties of tablets

The main purpose of this study was to investigate the effects of moisture content (MC) of different deformation granules (brittle, plastic, and elastic) and compression pressure (CP) on the physical properties of tablets. A general full factorial design was used with three blocks (deformation property of excipient) and two control factors: MC and CP. Lactose monohydrate (LM), microcrystalline cellulose (MCC), and corn starch (CS) were selected as brittle, plastic, and elastic materials, respectively. The granules were prepared with a high-shear granulator having a capacity of 0.9L by adding water using a peristaltic pump. This high-shear granulator allows recording of real-time impeller torque values with 1-s intervals. The torque curves can facilitate determination of the transition between saturation stages of a system. Analysis of variance was performed to determine the significance of each factor and their interactions with response variables. All control factors and deformation properties of excipient showed significant effects on the properties of tablets, including ejection force, tensile strength, and porosity (p<0.05). However, their mutual interaction was not significant on the response variables (p>0.05). Analysis of the relationship between ejection work and peak force (Fmax) demonstrated that the ejection work profiles were associated with the deformation properties of the excipient. Moreover, tablet strength was dependent on the control factors and the deformation nature of excipient. As these factors significantly influenced the physical properties of tablets, achieving high-quality tablets would require comprehensive information on the excipient properties while considering the compression process.

The influence of thermal treatment and type of insoluble poly(meth)acrylates on dissolution behavior of very soluble drug from hypromellose matrix tablets evaluated by multivariate data analysis

Hypromellose matrices exhibit extended burst effect immediately after contact with aqueous medium, especially when a water-soluble drug is incorporated. The objective of this study was to reduce burst effect and maintain complete dissolution of a very soluble levetiracetam over 12 h period from hypromellose K4M matrices to obtain zero-order kinetics. Desired changes were achieved by applying water dispersions of insoluble Eudragits® (NE, NM, RL, RS) as a granulation liquid to the drug/microcrystalline cellulose mixture during high-shear granulation (non-thermal treated set) and consequently by thermally treating granules or final tablets (TT), respectively. Applying Eudragit® water dispersions to the drug/microcrystalline cellulose mixture was recognized as an effective method of significantly reducing the burst release (25.4–33.7%) of levetiracetam in comparison with a reference sample without Eudragit®. Multivariate data analysis showed that the addition of Eudragit® reduced burst effect, increased fitting with zero-order kinetics, and supported matrix erosion as the supplementary mechanism to predominant diffusion. Moreover, resulting PCA sub-model revealed the addition of Eudragit® RL and thermal treatment of tablets to be the most suitable method of all. For a 12 h dissolution profile, characterized by low burst effect and drug release close to 100% at the 12th hour, sample RL_TT was the most suitable.

A novel approach for dry powder coating of pellets with Ethylcellulose. Part I: Evaluation of film formulation and process set up

An innovative dry powder coating technology was developed in a high-shear granulator using ethylcellulose (E10) as polymer. Several solid plasticizers were investigated with the aim of decreasing the polymer Tg at least to the highest possible working temperature (80°C). DSC analysis of physical mixtures of E10 and plasticizers evidenced that lauric acid (LA) was the most effective plasticizer. In order to reach the target temperature a liquid plasticizer, oleic acid (OA), was introduced in the coating formulation. Free films were then prepared and the target minimum film forming temperature (MFFT) was established in the range 70–80°C. Depending on the LA:OA weight ratio, Kollidon VA64 was included to decrease the LA recrystallization, while talc served as anti-sticking agent. Curing at the MFFT ensured the formation of homogeneous and stable films with good stability on storage. The dry powder coating process of placebo pellets was then developed, consisting of a combination of liquid assisted and thermal adhesion methods. The best coating formulations in terms of yields, coating efficiency (expressed as Relative Standard Deviation of the weight applied) and low pellets aggregation were based on E10:LA:OA in a weight ratio of 65:20:15 and 60:20:20. Moreover pellets remained stable after 1year of storage (25°C/60% R.H.).

Development and incorporation of lightweight waste-based geopolymer aggregates in mortar and concrete

Using industrial side streams as artificial aggregate precursors could increase waste utilization and save natural reserves. In this study, lightweight geopolymer aggregates were manufactured from fluidized bed combustion fly ash and mine tailings using high shear granulation and alkali activation. The results showed that geopolymer aggregates had physical properties comparable to commercial lightweight expanded clay aggregates (LECAs). Mortar and concrete prepared with geopolymer aggregates had higher mechanical strength, a higher dynamic modulus of elasticity, and higher density than concrete produced with LECAs, while the rheology and workability was the same.

Resolution and Sensitivity of Inline Focused Beam Reflectance Measurement During Wet Granulation in Pharmaceutically Relevant Particle Size Ranges

Real-time process monitoring using a process analytical technology for granule size distribution can enable quality-by-design in drug product manufacturing. In this study, the resolution and sensitivity of chord length distribution (CLD) measured inline inside a high shear granulator using focused beam reflectance measurement (FBRM) C35 probe was investigated using different particle size grades of microcrystalline cellulose (MCC). In addition, the impact of water and impeller tip speed on the measurement accuracy as well as correlation with offline particle sizing techniques (FBRM, laser diffraction [Malvern Mastersizer®], microscopy [Sympatec QicPic®], and nested sieve analysis) was studied. Inline FBRM resolved size differences between different MCC grades, and the data correlated well with offline analyses. Impeller tip speed changed the number density of inline CLD measurements while addition of water reduced the CLD of dry MCC, likely due to deagglomeration of primary particles. In summary, inline FBRM CLD measurement in high shear granulator provides adequate resolution and reproducible measurements in the pharmaceutically relevant size range both in the presence and in the absence of water. Therefore, inline FBRM can be a valuable tool for the monitoring of high shear wet granulation.

Statistical analysis and comparison of a continuous high shear granulator with a twin screw granulator: Effect of process parameters on critical granule attributes and granulation mechanisms

This study is concerned with identifying the design space of two different continuous granulators and their respective granulation mechanisms. Performance of a continuous high shear granulator and a twin screw granulator with paracetamol formulations were examined by face-centered cubic design, which focused on investigating key performance metrics, namely, granule size, porosity, flowability and particle morphology of granules as a function of essential input process parameters (liquid content, throughput and rotation speed). Liquid and residence time distribution tests were also performed to gain insights into the liquid-powder mixing and flow behavior. The results indicated that continuous high shear granulation was more sensitive to process variation and produced spherical granules with monomodal size distribution and distinct internal structure and strength variation. Twin screw granulation with such a particular screw configuration showed narrower design space and granules were featured with multimodal size distribution, irregular shape, less detectible porosity difference and tighter range of strength. Granulation mechanisms explored on the basis of nucleation and growth regime maps revealed that for most cases liquid binder was uniformly distributed with fast droplet penetration into the powder bed and that granule consolidation and coalescence mainly took place in the nucleation, steady growth and rapid growth regimes.

Investigating the Use of Polymeric Binders in Twin Screw Melt Granulation Process for Improving Compactibility of Drugs

Traditionally, the melt granulation for pharmaceutical products was performed at low temperature (<90°C) with high-shear granulators using low-melting waxy binders, and tablets produced using such granules were not amenable to large-scale manufacturing. The situation has changed in recent years by the use of twin screw extruder where the processing temperature could be increased to as high as 180°C and polymers with high Tg could be used as binders. In this study, different polymeric binders were screened for their suitability in improving compactibility of 2 drugs, metformin hydrochloride and acetaminophen, by twin screw melt granulation. Processing temperatures for the 2 drugs were set at 180°C and 130°C, respectively. Screw configuration, screw speed, and feed rate were optimized such that all polymeric binders used produced granules. Several hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, and methacrylate-based polymers, including Klucel® EXF, Eudragit® EPO, and Soluplus®, demonstrated good tablet tensile strength (>2 MPa) when granules were produced using only 10% wt/wt polymer concentration. Certain polymers provided acceptable compactibility even at 5% wt/wt. Thus, twin screw melt granulation process may be used with different polymers at a wide range of temperature. Due to low excipient concentration, this granulation method is especially suitable for high-dose tablets.

Process analytical technology (PAT) approach to the formulation of thermosensitive protein-loaded pellets: Multi-point monitoring of temperature in a high-shear pelletization

In the literature there are some publications about the effect of impeller and chopper speeds on product parameters. However, there is no information about the effect of temperature. Therefore our main aim was the investigation of elevated temperature and temperature distribution during pelletization in a high shear granulator according to process analytical technology. During our experimental work, pellets containing pepsin were formulated with a high-shear granulator. A specially designed chamber (Opulus Ltd.) was used for pelletization. This chamber contained four PyroButton-TH® sensors built in the wall and three PyroDiff® sensors 1, 2 and 3cm from the wall. The sensors were located in three different heights. The impeller and chopper speeds were set on the basis of 32factorial design. The temperature was measured continuously in 7 different points during pelletization and the results were compared with the temperature values measured by the thermal sensor of the high-shear granulator. The optimization parameters were enzyme activity, average size, breaking hardness, surface free energy and aspect ratio. One of the novelties was the application of the specially designed chamber (Opulus Ltd.) for monitoring the temperature continuously in 7 different points during high-shear granulation. The other novelty of this study was the evaluation of the effect of temperature on the properties of pellets containing protein during high-shear pelletization.

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.

Roles of the Main Physical Properties of the Wet Granulation Product of Hawthorn leaf Extract Mixtures in High Shear Granulation

The purpose of this study was to establish a relationship between the physical properties of powders and their behavior during high shear granulation. Hawthorn leaf extract was utilized as a model drug, and microcrystalline cellulose (MCC) and soluble starch were selected as excipients. The extract was mixed with each of the different excipients at ratios of 1:0.5, 1:1 and 1:2 by weight. The granules were prepared by high shear granulation (HSG). The wet granulated product was evaluated by monitoring responses such as the granule yield, the ratio of lumps to fine powder, the angle of repose of the granules (granule-AOR) and the Hausner ratio of the granules (granule-HR). The effect of the powder's physical properties on the granulation behavior was analyzed through stepwise regression. The critical relative humidity, particle size (d50), surface free energy, AOR, moisture content, equilibrium hygroscopic moisture content (f), specific surface area, pore volume, Carr index, contact angle with water and bulk density were the main factors linked to the granule product. The main physical properties of the extract powder were the important factors in HSG. The findings from this study are useful in preparing ideal granulation products by reasonably controlling the physical properties of powders. Practical Applications The present work investigated the influence of the physical properties of Hawthorn leaf extract on high shear granulation behavior. Results showed that critical relative humidity, particle size, surface free energy, angle of repose, moisture content, equilibrium hygroscopic moisture content, specific surface area, pore volume, Carr index, contact angle with water and bulk density were the main factors linked to the granule product. Taking into consideration that the food industry uses Hawthorn leaf extract not only to plant health product as nutrient supplement but to botanical drug in several countries, this work is a useful guide to prepare ideal granulation products by reasonably controlling the physical properties of powders.

Effects of Manufacturing Methods on Dissolution and Absorption of Ketoconazole in the Presence of Organic Acid as a pH Modifier.

Poorly water-soluble compounds have a potential risk of low and variable bioavailability caused by incomplete dissolution. Incorporation of organic acids as pH modifiers is effective method for solubility enhancement of basic compounds and requires no special technique and equipment. The purpose of this study was to evaluate the effect of manufacturing method on the extent of drug solubility enhancement. We successfully prepared the granules and tablets containing ketoconazole (KZ), which is weakly basic, as a model compound and citric acid as a pH modifier using conventional wet and dry granulations. KZ solubility under non-sink condition was enhanced with supersaturation using both wet and dry granulations. High-shear granulation was the most effective method in terms of KZ dissolution enhancement, because both an intimate contact and strong bonding between KZ and incorporated acid were achieved. KZ dissolved amount from the granules prepared by high-shear granulation was about eight times higher than that from the granules without the acid. The granulation involved to suppress a diffusion of acid dissolved, leading to the effectively maintained supersaturation state. The bioavailability of KZ after oral administration to rats was improved by applying high-shear granulation with citric acid independent of gastrointestinal pH. The granules prepared by high-shear granulation showed the bioavailability about 1.7-fold higher than that of the physical mixture in rats with and without neutralization of stomach. As a result, both the dissolution and absorption rates of KZ after oral administration were enhanced using conventional manufacturing technology.

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