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To investigate the installation damage of geogrids during roller compaction under rockfill condition, a three-dimensional discrete element model for roller compaction of geogrid-reinforced rockfill was established. The rockfill was modeled by irregular rigid block elements, while the geogrids were modeled by bonding basic ball elements. The model parameters were then calibrated by triaxial consolidated-drained and tensile tests. The displacements of the geogrids in three perpendicular directions, and the strength of the geogrids was analyzed. Additionally, the effects of compaction parameters on the installation damage of the geogrids were studied. The results showed that deformation of the geogrids was relatively small in the roller-driving direction but significant in the roller-axis and settlement directions. The damage modes of the geogrids could be mainly classified into three types: rib fracture, rib end fracture, and node fracture. The installation damage of the geogrid was derived mainly from its uneven deformation and fracture, and after roller compaction the strength distributions at different locations of the geogrid layer showed a normal distribution. Furthermore, the installation damage of the geogrids increased with increasing excitation force and compaction passes but decreased with increasing overlying rockfill thickness, roller velocity, and excitation frequency. • The installation damage of the geogrids was studied by the discrete element method. • The deformation and strength of the geogrids were analyzed. • The effects of compaction parameters were also investigated. [ABSTRACT FROM AUTHOR]

• Improvement to roller compaction model by considering roll speed dependency. • Model prediction and validation using literature and industrial data. • Built a custom model in gPROMS to incorporate the effect of mass throughput during process optimization and design. This study introduces a modification to the roller compaction model proposed by Sousa et al. 1 to account for the effect of roll speed on powder compaction in the dry granulation process. The proposed model enhances the prediction accuracy, particularly at higher roll speeds, which are often overlooked in existing models. The modified model is validated using literature data, demonstrating improved performance compared to the original model. Additionally, the model is applied to a pharmaceutical formulation, showing its applicability in an industrial context. The integration of the model into gPROMS allows for global sensitivity analysis and design space exploration, providing valuable insights for process optimization and scale-up. The study contributes to the understanding of roller compaction dynamics and offers a practical tool for decision-making in pharmaceutical manufacturing. [ABSTRACT FROM AUTHOR]

Two-dimensional digital image analysis (DIA) considered a cost-effective method for characterizing the microstructure of asphalt mixtures. In this study, a more sophisticated method for defining the internal structure of aggregates was utilized to reveal performance-related properties that serve as quality indicators of mixtures. Software architecture-wise, Avizo19 is both modular and object-oriented has been used in this study. Modules and data objects are its key components. Metadata can be identified as or computational actions performed using modules. The study's goal is to assess the influence of laboratory vs. field compaction on the engineering qualities of several kinds of aggregates in different locations in central, northern, and southern Iraq including AlDoz, AlNibaa'e, Dyala, Jalawlaa, AlKut, AlSimawa, and Southern AlRumela quarries. Aviso analysis have been classified into two groups of parameters: geometric forms involving geometry, shape, and texture indicators, also the internal structure of aggregate interlocking, including orientation, anisotropy, homogeneity, and directional distribution of aggregate. The results of statistical comparisons of average, standard deviation (SD), and coefficient of variation (CoV) demonstrate the fact that the Roller compacting approach predicts the asphalt mixture formation indicators more significantly than the Marshall technique and is most effective within field compaction. [ABSTRACT FROM AUTHOR]

Purpose: Although the mechanical properties of paracetamol and MCC are extensively described in literature, there still is a need for a better understanding of the material properties impacting them. Thus, this study systematically analyzed material properties of paracetamol-MCC blends to elucidate their influence on the mechanical tablet properties in roller compaction and direct compression with special focus on surface properties. Methods: Multiple material characteristics of binary mixtures of paracetamol and MCC with varying drug loads were analyzed, with particular emphasis on specific surface area and surface energy. Subsequently, mechanical tablet properties of the materials in direct compression and after roller compaction were examined. Results: It was demonstrated that the impact of the initial material properties on mechanical tablet properties prevailed over the impact of processing route for paracetamol-MCC blends, underlining the importance of material characterization for tabletability of oral solid dosage forms. By applying bivariate as well as multivariate analysis, key material properties influencing the tabletability of paracetamol, MCC and its mixtures such as surface area, surface energy, effective angle of internal friction and density descriptors were identified. Conclusions: This study highlighted the importance of comprehensive assessment of different material characteristics leading to a deeper understanding of underlying factors impacting mechanical tablet properties in direct compression and after roller compaction by the example of paracetamol-MCC mixtures with varying drug loads. Furthermore, it was shown that multivariate analysis could be a valuable extension to common bivariate analysis to reveal underlying correlations of material properties. [ABSTRACT FROM AUTHOR]

Vibratory rollers are mainly used for the near-surface compaction of granular media for a wide variety of construction tasks. In addition to the pronounced depth effect, vibratory rollers have offered the possibility of work-integrated compaction control (intelligent compaction) for decades. State-of-the-art measurement values for intelligent compaction (ICMVs) only take into account, if at all, a constant geometry of the contact area between the drum and soil. Therefore, this paper introduces a comparatively simple mechanical model, which describes the dynamic interaction between the vibrating drum and the underlying soil during compaction to investigate the influence of the changing geometry of the contact area on the motion behavior of the vibrating drum. The model is tested on realistic soil and machine parameters, and the results of the simulation with varying drum contact geometry are compared to a conventional simulation with a fixed contact geometry. The analysis shows that only a consideration of the varying drum contact geometry can map the dynamic interaction between the vibrating drum and soil sufficiently and provide a motion behavior of the drum that is in good accordance with the field measurements. [ABSTRACT FROM AUTHOR]

Roller compaction is a widely used continuous dry granulation process in the food and pharmaceutical industries. The flow and distribution of the powder across the rollers in the compaction area plays a crucial role in determining the quality of the final product. Non-uniform powder flow and distribution across the rollers can lead to variations in quality across the ribbon, resulting in uneven qualities in the granules. Hence, it is essential to enhance the powder flow and distribution across the rollers in the compaction area. Besides that, insufficient compaction stress on both sides of the roller edges can also contribute to presence of uncompacted fines during compaction process. This research aims to systematically study a whole range of customized guiders design (T-1 until T-14) that improves powder flow and distribution across the rollers and reduces the percentage of fines in the compaction zone. The 3D printed customized guiders with different grade (1 mm until 14 mm) were applied in roller compactor with horizontal feeding system to control the amount of powder passing through the roller width by guiding more powder to the sides between the rollers and less powder to the centre. The effectiveness of the design was validated by examining crystalline and spray dry lactose powders with varying flowabilities using online thermal imaging. The results demonstrate a significant trend, indicating improved uniformity of powder flow and distribution across the rollers and reduced production of fines. These findings have the potential to contribute to long-term sustainability and resource conservation in industrial applications by reducing the need for material recycling and lowering energy consumption in continuous processes. [Display omitted] • A systematic study of 14 customized guiders on powder distribution in roller compaction was conducted using PAT. • Crystalline and spray-dried lactose with varying flowability were utilized. • Powder with low flowability shows non-uniform distribution during compaction. • Customized guiders improved temperature distribution, uniformity, and reduced fines in low-flowability lactose powder. [ABSTRACT FROM AUTHOR]

The envelope density of the roll-compacted ribbon is a widely accepted physical property that serves as a criterion for the transferability of dry granulation processes. Existing methods of obtaining ribbon density data have drawbacks in their reliability and availability at production facilities. A novel method is proposed in this paper and the performance thereof is compared to other established techniques. A pilot study was conducted on several roller compactors to prepare various batches of ribbons under different process parameters using model and real formulations from the industry. The presented method measures the envelope volume of roll-compacted ribbons by solid volume displacement of glass microspheres. The solid displacement method for measuring envelope density is as precise as mercury porosimetry, provided that the ribbon quality is adequate, even in the presence of minor structural failures, it is nondestructive allowing sample reuse, and it is scalable to larger ribbon sizes. [Display omitted] • A novel method of measuring envelope density of compacted solids is proposed. • Method utilize solid volume displacement of glass microspheres. • Method performance validated on samples of pharmaceutical roll compacted ribbons. • Solid displacement method is as precise as mercury porosimetry, even in the presence of minor structural failures. [ABSTRACT FROM AUTHOR]

Developing a robust roller compaction process can be challenging, due to the diversity in process parameters and material properties of the components in a formulation. A major challenge in dry granulation is the reduction of tablet strength as a result of re-compaction of the materials. The aim of this study is to investigate the impact of excipient type and particle size distribution on tablet tensile strength after roller compaction. Lactose monohydrate, anhydrous lactose and microcrystalline cellulose with different particle sizes are roller compacted at varying specific compaction forces. Granules obtained are compressed into tablets to evaluate the reduction in tablet strength upon increasing the specific compaction force. The impact of particle size of the starting material is shown to be vastly different for the three types of excipients investigated, due to the differences in mechanical deformation mechanisms. The presence of rough surfaces and a high degree of fragmentation for anhydrous lactose appears to be beneficial for compaction and re-compaction process. Additionally, the particle size of anhydrous lactose hardly affects the tensile strength of tablets, which can be beneficial for the robustness of a roller compaction process.

The relevance of the polymorphic form, particle size, and processing of mannitol for the mechanical properties of solid oral dosage forms was examined. Thus, particle and powder properties of spray granulated β D-mannitol, β D-mannitol, and δ D-mannitol were assessed in this study with regards to their manufacturability. D-mannitol is a commonly used excipient in pharmaceutical formulations, especially in oral solid dosage forms, and can be crystallized as three polymorphic forms, of which β is the thermodynamically most stable form and δ is a kinetically stabilized polymorph. A systematic analysis of the powders as starting materials and their respective roller compacted granules is presented to elucidate the multidimensional effects of powder and granules characteristics such as polymorphic form, particle size, and preprocessing on the resulting tablets' mechanical properties. In direct compression and after roller compaction, δ polymorph displayed superior tableting properties over β mannitol, but was outperformed by spray granulated β mannitol. This could be primarily correlated to the higher specific surface area, leading to higher bonding area and more interparticle bonds within the tablet. Hence, it was shown that surface characteristics and preprocessing can prevail over the impact of polymorphism on manufacturability for oral solid dosage forms. [ABSTRACT FROM AUTHOR]

Ribbon porosity is a critical parameter to monitor in the roller compaction process. In this study, six techniques for measuring the porosity of solid compacts, i.e., manually by caliper (Caliper), X-ray microtomography (µCT), off-line near-infrared spectroscopy (NIR), laser triangulation (Laser), mercury intrusion porosimetry (MIP), and GeoPyc, were compared using a set of rectangular ribblets of microcrystalline cellulose (MCC). These ribblets, which were compressed at 8---130 MPa on a compaction simulator, exhibited porosities over the range of 0.09 - 0.52. Subsequently, porosities of MCC ribbons made on a roller compactor at specific roll forces of 1.8 kN/cm and 8.8 kN/cm were measured. The Caliper method is convenient for samples with a simple shape but not suitable for real ribbons. The accuracy of GeoPyc measurement relies on accurate conversion factor (unit in cm 3 /mm), sample shape and size, and sufficient sample volume percentage in the medium. The µCT data is more accurate at lower porosities (< 0.2), while the MIP data is more accurate at higher porosities (> 0.4). The Laser method has good accuracy and is more reproducible compared to other methods in the ribblets measurement. The NIR method is fast, which makes it suitable for in-line monitoring of changes in ribbon quality, but porosity quantification is sensitive to sample presentation, such as surface curvature and roughness. These insights could assist in the choice of the most appropriate method for monitoring ribbon porosity to guide the development and optimization of a roller compaction process for a given formulation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

The challenges of developing good quality low dose minitablets was assessed by systematically studying the effects of ibuprofen (IBU, a model compound) particle sizes (6-58 µm D 50 ) and concentrations (0.1-3 %w/w), roller compaction forces (3-7 kN/cm), and the minitablet sizes (1.2, 1.5 and 2 mm diameter). A novel compression approach, where all three minitablet sizes were simultaneously produced in a single compression run was used. Roller compacted ribbons, granules, minitablets were characterized for physico-mechanical properties and minitablets were also characterized for stratified content uniformity and weight uniformity. The results showed that roll force was the more dominant factor to ribbon solid fraction or tensile strength and granule size enlargement. Minitablets obtained from the granules had good weight uniformity; all but one batch met the criteria. The precise control of tooling lengths across the various sizes was found profoundly important for achieving expected weights, solid fraction, and tensile strength of the simultaneously produced minitablets. The roller compaction process considerably improved the CU variability of the minitablets as compared to the direct compression process. Smaller particle size and higher concentration of IBU, increased roller compaction force, and larger minitablet size improved the potency and content uniformity; however, only the minitablet size was a statistically significant factor in this study. As a product strategic design criterion, a threshold of 25 minitablets in a dosage unit would ensure robust downstream filling and weight verification operations as well as dose accuracy and uniformity (would pass stage 1 criteria). This study results demonstrated feasibility of the novel simultaneous compression approach and the roller compaction process in developing good quality minitablets., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Abstract Expansive soils are problematic due to their swell—shrinkage behavior and low compressive strength. They are modified generally with additives such as lime, fly ash, and various other inorganic and organic materials. Chemical stabilization treatments can improve expansive soil properties for its reuse in geotechnical applications. The present study investigates the properties of two types of subgrade soil treated with Lime and compacted by three different methods in the laboratory. The study is mainly focused to bring out the effect of different methods of compaction on the unconfined compressive strength of Lime treated soils and untreated soils. Laboratory investigation included pH, Atterberg limits, cation exchange capacity (CEC), compaction, unconfined compression strength (UCS), California Bearing Ratio (CBR), Scanning Electron Micrographs (SEM) and EDAX before and after lime treatment. Tests were performed on lime treated soils (2, 4, 6 and 8% of lime). The soil samples for unconfined compressive strength test were prepared by static, dynamic and roller compaction methods in the laboratory. Roller compaction was performed using indigenously fabricated Roller compactor cum Rutting Analyzer (RCRA). The results indicate that dry unit weight and UCS of roller compacted lime treated soil is lower than that of dynamic compacted soil. However, dry unit weight and UCS of lime treated roller compacted soil are closer to that of statically compacted soil. Cation exchange capacity of both soils before and after treatment with lime were examined, CEC reduced with increase in lime content.

Vibratory rollers are mainly used for the near-surface compaction of granular media for a wide variety of construction tasks. In addition to the pronounced depth effect, vibratory rollers have offered the possibility of work-integrated compaction control (intelligent compaction) for decades. State-of-the-art measurement values for intelligent compaction (ICMVs) only take into account, if at all, a constant geometry of the contact area between the drum and soil. Therefore, this paper introduces a comparatively simple mechanical model, which describes the dynamic interaction between the vibrating drum and the underlying soil during compaction to investigate the influence of the changing geometry of the contact area on the motion behavior of the vibrating drum. The model is tested on realistic soil and machine parameters, and the results of the simulation with varying drum contact geometry are compared to a conventional simulation with a fixed contact geometry. The analysis shows that only a consideration of the varying drum contact geometry can map the dynamic interaction between the vibrating drum and soil sufficiently and provide a motion behavior of the drum that is in good accordance with the field measurements.

[Display omitted] This research investigates the modeling of the pharmaceutical roller compaction process, focusing on the application of the Johanson model and the impact of varying roll speeds from 1 to 15 RPM on predictive accuracy of ribbon solid fraction. The classical Johanson's model was integrated with a dwell time parameter leading to an expression of a floating correction factor as a function of roll speed. Through systematic analysis of the effect of different roll speeds on the solid fraction of ribbons composed of microcrystalline cellulose, lactose, and their blends, corrective adjustment to the Johanson model was found to depend on both roll speed and formulation composition. Interestingly, the correction factor demonstrated excellent correlation with the blend's mechanical properties, namely yield stress (P y) and elastic modulus (E 0), representative of the deformability of the powder. Validated by a multicomponent drug formulation with ±0.4–1.3 % differences, the findings underscore the utility of this modified mechanistic approach for precise prediction of ribbon solid fraction when P y or E 0 is known for a given blend. Hence, this work advances the field by offering early insights for more accurate and controllable roller compaction operations during late-stage pharmaceutical manufacturing. [ABSTRACT FROM AUTHOR]

[Display omitted] • A roller compaction process has been extensively employed to manufacture tablets. • A mechanistic process model was successfully used for a high drug load formulation. • The throughput method was successfully deployed to estimate ribbon solid fractions. • Study provides an example of a model-based scale-up approach for roller compaction. • Impact of process parameters on solid fractions was studied by sensitivity analysis. The pharmaceutical industry has been shifting towards the application of mechanistic modeling to improve process robustness, enable scale-up, and reduce time to market. Modeling approaches have been well-developed for processes such as roller compaction, a continuous dry granulation process. Several mechanistic models/approaches have been documented with limited application to high drug-loaded formulations. In this study, the Johanson model was employed to optimize roller compaction processing and guide its scale-up for a high drug loaded formulation. The model was calibrated using a pilot-scale Minipactor and was validated for a commercial-scale Macropactor. Global sensitivity analysis (GSA) was implemented to determine the impact of process parameter variations (roll force, gap, speed) on a quality attribute [solid fraction (SF)]. The throughput method, which estimates SF values of ribbons using granule production rate, was also studied. The model predicted SF values for all 14 Macropactor batches within ± 0.04 SF. The throughput method estimated SF with ± 0.06 SF for 7 out of 11 batches. GSA confirmed that roll force had the largest impact on SF. This case study represents a process modeling approach to build quality into the products/processes and expands the use of mechanistic modeling during drug product development. [ABSTRACT FROM AUTHOR]

The importance of roller compaction is recently increasing. This study evaluates the combined effects of formulation factors, process parameters, and selected quality attributes on drug release from roller-compacted hypromellose-based matrix tablets containing carvedilol as a model drug. The influence of selected factors was statistically assessed and good predictive models were developed for various time points of the release profile. The results show that the release profile is mostly affected by the particle size distribution of granules and roll speed. This indicates that the roller compaction process has a major impact on drug release, which is also formulation dependent. A higher d50 and lower d90 value of spatial filtering technique-based particle size distribution results, a lower roll speed, increased hypromellose content, using microcrystalline cellulose as a filler, and higher tablet hardness, resulted in a decrease in the drug release rate. On the other hand, the effect of the roll pressure, size of screen apertures, and d10 values on drug release was insignificant. The significance of the factors was further explained by granule shape, their porosity, and friability evaluation, and by compressibility and compactibility studies of compression mixtures. Additionally, the spatial filtering technique demonstrated to be a promising tool in controlling the roller compaction process. [ABSTRACT FROM AUTHOR]

This article presents an overview of using process analytical technology in monitoring the roller compaction process. In the past two decades, near-infrared spectroscopy, near-infrared spectroscopy coupled with chemical imaging, microwave resonance technology, thermal effusivity and various particle imaging techniques have been used for developing at-, off-, on- and in-line models for predicting critical quality attributes of ribbons and subsequent granules and tablets. The common goal of all these methods is improved process understanding and process control, and thus improved production of high-quality products. This article reviews the work of several researchers in this field, comparing and critically evaluating their achievements.

Considering that most asphalt concrete pavement distresses are fracture-related, evaluating and quantifying mix fracture properties is essential to improved pavement design. Therefore, the first step of the study, a pre-development phase, determines the optimal value for adding waste aluminum scrap powder (WASP) with a fraction size of 2.36-0.075 mm to mixes. Based on previous digital image analysis (DIA), AlDoz and AlNibaa’e aggregates were selected from seven central, northern, and southern Iraq sources. The second post-development phase studies the testing factors of a reliable and practical semi-circular bending (SCB) test for assessing asphalt concrete mixture fracture properties at intermediate service temperatures. The development and calibration of the Marshall System into the SCB-Tester, which switched from analog to digital and computerized control, accurately predicted reference and modified mix fracture characteristics at 50.8 mm/min. Three notch lengths (25, 32, and 38) mm were selected to be studied. Five percentages of WASP (0.5, 1.0, 1.5, 2.0, and 2.5) percent were added by weight to the entire mix and compared to the reference mixture. Results indicate that 1.5% WASP decreases fracture severity and stiffen AlNibaa’e and AlDoz mixes. Increased fracture strength and toughness of modified mixes relative to the reference may dramatically increase asphalt concrete fracture resistance. Even though a higher evaluation for AlNibaa’e mixes than AlDoz with an expected difference, the impact of modifying appears to be an effective influence for AlDoz mixes with determination factors (R2) of 0.9788 and 0.9889 than that of AlNibaa’e modified coarse and fine mixes, which have R2 of 0.8535 and 0.8461, respectively.

Expansive soils are problematic due to their swell—shrinkage behavior and low compressive strength. They are modified generally with additives such as lime, fly ash, and various other inorganic and organic materials. Chemical stabilization treatments can improve expansive soil properties for its reuse in geotechnical applications. The present study investigates the properties of two types of subgrade soil treated with Lime and compacted by three different methods in the laboratory. The study is mainly focused to bring out the effect of different methods of compaction on the unconfined compressive strength of Lime treated soils and untreated soils. Laboratory investigation included pH, Atterberg limits, cation exchange capacity (CEC), compaction, unconfined compression strength (UCS), California Bearing Ratio (CBR), Scanning Electron Micrographs (SEM) and EDAX before and after lime treatment. Tests were performed on lime treated soils (2, 4, 6 and 8% of lime). The soil samples for unconfined compressive strength test were prepared by static, dynamic and roller compaction methods in the laboratory. Roller compaction was performed using indigenously fabricated Roller compactor cum Rutting Analyzer (RCRA). The results indicate that dry unit weight and UCS of roller compacted lime treated soil is lower than that of dynamic compacted soil. However, dry unit weight and UCS of lime treated roller compacted soil are closer to that of statically compacted soil. Cation exchange capacity of both soils before and after treatment with lime were examined, CEC reduced with increase in lime content. [ABSTRACT FROM AUTHOR]

The relevance of the polymorphic form, particle size, and processing of mannitol for the mechanical properties of solid oral dosage forms was examined. Thus, particle and powder properties of spray granulated β D-mannitol, β D-mannitol, and δ D-mannitol were assessed in this study with regards to their manufacturability. D-mannitol is a commonly used excipient in pharmaceutical formulations, especially in oral solid dosage forms, and can be crystallized as three polymorphic forms, of which β is the thermodynamically most stable form and δ is a kinetically stabilized polymorph. A systematic analysis of the powders as starting materials and their respective roller compacted granules is presented to elucidate the multidimensional effects of powder and granules characteristics such as polymorphic form, particle size, and preprocessing on the resulting tablets’ mechanical properties. In direct compression and after roller compaction, δ polymorph displayed superior tableting properties over β mannitol, but was outperformed by spray granulated β mannitol. This could be primarily correlated to the higher specific surface area, leading to higher bonding area and more interparticle bonds within the tablet. Hence, it was shown that surface characteristics and preprocessing can prevail over the impact of polymorphism on manufacturability for oral solid dosage forms.

In the current study, we demonstrate a structured approach to downstream process development for spray dried amorphous solid dispersions. Direct compression is generally not suitable due to typically poor flow of spray dried powders in tablets. Roller compaction (RC) is therefore the method of choice to enable spray dried dispersion downstream processing. Here, a structured experimental design of RC process parameters was used. The objective was to identify process conditions that lead to improved powder flow without compromising tablet robustness. Ten blends were compacted using different process parameters, and subsequently compressed into tablets. The impact of process parameters on granules and tablet properties was analyzed. We demonstrate that compaction force, gap and mesh aperture have major impact on RC outcomes. A combination of large gap and low force was identified as optimum combination of RC process parameters leading to powder flow improvement that could guarantee low tablet weight variation and at the same prevented loss of blend compressibility. [ABSTRACT FROM AUTHOR]

The importance of roller compaction is recently increasing. This study evaluates the combined effects of formulation factors, process parameters, and selected quality attributes on drug release from roller-compacted hypromellose-based matrix tablets containing carvedilol as a model drug. The influence of selected factors was statistically assessed and good predictive models were developed for various time points of the release profile. The results show that the release profile is mostly affected by the particle size distribution of granules and roll speed. This indicates that the roller compaction process has a major impact on drug release, which is also formulation dependent. A higher d50 and lower d90 value of spatial filtering technique-based particle size distribution results, a lower roll speed, increased hypromellose content, using microcrystalline cellulose as a filler, and higher tablet hardness, resulted in a decrease in the drug release rate. On the other hand, the effect of the roll pressure, size of screen apertures, and d10 values on drug release was insignificant. The significance of the factors was further explained by granule shape, their porosity, and friability evaluation, and by compressibility and compactibility studies of compression mixtures. Additionally, the spatial filtering technique demonstrated to be a promising tool in controlling the roller compaction process.

This study aimed initially to optimize the industrial tablet-manufacturing process using multivariate analysis, and then to validate the model obtained. The study also provides a comprehensive review of the influence of different factors on relevant biopharmaceutical parameters. This is the first time multivariate analysis has been applied to such a broad set of industrial data to investigate the influence of starting materials and the tablet-manufacturing processes on drug dissolution. Partial least squares regression was retrospectively applied to the data obtained from 2 years production, to study the influence of 90 factors on dissolution of tablets that contained two active pharmaceutical ingredients. The model established was verified using the worst-case approach and process validation. Croscarmellose sodium had the most significant influence on drug dissolution, with the next significant factors as sodium chloride and sodium glycolate content, settling volume, particle size, suspension pH, loss on drying, and maximum temperature during drying. Loss on drying of microcrystalline cellulose and specific surface area of magnesium stearate were also essential factors. Among the process parameters, auger speed during roller compaction, compression speed, and force feeder speed during tablet compression had significant impacts on the tablet dissolution rate. The multivariate model created satisfied the process validation. This multivariate analysis is a useful tool to predict and optimize critical material attributes and process parameters. The variability of the materials can be successfully compensated for using various process parameters, to ensure consistent approved drug quality, to thus provide better patient care. [ABSTRACT FROM AUTHOR]

Hydrogen, as a medical gas, is a promising emerging treatment for many diseases related to inflammation and oxidative stress. Molecular hydrogen can be generated through hydrogen ion reduction by a metal, and magnesium-containing effervescent tablets constitute an attractive formulation strategy for oral delivery. In this regard, saccharide-based excipients represent an important class of potential fillers with high water solubility and sweet taste. In this study, we investigated the effect of different saccharides on the morphological and mechanical properties and the disintegration of hydrogen-generating effervescent tablets prepared by dry granulation. Mannitol was found to be superior to other investigated saccharides and promoted far more rapid hydrogen generation combined with acceptable mechanical properties. In further product optimization involving investigation of lubricant effects, adipic acid was selected for the optimized tablet, due to regulatory considerations.

An approximate analytical solution to Johanson's rolling theory is derived. It is shown that the solution yields a single dimensionless parameter invariant in process scale-up or equipment transfer, which relates the densification factor with process parameters (roll force and gap), geometric parameters (roll diameter and width) and material properties. It is shown that, to a first approximation, the model prediction does not depend on the nip angle evading the need to powder rheometry measurements such as wall friction and internal shear angle. The model is benchmarked against data obtained from pilot-scale roller compactors from different manufacturers as well as literature data from Nesarikar. The model yields good ribbon density predictions even when calibrating material properties from uniaxial die compression. [ABSTRACT FROM AUTHOR]

In this paper, new scientific insights in relation to the re-compaction of microcrystalline cellulose (MCC; Avicel®® PH-101) under specific compaction conditions are reported. MCC was subjected to multiple compaction cycles (1st, 2nd, and 3rd) under high compaction pressures, up to 20,000 kPa, using a roller compactor of 100 kg/h capacity. Initially, granules from the 1st and 2nd compaction cycles produced tablets with lower crushing strength compared to those made from the original non-compacted MCC. Tablet weakness was found to be correlated to the generation of a higher intra-granular pore size (diameter) and hence higher tablet porosity compared to that of the original MCC particles. Using Kawakita and Heckel compression analyses, it is suggested that such behavior is attributed to the formation of harder granules of re-compressed powder with a larger diameter than non-compacted MCC particles. Moreover, these granules resulted in a reduction in powder bed volume after the powders were subjected to the 1st and 2nd compaction cycles. Surprisingly, granules resulting from the 3rd compaction cycle produced tablets displaying a higher crushing force than non-compacted MCC. Results from compression analysis indicated a reduction in both the intra-granular pore size (diameter) and in tablet porosity of Avicel PH-101-3rd compaction cycle compared to that of the original non-compacted MCC. It is concluded that intense compression causes shedding of one or more layer from MCC fibers exposing new surfaces with strong binding ability. The foregoing results infer that intensified roller compaction can be employed to improve MCC powder compactibility without any deleterious effects on compact strength. [ABSTRACT FROM AUTHOR]

Roller compaction (RC) is a dry granulation technique applied to improve the flow and compressibility of drug formulations. RC implementation for high drug load formulations can be challenging due to flow issues and a high consumption of active pharmaceutical ingredient (API) for robust process development. This work addresses these challenges using process modelling for design and scale-up of an RC process on the same equipment and transfer to different equipment. A modified application of existing models incorporating a new description of mass transport in the feed screw is evaluated for guaifenesin formulations with a 90% drug loading. The model is calibrated using low-throughput data on a Vector Freund TF Mini RC and used to predict ribbon density and throughput for various process settings at high-throughput. It is found that the modelling framework can reasonably predict high-throughput behaviour on the same RC but the predictive performance decreases for transfer between equipment. Unlabelled Image • Model based process development for roller compaction for high dose API (90%). • New mass transport description for feed screw based on screw speed and roll speed. • Successful process scale-up using model calibrated only on low-throughput data. • Model transfer to different equipment is challenging. [ABSTRACT FROM AUTHOR]

Roller compaction is a popular dry granulation method that has been associated with loss of tabletability. In this study, the effect of roller compaction on a model brittle elastic material, paracetamol, was examined. Roller compaction of paracetamol was carried out at three roll force to examine the effects of roll force on the tablet compaction properties. Paracetamol granules consisting of small fragmented crystals were created through the process of roller compaction. A compaction simulator was used to produce tablets from a sieved fraction of roller compacted paracetamol and non-roller compacted paracetamol. Despite the higher elastic energy to plastic energy ratio observed with tablets produced from roller compacted granules of higher forces, the table tensile strength obtained was higher with a lower capping coefficient. At the same time, tablet elastic recovery was found to be lower for tablets produced using roller compacted paracetamol granules. Prefragmentation during roller compaction process helped to reduce the energy required for fragmentation during tablet compaction, increasing the energy available for bond formation. Roller compaction of brittle elastic materials may be a viable option for improving tablet tensile strength and reducing tablet capping. [ABSTRACT FROM AUTHOR]

Using instrumented roll technology, statistical models relating process parameters such as hydraulic pressure, roll speed and screw speed of Vector TF mini roller compactor to ribbon normal stress and density were developed for placebo blends. Normal stress was found to be directly proportional to hydraulic pressure, roll speed and inversely to screw to roll speed ratio. A power-law relationship between ribbon density and normal stress was observed for placebo blends. Models developed for placebo were found to predict ribbon densities of active blends with good accuracy. Standard optimization of roller compaction process parameters involves the investment of a large amount of time and active ingredient. These models can, therefore, be utilized to predict starting instrument settings required to generate a ribbon of desired solid fraction during early-stage development where material availability & time is limited. [ABSTRACT FROM AUTHOR]

The objective of the study was application of SeDeM-ODT expert system for optimization of process variables for roller compaction and for the preparation of granules with better flow, compressibility, and disintegration behavior. In the present study, granules were prepared at pre-determined (on the basis of factorial design) process variables and characterized using SeDeM-ODT expert system. Compatibility of ribavirin with excipients (microcrystalline cellulose, tablettose-80, cross carmellose sodium, and magnesium stearate) was evaluated by binary mixture approach, using FTIR. According to the SeDeM-ODT expert system, granules were characterized for various parameters related to flow, compressibility and disintegration behavior and Index of Good Compressibility and Buccodispersibility (IGCB) was calculated. The process variables resulting in highest IGCB value were considered as optimum. Ribavirin was found compatible with all the excipients used in the study and characteristics peaks were present in FTIR spectra after subjecting to stress conditions (75% relative humidity at 45 ± 5 °C) for 30 days. Both Ribavirin powder and Ribavirin containing powder blend had poor flow and compressibility while disintegration behavior was good due to higher water solubility. Screw speed of 35 rpm and roller speed at 12 rpm resulted in granules with acceptable characteristics. The IGCB value (5.63) of the granules was highest of all, indicating its better characteristics. SeDeM-ODT expert system presents a more practical picture of the granules and also predicts the mechanical strength and disintegration behavior of the tablets prepared from the granules. By proper optimization of screw and roller speed, efficiency of the process can be improved. [ABSTRACT FROM AUTHOR]

Purpose: A dry coating technology has been evaluated as a dry agglomeration technique for a typical pharmaceutical formulation. Its efficiency was compared with that of the more commonly used roller compaction dry granulation. Methods: A commercially available system was selected as a representative technology. The selection was based on batch size, processing time, unit size, vendor support, preventive maintenance requirements, development stage, and maturity for pharmaceutical industry requirements. The comparison targets the behavior of the resulting materials in terms of flowability, compressibility, mixing efficiency, and prevention of segregation. Particle size distribution, bulk density, scanning electron microscopy, FT4 powder rheometer, and hardness were used for the characterization of the powders. A design of experiment was used to evaluate the impact of the dry coating equipment operating parameters (rotor speed and processing time) as well as the impact of formulation (grade of microcrystalline cellulose and ratio between dibasic calcium phosphate and lactose). Results: The tested dry coating technology shows (1) an improved compressibility, (2) that the powders are homogenous, and (3) that they do not have a tendency to segregate in downstream process steps and during handling and storage. The impact of the rotor speed is proven statistically not significant, but it seems that a lower rotor speed might lead to less attrition and better flow properties. Processing time does not seem to have an impact for the range of processing times evaluated. Compared to roller compaction, the main advantages of the tested technology are the shape and surface enhancement and the absence of work hardening. Conclusions: This work has shown that the blends produced by the targeted dry coating equipment has equal or better results than the powders processed by roller compaction for all the critical quality attributes that were evaluated. [ABSTRACT FROM AUTHOR]

The aim of this study was to develop a lactose excipient using a production-scale roller compactor suitable for use in the pharmaceutical industry. The physical properties and compression behavior of the roller compacted lactose were investigated using Kawakita analysis and force-displacement (F-D) techniques. a-lactose monohydrate and spray dried lactose were used for comparison purposes. Kawakita analysis of the aforementioned powders showed that roller compaction produced lactose powder with characteristics similar to those of spray dried lactose with some additional improvements. Compression and profile analysis of the F-D curve confirmed that the roller compacted lactose has similar flow behavior to spray dried lactose with the advantage of a lower level of compression energy. Drug preparations utilizing compacted lactose showed no effect, for example hindering, on drug dissolution. Consequently, using industrial scale roller compactor is suitable to turn a-lactose monohydrate into a direct compression (DC) excipient equivalent to spray dried lactose. This outcome can be accomplished in the context of in-house and commercial processing of lactose products. [ABSTRACT FROM AUTHOR]

Abstract This study focuses on improving the manufacturing process for a generic immediate-release tablet containing erlotinib hydrochloride by adding a fines recycling process during roller compaction. Due to the large fraction of small-sized API particles, the starting powder mixture was inconsistently fed into the roller compactor. Consequently, poorly flowing granules with a high ratio of fines were produced. A fines recycling step was, therefore, added to the existing roller compaction process to minimize the risks caused by the poor granule flow. A laboratory scale roller compactor and a tablet simulator were used to prepare granules at various process conditions. The effect of dry granulation parameters on size distribution, API distribution, powder flow, compaction properties, and dissolution profile was evaluated. The granule batch after fines recycling had markedly improved size distribution and flowability while maintaining acceptable tablet tensile strength and rapid dissolution profile. The application of the fines recycling process at commercial scale resulted in reliable dissolution performance and batch-to-batch consistency, which were further confirmed by bioequivalence to the reference product. Understanding how granule properties are impacted by the fines recycling process may enable fine-tuning of the dry granulation process for optimal product quality. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Roller compaction is the main technique employed in dry granulation. Ribbon sticking and splitting are among the major factors that can hinder the use of this process for some formulations. Ribbon splitting can occur either transversally (through the ribbon thickness) or longitudinally (through the ribbon width). It was observed that transverse splitting is commonly associated with sticking of the split ribbons to the rollers and results in an inferior performance of the process. Longitudinal splitting is associated with an across-width distribution of the ribbon density so that there may an adverse effect on the mechanical strength and dissolution properties of the tablets formed from the milled granules. The aim of the current work was to elucidate the mechanisms of splitting by an experimental study involving single component powders with a range of yield strengths, including those that are commonly used as excipients. Both smooth and knurled rollers were employed without and with lubrication by applying magnesium stearate to the rollers. The minimum gap was fixed and the maximum roll stress was varied. The observed trends for the smooth rollers were rationalised in terms of a splitting index, which is a measure of the residual stresses driving crack growth relative to the tensile strength of the ribbons. There was a lower limit at which splitting was observed but the occurrence of transverse splitting decreased and that for longitudinal splitting increased with increasing values of the index, which was accompanied by an increase in mixed transverse-longitudinal splitting. Transverse splitting was always associated with sticking to the rollers and was prevented by external lubrication. The main difference with the knurled rollers was that in some cases transverse splitting occurred without sticking to the rollers. A detailed discussion of the mechanisms involved is presented. [ABSTRACT FROM AUTHOR]

Abstract Compaction is commonly applied in pharmaceutical and food technology for enhancing the flowability, dosing accuracy as well as to reduce the dustiness of powdered products. It can also be applied to adjust the bulk density and to control reconstitution kinetics of beverage powders, leading to modified appearance or sensory profiles of the reconstituted beverages. While roller compaction of crystalline granules is well established, processing amorphous ingredients represents specific challenges linked to their moisture sensitivity. This contribution puts a spotlight on process-structure-property relationships for compaction of amorphous food particles. It relates the physical properties of the compacted granules to initial powder properties and process line settings. Linking food material science and process mastership, this work introduces the bonding regime map for roller compaction of amorphous materials. It frames the operational conditions and predicts the resulting product structure, which determines final product performance characteristics such as flowability, stability and reconstitution kinetics. Mastering the product structure allows prediction of its functionality. Graphical abstract Unlabelled Image Highlights • This contribution puts a spotlight on process-structure-property relationships for compaction of amorphous food particles. • The bonding regime map is introduced as a tool to predict the granule micro structure. • Product functionalities such as dissolution kinetics are linked to the structure of compacted beverage powders. [ABSTRACT FROM AUTHOR]

Roller compaction was used to prepare a direct-compressed lactose excipient using crystalline α-lactose monohydrate. The effect of various roller compaction process parameters (compaction pressure, compaction repetition, and speed ratio) on the characteristics of compacted α-lactose monohydrate was investigated. Results were compared with data obtained using industrial spray-dried lactose and lactose samples with different degrees of crystallinity. XRPD analysis revealed that roller compaction reduced the crystallinity of α-lactose monohydrate, and the resulting material is similar to spray-dried lactose in behavior as a direct compression excipient. Roller compaction introduced desirable characteristics to the raw α-lactose monohydrate by inducing changes in crystallinity and particle morphology. Scanning electron microscopy results indicated that the compaction process converted some of the original torpedo-shaped crystals of α-lactose monohydrate into a more cylindrical shape with rounded edges. Compaction pressure and repetition of compaction have a significant effect on the modification of the crystallinity of the processed, raw α-lactose monohydrate. [ABSTRACT FROM AUTHOR]

Understanding the compaction behaviour of the primary powder in the roller compaction process is necessary to be able to better control the quality of the product. In this study, the plastic deformation of the primary particles was evaluated by determining two mechanical properties: the nano-indentation hardness and the viscoelasticity of the primary powder. The nano-indentation hardness of eight different materials with a wide range of mechanical properties was determined by indenting the surface of the single primary particle, whereas the viscoelasticity was evaluated for a powder bed using the creep test. These were linked to fundamental ribbon properties such as ribbon strength and width in addition to the amount of fines. It was identified that the plastic deformation of the material had the potential to provide an indication for the ability of the primary powder to produce a good ribbon. For the range of the investigated process parameters, the optimum hardness range that produced ribbons with ideal properties and small amount of fines was suggested. [ABSTRACT FROM AUTHOR]

During roller compaction, not only the properties of the primary powder affect the product quality but also the process parameters. Any change in the process parameters during roller compaction will result in changing the properties of the ribbon. In this study, the temperature of the ribbon during production was monitored online using a thermal camera. The information from the thermal camera was used to explain the differences in ribbon properties at varying process parameters. Lactose powder was used as a primary powder, and ribbons were produced at different process parameters. The surface temperature of the ribbon during production was found to increase with increasing both the gap between the two rollers and the roller speed. This was attributed to the screw feeder speed, which increased to feed additional powder as required to adjust to the change in process parameters. Increasing the roller gap resulted in wider ribbons and decreased the percentage of fines in the product, which was a signature of better powder distribution across the roller width. The results were also supported by the uniform temperature distribution recorded across the ribbon width. It was found that increasing the roller speed during roller compaction decreased the width of the ribbon while increasing the percentage of fines in the product. The feeder screw speed was found to have a similar effect as the roller gap. [ABSTRACT FROM AUTHOR]

Abstract Purpose The purpose of this work is to demonstrate a process for the alteration of the shape of needle shaped crystals of an active pharmaceutical ingredient (API) using a combination of wet milling and temperature cycling. The effect upon powder handling metrics of the shape alteration approach was quantified and the impact upon a subsequent roller compaction process step demonstrated. Methods Particle shape was altered through a combination of wet milling and temperature cycling. Image analysis was used to measure the length and width of the needle shaped particles. Powder handling was quantified using shear cell and bulk density measurements. Roller compaction trials were used to demonstrate improvements in processability. Results Particle width and length could be altered independently of each other with appropriate application of wet milling and temperature cycling. Powder handling metrics were greatly improved by the shape alteration. A partial least square model was developed to help explain the link between particle properties and powder handling metrics. Conclusions A process for altering the shape of needle shaped particles was developed. This process manifested in an improvement in both powder handling metrics and the processability of the powder as demonstrated by roller compaction. Graphical abstract Unlabelled Image Highlights • Wet milling and temperature cycling was used to alter crystal shape and size. • A mechanism was proposed to understand the process and control demonstrated. • The impact of shape and size alteration was demonstrated during roller compaction. • A link between crystal production parameters and roller compaction was shown. • A poorly processable powder was transformed into a easily processable powder. [ABSTRACT FROM AUTHOR]

In this study, we developed a control strategy for a drug product prepared by high-shear wet granulation and roller compaction using integrated quality by design (QbD). During the first and second stages, we optimized the process parameters through the design of experiments and identified the intermediate quality attributes (IQAs) and critical quality attributes (CQAs) relationship, respectively. In the first stage, we conducted an initial risk assessment by selecting critical process parameters with high impact on IQAs and CQAs and confirmed the correlation between control and response factors. Additionally, we performed Monte Carlo simulations by optimizing the process parameters to deriving and building a robust design space. In the second stage, we identified the IQAs and CQAs relationship for the control strategy, using multivariate analysis (MVA). Based on MVA, in the metformin layer, dissolution at 1 h was significantly correlated with intrinsic dissolution rate and granule size, and dissolution at 3 h was significantly correlated with bulk density and granule size. In dapagliflozin layer, dissolution at 10 min and 15 min was significantly correlated with granule size. Our results suggest that the desired drug quality may result through IQAs monitoring during the process and that the integrated QbD approach utilizing MVA can be used to develop a control strategy for producing high-quality drug products.

[Display omitted] This study investigates the feasibility of a compaction simulator and oscillating mill to mimic a roller compactor as a material sparing approach for process development. Microcrystalline cellulose and dicalcium phosphate dihydrate were selected to represent soft and hard materials, respectively. The relative density of ribbons and riblets was determined using a pycnometer and granules size distribution was determined by laser diffraction. Tablet tensile strength and relative density were determined using a hardness tester and pycnometer, respectively. This study showed that the relative density of riblets and ribbons were similar between 1 and 12 kN/cm, which indicates that the compaction simulator adequately mimics the compaction of the roller compactor using a Kp of 1. The size distribution of granules produced by the oscillating mill and roller compactor were similar, which indicates that the oscillating mill adequately mimics the roller compactor when using a similar gap and sieve design. Finally, the tablet tensile strength and relative density were similar independent of the applied granulation method and deformation behaviour of the material. In conclusion, the use of a compaction simulator and an oscillating mill in combination adequality mimics the roller compactor, which ultimately can save large amounts of material and time during process development. [ABSTRACT FROM AUTHOR]

This study is part of an ongoing project to enable the full specification of the Design Space for roller compactor systems and shows how the processing parameters influence the behaviour of the product granulate from a placebo formulation. Granulate was produced using a proprietary roller compactor by varying the compaction pressure and gap width, and the dynamic, bulk and shear properties of the resultant granulates were measured. The results demonstrate several rheological properties of the granulate, which have been shown to be closely correlated with variance in die filling and tablet strength, and are predictably influenced by the processing parameters.