Roller Compaction Process Research Articles

Optimization of a tensile strength prediction model for compacted ribbons using NIR-HIS analysis

The tensile strength (TS) of compacted ribbon is a critical quality attribute in the roller compaction process that impacts the quality of the finished product. This study investigated the use of Near Infrared Hyperspectral Imaging Spectroscopy (NIR-HIS) technology for predicting TS of compacted ribbons, considering the effects of surface curvature, different spectral preprocessing methods, and variable selection methods on a predictive model based on Partial Least Squares regression (PLSr). The spectral preprocessing methods evaluated were Mean Centering (MC) and Standard Normal Variate (SNV). The variable selection methods were Filter by Regression Coefficient (REG), Variable Importance in Projection (VIP), Competitive Adaptive Reweighted Sampling (CARS), and Genetic Algorithm (GA). The results indicated that curved surfaces had no significant impact on the predictive performance of the model (p-value of 0.39 for RMSEP). The PLSr-CARS method, combined with MC spectral preprocessing, was successful in selecting and reducing the number of wavelengths from 182 to 5, as indicated by high values of R2pred and RPD, and a low RMSEP value (0.97, 5.75, and 7.60%, respectively). An MLR model using the 5 wavelengths was also developed, showing similar performance to the PLSr model. Both the MLR and PLSr models demonstrated high predictive accuracy and reliability. These models can perform well even when developed using only a few wavelengths, leading to significant reductions in processing time and measurement costs, making them valuable tools for quality control in the pharmaceutical industry.

An evaluation of six techniques for measuring porosity of ribbons produced by roller compaction

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 cm3/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.

The impacts of roller compaction on the quality attributes of simultaneously compressed micro and minitablets

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 D50) 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 <Ph. Eur. 2.9.5 > 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 <USP 905> stage 1 criteria). This study results demonstrated feasibility of the novel simultaneous compression approach and the roller compaction process in developing good quality minitablets.

A modified mechanistic approach for predicting ribbon solid fraction at different roller compaction speeds

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 (Py) and elastic modulus (E0), 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 Py or E0 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.

Implementation of mechanistic modeling and global sensitivity analysis (GSA) for design, optimization, and scale-up of a roller compaction process

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.

Modeling the vibratory roller compaction process of road soils

Modeling the vibratory roller compaction process of road soils

A tabletability change classification system in supporting the tablet formulation design via the roll compaction and dry granulation process

In this paper, the material library approach was used to uncover the pattern of tabletability change and related risk for tablet formulation design under the roll compaction and dry granulation (RCDG) process. 31 materials were fully characterized using 18 physical parameters and 9 compression behavior classification system (CBCS) parameters. Then, each material was dry granulated and sieved into small granules (125–250 μm) and large granules (630–850 μm), respectively. The compression behavior of granules was characterized by the CBCS descriptors, and were compared with that of ungranulated powders. The relative change of tabletability (CoTr) index was used to establish the tabletability change classification system (TCCS), and all materials were classified into three types, i.e. loss of tabletability (LoT, Type I), unchanged tabletability (Type II) and increase of tabletability (Type III). Results showed that approximately 65% of materials presented LoT, and as the granules size increased, 84% of the materials exhibited LoT. A risk decision tree was innovatively proposed by joint application of the CBCS tabletability categories and the TCCS tabletability change types. It was found that the LoT posed little risk to the tensile strength of the final tablet, when Category 1 or 2A materials, or Category 2B materials with Type II or Type III change of tabletability were used. Formulation risk happened to Category 2C or 3 materials, or Category 2B materials with Type I change of tabletability, particularly when high proportions of these materials were involved in tablet formulation. In addition, the risk assessment results were verified in the material property design space developed from a latent variable model in prediction of tablet tensile strength. Overall, results suggested that a combinational use of CBCS and TCCS could aid the decision making in selecting materials for tablet formulation design via RCDG.

Research on the challenges and improvements of the roller compaction process for dry granulation

The analysis of the challenges for roller compaction (RC) in the dry granulation (DG) pharmaceutical industry process and their relative improvements are presented based on the review of previous research done by others. According to research between the 2000s and 2010s, magnifying the benefit that already obtains has been the main improvement of RC, such as increasing production efficiency and stability. Although modifications also reduced some of the disadvantages, such as reducing the use of raw material and waste, these improvements are still too limited, and some serious limitations still hindered the application of RC: the three major issues were: the large number of fragments producing, relatively fragile tablet, and the easy breaking ribbon. However, some research that took place later quickly fixed the limitation and make RC more applicable. This review briefly summarizes the issues that exist in the RC process, the improvements that have already been done to improve RC, and the limitations that RC still has.

Influence of Formulation Factors, Process Parameters, and Selected Quality Attributes on Carvedilol Release from Roller-Compacted Hypromellose-Based Matrix Tablets.

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.

The effect of excipient particle size on the reduction of compactibility after roller compaction

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.

Using a Model-based Material Sparing Approach for Formulation and Process Development of a Roller Compacted Drug Product.

The present work details a material sparing approach that combines material profiling with Instron uniaxial die-punch tester and use of a roller compaction mathematical model to guide both formulation and process development of a roller-compacted drug product. True density, compression profiling, and frictional properties of the pre-blend powders are used as inputs for the predictive roller compaction model, while flow properties, particle size distribution, and assay uniformity of roller compaction granules are used to select formulation composition and ribbon solid fraction. Using less than 10g of a model drug compound for material profiling, roller compacted blend in capsule formulations with appropriate excipient ratios were developed at both 1.4% and 14.4% drug loadings. Subsequently, scale-up batches were successfullymanufactured based on the roller compaction process parameters obtained from predictive modeling. The measured solid fractions of roller compaction ribbon samples from the scale-up batches were in good agreement with the target solid fraction of the modeling. This approach demonstrated considerable advantages through savings in both materials and number of batches in the development of a roller-compacted drug product, which is of particular value at early development stages when drug substance is often limited and timelines are aggressive.

FORMULATION AND DEVELOPMENT OF FIXED-DOSE COMBINATION OF BI-LAYER TABLETS OF EFAVIRENZ, LAMIVUDINE AND TENOFOVIR DISOPROXIL FUMARATE TABLETS 600 MG/300 MG/300 MG

Objective: This study is to formulate bi-layer tablet as a multidrug regimen against each reference listed drugs of Brand SUSTIVA® (efavirenz tablets 600 mg), EPIVER®(lamivudine tablets 300 mg), and VIREAD®(tenofovir disoproxil tablets 300 mg) to treat human immunodeficiency virus (HIV) infections. Which provides highly active antiretroviral therapy to provide effective treatment. Methods: Bilayer formulation was developed with each blend of layer-I (efavirenz) and layer-II (lamivudine and tenofovir disoproxil fumarate) through wet granulation process and roller compaction process, respectively. Further, both layers were compressed by using bi-layer compression followed by film coating. Layer-I and II formulations were developed by using various concentrations of diluents, surfactants, and disintegrants to improve the solubility of efavirenz and improve the flowability and uniformity of layer-II. Finally, the optimum formulation was developed to compare the in vitro dissolution with each branded formulation. Results: Drug-excipients interaction results revealed that the mixtures of three drug substances in 50 °C/75 % relative humidity (RH) resulted in an increase in tenofovir IMP-E and the highest unknown impurity was significantly increased and additionally decreased tenofovir assay in the presence of efavirenz. Sodium lauryl sulfate is very critical and it acts as a wetting agent and increases the solubility of efavirenz, and directly influences the dissolution of a drug product. Microcrystalline and croscarmellose sodium have a chance to affect the dissolution and friability of tenofovir. Powdered cellulose was acting as a diluent and flow property of the lamivudine part and it also affects the uniformity and dissolution. So, these ranges were optimized. X-ray diffraction (XRD) indicates there are no polymorphic changes for the optimized formulation and there is no interaction between the three active substances, and finally, in vitro dissolution results for the optimized formulation against the reference drugs. Conclusion: Optimum formulation yielded consistent drug release against each branded drug to treat human immunodeficiency virus (HIV1) infections. This formulation is robust and easily scale up for the next stage.

Micromechanical analysis of roller compaction process with DEM

This study applies the discrete element method (DEM) to the roller compaction process for the analysis of particle flow behavior, porosity distribution in the compaction zone and in the final ribbon, as well as the pressure distribution on rollers. The roller compaction setup was implemented utilizing a piston feeder and smooth roller surfaces. The parameters of the elastoplastic DEM contact model were calibrated by uniaxial compression tests, interparticle and wall shear tests. Finally, the simulation results were validated by micro-computed tomography measurements of porosity profiles of manufactured lactose ribbons. From performed studies, it was observed that the particles passing the smallest gap possess higher velocity than the roller surface, and peak pressure is reached before the smallest gap. Furthermore, due to lateral relaxation, the particles in the center of the ribbon are faster than on the walls. The lateral stress can act as a further possible reason for the transversal ribbon splitting.

Laser triangulation as a fast and reliable method for determining ribbon solid fraction; focus on accuracy, precision, and measurement time

Roller compaction and dry granulation represent well-established unit operations in the pharmaceutical industry. The ribbon solid fraction is classified as a critical quality attribute, that directly impacts final product quality and performance. The development and evaluation of novel methods measuring ribbon solid fraction represent a subject of current research, since novel analyses strategies need to be established for at-, on–, or in-line process monitoring to overcome limitations of end product testing and to set the course for continuous manufacturing. In this study, a novel analytical device, using the principle of laser triangulation, was investigated to asses its potential being used as at-line process analytical technology tool during a roller compaction process. To this end, the laser triangulation device was compared with X-ray micro-computed tomography and powder based volume displacement measurement techniques using different statistical evaluation methods. Special focus was given to accuracy, precision, and total measurement time. The laser triangulation device was confirmed as highly accurate and precise, enabling the shortest total measurement time compared to the other methods. The findings of this study support the idea of implementing the laser triangulation device as a novel at-line process analytical technology tool into a roller compaction process.

Implementation of spatial filtering technique in monitoring roller compaction process

This study investigates the use of the spatial filtering technique (SFT11spatial filtering technique) to monitor the particle size distribution (PSD22particle size distribution) of granules obtained by roller compaction. In the first part of the study, the influence of the selected process and formulation parameters on the PSD2 of granules is monitored at-line using SFT1. The correlation between the PSD2 obtained by SFT1, sieve analysis, laser diffraction, and dynamic image analysis was satisfactory. The same trend was observed with all methods; however, SFT1 proved to be especially advantageous for monitoring the PSD2 of irregularly shaped granules obtained by roller compaction. Another aim of this study was to investigate the suitability of using the SFT1 method as a potential process analytical technology (PAT33process analytical technology) tool for monitoring and predicting the PSD2 of granules obtained by roller compaction. The SFT1 model for d10 was poor due to less precise detection of smaller particles by SFT; nevertheless, the models for d50 (R2 = 0.93) and d90 (R2 = 0.93) were very good. The at-line models were further tested in real time on samples collected during the milling of ribbons. The correlation between the predicted and achieved values was good; however, it was time and formulation dependent.

A Multi-variate Mathematical Model for Simulating the Granule Size Distribution in Roller Compaction-Milling Process

Granule size distribution (GSD) is one of the critical quality attributes in the roller compaction (RC) process. Determination of GSD for newly developed pharmaceutical compounds with unknown ribbon breakage behaviors at the RC milling step requires a quantitative insight into process parameters and ribbon attributes. Despite its pivotal role in mapping the process operating conditions to achieve desired granule size, limited work has been presented in literature with a focus on RC-milling modeling. In this study, a multi-variate mathematical model is presented to simulate the full size-distribution of granulated ribbons as a function of ribbon mechanical properties. Experimental data with a lab-scale oscillating milling apparatus were generated using ribbons made of various powder compositions. Model parameters were determined by fitting it to experimental data sets. Parameters obtained from the first step were correlated to ribbon Young's modulus. The model was validated by predicting GSD of data that were excluded in model development step. Predictive capabilities of the developed model were further explored by simulating GSD profiles of a granulated pharmaceutical excipient obtained at three different conditions of a real-scale Gerteis RC system. While maintaining the milling operating conditions similar to the lab-scale apparatus (i.e., screen size and spacing, and low rotor speed), the proposed modeling approach successfully predicted the GSD of roller compacted MCC powder as the model compound. This model can be alternatively utilized in conjunction with an RC model in order to facilitate the process understanding to obtain granule attributes as part of Quality-by-Design paradigm.

Population balance modeling (PBM) of ribbon milling in pharmaceutical roller compaction process

Granule size distribution (GSD) is considered as one of the major intermediate product attributes in roller compaction (RC) process. Quantitative understanding of the impacts of process conditions and ribbon properties on GSD is essential in implementing Quality-by-Design in product development. In this paper, a two-parameter population balance model (PBM) was formulated and fitted to experimental data, obtained from simulated RC granules using lab-scale oscillating mill. To establish a predictive approach, two mathematical models were devised to estimate PBM parameters as functions of ribbon properties. As a major novelty, Young's modulus was used as the input material mechanical property in model parameter determination, as well as ribbon solid fraction. Predictive capabilities of the proposed mathematical functions together with developed PBMs were examined by simulating the data that were excluded in model development step. While holding only two fitting parameters, the proposed methods demonstrated great success in predicting experimental GSD data sets.

Process analytical technology tools for process control of roller compaction in solid pharmaceuticals manufacturing.

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.

A first principle model for simulating the ribbon solid fraction during pharmaceutical roller compaction process

Solid fraction is a key intermediate product attribute which significantly affects the granule characteristics prepared in a roller compaction (RC) process. Implementing the quality by design (QbD) in pharmaceutical manufacturing requires quantitative insight into the impacts of process parameters and material properties on product attributes. Despite the efforts made towards modeling of RC process in pharmaceutical applications, the predictive capabilities of the current approaches still depend on model calibration using extensive experimental data. In this paper, a practical approach is presented that incorporates the process parameters and material properties into a set of first principal equations based on Johanson's theory. A material profiling procedure was devised in order to fully capture the powder behavior during roller compaction. The results showed that the model is capable to predict the solid fraction with a relative error of 1–7%. This approach may help expedite development timeline and reduce material usage while improving efficiency.

An evaluation of the Johanson model for roller compaction process development for a high dose API

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.