## No full-text available

To read the full-text of this research,

you can request a copy directly from the authors.

The thin layer model is based on the assumption that the deformation of powder during tableting can be transferred to the roller compaction process, provided that it was established with sufficient accuracy in the tableting experiments. In particular, the process of compaction between the rolls is presumed to consist of three parts, a rearrangement, an “exponential” and an elastic recovery phase. The rearrangement and “exponential” phases are used to calculate the densification of the material. The forces between the rolls during elastic recovery, the third phase, proved to be essential to the prediction, because 20% to 30% of the total roller compaction force is required to counteract ribbon recovery. Four different excipients and one powder blend were tested in the model. For two materials, the density and force predictions turned out to be accurate within ±2.5% and ±10%, respectively. For one excipient and the model blend, the predictions deviated systematically whereas those for the remaining excipient were within the above mentioned limits in ca. 50% of the experiments. For explaining these differences, we evaluated both the influence of the course of the force–time profile, at comparable densification times, and the influence of different compression times, for comparable force–time profiles. Finally, the impact of density distributions within ribbons on the prediction was estimated.

To read the full-text of this research,

you can request a copy directly from the authors.

... Several roller compaction models have been developed to minimize the material expenditure for process development. Von Karman formulated the slab model 2 ; later Johanson developed his rolling theory for granular solids 3 ; Cunningham made a significant contribution on modeling using finite element methods (FEM) in 2005 4 ; the Thin Layer model was published by Peter 5 ; and more recently Mazor combined DEM and FEM to model the particles flow in the feeding zone and the powder compaction between the rolls. 6 These can be considered the main modeling approaches which have been refined and tested in the scientific literature. ...

... 8,9 On the other hand, Peter estimated the material properties with measurements of density-pressure "in die" and obtained reasonable predictions of ribbon density "at gap". 5 Estimating the material properties without the contribution of the elastic recovery may improve the predictions by removing an additional variability source. Moreover, Gamble demonstrated that "at gap" ribbon density can be used to optimize the roller compaction process. ...

... This is akin to the thin-layer model which also does not consider powder rheology inputs whose characterization can be challenging and prone to error. 5 Furthermore, as Nesarikar showed, powder rheology measurements such as the wall friction angle can vary with the process parameters, which implies that considering a fixed value may lead to incorrect nip angle predictions and worsen the model predictability. 17 One can further simplify the previous equations to arrive to a closed-form analytical solution to the problem. ...

An approximate analytical solution to Johanson’s rolling theory is derived.¹ 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.² The model yields good ribbon density predictions even when calibrating material properties from uniaxial die compression.

... This leads to an accurate ribbon density prediction but with the drawback of high material consumption for the preliminary roll compaction experiments. Peter et al. (2010) developed the thin layer model to predict the density and force in roll compaction. To calculate the corresponding compaction pressure, the forces along the roll surface are summed up. ...

... The hybrid modeling approach used in this study is a further development of the thin layer model (Peter et al., 2010). Hybrid modeling is an easy to use approach for simulating and mimicking the roll compaction process with the uniaxial compaction simulator Styl'One Evolution (Medelpharm, France) using only a small amount of material and was described in detail by Reimer and Kleinebudde (2019). ...

... The roll compaction process on a Mini-Pactor was mimicked with the hybrid modeling approach on the uniaxial compaction simulator Styl'One Evolution (Medelpharm, France). The method is described in literature (Reimer and Kleinebudde, 2019) and is based on the thin layer model (Peter et al., 2010). It is summarised in the following. ...

Roll compaction/dry granulation is a widely used granulation method in the pharmaceutical industry. The simulation of the process is of great interest, especially in the early phase of formulation development of solid dosage forms. The hybrid modeling approach allows to predict the roll compaction process parameters to produce ribbons with a desired solid fraction. Based on the process parameters, compacts (ribblets) of the same solid fraction are produced on a single punch press. So far, the prediction accuracy for the solid fraction of the ribbons was not satisfactory. It was found that the lack in prediction accuracy was due to the elastic recovery, which was not considered in the model. In this study, the fast in-die and the slow out-of-die elastic recovery of different excipients with varying compaction properties were investigated. A method was established to compensate for the elastic recovery of compacts in roll compaction simulation and to improve the prediction accuracy of the solid fraction considerably. The results were successfully implemented into the model through an additional learning step. Moreover, the findings were transferred to the mimicking of an API containing formulation. By modeling, it was possible to accurately predict the process settings to obtain ribbons with the desired solid fraction using only a small amount of material.

... These parameters determine CQAs as granule size distribution and tabletability. Therefore, many approaches have been postulated to predict those parameters: Finite element analysis [12], thin layer model [13], slab method [8] or hybrid modeling [14]. Johanson's rolling theory for granular solids [15] provides a mathematical approach to predict using roll geometries (D,W), process parameters (roll force, , S, α) and material properties (wall/internal friction and compressibility). ...

... Further, 10.0 rpm was chosen as the highest roll speed feasible in this setup. The at-gap density ( ) was measured using the ribbon mass (m) and the calculated ribbon volume (V) (Equation (7)), which passed the S at a roll width (W) in a time period (t) of one minute at a given RS [13]. The (Equation (8)) was used to determine the (Equation (9)). ...

Influence of the roll speed (RS) during roll compaction on ribbon, granule, tablet properties and its effect on the prediction of the ribbon solid fraction at-gap is often neglected or controversially discussed. The aim of this study was to investigate the effect of the RS systematically. Microcrystalline cellulose (MCC) and lactose were compressed at several maximum roll pressures (Pmax) and RS combinations using a gap-controlled roll compactor. The ribbon solid fraction after elastic recovery (SFribbon), granule size distribution and tabletability of the granules as well as the ribbon solid fraction at-gap (SFgap) were measured. The Midoux number (Mi), derived from the Johanson model, was used to predict the ribbon solid fraction at-gap (SFMi). The measured SFgap and the predicted SFMi lead to a prediction accuracy (PA) of the Midoux number. The results are highly dependent on the material used and the applied Pmax. Higher plasticity of the material leads to a reduction in SFribbon and granule size with increasing RS. However, this effect can be overcome or reduced by adjusting Pmax above the yield pressure of the used material. These results allow for higher roll speeds as a potential upscaling method in roll compaction. On the other side, the PA of the Midoux number was also reduced with increased RS for MCC and had no effect for lactose. Thus, RS seems to be an important factor in the prediction of roll compaction processes and prediction models should include RS as a parameter to improve their accuracy.

... A recent update of the Styl'One Evolution allows to mimic the roller compaction process parameters with uniaxial compaction of the powder to ribbon-like tabletscalled ribblets -with a set of rectangular flat punches. This module, called RoCo Pack, uses a model based on the thin layer model described by Peter et al., as seen in Fig. 2 [23]. The model explains that in a roller compactor, the powder between the rolls is divided into thin layers that consist of a mass which remains constant during the process. ...

... Considering this evolution of the layer length, the density of each layer evolves as well. [23] The evolution of the in-die density according to the applied compression along with the characteristics of the formulation allows to convert a hydraulic pressure (expressed in MPa) into a roll force per unit (expressed in kN/cm or MPa) and vice versa. That learning phase of the module allows then to manufacture ribblets corresponding to specific roller compaction process parameters. ...

While it is common that understanding the impact of material attributes on drug product processes is key for designing robust products and processes, the identification of critical process parameters is indeed systematically performed and well understood, but the identification of critical material attributes remains a challenge at various levels. This chapter addresses the challenges associated with material attributes during drug product process development, process modification, and life cycle management. The type of challenges depends on the stage of the product life cycle. In early develpment stages, the main challenge is the limited amount and representativity of raw materials. During life cycle management, the challenge is mainly the batch-to-batch or source-to-source variability. For each of the challenges, a fit-for-purpose solution is presented using industrial case studies. As seen throughout the chapter, material science should not only be considered at development level but also should play an active role during the entire life of a product to ensure process robustness and therefore an improved product quality and undisturbed supply chains to meet patients’ needs.

... At present, there are few studies on the interaction between the paver screed and asphalt mixture during the construction process. In the compaction of an asphalt mixture, particularly for a thin layer, the vibratory roller is prone to over-compaction, and paving compaction plays a leading role [18][19][20][21][22]. Therefore, it is essential to combine vibration theory with engineering practice to establish a mathematical model for studying the relationship between density and construction parameters and obtain more effective and enough construction parameters to acquire the desired paving density. ...

... Based on the interaction model between screed plate and asphalt mixture, and combined with the Formula (19) and (20), the mathematical model of the paving material density changing with the vibration frequency was established, considering the nonlinear vibration characteristics, as shown in Formula (21). ...

Paving compaction has an important influence on the significant improvement of the asphalt mixture density during pavement construction, and the paving density is mainly affected by the paver response and material behavior. To improve the density of asphalt pavement, this paper proposes a nonlinear dynamic vibration system of the interaction between asphalt mixture and screed plate. Based on the harmonic balance principle, a multi-degree of freedom nonlinear system of the screed plate-asphalt mixture interaction was established. By considering material characteristics and energy absorption efficiency during paving compaction, a paving density tendency-vibration frequency theoretical model was applied to analyze the influence law of dynamic response of the asphalt-screed interaction on the material density. The analysis results indicated that 1) both the characteristics of the asphalt mixture and the vibration frequency of the screed affected the material density during the paving process; 2) the optimal vibration frequency was higher than the natural frequency, and further compaction with a lower vibration frequency can effectively improve the energy absorption efficiency; 3) for the screed in movement, only when the vibration frequency enters the resonance region of the high-density mixture can a better compaction effect be obtained. Finally, the nonlinear dynamic model was experimentally verified. The research results are beneficial for improving the paving density and the quality of asphalt pavement, providing a basis for the effective compaction of asphalt pavement.

... The ribbon quality control lies in modeling the powder deformation behavior undergoing the RC process. The first choice for predicting ribbon characteristics are one dimensional (1D) models like the Johanson model [21][22][23][24], the slab method [25] and the thin layer model [26]. Johanson's roll compaction model is the most popular, and it enables the nip angle, the maximum applied normal stress and ribbon relative density to be estimated from inlet material physical properties. ...

... This particular splitting mode is named as "LJ". The reason may be attributed to the oscillatory powder feeding and the friction of particles with the wall, which lead to non-uniform roll pressure and resulted ribbons across the ribbon width and along the rolling direction[26,70,[75][76][77]. For ribbons of Lac-F (No. 26), the splitting "T" occurs at 30, 50 and 70 bar, while the splitting L2 (i.e., the ribbon is divided into two sections through-width) occurs at 70, 90 and 110 bar. ...

The purpose of this study is to use a material library to investigate the effect of raw material properties on ribbon tensile strength (TS) and solid fraction (SF) in the roll compaction (RC) process. A total of 81 pharmaceutical materials, including 53 excipients and 28 natural product powders (NPPs), were characterized by 22 material descriptors and were compacted under five different hydraulic pressures. The transversal and longitudinal splitting behaviors of the ribbons were summarized. The TS-porosity and TS-pressure relationships were used to explain the roll compaction behavior of powdered materials. Through defining the target ribbon quality (i.e., 0.6 ≤ SF ≤ 0.8 and TS ≥ 1 MPa), the roll compaction behavior classification system (RCBCS) was built and 81 materials were classified into three categories. A total of 24 excipients and five NPPs were classified as Category I materials, which fulfilled the target ribbon quality and had less occurrence of transversal splitting. Moreover, the multivariate relationships between raw material descriptors, the hydraulic pressure and ribbon quality attributes were obtained by PLS regression. Four density-related material descriptors and the cohesion index were identified as critical material attributes (CMAs). The multi-objective design space summarizing the feasible material properties and operational region for the RC process were visualized. The RCBCS presented in this paper enables a formulator to perform the initial risk assessment of any new materials, and the data modeling method helps to predict the impact of formulation ingredients on strength and porosity of compacts.

... Local density variation in the ribbon may give rise to a broad size distribution after milling [17][18][19][20]. It was shown that finer granules were produced when weaker ribbons were milled [21][22][23]. In fact, the ribbon density distribution was identified as a critical parameter that influenced fines generation [18]. ...

... In fact, the ribbon density distribution was identified as a critical parameter that influenced fines generation [18]. Because variations in process parameters inherently affect ribbon density and properties, the size distribution of DG granules was found to depend on RC parameters (e.g., roll pressure, roll speed, horizontal feed screw speed, vertical feed screw speed, sealing system design) [12,24], properties of ribbon (e.g., density, porosity, and tensile strength,) [21,23], milling parameters (e.g., impeller speed, screen size, screen type) [25], and material properties (e.g., plasticity, brittleness, and breakage mode) [26], as well as ribbon thickness [27]. These previous studies, although qualitatively correlated ribbon density and milling parameters to fines generation, did not provide the detailed quantitative relationships among these parameters. ...

A challenge in the dry granulation (DG) process is the generation of an excessive amount of fines during milling, which can cause problems in die filling due to poor flowability and content uniformity of tablets. Using a design of experiments (DOE) approach, we show that the amount of fines generated during milling decreases with either increasing ribbon density or screen size, while impeller speed has negligible effect. Moreover, under identical milling conditions, the percent fines can be accurately predicted from ribbon density. Thus, controlling ribbon density and screen size is important for optimizing the amount of fines produced during DG process. Because density has a central role in the outcome, it is a critical ribbon property that needs to be controlled to improve robustness of the DG process.

... These deviations lie in the range of a few micrometres and are therefore at the lower accuracy limit of the measuring technology used. This is also the range of the relaxation of the particle bed in which viscoelastic deformation of the particle bed is superimposed on the elastic recovery (Peter et al., 2010). Apart from these two boundary areas the model equation agrees well with the experimental data. ...

... It follows from the change of the compaction mechanism from an initial rearrangement of particles to the size reduction and plastic deformation (see Section 1). With this in mind and according to (Peter et al., 2010) a split model was developed utilizing a limit pressure p lim . Fig. 7 illustrates the splitted compression of two particle beds: ...

The stress behaviour of particle beds describes the relationship between the forces acting on the particle bed and the total energy input supplied. The stress behaviour is closely related to the compaction of the particle bed, which has to be distinguished into a purely elastic and purely plastic deformation. The elastic deformation can be characterized by the elasticity Ε of the particle bed as a material-specific parameter which is different to the E-modulus of solids. The description of the purely plastic deformation of a particle bed allows to deduce a model of the stress behaviour.

... A roll press design model developed by Johanson (1965) has been widely used for optimizing roll press process for various materials (Dec et al., 2003;Sommer and Hauser, 2003;Bindhumadhavan et al., 2005;Yusof et al., 2005). Other roll press design modeling concepts have also been developed (Blake et al., 1963;Yehia, 2007;Peter et al., 2010); however, these models are not commonly used for the roll press process development due to the inherent disadvantages of these models such as complexity and lack of adequate validation of these models. ...

... One reason for predicting the roll force with a higher mean relative percent error is that Johanson (1965) model considers only the densification effect on the roll force and neglects the effect of elastic springback of compacts on the roll force. Peter et al. (2010) reported that the roll force due to elastic spring-back of compacts in the roll press can be as much as 30% of the total roll force. Yusof et al. (2005) found that Johanson (1965) model predicted the roll force and roll torque with an accuracy of 20% for maize powder with compressibility factor of 9.0. ...

The objective of this study was to validate roll press design equations given by Johanson (1965) and Blake et al. (1963). The roll press design equations were validated for pilot-scale roll press compaction data collected for corn stover and native perennial grasses (initial moisture contents of < 20% w.b.) ground using three Mighty Giant tub-grinder round-hole screen opening sizes (25.4, 76.2, and 127.0 mm), three roll forces (24, 40, and 60 ton), and two roll gap sizes (0.012 and 0.022 m). Laboratory compaction data collected for three compression pressures of about 15, 30, and 60 MPa were used to obtain input parameters (compressibility factor, and pressure-deformation relationship) needed by the roll press design equations. Johanson (1965) model predicted the roll force with a mean relative percent error of 47% to 61%. Blake et al. (1963) model calculated the unit density of compacts (measured after curing) with a mean relative percent error of 18% to 30%. The mean relative percent error in prediction of specific energy consumption for rolls (excluding no-load roll motor energy consumption) was 48% to 83% for Johanson (1965) model, and 37% to 71% for Blake et al. (1963) model. The validated roll press design equations will be used for deriving design specifications for a production scale roll press compactor.

... A more material sparing method is to use a uniaxial compaction simulator in lieu of a mini roller compactor. For example, a hybrid modeling approach developed by Reimer was able to predict the appropriate process settings to obtain a desired SF with only a few experiments and 10 times less material by combining a mathematical model based on a thin layer model developed by Peter [25] with a mechanical mimicking of the RC process by uniaxial compaction [26]. In an earlier study, a lab-scale compaction simulator was employed for simulation of the RC process. ...

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 10 g 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 successfully manufactured 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.

... A pre-densification takes place in the slip zone, but the main densification happens in the nip zone. Many models assume that velocity of the material in the nip zone is uniform span-wise, i.e. the mass flow between the rolls is constant along the axis perpendicular to the rolls 3,4 . With this assumption, a densification factor (DF) can be defined as the ratio of N/S (Fig. 1), where N is the nip width. ...

Roll compaction/ dry granulation is gaining importance. Numerous papers have been published and many attempts to model the process are available in the meantime. Johanson published a model in 1965, which is the basis for many further modifications until today. The aim of the paper is to improve process understanding in roll compaction, which can be used to setup a roll compaction process, to design a scale-up strategy or to help in process transfer between different types of roll compactors. Based on some assumptions, simple considerations help to estimate a required densification factor and to visualize the relations between roll diameter, gap width and nip angle. Two recently published papers based on simplified Johansen models are used to visualize the relations between specific compaction force and the maximal pressure experienced by the material. The influence of roll diameter, gap width and compressibility constant are discussed. This helps to estimate, if a scale-up or process transfer is reasonable. The recently introduced dimensionless Midoux-number can also be used to design scale-up or process transfer of roll compaction without knowledge about the maximal pressure. Exploring the simple concepts can help to improve process understanding even without a background in engineering.

... Roller compaction has become the method of choice for dry granulation in the pharmaceutical industry due to its lower economic cost compared to wet granulation (Peter et al., 2010;Shlieout et al., 2000). Dry granulation improves content uniformity and material flow behaviour, but also possesses other advantages over wet granulation, as there is no need to use water or other solvent, which is beneficial in the context of avoiding degradation of certain compounds. ...

Roller compaction is a low cost granulation process which application is sometimes limited by the granular loss of compactability and reduced drug dissolution rate. Hence, the design of a robust manufacturing process is key in order to ensure quality of tablets. In this study, for ibuprofen tablets with high drug loading (<7% excipients), the correlations between two critical process parameters (CPPs), namely roller force during granulation and compaction pressure during tabletting, and several critical quality attributes (CQAs) were investigated using a design of experiment (DoE) approach. Multivariate analysis (MVA) was utilized to identify the best regression model to predict CQAs such as disintegration, dissolution, weight uniformity, hardness, porosity and tensile strength for 200 and 600 mg ibuprofen tablets. The tabletting compaction pressure had a greater impact on the aforementioned CQAs than compactor roller force. The Principal Component Analysis (PCA) correlation loading plot showed that compaction pressure was directly related to disintegration time, tensile strength and hardness, and inversely related to both the percentage of drug dissolved and porosity. The inverse correlations were observed for the roller force applied during dry granulation. Amongst all the regression models constructed, multiple linear regression (MLR) showed the best correlation between CPPs and CQAs.

... Both of the above factors influence the prediction of ribbon density and resulting throughput. Several theoretical and empirical efforts have been undertaken to account for the elastic recovery and to improve the compression profile in a roller compactor (Cunningham, 2005;Peter et al., 2010). ...

This work presents a new model based approach to process design and scale-up within the same equipment of a roller compaction process. The prediction of the operating space is not performed fully in-silico, but uses low-throughput experiments as input. This low-throughput data is utilized in an iterative calibration routine to describe the behavior of the powder in the roller compactor and improves the predictive quality of the mechanistic models at low and high-throughput. The model has been validated with an experimental design of experiments of two ibuprofen formulations. The predicted sweet spots in the operating space are in good agreement with the experimental results.

... Grated screens are more effective in ribbon milling than smooth round screen (Vanarase et al., 2015). Size distribution of the granules is also affected by the strength of ribbons (Akseli et al., 2011;Lim et al., 2011;Miguélez-Morán et al., 2008), where weaker ribbons tend to form finer granules under a given milling condition (Inghelbrecht and Remon, 1998;Peter et al., 2010;von Eggelkraut-Gottanka et al., 2002). Here, we report our recent finding that ribbon thickness is another factor that can significantly affect fines generation during dry granulation by the RC process. ...

Uncontrolled fine generation during the milling process is a challenge for dry granulation by roller compaction. Here, we report the observation that ribbon thickness can significantly influence percentage of fines. Thus, among other parameters, ribbon thickness needs to be controlled for the development of a robust roller compaction process and ensure successful scale up.

... Likewise under-densification at roller compaction fails to adequately improve the materials flow. The greater the ribbon density, the lower the fine fraction and therefore, the better the flowability of the resulting granules (Peter et al., 2010). ...

The aim of this study was to highlight how variability in roller compacted ribbon quality can impact on NIR spectral measurement and to propose a simple method of data selection to remove erroneous spectra. The use of NIR spectroscopy for monitoring ribbon envelope density has been previously demonstrated, however to date there has been limited discussion as to how spectral data sets can contain erroneous outliers due to poor sample presentation to the NIR probes.

... Roller compaction also offers the potential to control various parameters during granulation, such as screw feed rate, roller speed and crusher speed and mesh size [18,19]. During roller compaction it is possible to control the thickness, strength and porosity of the ribbon and the size of the granules produced via variation of the process parameters [20][21][22][23]. ...

Tablet disintegration is a fundamental parameter that is tested in-vitro before a product is released to the market, to give confidence that the tablet will break up in-vivo and that active drug will be available for absorption. Variations in tablet properties cause variation in disintegration behaviour. While the standardised pharmacopieal disintegration test can show differences in the speed of disintegration of different tablets, it does not give any mechanistic information about the underlying cause of the difference. With quantifiable disintegration data, and consequently an improved understanding into tablet disintegration, a more knowledge-based approach could be applied to the research and development of future tablet formulations.

The dynamic response of the rotor system in a ring die granulator is complex and difficult to solve when it operates under joint external, support and gear mesh forces. To solve this problem, a finite element method and extrusion theory was applied in this study to develop a dynamic coupling model for a hollow overhung rotor with external load excitation. A Newmark-β numerical integration method was used to solve for the dynamic response of the overhung rotor under multiple excitation forces. The results included time-domain response diagrams, frequency-domain response diagrams, phase diagrams, Poincaré section diagrams, and bifurcation diagrams. The model and the method were verified by testing a ring die granulator. On this basis, the dynamic response of the system is predicted according to the influence of different parameters. As the bearing support distance increased, the roller eccentricity decreased, the bearing clearance decreased, the response of the rotor system was significantly optimized, and the system tended to stabilize gradually. Therefore, this paper provides a theoretical basis and experimental verification for the optimization of a pelleting machine transmission structure.

This chapter offers a review of roller compaction process that produces ribbons and a subsequent milling process that produces granules for continuous manufacturing of tablets. Specifically, characterization methods, modeling approaches, and quality control mechanisms for the ribbons as well as the milled granules are discussed. For ribbons, the near-infrared spectroscopy method that characterizes chemical composition and physical properties of ribbons such as density and tensile strength is discussed. For granules, several online and offline granule property measurement techniques are detailed. In addition, mechanistic modeling approaches for ribbons and granules using the discrete element method and population balance modeling approaches for the milled granules are discussed.

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.

Dry granulation through roll compaction followed by milling is a widely used pharmaceutical process. The material properties of powders and the roll compaction process conditions affect the strength of ribbons, and subsequently the granule size distribution (GSD). Accurate prediction of the granule size distribution from milling of ribbons with different properties is essential for ensuring tablet quality in the final compaction stage. In this study, MCC, PH-102 ribbons with precisely controlled porosities were produced and milled in a cutting mill and granule size distribution was analysed using QicPic. A population balance model with a new breakage function based on the Weibull function was developed to model the ribbon milling process. Eight model parameters were initially obtained for each ribbon porosity and very good agreement between the model and experimental results was obtained. Sensitivity analysis was then performed and thus reduced the number of model parameters that changed with ribbon porosity to two in the breakage function. The refined model was able to predict the granule size distribution both within and outside the experimental boundaries. It was shown that the model developed in this study has a great potential for predicting granule properties and therefore the optimisation of the dry granulation process.

Roll compaction/dry granulation is a widely used and cost effective dry granulation method. To save time and material in formulation development, some approaches have been made to predict the most important parameters in roll compaction (RC) like gap width, specific compaction force (SCF) and ribbon solid fraction (SF).
A novel approach is the hybrid modeling of roll compaction with the Styl'One Evolution. It combines a mechanical mimicking by uniaxial compression of the powder with a mathematical model that converts the applied compaction pressure into a computed SCF.
It was tested whether the Styl'One Evolution can mimic a RC process correctly. Powder was compacted at different gap widths and SCFs, both on a Mini-Pactor (Gerteis) and on the Styl'One Evolution. Two excipients, lactose and microcrystalline cellulose (MCC), were used for the trials. The ribbons and ribbon like tablets, called ribblets, were characterised regarding their SF.
Compaction of lactose prepared at a certain SCF resulted in ribbons and ribblets with higher SF than for MCC. The Styl'One Evolution provided results with similar curve shapes but with systematically higher SF. Nevertheless, the results for ribbons and ribblets from both materials were aligned by adjusting the roll compactor specific correction factor Kp in the mathematical model. The SF of lactose ribblets was more accurately predicted than of MCC ribblets. That could be due to the bigger elastic recovery of MCC. The findings also suggest that mechanical mimicking gives hints whether a material is suitable for RC.
In conclusion, hybrid modeling can identify the appropriate settings to obtain ribbons with the desired SF.

Ribbons from microcrystalline cellulose, mannitol and their 50:50% mixture were produced using the roll compactors AlexanderWerk BT120, Hosokawa Alpine Pharmapaktor C250, L.B. Bohle BRC 25 and Gerteis Mini-Pactor in the frame of multilevel full factorial experimental plans. The specific compaction force/hydraulic pressure, gap width, roll speed and fraction of microcrystalline cellulose were analysed as quantitative factors, while the roll surface and sealing system were examined as qualitative factors. Ribbon relative density was investigated as response of the models. The specific compaction force/hydraulic pressure is found to be the most significant factor in each model. A significant inverse effect of the gap width is obtained in the models of AlexanderWerk BT120, Pharmapaktor C250 and BRC 25 roll compactors, using smooth rolls. The principle of the establishment of a conversion factor is introduced based on the obtained data sets of AlexanderWerk BT120 and Mini-Pactor. This can facilitate the transfer of a roll compaction process between different types of roll compactors.

This chapter focuses on the application and development of unit operation and process models of the major routes of continuous solid dose manufacturing. Process models developed in the chapter are very important tools for the design of control system. The chapter also focuses on the current models available and their applications in process simulation and control systems. The chapter provides an introduction to process modeling in the pharmaceutical industry. The process flowsheet model has been used to understand the continuous tablet manufacturing process in order to design an efficient control system. The critical control variables of direct compaction continuous tablet manufacturing process have been identified based on process understanding and sensitivity analysis. The control system design, tuning, control hardware and software integration, and control system implementation into the pilot plant is demonstrated in detail via direct compaction continuous tablet manufacturing case study.

A new dry granulation technique, gas-assisted roller compaction (GARC), was compared with conventional roller compaction (CRC) by manufacturing 34 granulation batches. The process variables studied were roll pressure, roll speed, and sieve size of the conical mill. The main quality attributes measured were granule size and flow characteristics. Within granulations also the real applicability of two particle size analysis techniques, sieve analysis (SA) and fast imaging technique (Flashsizer, FS), was tested. All granules obtained were acceptable. In general, the particle size of GARC granules was slightly larger than that of CRC granules. In addition, the GARC granules had better flowability. For example, the tablet weight variation of GARC granules was close to 2%, indicating good flowing and packing characteristics. The comparison of the two particle size analysis techniques showed that SA was more accurate in determining wide and bimodal size distributions while FS showed narrower and mono-modal distributions. However, both techniques gave good estimates for mean granule sizes. Overall, SA was a time-consuming but accurate technique that provided reliable information for the entire granule size distribution. By contrast, FS oversimplified the shape of the size distribution, but nevertheless yielded acceptable estimates for mean particle size. In general, FS was two to three orders of magnitude faster than SA.

A pharmaceutical roller compaction process was modelled using the Johanson powder mechanics model, which may be employed to achieve desired process performance. Mathematical modelling of the compaction of microcrystalline cellulose (PH102) was used to determine optimal process conditions for an industrial scale roll compactor (Freund, Model TF-MINI). The critical process parameters investigated were screw speed and roll pressure, while the rolls were kept at constant speed and the roll gap as variable. The roll-compacted ribbon density was considered the quality attribute of interest, as it is directly linked to the granule properties, particle size distribution and tablet mechanical properties. Experimental process data were used for model calibration and validation. This was followed by utilisation of the predictive capability of the model to achieve desired process performance of the compactor. The model findings indicated that the developed mechanistic model for the roller compactor can provide a design space to correlate the process parameters and materials properties to the critical quality attributes of granules which would be useful for implementation of Quality-by-Design paradigm in pharmaceutical manufacturing.

Limited work has been performed regarding the scalability in the roll compaction process. Most of those studies available focus their efforts on developing models to successfully scale-up the process and only few of them strive to analyse the effect of the roll compaction scale on the product's properties. Therefore, in this work a double evaluation is performed focusing on process understanding and modelling application. In order to achieve this aim, ribbons of MCC, mannitol and a binary 1:1 mixture were roll compacted on 2 scales of compactors developed by Gerteis and L.B. Bohle, respectively. All compactors have a roll diameter of 250 mm in common but they differ in the roll width. The production was carried out following a common design of experiments in which the effect of the specific compaction force, the gap width and the roll speed were also investigated. The ribbons obtained were collected and characterized regarding their relative density. After statistical evaluation, it was found that the relative density of the mannitol and the mixture's ribbons produced using the Gerteis and L.B. Bohle compactors, are significantly affected by the scale, i.e. the roll width. For MCC, the impact of the compactor scales on the process was not so critical. The data collected was also modelled using the approach developed by Reynolds et al. 2010 in order to successfully scale-up the process. Excellent prediction was found for MCC, and although for mannitol and the mixture, the quality of the models decreased, they are still in good agreement, indicating the great utility of this approach when scaling-up a roll compaction process.

Dry granulation via a roll compactor was simulated in this study based on artificial neural network methodology. Two process parameters, including roll force and screw speed, were considered as input of the simulation whereas ribbon density was considered as output. Experimental work was carried out using an industrial scale roll compactor. The results showed an excellent agreement between simulation and experiments. The results were compared as well with the results obtained in a previous study employing Johanson model, which is the predominant model for the simulation of roll compaction process. The overall deviation of 0.9 % was observed for the developed ANN model, which is a significant improvement in comparison with the deviation of 4.4 % obtained for Johanson model. The results showed a very good capability and robustness of the developed ANN model in the design and optimisation of roll compaction process.

The aim of this study is to perform a statistical analysis on a pharmaceutical roller compaction process using an industrial-scale roller compactor “Freund TF-MINI model”. The process was modelled using response surface methodology (RSM) to better understand and control the process in order to produce ribbons and granules with optimised quality. The significant process parameters were determined to be (i) the screw speed to roll speed ratio and (ii) the roll pressure. The roll speed was kept constant and the roll gap was uncontrolled. The quality attributes of interest are: ribbon density, granule size (D10, D50, D90), amount of fines (granule size <157 μm), and tablet hardness. Microcrystalline cellulose (MCC) PH 102 was used as a model material. Design-Expert V9 was utilised to establish the design matrix and to analyse the experimental data. The relationships between the process parameters and the resultant ribbon/granule/tablet characteristics were established. This was followed by an optimisation of the process parameters to obtain the target responses. The results confirmed the attainment of significant models with satisfactory accurate measures. The optimisation allowed for the determination of the process parameters required to produce the best quality tablets.

Urea granules are one of the popular fertilizers among synthetic fertilizer industry. Its main function is to provide nitrogen which enhances leaf growth on plant. Urea granules are produced from the process of granulation. Granulation process is divided to wet and dry granulation. Generally, there are two type of dry granulator which is slugger and roller compactor. Roller compactor or also known as roll press is using two counter rotating rolls to compact raw material such as powder to become ribbons or granules. If ribbons instead of granules are produced from compaction, milling will be used to produce granules. It is difficult obtain a numerical result of the process due to the variety of parameters. Therefore, this work will only consider the parameters which are related to feeder system and roller. The parameters include the feeding rate of feeder, roller force, roller pressure, and roller gap size. While powder flow to roller from feeder, overfeeding may occurs. Overfeeding is harmful because it will cause motor failure. To overcome this problem, the function of roller needs to be improved. The roller will be modified and hence, a new design will be produced.

In this chapter, the main processing steps and manufacturing aspects of solid dosage forms are described and the relevant literature is reviewed. Starting with powder feeding, powder blending, granulation (dry and wet), and drying the most important unit operations to make compactable granules are reviewed. As an alternative to granulation, hot-melt extrusion is introduced, together with the various downstream processing choices. Next, tableting and capsule filling—for making a final dosage form—are discussed, followed by a section on coating. In all sections scale-up methods are reviewed and an outlook for future developments is provided. The last two sections are devoted to process analytical technology (PAT) and continuous manufacturing.

Roller compaction is the most commonly employed dry granulation process in the pharmaceutical industry. While this process is increasingly used as an alternative to wet granulation, there are no parameter sets or system of equations to quickly scale up or transfer a formulation between two pieces of equipment. In this work, dimensionless variable was examined as a method to transfer the operating parameters of a formulation between two different pieces of equipment. This work was completed to establish the ground work for the development of a dimensionless relationship relating the operating parameters of the equipment to the porosity of the ribbon. The working hypothesis was three-fold, namely (i) that ribbons of the same porosity made with different equipment will have similar properties, (ii) that it is possible to establish an objective relationship between ribbon porosity and a combination of operating parameters and raw material attributes and (iii) that by expressing such parameter combination as a dimensionless variable, it will be possible to use the same relationship for different pieces of roller compaction equipment. The dimensionless variable RP/RS*HFS*True Density*D(2) was found to correlate well with the ribbon porosity for the formulations and equipment used in these experiments. Depending on the formulation, the average difference in ribbon porosity between the two units varied between 0.012 and 0.024.

Permeating air is known to have a negative impact on the roller compaction process, because the feed is destabilized by the flow of escaping gas, causing pressure to build-up and potentially damage compacts at release. Airflow during powder roller compaction and its effect on the rolling process are investigated in the rolling direction (1D), using an extension of the Johanson model for the solid. Fluid transport obeys Darcy's law, with permeability being a function of both material density and particle size, through the Kozeny-Carman relationship. In this modeling, the effect of the air pressure on the solid is neglected in the compaction zone. Assuming air at atmospheric pressure at the feeding angle and ignoring airflow through the gap, predictions of air pressure as a function of the rolling angle for bentonite material powder are presented and discussed. Results suggest the existence of two different stability zones within the operating conditions, where industrial systems could function without being affected by airflow effects. The model highlights the importance of the permeability/rotation speed ratio, which governs the proportion of air trapped in the compacts to the portion evacuated through the feed. We also investigate the effect of particle fragmentation during the rolling process. Finally, we provide guidelines for the scale-up of roller presses subjected to air flow issues, through a study of the effect of the system dimensions and rotation speed on the elimination of air. In spite of the lack of available experimental data, this model allows for a better understanding of how air escapes by diffusing through the material during the rolling process, and opens interesting perspectives for the mitigation of its effect on the process.

Objective:
While previous research has demonstrated roller compaction operating parameters strongly influence the properties of the final product, a greater emphasis might be placed on the raw material attributes of the formulation. There were two main objectives to this study. First, to assess the effects of different process variables on the properties of the obtained ribbons and downstream granules produced from the rolled compacted ribbons. Second, was to establish if models obtained with formulations of one active pharmaceutical ingredient (API) could predict the properties of similar formulations in terms of the excipients used, but with a different API.
Materials and methods:
Tolmetin and acetaminophen, chosen for their different compaction properties, were roller compacted on Fitzpatrick roller compactor using the same formulation. Models created using tolmetin and tested using acetaminophen. The physical properties of the blends, ribbon, granule and tablet were characterized. Multivariate analysis using partial least squares was used to analyze all data.
Results:
Multivariate models showed that the operating parameters and raw material attributes were essential in the prediction of ribbon porosity and post-milled particle size. The post compacted ribbon and granule attributes also significantly contributed to the prediction of the tablet tensile strength.
Conclusions:
Models derived using tolmetin could reasonably predict the ribbon porosity of a second API. After further processing, the post-milled ribbon and granules properties, rather than the physical attributes of the formulation were needed to predict downstream tablet properties. An understanding of the percolation threshold of the formulation significantly improved the predictive ability of the models.

Das Beanspruchungsverhalten von Gutbetten beschreibt den Zusammenhang zwischen der Kraft, die auf ein Gutbett wirkt, und der Energie, die dem Gutbett insgesamt zugeführt wird. Es ist eng mit der Verdichtung des Gutbetts verknüpft, wobei hier eine rein elastische und eine rein plastische Verformung zu unterscheiden ist. Die elastische Verformung kann durch die Elastizität E des Gutbetts als materialspezifische und vom E-Modul des Feststoffs unabhängige Kenngröße charakterisiert werden. Die Modellierung des Beanspruchungsverhaltens baut auf dem plastischen Verformungsverhalten auf.The stress behavior of particle beds describes the relationship between the forces acting on the particle bed and the total energy input supplied. The stress behavior is closely related to the compaction of the particle bed, which has to be distinguished into a purely elastic and purely plastic deformation. The elastic deformation is characterized by the elasticity E of the particle bed as a material-specific parameter which is independent of the E-module of solids. The modeling of the stress behavior is based on the plastic deformation behavior.

Although the roller compaction process appears simple, efforts to quantitatively model the process have proven challenging because of complex material behavior in the feeding and compaction zones. To date, implementation of roller compaction models to experimental work has been limited because these models typically require large experimental data sets or obscure input parameters that are difficult to obtain experimentally. In this work, an alternative approach has been established, expanding upon a widely used roller compaction model, Johanson's model, to enable its incorporation into a daily workflow. The proposed method requires only standard, routinely measured parameters as inputs. An excellent correlation between simulated and experimental results has been achieved for placebo and active blends up to 22% (w/w) drug load. Furthermore, a dimensionless relationship between key process parameters and final compact properties was elucidated. This dimensionless parameter, referred to as the modified Bingham number (Bm *), highlights the importance of balancing yield and viscous stresses during roller compaction to achieve optimal output properties. By maintaining a constant ratio of yield-to-viscous stresses, as indicated by a constant Bm *, consistent products were attained between two scales of operation. Bm * was shown to provide guidance toward determining the design space for formulation development, as well as to facilitate scale-up development. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.

Introduction:
Solid dosage form manufacture still remains the most common in the production of pharmaceutical products. Established granulation processes can benefit from novel technical improvements, which can in turn enhance the behavior and properties of the process intermediates, that is, granules. These improvements in the manufacturing process can ultimately shorten development times, provide processing solutions for challenging materials and improve quality of drug delivery systems.
Areas covered:
The aim of this review is to give the reader an overview of the latest trends in research with regard to roller compaction technology. Pneumatic dry granulation is also discussed as a new development with the potential to improve and extend the use of dry granulation processes, which can result in a substantial contribution to drug delivery system development and drug product manufacture.
Expert opinion:
Dry granulation techniques, and more specifically roller compaction, can provide many advantages over the more established wet granulation techniques. There are still problems with roller compaction such as high amounts of fines and poor flow of granulate. Technical innovations that improve existing processes will have a considerable impact on development times and contribute to improved material processability and behavior of the end product. Pneumatic dry granulation has the potential to provide such alternatives.

The Gerteis 3-W-Polygran roller compactor consists of three main units: the feeding unit, the compaction unit and the granulation unit. Powder transport to the compaction area is performed by a feeding and a tamping auger. In the compaction area, the force on the rolls and the distance between the rolls (gap width) can be controlled. Furthermore, the roll speed and torque distribution between the rolls can be adjusted. The surface of the rolls can be varied, smooth or knurled.

Effects of adhesive force and roll speed on the compressive flow property of particles in Roll-type presses were studied by using Discrete Element Method (D. E. M.). A constant attractive force was applied between the particles in the present model. In the absence of adhesive force, the particle motion was governed by the gravity being little affected by the roll speed and the particles between the rolls were not compressed. However, the flow of particles was changed significantly by the presence of adhesive force and the particles were well compressed by the rotating rolls. In the case with adhesive force the predicted results of the particle flow rate and the pressure distribution on the roll surface were found to agree qualitatively with previously-reported experimental data.

In spite of the widespread use of tablets, the theoretical understanding of the tableting process has been limited. During the last decades considerable research has been done in the field of powder technology and compaction. A survey of the literature and compression equations reveals many studies on the characterization of powder properties, most of which relate to volume reduction under pressure, i.e., to the compressibility of the powder bed. For practical purposes, however, it is also important to know the compactibility of a powder bed, i.e., the ability of a powdered material to be compressed into a compact of specified strength. This strength has to be defined, e.g., as radial tensile strength or deformation hardness. Thus the first part of this review comprises the theory of powder compression of individual substances, compression parameters, compression equations, and mechanical properties of compacts, including compact strength tests and compact hardness tests.

A Fitzpatrick L83 Chilsonator was instrumented in order to understand and to optimize the roll compaction process using drum-dried waxy maize starch, a plastic deforming material as a model compound. The interrelation of the four adjustable roll compactor parameter settings namely the velocity of the rolls (RS), the speed of the horizontal (HS) and of the vertical screw (VS), and the air pressure (Pair) influenced the compact and the granule quality. The granule quality was defined by the friability and particle size distribution. As a second order polynomial was not successful to model the behaviour of the friability in function of the four roll compactor parameters, a Multilayer Feed-Forward neural network (MLF) was used. It was shown that the MLF network models the friability more accurately than a second order polynomial. The HS and the Pair mostly influenced granule quality and should be kept at a high level. The VS had no significant influence on compact quality.

Roll compaction is a dry, continuous granulation process, which is widely used in the pharmaceutical, chemical, metallurgical, mineral and agricultural industries to produce dust-free and free-flowing agglomerates. Intelligent software has been used to predict the relationships between tablet formulations, roll compaction process parameters and the roll compacted ribbon, from which granules for tablet manufacture can be produced. The software exploits the strengths of artificial neural networks, genetic algorithms and fuzzy logic to predict multivariate relationships from experimental data. Input data were generated from material characterisation studies and from investigations conducted on a 20 cm diameter laboratory-scale roll press with side plates, where process parameters such as roll speed (1–5 rpm), roll gap (0.5–1.4 mm) and compaction pressure (up to 230 MPa) could be manipulated. The relative significance of inputs on various outputs such as ribbon properties, nip angle and maximum roll compaction pressure was investigated using the commercially available artificial intelligence software FormRules (Intelligensys, Teeside, UK). The important inputs and required outputs were subsequently used in the model-development software INForm (Intelligensys, Teeside, UK) so that the conditions necessary to produce ribbons with specific desired properties could be predicted.

Based on the continuous plane-strain deformation of an isotropic, frictional, cohesive, compressible solid, a rolling theory for granular solids has been developed. The pressure exerted by the press is predicted as a function of the flow properties of the solid, roll size, roll gap, roll surface condition, and feed pressure. Calculated results of the theory are presented in terms of roll-separating force, roll torque, and the ratio of maximum to minimum pressure existing in the press. Examples of the effect of material properties on these results are given.

A Fitzpatrick L83 Chilsonator was instrumented in order to understand and to optimize the roll compaction process using drum-dried waxy maize starch, a plastic deforming material as a model compound. The interrelation of the four adjustable roll compactor parameter settings namely the velocity of the rolls (RS), the speed of the horizontal (HS) and of the vertical screw (VS), and the air pressure (Pair) influenced the compact and the granule quality. The granule quality was defined by the friability and particle size distribution. As a second order polynomial was not successful to model the behaviour of the friability in function of the four roll compactor parameters, a Multilayer Feed-Forward neural network (MLF) was used. It was shown that the MLF network models the friability more accurately than a second order polynomial. The HS and the Pair mostly influenced granule quality and should be kept at a high level. The VS had no significant influence on compact quality.

Abstract The factors affecting the distribution of compacting pressure during the process of dry granulation with a roller compactor, have been elucidated experimentally. Lactose powder was used with incorporation of a small amount of riboflavine as a pressure indicator. The rollers used in this study had been designed as a concavo-convex pair that exactly keep their mutual fit while rotating. The flanges formed by the concavity of the concave roller at its both ends, called “rims” in this paper, were subjected to several experimental variations in the angles of wall siopes, namely, 45°, 65°, 75°, and 90°. These inclined gripping walls acted as compensators, cancelling the resistance in the powder flow due to the side seals attached to both ends of the rollers. The overall effect was that the pressure of compaction was adjusted uniformly over the whole width of the rollers, and the best result was obtained at a rim angle of 65°. In this experiment, however, a rectangular-aperture chute, when equipped at the delivery end of the screw feeder, contributed little to the uniformity of pressure distribution in compaction. From these observations, the authors have established a new type of roller compacting system that is superior, in the sense of uniformity of compression, to any conventional roller compactor.

As a result of an analytical examination of specific pressure distribution during the rolling of metal powders, formulas are derived for determining specific pressure in the lag and forward-slip zones. A relationship is found between the deformation resistance of porous metal, maximum specific pressure, and other rolling parameters. Full and simplified formulas are obtained for determining the total pressure during the rolling of metal powders.

Several pharmaceutical materials together with some model substances were compressed in an instrumented single-punch press. During compression, compact heights and compression loads were measured at 1 ms intervals. From these data, the porosity—pressure function according to Heckel was calculated for both the compression and decompression phases. By dividing the entire compression cycle into three main phases, the dominating volume-reduction mechanisms for the materials tested were discussed. It was shown that fragmentation behaviour could be evaluated by linear regression from the initial phase of compression (phase I). By evaluating the decompression (phase III), information regarding both elastic and plastic deformation behaviour was obtained. The slope of the linear part of the compression curve (phase II) was shown to reflect the total deformation ability. The relationship between the information obtained and the bonding properties of the materials is briefly discussed.

Recently used models relating basic properties of the feed material, roller press design and its operating parameters are reviewed. In particular, we discuss the rolling theory for granular solids proposed by J.R. Johanson in the 1960s, later trials utilizing slab method and newly developed final element models. These methods are compared in terms of efficiency and accuracy of predicting the course of basic process variables like nip angle, pressure distribution in roll nip region, neutral angle, roll torque and roll force.The finite element method offers the most versatile approach because it incorporates adequate information about powder behavior, geometry and frictional conditions. This enables to perform realistic computer experiments minimizing costs, time and resources needed for process and equipment optimization.

Roll compaction is widely used in industry to produce free flowing agglomerates from a fine particulate feed. Two of the main advantages of this process are that it is dry and continuous. Despite being superficially a simple process, a quantitative understanding has proved difficult to develop because of the complex behaviour of particulate materials. Sub-optimal design and operation of the equipment can lead to unsatisfactory products. Johanson (1965, ASME, Journal of Applied Mechanics Series E, 32(4), 842–848) developed a theoretical model that enables the surface pressure, torque and separating force of the rolls to be predicted from the physical characteristics of the powder and the dimensions of the rolls. However, a detailed experimental validation of the theory has yet to be accomplished. The current paper describes such a study using a gravity fed instrumented roll press and a microcrystalline cellulose powder. The measured pressure profiles in the nip region of the roll press were comparable to the calculated values. The theory was also found to predict the effect of material properties on the nip angle and the peak pressure but it was unable to account for the influence of roll speed.

During roller compaction in the pharmaceutical industry, mixtures of active and inert powders are fed via a screw to counter-rotating rolls, drawn into the nip and compacted under hydrostatic and shear stresses. Experimental studies were conducted using microcrystalline cellulose on a roller compactor that measured feed force, surface roll pressure and shear stress. The following observations were made: densification correlated with maximum roll pressure; increasing feed force increased roll gap; and significant variation in roll pressure and shear stress exists in the transverse and rolling directions. A slab model highlighted the importance of roll friction, feed stress and entry angle on pre-densification in the feed zone. 2-D and 3-D explicit finite element models with adaptive meshing and arbitrary Eulerian-Lagrangian capabilities were developed. A Drucker-Prager/cap model was calibrated using diametrical and simple compression and die compaction tests. The roll friction was estimated using a die instrumented to measure radial stress. The effects of roll friction, feed stress, roll gap to diameter and entry angle on roll force, torque, profiles of roll pressure and roll shear stress, nip angle, neutral angle, and relative density were evaluated. The results indicated increasing entry angle, decreasing roll gap to diameter, increasing feed stress and/or increasing roll friction lead to higher maximum roll surface pressure and attendant relative density at the exit. The results may be explained by the nip angle and amount of pre-densification. Simulations with pressure-dependent frictional coefficients indicated significant difference in densification. Oscillating feed stress conditions revealed periodic variations in roll pressures and relative densities. Variations in the through-the-thickness were significant in the slip region and diminished in the nip region. The 3-D model predicted lower roll pressure and densities near the edges due to side seal friction. In addition, variable inflow of material along the roll width was related to variation in roll pressure. Overall, the model predictions followed experimental trends. Microcrystalline cellulose experienced higher expansion on release than predicted - related to its non-linear elastic behavior. Various combinations of boundary conditions and geometrical parameters resulted in similar roll pressure profiles and densification thus accurate experimental inputs are essential for model verification.

Three techniques were used to compare the time-dependent deformation of microfine cellulose (Elcema G250), anhydrous lactose, dicalcium phosphate dihydrate (Emcompress), modified starch (Sta-Rx 1500) and sodium chloride. (1) In stress-relaxation experiments using a reciprocating tablet machine, none of the materials behaved as a Maxwell body in contrast to recent published work (David & Augsburger, 1977). Possible reasons for this disagreement are discussed. (2) Heckel plots showed that increasing the time for which a material was under compression (contact times of 0.17 and 10 s) had no effect on dicalcium phosphate compacts but increased the consolidation of other materials in the rank order sodium chloride less than lactose less than cellulose less than starch. (3) Deformation tests on preformed compacts were carried out in diametral compression by loading compacts to 75% of their breaking force at four different strain rates between 0.05 and 6.5 mm min-1. The deformation of Sta-Rx compacts was time-dependent. Sodium chloride compacts exhibited brittle behaviour in the diametral compression test and in the 10 s contact time experiment. This was apparently due to work-hardening, following the extensive plastic deformation of crystals during compaction as indicated by the stress relaxation results.

For the calibration of a compaction simulator for punch displacement measurements, the displacement of the punch must be related to the voltage output of a linear variable displacement transducer (LVDT) which is attached to the punch via its movable core, with correction for any deformation of the machine parts which are inherently incorporated in the LVDT readings. Contrary to common assumptions the relationship between the displacement of the movable core and the voltage output of the LVDTs used is not linear. Similarly, the deformation of the machine parts did not follow Hooke's law of linear elasticity but exhibited characteristics of nonlinear elasticity. The data demonstrate the need for careful validation of the calibration of a compaction simulator when accurate punch displacements are required.

The quality of the determination of punch separation in an eccentric tabletting machine equipped with two inductive displacement transducers was carefully investigated, since this tabletting machine is used as an 'analytical instrument' for the evaluation of the compression behaviour of pharmaceutical materials. For a quasistatic calibration procedure using gauge blocks, the repeatability under standard conditions and the robustness against variations in machine settings, installation conditions, equipment and methods were examined. The readings during calibration can be easily influenced by machine parameters as a result of deficiencies in the construction of the machine and in the mode of instrumentation. The poor plane-parallelism of the punch faces has a further negative effect on the accuracy of punch separation. In addition, the response at loading to lower and higher forces as during calibration was investigated. While at loading up to 100 N, the response of the system to the gauge blocks is systematically influenced by punch separation, for slow manually applied punch-to-punch loading up to 16.5 kN at a broad range of penetration depths, no significant effects were observed in the region of interest for tabletting. To get an indication of the transferability of the calibration and the determination of punch deformation to normal operating conditions, the lateral tilting of the punches during dynamic idle runs, punch-to-punch loading, and compression of microcrystalline cellulose was analyzed. A transfer of the response derived from punch-to-punch compression to tabletting conditions seems to be possible, although this must be questioned on grounds of theoretical considerations. From all the experiments performed, a total error of about +/- 30 microns must be assessed for the determination of punch separation.

The effect of roll compaction/dry granulation on the particle and bulk material characteristics of different magnesium carbonates was evaluated. The flowability of all materials could be improved, even by the application of low specific compaction forces. The tablet properties made of powder and dry granulated magnesium carbonate were compared. Roll compaction/dry granulation resulted in a modified compactibility of the material and, consequently, tablets with reduced tensile strength. The higher relative tap density of the compacted material does not allow a densification to the same extent as the uncompacted powder. The degree of densification during tableting can be expressed as the ratio of the relative tablet density to the relative tap density of the feed material. Increasing the specific compaction forces resulted in higher apparent mean yield pressure, gained from Heckel plots, of all materials analysed. The partial loss of compactibility leads to the demand of low loads during roll compaction. Comparing the tablet properties of different magnesium carbonates reveals an obvious capping disposition. However, it depends on the type of magnesium carbonate, the specific compaction force and also on the tableting force applied.

A method for simulation of the roller compaction process using a laboratory scale compaction simulator was developed. The simulation was evaluated using microcrystalline cellulose as model material and ribbon solid fraction and tensile strength as key ribbon properties. When compacted to the same solid fractions, real and simulated ribbons exhibited similar compression behavior and equivalent mechanical properties (tensile strengths). Thus, simulated and real ribbons are expected to result in equivalent granulations. Although the simulation cannot account for some roller compaction aspects (non-homogeneous ribbon density and material bypass) it enables prediction of the effects that critical parameters such as roll speed, pressure and radius have on the properties of ribbons using a fraction of material required by conventional roller compaction equipment. Furthermore, constant ribbon solid fraction and/or tensile strength may be utilized as scale up and transfer factors for the roller compaction process. The improved material efficiency and product transfer methods could enable formulation of tablet dosage forms earlier in drug product development.

The effect of roll compaction/dry granulation on the ribbon and tablet properties produced using different magnesium carbonates was evaluated. The ribbon microhardness and the pore size distribution of tablets were used as evaluation factors. Increasing the specific compaction force resulted in higher microhardness for ribbons prepared with all four magnesium carbonates accompanied with decreased part of fine. Consequently, the corresponding produced tablets displayed a lower tensile strength. A possible correlation between the particle shape, surface area and the resulting pore structure of tablets produced with the four different types of magnesium carbonate was observed. The tensile strength of tablets prepared using granules was lower than tensile strength of tablets produced using starting materials. The partial loss of compactibility resulted in a demand of low loads during roll compaction. However, the impact of changes in the material properties during the roll compaction depended greatly on the type of magnesium carbonate, the specific compaction force and the tableting pressure applied.

Control of Production Quality During Dry Granulation with Roller Compactors

- R F Lammens
- C Pörtner

R.F. Lammens, C.Pörtner, Control of Production Quality During Dry Granulation with Roller Compactors, Proceedings of 3rd World Meeting APV/APGI, 3rd to 6th of April 2000, Berlin, Germany.

An analysis of powder compaction phenomena

- Heckel

R.W. Heckel, An analysis of powder compaction phenomena, Trans. Metall. Soc. of AIME 221 (1961) 1001–1008.

The evaluation of force-displacement measurements during one-sided powder compaction in cylindrical dies

- R F Lammens

R.F. Lammens, The evaluation of force-displacement measurements during one-sided powder compaction in cylindrical dies, PhD thesis, University of Leiden, Netherlands (1980).

Porositätsberechnung der Schülpe während der Kompaktierung mit einer 3-W-Polygran Walzenpresse und Qualifizierung/Kalibrierung dieses Kompaktors, Diploma thesis

- S Körschgen

S. Körschgen, Porositätsberechnung der Schülpe während der Kompaktierung mit einer 3-W-Polygran Walzenpresse und Qualifizierung/Kalibrierung dieses Kom-paktors, Diploma thesis, University of Applied Sciences of Düsseldorf, Germany (1996).

Trockengranulation: Entwicklung einer Basisrezeptur für die Walzenkompaktierung mit Hilfe von Exzenterpresse, Mikropaktor und Produktionskompaktor, Diploma thesis

- S Erling

S. Erling, Trockengranulation: Entwicklung einer Basisrezeptur für die Walzen-kompaktierung mit Hilfe von Exzenterpresse, Mikropaktor und Produktionskom-paktor, Diploma thesis, University of Bonn, Germany (2001).

Contribution à l'étude de l'agglomération des poudres en press à rouleaux lisses

- B Michel

Michel, B., Contribution à l'étude de l'agglomération des poudres en press à rouleaux lisses, Thèse de doctorat (PhD thesis), Université de Technologie de Compiègne, France, (1994).

Trockengranulation mit Hilfe des Micropactor

- F Bicane

F. Bicane, Trockengranulation mit Hilfe des Micropactor, PhD thesis, University of Bonn, Germany (2003).

Pressure–density relationships in powder compaction

- Heckel