How do roll compaction/dry granulation affect the tableting behaviour of inorganic materials? Microhardness of ribbons and mercury porosimetry measurements of tablets.

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.     

Roller compaction: Application of an in-gap ribbon porosity calculation for the optimization of downstream granule flow and compactability characteristics

This paper reports the use of an in-gap ribbon porosity calculation for the optimisation of roller compaction ribbon parameters in order to control downstream granule and tablet properties for a typical pharmaceutical formulation. The study demonstrates the effect of changes to roll speed and roll gap on the relative level of ribbon compaction for ribbons with equivalent in-gap porosities. It is demonstrated that in-gap ribbon porosity can be applied to enable optimization of the downstream granule processability characteristics for a typical pharmaceutical formulation and an understanding of the control space of a roller compaction process.     

Simulation of roller compaction using a laboratory scale compaction simulator

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.     

Combining experimental design and orthogonal projections to latent structures to study the influence of microcrystalline cellulose properties on roll compaction

Roll compaction is gaining importance in pharmaceutical industry for the dry granulation of heat or moisture sensitive powder blends with poor flowing properties prior to tabletting. We studied the influence of microcrystalline cellulose (MCC) properties on the roll compaction process and the consecutive steps in tablet manufacturing. Four dissimilar MCC grades, selected by subjecting their physical characteristics to principal components analysis, and three speed ratios, i.e. the ratio of the feed screw speed and the roll speed of the roll compactor, were included in a full factorial design. Orthogonal projection to latent structures was then used to model the properties of the resulting roll compacted products (ribbons, granules and tablets) as a function of the physical MCC properties and the speed ratio. This modified version of partial least squares regression separates variation in the design correlated to the considered response from the variation orthogonal to that response. The contributions of the MCC properties and the speed ratio to the predictive and orthogonal components of the models were used to evaluate the effect of the design variation. The models indicated that several MCC properties, e.g. bulk density and compressibility, affected all granule and tablet properties, but only one studied ribbon property: porosity. After roll compaction, Ceolus KG 1000 resulted in tablets with obvious higher tensile strength and lower disintegration time compared to the other MCC grades. This study confirmed that the particle size increase caused by roll compaction is highly responsible for the tensile strength decrease of the tablets.     

Multiple compaction of microcrystalline cellulose in a roller compactor.

The effect of multiple roller compaction was investigated using microcrystalline cellulose as a model substance. Granules were prepared, examined and recompacted in a Gerteis 3 W-Polygran roller compactor up to ten times. Examinations were carried out for granule size distribution, density and flow properties. Ribbons were investigated for quality, and adhesion of ribbons to the rolls was traced. Finally tablets were produced from the granule samples and examined for their compression behaviour. Multicompression reduces the amount of fines, increases mean granule size and flow properties and also improves size distribution. Although roll adhesion diminishes with increasing cycles, this decrease is not sufficient enough to result in a visibly reduced gap variability. By multicompaction, bulk density increases which indicates that the porosity of granules decreased during the multiple compaction cycles. However, the ability of MCC to form bondings with neighbouring particles is diminished during various cycles which results in decreasing crushing forces of the subsequently prepared tablets.     

Unified compaction curve model for tensile strength of tablets made by roller compaction and direct compression

A model that describes the relationship between roller-compaction conditions and tablet strength is proposed. The model assumes that compaction is cumulative during roller compaction and subsequent granule compaction, and compact strength (ribbon and tablet) is generated irreversibly as if strength is controlled by plastic deformation of primary particles only. Roller-compaction is treated as a compaction step where the macroscopic ribbon strength is subsequently destroyed in milling. This loss in strength is irreversible and tablets compressed from the resulting granulation are weaker than those compressed by direct compression at the same compression force. Roller-compacted ribbons were produced at a range of roll forces for three formulations and subsequently milled and compacted into tablets. Once the total compaction history is taken in account, the compaction behavior of the uncompacted blends and the roller-compacted granules ultimately follow a single master compaction curve--a unified compaction curve (UCC). The model successfully described the compaction behavior of DC grade starch and formulations of lactose monohydrate with 50% or more microcrystalline cellulose, and may be more generally applicable to systems containing significant proportions of any plastically deforming material, including MCC and starch.     

Small-Scale Modeling of Pharmaceutical Powder Compression from Tap Density Testers,to Roller Compactors,and to the Tablet Press Using Big Data

Introduction

Roller compaction is commonly used in the pharmaceutical industry to improve powder flow and compositional uniformity. The process produces ribbons which are milled into granules. The ribbon solid fraction (SF) can affect both the granule size and the tensile strength of downstream tablets. Roll force, which is directly related to the applied stress on the powder in the nip region, is typically the most dominant process parameter controlling the ribbon solid fraction. This work is an extension of a previous study, leveraging mathematical modeling as part of a Quality by Design development strategy (Powder Technology, 2011, 213: 1–13).

Methods

In this paper, a semi-empirical unified powder compaction model is postulated describing powder solid fraction evolution as a function of applied stress in three geometries: the tapped cylinder (uniaxial strain—part of a standard tapped density measurement), the roller compaction geometry (plane strain deformation), and tablet compression (uniaxial strain). A historical database (CRAVE) containing data from many different formulations was leveraged to evaluate the model. The internally developed CRAVE database contains all aspects of drug product development batch records and was queried to retrieve tablet compression data along with corresponding roller compaction and tap density measurements for the same batch. Tablet compaction data and tap density data were used to calibrate a quadratic relationship between stress and the reciprocal of porosity. The quadratic relationship was used to predict the roll stress and corresponding roll force required to attain the reported ribbon SF.

Results

The predicted roll force was found to be consistent with the actual roll force values recorded across 136 different formulations in 136 batch records. In addition, significant correlations were found between the first and the second order constants of the quadratic relationship, suggesting that a single formulation-dependent fitting parameter may be used to define the complete SF versus stress relationship. The fitting parameter could be established by compressing a single tablet and measuring the powder tapped density.

Conclusion

It was concluded that characterization of this parameter at a small scale can help define the required process parameters for both roller compactors and tablet presses at a large scale.

     

Impact of Different Dry and Wet Granulation Techniques on Granule and Tablet Properties: A Comparative Study

Four granulation techniques were compared evaluating their impact on granule properties and the tablet tensile strength. A common formulation was chosen to be processed with both wet and dry granulation techniques: roll compaction/dry granulation, high-shear granulation, twin-screw granulation, and fluidized-bed granulation. The produced granules were characterized in terms of granule size distribution, X-ray powder diffraction, scanning electron microscopy, porosity, and strength. Granules were tableted, and the tablets were evaluated in terms of tensile strength and mass variation. A particular focus was given to granule strength measurements. Granule strength showed to be strongly affected by the used granulation technique. Moreover, a nonlinear inverse correlation was identified between granule strength and tablet tensile strength. High-shear granulation produced the densest and strongest granules, which presented the lowest tablet tensile strength. Granules manufactured by roll compaction/dry granulation showed no loss in tabletability with the used formulation even for the more compacted and strong granules. Tablets produced by the fluidized-bed granulation showed the best properties in terms of tensile strength and mass variation. However, twin-screw granulation presented comparable results for the specific formulation evaluated in the study, thus revealing a great potential of this technique.     

Compaction behavior of roller compacted ibuprofen

The effect of roller compaction pressure on the bulk compaction of roller compacted ibuprofen was investigated using instrumented rotary tablet press. Three different roller pressures were utilized to prepare granules and Heckel analysis, Walker analysis, compressibility, and tabletability were performed to derive densification, deformation, course of volume reduction and bonding phenomenon of different pressure roller compacted granules. Nominal single granule fracture strength was obtained by micro tensile testing. Heckel analysis indicated that granules prepared using lower pressure during roller compaction showed lower yield strength. The reduction in tabletability was observed for higher pressure roller compacted granules. The reduction in tabletability supports the results of granule size enlargement theory. Apart from the granule size enlargement theory, the available fines and relative fragmentation during compaction is responsible for higher bonding strength and provide larger areas for true particle contact at constant porosity for lower pressure roller compacted granules. Overall bulk compaction parameters indicated that granules prepared by lower roller compaction pressure were advantageous in terms of tabletability and densification. Overall results suggested that densification during roller compaction affects the particle level properties of specific surface area, nominal fracture strength, and compaction behavior.     

Characterisation of density distributions in roller-compacted ribbons using micro-indentation and X-ray micro-computed tomography

Roller compaction is one stage in a dry granulation process to produce free flowing granules. Its proper understanding is essential in optimising manufacturing efficiency and product quality. Roller compaction produces a compacted strip or “ribbon”, which is then milled to produce granules. For a given milling condition, the density distribution in the ribbons determines the properties of the granules (particularly their size distribution and strength). Therefore, knowing the density distributions in the ribbons is very important in improving the effectiveness of the roller compaction process and the quality of the granules produced. In this paper, the density distribution in roller-compacted ribbons of microcrystalline cellulose (Avicel PH102) has been examined using three different techniques: (1) sectioning; (2) micro-indentation and (3) X-ray micro-computed tomography. It has been shown that with proper calibration all three techniques can essentially produce the same results, but with a different degree of resolution (scale of scrutiny). In addition, the influence of process conditions, such as roll gap, roll speed and the presence or absence of lubrication, on the ribbon density distributions has also been investigated. Flow into the press is often constrained by the presence of “cheek plates”, which prevent lateral powder movement. In this type of arrangement, it is found that non-uniform powder feeding occurs in the compaction region, induced by the friction between the powder and the cheek plates; as a result, the densities in the middle of the ribbon width are generally higher than those close to the edges. It has also been shown that higher average ribbon densities are obtained when the roll gap, roll speed, or the friction between the powder and the side cheek plates is reduced.     

Roll compaction/dry granulation: effect of raw material particle size on granule and tablet properties

The influence of particle size of MCC, as a binder, and theophylline, as an active pharmaceutical ingredient on the process of roll compaction/dry granulation was investigated using a D-optimal design of experiments. Examined parameters were particle size of both starting materials, fraction of theophylline and ribbon porosity. Therefore, different binary mixtures were roll compacted, dry granulated and compressed into tablets. Flowability of powders and granules and tensile strength of tablets made from powders or granules were the focus of this study. This study showed that a decrease in particle size of MCC or theophylline resulted in an increase of tensile strength even after roll compaction/dry granulation. Comparing tensile strength of tablets made from powder using large size MCC with ones made from granules with small sized MCC revealed that the tensile strength of tablets produced from granules was equal or even higher than tensile strength from direct compressed tablets. Furthermore, using small sized MCC instead of large sized MCC led to larger granules with better flowability. It is shown that the fraction of binder can be reduced without a loss of tensile strength of the final tablets by size reduction of MCC.     

Improving the content uniformity of a low-dose tablet formulation through roller compaction optimization

In this investigation, the potency distribution of a low-dose drug in a granulation was optimized through a two-part study using statistically designed experiments. The purpose of this investigation was to minimize the segregation potential by improving content uniformity across the granule particle size distribution, thereby improving content uniformity in the tablet. Initial operating parameters on the Gerteis 3-W-Polygran 250/100/3 Roller Compactor resulted in a U-shaped potency function (potency vs. granule particle size) with superpotent fines and large granules. The roller compaction optimization study was carried out in two parts. Study I used a full factorial design with roll force (RF) and average gap width (GW) as independent variables and Study II used a D-optimal response surface design with four factors: RF, GW, granulating sieve size (SS), and granulator speed (GS). The planned response variables for Study I were bypass weight % and potency of bypass. Response variables for Study II included mean granulation potency with % relative standard deviation (% RSD), granulation particle size, sieve cut potency % RSD, tablet potency with % RSD, compression force at 7 kP crushing strength, and friability of 7-kP tablets. A constraint on GW was determined in Study I by statistical analysis. Bypass and observations of ribbon splitting were minimized when GW was less than 2.6 mm. In Study II, granulation potency, granulation uniformity, and sieve cut uniformity were optimized when the SS was 0.8 mm. Higher RF during dry granulation produced better sieve cut uniformity and tablets with improved uniformity throughout the run, as measured by stratified tablet samples taken during compression and assayed for potency. The recommended optimum roller compaction and milling operating parameters that simultaneously met all constraints were RF = 9 kN, GW = 2.3 mm, SS = 0.8 mm, and GS = 50 rpm. These parameters became the operating parameter set points during a model confirmation trial. The results from the confirmation trial proved that the new roller compaction and milling conditions reduced the potential for segregation by minimizing the granulation potency variability as a function of particle size as expressed by sieve cut potency % RSD, and thus improved content uniformity of stratified tablet samples.     

Improving the Content Uniformity of a Low-Dose Tablet Formulation Through Roller Compaction Optimization

In this investigation, the potency distribution of a low-dose drug in a granulation was optimized through a two-part study using statistically designed experiments. The purpose of this investigation was to minimize the segregation potential by improving content uniformity across the granule particle size distribution, thereby improving content uniformity in the tablet. Initial operating parameters on the Gerteis 3-W-Polygran 250/100/3 Roller Compactor resulted in a U-shaped potency function (potency vs. granule particle size) with superpotent fines and large granules. The roller compaction optimization study was carried out in two parts. Study I used a full factorial design with roll force (RF) and average gap width (GW) as independent variables and Study II used a D-optimal response surface design with four factors: RF, GW, granulating sieve size (SS), and granulator speed (GS). The planned response variables for Study I were bypass weight % and potency of bypass. Response variables for Study II included mean granulation potency with % relative standard deviation (% RSD), granulation particle size, sieve cut potency % RSD, tablet potency with % RSD, compression force at 7 kP crushing strength, and friability of 7-kP tablets. A constraint on GW was determined in Study I by statistical analysis. Bypass and observations of ribbon splitting were minimized when GW was less than 2.6 mm. In Study II, granulation potency, granulation uniformity, and sieve cut uniformity were optimized when the SS was 0.8 mm. Higher RF during dry granulation produced better sieve cut uniformity and tablets with improved uniformity throughout the run, as measured by stratified tablet samples taken during compression and assayed for potency. The recommended optimum roller compaction and milling operating parameters that simultaneously met all constraints were RF = 9 kN, GW = 2.3 mm, SS = 0.8 mm, and GS = 50 rpm. These parameters became the operating parameter set points during a model confirmation trial. The results from the confirmation trial proved that the new roller compaction and milling conditions reduced the potential for segregation by minimizing the granulation potency variability as a function of particle size as expressed by sieve cut potency % RSD, and thus improved content uniformity of stratified tablet samples.     

A comparative study of the influence of alpha-lactose monohydrate particle morphology on granule and tablet properties after roll compaction/dry granulation

The influence of particle morphology and size of alpha-lactose monohydrate on dry granules and tablets was studied. Four different morphologies were investigated: Two grades of primary crystals, which differed in their particle size and structure (compact crystals vs. agglomerates). The materials were roll compacted at different specific compaction forces and changes in the particle size distribution and the specific surface area were measured. Afterwards, two fractions of granules were pressed to tablets and the tensile strength was compared to that from tablets compressed from the raw materials. The specific surface area was increased induced by roll compaction/dry granulation for all materials. At increased specific compaction forces, the materials showed sufficient size enlargement. The morphology of lactose determined the strength of direct compressed tablets. In contrast, the strength of granule tablets was leveled by the previous compression step during roll compaction/dry granulation. Thus, the tensile strength of tablets compressed directly from the powder mixtures determined whether materials exhibited a loss in tabletability after roll compaction/dry granulation or not. The granule size had only a slight influence on the strength of produced tablets. In some cases, the fraction of smaller granules showed a higher tensile strength compared to the larger fraction.     

Effect of the variation in the ambient moisture on the compaction behavior of powder undergoing roller-compaction and on the characteristics of tablets produced from the post-milled granules

Effect of variation in the ambient moisture levels on the compaction behavior of a 10% acetaminophen (APAP) powder blend in microcrystalline cellulose (MCC) powder was studied by comparing the physical and mechanical properties of ribbons prepared by roller compaction with those of simulated ribbons, i.e., tablets prepared under uni-axial compression. Relative density, moisture content, tensile strength, and Young's modulus were used as key compact properties for comparison. Moisture was found to facilitate the particle rearrangement of both, the APAP and the MCC particles, as well as the deformation of the MCC particles. The tensile strength of the simulated ribbons also showed an increase with increasing moisture content. An interesting observation was that the tensile strength of the roller compacted samples first increased and then decreased with increasing moisture content. Variation in the ambient moisture during roller compaction was also found to influence the characteristics of tablets produced from the granules obtained post-milling the ribbons. A method to study this influence is also reported.     

How do roll compaction/dry granulation affect the tableting behaviour of inorganic materials? Comparison of four magnesium carbonates.

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.     

Mechanistic study of the effect of roller compaction and lubricant on tablet mechanical strength

Heckel analysis, tablet tensile strength, and indentation hardness were determined for a series of sieved and roller compacted microcrystalline cellulose mixtures under both unlubricated and lubricated conditions with magnesium stearate. These results have been used to evaluate the loss of reworkability following roller compaction for microcrystalline cellulose and show the extent of impact on tableting properties when magnesium stearate is added intragranularly prior to roller compaction. While results consistent with traditional work-hardening are observed as shown by a modest increase in dynamic hardness and mean yield pressure for unlubricated, roller compacted microcrystalline cellulose, it is overshadowed by the overlubrication effect seen during roller compaction and in particular, the subsequent milling step. The common practice of lubricating the feedstock with magnesium stearate to avoid sticking of the material to the compaction rolls appears to be the major cause of decreased mechanical strength of the final compressed tablets.     

Insensitivity of compaction properties of brittle granules to size enlargement by roller compaction

Pharmaceutical granules prepared by roller compaction often exhibit significant loss of tabletability, that is, reduction in tensile strength, when compared to virgin powder. This may be attributed to granule size enlargement for highly plastic materials, for example, microcrystalline cellulose. The sensitivity of powder compaction properties on granule size variations impacts the robustness of the dry granulation process. We hypothesize that such sensitivity of compaction properties on granule size is minimum for brittle materials because extensive fracture of brittle granules during compaction minimizes differences in initial granule size. We tested the hypothesis using three common brittle excipients. Results show that the fine (44-106 microm), medium (106-250 microm), and coarse (250-500 microm) granules exhibit essentially identical tabletability below a certain critical compaction pressure, 100, 140, and 100 MPa for spray-dried lactose monohydrate, anhydrous dibasic calcium phosphate, and mannitol, respectively. Above respective critical pressure, tabletability lines diverge with smaller granules exhibiting slightly higher tablet tensile strength at identical compaction conditions. Overall, tabletability of brittle granules is insensitive to granule size enlargement. The results provide a scientific basis to the common practice of incorporating brittle filler to a typical tablet formulation processed by roller compaction granulation.     

Effects of initial particle size on the tableting properties of L-lysine monohydrochloride dihydrate powder

L-lysine monohydrochloride (LMH) dihydrate was crystallized and the resulting powder was sieved to obtain various size fractions. The influence of other factors, such as crystallinity and crystal shape, was minimized by using the same batch of crystals. Compression of smaller particles at low compaction pressures resulted in tablets of greater porosity. The differences in porosity decreased with increasing compaction pressure. At the same compaction pressure, smaller particles formed tablets of greater tensile strength. However, fragmentation of the larger particles tended to equalize the particle size and reduce its influence. The differences were reduced for particles larger than 710 microm. For crystals of all size fractions, tensile strength increased with increasing compaction pressure. The tensile strength increased more rapidly for smaller crystals. Tensile strength decreased exponentially with increasing porosity for all fractions. The dependence of tensile strength on porosity is explained in term of tablet structure. Yield strength, calculated from 'out-of-die' Heckel analysis, increased with increasing particle size.     

Roller Compaction and Tabletting of St. John's Wort Plant Dry Extract Using a Gap Width and Force Controlled Roller Compactor. I. Granulation and Tabletting of Eight Different Extract Batches

The purpose of this study was to investigate the influence of roller compaction parameters on granule and tablet quality of a dry herbal extract from St. John's wort (Hypericum perforatum L.), which is widely used in the treatment of mild to moderate depressive disorders. Eight different extract batches were blended with 0.5, 2, and 5% of magnesium stearate and were compacted at different compaction forces using a gap width and force controlled roller compactor. The ribbon formed was milled into granules having mean particle sizes up to 700 μm. The roller compaction of the extracts decreased significantly the angle of repose from about 45 to 32° and the Hausner ratio from about 1.2 to 1.1. Tabletting of granulated extract instead of extract powder effectively reduced not only dust and feeding problems during the tabletting process but also prevented capping. The incorporation of 2 and 5% of magnesium stearate into the roller compacted extract reduced significantly the sticking of the dry herbal extracts to the punch faces without affecting the crushing strength of the tablets. Tablets containing granulated extracts exhibited a 3-fold lower disintegration time of about 12 min compared to tablets containing extract powder. Dissolution studies revealed that hyperforin, hypericin, and rutin were more rapidly released from tablets containing granulated extract. Therefore, roller compaction leveled out the differences in technological properties between the eight dry herbal extracts and compression of granulated extract significantly improved tablet quality.