Calculation of punch displacement and work of powder compaction on a rotary tablet press

To calculate the work of compaction during tableting it is necessary to have accurate values of force and punch displacement. The direct measurement of punch displacement on a rotary press is both costly and complicated but calculated displacements will be in considerable error unless deflections in the press during compression, are taken into account. By analysing the physical restraints imposed on the punches during tablet compression, an expression for punch displacement was derived. From preliminary measurements made on the table press of machine deflections and punch displacement under static conditions, the terms of this expression were evaluated for dynamic conditions. This analytic solution was then used to determine the true punch displacement and work of compaction from direct measurements of vertical force and turret position.     

Development of New Punch Shape to Replicate Scale-Up Issues in Laboratory Tablet Press II: A New Design of Punch Head to Emulate Consolidation and Dwell Times in Commercial Tablet Press

Differences between laboratory and commercial tablet presses are frequently observed during scale-up of tableting process. These scale-up issues result from the differences in total compression time that is the sum of consolidation and dwell times. When a lubricated blend is compressed into tablets, the tablet thickness produced by the commercial tablet press is often thicker than that by a laboratory tablet press. A new punch shape design, designated as shape adjusted for scale-up (SAS), was developed and used to demonstrate the ability to replicate scale-up issues in commercial-scale tableting processes. It was found that the consolidation time can be slightly shortened by changing the vertical curvature of the conventional punch head rim. However, this approach is not enough to replicate the consolidation time. A secondary two-stage SAS punch design and an embossed punch head was designed to replicate the consolidation and dwell times on a laboratory tablet press to match those of a commercial tablet press. The resulting tablet thickness using this second SAS punch on a laboratory tablet press was thicker than when using a conventional punch in the same laboratory tablet press. The secondary SAS punches are more useful tools for replicating and understanding potential scale-up issues. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:1921–1927, 2014     

Real-Time Monitoring of Powder Mass Flowrates for Plant-Wide Control of a Continuous Direct Compaction Tablet Manufacturing Process

While measurement and monitoring of powder/particulate mass flow rate are not essential to the execution of traditional batch pharmaceutical tablet manufacturing, in continuous operation, it is an important additional critical process parameter. It has a key role both in establishing that the process is in a state of control, and as a controlled variable in process control system design. In current continuous tableting line operations, the pharmaceutical community relies on loss-in-weight feeders to monitor and understand upstream powder flow dynamics. However, due to the absence of established sensing technologies for measuring particulate flow rates, the downstream flow of the feeders is monitored and controlled using various indirect strategies. For example, the hopper level of the tablet press is maintained as a controlled process output by adjusting the turret speed of the tablet press, which indirectly controlling the flow rate. This gap in monitoring and control of the critical process flow motivates our investigation of a novel PAT tool, a capacitance-based sensor (ECVT), and its effective integration into the plant-wide control of a direct compaction process. First, the results of stand-alone experimental studies are reported, which confirm that the ECVT sensor can provide real-time measurements of mass flow rate with measurement error within -1.8 ~ 3.3% and with RMSE of 0.1 kg/h over the range of flow rates from 2 to 10 kg/h. The key caveat is that the powder flowability has to be good enough to avoid powder fouling on the transfer line walls. Next, simulation case studies are carried out using a dynamic flowsheet model of a continuous direct compression line implemented in Matlab/Simulink to demonstrate the potential structural and performance advantages in plant-wide process control enabled by mass flow sensing. Finally, experimental studies are performed on a direct compaction pilot plant in which the ECVT sensor is located at the exit of the blender, to confirm that the powder flow can be monitored instantaneously and controlled effectively at the specified setpoint within a plant-wide feedback controller system.     

Influence of tableting on the enzymatic activity of different alpha-amylases using various excipients.

The purpose of the study was to show the influence of compression pressure on the enzymatic activity of different types of alpha-amylases and to analyze the loss of activity of alpha-amylase in mixtures with different excipients. Following that, the properties of excipients used for tableting enzymes were evaluated. Tablets were produced on an instrumented single punch tableting machine. The pure amylases were tableted with increasing graded compaction pressures. Mixtures were tableted to different maximum relative densities, rho(rel,max). The remaining enzymatic activity of the alpha-amylase in the tablets was determined by the starch iodine reaction. The results show a difference between different types of alpha-amylase depending on their origin and additives. Enzymatic inactivation occurs for the pure materials at all pressures used. It is initiated during and continues after compaction. It can be inhibited by freezing the tablets. Another possibility is to tablet the enzyme in a mixture with excipients, which prevent inactivation by softly embedding the enzyme. One example which even stabilizes alpha-amylase at high volume reduction is kappa-carrageenan. In conclusion, enzymatic inactivation can be markedly reduced when excipients are used for tableting, which require little compaction pressure and are able to release the mechanical stress in the form of expansion.     

Investigating the effect of punch geometry on high speed tableting through radial die-wall pressure monitoring

Dwell time mainly depends on punch geometry, so some tableting problems such as capping and lamination could occur at high speed compaction. Robust tools are required to monitor the interaction of punch tip and powder bed at these high speeds. Our aim was to investigate the effect of punch geometry (flat and standard concave) on powder compaction at high speed using radial die-wall pressure (RDWP) as a monitoring tool. Instrumented die guided by compaction simulation was applied for five materials with different compaction behaviors. Flat-faced punch showed higher residual, maximum die-wall pressures, and axial stress transmission than concave punches, p?p?p?相似文献   

The Role of the Displacement-time Waveform in the Determination of Heckel Behaviour Under Dynamic Conditions in a Compaction Simulator and a Fully-instrumented Rotary Tablet Machine

Abstract— The Heckel equation has been used widely to characterize the compression behaviour of pharmaceutical powders, yet very little attention has been paid to the role of the displacement-time profile used to generate this relationship. The objective of this study was to evaluate and compare selected standard waveforms with actual and theoretical tablet press waveforms in the Heckel analysis of representative formulations under dynamic conditions in a compaction simulator and to compare such data with that determined on the same formulation using an actual fully-instrumented rotary tablet press. Increased tableting rate and different programmed displacement-time waveforms with the same gross punch-speed changed the Heckel behaviour of all formulations. The results of this study suggest the pressure-volume relationship determined during powder-bed compression is affected by the instantaneous punch-speed profile of the displacement-time waveform for all materials studied, even though they deform by different mechanisms. It appears that the instantaneous punch-speed profile of the particular displacement-time waveform is a confounding factor of Heckel analysis. Compaction simulators programmed to deliver saw-toothed displacement-time traces have the advantage of constant punch-speed and may be a better choice for characterizing a formulation by Heckel indices and the strain-rate sensitivity index. On the other hand, they also carry the liability of not being a realistic representation of tableting on a rotary tablet press.     

Evaluation of the plug formation process of silicified microcrystalline cellulose

To investigate the powder plug formation process of silicified microcrystalline cellulose (SMCC) under compression forces consistent with automatic capsule-filling machines, a single-ended saw-tooth wave was used to make powder plugs with different heights (6, 8, 12 mm), at two different punch speeds (1 and 50 mm/s) on a tablet compaction simulator. SMCC was compared to Starch 1500, anhydrous lactose (direct tableting grade), and microcrystalline cellulose. Heckel analysis showed that 'apparent mean yield pressures' (AMYP) of all tested materials increased with an increase in the plug height and punch speed. AMYP appeared to depend on the material type and punch speed. Not all materials fit the Shaxby-Evans relationship at such low compression forces (less than 250 N). Only SMCC 90, SMCC HD90 and anhydrous lactose data fit the equation at both punch speeds. Due to poor axial load transmission, the R values of all tested materials decreased with an increase in the plug height. The experimental data fit the Kawakita equation quite well. Overall, Kawakita's b values were inversely related to AMYP values. The maximum breaking force (MBF) of a 12 mm plug formed at a punch speed of 50 mm/s correlated well with the work of compaction, except for SMCC HD90 and SMCC X, which exhibited very high MBF values. This research demonstrated that several grades of SMCC produced plugs having higher MBF than anhydrous lactose and Starch 1500 under similar compression conditions. The apparently higher compactability of these materials at low plug formation forces may be beneficial in developing direct fill formulations for automatic capsule filling machines.     

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.     

Evaluation of a Rotary Tablet Press Simulator as a Tool for the Characterization of Compaction Properties of Pharmaceutical Products

The Stylcam 100R, a rotary press simulator, was designed to simulate speed profiles of rotary tablet presses. Such a simulator was qualified by numerous laboratories and, actually, its ability to be used for studying the behaviour of powders under pressure should be examined. Then, the purpose of this work was to investigate the performances of the Stylcam 100R for characterizing the compaction behaviour and the tabletting properties of pharmaceutical powders. The compressibility of three pharmaceutical excipients (microcrystalline cellulose, dicalcium phosphate dihydrate and a-lactose monohydrate) was studied. Four compression speeds were used on the compaction simulator. Force-displacement cycles were associated with two energy parameters, the specific total energy (Es_tot) and the specific expansion energy (Es_exp). The mean yield pressure was calculated from Heckel’s plots obtained with the in-die method. The diametral tensile strength of compacts was measured in order to evaluate mechanical properties. To evaluate the accuracy of all these parameters, a comparative study was carried out on an eccentric instrumented press. The values of energy parameters and tensile strengths of tablets are close between the eccentric press and the compaction simulator, whatever the compression speed on the latter. The mean yield pressure values obtained using the two presses are different. Finally, the Stylcam 100R seems to be a good tool for characterising tabletting properties of powders, except for the Heckel’s model probably due to an unadapted equation of deformation and a lack of accuracy of the displacement transducers. Future improvements should allow correcting these two points.     

Development of New Shaped Punch to Predict Scale‐up Issue in Tableting Process

Scale‐up issues in the tableting process, such as capping, sticking, or differences in tablet thickness, are often observed at the commercial production scale. A new shaped punch, named the size adjusted for scale‐up (SAS) punch, was created to estimate scale‐up issues seen between laboratory scale and commercial scale tableting processes. The SAS punch's head shape was designed to replicate the total compression time of a laboratory tableting machine to that of a commercial tableting machine. Three different lubricated blends were compressed into tablets using a laboratory tableting machine equipped with SAS punches, and any differences in tablet thickness or capping phenomenon were observed. It was found that the new shaped punch could be used to replicate scale‐up issues observed in the commercial tableting machine. The SAS punch was shown to be a useful tool to estimate scale‐up issues in the tableting process. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:235–240, 2014     

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.     

Modeling of adhesion in tablet compression. II. Compaction studies using a compaction simulator and an instrumented tablet press

Adhesion problems are usually not identified until prolonged compression runs are studied near the end of the drug development process. During tablet manufacturing, adhesion problems encountered are usually addressed by statistically designed experiments based on experience. It would be a significant benefit for the pharmaceutical industry if adhesion problems could be identified early in drug development based on molecular considerations of the drug substance and/or prototype formulations. Drug substance-punch face interactions were reported in the first of the articles in this series, and focused on the elucidation of adhesion problems in tablet compression. It was hypothesized that the intermolecular interactions between drug molecules and the punch face was the first step (or criterion) in the adhesion process, and that the rank order of adhesion during tablet compression should correspond with the rank order of these energies of interaction. That is, the interaction between the molecular structure of the drug and the metal surface determines the primary interaction event or relative potential for adhesion, while the mechanical processes and/or lubrication effects may subsequently impact the extent of adhesion. Molecular simulations and atomic force microscopy were used to establish the rank order of the work of adhesion of a series of profen compounds. The results predicted that the relative degree of drug substance-punch face adhesion should decrease in the order of ketoprofen > ibuprofen > flurbiprofen. In this study, the authors investigated whether the rank order of the work of adhesion established on the molecular level and interparticulate level holds true in the tableting environment by measuring tablet take-off force, ejection force, and visual observation of the punch surfaces for both pure drug compacts and formulated tablets. The compaction simulator was used for pure profen compacts, while the instrumented tablet press for formulated tablets. Due to the inability to extract the adhesion force component from the total ejection force measurement, tablet ejection force was not used as a criterion to judge the adhesion behavior of the model compounds. The criteria used for judgement of punch face adhesion were tablet take-off force and visual observation of the punch faces. The rank order of adhesion for both pure drug and formulated tablets was determined to follow the order of ketoprofen > ibuprofen > flurbiprofen. The effect of run time on adhesion behavior was also investigated. Therefore, the rank order of the punch-face adhesion tendencies for the series of profen compounds was determined, and found to agree with the data from the predictive methods reported in the first article.     

Die wall pressure measurement for evaluation of compaction property of pharmaceutical materials

The aim of this study was to evaluate the compaction property of several pharmaceutical materials by measuring the die wall pressure. The profile of die wall force during tabletting process was measured with the compaction process analyzer (TabAll). Several compaction parameters such as maximum die wall pressure (MDP), residual die wall pressure (RDP) and pressure transmission ratio (PTR) from upper punch to lower punch were calculated. The ejection pressure (EP) of tablet compacted was also measured as a parameter for sticking property of the compacts. The profile of die wall force observed was classified to the typical two types, a small type and a large one. Partly pre-gelatinized starch (PCS), cornstarch and low substituted hydroxypropylcellulose (L-HPC) were the small type, while crystalline lactose, ascorbic acid and potassium chloride were the large type. The die wall force of crystalline lactose remarkably increased at the ejection of tablet and then capping was observed. RDP value of PCS, cornstarch, L-HPC was smaller than that of crystalline lactose, ascorbic acid, potassium chloride. As the higher pressure transmission ratio from upper punch to lower punch means a good compressing property of the powder, we proposed that RDP/MDP is a useful parameter for evaluating the compaction property of powders. Although potassium chloride which is strongly plastic deformable powder showed the highest RDP value among the powders tested, the RDP/MDP value was lower than that of crystalline lactose or ascorbic acid and the tensile strength of resultant tablet of potassium chloride was much higher than these powders.     

A classification system for tableting behaviors of binary powder mixtures

The ability to predict tableting properties of a powder mixture from individual components is of both fundamental and practical importance to the efficient formulation development of tablet products. A common tableting classification system (TCS) of binary powder mixtures facilitates the systematic development of new knowledge in this direction. Based on the dependence of tablet tensile strength on weight fraction in a binary mixture, three main types of tableting behavior are identified. Each type is further divided to arrive at a total of 15 sub-classes. The proposed classification system lays a framework for a better understanding of powder interactions during compaction. Potential applications and limitations of this classification system are discussed.     

Influence of crystal structure on the tableting properties of n-alkyl 4-hydroxybenzoate esters (parabens)

Certain crystallographic features, such as the existence of slip planes, can greatly facilitate the ability of crystals to deform plastically. An investigation of the relationship between the slip planes and the tableting performance of the crystals of methyl, ethyl, n-propyl, and n-butyl 4-hydroxybenzoate (parabens) was conducted. The absence of slip planes in methyl paraben crystal structure results in significantly poorer tableting performance than the other three parabens. While slip planes are present in the crystal structures of ethyl, propyl, and butyl parabens, they exhibited different plasticity as confirmed by crystal free volume analysis, crystal nano-indentation hardness, and Heckel analysis. Sieved fraction, 150-250 microm, of each paraben powder was compressed into tablets under different conditions. Tablet tensile strength, porosity, and Indices of tableting performance (ITP) were obtained. Under the same compaction pressure, tablet tensile strength was higher for crystals with higher plasticity. Tableting performance, assessed using the ITP, also improved with increasing crystal plasticity. The results confirm that high levels of plasticity, which can result from the presence of slip planes in crystal lattice, plays a critical role in the formation of strong and intact tablets by means of powder compaction.     

Effects of the metal type and the roughness of the die wall on the expended work for tablet ejection

The aim of the present work was to obtain an impression about the consequences for the tableting process when dies of different quality are used. Two hard metal dies and one die made from tool steel, each with a distinct roughness of the die wall, were compared by compacting dry-blended powder mixtures on an eccentric tablet press. The feasibility of the tableting process was assessed by quantifying the ejection force and the work expended by the lower punch during a first phase of the ejection process. With decreasing amounts of lubricant, abrupt permanent impacts were observed leading to conditions at which an ejection was no longer possible. This observation did not depend on the roughness of the die wall used or on the compaction pressure, but strongly depended on the metal type of the die used and on the tested formulation. For the tool steel no difference was found in this respect between the two tested formulations (0.5% versus 2% silica aerogel). In either case, a concentration of 0.3% magnesium stearate was sufficient; however, a concentration of 0.2% magnesium stearate was not sufficient. For both hard metal dies, concentrations of 0.3% (0.5% silica aerogel) and 0.5% magnesium stearate (2% silica aerogel) were definitely not sufficient. Within the ranges above a minimum lubrication, the ejection force and the ejection work increased with the degree of the die wall roughness on a scale comparable to that of the tested formulation factors. In particular, if changes of the die tooling are likely to occur in the life cycle of a product, it is highly recommended that the quality of the dies be considered in the development phase.     

干法制粒中黏合剂的比较

目的 比较干法制粒压片工艺中粘合剂的表现。方法 以盐酸二甲双胍和扑热息痛为模型药,分别以羟丙纤维素(hydroxypropylScellulose,HPC),共聚维酮(copovidone,PVP/VA),羟丙甲纤维素(hypromellose,HPMC),聚维酮(povidone,PVP)和乙基纤维素(ethyl cellulose,EC)为粘合剂干法制粒并压片,测定颗粒密度,流动性和粒径分布,片剂硬度、脆碎度和体外溶出度等。结果 对于盐酸二甲双胍和扑热息痛这两种药物,羟丙纤维素均能制得机械性能最佳的片剂,共聚维酮也表现较好。结论 羟丙纤维素是较适合干法制粒压片工艺的优异粘合剂。     

The effect of dimensions on the compaction properties of sodium chloride

Using a tablet press instrumented with strain gauges, anhydrous particulate sodium chloride was compressed to form compacts of different lengths in three dies of different diameters. For the limited range of dimensions applicable to most pharmaceutical tablets, there was a common linear relation between the applied compaction pressure and the force lost to the die wall per unit area of apparent die wall contact, during compression. Ejection forces were correlated using a similar expression. The mechanical strength of compacts was determined by diametrical compression. A relation was proposed to express the strength (F_e), of the compacts of different sizes in terms of the diametrical cross-sectional area at zero porosity (D.L_o), the relative volume (V_r) and the mean compaction pressure (P_m): , where k and c are constants.     

Effects of tableting pressure on hydration kinetics of theophylline anhydrate tablets.

The effects of tableting pressure on hydration kinetics of types I and II theophylline anhydrate tablets at 95% relative humidity, 35 degrees C, have been studied by using various kinetic equations. Relations between tablet expansion and hydration were studied. Samples of 2 cm diameter tablets (1 g) were compressed at 5, 10 and 20 MPa. The hydration of types I and II tablets decreased with increased tableting pressure. The time required for 50% hydration of 2 cm diameter tablets, compressed at various pressures suggests that the tablet hydration rate was affected by the tableting pressure. Types I and II tablets expanded 11.37-16.75% in volume during hydration to the monohydrate. The thickness expansion of the tablets exceeded the diameter expansion as the tablet structure was not uniform owing to the orientation of particles during the compression. The final expansion ratio of the tablets increased with increased tableting compression pressure. The Hancock Sharp constant (m) and fitting of the kinetic data to a suitable model suggested that the hydration of theophylline anhydrate tablets followed the two-dimensional phase boundary equation (type I tablets) or the three-dimensional phase boundary equation (type II tablets).     

Infrared Imaging of Pharmaceutical Materials Undergoing Compaction

The goal of this study was to use infrared thermography as a new technique to investigate the heat released during compaction and consolidation of pharmaceutical powders and granules. Real-time temperature measurements without physical contact with tablets were provided by a highly sensitive (±0.1°C at 30°C) infrared camera (Agema Infrared Systems, Model 470 with CM-SOFT software). High-resolution images were captured at the takeoff point, i.e., less than 1 sec after compaction, stored on floppy disks, and then analyzed on a regular PC equipped with a VGA color monitor. Thermal surface profiles of tablets were obtained with high geometric and temperature resolution. Reproducibility of the camera readouts was better than 3%. The model granulation used was a direct compression blend of microcrystalline cellulose, spray-dried lactose, and magnesium stearate. This blend was compressed using an instrumented Korsch PH106 rotary press fitted with 1 station of 19.1 × 7.9-mm (0.750 × 0.312-in.) capsule-shaped tools. The effects of compaction force (6–20 kN), rate (130- to 360-msec contact time), and lubricant level (0.5 and 1.0%) on postcompaction temperature rise, caused by heat released during compaction, were investigated. The presence and location of nonhomogeneous heat distribution were assessed as well. Results have shown that the heat released during compaction increases with compaction force. Tablet surface temperatures of 33.8 ± 0.7°C were observed at 20 kN compaction force in contrast to 29.5 ± 0.3°C at 6.7 kN. The compression rate, as determined by the upper punch contact time did not have any significant effect on the heat released during compaction at 15-kN force. However, magnesium stearate level had a significant effect on the heat released during a compaction run. Tablets lubricated with 1.0% magnesium stearate had surface temperatures of 39–40°C after a 20-min run time, as opposed to 50–51°C for tablets lubricated with 0.5% magnesium stearate. Hot spots were seen at tablet edges where the die-wall friction occurs. Tablet cross-sectional thermal profiles revealed a 3–4°C temperature gradient across the tablet. These experiments show that infrared imaging is a unique tool for semiquantitative evaluation of heat released during compaction because it provides direct visualization with good temperature resolution of the heat evolved during the process.