Determination of precompression and compression force levels to minimize tablet friability using simplex

Abstract

Pilot simplex experiments for improving the tablet strength of three aspirin tablet formulations based on precompression and compression forces were presented. As each simplex moved towards the direction of the optimum, the friability was being minimized and the crushing strength was concomittantly being maximized. Because it followed a systematic direction, simplex process would locate a local optimum rapidly. The appropriate levels of precompression and compression forces that produced tablets with the desired strength were attained in five trials. By contrast, random search for this force combination required at least ten trials. Simplex technique is a cost and time effective means for determining the precompression and compression forces that will reduce the friability or increase the hardness of a tablet formulation. Results appeared to also indicate that crushing strength might be a more reliable measure of tablet strength than friability.     

The effect of precompression in a rotary machine on tablet strength

The effects of precompression on tablet strength/main compression pressure profiles have been studied with an instrumented rotary tabletting machine. The advantages of precompression are dependent upon individual formulation components and their behaviour under stress, tablet shape, and machine speed. Model systems and the mechanisms by which precompression may improve tablet strength, are discussed.     

The effect of precompression in a rotary machine on tablet strength

Abstract

The effects of precompression on tablet strength/main compression pressure profiles have been studied with an instrumented rotary tabletting machine. The advantages of precompression are dependent upon individual formulation components and their behaviour under stress, tablet shape, and machine speed. Model systems and the mechanisms by which precompression may improve tablet strength, are discussed.     

Effect of compression force, compression speed, and particle size on the compression properties of paracetamol.

The compression characteristics of two particle size fractions (< 90 microm, 105-210 microm) of paracetamol were examined. Each fraction produced extremely weak tablets and displayed a high tendency to cap. Low correlation coefficients of the initial parts of the Heckel plots, a low strain rate sensitivity, and an increase in mean yield pressure (from 34.2 to 45.5 MPa) with decrease in particle size all confirmed that the main mechanism during the compaction of paracetamol was fragmentation. The 105-210-microm particles underwent more fragmentation than the less than 90-microm powder. Heckel analysis confirmed that the larger size fraction of paracetamol produced denser compacts than the smaller fraction. The 105-210-microm fraction resulted in tablets with lower elastic recoveries and elastic energies. The elastic, plastic energy ratios indicated that the majority of energy involved during the compaction of paracetamol was utilized as elastic energy, indicative of massive elastic deformation of paracetamol particles under pressure.     

Shape optimization of pulsatile ventricular assist devices using FSI to minimize thrombotic risk

In this paper we perform shape optimization of a pediatric pulsatile ventricular assist device (PVAD). The device simulation is carried out using fluid–structure interaction (FSI) modeling techniques within a computational framework that combines FEM for fluid mechanics and isogeometric analysis for structural mechanics modeling. The PVAD FSI simulations are performed under realistic conditions (i.e., flow speeds, pressure levels, boundary conditions, etc.), and account for the interaction of air, blood, and a thin structural membrane separating the two fluid subdomains. The shape optimization study is designed to reduce thrombotic risk, a major clinical problem in PVADs. Thrombotic risk is quantified in terms of particle residence time in the device blood chamber. Methods to compute particle residence time in the context of moving spatial domains are presented in a companion paper published in the same issue (Comput Mech, doi:10.1007/s00466-013-0931-y, 2013). The surrogate management framework, a derivative-free pattern search optimization method that relies on surrogates for increased efficiency, is employed in this work. For the optimization study shown here, particle residence time is used to define a suitable cost or objective function, while four adjustable design optimization parameters are used to define the device geometry. The FSI-based optimization framework is implemented in a parallel computing environment, and deployed with minimal user intervention. Using five SEARCH/POLL steps the optimization scheme identifies a PVAD design with significantly better throughput efficiency than the original device.     

A fractional filter-based beamformer architecture using postfiltering approach to minimize hardware complexity

A novel beamformer architecture using fractional delay filters is proposed and verified through experiments. By performing interchannel summation prior to filtering operation in the manner producing no error, the proposed architecture requires only three four-tap filters for the whole beamformer and four simple demultiplexers per each channel.     

Development of terfenadine-pseudoephedrine double-layer tablet dissolution-equivalent to core tablet

The terfenadine-pseudoephedrine dosage form discussed here is the sustained-release core tablet composed of outer (fast-release) and inner (sustained-release) layers. To develop the double-layer tablet dissolution-equivalent to a core tablet, the fast-release and sustained-release layers were prepared using various disintegrants and polymers, respectively. The layer composed of terfenadine/pseudoephedrine/lactose/cornstarch/sodium bicarbonate/hydroxypropylcellulose (HPC)/sodium lauryl sulfate/microcrystalline cellulose (60/10/90/30/20/1/40/1/293 mg), which gave the fast disintegration time and high dissolved amounts of drugs, was selected as the fast-release layer. The dissolved amounts of pseudoephedrine from sustained-release layers increased more with a smaller ratio of ethylcellulose and hydroxypropylmethylcellulose (HPMC). Dissolution mechanism analysis showed the release of pseudoephedrine was proportional to the square root of time, indicating that drug might be released from the layers by Fickian diffusion. The layer composed of pseudoephedrine/ethylcellulose/HPMC (110/30/155 mg), which had similar dissolution amounts of pseudoephedrine as the inner layer of a core tablet, was selected as the sustained-release layer. Furthermore, the dissolved amounts of drugs from the core and double-layer tablets had deviations of less than 5% against the average dissolved amounts of drugs at each time. There was no significant difference between the dissolved amounts of drugs from these tablets at each time in pH 1.2, 4.0, and 6.8 (P > .05). Our results suggest that this double-layer tablet was a dissolution equivalent to the core tablet.     

Continuous direct tablet compression: effects of impeller rotation rate,total feed rate and drug content on the tablet properties and drug release

Context: Continuous processing is becoming popular in the pharmaceutical industry for its cost and quality advantages.

Objective: This study evaluated the mechanical properties, uniformity of dosage units and drug release from the tablets prepared by continuous direct compression process.

Materials and methods: The tablet formulations consisted of acetaminophen (3–30% (w/w)) pre-blended with 0.25% (w/w) colloidal silicon dioxide, microcrystalline cellulose (69–96% (w/w)) and magnesium stearate (1% (w/w)). The continuous tableting line consisted of three loss-in-weight feeders and a convective continuous mixer and a rotary tablet press. The process continued for 8?min and steady state was reached within 5?min. The effects of acetaminophen content, impeller rotation rate (39–254?rpm) and total feed rate (15 and 20?kg/h) on tablet properties were examined.

Results and discussion: All the tablets complied with the friability requirements of European Pharmacopoeia and rapidly released acetaminophen. However, the relative standard deviation of acetaminophen content (10% (w/w)) increased with an increase in impeller rotation rate at a constant total feed rate (20?kg/h). A compression force of 12?kN tended to result in greater tablet hardness and subsequently a slower initial acetaminophen release from tablets when compared with those made with the compression force of about 8?kN.

Conclusions: In conclusion, tablets could be successfully prepared by a continuous direct compression process and process conditions affected to some extent tablet properties.     

Microwave reflection and dielectric properties of mortar subjected to compression force and cyclically exposed to water and sodium chloride solution

Corrosion of the reinforcing steel is a major cause of damage and deterioration in reinforced concrete structures such as concrete bridge decks and columns. Chloride intrusion into concrete can lead to depassivation of the steel and initiation of corrosion. Thus, it is very important to be able to nondestructively detect and evaluate the free chloride content in concrete. Near-field microwave nondestructive testing techniques, using open-ended rectangular waveguide probes, have shown great potential for evaluating various properties of concrete, including the successful detection of sodium chloride added to mortar mixing water. In this study, several mortar samples are cyclically soaked in distilled and salt water while also experiencing compression force. Compression force, simulating in-service loading, causes microcracking, which results in increased microcracking and permeability, promoting chloride ingress. The daily microwave reflection and dielectric properties of these samples were measured at 3 GHz. The results show the capability of these microwave measurements for detecting the increased level of chloride permeation and loading as a function of the increasing number of soaking cycles. The influence of salt ingress is shown to be more prominent in the loss factor, while the effect of loading is more evident in the permittivity of the samples.     

Determination of the elastic modulus of adherent cells using spherical atomic force microscope probe

When the conventional Hertz formula is used to extract the elastic modulus, E, of cells based on the compression test using atomic force microscope spherical probe, the inconsistency between the actual situation and the assumption of the formula will lead to a large error. Using the ABAQUS for finite element modeling and analysis, here, a modified Hertz formula was developed to reduce the effects of cell radius, cell thickness, probe radius and compression depth on the extracted E of cells. Experimentally, the insensitivity of the extracted E to the compression region of cell and probe radius reflects the validity of the modified formula. Owing to the poor resolution of spherical probes, it's unlikely to know the actual thickness of cell at the measured point, which can lead to a huge error. Based on the modified formula, we further proposed an approach to control the effect of the uncertainty of cell thickness and ensured that a 10% difference in cell thickness does not incur over 10% variation in the obtained elastic modulus.

     

Essential algorithms to minimize dynamic effects in using explicit codes for stamping process simulations

A key problem, when using dynamic codes to run the static or quasi‐static jobs, in particular, for a stamping process simulation attaching spring‐back calculation, is the dynamic effect. In order to minimize the dynamic effects, some kinds of loading algorithms should be performed. The enhancement of these is proposed in this paper, as well as making up for a deficiency that current damping models have when used to reduce the dynamic effects. Essential conditions that can be followed to generate an ideal loading curve are brought forward here including the starting and ending condition. A concerned model is recommended that satisfies all ideal requirements, which can be used directly for the stamping process simulation. Associated criteria and how to optimize the loading curves are also presented. Finally, a simple case has been done to describe its practical application in simulations. Meanwhile, several kinds of loading curves, which have been used commonly in the stamping process simulation, are selected to compare with the proposed loading curve. The different features of them are also discussed. Copyright © 2003 John Wiley & Sons, Ltd.     

Characterising the surface adhesive behavior of tablet tooling components by atomic force microscopy

Purpose: The aim of this study is to develop an atomic force microscopy (AFM) based approach to study the adhesive forces between tabletting punches and model formulation ingredients, that can ultimately be used to understand and predict issues such as sticking during tabletting compression.

Methods: Adhesive interactions were studied between single lactose particles and coated tablet punches. The adhesion was measured at varying relative humidities (RHs) and the influence of surface roughness was investigated. Roughness parameters were measured with AFM imaging and a modeling approach used to predict the influence of roughness on adhesion.

Results: Surface roughness was found to play a significant role in the observed lactose-punch adhesion and the variation of this adhesion across the punch surface. Such differences between punches can be correlated to observations from industrial use. Adhesion forces were spatially mapped to indentify “hot spots” of high adhesion. A modeling approach can predict the relative adhesion of different surfaces from roughness data. The adhesion was also significantly affected by RH, for one type of punch causing a greater than 3× increase in adhesion between 30 and 60% RH. Interestingly, different punches showed different RH-adhesion behavior, relating to their hydrophilicity.

Conclusions: The work introduces a new method for screening tablet punch materials and tabletting conditions. Important factors to be considered when evaluating adhesive interactions in tablet compression have been highlighted. Correlations are observed between AFM adhesion results and tabletting behavior during manufacture. This provides a promising basis for a predictive approach toward combating tabletting issues.     

Microwave reflection properties of concrete periodically exposed to chloride solution of 3% salinity and compression force

Corrosion of steel rebar in a concrete structure compromises its structural integrity and hence its performance. Chloride intrusion into concrete can lead to depassivation of the steel and initiation of corrosion. Methods exist to detect chlorides in concrete, but the practical use of many of these may be problematic because they are destructive and time consuming, and cannot be used to analyze large structures. Microwave nondestructive evaluation techniques applied to mortar have proven successful for detecting mixture constituents, chloride ingress, and cure-state monitoring. In this paper several concrete samples are cyclically soaked in distilled water and saltwater while also experiencing compression force. Compression force, simulating in-service loading, results in increased microcracking and permeability, which promotes chloride ingress. The daily microwave reflection properties of these samples were measured at 3 GHz. The results show the capability of these microwave measurements for detecting the increased level of chloride permeation as a function of increasing number of soaking cycles. In addition, comparisons between the reflection properties of mortar and concrete cubes soaked in distilled water exhibit similarity in trends, indicating that the various phenomena that occur within them are systematically similar.     

Investigation of flow properties of powders by means of a uniaxial tester, in relation to direct tablet compression

Unexpected poor flowability during commercial production of a direct compression tablet formulation initiated an investigation of the flow properties of the powder mixture and its components by means of a uniaxial tester. The failure function—a curve describing the strength of the powder bed as a function of the maximum main stress that has consolidated the bed—of the powder mixture and its components was determined. The drug was more cohesive than the filler, which was somewhat more cohesive than the powder mixture. Three excipients—a binder, a glidant and a lubricant—constituting 3.5 w/w% of the formulation improved the flowability of the mixture of active ingredient and filler. The failure function discriminated powder mixtures with poor flow from mixtures with medium or good flow. However, it was not possible to discriminate medium from good flow by means of the failure function. Attempts to correlate univariately the flow property parameters of the powder mixtures with particle size data or flow property data of included active ingredient and filler batches failed. Therefore a multivariate approach was tested. Principal component analysis (PCA) and projection to latent structures by means of partial least squares (PLS) were employed. An excellent PCA model was obtained with the flow properties of the powder mixture. A good PCA model of tableting performance—based on tablet weight variation and tablet machine speed—was obtained.     

The role of several l-HPCs in preventing tablet capping during direct compression of metronidazole

Several low-hydroxypropyl cellulose (l-HPC) derivatives (LH-11, 21, 22, 31, and 32) differing in granulometric particle size or in hydroxypropyl content were considered in the present study. The l-HPC grades were characterized as pure powders, in order to determine both compression and densification behavior, in presence or in absence of magnesium stearate as lubricant, and then, were physically mixed in different proportions with metronidazole, which was also previously characterized as pure powder. The tabletability and compressibility of these binary mixtures were then evaluated, in presence or in absence magnesium stearate as lubricant at two different compression speeds (20 and 70 mm/sec). It was observed that both binary mixture compression behavior and capping tendency were influenced by compression speed and by the presence of lubricant. Differences in anti-capping efficiency between the l-HPCs may be related to their hydroxypropyl content. This parameter influences the interaction between the metronidazole and the polymer particles, and consequently the ability of the binary system to undergo densification under compression.     

Monitoring of the manufacturing process for ambroxol hydrochloride tablet using NIR-chemometric methods: compression effect on content uniformity model and relevant process parameters testing

This study aimed at using near-infrared (NIR) spectroscopy to monitor compaction pressure for simultaneously determining the tensile strength and content uniformity, as well as moisture and mean particle size of ambroxol hydrochloride tablets. The content uniformity, compression force and tensile strength of the laboratory samples were obtained by pressing a mixture of active principle and excipient components into tablets. To reduce the spectral baseline shift of the laboratory samples, the compaction pressure applied to the mixture was assessed by a variable pressure test. Production samples were added to the test and subjected to principal component analysis. The expanded partial least-squares (PLS) calibration model used to quantify the active content was more accurate than the model constructed from laboratory samples using the production tablets included in the calibration set. The model showed good predictability, with correlation coefficient (R) 0.9977. The validation and reliability of the content model were evaluated to determine trueness and reliability for the measurement of individual production tablets and the laboratory tablets with drug content ranging from 24 to 36?mg. The PLS calibration models for compression force and tensile strength were constructed using the same spectral set assuming both were highly related. These models yielded high R values (0.9955 and 0.9910). The R values of the moisture and mean particle size were 0.9994 and 0.9919, respectively. This study demonstrated that NIR spectroscopy combined with chemometric techniques can be successfully used to quantitatively monitor the tablet manufacturing process in the pharmaceutical industry.     

Measurement of the adhesive force of fine particles on tablet surfaces and method of their removal

The adhesion force of fine particles on the surface of tablets was measured by a centrifugal force and impact separation method. A Finededuster (FDD) was employed to remove fine particles from the tablet surface. The centrifugal force and impact separation method was suggested to be effective for measuring the adhesive forces between particles and the tablet surface, and effective disjoining force in the FDD could be estimated by comparison of the results obtained using these two methods. The FDD showed high removal efficiency regardless of how many tablets were processed at the same time. In either of these methods, critical particle size was about 10-20 μm, and larger particles were removed more efficiently. This critical particle size was similar to that observed for other mechanical properties of powders, such as angle of repose and flowability. We simulated particle residual percentage under various operation conditions by ANN (artificial neural network) analysis and multiple regression analysis. This simulation enabled us to predict how the efficiency of particle removal is affected by the interaction of the experimental and material factors.     

Comparative tablet and rheological properties of new microcrystalline cellulose: direct compression and wet granulation methods.

The overall objective of this study was to compare the rheological properties and tablet characteristics of two new varieties of celluloses (Vivacel 101 and 102), recently produced and commercialized, with the classical varieties of celluloses (Avicel and Elcema). The results showed no significant differences in the rheological properties of Vivacel and Avicel, while significant differences were found between the two celluloses and Elcema. Furthermore, there were no statistically significant differences in the disintegration times and Td values of Vivacel and Avicel. In conclusion, it was found that these new celluloses offer all the known advantages of Avicel.