Using an Experimental Design to Identify and Quantify the Effects of Environment Related Test Parameters on the In Vitro Mucoadhesivity Testing of a Propanolol Buccal Tablet

ABSTRACT

This study sought to identify and quantify the effects of environmental test parameters on the mucoadhesivity of a propranolol tablet. Their effects on Maximum Detachment Force (MDF) measurements were evaluated using a Box-Behnken design matrix. Prehydration time (PT) had a statistically significant negative main effect while contact force (CF) had no significant effect on in vitro MDF measurements. While contact time (CT) had no significant main or quadratic effects, it had a positive interaction effect with PT. The mathematical model was statistically validated and a PT of 3.5 min and a CT of 5 min was proposed for mucoadhesion testing by the tensile method during formulation optimization.     

Using experimental design to optimize the process parameters in fluidized bed granulation

In this study many parameters were screened for a small-scale granulation process for their effect on the yield of granules between 75 and 500 μm and the geometrical granule mean size (d50). First a Plackett-Burman design was applied to screen the inlet air temperature, the inlet flow rate, the spray rate, the nozzle air pressure, the nozzle spray diameter, and the nozzle position. The Plackett-Burman design showed that the key process parameters were the inlet flow rate and the spray rate and probably also the inlet air temperature. Afterward a fractional factorial design (2^5-2) was applied to screen the remaining parameters plus the nozzle aircap position and the spraying time interval. The fractional factorial design showed that the nozzle air pressure was also important. As the target values for the granule yield (between 75 and 500 μm) and the geometric mean granule size (between 300 and 500 μm) were reached during the screening experiments, further optimization was not considered necessary.     

Power of experimental design studies for the validation of pharmaceutical processes: case study of a multilayer tablet manufacturing process

Experimental design studies (EDS) are already widely used in the pharmaceutical industry for drug formulation or process optimization. Rare are the situations in which this methodology is applied for validation purposes. The power of this statistical tool, key element of a global validation strategy, is demonstrated for a multilayer tablet manufacturing process. Applied to the Geomatrix® system generally composed of one compression and three granulation processes, time and strictness gains are non-negligible. Experimental design studies are not used in this work for modeling. Introduced at each important step of the process development, they allow for the evaluation of process ruggedness at pilot scale and specifications for full production. A demonstration of the complete control of key process parameters is given, identified throughout preliminary studies.     

From hexafluorotitanate waste to TiO2 powder: Characterization and evaluation of the influence of synthesis parameters by the experimental design method

This paper was focused on the possible chemical synthesis routes to obtain titanium dioxide, TiO₂, from hexafluorotitanate waste and it was aimed to identify the parameters affecting the formation of crystalline titanium dioxide, TiO₂, phases (anatase or rutile). An experimental design method, inspired from the Taguchi approach, was used to assess the positive or negative impact of input factors on the formation of rutile and anatase, which were the output factors of interest. An experimental matrix was built up with coded values for each factor and coefficients were computed to point out a correlation between outputs and inputs. Particular attention was paid to the chemical compounds (decomplexing agents) added to precipitate TiO₂ from hexafluorotitanates and to the dehydration temperature used to obtain TiO₂ crystallized phases. The powders resulting from the syntheses were investigated by X-Ray diffraction analysis. Their chemical compositions were determined by Inductively Coupled Plasma Atomic Emission Spectroscopy. Data-matching revealed the best synthesis conditions in terms of crystallized TiO₂ content, and this was confirmed by calculating the processing yields. The results showed that silica and calcium hydroxide were the most efficient decomplexing agents leading to the formation of anatase.     

Formulation design of an HPMC-based sustained release tablet for pyridostigmine bromide as a highly hygroscopic model drug and its in vivo/in vitro dissolution properties

Pyridostigmine bromide (PB), a highly hygroscopic drug was selected as the model drug. A sustained-release (SR) tablet prepared by direct compression of wet-extruded and spheronized core pellets with HPMC excipients and exhibited a zero-order sustained release (SR) profile. The 2³ full factorial design was utilized to search an optimal SR tablet formulation. This optimal formulation was followed zero-order mechanism and had specific release rate at different time intervals (released % of 1, 6, and 12 hr were 15.84, 58.56, and 93.10%). The results of moisture absorption by Karl Fischer meter showed the optimum SR tablet could improve the hygroscopic defect of the pure drug (PB). In the in vivo study, the results of the bioavailability data showed the T_max was prolonged (from 0.65 ± 0.082 hr to 4.83 ± 1.60 hr) and AUC_0-t (from 734.88 ± 230.68 ng/ml.hr to 1153.34 ± 488.08 ng/ml.hr) and was increased respectively for optimum PB-SR tablets when compared with commercial immediate release (IR) tablets. Furthermore, the percentages of in vitro dissolution and in vivo absorption in the rabbits have good correlation. We believe that PB-SR tablets designed in our study would improve defects of PB, decrease the frequency of administration and enhance the retention period of drug efficacy in vivo for personnel exposed to contamination situations in war or terrorist attacks in the future.     

Comparison of two paddle wheel geometries within the filling chamber of a rotary tablet press feed frame with regard to the distribution behavior of a model powder and the influence on the resulting tablet mass

Objective: The purpose of this study was to compare the influence of two different paddle wheel geometries on the distribution behavior of a model powder within the filling chamber of the modified feed frame of a rotary tablet press. Moreover, both paddle wheels were compared regarding their influence on the resulting tablet mass during the tableting process.

Significance: Insights are provided regarding the influence of the paddle wheel geometry on the powder distribution to optimize the die filling process.

Materials and methods: Avicel PH 102 served as model powder. A laser triangulator was used to scan the powder surface level within the feed frame and, combined with the determination of the angle position of the paddle wheel, an in-house written software was used to calculate the powder surface profiles and filling levels. Two experimental setups, one based on the filling chamber filled with a defined amount of powder (offline) and one using the filling chamber during tableting (inline) were applied.

Results: Both paddle wheel geometries caused a significantly different distribution behavior of the powder within the filling chamber. The tablets obtained with the round rod filling wheel showed significantly higher tablet masses and significantly lower standard deviations. The inflow of powder into the filling chamber appeared to be improved with the round rod filling wheel.

Conclusions: Under the applied experimental conditions, the round rod filling wheel showed obvious advantages compared to that with flat rods in terms of the uniformity of tablet masses and the extent of die filling.     

Influence of different parameters and their coupled effects on the stability of alumina nanofluids by a fractional factorial design approach

Nanofluids have been introduced as new-generation fluids able to improve energy efficiency in heat exchangers. However, stability problems related to both agglomeration and sedimentation of nanoparticles have limited industrial-level scaling. A fractional factorial experimental 2^k?1 design was applied in order to evaluate the effects of nanoparticle concentration, surfactant type and concentration, ultrasonic amplitude as well as ultrasonic time on the stability of alumina (Al₂O₃) nanofluids. Commercial alumina nanoparticles (particle diameter <50 nm) were dispersed in deionized water using ultrasonic probe dispersion equipment. Sodium dodecylbenzenesulfonate (SDBS) and cetyltrimethylammonium bromide (CTAB) were used as surfactants. The stability of the nanofluids in static mode was monitored by visual inspection and UV visible spectroscopy. The results of the experimental design showed that the coupled effects between surfactant type and surfactant concentration and between ultrasonication tip amplitude and ultrasonication time had the most pronounced effects on nanofluid stability. The experimental conditions providing the best stability were 0.5 wt% of Al₂O₃, CTAB, critical micelle surfactant concentration, 30% ultrasonic amplitude and 30 min of ultrasonication.     

Numerical and experimental investigation of mixed‐mode fracture parameters on silicon nitride using the Brazilian disc test

Engineering applications of ceramics can often involve mixed‐mode conditions involving both tensile and shear loading. Mixed‐mode fracture toughness parameters are evaluated for applicability to ceramics using the Brazilian disc test on silicon nitride. Semi‐elliptical centrally located surface flaws are induced on the disc specimens using Vickers indentation and compression loaded to fracture with varying levels of mode mixity. The disc specimens are modelled via 3D finite element analysis and all three modes of stress intensity factors computed along the crack front, at failure load. We present a numerical and experimental investigation of four widely used mixed‐mode fracture criteria and conclude that the critical strain energy release rate criterion is simple to implement and effective for silicon nitride under mixed‐mode conditions.     

Using response surface design to determine the optimal parameters of genetic algorithm and a case study

Genetic algorithms (GAs) are efficient stochastic search techniques for approximating optimal solutions within complex search spaces and used widely to solve NP-hard problems. Genetic algorithm includes a number of parameters whose different levels strictly affect the performance of the algorithm. The general approach to determine the appropriate parameter combination of GA depends on too many trials of different combinations, and the best one of them that produces good results is selected for the programme, which would be used for problem solving. A few researchers studied on the parameter optimisation of GA. In this paper, response surface-dependent parameter optimisation is proposed to determine the optimal parameters of GA. Results are tested for benchmark problems that are most common in mixed-model assembly line balancing problems of type-I.     

An experimental approach to determining the residual lifetimes of wheelset axles on a full-scale wheel-rail roller test rig

The paper describes an experimental method for determining the residual lifetime of wheelset axles which was developed and proved. The procedure includes all necessary steps: crack initiation from an artificially generated surface defect, monitoring of crack growth, and specification of the end-of-test criterion. The crack propagation tests described in this paper were carried out on a complete wheelset that was installed on a full-scale wheel-rail roller test rig using a measured load spectrum. During both the test planning and test implementation phases, considerable attention was paid to the complex processes involved in crack propagation in wheelset axles. In addition to axle material and design issues, important factors that have to be taken into account include sequence effects, the reliability of load cycle omission strategies to reduce the overall duration of testing, static stresses introduced by press-fitting procedures and residual stresses caused by manufacturing processes, and crack closure effects. The results obtained indicate that the method produces reliable results that are of practical relevance. Examples were also presented that indicated how far experimentally determined residual axle lifetimes could still differ from lifetimes calculated using current fracture mechanics modelling techniques.     

DEM study of the effect of impeller design on mixing performance in a U-shape ribbon mixer

The mixing of powders in a U-shape mixer is significantly influenced by the mixer design, especially impellers, but the studies on the mixing processes are still insufficient. In this study, the effect of impeller designs on mixing performance in an industrial-scale U-shaped ribbon mixer is studied using DEM simulations. Three impeller designs are studied: 2-bladed impeller spiralling in the same direction (i.e., Design I) and the opposite direction (i.e., Design II), and 4-bladed impeller (i.e., Design III). Different particle mixing behaviours in three different impeller designs are studied in aspects of mixing status, particle path line, velocity distribution, and forces. The radial direction has the highest dispersion coefficient while the axial direction has the lowest dispersion coefficient. Most particles in the mixers are imposed a weak force. Design III shows the best mixing performance among the three with the front-by-back and top-by-bottom loading used. Design II shows a better mixing performance used than Design I and III with the side-by-side loading but takes a longer time to reach the stable status. This work evaluates the effect of different impeller designs on the mixing performance in an industrial-scale U-shaped ribbon mixer and provides an effective way to assist industrial design in an economical and safe manner.     

High shear wet granulation: Improved understanding of the effects of process variables on granule and tablet properties of a high-dose,high-hydrophobicity API based on quality by design and multivariate analysis approaches

High shear wet granulation (HSWG), as a widely used granulation technology, has been studied extensively. However, for the HSWG of formulations containing hydrophobic components, the influence of process variables on the properties of granules and tablets has not been reported. In the present study, based on a combination of quality by design and multivariate analysis (MVA) approaches, quercetin with high-dose and high-hydrophobicity was used to study the relationship between process variables, granule properties, and tablet properties in HSWG systematically. Control and response variables were determined using risk assessment. The optimal fitting empirical models established by Box-Behnken design showed that the liquid to solid ratio and impeller speed were the most important factors, which affected all product properties except Carr’s index and yield pressure. Instead, the influence of wet massing time was relatively small (only the effects on yield, granule size, granule hardness, and compression ratio were significant). Then, the process design space was obtained by limiting the related critical quality attributes, which was verified effectively. Scanning electron microscope images showed that smooth granules were produced using higher process parameters, whereas rough and porous granules resulted at lower process parameters. Furthermore, the MVA results demonstrated that increasing the granule hardness led to an increase in the compression ratio and a decrease in tensile strength of the tablets. Tablet fragility and disintegration time were mainly affected by granule density and bulk density, respectively, and both were negatively correlated. The established research paradigm is not only conducive to the successful development of quercetin products, but also provides valuable guidance for improving HSWG–based product development with such formulation characteristics.     

An experimental investigation as to the effect of cutting parameters on roundness error and surface roughness in cylindrical grinding

This paper presents the results of an experimental investigation as to the effects of grinding parameters on roundness error and surface roughness in cylindrical grinding. Many variables including the wheel materials, wheel loading and dressing, workpiece metallurgy, work drive mechanisms, work holding methods, coolant types, feeds and speeds, machine stiffness and age, surface conditions, centre conditions, floor vibrations all influence the quality of ground parts. However, the composite sum of these grinding parameters creates static and dynamic forces. It is obvious that the roundness error and surface roughness are created by many parameters, but in this study, only the effects of the depth of cut, work speed and feed rate which create the grinding forces in cylindrical grinding are investigated. The grinding experiments were planned according to the principles of orthogonal arrays (OAs), developed by Taguchi, and were performed so as to understand the effects of these parameters on roundness error and surface roughness. The experimental data was analysed by using statistical tools: the percent contribution from an analysis of variance (ANOVA) and the correlation between machining parameters with roundness error (R) and also surface roughness (Ra). Roundness was found to be the most related with the cutting speed, grinding force and depth of cut, while surface roughness is related to feed rate and work speed.     

Proposed method to test the relative seal strength of plastic bottles and its use in optimizing sealing parameters

A test method for measuring the strength of the seal on a flexible bottle is proposed. The method measures seal strength as the compression force applied to the side of the bottle required to make the seal fail. The technique has the advantage of using standard equipment and reproduced failure conditions as closely as possible. The method was used to compare the seal strengths of a foil laminate heat-seal on a retortable gamma bottle under various sealing conditions. The results for various sealing pressures, temperatures and times are reported and optimum conditions are identified.     

Using a linear systems model to assess the influence of some design,constructional and measurement parameters on the performance of NDT probe assemblies

Single and multidimensional models of the piezoelectric transducer are used to evaluate the performance of NDT probe assemblies. Based on a linear systems approach, the models are used to highlight the influence of electrical, mechanical and piezoelectric parameters on probe behaviour through a series of simulation diagrams. Where necessary, techniques for the assessment, measurement and calibration of the probe system are recommended. It is intended that this work should complement that of other workers and may eventually lead to an improved understanding of NDT probe performance and the important factors which link this to the external electrical and mechanical parts of any probe system.     

An investigation on the impact fatigue characteristics of valve leaves for small hermetic reciprocating compressors in a new automated test system

This paper presents an investigation on the impact fatigue characteristics of valve leaves that are prevalently used in hermetic reciprocating compressors especially for the household type refrigerators. A unique automated impact fatigue test system has been designed and produced, which enables to carry out impact fatigue tests of the compressor valve leaves under the desired impact velocities. The test system incorporates a noncontact actuation, a data acquisition system and an acoustic‐based damage detection technique, which continuously monitors the health of the structure. The damage detection system allows parametrical investigation on the impact fatigue life by detecting any possible damage and automatically terminating the test. The investigation relates the impact fatigue lifetime of the valve leaves with the impact velocity, asymmetrical impact, operation temperature, material type (carbon strip steel, stainless strip steel and new stainless strip steel grade) and tumbling operation duration. The observations show that the cracks have initiated from the edges of the valve leaf where is in contact with the valve plate. Subsequently, the cracks initially have propagated in the radial direction inwards the center of the impact area. Various failure cases have been resulted in by either a single crack or inter‐related multiple cracks. Microscopic and metallographic observations have been performed on the specimens to enhance the understanding of the damage mechanisms. The investigation and introduced test system guide the design optimization of the valve leaves in terms of compressor performance due to the energy consumption and lifetime of the valve leaf.     

Using Krylov‐Padé model order reduction for accelerating design optimization of structures and vibrations in the frequency domain

In many engineering problems, the behavior of dynamical systems depends on physical parameters. In design optimization, these parameters are determined so that an objective function is minimized. For applications in vibrations and structures, the objective function depends on the frequency response function over a given frequency range, and we optimize it in the parameter space. Because of the large size of the system, numerical optimization is expensive. In this paper, we propose the combination of Quasi‐Newton type line search optimization methods and Krylov‐Padé type algebraic model order reduction techniques to speed up numerical optimization of dynamical systems. We prove that Krylov‐Padé type model order reduction allows for fast evaluation of the objective function and its gradient, thanks to the moment matching property for both the objective function and the derivatives towards the parameters. We show that reduced models for the frequency alone lead to significant speed ups. In addition, we show that reduced models valid for both the frequency range and a line in the parameter space can further reduce the optimization time. Copyright © 2012 John Wiley & Sons, Ltd.