Formulation Optimization of Diltiazem Hydrochloride Matrix Tablets Containing Modified Ispaghula Husk Using Factorial Design

The purpose of this study was to develop modified-release tablets of diltiazem hydrochloride using physically modified ispaghula husk as a hydrophilic matrixing agent. Ispaghula husk and water were exposed to heat in a hot air oven or microwave oven. The treated samples were evaluated for swelling and rigid gel formation. Microwave oven treated samples showed rigid gel formation and hence they were systematically studied using 3² factorial design using heating time and amount of water as independent variables. Diltiazem tablets were prepared using treated samples and analyzed for in vitro drug release. A polynomial equation was generated using statistically significant terms such as heating time, X₁, amount of water, X₂, and X₁X₂ and X₁² for predicting time required for 80% drug dissolution. Heating time was found to have a predominant effect in sustaining the drug release. A contour plot is presented for interpretation of the results. The tablets exhibited more axial swelling than radial swelling. The results of F-statistics revealed that the drug release pattern fit well in the Higuchi model.     

Preparation,Optimization, and Characterization of Topotecan Loaded PEGylated Liposomes Using Factorial Design

This study reports the development of liposomal system for a potent antitumor drug, topotecan. To achieve this goal conventional and PEGylated liposomes were prepared according to a factorial design by hydration method followed by extrusion. Parameters such as type of lipid, percentage of cholesterol, percentage of phosphatidylglycerols, percentage of polyethylene glycol (PEG)-lipids, and drug to lipid molar ratio were considered as important factors for the optimizing the entrapment and retention of topotecan inside the liposomes. The size and zeta-potential of the PEGylated and conventional liposomes were measured by particle size analyzer and zeta-potentiometer, respectively. The stability and release characteristics of PEGylated liposome loaded topotecan were compared with conventional liposomes and free topotecan.

The optimized PEGylated [distearoyl phosphatidylcholine (DSPC)/cholesterol/ distearoyl phosphatidylglycerol (DSPG)/ distearoyl phosphatidylethanolamine-PEG₂₀₀₀ (DSPE-PEG₂₀₀₀); 7:7:3:1.28] and related conventional [DSPC/cholesterol/DSPG; 7:7:3] liposomes showed a narrow size distribution with a polydipersity index of 0.15 and 0.10, an average diameter of 103.0 ± 13.1 and 95.2 ± 11.10 nm, and with drug loading of 11.44 and 6.21%, respectively. Zeta-potential was ?10 ± 2.3 and ?22 ± 2.8 mV for PEGylated and conventional liposomes, respectively. The results of stability evaluation showed that the lactone ring of topotecan was notably preserved upon liposome encapsulation. PEGylated liposomes containing topotecan showed a significant decrease (P < 0.001) in release rate in comparison with conventional leptosomes. These results indicate the suitability of PEGylated liposomes in controlling topotecan release.

The prepared liposomes (especially PEGylated liposomes) as those described here may be clinically useful to stabilize and deliver topotecan for the treatment of cancer.     

Investigation of the Stability of Doxorubicin Hydrochloride Using Factorial Design

Abstract

Using drug concentration remaining at a given time as the criterion, a 2⁴x3 factorial design has been employed to investigate the effects of temperature, light, media (aqueous or organic/aqueous), ionic strength and pH on the stability of doxorubicin hydrochloride. Following the application of first order kinetics, and assuming an additive model, the statistical significance of the factors and their interactions have been determined using analysis of variance (ANOVA) on the dependent variable ln(lnC_o-InC). The results indicate that temperature, pH and media are the major factors responsible for the stability of drug. The two-way interaction between temperature and pH, and the three-way interaction between temperature, light and ionic strength are also significant. It is found that doxorubicin is more stable in non-aqueous media at low temperature and low pH values. A combination of darkness and low ionic strength is also conducive to its stability.     

Preparation and Evaluation of Insulin-Loaded Polylactide Microspheres Using Factorial Design

The aim of this work was to study the influence of the concentration and molecular weight of poly(DL-lactide) (PLA) on the characteristics and in vivo biological activity of protein-loaded microspheres. At the same time, an attempt was made to achieve further optimization of the formulation. In the study, insulin was chosen as a model of protein drugs. Nine formulations of injectable insulin-loaded PLA microspheres were prepared using an emulsification and solvent evaporation process according to a factorial design. The trapping efficiency, drug loading, and the drop percentages of blood glucose levels at 24 hr and 72 hr in mice were used to evaluate the formulations. The results showed that PLA molecular weight and, especially, PLA concentration exerted influences on the characteristics and in vivo biological activity of insulin-loaded microspheres. The drug-trapping efficiency increased with the increase of the polymer concentration. The drug loading decreased with the increase of the polymer concentration and was not obviously affected by PLA molecular weight. The drop percentage of blood glucose level at 24 hr increased with the increase of polymer concentration and molecular weight. At 72 hr, the drop percentages of blood glucose levels were slightly increased with the increase of PLA concentration and then significantly decreased after the PLA concentration was above 150 mg/ml. An optimized formulation was prepared with PLA-10k at a concentration of 200 mg/ml. The experimental values of the response variables were close to the predicted values. The results suggest that the in vivo release behavior should be taken into consideration in the design of protein-loaded PLA microspheres.     

Using a Fractional Factorial Design to Increase Direct Mail Response at Mother Jones Magazine

Experimental design methods have been widely applied to problems in manufacturing, but little attention has been given to applying these tools to service problems. In the world of direct marketing, the traditional approach is called A/B testing and involves changing one factor at a time. In this article we address the problem of improving direct mail response at Mother Jones magazine, employing a 16-run two-level fractional factorial design that tests seven factors simultaneously. We compare this design to other possible design choices, discuss sample size determination, and show how we labeled factors to isolate likely two-factor interactions. We discuss the results and conclusions of our study and the benefits to Mother Jones magazine.     

Investigating the Machinability of AISI 420 Stainless Steel Using Factorial Design

This work aims at studying the machining characteristics of high-strength materials using carbide cutting tool inserts at different cutting conditions. This is an essential step in building up an accurate machining information system. The tested material is high-strength stainless steel of the AISI 420 type. Machining tests were carried out using orthogonal cutting conducted to investigate the machining characteristics for high-strength stainless steel AISI 420 at different cutting conditions and tool rake angles. This assessment is achieved by investigating the effect of cutting parameters (cutting speed, feed, depth of cut, and tool geometry) on cutting forces, specific cutting energy, shear angle, coefficient of friction, shear stress, shear strain, and shear strain rate. Empirical equations and a correlation for the behavior of each of the output responses were investigated as a function of the independent variables. Main effect and interaction plot were presented for the most influential factors affecting the main cutting force and the power consumed.     

Factorial Design of Phenylpropanolamine Prolonged Release Tablets Formulations Using Fluid Bed Dryer Granulator

A two level factorial design approach was applied to the formulation of prolonged release phenylpropanolamine tablets using three factors: Ethylacrylate-methyl meth-acrylate co-polymer (Eudragit NE-40D) concentration, Microcrystalline cellulose (Avicel PH102) addition to the tablets formula, and the milling of the granulations before compression. The release rate of the drug was the measured parameter. The rate of drug release was mainly affected by the level of the Eudragit. Avicel promotes the release of the drug, specially at low Eudragit level concentrations. Tablets prepared from unmilled lots showed slower drug release than the corresponding lots of milled granules.     

Evaluation of Chitosan Citrate Complexes as Matrices for Controlled Release Formulations Using a 32 full Factorial Design

Chitosan citrate complexes of several viscocity grades were synthesized, isolated, purified and identified. These complexes were found to form viscous gels of varying viscosities, upon dispersion in water. The ability of these complexes in sustaining drug release from matrix tablets was evaluated using a two factor three level full factorial design with theophylline as the model drug. Viscosity and concentration of the polymer complexes were optimized to achieve the desired in-vitro release profile. In-vitro dissolution characteristics were evaluated in deionized water as the dissolution medium. Data were fit to a quadratic model and polynomial equations were generated and used to predict the optimum formulation composition with desired release characteristics. These complexes were found to be very effective in sustaining the release of theophylline and were directly compressible. The release mechanism appears to be diffusion controlled. Excellent correlation was obtained between predicted and actual release profiles of the optimum formula.     

考虑客车平顺性的悬架参数优化设计

基于车辆系统动力学分析与最优化设计,按照客车行驶平顺性的评价标准,选取后桥上方乘客的加权加速度均方根值为评价指标,根据前、后悬架偏频的设计要求和前、后悬架频率的匹配关系,根据汽车的阻尼比、动挠度、动载荷的设计要求,优化前、后悬架的刚度值与阻尼值,使得加权加速度均方根值最小.仿真结果表明:原车的行驶平顺性得到了改善.     

Evaluation of Xylitab 200, a New Filler/ Binder for Direct Compression, Using Factorial Design

The influence of a number of tablet factors were used to evaluate Xylitab 200®, a new filler/binder for direct compression, following a factorial design. The factors include types of filler/binder, drug, disintegrant, and amount of compression force. In the extended design, two storage conditions were selected. Factors found to have strong influence on tablet qualities from time after manufacturing to storage were drug solubility, amount of compression force, and storage condition. Comparison between tablets manufactured with the new filler/binder and those prepared with a known good filler/binder have shown that the latter is better than the former.     

Evaluation of Chitosan Citrate Complexes as Matrices for Controlled Release Formulations Using a 32 full Factorial Design

Abstract

Chitosan citrate complexes of several viscocity grades were synthesized, isolated, purified and identified. These complexes were found to form viscous gels of varying viscosities, upon dispersion in water. The ability of these complexes in sustaining drug release from matrix tablets was evaluated using a two factor three level full factorial design with theophylline as the model drug. Viscosity and concentration of the polymer complexes were optimized to achieve the desired in-vitro release profile. In-vitro dissolution characteristics were evaluated in deionized water as the dissolution medium. Data were fit to a quadratic model and polynomial equations were generated and used to predict the optimum formulation composition with desired release characteristics. These complexes were found to be very effective in sustaining the release of theophylline and were directly compressible. The release mechanism appears to be diffusion controlled. Excellent correlation was obtained between predicted and actual release profiles of the optimum formula.     

Reliability Based Design Optimization Using Design Explorer

Experimental design methods can be applied to engineering design activities to understand which variables affect the system under consideration, how these variables affect the system, and how to select variable settings that will give uniformly long life to the system. The objective of this paper is to demonstrate the use of Design and Analysis of Computer Experiment (DACE) methods (Sacks, J. et al., 1989) and design optimization via the Surrogate Management Framework (Booker, A. J. et al., 1999; Audet, C. et al., 2000) on reliability optimization problems. Reliabilities are calculated using the Probabilistic Structural Analysis Method (Palle Thoft&#x2013;Christensen and Baker, 1982; Achintya Haldar and Sankaran Mahadevan, 2000), a method for estimation of reliabilities and reliability indices for a structural model given probability distributions for design variables and &#x201C;environmental&#x201D; variables such as loads. By maximizing reliability, or minimizing the probability of failure, we attempt to achieve a minimum cost design that is affected minimally by the variability in the design variables.     

Statistical Optimization of a Controlled Release Formulation Obtained by a Double Compression Process: Application of an Hadamard Matrix and a Factorial Design

A formulation containing an antiinflammatory agent (diclofenac sodium), two inert matrices (ethylcellulose and polyvinyl chloride) and two lubricants (magnesium stearate and talc) was optimized by a double compression process

In a first stage, preliminary trials were performed in order to study the effect of lubricants added before and after precompression

An Hadamard matrix H(8) was applied to estimate the main effects of four parameters: applied force at the upper punch (UPF) during precompression, particle size range after grinding, UPF during the final compression and concentration of ethylcellulose added before the final compression

Following the Hadamard matrix, a factorial design 2² was built. The complete linear models were fitted by regression for each response reflecting the compression behaviour and dissolution kinetics

In an optimal point, the validation was carried out with the area under the dissolution curve, being the major response to be optimized

The dissolution curves were well fitted by the Weibull distribution     

Statistical Optimization of a Controlled Release Formulation Obtained by a Double Compression Process: Application of an Hadamard Matrix and a Factorial Design

Abstract

A formulation containing an antiinflammatory agent (diclofenac sodium), two inert matrices (ethylcellulose and polyvinyl chloride) and two lubricants (magnesium stearate and talc) was optimized by a double compression process

In a first stage, preliminary trials were performed in order to study the effect of lubricants added before and after precompression

An Hadamard matrix H(8) was applied to estimate the main effects of four parameters: applied force at the upper punch (UPF) during precompression, particle size range after grinding, UPF during the final compression and concentration of ethylcellulose added before the final compression

Following the Hadamard matrix, a factorial design 2² was built. The complete linear models were fitted by regression for each response reflecting the compression behaviour and dissolution kinetics

In an optimal point, the validation was carried out with the area under the dissolution curve, being the major response to be optimized

The dissolution curves were well fitted by the Weibull distribution     

汽车悬架及司机座椅动态参数优化

汽车悬架及司机座椅动态参数对汽车行驶的平顺性有着重要影响。本文以八自由度三维空间质弹系统作为汽车振动系统的力学模型，用前后四轮路面随机激励作为系统输入，对车厢及司机座椅的输入功率谱进行分析，在此基础上对该模型的悬架及司机座椅动态参数进行优化，并给出悬架参数及司机座椅参数的优化结果。     

Optimization of a Granulation Procedure for a Hydrophilic Matrix Tablet Using Experimental Design

An experimental design was used in order to optimize a granulation procedure in a high-shear mixer for a hydrophilic matrix tablet formulation. The parameters tested were the amount of water in the hydroalcoholic granulation liquid, the amount of granulation liquid, and the massing time. The amount of granulation liquid was the most important parameter, followed by the amount of water in the granulation liquid. The influence of the massing time was negligible. A granule with a friability below 20% was obtained.     

Particle Size Design Using Computer Optimization Technique

The effect of binder solution (amount and composition) on the mean particle size and its distribution of granule was investigated by using a computer optimization technique. The granules were manufactured by two continuous processes, granulating and sizing using a high-speed mixer granulator and a hammer mill, respectively. The particle size distribution pattern of granules was markedly varied with the change in the amount and composition of the binder solution. The distribution pattern could be well expressed by the log-normal distribution model. For designing the optimal particle, a computer optimization technique was applied to the experimental results obtained in this study. The technique was found to be useful for searching the optimal formula in the practical scale.     

Influence of Hydroxypropyl Methylcellulose Mixture,Apparent Viscosity,and Tablet Hardness on Drug Release Using a 23 Full Factorial Design

ABSTRACT

This study investigates the effects of three factors: (1) use of a mixture of two different grades of hydroxypropyl methylcellulose (HPMC), (2) apparent viscosity, and (3) tablet hardness on drug release profiles of extended-release matrix tablets. The lot-to-lot apparent viscosity difference of HPMC K15M on in vitro dissolution was also investigated. Four test formulations were made, each containing 10% of a very water-soluble active pharmaceutical ingredient (API), 32% HPMC K15M, or a mixture of HPMC K100LV and HPMC K100M, 56% diluents, and 2% lubricants. Each formulation was made at two hardness levels. A 2³ full factorial design was used to study various combinations of the three factors using eight experiments conducted in a randomized order. Dissolution studies were performed in USP apparatus I. The values of t_50% (time in which 50% drug is released) and t_lag (lag time, the time taken by the matrix tablet edges to get hydrated and achieve a state of quasi-equilibrium before erosion and the advance of solvent front through the matrix occur) were calculated from each dissolution profile. The similarity factor (f₂) was also calculated for each dissolution profile against the target dissolution profile. A simple Higuchi-type equation was used to analyze the drug release profiles. Statistical analysis using analysis of variance (ANOVA) and similarity factor (f₂) values calculated from the data indicated no significant difference among the t_50% values and dissolution profiles respectively for all formulations. Within the 3.3–6 kp hardness range investigated, dissolution rates were found to be independent of tablet hardness for all the formulations. Although significantly shorter lag times were observed for the tablets formulated with low- and high-viscosity HPMC mixtures in comparison to those containing a single grade of HPMC, this change had no significant impact on the overall dissolution profiles indicated by the similarity factor f₂ values. From this study it can be concluded that lot-to-lot variability in apparent viscosity of HPMC should not be a concern in achieving similar dissolution profiles. Also, results indicated that within the viscosity range studied (12,000–19,500 cps) an HPMC mixture of two viscosity grades can be substituted for another HPMC grade if the apparent viscosity is comparable. Also, the drug release is diffusion-controlled and depends mostly on the viscosity of the gel layer formed.     

Preparation and In Vitro Evaluation of Controlled Release Hydrophilic Matrix Tablets of Ketorolac Tromethamine Using Factorial Design

Controlled release matrix tablets of ketorolac tromethamine (KT) were prepared by direct compression technique using cellulose derivatives as hydroxypropylmethyl cellulose (HPMC), hydroxyethyl cellulose (HEC), and carboxymethyl cellulose (CMC) in different concentrations (10–20%). The effect of polymer type and concentration was investigated on drug release by 2³ factorial design. For the quality control of matrix tablets, weight deviation, hardness, friability, diameter–height ratio, content uniformity of KT, and in vitro dissolution technique were performed. UV Spectrophotometric method was used to detection of KT in matrix tablets. This method was validated. Dissolution profiles of the formulations were plotted and evaluated kinetically. An increase in polymer content resulted with a slow release rate of drug as was expected. According to the dissolution results, tablets prepared with HPMC + HEC + CMC (F1 and F8) were found to be the most suitable formulation for KT. About 99.27% KT was released from F8 in 7 h.     

基于环境振动测量值的悬索桥结构动力模型修正

以主跨1385米的江阴长江公路大桥为背景，研究利用环境振动测量值进行悬索桥结构有限元模型修正的可行性。采用的模型修正方法以结构特值灵敏度分析为基础，通过迭代求解二次规划问题修正有限元模型参数。根据江阴长江公路大桥的设计图纸建立悬索桥三维有限元模型固有振动分析。同时利用大桥现场环境振动测量值得到一组结构实测模态参数，用以作为有限元模型修正的基准，根据结构特征值灵敏度分析结构选择了一组待修正结构参数并予以修正，修正后有限元模型的动力特征更加趋近于环境振动实测值，最后指出了模型修正不能完全消失大桥结构理论－实测频率差的可能原因。