Stochastic analysis and robust optimization for a deck lid inner panel stamping

FE-simulation and optimization are widely used in the stamping process to improve design quality and shorten development cycle. However, the current simulation and optimization may lead to non-robust results due to not considering the variation of material and process parameters. In this study, a novel stochastic analysis and robust optimization approach is proposed to improve the stamping robustness, where the uncertainties are involved to reflect manufacturing reality. A meta-model based stochastic analysis method is developed, where FE-simulation, uniform design and response surface methodology (RSM) are used to construct meta-model, based on which Monte-Carlo simulation is performed to predict the influence of input parameters variation on the final product quality. By applying the stochastic analysis, uniform design and RSM, the mean and the standard deviation (SD) of product quality are calculated as functions of the controllable process parameters. The robust optimization model composed of mean and SD is constructed and solved, the result of which is compared with the deterministic one to show its advantages. It is demonstrated that the product quality variations are reduced significantly, and quality targets (reject rate) are achieved under the robust optimal solution. The developed approach offers rapid and reliable results for engineers to deal with potential stamping problems during the early phase of product and tooling design, saving more time and resources.     

D-optimal mixture design: optimization of ternary matrix blends for controlled zero-order drug release from oral dosage forms

The objective of the present study was to develop a tablet formulation with a zero-order drug release profile based on a balanced blend of three matrix ingredients. To accomplish this goal, a 17-run, three-factor, two-level D-Optimal mixture design was employed to evaluate the effect of Polyox^™ (X₁), Carbopol® (X₂), and lactose (X₃) concentrations on the release rate of theophylline from the matrices. Tablets were prepared by direct compression and were subjected to an in vitro dissolution study in phosphate buffer at pH 7.2. Polynomial models were generated for the responses Y₄ (percent released in 8 h) and Y₆ (similarity factor or f₂). Fitted models were used to predict the composition of a formulation that would have a similar dissolution profile to an ideal zero-order release at a rate of 8.33% per hour. When tested, dissolution profile of the optimized formulation was comparable to the reference profile (f₂ was 74.2, and n [release exponent] was 0.9). This study demonstrated that a balanced blend of matrix ingredients could be used to attain a zero-order release profile. Optimization was feasible by the application of response surface methodology, which proved efficient in designing controlled-release dosage forms.     

CFD simulation and performance optimization of a new horizontal turbo air classifier

A new horizontal turbo air classifier equipped with two inclined air inlets has been introduced. The flow field and classification performance of the classifier have been investigated using CFD method and response surface methodology (RSM). Simulation results show that the flow field is composed of the primary swirling flow and the secondary upward washing air, and the uniformly distributed swirling flow occupies the classifying chamber. The tangential gas velocity reaches the maximum value on the outer surface of the rotor cage, generating strong centrifugal force for the particle classification. The discrete phase model (DPM) can predict the cut sizes, but cannot present the fish-hook phenomenon. The desirable experimental condition by targeting the cut size of 20 μm and minimizing the classifying accuracy index is, rotor speed of 1373.6 rpm, primary air volume flow rate of 261.8 m³/h and secondary air volume flow rate of 42.4 m³/h. The corresponding fine and coarse fraction loss are less than 1.42% and 7.24%, respectively. This study provides a new strategy to design the horizontal turbo air classifier.     

Application of rotatable central composite design in the preparation and optimization of poly(lactic-co-glycolic acid) nanoparticles for controlled delivery of paclitaxel

Context: Polymeric carrier systems of paclitaxel (PCT) offer advantages over only available formulation Taxol® in terms of enhancing therapeutic efficacy and eliminating adverse effects. Objective: The objective of the present study was to prepare poly (lactic-co-glycolic acid) nanoparticles containing PCT using emulsion solvent evaporation technique. Methods: Critical factors involved in the processing method were identified and optimized by scientific, efficient rotatable central composite design aiming at low mean particle size and high entrapment efficiency. Twenty different experiments were designed and each formulation was evaluated for mean particle size and entrapment efficiency. The optimized formulation was evaluated for in vitro drug release, and absorption characteristics were studied using in situ rat intestinal permeability study. Results: Amount of polymer and duration of ultrasonication were found to have significant effect on mean particle size and entrapment efficiency. First-order interactions of amount of miglyol with amount of polymer were significant in case of mean particle size, whereas second-order interactions of polymer were significant in mean particle size and entrapment efficiency. The developed quadratic model showed high correlation (R² > 0.85) between predicted response and studied factors. The optimized formulation had low mean particle size (231.68 nm) and high entrapment efficiency (95.18%) with 4.88% drug content. The optimized formulation showed controlled release of PCT for more than 72 hours. In situ absorption study showed faster and enhanced extent of absorption of PCT from nanoparticles compared to pure drug. Conclusion: The poly (lactic-co-glycolic acid) nanoparticles containing PCT may be of clinical importance in enhancing its oral bioavailability.     

Crashworthiness design optimization using successive response surface approximations

 Finite Element (FE) method is among the most powerful tools for crash analysis and simulation. Crashworthiness design of structural members requires repetitive and iterative application of FE simulation. This paper presents a crashworthiness design optimization methodology based on efficient and effective integration of optimization methods, FE simulations, and approximation methods. Optimization methods, although effective in general in solving structural design problems, loose their power in crashworthiness design. Objective and constraint functions in crashworthiness optimization problems are often non-smooth and highly non-linear in terms of design variables and follow from a computationally costly (FE) simulation. In this paper, a sequential approximate optimization method is utilized to deal with both the high computational cost and the non-smooth character. Crashworthiness optimization problem is divided into a series of simpler sub-problems, which are generated using approximations of objective and constraint functions. Approximations are constructed by using statistical model building technique, Response Surface Methodology (RSM) and a Genetic algorithm. The approximate optimization method is applied to solve crashworthiness design problems. These include a cylinder, a simplified vehicle and New Jersey concrete barrier optimization. The results demonstrate that the method is efficient and effective in solving crashworthiness design optimization problems. Received: 30 January 2002 / Accepted: 12 July 2002 Sponsorship for this research by the Federal Highway Administration of US Department of Transportation is gratefully acknowledged. Dr. Nielen Stander at Livermore Software Technology Corporation is also gratefully acknowledged for providing subroutines to create D-optimal experimental designs and the simplified vehicle model.     

Formulation optimization and pharmacokinetics evaluation of oral self-microemulsifying drug delivery system for poorly water soluble drug cinacalcet and no food effect

The present research indicated that a new self-microemulsifying drug delivery systems (SMEDDS) were used to reduce the food effect of poorly water-soluble drug cinacalcet and enhance the bioavailability in beagle dogs by oral gavage. Ethyl oleate, OP-10, and PEG-200 was selected as the oil phase, surfactant and co-surfactant of cinacalcet-SMEDDS by the solubility and phase diagram studies. Central Composite Design-Response Surface Methodology was used to determine the ratio of surfactant and co-surfactant, the amount of oil for optimizing the SMEDDS formation. The prepared formulations were further characterized by the droplet size, self-microemulsifying time, zeta potential, polydispersity index (PDI), and robustness to dilution. The in vitro release profile of cinacalcet-SMEDDS was determined in four different release medium and in fasted state and fed state of simulated gastrointestinal fluid. Cinaclcet-SMEDDS were implemented under fed and fasted state in dogs and product REGPARA^® was used as a comparison to the prepared formulation in the pharmacokinetics. The result showed the components of SMEDDS, the amount of oil, the ratio of surfactant, and co-surfactant was optimized using solubility, pseudo-ternary phase diagram studies, and response surface methodology. In vitro drug release studies indicated that the cinacalcet-SMEDDS eliminated the effect of pH variability in release medium and variational gastroenteric environments with improved drug release performance. Pharmacokinetic studies revealed that the profiles of cinacalcet-SMEDDS were similar both in the fasted and fed state compared with commercial product, indicating the formulation significantly promoted the absorption, enhanced bioavailability and had no food effect essentially. It is concluded that poorly water-soluble drug cinacalcet was improved in the solubility and bioavailability by using a successful oral dosage form the SMEDDS, and eliminated food effect as well.     

Anti-hyperuricemic property of 6-shogaol via self-micro emulsifying drug delivery system in model rats: formulation design,in vitro and in vivo evaluation

The prevalence of hyperuricemia is relatively high worldwide, and a great number of patients are suffering from its complications. 6-shogaol, an alkylphenol compound purified from the root of ginger (Zingiber officinale Roscoe), has been proved to possess diverse pharmacological activities. However, its poor aqueous solubility usually leads to low bioavailability, and further clinical applications will be greatly discounted. The current study aimed to formulate a 6-shogaol-loaded-Self Microemulsifying Drug Delivery System (SMEDDS) to amend low aqueous solubility and bioavailability orally, as well as, potentiate the hyperuricemic activity of the 6-shogaol. SMEDDS was developed with central composite design established on a two system components viz., 18.62% W/W ethyl oleate (oil phase) and ratio of tween 80 (surfactant) to PEG 400 (co-surfactant) (1.73:1, W/W). Based on quadratic model, the navigation of the design space could generate spherically-shaped and homogenous droplets with respective mean particle diameter, polydispersity and of 20.00?±?0.26?nm and 0.18?±?0.02. The 6-shogaol-SMEDDS showed significant elevation of cumulative release compared with the free 6-shogaol and more importantly a 571.18% increment in the relative oral bioavailability of the drug. The predominant accumulation of 6-shogaol-SMEDDS in the liver suggested hepatic-targeting potentiality of the drug. Oral administration of 6-shogaol-SMEDDS in hyperuricemic rats also significantly decreased uric acid level and xanthine oxidase activity. Histological studies confirmed formulation groups indeed could provide better protection of kidney than free drug groups. Collectively, these findings indicated that the SMEDDS hold much promise in enhancing the oral delivery and therapeutic efficacy of 6-shogaol.     

Multiobjective optimization of multi-cell sections for the crashworthiness design

Plastic deformation of structures absorbs substantial kinetic energy when impact occurs. For this reason, energy-absorbing components have been extensively used in the structural design of vehicles to intentionally absorb a large portion of crash energy to reduce the severe injury of occupants. On the other hand, high peak crushing force may to a certain extent indicate the risk of structural integrity and biomechanical damage of occupants. For this reason, it is of great significance to maximize the energy absorption and minimize the peak force by seeking for optimal design of these components. This paper aims to design the multi-cell cross-sectional thin-walled columns with these two crashworthiness criteria. An explicit finite element analysis (FEA) is used to derive higher-order response surfaces for these two objectives. Both the single-objective and multi-objective optimizations are performed for the single, double, triple and quadruple cell sectional columns under longitudinal impact loading. A comparative analysis is consequently given to explore the relationship between these two design criteria with the different optimization formulations.     

Quality Management: Tools and Methods for Improvement

Results from the comparison of D, G, and A efficiencies and the scaled average prediction variance IV criterion are presented for the central composite, small composite, Notz, Hoke, Box–Draper, and computer-generated designs. These design optimality criteria are evaluated over the cuboidal design region for three, four, and five design variables.     

Adaptive improved response surface method for reliability-based design optimization

Reliability-based design optimization (RBDO) requires the evaluation of probabilistic constraints (or reliability), which can be very time consuming. Therefore, a practical solution for efficient reliability analysis is needed. The response surface method (RSM) and dimension reduction (DR) are two well-known approximation methods that construct the probabilistic limit state functions for reliability analysis. This article proposes a new RSM-based approximation approach, named the adaptive improved response surface method (AIRSM), which uses the moving least-squares method in conjunction with a new weight function. AIRSM is tested with two simplified designs of experiments: saturated design and central composite design. Its performance on reliability analysis is compared with DR in terms of efficiency and accuracy in multiple RBDO test problems.     

3D preform shape optimization in forging using reduced basis techniques

Three-dimensional preform shape optimization of complex forgings with a weighted summation of multiple basis shapes is presented in this article. Currently, 2D preform shape optimization is well developed; however, in cases in which the parts are neither axisymmetric nor plane strain, 2D assumptions do not hold well. The number of design variables required to define the 3D preform shape is high, making most iterative design methods impractical for shape optimization. The goal here is to make design optimization practical and efficient by developing reduced-order modeling techniques for 3D preform shape optimization. The preform shape is treated as a linear combination of various billet shapes, called basis shapes, with the weights for each basis shape used as design variables, thereby reducing the number of design variables. It is very difficult to obtain the necessary gradient information for 3D forging simulations, so a non-gradient method is used to build the surrogate model on which optimization is performed. The optimization problem is formulated to minimize strain variance while placing constraints on underfill. Representative problems are used to demonstrate the effectiveness of the approach.     

Development of a solid self-microemulsifying drug delivery system (SMEDDS) for solubility enhancement of naproxen

Context: Comparative evaluation of liquid and solid self-microemulsifying drug delivery systems (SMEDDS) as promising approaches for solubility enhancement.

Objective: The aim of this work was to develop, characterize, and evaluate a solid SMEDDS prepared via spray-drying of a liquid SMEDDS based on Gelucire® 44/14 to improve the solubility and dissolution rate of naproxen.

Material and methods: Various oils and co-surfactants in combination with Gelucire® 44/14 were evaluated during excipient selection study, solubility testing, and construction of (pseudo)ternary diagrams. The selected system was further evaluated for naproxen solubility, self-microemulsification ability, and in vitro dissolution of naproxen. In addition, its transformation into a solid SMEDDS by spray-drying using maltodextrin as a solid carrier was performed. Scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and X-ray diffraction (XRD) were used to evaluate the physical characteristics of the solid SMEDDS obtained.

Results: The selected formulation of SMEDDS was comprised of Miglyol 812®, Peceol?, Gelucire® 44/14, and Solutol® HS 15. The liquid and solid SMEDDS formed a microemulsion after dilution with comparable average droplet size and exhibited uniform droplet size distribution. In the solid SMEDDS, liquid SMEDDS was adsorbed onto the surface of maltodextrin and formed smooth granular particles with the encapsulated drug predominantly in a dissolved state and partially in an amorphous state. Overall, incorporation of naproxen in SMEDDS, either liquid or solid, resulted in improved solubility and dissolution rate compared to pure naproxen.

Conclusion: This study indicates that a liquid and solid SMEDDS is a strategy for solubility enhancement in the future development of orally delivered dosage forms.     

Characterization and formulation optimization of solid lipid nanoparticles in vitamin K1 delivery

Background: Solid lipid nanoparticle (SLN) systems have been applied to various drugs and delivery routes. Vitamin K1 is an important cofactor for maintaining hemostasis and preventing hemorrhage. Method: Vitamin K1-loaded SLNs are systematically being developed by optimizing triglycerides and lipophilic and hydrophilic surfactants based on the size and stability of the resulting SLNs. Concentrations of the surfactants, Myverol and Pluronic, were optimized by a central composite design and response surface methodology. Vitamin K1 (phylloquinone) was used as a lipophilic drug in the SLN system to evaluate the potential for oral delivery. Results: Vitamin K1-loaded SLNs had a mean size of 125 nm and a zeta potential of ?23 mV as measured by photon correlation spectroscopy. The prepared SLNs were examined by differential scanning calorimetry and transmission electron microscopy and found to have an imperfect crystalline lattice and a spherical morphology. Effects of ultrasonication duration and drug load on the particle size and entrapment efficiency of the SLNs were also evaluated. Conclusion: More than 85% of the vitamin K1 was entrapped in SLNs when the payload was <5%. The vitamin K1 in SLNs was stable for a 54-h duration in simulated gastric and intestinal fluids. The particle size and vitamin K1 entrapped in the SLN were stable after 4 months of storage at 25°C. The results demonstrated that SLNs prepared herein can potentially be exploited as carriers for the oral delivery of vitamin K1.     

Formulation,optimization, hemocompatibility and pharmacokinetic evaluation of PLGA nanoparticles containing paclitaxel

Objective: Paclitaxel (PTX)-loaded polymer (Poly(lactic-co-glycolic acid), PLGA)-based nanoformulation was developed with the objective of formulating cremophor EL-free nanoformulation intended for intravenous use.

Significance: The polymeric PTX nanoparticles free from the cremophor EL will help in eliminating the shortcomings of the existing delivery system as cremophor EL causes serious allergic reactions to the subjects after intravenous use.

Methods and results: Paclitaxel-loaded nanoparticles were formulated by nanoprecipitation method. The diminutive nanoparticles (143.2?nm) with uniform size throughout (polydispersity index, 0.115) and high entrapment efficiency (95.34%) were obtained by employing the Box–Behnken design for the optimization of the formulation with the aid of desirability approach-based numerical optimization technique. Optimized levels for each factor viz. polymer concentration (X1), amount of organic solvent (X2), and surfactant concentration (X3) were 0.23%, 5?ml %, and 1.13%, respectively. The results of the hemocompatibility studies confirmed the safety of PLGA-based nanoparticles for intravenous administration. Pharmacokinetic evaluations confirmed the longer retention of PTX in systemic circulation.

Conclusion: In a nutshell, the developed polymeric nanoparticle formulation of PTX precludes the inadequacy of existing PTX formulation and can be considered as superior alternative carrier system of the same.     

Ondansetron-loaded chitosan microspheres for nasal antiemetic drug delivery: an alternative approach to oral and parenteral routes

Background: The aim of this study was to develop chitosan microspheres for nasal delivery of ondansetron hydrochloride (OND). Method: Microspheres were prepared with spray-drying method using glutaraldehyde as the crosslinking agent. Microspheres were characterized in terms of morphology, particle size, zeta potential, production yield, drug content, encapsulation efficiency, and in vitro drug release. Results: All microspheres were spherical in shape with smooth surface and positively charged. Microspheres had also high encapsulation efficiency and the suitable particle size for nasal administration. In vitro studies indicated that all crosslinked microspheres had a significant burst effect, and sustained drug release pattern was observed until 24 hours following burst drug release. Nasal absorption of OND from crosslinked chitosan microspheres was evaluated in rats, and pharmacokinetic parameters of OND calculated from nasal microsphere administration were compared with those of both nasal and parenteral administration of aqueous solutions of OND. In vivo data also supported that OND-loaded microspheres were also able to attain a sustained plasma profile and significantly larger area under the curve values with respect to nasal aqueous solution of OND. Conclusion: Based on in vitro and in vivo data, it could be concluded that crosslinked chitosan microspheres are considered as a nasal delivery system of OND.     

Process optimization using sequential design of experiment: A case study

In practice, engineers seek to find reasonable solutions for complex and unstructured problems, which are common in many areas. The workable solutions for these problems are never a one-shot experiment and data analysis procedure. Rather, the proper solution for these problems requires an inductive-deductive process which involves a series of experiments. To teach engineers the sequential learning strategy in solving complex problems, this article presents a case study on the startup of an ethanol–water distillation column that illustrates the scientific process of response surface methodology. The goal of this experiment is generally to find a good, robust solution that produces high grade concentration of ethanol with maximum profit. This case illustrates the sequential application of response surface methodology and consists of an initial fractional factorial design, a steepest ascent design, a full factorial design, and a central composite face-centered cube design. The analysis of the data in the previous steps gives engineers a guidance about the design of experiment in the next step. This study uses the desirability function approach to obtain a compromise optimization between the concentration of ethanol and the profit, which gives a robust solution to the complex problem. Finally, we conduct appropriate confirmation experiments to verify the optimization results. The case study emphasizes the importance of sequential nature and provides a useful guidance for engineers to solve complex problems.     

Electrochemical treatment of deproteinated whey wastewater and optimization of treatment conditions with response surface methodology

Electrochemical treatment of deproteinated whey wastewater produced during cheese manufacture was studied as an alternative treatment method for the first time in literature. Through the preliminary batch runs, appropriate electrode material was determined as iron due to high removal efficiency of chemical oxygen demand (COD), and turbidity. The electrochemical treatment conditions were optimized through response surface methodology (RSM), where applied voltage was kept in the range, electrolyte concentration was minimized, waste concentration and COD removal percent were maximized at 25 degrees C. Optimum conditions at 25 degrees C were estimated through RSM as 11.29 V applied voltage, 100% waste concentration (containing 40 g/L lactose) and 19.87 g/L electrolyte concentration to achieve 29.27% COD removal. However, highest COD removal through the set of runs was found as 53.32% within 8h. These results reveal the applicability of electrochemical treatment to the deproteinated whey wastewater as an alternative advanced wastewater treatment method.     

响应面法优化ZnCl2/AlCl3改性生物炭吸附甲基紫工艺

利用高温热解法制备ZnCl₂/AlCl₃改性生物炭,将其用于吸附甲基紫染料。探究ZnCl₂/AlCl₃-AC投加量、溶液pH、甲基紫浓度、反应时间和吸附温度这5个因素对甲基紫吸附率的影响。利用Plackett-Burman设计联合响应面分析法,筛选优化出对甲基紫吸附率影响较为显著的因素,并探究各因素间的交互影响作用,确定ZnCl₂/AlCl₃-AC吸附甲基紫的最佳工艺条件。结果表明:在选取的五个因素中,对甲基紫吸附率影响显著的因素为ZnCl₂/AlCl₃-AC投加量>甲基紫浓度>吸附温度;其中ZnCl₂/AlCl₃-AC投加量和吸附温度对甲基紫吸附率影响最明显,甲基紫浓度和吸附温度影响最不显著;ZnCl₂/AlCl₃-AC吸附甲基紫最佳工艺条件为:活性炭投加量为47.00 mg、甲基紫溶液浓度为82.00 mg/L、吸附温度为22.90℃,pH为7、反应时间为120 min,其甲基紫吸附率可达到93.04%,与模型预测值的误差仅为3.51%。     

Preparation and evaluation of poly(lactic-co-glycolic acid) microparticles as a carrier for pulmonary delivery of recombinant human interleukin-2: II. In vitro studies on aerodynamic properties of dry powder inhaler formulations

Objective: The aim of this study was the preparation and evaluation of dry powder formulations of recombinant human interleukin-2 (rhIL-2)-loaded microparticles to be administered to the lung by inhalation.

Methods: As indicated in our previous study, the microparticles were prepared by modified water-in-oil-in-water (w₁/o/w₃) double emulsion solvent extraction method using poly(lactic-co-glycolic acid) (PLGA) polymers. The dry powder formulations were prepared with blending of microparticles and mannitol as a coarse carrier. The actual aerodynamic characteristics of the microparticles alone and prepared mixtures with mannitol are evaluated by using the eight-stage Andersen cascade impactor.

Results: Due to the low tapped density of microparticles (<0.4?g/cm³), the theoretical aerodynamic diameter (MMADt) values were calculated (<5 μm) on the basis of the geometrical particle diameter and tapped density values. The lowest tapped density value (0.17?g/cm³) belongs to the cyclodextrin-containing formulation. According to the results obtained using the cascade impactor, the emitted doses for all microparticle formulations were found to be rather high and during the aerosolization for all the formulations except F3 and F5, >90% of the capsule content was determined to be released. However, the actual aerodynamic diameter (MMADa) values were seen to be higher than the MMADt values. The blending of the microparticles with mannitol allowed their aerodynamic diameters to decrease and their fine particle fraction values to increase.

Conclusion: The obtained results have shown that the mixing of rhIL-2-loaded microparticles with mannitol possess suitable aerodynamic characteristics to be administered to the lungs by inhalation.     

Development of a Soluplus budesonide freeze-dried powder for nasal drug delivery

Objective: The aim of this work was to develop an amorphous solid dispersions/solutions (ASD) of a poorly soluble drug, budesonide (BUD) with a novel polymer Soluplus^® (BASF, Germany) using a freeze-drying technique, in order to improve dissolution and absorption through the nasal route.

Significance: The small volume of fluid present in the nasal cavity limits the absorption of a poorly soluble drug. Budesonide is a corticosteroid, practically insoluble and normally administered as a suspension-based nasal spray.

Methods: The formulation was prepared through freeze-drying of polymer-drug solution. The formulation was assessed for its physicochemical (specific surface area, calorimetric analysis and X-ray powder diffraction), release properties and aerodynamic properties as well as transport in vitro using RPMI 2650 nasal cells, in order to elucidate the efficacy of the Soluplus–BUD formulation.

Results: The freeze-dried Soluplus–BUD formulation (LYO) showed a porous structure with a specific surface area of 1.4334?±?0.0178 m²/g. The calorimetric analysis confirmed an interaction between BUD and Soluplus and X-ray powder diffraction the amorphous status of the drug. The freeze-dried formulation (LYO) showed faster release compared to both water-based suspension and dry powder commercial products. Furthermore, a LYO formulation, bulked with calcium carbonate (LYO-Ca), showed suitable aerodynamic characteristics for nasal drug delivery. The permeation across RPMI 2650 nasal cell model was higher compared to a commercial water-based BUD suspension.

Conclusions: Soluplus has been shown to be a promising polymer for the formulation of BUD amorphous solid suspension/solution. This opens up opportunities to develop new formulations of poorly soluble drug for nasal delivery.