Improved Multiple Comparisons With a Control in Response Surface Analysis

Quadratic response surface methodology often focuses on finding the levels of some (coded) predictor variables x = (x ₁, x ₂,…, x _k) that optimize the expected value of a response variable y. Typically the experimenter starts from some best guess or “control” combination of the predictors (usually coded to x = 0) and performs an experiment varying them in a region around this center point. The question of interest addressed here is whether any x in the experimental region provides a long-run mean response E(y) preferable to that of the control, and if so, by what amount? This article approaches this question via simultaneous confidence intervals for δ(x) = E(y|x) = E(y|0) for all x within a specified distance of 0. A new method for two or more predictors is introduced that gives sharper intervals than the Scheffé method and also the Sa and Edwards adaptation of the Casella and Strawderman method. The new method does not require a rotatable design and allows for one-sided simultaneous bounds for δ(x). Approximate sample-size savings of the improved method over the Sa and Edwards adaptation of the Casella and Strawderman method ranged from 12%–45% for two-sided intervals and 19%–40% for one-sided intervals for designs with two or three predictors. Approximate sample-size savings of the improved method over the Scheffe method ranged from 14%–47% for two-sided intervals and 22%–62% for one-sided intervals.     

A modified collocation method and a penalty formulation for enforcing the essential boundary conditions in the element free Galerkin method

The Element free Galerkin method, which is based on the Moving Least Squares approximation, requires only nodal data and no element connectivity, and therefore is more flexible than the conventional finite element method. Direct imposition of essential boundary conditions for the element free Galerkin (EFG) method is always difficult because the shape functions from the Moving Least Squares approximation do not have the delta function property. In the prior literature, a direct collocation of the fictitious nodal values & u circ; used as undetermined coefficients in the MLS approximation, u ^h (x) [u ^h (x)=Φ·& u circ;], was used to enforce the essential boundary conditions. A modified collocation method using the actual nodal values of the trial function u ^h (x) is presented here, to enforce the essential boundary conditions. This modified collocation method is more consistent with the variational basis of the EFG method. Alternatively, a penalty formulation for easily imposing the essential boundary conditions in the EFG method with the MLS approximation is also presented. The present penalty formulation yields a symmetric positive definite system stiffness matrix. Numerical examples show that the present penalty method does not exhibit any volumetric locking and retains high rates of convergence for both displacements and strain energy. The penalty method is easy to implement as compared to the Lagrange multiplier method, which increases the number of degrees of freedom and yields a non-positive definite system matrix.     

Appropriate selection of an aggregation inhibitor of fine particles used for inhalation prepared by emulsion solvent diffusion

Abstract

Context: Dry powder inhaler (DPI) formulations have been developed to deliver large amounts of drugs to the lungs.

Objective: Fine particles of a poorly water-soluble drug, the model drug ONO-2921, were prepared by the emulsion solvent diffusion (ESD) method for use in a DPI.

Methods: The effects of additives on the fine particle formation of ONO-2921 were estimated when droplets of an ethanolic drug solution were dispersed into aqueous media containing various additives. Subsequently, the suspensions were freeze-dried to create powdered samples to estimate the inhalation properties using a twin impinger and an Andersen cascade impactor.

Results: This simple ESD method produced submicron-sized ONO-2921 particles (approximately 600?nm) in combination with suitable additives. In addition, the freeze-dried powder produced using additives exhibited superior in vitro inhalation properties. Among these methods, the freeze-dried powder produced with 0.50% weight/volume one type of polyvinyl alcohol (PVA-205) displayed the most efficient features in the fine particle fraction (FPF). These results could be explained by the stabilization of the ONO-2921 suspension by PVA-205, indicating that PVA-205 acts as an aggregation inhibitor of fine particles.

Conclusions: The ESD method, in combination with appropriate types and amounts of additives, may be useful for preparing a DPI suitable for delivering drugs directly to the lungs without the assistance of carrier particles.     

A study of ultrasonic velocity and attenuation on polycrystalline Ni-Zn ferrites

Polycrystalline NiZn ferrites with different grain sizes (1.2 (Am to 10.2 (Am) were prepared by the usual ceramic method. The magnetic properties were measured at room temperature. The ultrasonic velocity and attenuation were measured on Ni-Zn ferrite by using the pulse transmission method at 1 MHz, in the temperature range 300–600 K. The velocity was found to be slightly sample dependent at room temperature and decreased with increasing temperature, except near the Curie temperature, T _c ,where a small anomaly was observed. The longitudinal attenuation (α ₁ )at room temperature was found to be more sample dependent. The temperature variation of ultrasonic longitudinal attenuation exhibited a broad maximum around 400 K and a sharp maximum just below Curie temperature ( T _c ).The above observations were carried out in the demagnetized state. The application of a 380 mT magnetic field allowed us to reach the saturated state of the sample at all the measuring temperatures. The anomaly observed in the thermal variation of velocities (longitudinal and transverse) and attenuation has been qualitatively explained with the help of the temperature variation of the magneto-crystalline anisotropy constant.     

The Lie-Group Shooting Method for Solving Classical Blasius Flat-Plate Problem

In this paper, we propose a Lie-group shooting method to deal with the classical Blasius flat-plate problem and to find unknown initial conditions. The pivotal point is based on the erection of a one-step Lie group element$\mathbf G(T) and the formation of a generalized mid-point Lie group element$\mathbf G(r). Then, by imposing G(T) = G(r) we can derive some algebraic equations to recover the missing initial conditions. It is the first time that we can apply the Lie-group shooting method to solve the classical Blasius flat-plate problem. Numerical examples are worked out to persuade that the novel approach has better efficiency and accuracy with a fast convergence speed by searching a suitable r ∈(0, 1) with the minimum norm to fit the targets.     

Numerical solution of Cauchy type singular integral equations with logarithmic weight,based on arbitrary collocation points

Singular integral equations with a Cauchy type kernel and a logarithmic weight function can be solved numerically by integrating them by a Gauss-type quadrature rule and, further, by reducing the resulting equation to a linear system by applying this equation at an appropriate number of collocation points x _k. Until now these x _k have been chosen as roots of special functions. In this paper, an appropriate modification of the original method permits the arbitrary choice of x _k without any loss in the accuracy. The performance of the method is examined by applying it to a numerical example and a plane crack problem.     

Preparation and evaluation of wet-milled usnic acid nanocrystal suspension for better bioaffinity

Objective: To prepare a new nanosystem of usnic acid (UA) with higher solid content and higher bioavailability.

Methods: Usnic acid nanocrystal suspensions were prepared by the wet milling method, and then the particle size distributions and zeta potential were determined with the Nano ZS90 laser diffraction particle size analyzer. The particles morphology of UA-NCS were observed by scanning electron microscopy method. In addition, solubility and dissolution of UA-NCS in water and phosphate buffer solution were determined in vitro, analyzed by the HPLC method, and then the cellular uptake and pharmacokinetic were carried out on the Caco-2 cells and rats, analyzed by the UPLC-MS/MS method.

Results: Particle size distributions and zeta potential of the UA nanocrystal suspension were 268.7?±?4.0?nm and –23.1?±?0.7?mV, respectively. About the dissolution rate of UA, nanosuspension were significantly faster and higher than common suspension in water and phosphate buffer. And in cellular uptake experiments, the ratio of the maximum amount of drug in unit protein of UA nanosuspension to common suspension was 2.8 times. In rats, oral absorption of nanocrystal UA were superior to the ordinary groups, with the 348% of the maximum concentration and 181% of the AUC after the same dosage administration.

Conclusion: The wet-milling technique was suitable for the preparation of UA nanocrystal suspension, and a new nanosystem of UA with higher solid content and higher bioavailability was achieved.     

Enhanced solubility of piperine using hydrophilic carrier-based potent solid dispersion systems

Context: Piperine alkaloid, an important constituent of black pepper, exhibits numerous therapeutic properties, whereas its usage as a drug is limited due to its poor solubility in aqueous medium, which leads to poor bioavailability.

Objective: Herein, a new method has been developed to improve the solubility of this drug based on the development of solid dispersions with improved dissolution rate using hydrophilic carriers such as sorbitol (Sor), polyethylene glycol (PEG) and polyvinyl pyrrolidone K30 (PVP) by solvent method. Physical mixtures of piperine and carriers were also prepared for comparison.

Methods: The physicochemical properties of the prepared solid dispersions were examined using SEM, TEM, DSC, XRD and FT-IR. In vitro dissolution profile of the solid dispersions was recorded and compared with that of the pure piperine and physical mixtures. The effect of these carriers on the aqueous solubility of piperine has been investigated.

Results: The solid dispersions of piperine with Sor, PEG and PVP exhibited superior performance for the dissolution of piperine with a drug release of 70%, 76% and 89%, respectively after 2?h compared to physical mixtures and pure piperine, which could be due to its transformation from crystalline to amorphous form as well as the attachment of hydrophilic carriers to the surface of poorly water-soluble piperine.

Conclusion: Results suggest that the piperine solid dispersions prepared with improved in vitro release exhibit potential advantage in delivering poorly water-soluble piperine as an oral supplement.     

In vitro dissolution method fitted to in vivo absorption profile of rivaroxaban immediate-release tablets applying in silico data

Objective: This study aimed to develop and validate an in vitro dissolution method based on in silico–in vivo data to determine whether an in vitro–in vivo relationship could be established for rivaroxaban in immediate-release tablets.

Significance: Oral drugs with high permeability but poorly soluble in aqueous media, such as the anticoagulant rivaroxaban, have a major potential to reach a high level of in vitro–in vivo relationship. Currently, there is no study on scientific literature approaching the development of RIV dissolution profile based on its in vivo performance.

Methods and results: Drug plasma concentration values were modeled using computer simulation with adjustment of pharmacokinetic properties. Those values were converted into drug fractions absorbed by the Wagner–Nelson deconvolution approach. Gradual and continuous dissolution of RIV tablets was obtained with a 30?rpm basket on 50?mM sodium acetate +0.2% SDS, pH 6.5 medium. Dissolution was conducted for up to 180?min. The fraction absorbed was plotted against the drug fraction dissolved, and a linear point-to-point regression (R²?=?0.9961) obtained.

Conclusion: The in vitro dissolution method designed promoted a more convenient dissolution profile of RIV tablets, whereas it suggests a better relationship with in vivo performance.     

An evaluation of the pharmacokinetics of tiotropium following a single-dose inhalation in healthy subjects using an ultra-sensitive bioanalytical method

Abstract

Objective and significance: The systemic bioavailability of tiotropium following administration via inhalation is known to be very low. A validated ultra-sensitive bioanalytical method with the lowest lower limit of quantitation (LLOQ) was developed and used to evaluate the complete pharmacokinetic profile of tiotropium.

Methods: This was a pharmacokinetic study performed in 18 healthy subjects. Each subject was administered a dose of 18?mcg of tiotropium from a dry powder inhaler (DPI). The subjects’ plasma tiotropium concentrations were assayed with LLOQ of 0.1?pg/mL.

Results: The results showed a mean C_max of 4.98 ± 3.55?pg/mL, and a median (t_max) of 3.6?minutes (range: 1.8–12?minutes). The means for area under the concentration–time curve (AUC) from time zero hours to infinity (AUC_inf) and AUC from time zero hours to the time of the last measurable tiotropium concentration (AUC_t) were 51.11 ± 27.4?pg*h/mL and 37.37 ± 23.38?pg*h/mL, respectively. The mean apparent elimination half-life (t_1/2) was 68.02 ± 24.55?hours. This calculated half-life is longer than what others have reported where a less sensitive LLOQ was used.

Conclusion: The lower LLOQ enabled further insight into the pharmacokinetics of tiotropium that was not possible with other analytical methods. With this method, we were able to quantify tiotropium concentrations as early as one minute following drug administration and up to 144?hours after dosing. The application of this method will allow for studies to be designed properly and enable further investigations into the pharmacokinetics of tiotropium.     

Total energy calculation of perovskite,BaTiO<Subscript>3</Subscript>, by self-consistent tight binding method

We present results of numerical computation on some characteristics of BaTiO3 such as total energy, lattice constant, density of states, band structure etc using self-consistent tight binding method. Besides strong Ti-O bond between 3 d on titanium and 2 p orbital on oxygen states, we also include weak hybridization between the Ba 6 s and O 2 p tates. The results are compared with those of other more sophisticated methods.     

An LGEM to Identify Time-Dependent Heat Conductivity Function by an Extra Measurement of Temperature Gradient

We consider an inverse problem for estimating an unknown heat conductivity parameter α(t) in a heat conduction equation T_t(x,t) = α(t)T_xx(x,t) with the aid of an extra measurement of temperature gradient on boundary. Basing on an establishment of the one-step Lie-group elements G(r) and G(l) for the semi-discretization of heat conduction equation in time domain, we can derive algebraic equations from G(r) = G(l). The new method, namely the Lie-group estimation method (LGEM), is examined through numerical examples to convince that it is highly accurate and efficient; the maximum estimation error is smaller than 10^-5 for smooth parameter and for discontinuous and oscillatory parameter the accuracy is still in the order of 10^-2. Although the estimation is carried out under a large measurement noise, the LGEM is also stable.     

Continuous low-dose feeding of highly active pharmaceutical ingredients in hot-melt extrusion

Context: Manufacturing solid low-dose pharmaceutical products has always the homogeneity challenge. In continuous manufacturing, there is the additional challenge of feeding active pharmaceutical ingredient (API) dry powder at low rates. This paper presents a method for feeding API particles into a continuous extrusion process using a suspension. The challenges for feeding and the product homogeneity are both addressed.

Objective: The objective of this study is to demonstrate the feasibility of manufacturing low-dose extrudates by feeding the API particles in a diluted anti-solvent suspension.

Materials and methods: Extrudates with an Ibuprofen content of 0.021% and 0.043% (w/w) were prepared by feeding a 0.9% w/w suspension of Ibuprofen particles into a Coperion extruder.

Results and discussion: The homogeneity (RSD) of extrudates was tested during a time span of 30?min and had values between 2% and 7%.

Conclusion: Feeding particles in an anti-solvent suspension offers a simple feeding option for API and minor components which yield products of desired homogeneity. The liquid feeding approach offers a simplified process with enhanced process control possibilities.     

Synthesis and luminescence properties of Eu2+-activated Ca4Mg5(PO4)6 for blue-emitting phosphor

Ca ₄ Mg ₅ (PO ₄ ) ₆ :Eu²⁺^{\boldsymbol{2+}} blue-emitting phosphor was synthesized by the combustion-assisted synthesis method under reductive atmosphere. The products were characterized by powder X-ray diffraction (XRD), transmission electron microscopy (TEM) and photoluminescence (PL) spectrum. XRD analysis confirmed the formation of Ca ₄ Mg ₅ (PO ₄ ) ₆ pure phase. Photoluminescence results showed that the phosphor can be excited efficiently by UV light range from 230–400 nm, and then exhibited bright blue light with peak wavelength at 431 nm. It is a very promising candidate as a blue-emitting phosphor for potential applications in display devices.     

Effect of the preparation route,PEG and annealing on the phase stability of Fe3O4 nanoparticles and their magnetic properties

Fe₃O₄ nanoparticles are synthesised via two different methods: (1) co-precipitation of Fe²⁺ and Fe³⁺ ions and (2) oxidative alkaline hydrolysis of Fe²⁺ ions under atmospheric pressure using different protective agents (PEG 200 and PEG 3000) and urea as a base. The preparation method and the polyethylene glycol (PEG) used are concurrently affecting the phase stability of the formation of the iron oxides: the co-precipitation method using PEG 200 (E4a) or PEG 3000 (E4b) leads to the formation of different ratios of Fe₂O₃ and Fe₃O₄, whereas the oxidative hydrolysis of Fe²⁺ using PEG 200 gives Fe₃O₄ (E2) powder as a major product. The average crystallites size of E4a and E4b is almost identical, i.e. around 19?nm but the saturation magnetisation of E4b is three times larger than that of E4a. The sample E2 shows the highest saturation magnetisation value 74?emu/g, with an average crystallites size of 71?nm. Transmission electron microscopy analysis confirmed that the E2 sample shows the presence of needles crystals with typical sizes around 10 and 50?nm and its selected area diffraction (SAD) shows a typical diffraction of the spinel structure of magnetite. On the other hand, E4b sample shows elongated nanoparticles with typical sizes around 24?nm and its SAD confirmed the presence of a mixture of Fe₂O₃ and Fe₃O₄ as many dispersed spots were obtained.     

Development and characterization of a mucoadhesive sublingual formulation for pain control: extemporaneous oxycodone films in personalized therapy

Objective: The aim of this work was the development of mucoadhesive sublingual films, prepared using a casting method, for the administration of oxycodone.

Materials and methods: A solvent casting method was employed to prepare the mucoadhesive films. A calibrated pipette was used to deposit single aliquots of different polymeric solutions on a polystyrene plate lid. Among the various tested polymers, hydroxypropylcellulose at low and medium molecular weight (HPC) and pectin at two different degrees of esterification (PC) were chosen for preparing solutions with good casting properties, capable of producing films suitable for mucosal application.

Results and discussion: The obtained films showed excellent drug content uniformity and stability and rapid drug release, which, at 8?min, ranged from 60% to 80%. All films presented satisfactory mucoadhesive and mechanical properties, also confirmed by a test on healthy volunteers, who did not experience irritation or mucosa damages. Pectin films based on pectin at lower degrees of esterification have been further evaluated to study the influence of two different amounts of drug on the physicochemical properties of the formulation. A slight reduction in elasticity has been observed in films containing a higher drug dose; nevertheless, the formulation maintained satisfactory flexibility and resistance to elongation.

Conclusions: HPC and PC sublingual films, obtained by a simple casting method, could be proposed to realize personalized hospital pharmacy preparations on a small scale.     

Application of photoconductivity decay and photocurrent generation methods for determination of minority carrier lifetime in silicon

Minority carrier lifeline, τ, is one of the most important parameters which has a decisive effect on the performance of silicon devices based on excess carriers. The value of τ is greatly affected by the presence of impurities and defects in silicon and its value provides a fair indication of quality of the material. Photoconductivity decay (PCD) and photocurrent generation (PCG) methods are simple and low cost methods of measurement of minority carrier lifetime in silicon wafers. However, their application requires care. The PCD method can give quite misleading results in case of polycrystalline wafers if there exists potential barriers at the grain boundaries which may affect majority carrier mobility significantly. PCG needs creation of an inducedp ₊-p-n ₊ structure of substantially good quality that should not degrade with time. For PCG method the T measurement under vacuum conditions provides correct and consistent results.     

Characterization of phyto-nanoparticles from Ficus krishnae for their antibacterial and anticancer activities

Background: Ovarian cancer is deadliest of fifth leading cause of death in women worldwide. This is due to advanced-stage disease rate associated with the development of chemoresistance. Hence, the current study emphasizes the process of synthesis of silver nanoparticles (AgNPs) from green chemistry method. Ficus krishnae is a perennial plant, native to India, used in folklore medicine to treat various diseases.

Objective: For the development of reliable, ecofriendly, less expensive process for the synthesis of AgNPs against bacterial and ovarian cancer.

Methodology: The synthesis of silver nanoparticles from stem bark of Ficus krishnae was carried out. The synthesized nanoparticles are subjected by UV-Vis spectrophotometer, scanning electron microscopy (SEM), X-ray diffraction (XRD) analysis and FTIR analysis. The antibacterial efficacy also determined by disc diffusion method, MIC, CFU and growth curve. In vitro cytotoxicity effect of aqueous extract and AgFK nanoparticle in ovarian cancer cell line by MTT assay was performed.

Results: The formation of AgNPs was confirmed by UV-VIS spectroscopic absorbance shown that peak at 435?nm. XRD photograph has indicated the face-centered cubic structure of the synthesized AgNPs. SEM study demonstrated that the size from 160 to 260?nm with interparticle distance, whereas shape is spherical. The particle size were ranging from 15 to 28?nm determined by XRD pattern. The antibacterial and cytotoxicity activity of this nanoparticle has showed a potential activity when compared with standards.

Conclusion: The present study confirms that the biosynthesized AgNPs from Ficus krishnae stem bark extract have a great affiance as antibacterial and anticancer agent.     

Computation of X-ray powder diffractograms of cement components and its application to phase analysis and hydration performance of OPC cement

The importance of computed X-ray diffraction patterns of various polymorphs of alite (M₃, T₁, R{\bf \emph{M}_{3}, \emph{T}_{1}, \emph{R}}), belite (b\boldsymbol{\beta}, g\boldsymbol{\gamma}), aluminate (cubic, orthorhombic), aluminoferrite, gypsum and hemihydrate in the quantitative phase analysis of cement and its early stage hydration performance is highlighted in this work with three OPC samples. The analysis shows that the predominant silicate phases present in all the samples are M₃{\bf \emph{M}_{3}}-alite phase and b\boldsymbol{\beta}-belite phase, respectively. Both cubic and orthorhombic phases of C ₃ A, brownmillerite, gypsum and hemihydrates are present at different levels. Quantitative phase analysis of cement by Rietveld refinement method provides more accurate and comprehensive data of the phase composition compared to Bogue method. The comparative hydration performance of these samples was studied with w/c{\bf \emph{w/c}} ratio, 0·5 and the results are interpreted in the light of difference in phase compositions viz. b\boldsymbol{\beta}-C ₂ S/C ₃ S ratio, fraction of finer cement particles present in the samples and theoretical modeling of C ₃ S hydration.