Novel insights into controlled drug release from coated pellets by confocal Raman microscopy

The development of novel therapeutics with improved efficacy implies increasing complexity of drug delivery systems, which in turn require advanced methods for their analytical characterization. Among these systems, pellets represent upcoming carrier systems, which show several advantages like simplified dosing and improved compliance among children and the aged population. However, rational development of such systems is hampered by the lack of non‐destructive, chemically selective analytical insight into compound distribution and drug release mechanisms. The aim of this study was to evaluate confocal Raman microscopy (CRM) for investigation of coated drug‐loaded pellets based on visualization of compound distribution and elucidation of drug release mechanisms. Three complementary approaches were applied for pellet characterization: analysis of cross sections after bisectioning, non‐invasive visualization of the pellet surface, and virtual cross sectioning in x–z direction. As the surface of such pellets is structured, a complementary approach of optical topography and CRM was applied for three‐dimensional analysis. Based on the individual Raman peak patterns, the drug and excipients forming the matrix of the pellets and the film coating were successfully visualized with high spatial resolution, verifying homogeneous drug distribution and intact polymer coating of the pellet. Further, analysis of the pellets after certain time intervals during drug release testing revealed pore formation in the polymer coating facilitating drug release and preceding drug depletion in the pellets matrix. CRM represents an upcoming technique for analytical characterization of carrier systems and elucidation of their complex drug release mechanisms, thus supporting rational development of novel therapeutics. Copyright © 2016 John Wiley & Sons, Ltd.     

Synchrotron μ‐XRF study on compositional uniformity of uranium–thorium oxide pellets prepared by different processes

A μ‐XRF study to assess the distribution of uranium and thorium in (U,Th)O₂ pellets covering the composition of advanced heavy water reactor (AHWR) fuel pellets prepared by powder metallurgical compaction (PMC) and coated agglomerate pelletization (CAP) routes was made using micro‐focus beam line (BL‐16) of Indus‐2 synchrotron radiation facility. The methodology thus developed was successfully applied to these pellets. The study reveals that the uranium distribution in pellets prepared by PMC route is uniform, whereas the pellets prepared through CAP route have a wide range of compositional variation. In addition, the uniformity in CAP route‐prepared pellets improves with increase in the relative amount of uranium in the pellets. The sample preparation in present methodology is very simple compared with scanning electron microscopy. The study reveals the utility of synchrotron‐based μ‐XRF for fuel pellet characterization of AHWR reactors. Alhough CAP route of fuel pellet preparation requires less exposure of personnel to high radiation dose, the non‐uniformity in the fuel pellet must be considered when using these pellets in reactors. Copyright © 2014 John Wiley & Sons, Ltd.     

Accurate determination of polyethylene pellet density using transmission Raman spectroscopy

In this study, transmission Raman spectroscopy was explored for the direct measurement of the density of packed polyethylene (PE) pellets. A simple and direct transmission Raman measurement of packed, solid granules or pellet samples without pretreatment is greatly advantageous. Initially, the optimal packing thickness of PE pellets for transmission Raman measurement was determined by investigating the reproducibility of triplicate spectra collected by varying the thickness from 2 to 9 cm. Once determined, transmission Raman spectra were collected for 25 different grades of PE pellets and the partial least squares method was used to determine the sample density. The resulting accuracy was 0.00067 g·cm⁻³, while that obtained using backscattering measurements was 0.00083 g·cm⁻³. To investigate possible inhomogeneity within a pellet, Raman line mapping was performed over the face of a sectioned pellet and spectral variations among the mapped spectra were examined using principal component analysis. In addition, differential scanning calorimetry was performed on three samples prepared separately by cutting a pellet into left, middle, and right sections. Based on both studies, internal pellet inhomogeneity was found to be minute, but was clearly present. The correct sample representation of internally inhomogeneous PE pellets by the transmission Raman measurement eventually improved the accuracy for density determination. Finally sample‐to‐sample two‐dimensional correlation analysis was used to further examine the origin of the improved accuracy. Copyright © 2011 John Wiley & Sons, Ltd.     

Mean Particle Diameters. Part VIII. Computer Program to Decompose Mixtures of (Truncated) Lognormal Particle Size Distributions Using Differential Evolution to Generate Starting Values for Nonlinear Least Squares

Multimodal size distributions can result from a mixing of two or more component distributions and arise in quite different application areas. Physical and statistical approaches are described for decomposition of a multimodal particle size distribution into a number of lognormal components. These approaches, incorporated in the Fortran computer program FitDist, use a nonlinear least‐squares (NLLS) optimization, requiring initial parameter estimates. A hybrid deconvolution method has been developed. Differential Evolution (DE), is used for generation of initial parameter values, followed by an NLLS optimization to derive precise parameter values at the local optimum. The DE algorithm is required to decide on the proper number of modes to be fitted. Mathematical relationships have been derived to convert the parameter values of one multimodal lognormal moment distribution, e.g., a number distribution, to those of another moment distribution, e.g., a volume distribution. Moreover, mathematical relationships have been derived to compute mean diameters (Moment‐Ratio notation) from the parameters of a multimodal lognormal size distribution. Fitting a 1.5th moment distribution, being just in between a number and a volume distribution, has been introduced as an instrument to balance inaccuracies in both tails of a distribution due to sampling inaccuracies or truncation of these tails. The program fits a truncated size distribution by fitting its frequency density distribution, whereas a complete size distribution is fitted by fitting the cumulative distribution. Some guidelines are given for fitting Number, Diameter, Surface area, and Volume distributions to measured size distributions. Although fitting of multimodal normal distributions is an option, higher moment distributions will not be fitted as these distributions are not normally distributed. Practical examples demonstrate the validity of the method to decompose multimodal particle size distributions by use of DE.     

Numerical simulation of fueling pellet ablation and transport in the EAST H-mode discharge

To understand the effect of injected deuterium (D) pellets on background plasma, the ablation of D pellets and the transport of D species in both atomic and ionic states in the EAST device are simulated using a modified dynamic neutral gas shield model combined with the edge plasma code SOLPS-ITER. The simulation results show that there is a phenomenon of obvious atomic deposition in the scrape-off layer (SOL) after pellet injection, which depends strongly on the injection velocity. With increasing injection velocity, the atomic density in the SOL decreases evidently and the deposition time is relatively shortened. Possible effects for triggering of edge localized modes (ELMs) by D and Li pellets are also discussed. With the same pellet size and injection velocity, the maximum perturbation pressure caused by D pellets is obviously higher. It is found that the resulting maximum perturbed pressure is remarkably enhanced when the injection velocity is reduced from 300 m/s to 100 m/s for a pellet with a cross section of 1.6 mm, which indicates that the injection velocity is important for ELM pacing. This work can provide reasonable guidance for choosing pellet parameters for fueling and ELM triggering.     

Amplitude Statistics of Sea-Ice Clutter Using a Millimeter Wave Radar

Sea-ice clutter was measured using a millimeter wave radar with frequency of 34.86GHz and pulse length of 30ns. To determine the sea-ice clutter amplitude statistics, we investigated the log-normal, Weibull, log-Weibull and K-distributions using the Akaike Information Criterion (AIC), which is more rigorous fit of the distribution to the data than the least-squares method. It is shown that the amplitude of sea-ice clutter obeys almost a log-Weibull distribution.     

A Study of the Fracture of Pellets Fired Against a Target

Pellets of sintered Al₂O₃ of approximately 3 mm diameter and length were broken in the Brazilian mode and the distribution of strength obtained. It was found that there was also a distribution of Young's modulus E. Hertzian theory implies that the maximum impact force of a pellet fired against a rigid target would depend on E. However, since the pellets can strike in different geometries there is a distribution of impact force for a fixed E. Comparison of theory with data obtained with a force-time transducer as the target showed that the major variation of maximum recorded force could be assigned to the variation of E. The median of the maximum recorded force varied with velocity as v^6/5, implying that the pellets behaved approximately as impacting spheres. An attempt was made to predict the probability of breakage in one impact from convoluting the distribution of impact force with the strength distribution from the Brazilian test converted to the equivalent strength distribution expected for impacting spheres. This gave the correct order of magnitude but did not accurately predict the experimental values.     

Characterizing the Evolution of Porosity during Controlled Drug Release

Nuclear magnetic resonance (NMR) techniques have been successfully used to characterize the evolving pore structure of partially soluble pharmaceutical pellets as they absorb water and release soluble components. The restricted diffusivity of water trapped within pellets, which have been immersed in water for differing times, has been measured by pulsed field gradient NMR. These measurements have been used to calculate the surface-to-volume ratio and tortuosity of the pore structure. A one-shot Carr–Purcell–Meiboom–Gill sequence has been used to measure the spin–spin (T ₂) relaxation time of water trapped within the pellets. These data have been regularized and then analyzed by the Brownstein–Tarr model to provide a pore size distribution for the pellets as a function of increasing immersion time. It has been found that pore structure changes significantly as water enters the pellet matrix. Two pellet formulations (herein referred to as placebo and drug-loaded) were studied and showed the same trends of a decreasing surface-to-volume ratio and tortuosity with increasing immersion time. At an immersion time of 10 min, both of these parameters decreased to approximately 70% of their values compared to an immersion time of 2 min. The placebo material tested consistently had both a higher tortuosity and surface-to-volume ratio than the drug-loaded material. At an immersion time of 2 min, the tortuosity for the placebo and drug-loaded materials were about 18 and about 10, respectively, and surface-to-volume ratios of about 6 μm⁻¹ and about 5 μm⁻¹, respectively. The materials tested also show changes in their pore size distribution with immersion time. In both formulations the mean and modal pore sizes increase with immersion time. The placebo material maintains an approximately similar mean and modal pore size, about 2 μm over the timescales studied, suggesting a more symmetric pore size distribution. In the drug-loaded pellets the mean pore size is much higher than the modal pore size, their values being 6.5 and 2.1 μm after 10 min immersion time, respectively. Authors' address: Michael D. Mantle, Department of Chemical Engineering, University of Cambridge, Pembroke Street, Cambridge CB2 3RA, UK     

On the Capability of the Generalized Gamma Function to Represent Spray Drop‐Size Distribution

The three‐parameter, Generalized Gamma function solution of a recent MEF formulation used to derive liquid spray drop‐size distribution, is applied to sprays resulting from three different atomization processes. The objectives of these applications are to determine the sign of the parameters for which this function reports a more reliable fit and to further understand the parameter stability problem reported elsewhere. It is found that the lack of stability of the parameters is related to a characteristic feature of the mathematical function and appears for a series of spray drop‐size distributions with constant shape. For each situation analyzed in the present study, the Generalized Gamma function provides a very good fit with parameters that are either constant or correlated to the working conditions. As far as the sign of the parameters is concerned, the results show that the best formulation is a function of the spray and that it is impossible to know, a priori, which parameter sign will report the best fit. Finally, for one situation, it is found that the Generalized Gamma function allows extrapolation of drop sizes outside the measured values. All of the results converge to conclude that the three‐parameter Generalized Gamma function, which is identical to the well‐known Nukiyama‐Tanasawa distribution, accumulates valuable attributes to represent liquid spray drop‐size distributions.     

Polydispersity effects on the magnetization of diluted ferrofluids: a lognormal analysis

Based on a lognormal particle size distribution, this paper makes a model analysis on the polydispersity effects on the magnetization behaviour of diluted ferrofluids. Using a modified Langevin relationship for the lognormal dispersion, it first performs reduced calculations without material parameters. From the results, it is extrapolated that for the ferrofluid of lognormal polydispersion, in comparison with the corresponding monodispersion, the saturation magnetization is enhanced higher by the particle size distribution. It also indicates that in an equivalent magnetic field, the lognormally polydispersed ferrofluid is magnetically saturated faster than the corresponding monodispersion. Along the theoretical extrapolations, the polydispersity effects are evaluated for a typical ferrofluid of magnetite, with a dispersity of σ =0.20. The results indicate that the lognormal polydispersity leads to a slight increase of the saturation magnetization, but a noticeable increase of the speed to reach the saturation value in an equivalent magnetic field.     

The grain size distribution in nanocomposite films

The grain size distributions and related mechanisms in nanocomposite films with nanostructures comprising a nanocrystalline (nc) phase surrounded by an amorphous (a) matrix under different amorphous phase amounts (V _a) have been analyzed by using a Monte Carlo grain growth model. The results show that with the V _a value increasing to a critical value of ～28%, the grain size distribution approaches lognormality, and it becomes off-lognormal when the V _a value is larger or smaller than ～28%. The simulated results are in a good agreement with the experiment. It is shown that the homogenous or inhomogeneous grain growth mode, determined by the energy exerted on the grain boundary, originates in lognormal or off-lognormal grain size distributions in nanocomposite films. Also, in a system with lognormal grain size distribution, the amorphous phase just covers all grain boundaries (GBs) and the length obtained by summing the boundary circumference of all nanograins is the longest. It is expected that this microstructure can result in exceptional properties of nanocomposite films.     

基于贝叶斯方法的设备级电磁脉冲效应评估

在电磁脉冲效应试验中,由于所获得的效应数据量一般较少,利用经典的数理统计方法对效应阈值场强进行概率拟合非常困难。基于贝叶斯数理统计方法,对油气管道数据采集与监视控制系统的中心控制系统客户端的电磁脉冲效应数据拟合分析。选择了Weibull分布模型和正态分布模型作为假设模型,并依次求得这两种模型参数的先验分布、似然函数和后验分布。通过拟合优度检验,最后基于贝叶斯信息准则选择形状参数、尺度参数分别为8.87,21.11的Weibull模型作为更合理的阈值场强概率分布模型。     

Rain Attenuation Ratios on Short Microwave and Millimeter Wave Bands Earth-Space Paths

The knowledge of the ratio of rain attenuation at one frequency to that at another on slant paths is useful for the design of satellite-to-Earth communication links and up-link power control systems. It is well known that the rain attenuation is influenced by parameters of precipitation along the slant path such as DSD (raindrop size distribution), raindrop temperature, rainfall rate, and so on. In this paper, based on several DSDs applied to various climate zones, at short microwave and long millimeter wave bands, the attenuation ratios are estimated on Earth-space paths. A comparison of the prediction results with the experiment data in Boston and Kashima areas is carried out. It is shown that the M-P and Weibull DSD applied to rain attenuation ratios estimation are better DSD at higher latitude regions. The Guangzhou DSD applied to rain attenuation ratios prediction is better in tropical and subtropical areas in China. The lognormal DSD may be a appropriate DSD applied to predict rain attenuation ratios in tropical areas at A_down>1dB or R>15mm/h. However, the attenuation ratios predicted by the Guangzhou DSD disagree with by the lognormal DSD, it requires that the DSD applied to predict rain attenuation ratios are further studied in tropical areas.     

Nonequilibrium statistical mechanical formulation for grain growth

A nonequilibrium statistical mechanical theory for grain growth is presented in this paper. The fluctuation of grain growth is determined from the self similarity of grain size distribution. The grain size distribution scaled by the averaged size is derived under the condition that the volume of specimen is strictly conserved. The growth law of grain is also derived. The scaled grain size distribution are compared with the associating lognormal distribution which is usually used in the analysis of the experimental results. It has been found that the theoretical results is in good agreement with experimental results.     

Nonequilibrium statistical mechanical formulation for grain growth

A nonequilibrium statistical mechanical theory for grain growth is presented in this paper. The fluctuation of grain growth is determined from the self similarity of grain size distribution. The grain size distribution scaled by the averaged size is derived under the condition that the volume of specimen is strictly conserved. The growth law of grain is also derived. The scaled grain size distribution are compared with the associating lognormal distribution which is usually used in the analysis of the experimental results. It has been found that the theoretical results is in good agreement with experimental results.     

Adjustment and control of SERS activity of metal substrates by pressure

Metal pellets of silver and copper for surface‐enhanced Raman scattering (SERS) spectroscopy were prepared by compression with different pressures. It was found that the SERS activity of the pellet could be controlled by pressure. Enhanced Raman scattering properties of the metal pellets in the presence of adsorbed 4‐mercaptobenzoic acid (4‐MBA) with excitation at 632.8 or 514 nm could be obtained by choosing proper pressure of pellatization. The SERS peak intensity of the band at ∼1584 cm⁻¹ of 4‐MBA adsorbed on the metal pellets varies as a function of applied pressure, and which is about 1.2–32 times greater than when it is adsorbed on silver and copper particles. The calculated results of three‐dimensional finite‐difference time‐domain method (3D‐FDTD) are in good agreement with the experimental data. Moreover, no spurious peaks appear in the SERS spectra of the samples because no other chemicals are involved in the simple preparation process of the metal pellets, which will facilitate its use as an SERS‐active substrate for analytical purposes. In summary, SERS‐active metal pellets can be produced simply and cost effectively by the method reported here, and this method is expected to be utilized in the development of SERS‐based analytical devices. Copyright © 2009 John Wiley & Sons, Ltd.     

Dependence of fracture stress upon diameter in strong polymeric fibers

The axial and radial dimensions of a fiber are known to be key factors with respect to the mechanical stress necessary to promote failure, this being known as the size effect. Usually different methods are used to quantify the two types of size effects: Linear elastic fracture mechanics (lefm) and related schemes provide the theoretical basis for the effect of diameter variability upon strength whereas statistical theories, generally based upon the Weibull probability distribution combined with the weakest-link theorem, describe length effects. Here we show that simple modifications of the classical Poisson/Weibull form yield a new failure probability function which provides a more adequate explanation for diameter effects on strength in polydiacetylene fibers, and also resolves in a satisfactory way a current problematic issue inherent to the Weibull/weakest-link model. A maximum likelihood estimation procedure is presented for the evaluation of the most appropriate parameters of the proposed failure probability function.     

A pellet tracking system for the PANDA experiment

Frozen microspheres of hydrogen (pellets) will be one of the target types for the future hadron physics experiment PANDA at FAIR (GSI, Darmstadt, Germany) [1]. Pellets with a diameter of 25– μm are generated about 3 meters above the interaction region, to which they travel with a velocity around 80 m/s inside a narrow pipe. The interaction region is defined by the overlap of the pellet stream and the accelerator beam and has a size of a few millimeters. One would like to know the interaction point more precisely, to have better possibilities to reconstruct particle tracks and events e.g. in charmonium decay studies. One would also like to suppress background events that do not originate in a pellet, but e.g. may occur in rest gas, that is present in the beam pipe. A solution is provided by the presented pellet tracking system together with a target operation mode that provides one and only one pellet in the interaction region most of the time. The goal is to track individual pellets in order to know their position with a resolution of a few tenths of a millimeter at the time of an interaction. The system must also be highly efficient and provide tracking information for essentially all pellets that pass the interaction region. Presented results from the design studies show that the goals can be fulfilled by this solution.