Ultrafast laser processing of drug particles in water for pharmaceutical discovery

The laser fragmentation technique has been extensively used to produce inorganic nanoparticles, but its practice on organic materials, especially on drugs, is less common. Here, we briefly review the recent advances in laser micro-/nanonization of organic materials and the rationale of using laser fragmentation for drug discovery. We present our case studies of two drug models: fenofibrate and naproxen. Both drugs were fragmented in water with femtosecond (fs) laser and characterized in terms of particle size distribution and physicochemical properties. Effects of fs laser fragmentation were also compared with nanosecond (ns) laser fragmentation and with conventional media milling technique. Fs laser was more suitable to produce sub-micron size drug particles than ns laser, but degradation of drugs after nanonization was also more pronounced than micronization. Physicochemical transformations such as oxidation, hydration and amorphisation might occur during the laser–material interactions. Laser nanonization showed improved dissolution kinetics, similar to media milling. Unlike the conventional milling techniques, laser fragmentation enabled the treatment of minute amount (as small as several milligrams) of drugs with high efficiency, thus is a useful tool for particle size reduction during the early phases of drug discovery.     

Characterizing char particle fragmentation during pulverized coal combustion

A particle population balance model was developed to predict the oxidation characteristics of an ensemble of char particles exposed to an environment in which their overall burning rates are controlled by the combined effects of oxygen diffusion through particle pores and chemical reactions (the zone II burning regime). The model allows for changes in particle size due to burning at the external surface, changes in particle apparent density due to internal burning at pore walls, and changes in the sizes and apparent densities of particles due to percolation type fragmentation. In percolation type fragmentation, fragments of all sizes less than that of the fragmenting particle are produced. The model follows the conversion of particles burning in a gaseous environment of specified temperature and oxygen content. The extent of conversion and particle size, apparent density, and temperature distributions are predicted in time.Experiments were performed in an entrained flow reactor to obtain the size and apparent density data needed to adjust model parameters. Pulverized Wyodak coal particles were injected into the reactor and char samples were extracted at selected residence times. The particle size distributions and apparent densities were measured for each sample extracted. The intrinsic chemical reactivity of the char to oxygen was also measured in experiments performed in a thermogravimetric analyzer. Data were used to adjust rate coefficients in a six-step reaction mechanism used to describe the oxidation process.Calculations made allowing for fragmentation with variations in the apparent densities of fragments yield the type of size, apparent density, and temperature distributions observed experimentally. These distributions broaden with increased char conversion in a manner that can only be predicted when fragmentation is accounted for with variations in fragment apparent density as well as size. The model also yields the type of ash size distributions observed experimentally.     

Polydispersed Powders (Nd3+:YVO4) for Ultra Efficient Random Lasers

Random lasers hold the potential for cheap, coherent light sources that can be miniaturized and molded into any shape with several other added benefits such as speckle‐free imaging; however, they require improvements specifically in terms of efficiency. This paper details for the first time a strategy for increasing the efficiency of a random laser that consists in using smaller particles, trapped between large particles to serve as absorption and gain centers whereas the large particles control mainly the light diffusion into the sample. Measurements of backscattering cone, sample absorption, reflection, and laser emission are used to determine the samples' transport mean free path, fill fractions, laser efficiency, and the average photon path lengths inside the scattering medium for backscattered pump photons. A record slope efficiency of 50% is reached by optimizing pump photon diffusion and absorption in a powder pellet composed by a polydispersed particle size distribution (smaller particles between bigger ones) from a grinded and sieved 1.33 mol% yttrium vanadate doped with neodymium crystal with mean particle size of 54 µ m.     

Influence of fractal surface dimension on the dissolution process of sparingly soluble CaCO<Subscript>3</Subscript> microparticles

The dissolution process of sparingly soluble CaCO₃ microparticles and how the fractal surface dimension of the particles changes during dissolution is analyzed. The particles and the dissolution process are studied using scanning electron microscopy, X-ray diffraction, nitrogen adsorption, laser diffraction and conductance measurements. Ball milling of the particles is shown to maintain the particle crystallinity, and to introduce an increased fractal surface dimension in the 1–10 μm size range. Dissolution is found to increase the surface dimension of initially smooth particles and to maintain the fractal surface roughness of milled particles. The dissolution process increases the relative number of small particles (50 nm–1 μm) whereas the larger ones decrease in size. The solubility of the milled fractal particles was ∼1.8 times higher than that for the initially smooth ones. The presented findings show that developing methods for increasing the fractal surface roughness of particles should be of interest for improving the solubility of poorly soluble drug candidates.     

固体壁面附近激光空泡的动力学特性研究

关键词：     

大气颗粒物多参数激光自混合传感的数值模拟与特性分析

基于颗粒物米氏散射特性、激光自混合三镜腔理论和激光器稳态条件,推导出在大气颗粒物光反馈下激光器频率、功率、线宽的理论表达式,建立了大气颗粒物光反馈下的激光自混合理论模型。同时,数值模拟和分析了大气颗粒物物理参数对激光自混合干涉信号的影响。结果表明,在一定粒径范围内,激光自混合反馈强度随大气颗粒物粒径增大先增大后减小,且反馈强度峰值出现的位置随颗粒物折射率实部的增大、虚部的减小向粒径较大处移动;自混合系统的外腔长度影响自混合干涉信号的波动深度,激光器输出光信号的幅值随外腔长度增大呈指数衰减;自混合干涉信号波动频率与大气颗粒物运动速度呈线性关系。分析结果对基于激光自混合效应的大气颗粒物多物理参数传感具有重要作用。     

Fragmentation of pulverized coal in a laminar drop tube reactor: Experiments and model

Fragmentation during pulverized coal particles conversion shifts the particle size distribution of the fuel towards smaller particle sizes, affecting both conversion rates and heat release. After pyrolysis of a high volatiles Colombian coal in CO₂ atmosphere in a drop tube reactor at 1573?K, solid carbonaceous particles of different size, from 100?µm of the particle feed down to the nanometric size, have been observed. A fragmentation model has been used to predict the fate of Colombian coal particles under the experimental conditions of the drop tube experiment and predict the particle size distribution (PSD). Model and experimental results are in very good agreement and indicate that in the DTR experiment the coal underwent almost complete pyrolysis and that fragmentation generated a 36?wt% population of particles with size close to 30?µm. The close match between the PSDs obtained from experiments and from the fragmentation model is an important novelty. It demonstrates that fragmentation occurs not only under fluidized bed conditions but also under the conditions of pulverized coal combustion. Experimentalists are warned against the fact that the fine particulate sampled at the outlet of laminar flow reactors and boilers is not always composed of soot only. Char fragments can be misidentified as soot. The implementation of fragmentation submodels in pulverized fuel combustion and gasification codes is highly recommended.     

炸药爆炸作用下液体破碎后颗粒尺寸分布的研究

 对液体抛撒的液滴尺寸进行研究在军事和民用上是很重要的,国内刚开始使用激光散射仪开展此项研究工作。利用R. A. Dobbins等人的液体颗粒测量技术,研制了一套既简单又实用的测量液体抛撒过程中液滴尺寸的实验装置——激光散射仪。对于激光与液体微粒的相互作用,当微粒的反射与折射和吸收效应可被忽略时,可导出液体微粒对激光散射的光强公式。只要测量激光被微粒散射的光强,就可推算出微粒的Sauter平均直径。在使用激光散射仪测量液体抛撒液滴尺寸的实验中,用水代替爆炸抛撒液体,测量结果表明：液体抛撒二次破碎中,在固定位置测量到的云雾区液滴Sauter平均直径随测量时间的增加呈现出减小的趋势;而云雾区的宽度则随着与抛撒中心距离的增大而呈现出增加的趋势;云雾区前沿的液滴Sauter平均直径随着与抛撒中心距离的增加而呈现出先逐渐增大然后迅速减小的趋势。为便于比较,对燃料抛撒二次破碎进行了回收法测量和数值模拟计算,其测量与计算结果与用激光散射仪测量的结果有较好的一致性。     

激光熔覆中金属粉末粒子与激光相互作用模型

为了对同轴激光熔覆过程中运动的金属粉末粒子的速度和温度进行理论分析,并研究各工艺参量的影响,建立了运动中金属粉末粒子的运动模型和热模型.模拟结果表明,粉嘴几何尺寸、粒子直径以及气/粉两相流初始速度是影响粒子运动行为的重要因素;粉嘴几何尺寸、激光焦点位置、激光发散角、激光功率、粒子直径以及气/粉两相流初始速度是影响粒子热行为的重要因素.在相同的工艺参量下(粉嘴出口内径r=2 mm,粉嘴倾角α=60°,初始气流速度v0=0.8 m/s),基于数字粒子图像测速(DPIV)技术,对316L不锈钢粉末粒子运动模型进行了实验验证.结果表明,运动理论模型是可靠的.该模型是掌握同轴激光熔覆过程中金属粉末粒子运动行为的有效工具;同时,热模型也是分析粉末粒子温度随不同参量变化的重要工具.     

脉冲激光作用下气溶胶导致大气击穿研究

 利用锁模Nd:YAG激光及其倍频激光照射漂浮在大气中的Al₂O₂、ZnO、ZrO₂、18号玻璃粉等气溶胶粒子，在不同光学参数下对光致大气击穿阈值进行了测量。测量结果表明：空气中含较大粒子(d >30 μm)的光致击穿阈值比含较小粒子(d <1μm)的空气击穿阈值低2~3个数量级；含杂空气的击穿阈值随入射激光束直径的增大而下降，随气溶胶粒子直径的增大而减小，且随气溶胶成份的不同而不同；光致击穿阈值随波长的减小而增大。     

Preparation of fenofibrate nanoparticles by combined stirred media milling and ultrasonication method

The production of fenofibrate nanoparticles combining stirred media milling and ultrasonication method was investigated in the current work. The fenofibrate drug sample was first wet milled in stirred media mill for different times and subsequently processed by ultrasonication. The effects of ultrasonication time, power on final product particle sizes were studied. The pre milling by stirred media milling was resulted into reduction of comminution resistance of material. Subsequent treatment by ultrasonication produced smaller particles than obtained by stirred media milling alone. The resulting nanoparticles were found to exhibit excellent stability as investigated by particle size, zeta potential, and multiple light scattering measurement techniques. Further, qualities of nanoparticles obtained by combined approach were characterized by TEM and XRD analysis.     

Determination of the Refractive Index of Water‐dispersible Granules for Use in Laser Diffraction Experiments

Modern laser light scattering equipment can cover a very broad particle size range by using complex algorithms, such as the Mie theory. A disadvantage of this theory, however, is that it requires the knowledge of the refractive index of the particles, which is not straightforward for powdered organic substances. In this study, thiram, a common dithiocarbamate fungicide, was used as a model compound. In a first part, a method was elaborated to determine the refractive index, based on refractive index measurements of solutions of the compound of interest in a range of solvents. Two different extrapolation techniques were compared. Both techniques were validated by applying them to the determination of the refractive indices of poly(vinyl acetate) and poly(methyl methacrylate). Secondly, the influence of the refractive index value on the generated particle size distribution in the laser diffraction software was investigated. It was observed that widely different particle size distributions can be generated by the laser diffraction software for a single experimental data‐set. Therefore, accurate refractive index information is required to obtain reliable particle size distribution results.     

Ash characteristics in controlled diode laser pyrolysis of chlorinated rubber

This paper describes the effects of 60 W High Power Diode Laser (HPDL) beams on the removal of chlorinated rubber (CR) paint from concrete surfaces and the ash particles generated from this process. The physical characteristics, including shape and size distribution of the removed and collected airborne CR particles, down to a size of around 1 μm in diameter, were determined using optical microscopy and image analysis. The shape of the particles observed was highly irregular, displaying no symmetry. The size distribution of the collected particles was found to range between 1–2000 μm, with the maximum concentration being found between 29 and 60 μm. The chemical characteristics of the CR ash particles were investigated by means of ESEM and EDX techniques. From a comparative analysis, it was found that the concentration of chlorine within the CR material was significantly reduced after HPDL treatment. This, together with DTA/TGA results indicated a combustive degradation of the CR polymer through the interaction with the process gas, oxygen, and the laser irradiation. Also, a strong correlation between laser power and average particle sizes has been found, with higher powers generally producing larger particle sizes. Opposite effects have been found by changing the oxygen flow rate, with higher oxygen flow producing, on average, smaller particles. An interpretation of the combustion process, as well as a brief discussion on operational safety and environmental impact of the products is attempted.     

Spray Freeze-drying – The Process of Choice for Low Water Soluble Drugs?

Most of the novel highly potent drugs, developed on the basis of modern molecular medicine, taking into account cell surface recognition techniques, show poor water solubility. A chemical modification of the drug substance enhancing the solubility often decreases the pharmacological activity. Thus, as an alternative an increase of the solubility can be obtained by the reduction of the size of the drug particles. Unfortunately, it is often difficult to obtain micro or nanosized drug particles by classical or more advanced crystallization using supercritical gases or by milling techniques. In addition, nanosized particles are often not physically stable and need to be stabilized in an appropriate matrix. Thus, it may be of interest to manufacture directly nanosized drug particles stabilized in an inert hydrophilic matrix, i.e. nanostructured and nanocomposite systems. Solid solutions and solid dispersions represent nanostructured and nanocomposite systems. In this context, the use of the vacuum-fluidized-bed technique for the spray-drying of a low water soluble drug cosolubilized with a hydrophilic excipient in a polar organic solvent is discussed. In order to avoid the use of organic solvents, a special spray-freeze-drying technique working at atmospheric pressure is presented. This process is very suitable for temperature and otherwise sensitive drugs such as pharmaproteins.     

Preparation of nanoparticles of poorly water-soluble antioxidant curcumin by antisolvent precipitation methods

The objective of this study was to enhance the solubility and dissolution rate of a poorly water-soluble antioxidant, curcumin, by fabricating its nanoparticles with two methods: antisolvent precipitation with a syringe pump (APSP) and evaporative precipitation of nanosuspension (EPN). For APSP, process parameters like flow rate, stirring speed, solvent to antisolvent (SAS) ratio, and drug concentration were investigated to obtain the smallest particle size. For EPN, factors like drug concentration and the SAS ratio were examined. The effects of these process parameters on the supersaturation, nucleation, and growth rate were studied and optimized to obtain the smallest particle size of curcumin by both the methods. The average particle size of the original drug was about 10–12 μm and it was decreased to a mean diameter of 330 nm for the APSP method and to 150 nm for the EPN method. Overall, decreasing the drug concentration or increasing the flow rate, stirring rate, and antisolvent amount resulted in smaller particle sizes. Differential scanning calorimetry studies suggested lower crystallinity of curcumin particles fabricated. The solubility and dissolution rates of the prepared curcumin particles were significantly higher than those the original curcumin. The antioxidant activity, studied by the DPPH free radical-scavenging assay, was greater for the curcumin nanoparticles than the original curcumin. This study demonstrated that both the methods can successfully prepare curcumin into submicro to nanoparticles. However, drug particles prepared by EPN were smaller than those by APSP and hence, showed the slightly better solubility, dissolution rate, and antioxidant activity than the latter.     

Study on the Projection Non-mode Algorithm of Laser Particle Size Measurement

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A Double Gaussian Beam Method for the Determination of Particle Size,Direction and Velocity

This paper describes a technique aimed at measuring particle size by light scattering from gaussian laser beams. The uncertainties in illumination due to the beam shape are avoided by determination of the direction and velocity. The method, which we arbitrarily called the Two Beam System (TBS), uses a simple birefringent prism to separate the incident laser beam into two orthogonally polarised overlapping parallel beams. The relative delay and amplitudes of the intensities scattered out of the orthogonal polarisations are indicative of the particle direction and velocity. Having obtained the direction of travel of the particle, its size is then obtained from the scattered intensity using Mie theory.     

Characterization of TiO2 Smoke Prepared Using Gas‐Phase Hydrolysis of TiCl4

The formation of submicron TiO₂ smoke (a gas‐phase suspension) from titanium tetrachloride in a low‐pressure hydrolysis reaction in a simple reactor configuration has been studied. Particle size distribution, particle morphology and degree of crystallinity have been characterized as a function of reaction conditions. Highly crystalline anatase TiO₂ particles with narrow size distribution and smaller particle size were formed at high reactor temperature, while larger, amorphous particles were found at lower reactor temperatures. These results are consistent with literature studies. At 817 °C, small (450 nm), spherical, unagglomerated particles could be produced. A gas‐phase dispersion of these particles is intended for use as seeds in subsequent kinetic studies of titanium dioxide formation reactions involving a rapid compression methodology.     

Analysis on plasma chemistry and particle growth in corona discharge process for NO/sub x/ removal using discrete-sectional method

The particle formation and growth combined with plasma chemistry in the pulsed corona discharge process (PCDP) to remove NO/sub x/ were analyzed by the discrete-sectional model. In the PCDP, most of the NO is converted into NO/sub 2/ and, later, into HNO/sub 3/ which reacts with NH/sub 3/ to form the NH/sub 4/NO/sub 3/ particle. In the beginning of the reactor, we have the high concentration of small size particles and, later, the particle size distribution in the reactor becomes bimodal with the large size and small size particles and, finally, becomes monodisperse with the large size particles. As the average electron concentration increases, it takes a shorter reactor length to remove the NO/sub x/. As the initial NO and H/sub 2/O concentrations decrease, the NH/sub 3/ is consumed more slowly to form the ammonium nitrates particles. As the averaged electron concentration and initial H/sub 2/O concentration increase, the large size particles grow more quickly and the particle size distribution becomes bimodal earlier. As the initial NO and NH/sub 3/ concentrations increase, the diameter of large size particles becomes larger by the faster coagulation between particles. The predicted NO/sub x/ conversion and particle size distribution were in close agreements with the published experimental results at the averaged electron concentration of 2/spl times/10/sup 5/ cm/sup -3/ in this study.     

Laser-induced incandescence of titania nanoparticles synthesized in a flame

Laser induced incandescence experiments were carried out in a flame reactor during titania nanoparticle synthesis. The structure of the reactor employed allowed for a rather smooth particle growth along the flame axis, with limited mixing of different size particles. Particle incandescence was excited by the 4th harmonic of a Nd:YAG laser. The radiation emitted from the particles was recorded in time and checked by spectral analysis. Results were compared with measurements from transmission electron microscopy of samples taken at the same locations probed by incandescence. This was done covering a portion of the flame length within which a particle size growth of a factor of about four was detected. The incandescence decay time was found to increase monotonically with particle size. The attainment of a process control tool in nanoparticle flame synthesis appears to be realistic.