Evaluation of characteristic deuterium distributions of ephedrines and methamphetamines by NMR spectroscopy for drug profiling

We have established a method for quantitative analysis of the deuterium contents (D/H) at the phenyl, methine, benzyl, N-methyl and methyl groups of l-ephedrine/HCl, d-pseudoephedrine/HCl and methamphetamine/HCl by 2H NMR spectroscopy. Comparison of the 5 position-specific D/H values of l-ephedrine/HCl and d-pseudoephedrine/HCl prepared by three methods (chemical synthesis, semichemical synthesis, and biosynthesis) showed that chemically synthesized ephedrines and semisynthetic ephedrines have highly specific distributions of deuterium at the methine position and at the benzyl position, compared with the other positions. The classification of several methamphetamine samples seized in Japan in terms of the D/H values at these two positions clearly showed that the methamphetamine samples had been synthesized from ephedrines extracted from Ephedra plants or semisynthetic ephedrines but not from synthetic ephedrine. This isotope ratio analysis method should be useful to trace the origins of seized methamphetamine in Southeast Asia.     

Impurity profiling to match a nerve agent to its precursor source for chemical forensics applications

Chemical forensics is a developing field that aims to attribute a chemical (or mixture) of interest to its source by the analysis of the chemical itself or associated material constituents. Herein, for the first time, trace impurities detected by gas chromatography/mass spectrometry and originating from a chemical precursor were used to match a synthesized nerve agent to its precursor source. Specifically, six batches of sarin (GB, isopropyl methylphosphonofluoridate) and its intermediate methylphosphonic difluoride (DF) were synthesized from two commercial stocks of 97% pure methylphosphonic dichloride (DC); the GB and DF were then matched by impurity profiling to their DC stocks from a collection of five possible stocks. Source matching was objectively demonstrated through the grouping by hierarchal cluster analysis of the GB and DF synthetic batches with their respective DC precursor stocks based solely upon the impurities previously detected in five DC stocks. This was possible because each tested DC stock had a unique impurity profile that had 57% to 88% of its impurities persisting through product synthesis, decontamination, and sample preparation. This work forms a basis for the use of impurity profiling to help find and prosecute perpetrators of chemical attacks.     

The effects of the silica source on the crystallization of zeolite NaX

The effects of varying the starting silica source on the synthesis of molecular sieve zeolite NaX were investigated, while all other reaction parameters were kept constant. The silica sources were all powders of varying types and purity. Characterizations of the silica sources, the silicate solutions, and the synthesis products were completed by powder X-ray diffraction, electron microscopy, particle-size analysis, n.m.r, spectroscopy, laser light scattering, and elemental analysis. The use of different silica sources significantly influenced the outcome of the synthesis experiments. There were large differ- ences in the results from the various batch synthesis mixtures, even though the batch compositions were all the same (neglecting impurities). The experiments, all conducted at 115°C in sealed 6 ml autoclaves, yielded products of different particle sizes, different amounts of impurity zeolite phases, and different conversion rates to zeolite NaX. The n.m.r. spectra of the dissolved silica sources were all effectively the same; however, the levels of trace impurities were very different. The extent to which nuclei formed in these experiments was shown to correlate to the impurity level of any one of several elements in the silica sources, but not to the turbidity of the filtered solutions as noted by a simple light-scattering measurement.     

The trouble with TOPO; identification of adventitious impurities beneficial to the growth of cadmium selenide quantum dots, rods, and wires

Tri-n-octylphosphine oxide (TOPO) is a commonly used solvent for nanocrystal synthesis. Commercial TOPO samples contain varying amounts of phosphorus-containing impurities, some of which significantly influence nanocrystal growth. Consequently, nanocrystal syntheses often give irreproducible results with different batches of TOPO solvent. In this study, we identify TOPO impurities by (31)P NMR, and correlate their presence with the outcomes of CdSe nanocrystal syntheses. We subsequently add the active impurity species, one by one, to purified TOPO to confirm their influence on nanocrystal syntheses. In this manner, di-n-octylphosphine oxide (DOPO) is shown to assist CdSe quantum-dot growth; di-n-octylphosphinic acid (DOPA) and mono-n-octylphosphinic acid (MOPA) are shown to assist CdSe quantum-rod growth, and DOPA is shown to assist CdSe quantum-wire growth. (The TOPO impurity n-octylphosphonic acid, OPA, has been previously shown to assist quantum-rod growth.) The beneficial impurities are prepared on multigram scales and can be added to recrystallized TOPO to provide reproducible synthetic results.     

Using Structural Equation Modeling (SEM) for the Study of Impurity Profiles of Drug Substances

The impurity profile is one of the most important quality characteristics of a drug substance. Although it is always desirable to determine the chemical structure of all impurities forming the impurity profile, unfortunately this is not always economically and technically feasible because of the extremely low concentrations at which some impurities may be found in the drug substance. Therefore, alternative approaches to the chemical analysis are needed for trying to determine the origin of the unidentified impurities.

In a previous study conducted by our group, based on exploratory (principal component and hierarchical cluster) analysis, we were able to suggest a hypothesis for explaining the origin of the unidentified impurities of a drug substance. However, there was still a concern that alternative hypotheses might explain the same phenomenon equally well. This article explores the application of recent developments in structural equation modeling for the systematic generation and selection of hypotheses (models) worthy of being confirmed by chemical research.     

Effect of As,Cu and Sb impurities on performance of Pb‐Ca‐Sn grids of lead‐acid batteries

The performance of Pb‐Ca‐Sn grids of lead‐acid batteries made from recycled lead in 4 M H₂SO₄ in the absence and presence of traces of Cu, As and Sb, as potential impurities in the recycling process at 0.1% level, is investigated by electrochemical methods. The study includes the effect of each impurity and impurities combined on the alloy corrodibility, the efficiency of PbO₂ formation, the rate of the self‐discharge and the hydrogen evolution reaction (HER) and the oxygen evolution reaction (OER). The results show that individual impurity enhances the corrosion resistance but increases the anode corrosion and the self‐discharge rate. Impurities play opposite effects on hydrogen evolution reaction and oxygen evolution reaction either individually or combined. Concerning water loss problem, the harmful effect of individual impurity on increasing oxygen evolution reaction is compensated by their suppression of hydrogen evolution reaction. The impurities combined suppress effectively both hydrogen evolution reaction and oxygen evolution reaction relative to alloy without any impurity. Sb has the highest harmful effects on oxygen evolution reaction and the self‐discharge but it is the best in the suppression of hydrogen evolution reaction. The impurities combined relatively improve the general corrosion resistance, the anode corrosion resistance and the self‐discharge. The study supports higher tolerance levels of Cu, As and Sb in Pb‐Ca‐Sn grids, especially when present combined, than the recommended levels in the industry standards.     

A simple thermodynamic model for the doping and alloying of nanoparticles

Impurity incorporation into nanoparticles is modeled using thermodynamics. For small particles, entropically driven impurity incorporation is reduced, rendering doping difficult. We show that the free energy of surface impurities in small nanoparticles is lower than core impurities, surface doping therefore occurs preferentially. A critical size for core doping is identified, below which it is energetically unfavorable. In all cases, core impurity concentration is reduced as particle size decreases. We show larger than bulk impurity concentrations are possible, corresponding to increased alloying.     

Discrete deterministic and stochastic blending problems with two quality characteristics: aluminum blending

This research is motivated by the problem of assigning the output of electrolytic cells to oven batches in the production of aluminum, so as to maximize the expected revenue. Cell output cannot be split between batches, and the batch sizes are constrained. Each batch is classified into a revenue category based on the levels of two impurities. The impurity levels differ from cell to cell and additional random quantities of impurities are added during the oven process. We develop optimal and heuristic solution approaches for the deterministic version of the problem (known amount of impurities) and use them as the basis for a heuristic procedure for the stochastic version. Using data from a high-grade aluminum manufacturer, we demonstrate that our approach finds near-optimal solutions to the stochastic problem, with significant gains over solving deterministic versions in which the stochasticity is modeled only approximately.     

Microstructure and properties of sintered mullite developed from Indian bauxite

Dense mullite aggregates with 72% Al₂O₃ have been synthesized by reaction sintering of two varieties of Indian bauxite and silica sol. The bauxites used are of inferior grade with different levels of accessory impurities such as Fe₂O₃, TiO₂, CaO. The phase and microstructure development of sintered samples were investigated by XRD and SEM. It was found that morphology of the sintered grain is very much dependent on the impurity level. Mullite formed from bauxite-1 with low impurity is mostly equiaxed, whereas mullite developed from bauxite 2 with higher impurity particularly CaO is needle shaped. Presence of CaO in bauxite was found to be more detrimental than TiO₂ and Fe₂O₃.     

Estimating the Contribution of Impurities to the Uncertainty of Metal Fixed-Point Temperatures

The estimation of the uncertainty component attributable to impurities remains a central and important topic of fixed-point research. Various methods are available for this estimation, depending on the extent of the available information. The sum of individual estimates method has considerable appeal where there is adequate knowledge of the sensitivity coefficients for each of the impurity elements and sufficiently low uncertainty regarding their concentrations. The overall maximum estimate (OME) forsakes the behavior of the individual elements by assuming that the cryoscopic constant adequately represents (or is an upper bound for) the sensitivity coefficients of the individual impurities. Validation of these methods using melting and/or freezing curves is recommended to provide confidence. Recent investigations of indium, tin, and zinc fixed points are reported. Glow discharge mass spectrometry was used to determine the impurity concentrations of the metals used to fill the cells. Melting curves were analyzed to derive an experimental overall impurity concentration (assuming that all impurities have a sensitivity coefficient equivalent to that of the cryoscopic constant). The two values (chemical and experimental) for the overall impurity concentrations were then compared. Based on the data obtained, the pragmatic approach of choosing the larger of the chemical and experimentally derived quantities as the best estimate of the influence of impurities on the temperature of the freezing point is suggested rather than relying solely on the chemical analysis and the OME method to derive the uncertainty component attributable to impurities.     

TEM study of silicon carbide whisker microstructures

-SiC whiskers produced by a number of manufacturers have been examined in the transmission and scanning electron microscopes. In all cases defective microstructures were found with high densities of planar defects such as stacking faults and microtwins. Two distinct types of defective whisker can be identified. The first contains regions of very closely spaced twins on {111} planes arranged perpendicular to the whisker axis [111], these were sometimes separated by defect-free regions. In these whiskers a rough surface profile was normal with the roughness closely associated with the highly defective regions of the whisker. The second type of whisker contained stacking faults spaced relatively widely also on {111} planes but now on the planes inclined to the [111] axis of the whisker. This leads to a characteristic chevron contrast in the TEM. This second type of whisker had a much smoother surface profile than the first type with perpendicular defects. No whisker contained both defect types but some batches of whiskers contained populations of both types of whisker. The first type of whisker is shown to have defects similar to those reported as common during vapour-liquid-solid whisker growth. This is also consistent with the higher impurity content and the presence of voids found in these whiskers. The second type may be indicative of a different growth mechanism possible under certain conditions of SiC whisker synthesis.     

Rapid nondestructive on-site screening of methylamphetamine seizures by attenuated total reflection fourier transform infrared spectroscopy

The identification and quantification of illicit substances in the field is often desirable. Fourier transform infrared spectroscopy (FT-IR) has both qualitative and quantitative capabilities and field portable instruments are commercially available. Transmission infrared spectra of mixtures containing ephedrine hydrochloride, glucose, and caffeine and attenuated total reflection (ATR) infrared spectra of mixtures composed of methylamphetamine hydrochloride, glucose, and caffeine were used to develop principal component regression (PCR) calibration models. The root mean sum of errors of predictions (RMSEP) of all individual components in a mixture from a single measurement was <6% w/w, which reduced to approximately 3% w/w when triplicates were averaged. Sample mixing and grinding are essential to minimize the effect of heterogeneity, as deviations of up to 20% w/w were observed for single measurements of unground samples. Poor predictions of the components in a mixture occurred when samples were "contaminated" with substances not present in the calibration set, as would be expected. When only a single analyte (drug) was targeted, using a calibration set that contained both contaminated and uncontaminated samples, an RMSEP of approximately 4% w/w was achieved. The results demonstrate that ATR-FT-IR has the potential to quantify methylamphetamine samples, and possibly other licit or illicit substances, in at-seizure and on-site scenarios.     

Ferromagnetism in C60 polymers: pure carbon or contamination with metallic impurities?

A review of ferromagnetism in C60 polymeric materials synthesized by high pressure high temperature (HPHT) treatment is presented. Analysis of published data proves that the reported ferromagnetism cannot be assigned to polymeric structure in either perfect or defect states. Most recent experimental studies have not confirmed previously reported levels of magnetization in polymeric samples while it appears that ferromagnetism of "magnetic carbon" is preserved above the depolymerization point of any C60 polymer. Identical ferromagnetic properties in some samples of fullerene polymer and graphite like hard carbon phase also show that the effect is most likely not connected to fullerenes at all. Most of the data published previously as an evidence of ferromagnetism in C60 polymers synthesized at HPHT conditions can be explained by contamination with magnetic impurities. Formation of iron carbide (Fe3C) due to reaction of metallic iron with fullerene molecules allows to explain observed Curie temperature of approximately 500 K and levels of magnetization reported for "magnetic carbon".     

Purity-enhanced bulk synthesis of thin single-wall carbon nanotubes using iron-copper catalysts

We report high purity and high yield synthesis of single-wall carbon nanotubes (SWCNTs) of narrow diameter from iron-copper bimetal catalysts. The SWCNTs with diameter of 0.8-1.2 nm are synthesized using the zeolite-supported alcohol chemical vapour deposition method. Single metal and bimetal catalysts are systematically investigated to achieve both the enhancement of SWCNT yield and the suppression of the undesired formation of graphitic impurities. The relative yield and purity of SWCNTs are quantified using optical absorption spectroscopy with an ultracentrifuge-based purification technique. For the single metal catalyst, iron shows the highest catalytic activity compared with the other metals such as cobalt, nickel, molybdenum, copper, and platinum. It has been found that the addition of copper to iron results in the suppression of carbonaceous impurity formation without decreasing the SWCNT yield. The purity-enhanced SWCNT shows fairly low sheet resistance due to the improvement of inter-nanotube contacts. This scalable design of SWCNT synthesis with enhanced purity is therefore a promising tool for shaping future high performance devices.     

Impurity effects on particle properties of hydrocalumite synthesized from concentrated seawater

In this study, continuous crystallization of hydrocalumite (HC) using a Taylor vortex crystallizer was carried out as a recovery method of Ca dissolved in concentrated seawater. Further, in order to apply the crystallized HC to anion removal materials, the mechanism of anion removal properties of HC was investigated. Application of the Taylor vortex flow induces an acceleration mass transfer rate, and an effective crystallization of HC fine particles in a short period is expected. In the experiment, solution with metal ions and NaOH solution were continuously supplied into the Taylor vortex crystallizer, and HC was crystallized. For investigating the influences of impurity ions derived in seawater on crystallization of HC, the solution with impurity ions was also prepared. Moreover, in order to evaluate the anion removal properties, the synthesized HC particles were immersed into a solution with phosphate ion or albumin. Consequently, little change because of impurity ions was observed for the particle size and trivalent cation ratio of HC. The crystallinity and surface potential of HC were decreased as the presence of impurities. Additionally, anion removal reaction was suggested to proceed at the interlayers and crystal surfaces of particles depending on ionic radius.     

Properties of amorphous silica generated by the fluoride method

A study of amorphous silica generated from mineral material by the fluoride method and by different procedures of analysis, i.e., x-ray diffraction, x-ray fluorescence, IR spectroscopy, and nuclear magnetic resonance, is reported. Direct fluoridation of amorphous silica was performed by using gaseous F₂ and different conditions of processing, which allowed us to assess the reduction of impurities in amorphous silica and to show that (NH₄)(Si(NH₃)F₅) was not present in the sample as an impurity.     

Phase Shift of the Asymmetric Friedel-Anderson Impurity

The ground state of the asymmetric Friedel-Anderson (aFA) impurity is calculated within the FAIR (Friedel artificially inserted resonance) theory. Its properties are investigated by means of the fidelity with different Friedel impurities and by its Friedel oscillations. Friedel impurities with a specific phase shift δ at the Fermi level possess a finite fidelity with the aFA impurity. This phase shift δ determines other properties of the aFA impurity such as the amplitude and displacement of its Friedel oscillations. One can find the parameters of a Friedel impurity which coincides in its Friedel oscillations almost perfectly with the aFA impurity, thereby avoiding an Anderson orthogonality catastrophe.     

杂质对氧化锆热障涂层性能的影响

降低热障涂层面层中的低熔点杂质含量, 可提高涂层的高温稳定性和延长服役寿命。SiO₂、Al₂O₃和Fe₂O₃是氧化钇稳定氧化锆(Yttria-Stabilized Zirconia, YSZ)热障涂层中几种常见的低熔点氧化物杂质, 均会对涂层的性能产生一定的影响。本研究采用大气等离子喷涂法, 制备SiO₂、Al₂O₃和Fe₂O₃的含量从小于0.01wt%增加至1.00wt%的YSZ热障涂层。采用扫描电镜(SEM)和透射电镜(TEM)研究了上述涂层的微观结构; 采用激光热导仪测试了涂层的热扩散系数和抗热震次数。研究结果表明, 低熔点氧化物杂质对YSZ涂层的导热性、热处理状态的孔隙率具有明显影响, 且更容易引起涂层的热震失效。当杂质氧化物含量在小于0.2wt%范围内变化时, 涂层的性能变化更为显著。     

Quality-by-design approach for the development of telmisartan potassium tablets

A quality-by-design approach was adopted to develop telmisartan potassium (TP) tablets, which were bioequivalent with the commercially available Micardis^® (telmisartan free base) tablets. The dissolution pattern and impurity profile of TP tablets differed from those of Micardis^® tablets because telmisartan free base is poorly soluble in water. After identifying the quality target product profile and critical quality attributes (CQAs), drug dissolution, and impurities were predicted to be risky CQAs. To determine the exact range and cause of risks, we used the risk assessment (RA) tools, preliminary hazard analysis and failure mode and effect analysis to determine the parameters affecting drug dissolution, impurities, and formulation. The range of the design space was optimized using the face-centered central composite design among the design of experiment (DOE) methods. The binder, disintegrant, and kneading time in the wet granulation were identified as X values affecting Y values (disintegration, hardness, friability, dissolution, and impurities). After determining the design space with the desired Y values, the TP tablets were formulated and their dissolution pattern was compared with that of the reference tablet. The selected TP tablet formulated using design space showed a similar dissolution to that of Micardis^® tablets at pH 7.5. The QbD approach TP tablet was bioequivalent to Micardis^® tablets in beagle dogs.