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.     

Application of the Multivariate T2 Control Chart and the Mason-Tracy-Young Decomposition Procedure to the Study of the Consistency of Impurity Profiles of Drug Substances

A case study from the chemical and pharmaceutical industry is used to show the value of the application of the multivariate T² control chart and the Mason-Tracy-Young decomposition procedure to the study of the consistency of the impurity profiles of drug substances. The impurity profile of a drug substance is one of the most important quality characteristics, is almost always multivariate in nature, and is complicated by the relationships among the impurity levels. This prohibits examining each impurity by univariate statistical procedures. Several of the possible benefits of applying these multivariate statistical procedures to the manufacture of drug substances are illustrated through the presentation and discussion of the case study.     

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.     

High-Purity Fixed Points of the ITS-90 with Traceable Analysis of Impurity Contents

The International Temperature Scale of 1990 (ITS-90) is based on thermodynamic equilibrium states of ideally pure substances. The largest contribution to the uncertainty budgets of most metallic fixed points is the influence of impurities on the fixed-point temperature. Therefore, a traceable chemical analysis of the remaining impurities with small uncertainty is the basis of further progress. Further requirements are better knowledge of the phase diagrams at very low impurity contents, impurity segregation, and the quantification and correction of thermal effects during a fixed-point realization. In this article, current and future activities at PTB and BAM in order to develop improved metallic fixed-point cells of the ITS-90 are reviewed.     

An evaluation of the purity of volatile compounds on the elemental composition of impurities

By the example of chemical elements in the form of elementary substance it was shown that the total content of elemental impurities can be considered as an objective and generalized index of the purity of individual matter. Impurity composition of the volatile compounds evaluated on the experimental results was presented in the form of two information files: (i) the content of chemical elements for low-volatile impurities, and (ii) the content of impurities with specified molecular structure (taking into account that the volatility of impurity and base is comparable). A unified approach to the presentation of the impurity composition data of volatile compounds, which considers the elemental composition of both groups of impurities and allows estimating of the total content of elemental impurities in compound, has been developed. In the framework of this approach the average total impurity content of the high-purity volatile chloride samples, which are available at the Collection Exhibition of Special Purity Substances, were evaluated.     

Assessment of Methods for Determining the Impurity Concentration in Mercury Cells

The uncertainty arising from chemical impurities is the principle contribution in the uncertainty budget of primary level temperature measurements. Impurities in any substance generally decrease the freezing (or triple) point temperature of a substance, and their influence is governed primarily by their behavior at low concentrations in the host material. The depression in temperature due to impurities is theoretically expressed by Raoult??s law which, at final analysis, expresses the linearity between ??T (T _observed?T _pure) and the inverse of the melted fraction (1/F). Recently, TUBITAK UME carried out a new project on the construction of new reference mercury fixed-point cells. Within the scope of this study, three different sets of mercury cells with different purity values were fabricated. Three methods were employed to assess the impurity concentration in the cells. The first method is known as the mole fraction sum of impurity components, and the chemical assays form the basis for this kind of assessment. The second method of evaluation is based on a 1/F versus ??T curve, and the slope values obtained from these curves are important. The final method is to directly compare the new cells with a national (or reference) standard mercury cell. The results obtained from three methods of evaluation showed consistency in terms of qualitative analysis.     

Key issues in the targeted synthesis of inorganic substances

Chemistry is a science concerned with conversion of substances. From the chemical point of view, a substance is an assemblage of interacting particles, which is characterized by four properties: composition, structure, type of chemical bonding, and particle size. A conversion of a substance is a change in one or several of its properties. Targeted synthesis is a way of controlling a conversion of a substance. This paper considers thermodynamic and kinetic issues in targeted synthesis that are associated with control over the composition, structure, characteristic features of chemical bonding, and particle size and, hence, with the identification of conditions for the preparation of a substance with tailored properties. The concept of pure substance is discussed, which is an important issue for materials research and inorganic chemistry. It is pointed out that the composition of compounds should be characterized not only by their stoichiometry and impurity concentration but also by the related concentrations of native defects and impurities. In connection with this, a defect classification is presented and defect formation processes and techniques for controlling the defect composition are analyzed. Statistical criteria for assessing the compositional homogeneity of a pure substance are considered.     

Bound States and Impurity Averaging in Unconventional Superconductors

The question of anomalous transport due to a band of impurity states in unconventional superconductors is discussed. In general, the bound state energies are not in midgap, even in the unitarity limit. This implies that, generically, the states associated with impurities are broad resonances, not true bound states. There is no impurity band in the usual sense of the phrase. The wavefunctions of these resonances possess interesting anisotropies in real space, but this does not result in anomalous hopping between impurities. I conclude that the system of resonances produces no qualitative modifications to the T-matrix theory with impurity averaging which is normally used to treat the low-temperature transport of unconventional superconductors. However, users of this method often assume a density of states which is symmetric around the chemical potential. This is not normally the case. It is found that the non-crossing approximation is not valid in a strictly twodimensional system.     

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.     

Controlling the strength of Zr(10 1 2) grain boundary by nonmetallic impurities doping: A DFT study

Impurity segregation even small amounts,can drastically change the cohesive properties of the grain boundaries(GB),eventually leading to intergranular embrittlement and failure of the materials,thereby effectively controlling the types and the concentrations of the impurity is very important.In this work,the nonmetallic impurities(C,H,O,N) segregation and their effects on the strength of Zr(10 1 2) GB were thoroughly investigated using first-principles calculations based on density functional theory.A comprehensive analysis of the interstitial configurations and the relative site energies indicating that C,N and O overwhelmingly prefer the octahedral sites,only H,prefers to reside in the tetrahedral sites.Moreover,the strengthening/embrittlement potency of impurity atoms on the GB was estimated using both the Rice-Wang model and first-principles tensile test calculations.The results show that all impurities,exhibit a strong segregation tendency near the GB region.The segregation of C,N and O has a remarkable strengthening effect on strength of the GB,whereas the presence of impurity H weaken the GB.Most importantly,the underlying mechanism of the strength change of the GBs due to the segregation of impurities was profoundly discussed by charge density and the bond lengths analyses,revealing that the strengthening effect especially for C-doped GB,mainly comes from an enhancement of the charge density across the GB plane.In the end,we expect that our results will be certainly useful for future theoretical and experimental investigations on Zr and its alloys.     

A new technique for estimating the average and total impurity concentrations in samples of high-purity substances

A new technique in which the entire set of impurities in a substance is represented as a set of impurity classes has been developed for estimating the most likely and total concentrations of elemental impurities in samples of high-purity substances. Estimates of the purity of samples with the use of this technique have lower random and systematic errors in comparison with estimates without impurity classification. It has been shown that estimates of the integral characteristics of individual impurity classes in the total set of samples allow one to find the expectation of the total concentration for impurity classes which are represented in particular samples only by detection limits. The results are illustrated by the example of the rare-earth oxide samples in the Exhibition–Collection of Extrapure Substances.     

Investigation of the reaction impurities associated with methylamphetamine synthesized using the Nagai method

The synthesis of methylamphetamine hydrochloride from l-ephedrine or d-pseudoephedrine hydrochloride via reduction with hydriodic acid and red phosphorus was investigated. Eighteen batches of methylamphetamine hydrochloride were synthesized in six replicate batches using three different reaction times. This allowed the investigation of the variation of impurities in the final product with reaction time. The results obtained have resolved previously conflicting impurity profile data reported in the literature for this synthesis route. The impurity profile was shown to change with reaction time, and all previously reported impurity components were identified but not in all batches. Additionally, 20 batches of methylamphetamine hydrochloride were synthesized from either from l-ephedrine or d-pseudoephedrine hydrochloride in reactions which were allowed to proceed for 24 h. The impurities present in the resulting batches were investigated, and route-specific impurities present in all batches were identified. Batch-to-batch fluctuations in the resultant chromatographic impurity profile, despite careful synthetic monitoring and control, were also noted.     

Combined approach to the analysis of recombinant protein drugs using hollow-fiber flow field-flow fractionation, mass spectrometry, and chemiluminescence detection

The impurities present in recombinant protein drugs produced by large-scale refolding processes can not only affect the product safety but also interact with the expressed protein. To relate the impurity profile to conformation and functionality of the protein drug, analytical methods able not to degrade the sample components should be preferred. In this work, an urate oxidase (uricase) drug from Aspergillus flavus expressed in Saccharomyces cerevisiae, and a reagent-grade uricase from Candida sphaerica expressed in Escherichia coli, are analyzed by combining hollow-fiber flow field-flow fractionation with matrix-assisted laser desorption-ionization time-of-flight mass spectrometry (MALDI/TOFMS) and with chemiluminescence enzyme activity assay. Preliminary detection and identification of sample impurities is performed by means of conventional methods such as RP HPLC with electrospray ionization quadrupole-TOF MS and MALDI/TOFMS with SDS PAGE and 2D SDS PAGE. Results show that the recombinant uricase samples obtained from different microorganisms have different impurities and different enzymatic activity and that different uricase oligomers are present in solution.     

Impurity states in the excitonic phase

The influence of impurities on the excitonic phase is reinvestigated. Treating the scattering of a particle or a hole by an impurity exactly, we find that a single impurity gives rise to a bound state in the energy gap of the excitonic state. For finite concentrations of impurities the superposition of such bound states leads to the formation of an impurity band. The occurrence of such structures in the gap is due to the pair-breaking effect that normal impurities have on the excitonic state. The reduction in the transition temperature caused by impurities is also considered. It is found that the magnitude of the critical concentration at which the excitonic state is completely destroyed depends on the charge of the impurities.     

Significance and systematic analysis of metallic impurities of carbon nanotubes produced by different manufacturers

Commercially available carbon nanotubes (CNT) often contain some quantities of metallic and carbonaceous impurities. These impurities influence their physicochemical properties and performance, and accordingly a number of potential applications. The lack of information of metal impurities may also preclude accurate environmental and health risk assessments for specific CNT materials. To address these needs, a quantitative analysis of the metal contents has been made in a number of commercial carbon nanotubes produced by different manufacturers. More than 20 metals or metalloids were determined by neutron activation analysis. The results indicate arranging from 0.44 to 3 wt% of catalyst residues remained although the producers claim to provide a catalyst-free product. Most of the impurity elements are transition metals, such as Fe, Ni, Mo, Y, Co and Cr. In addition to the expected catalyst residues, other unexpected impurity elements were detected including As, Gd, W, Yb, Sm and so on. Metallic impurities in carbon nanotube materials should come from the large-scale production procedures, post fabrication and post-purification treatments. The analytical results determined by inductively-coupled plasma mass spectrometry show that a further deep purification using conventional acid reflux cannot completely remove the metallic impurities from carbon nanotubes. Post-production clean up is difficult and often incompletely.     

On a weak-coupling theory of superconducting magnetic alloys

The interaction of electrons with magnetic impurities in superconducting magnetic alloys is calculated to second order in the spin exchange coupling. Its effects on the transition temperature, the order parameter, the density of states, and the conductance are studied. The results are as follows. (1) The variation of the transition temperature with impurity concentration is the same as in the Abrikosov-Gor'kov theory; that of the order parameter is similar. (2) The density of states is finite at all nonzero impurity concentrations. Superconductivity with magnetic impurities is always gapless. (3) There are far more states about the Fermi level than in the Abrikosov-Gor'kov theory. At an impurity concentration equal to two-thirds its critical value, the density of states at the Fermi level surpasses one-half the normal value. The conductance curve loses all semblance of an energy gap.     

Impurity Effect in Silver-Point Realization

CCT-WG1 has recommended the sum of individual estimates (SIE) method to correct for the influence of impurities on the realization of temperature fixed points when a detailed impurity analysis is available. The method to estimate the uncertainty of the SIE has also been reported. On the other hand, most cells are fabricated from commercial fixed-point metals that often have no detailed impurity analysis, so the SIE calculation is impossible in that case. Due to this circumstance, and with the focus on the silver fixed point, a new fixed-point cell was fabricated in such a way that a portion of the silver ingot used was extractable during the silver casting. This portion was then analyzed by glow discharge mass spectrometry (GDMS), and the result used to calculate the SIE correction and its uncertainty. Temperature measurements during melting and freezing were collected using new and existing silver fixed-point cells under various conditions. These measurements were used to derive the slope of the silver freezing curve, from which the effect of impurities was evaluated by thermal analysis. The difference between the SIE and the thermal analysis method was evaluated to check the inaccuracy of the thermal analysis from the SIE point of view.     

冶金硅中杂质相存在形式研究

详细研究了工业硅中杂质存在形式及分布。工业硅中多数杂质偏析在硅晶界,组成深浅不同的杂质相,组分能谱分析证明颜色差异由铁、钛、铝、硅含量不同造成。白色区域是富Fe-Al-Si合金相,其中铁、硅含量分别大于35%和45%;黑色区是富Fe-Ti-Si合金相,钛和铁分别大于20%和30%;其余区域为富Fe-Si合金相,Al、Ti含量较少,Ti含量高颜色深,Al含量多颜色浅,其它金属杂质元素则无规律地分布于杂质相中。杂质分布规律与其含量和分配系数相一致。     

Selective impurity segregation at a near-Σ5 grain boundary in MgO

Grain boundaries (GBs) together with their associated impurity segregation often affect or alter properties of many polycrystalline materials. However, their atomic-scale structures remain difficult to resolve spatially, especially for those with an orientation misalignment. Here, we apply a bicrystal technique to fabricate the near-Σ5 GBs of MgO with a misalignment angle from the exact Σ5 orientation relationship and show an unexpected selective impurity segregation behavior at this GB. We find that the near-Σ5 GB comprises an alternating array of five exact Σ5 GB structural units and one deformed Σ17 GB unit, and interestingly that the Ca and Ti impurities are co-segregated to the Σ5 GB structural units, yet are not to the deformed Σ17 GB structural units. The findings are important for the understanding of GBs with a misalignment and impurity segregation and for correlating structures with properties in polycrystalline materials.     

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.