药物中磺酸酯类基因毒性杂质研究进展

该文概述了近10年来有关药物中基因毒性杂质监管指南的完善历程与相关检测方法的研究进展。介绍了基因毒性杂质从早期的完全避免到目前的阶段化毒理学关注阈值（TTC）的风险控制理念以及各主流监管机构的具体要求。作为一类重要的基因毒性杂质,磺酸酯主要来源于磺酸及衍生物与低级醇（如甲醇、乙醇、异丙醇等）之间发生的副反应,具有化学结构类型多样化的特点。该文较为详尽地介绍了磺酸酯的形成机理和文献所采用的液相色谱法和气相色谱法,并对色谱方法的选择、预处理方式、衍生化方法及相应痕量水平的灵敏度和回收率等进行了评述。由此期望为合理控制药物中磺酸酯类基因毒性杂质,为保证药物的质量安全性提供有益的指导意见。     

Synthesis of (Carbo)nucleoside Analogues by [3+2] Annulation of Aminocyclopropanes

(Carbo)nucleoside derivatives constitute an important class of pharmaceuticals, yet there are only few convergent methods to access new analogues. Here, we report the first synthesis of thymine‐, uracil‐, and 5‐fluorouracil‐substituted diester donor–acceptor cyclopropanes and their use in the indium‐ and tin‐catalyzed [3+2] annulations with aldehydes, ketones, and enol ethers. The obtained diester products could be easily decarboxylated and reduced to the corresponding alcohols. The method gives access to a broad range of new (carbo)nucleoside analogues in only four or five steps and will be highly useful for the synthesis of libraries of bioactive compounds.     

Biosensors for pharmaceuticals based on novel technology

The availability of pharmaceuticals to treat and to prevent disease has brought great benefit. Nevertheless, attention is being drawn to the uncontrolled use and careless disposal of medications for humans and animals. These compounds and their metabolites are found in the environment and foodstuffs, with possible adverse risks to human health.Detection of pharmaceuticals and residues in environmental and biological matrices has become a priority for governmental agencies. However, current analytical methods capable of detecting pharmaceuticals at very low levels require time-consuming sample preparation, concentration and/or extraction prior to analysis.Biosensors offer several advantages over existing techniques (e.g., less time, high-throughput screening, improved sensitivity, real-time analysis and the possibility of developing label-free detection methods and devices). Also, incorporation of nanotechnology into biosensor systems may increase the speed and the capability of the diagnostic methods. Moreover, the possibility of using biosensor systems in different configurations allows us envisaging their implementation as point-of-care systems or multiplexed devices.This review provides a general overview of the progress, the limitations and the future challenges of biosensors for detecting pharmaceuticals.     

HPLC Coupled with in-line photolysis, hydride generation and flame atomic-absorption spectrometry for the speciation of tin in natural waters

The use of an in-line photolysis coil in a continuous-flow system of high-performance liquid chromatography coupled with hydride generation and flame atomic-absorption spectrometry for the speciation of tin in natural waters is described. Irradiation with ultraviolet light is shown to convert tributyltin into organic tin(IV), from which a volatile hydride can be produced in the conventional way. The effect of various conditions on the analytical performance is discussed. A detection limit of 2 ng for tin was obtained, and the tin species could be completely separated within 6 min. Use of the technique for quantification of tributyltin compounds in local coastal waters is described.     

Background theory and applications of microemulsion electrokinetic chromatography

Microemulsion electrokinetic chromatography (MEEKC) is an electrodriven separation technique. Separations are achieved using microemulsions which are nanometre-sized oil droplets suspended in aqueous buffer. The surface tension between the oil and water components is reduced by covered the oil droplet with an anionic surfactant such as sodium dodecyl sulphate and a co-surfactant such as a short-chain alcohol. This review summarises the various microemulsion types and compositions that have been used in MEEKC. The effects of key operating variables such as pH and temperature are also described. The application areas of MEEKC are also described in some detail. MEEKC has been applied to a wide range of water-soluble and insoluble both charged and neutral compounds. Examples are described which include analysis of derivatised sugars, proteins, pesticides and a wide range of pharmaceuticals. At present there are only a limited number of publications describing the use of MEEKC but it is anticipated that this number will increase rapidly in the near future as more awareness of the separation possibilities that MEEKC presents increases.     

Copper‐Catalyzed Aerobic Oxidative C?C Bond Cleavage for C?N Bond Formation: From Ketones to Amides

A novel copper‐catalyzed aerobic oxidative C(CO) C(alkyl) bond cleavage reaction of aryl alkyl ketones for C N bond formation is described. A series of acetophenone derivatives as well as more challenging aryl ketones with long‐chain alkyl substituents could be selectively cleaved and converted into the corresponding amides, which are frequently found in biologically active compounds and pharmaceuticals.     

Copper‐Catalyzed Aerobic Oxidative CC Bond Cleavage for CN Bond Formation: From Ketones to Amides

A novel copper‐catalyzed aerobic oxidative C(CO)? C(alkyl) bond cleavage reaction of aryl alkyl ketones for C? N bond formation is described. A series of acetophenone derivatives as well as more challenging aryl ketones with long‐chain alkyl substituents could be selectively cleaved and converted into the corresponding amides, which are frequently found in biologically active compounds and pharmaceuticals.     

A simplified procedure for the determination of butyltin species in water

A method is described for the analysis of solutions containing inorganic tin and butyltin compounds. It can be used to determine total tin at a concentration of 20 ng dm^?3 using a 5 dm³ sample. The method is based on solvent extraction with dichloromethane containing tropolone and determination of the tin as inorganic tin by atomic absorption spectroscopy using electrothermal atomization. The extracted butyltin compounds can be separated by paper chromatography and the tin content of the individual spot determined as above. Observations on the stability of butyltin compounds in water at the ～2 mg dm^?3 (Sn) are included.     

Fluorine chemistry at Central Glass

Central Glass produces a diverse range of fluorocompounds for pharmaceuticals, agrochemicals as well as for semiconductor industries. Some of its products and chemistry developed at Central Glass in the field of industrial fluorine compounds are described.     

Speciation of n-butyltin compounds by atomic absorption spectrometry with an electrothermal quartz furnace after hydride generation

A method is described for the speciation of n-butyltin compounds. The compounds are volatilized from aqueous solution, trapped on a chromatographic packing material contained in a teflon column, and separated on the basis of differing boiling points. The column is attached directly to an electrothermal quartz furnace of an atomic absorption spectrometer for detection at 224.61 nm. Absolute detection limits (3σ) are 11–45 pg as tin, calibration curves are linear to 13 ng, and reproducibility at the 2-ng level ranges from 5% for mono-n-butyltin to 18% for tri(n-butyl)tin.     

Characteristics and flow behavior of molten tin-polypropylene blend systems

An experimental study of tin-polypropylene compounds involving melt mixing and melt extrusion and molding over a range of temperatures is described. Problems of coalescence which make continuous mixing impossible above the melting temperature are described. Significant coalescence of the tin also results in extrusion and injection-molding problems. The influence of tin content and melt temperature on shear viscosity and extrusion character is discussed and interpreted. The electrical properties of the compounds are investigated.     

Studies of human and veterinary drugs' fate in environmental solid samples--analytical problems

The improvement of medical care worldwide is one of the reasons for the increasing production of pharmaceutical products. Human medicines are affordable to a greater proportion of the world's population. But a significant amount of used pharmaceuticals can create problems--accessibility to high volume production pharmaceuticals contributes to an increased contamination in the environment and the possibility of adverse effects on humans and animals. Many of these substances and their metabolites end up in the soil, sediments, and sludge. Knowledge regarding the environmental occurrence of pharmaceutical products is increasing, but information in the peer-reviewed literature regarding the fate and effects of most pharmaceuticals is limited. One of the reasons for this lack of data is that, until now, there have been few analytical methods capable of detecting these compounds at the low levels, which might be expected in the environment. This review article covers recent developments in the analysis of pharmaceuticals in environmental solid matrices (including soil, sediments, and sludge). We will report applications of different solid sample extraction methods, and current advances in liquid chromatography coupled with mass spectrometry for detection and identification of selected drugs in sludge, soils, manure, and sediments.     

Simultaneous determination of butyltin and phenyltin compounds in oysters by capillary gas chromatography

A method is described for the simultaneous determination of butyl- and phenyltin compounds in oyster samples. The organotin compounds were extracted (as chlorides) from oyster homogenates with hydrochloric acid and benzene in the presence of 0.05% tropolone. These compounds were converted into pentyl derivatives with pentyl Grignard reagent and then analysed by capillary gas chromatography with a flame photometric detector equipped with a 393-nm filter. The recoveries of six organotin compounds added to oyster samples ranged from 71 to 74%. The detection limits of butyl- and phenyltin compounds were in the 5-9 pg range as tin. We detected significant amounts of three organotin compounds (di- and tributyltin and triphenyltin) in oyster samples.     

A review on synthetic approaches of heterocycles via insertion-cyclization reaction

Abstract

Heterocyclic compounds have a wide range of applications: they are predominant among the type of compounds used as pharmaceuticals, agrochemicals, fine chemicals, electronic components, polymers, and veterinary products. There is a vast scope to develop new heterocyclic compounds considering the high yield, low waste, and green synthesis. In this review, we have described the synthesis of heterocycles via insertion and cyclization which is achieved in recent years with the ideas, challenges, and milestone reactions.     

An evaluation of reversed-phase and ion-exchange chromatography for use with inductively coupled plasma—mass spectrometry for the determination of organotin compounds

An evaluation of reversed-phase high-performance liquid chromatography (HPLC) employing mobile phases compatible with direct coupling to inductively coupled plasma-mass spectrometry (ICP-MS) is described for the selective and sensitive detection of organotin species. The findings of this study are compared with established methods, employing ion-exchange chromatography. In order to achieve optimum performance, both the HPLC and ICP-MS were optimized for speciation work. The results from studies using various mobile phases for the separation of a range of tin compounds (inorganic tin, tributyltin, dibutyltin and monobutyltin) are discussed both in terms of resolution and compatibility with ICP-MS instrumentation. Tropolone, a commonly used complexing agent for organotin species, is also discussed with reference to the chromatographic separation of tin species. Finally, the role of isotope dilution analysis in conjunction with HPLC-ICP-MS for organotin speciation is described with respect to the European Community Standards, Measurements and Testing (BCR) certified material programme.     

Determination of caffeine and associated compounds in food, beverages, natural products, pharmaceuticals, and cosmetics by micellar electrokinetic capillary chromatography

A method is described for quantitating caffeine, theobromine, theophylline, paracetamol, propyphenazone, acetylsalicylic acid, salicylic acid, and codeine phosphate in corresponding real samples of food, beverages, natural products, pharmaceuticals, and cosmetic preparations by micellar electrokinetic capillary chromatography. The separation is carried out at 25 degrees C and 25 kV, using a 20mM phosphate buffer (pH 9.0), 80mM sodium dodecyl sulfate, and 7.5% (v/v) acetonitrile. UV detection is at 210 nm. The method is shown to be specific, accurate (recoveries over the range 98.9-101.2%), linear over the tested range (correlation coefficients >/= 0.9993), and precise (relative standard deviation below 2.1%). The method is applied for the quantitative analysis of these compounds in different foods, beverages, natural products, pharmaceuticals, and cosmetic products.     

Application of microemulsion electrokinetic chromatography to the analysis of a wide range of pharmaceuticals and excipients

Microemulsion electrokinetic chromatography (MEEKC) is a capillary electrophoresis (CE) technique in which solutes partition with moving oil droplets present in a microemulsion buffer. Ionised species will also separate by electrophoresis. In this paper MEEKC is shown to give highly efficient and relatively rapid separations for a wide range of pharmaceuticals, vitamins and excipients. A single set of operating conditions was used to resolve both water-soluble and insoluble compounds. The method was also used to separate both ionic and neutral compounds. The method was especially useful in the analysis of water-insoluble neutral compounds such as steroids and lecithin, which are difficult to analyse by CE. The method was found to be both quantitative and highly repeatable. The quality of the separation was found to be dependent upon the sample diluent used if large injection volumes are employed. The use of MEEKC for the determination of complex mixtures such as multi-ingredient formulations and drug-related impurities was successfully demonstrated. MEEKC offers significant advantages over many forms of CE and capillary electrochromatography (CEC) and should be considered as an extremely useful option in pharmaceutical analysis.     

Speciation and determination of tin(IV) and organotin compounds in sea-water by hydride generation-atomic-absorption spectrometry with an electrically heated long absorption cell

A method is described for the determination of nanogram or subnanogram amounts of Sn(IV) and the halides of methyltin, dimethyltin, trimethyltin, n-butyltin, dibutyltin, and tributyltin. These compounds are volatilized from water samples by hydride generation, collected on a chromatographic stationary phase, desorbed in order of increasing boiling point, and detected by atomic-absorption spectrometry with atomization in a long electrothermally heated alumina tube furnace. The absolute detection limits are in the range 0.4-1.5 ng with a reproducibility of 4-15% for inorganic tin and organotin compounds.     

Applications of capillary electrophoresis with electrochemical detection in pharmaceutical and biomedical analyses

As a high efficiency separation technique, capillary electrophoresis has been widely used in various fields of analytical science. This review discusses the applications of electrochemical detection systems combined with capillary electrophoresis in pharmaceutical and biomedical analysis. These detection methods mainly involve amperometric detection but also include conductivity detection and potentiometric detection. Its applications in the field are divided into six parts, including catechol compounds, thiols, amino acids and peptides, carbohydrates, general pharmaceuticals, and other related compounds. A relatively detailed discussion is described for each compound under the current studied. On this basis, we have suggested several conceivable directions for capillary electrophoresis with electrochemical detection in the future.