ISSN: 1573-4129

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Recent Advances in Solid-Phase Microextraction and Related Techniques for Pharmaceutical and Biomedical Analysis
Hiroyuki Kataoka

Sample preparation is essential for isolating desired components from complex matrices and greatly influences their reliable and accurate analysis. Solid-phase microextraction (SPME) is a new and effective sample preparation technique. Fibers and capillary tubes coated with an appropriate stationary phase are usually used for SPME, but alternative microextraction techniques, including solid-phase dynamic extraction using an internal coated needle, microextraction in a packed syringe and stir-bar-sorptive extraction using a coated magnetic stir bar, have been developed recently. These techniques, in combination with gas chromatography (GC), GC-mass spectrometry (GC-MS), high performance liquid chromatography (HPLC), LC-MS or capillary electrophoresis, can be used for analysis for complex mixtures. These microextraction techniques save preparation time, as well as solvent purchase and disposal costs. This review summarizes recent advances in SPME and related microextraction techniques and their applications in pharmaceutical and biomedical analysis.


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Physicochemical Profiling by Capillary Electrophoresis
Zhongjiang Jia

The physicochemical properties of pharmaceuticals such as acid dissociation constant (pKa), octanol-water partition coefficient (logP_ow), protein binding constant, inclusion complex constant with cyclodextrin (CD), and selfassociation are very important in drug design, candidate selection, and drug delivery. Capillary electrophoresis (CE) is a simple, versatile, automated, and powerful separation technique and widely applied in physicochemical profiling for pharmaceuticals. It has advantages over traditional potentiometric, spectrophotometric, chromatographic, and other methods, as CE requires very small amounts of sample and can measure compounds with impurities and low aqueous solubility. Principles and applications of CE in profiling various physicochemical properties will be reviewed.


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Critical Review of Development, Validation, and Transfer for High Throughput Bioanalytical LC-MS/MS Methods
Shaolian Zhou, Qi Song, Yong Tang and Weng Naidong

Swift growth in the use of LC-MS/MS for the analysis of drugs in biological matrices has been compelled by the need for timely and high-quality data at many stages in drug discovery and development process: from high throughput screening of drug candidates and rapid data generation for pre-clinical studies to almost 'real-time' analysis of clinical samples. Prompt and rational method development, validation, and transfer play a pivotal role in achieving the goals of "faster, better, and cheaper" for pharmacokinetic studies since this could easily account for more than 50% of the time and labor resources for a moderate-sized project. Strategy for rational method development, validation and transfer has been largely kept as institutional knowledge but rarely appeared in literature. In this review article, strategies for developing and validating robust high throughput LC-MS/MS methods will be critically reviewed and discussed. Automated sample preparation, fast chromatography, minimization of matrix effects, and strategy of narrowing the gap between validation and incurred sample analysis are just a few topics covered in this review. Other interesting approaches for improving method efficiency and ruggedness such as direct injection SPE and liquid/liquid extracts as well as multiplexing of LC columns will also be discussed. Potential pitfalls during method development and validation are pointed out. At the end, the question "how fast is fast enough and how fast is too fast?" will be answered after considering all aspects of the method development and validation.


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Analysis of the L-Arginine/Nitric Oxide Pathway: The Unique Role of Mass Spectrometry
Dimitrios Tsikas

Nitric oxide (NO) is a gaseous radical molecule. In human organism NO is produced in various cells from Larginine by the catalytical action of NO synthases (NOS). The L-arginine/NO pathway powerfully contributes to maintain multiple physiological functions, including vascular tone, platelet function and neurotransmission. The metabolic fate of NO is very complex due to the participation of numerous compounds resulting from the ability of NO to react practically with any biomolecule to produce biologically active metabolites (e.g. S-nitrosothiols) and biologically inactive metabolites (e.g. nitrate). The concentration in biological fluids and tissues of members of the L-arginine/NO family is of particular interest, as it may characterize the status of this pathway in health and disease as well as to monitor the progress of pharmacological interventions. Thus, measurement of the NO metabolites nitrate and nitrite is suitable to assess NO synthesis in vivo. On the other hand, measurement of the circulating NOS inhibitor asymmetric dimethylarginine (ADMA) was found to reliably identify pathological conditions associated with NO-related endothelial dysfunction. Among the various analytical methods currently available for the analysis of the L-arginine/NO family, mass spectrometry (MS)-based approaches such as gas chromatography-mass spectrometry (e.g. GC-MS/MS) and liquid chromatographymass spectrometry (e.g. LC-MS/MS) emerged indispensable analytical tools for the reliable quantitative analysis of the whole NO family. The present article discusses the currently available analytical methods especially emphasizing the importance of the MS technology to the NO field of research.


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Alkyl Chloroformates in Sample Derivatization Strategies for GC Analysis Review on a Decade Use of the Reagents as Esterifying Agents
Petr Hušek and Petr Šimek

The neccessity to derivatize polar analytes prior to separation often disqualifies gas chromatography (GC) as a method of choice in the field of biomedical/pharmaceutical analysis. Laborious and lengthy protocols for treating compounds prior to the analysis were discouraging. Only few derivatization approaches were well-established over decades, primarily silylations. To its assets belongs universality and efficacy, to shortcomings necessity for dry residue and prolonged reaction time, often under heating. Similarly, the next field-proven esterification-acylation two-step procedures suffered from the same pre-requisites. Current investigations in the field of derivatization turned attention to chemical reactions proceeding in aqueous environment and obviating multiple reaction steps and heating. Application of alkyl chloroformates (RCF), under conditions discovered more than a decade ago, met such criteria. Instantaneous conversion of hydrophilic compounds to organophilic ones became often an integral part of sample preparation procedures with neg-ligible time and costs required. This review attempts to bring forward some of the most important studies on RCF-mediated derivatizations in the last decade and to figure out general utility of the approach in analyzing polar organic compounds by GC, with particular attention to polyfunctional organic acids, especially amino acids (AAs).


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Multicomponent Determination of Drugs Using Flow-Injection Analysis
Leah Hlabangana, Santiago Hernández-Cassou and Javier Saurina

This paper reviews the principal strategies for multicomponent determinations of pharmaceutical products and related compounds using flow-injection analysis (FIA). The relevancy of this topic in the pharmaceutical field and close areas such as clinical, food and biochemical analysis is pointed out. As an alternative to chromatographic and electrophoretic methods, multicomponent FIA is specially suitable for a rapid quantification of analytes and processing large sets of samples. The achievement of selective measurement conditions to carry out the quantification of each drug without interferences is commonly needed in multicomponent analysis. The main approaches for gaining selectivity are based on specific reagents, multi-way or fast-scanning detectors, serial and parallel multi-channel manifolds. Alternatively, chemometric methods for data analysis can be used when selectivity is not fully accomplished.


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Fluorescent Chiral Derivatization Reagents Possessing Benzofurazan Structure for the Resolution of Optical Isomers in HPLC: The Synthesis, Characteristics and Application
Toshimasa Toyooka

Indirect resolution of chiral molecules, based upon pre-column derivatization and diastereomer formation using benzofurazan bearing chiral labeling reagents, by high-performance liquid chromatography are described in this minireview. The synthesis, characteristics and application of the fluorescent chiral derivatization reagents for various functional groups, i.e. amine (NBD-PyNCS, DBD-PyNCS, DBD-β-Pro, DBD-hydroxyproline), carboxyl (NBD-APy, DBD-APy, ABD-APy), carbonyl (NBD-ProCZ, DBD-ProCZ), hydroxyl (NBD-Pro-COCl, DBD-Pro-COCl) and thiol, etc., are including in the text.


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Profiling Drug Membrane Transport via Immobilized Artificial Membrane Chromatography
Jin Sun, Tian-Hong Zhang and Zhong-Gui He

The preclinical and clinical development attrition rates of new drugs are high due to the unfavorable pharmacokinetic properties such as poor intestinal absorption and inadequate target tissue penetration, etc. Drug disposition performance in nature consists of in vivo sequential membrane transporting processes and is based on the entry into and exit of drugs from cell, even for metabolism process requiring drug to be delivered to the site of metabolic enzymes. Efficient and reliable high throughput screening that predicts these membrane permeability properties as early as possible, in drug discovery and development program is accordingly desirable.

Immobilized artificial membrane (IAM) chromatography, one of the biopartitioning modeling systems, covalently bonds monolayer of phospholipid analogs onto the solid surface of silica particles and emulates the process of drug–biomembrane interactions in terms of rapid chromatographic method. It is a valuably predictive model of drug membrane permeability and biological activity. The implementation of IAM chromatography in early drug discovery and development would effectively lower the preclinical and clinical development attrition rates, and would be able to increase the fraction of more drug-like drug candidates. The interaction mechanism of drug–IAM and its profiling in membrane transport were described in this review.


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Electrochemical Biosensors as a Screening Tool of In Vitro DNA Drug Interaction
Graziana Bagni, Mauro Ravera, Domenico Osella and Marco Mascini

The interaction of some antitumoural drugs with double stranded DNA immobilised on screen-printed electrodes was studied as a screening tool for in vitro DNA-drug interaction. In this case DNA biosensors are used for qualitative analysis as a rapid indication of the behaviour of DNA with different metal complexes and are proposed as an alternative method of the most common techniques. In fact, DNA based electrochemical biosensors represent a new research field with interesting possibilities for practical application in various areas such as environmental and pharmaceutical screening. Interactions of DNA with chemicals can result in various types of DNA damage. Many small molecules show a high affinity for DNA and they can interact with the nucleic acids immobilised on the electrode surface. The interactions between DNA and drugs can cause chemical and conformational modifications of nucleic acids and thus variation of the electrochemical properties of DNA. The presence of compounds with affinity for DNA is measured by their effect on the guanine or adenine oxidation peak. A great advantage of this kind of biosensors is that they are cost effective and they can be used with a small portable potentiostat with disposable screen-printed electrodes (SPE).

In this work, screening of some antitumoural drug is reported as example of in vitro interaction. Preliminary results have been obtained analysing different type of DNA-interacting agents as metal (Pt, Ru and Ti) complexes. The drugs analysed were cis-diaminedichloroplatinum(II) cis-[Pt(Cl)₂(NH₃)₂] (cisplatin); diamine(1,1-cyclobutanedicarboxylate)platinum(II) [Pt(NH₃)₂C₄H₆C₂O₄] (carboplatinum);cis-diamineplatinum(II)malonate cis-[Pt(NH₃)₂ C₃H₂O₄] (cis-malonate); platinum(bipyridile(pyridine)₂)²⁺ [Pt(bpy)(py)₂]²⁺; titanocene dichloride [(η⁵-C₅H₅)₂TiCl₂] (titanocene); titanocenebisglycine [(η⁵-C₅H₅)₂Ti(gly)₂] and imidazolium trans-imidazoledimethylsulfoxidetetrachloro-ruthenate [Ru(III)Cl₄(DMSO)(Im)][ImH] (NAMI-A). Groove binding, electrostatic interactions, hydrogen and/or van der Waals bonds and intercalation of planar condensed aromatic ring systems between adjacent base pairs are the interactions that the DNA electrochemical biosensor can detect. Different response behaviour has been observed with these drugs according to different interaction with DNA.


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Advances in Chromatographic Analyses of Fluoroquinolones in Pharmaceuticals and Biological Samples - A Review Article
Victoria F. Samanidou, Eleni A. Christodoulou and Ioannis N. Papadoyannis

Fluoroquinolones constitute a member of quinolone antibiotics, an expanding group of synthetic antibiotics, which are effective towards pathogens resistant to other antibacterials. They are broadly used for the treatment of several infections, both in human and veterinary medicine, due to their favourable kinetics and broad antibacterial activity.

Herein recent advances in chromatographic methods for determination of fluoroquinolones and their metabolites are reviewed, focusing on sample pretreatment, chromatographic conditions, detection techniques, method validation and application to real samples. Results of published methods are comparatively presented and criticized.