Combinatorial Chemistry & High Throughput Screening - Volume 13, Issue 8, 2010

Analytical chemistry is one of the oldest scientific disciplines. The development of chemistry itself has progressed significantly by analytical findings over several centuries. In recent times, analytical chemistry has stimulated not only chemistry but many fields of science, technology and society. Conversely, analytical chemistry itself has always been heavily influenced by fields like environmental protection, biology, and medicine. Analytical chemistry in the new millennium will continue to develop greater degrees of sophistication. The use of automation system for routine work will increase and the role of ever more powerful computers and software, such as 'intelligent' expert systems, will be a dominant factor. Pharmaceutical Sciences have contributed to drug development, synthesis, formulations and analysis through extensive studies in drug assays. Analytical chemists and pharmaceutical scientists play important roles in monitoring the drugs in their dosage forms and biological samples. The sensitivity of the analytical assay has a direct impact on the validity of the pharmacokinetic model which is built up from plasma concentration data. The precision and accuracy of the assay is also important, and it is not always straightforwardly estimated. Analytical methods widely utilize the knowledge of all the other disciplines such as biology, pharmaceutical chemistry, pharmaceutical technology, biotechnology and many other fields. A new significant parameter is the speed of analysis, and the resulting massive production of analytical data. From the viewpoints mentioned above, the title of this special issue, “Applications of Analytical Methods: Prospects for High Throughput Screening of Pharmaceutically Active Compounds”, was chosen so as to ask analytical chemists and pharmaceutical scientists to appreciate their great roles in pharmaceutical science. The third part of this special issue feature 4 Reviews and 6 Original Papers. Recent developments of separation techniques such as liquid chromatography, high throughput screening methodologies and spectrophotometric methods and their biological and pharmaceutical applications are presented. The third issue represents all important sensors, analytical, electroanalytical and separation methods. In the last issue, chromatographic, electroanalytical, sensor, atomic, spectroscopic and colorimetric techniques and their applications were reported. The purpose of this special issue will be to serve as a guide to what analytical methods bring to analytical and medicinal chemistry and other pharmaceutical sciences as well as briefly review their role in drugs and the new developments and validation of assay methods of pharmaceutically active compounds. This special issue is multidisciplinary. Also recent developments of application, evaluation and validation of analytical methods are focused by key topics in drug developments and analysis by assessment of the distinguished authors of this special issue. New drugs coming from biotechnology, and their dosage forms, like targeted drugs, may produce new analytical problems in the future. The various analytical methods that permit the determination of drugs in their dosage forms, raw material, biological media etc, and also their metabolites to be separated, identified and quantitatively assayed are briefly reviewed. The current significance of separation, electrochemical, spectrophotometric and other methods is highlighted, as well as the limits of trace assays. In addition to other analytical methods, the use of electrochemical methods to gain key information about drug molecules and their mechanism of action is getting one of the important ways in drug discovery. Applications of electrochemical techniques to redox-active drug development and mechanistic studies are one of the recent interests in drug discovery. Thus, I expect this special issue will assist readers to find out new information and to encourage them to contribute more to recent development on drug development and its analysis using different methods. I would like to thank to all of the authors for their excellent contributions, and the Editor-in-Chief of Combinatorial Chemistry & High Throughput Screening for his kind invitation to act as guest editor for this special issue.

A biomimetic sensor is proposed as a promising new analytical method for determination of captopril in different classes of samples. The sensor was prepared by modifying a carbon paste electrode with iron (II) phthalocyanine bis(pyridine) [FePc(dipy)] complex. Amperometric measurements in a batch analytical mode were first carried out in order to optimize the sensor response. An applied potential lower than 0.2 V vs Ag|AgCl in 0.1 mol L-1 of TRIS buffer at pH 8.0 provided the best response, with a linear range of 2.5 x 10-5 to 1.7 x 10-4 mol L-1. A detailed investigation of the selectivity of the sensor, employing seventeen other drugs, was also performed. Recovery studies were carried out using biological and environment samples in order to evaluate the sensor's potential for use with these sample classes. Finally, the performance of the biomimetic sensor was optimized in a flow injection (FIA) system using a wall jet electrochemical cell. Under optimized flow conditions, a broad linear response range, from 5.0 x 10-4 to 2.5 x 10-2 mol L-1, was obtained for captopril, with a sensitivity of 210 ± 1 μA L mol-1.

Colorimetric and atomic absorption spectrometric methods have been developed for the determination of mucolytic drug Ambroxol. These procedures depend upon the reaction of iron(III) metal ion with the drug in the presence of thiocyanate ion to form stable ion-pair complex which is extractable in chloroform. The red-colored complex was determined either colorimetrically at 510 nm or by indirect atomic absorption spectrometry (AAS) via the determination of the iron content in the formed complex. The optimum experimental conditions for pH, concentrations of Fe3+ and SCN, shaking time, phase ratio, and the number of extractions were determined. Under the proposed conditions, linearity was obeyed in the concentration ranges 4.1x10-6 - 5.7x10-5 M (1.7-23.6 μg mL-1) using both methods, with detection limits of 4.6x10-7 M (0.19 μg mL-1) for colorimetry and 1.1x10-6 M (0.46 μg mL-1) for AAS. The proposed methods were applied for the determination of Ambroxol in tablet dosage forms. The results obtained were statistically analyzed and compared with those obtained by applying the high-performance liquid chromatographic method with diode-array detection.

A novel oral controlled delivery system for benzydamine hydrochloride (BN) was developed and optimized. Hydrophilic matrix tablets of BN were prepared by using hydroxypropylmethylcellulose (HPMC) and chitosan as polymer substance to achieve required sustained release profile. The matrix tablets were prepared by both direct compression and wet granulation method. The influence of matrix forming agents and binary mixtures of them on BN release was investigated. The formulated tablets were characterized by hardness, friability, thickness, weight variation and in vitro drug release. The formulated tablets had acceptable physicochemical characters. The quantity of BN present in the tablets and the release medium were estimated by a simple, sensitive, rapid and validated HPLC method. The dissolution results show that increased amount of polymer resulted in reduced and extended drug release. F7 formulation containing 12.5% HPMC and 12.5% chitosan with direct compression method is the optimum formulation due to its better targeting profile in terms of release. Higuchi (diffusion) and Hixon-Crowell (erosion) kinetic profiles were achieved and this codependent mechanism of drug release was established. This formulation may provide an alternative for oral controlled delivery of BN and be helpful in the future treatment of primary normoreactive types of inflammation.

Butaclamol is an antipsychotic drug used in the treatment of schizophrenia. The macrocyclic antibiotics, vancomycin and teicoplanin, are proposed as chiral selectors for the design of enantioselective, potentiometric membrane electrodes (EPMEs) for the assay of (-)butaclamol. The slopes of the electrodes are near-Nernstian for the assay of (-) butaclamol with linear concentration ranges between 10-10 and 10-7 mol/L and between 10-9 and 10-7 mol/L for vancomycin and teicoplanin based EPMEs. Limits of detections varied. The electrodes were used reliably for the enantioanalysis of (-) butaclamol in serum samples.

The anodic voltammetric behavior and electroanalytical determination of rosiglitazone were studied using cyclic, linear sweep, differential pulse and square wave voltammetric techniques on a glassy carbon electrode. The oxidation of rosiglitazone was irreversible and exhibited diffusion controlled process depending on pH. Different parameters were tested to optimize the conditions for the determination of the oxidation mechanism of rosiglitazone. The dependence of current intensities and potentials on pH, concentration, scan rate, nature of the buffer was also investigated. According to the linear relationship between the peak current and the concentration, differential pulse and square wave voltammetric methods for rosiglitazone assay in pharmaceutical dosage forms and biological fluids were developed. A linear response was obtained within the range of 1x10-6M - 6x10-5M in 0.1 M H2SO4 and acetate buffer at pH 5.70 for both voltammetric methods in human serum samples. The practical analytical value of the method was demonstrated by quantitative determination of rosiglitazon in pharmaceutical formulation and human serum, without the need for separation or complex sample preparation, since there was no interference from the excipients and endogenous substances. The methods were fully validated and successfully applied to the high throughput determination of the drug in tablets and human serum with good recoveries.

This paper is the first report describing the characterization of local diatomite of Caldiran-Van region (Eastern Anatolia, Turkey). Special attention was paid to the ability of its electroanalytical performance at modified electrodes and to the potential application of diatomite-modified electrode. For this purpose, the determination of Naratriptan which is a novel oral triptan (5-hydroxytryptamine receptor agonist) in migraine treatment, by means of a carbon paste electrode modified with 10% (w/w) of diatomite was studied using cyclic and square-wave voltammetry. The experimental conditions that affect the electrode reaction process were studied in terms of pH of the supporting electrolyte, scan rate, accumulation variables, modifier composition and square-wave parameters. Using square-wave stripping mode, the drug yielded a well-defined voltammetric response in Britton-Robinson buffer, pH 4.0 at 0.84 V (vs Ag/AgCl) (a preconcentration step being carried out with an open circuit at 120 s). The process could be used to determine Naratriptan concentrations in the range 5x10-7-9x10-7 M, with a detection limit of 1.25x10-7 M (46.5 μg L-1). The applicability of the method to spiked human urine samples was illustrated.

This review is focused on the use of the electrochemical techniques, voltammetry and polarography, as well as biosensors, for the study of drug stability. In addition, this review also details the study of drug metabolism by electrochemistry and mass spectrometry. This is used as a tool to mimic drug metabolism and because it is a purely instrumental method, may have advantages over, or be complementary to, the existing biological assays.

This review article has gathered different types of electrode modification with a brief introduction given to explain several phenomena occurring at chemically modified electrodes and the mechanism of detection, followed by some interesting applications of chemically modified electrodes (CMEs) in pharmaceutical analysis, emphasizing on the biosensors and CNT-based chemical sensors.

For many years mercury electrodes were commonly used in stripping voltammetry for determination of organic compounds, owing to their high sensitivity, reproducibility and renewability. However, because of the toxicity of mercury, alternative (less toxic) electrode materials are searched. The review describes recent results regarding adsorptive stripping voltammetric determination of trace concentration of biologically active organic substances using an in situ plated lead film electrode (LFE). Such an electrode exhibits the distinct advantage of simple preparation, good reproducibility and electrochemical surface renewal. The article reviews the development, behavior and application of a lead film electrode for stripping voltammetry of biologically active organic compounds.

In the last two decades different electroanalytical methods were used for sensitive and selective determination of cephalosporins. The paper was focused on the electrochemical behavior of methoxyimino cephalosporins, reduction mechanism and nature of the process at the mercury electrode surface. Special attention was paid to the cephalosporins adsorption at the mercury surface. Based on this phenomenon, the adsorptive stripping methods were established for determination of the low concentration of these drugs in urine samples, both in vitro, and in vivo conditions. The application of Adsorptive Stripping Differential Pulse Voltammetry (AdSDPV) for the determination of cefpodoxime proxetil (CP), cefotaxime (CF), desacetylcefotaxime (DCF) and cefetamet (CEF) was summarized. The best sensitivity of in vitro determination in urine was achieved for CP, in acid solutions (LOD 7.4 10-9M and LOQ 2.4 10-8M), followed by CF, CEF and DCF. This is in accordance with the strength of their adsorption. Determination of CF and DCF by AdSDPV in vivo was also presented. Compared to other analytical methods, AdSDPV showed advantages in the simplicity of sample preparation, and over the other voltamperometric methods, higher sensitivity and selectivity.

Sibel A. Ozkan studied at Ankara University, from where she received her Pharmacy degree in 1985. She obtained her Master's (1988) and PhD (1994) degrees in the same university, Analytical Chemistry Department. She has become full professor 2003. She has been involved in several analytical chemistry projects related to electroanalytical chemistry and separation techniques on drug active compounds and DNA-Drug interactions. She has organized and participated in organizing committees of a number of international meetings related to Pharmaceutical Sciences (Series of ISOPS-Ankara-Turkey). Her research interest focuses on the electrochemical investigations of pharmaceutically active compounds and their analysis using electroanalytical, chromatographic and spectrophotometric methods, and their validations. Her research area currently moves to the development of DNA biosensors and their interactions with drugs. She is currently a faculty member at the Analytical Chemistry Department at Faculty of Pharmacy, Ankara University. Prof. Ozkan is active as a referee with Talanta, Electrochimica Acta, Analytica Chimica Acta, Chromatographia, Analytical Letters, Sensor and Actuator B, Biosensors & Bioelectronics, Journal of Separation Science and etc. She is a member of Editorial Board of Chromatographia, Talanta, The Open Analytical Chemistry Journal, The Global Journal of Analytical Chemistry, Journal of Hacettepe University, Faculty of Pharmacy, and Journal of Pharmaceutical Sciences (FABAD). She was Vice Editor of the Special Issue of CHROMATOGRAPHIA Vol. 66, 2007, “Application of Separation Techniques in Turkey” with Dr. Henk LINGEMAN (CHROMATOGRAPHIA Editor). She received Ankara University Scientific Promotion Award in 2003 and Turkish Pharmaceutical Association, Academy of Pharmacy Science Award in 2008. Prof. Ozkan is an author of 124 original and review papers. Some selected publications are cited below.