G. Musch

Expert system for pharmaceutical analysis : I. Selection of the detection system in high-performance liquid chromatographic analysis: UV versus amperometric detection

The usefulness of amperometric detection in pharmaceutical analyses was investigated for different groups of drugs. The UV response at 254 nm and that at the absorption maximum of the solute were compared with the electrochemical signal obtained. The minimum detectable concentration (nanograms on-column) of each substance is reported for the three different detection systems. This comparison was performed for 72 drugs (local anaesthetics, antipyretics, tricyclic antidepressants, sulphonamides, sex hormones, beta-adrenoceptor blocking agents, phenothiazines, alkaloids, diuretics and penicillins). The median limit of detection of the amperometric detector (see definition in the text) is 1.0 ng on-column and the median gain in sensitivity, compared with UV detection is 22.5.

A strategy for the determination of beta blockers in plasma using solid-phase extraction in combination with high-performance liquid chromatography

This paper describes a general approach for the therapeutic drug monitoring of 13 different beta blockers in plasma. The chromatographic system contains a cyanopropyl-bonded phase as a stationary phase in combination with a mobile phase composed of acetonitrile and phosphate buffer (pH = 3, mu = 0.05). Two modes of detection are used, namely, UV detection and fluorescence detection. The sample pretreatment is performed with a nitrile-sorbent in combination with methanol-phosphate buffer (pH = 3, mu = 0.05) or with methanol containing 0.1% propylamine as eluent. Acceptable recoveries are obtained for practolol, acebutolol, pindolol, oxprenolol, mepindolol, atenolol, propranolol, prenalterol, alprenolol, metoprolol, sotalol and nadolol. For labetalol, however, the elution recovery has to be improved. Finally, this approach is illustrated by the assay of nadolol in the plasma of patients suffering from hypertension, who had received an oral formulation of the drug.

Isolation of basic drugs from plasma using solid-phase extraction with a cyanopropyl-bonded phase.

The use of a CN sorbent for the isolation of basic compounds from plasma is described. Adsorption from water and plasma was investigated for a test set of 30 basic drugs. It was found that compounds with a carbon chain length greater than or equal to 11 are totally retained and that the competitive effect of the matrix on the adsorption is minimal. Methanol-phosphate buffer (pH 3, mu = 0.05) (50:50) yielded good recoveries for more polar compounds; apolar basic drugs can be efficiently eluted using methanol containing 0.1% propylamine. Water up to 3 ml can be used for the washing step. This approach was applied to the determination of eight drugs in plasma at therapeutic levels. The absolute recoveries (n = 6) obtained were 98.8 +/- 7.3% for papaverine, 82.3 +/- 3.9% for practolol, 83.4 +/- 2.6% for metoclopramide, 87.3 +/- 5.8% for imipramine, 82.8 +/- 3.3% for procaine, 82.7 +/- 4.6% for morphine, 87.5 +/- 7.2% for propranolol and 90.4 +/- 6.2% for yohimbine.

An expert system for the optimization of columns, operating conditions and instrumentation for high-pressure liquid chromatography

SummaryGiven the mobile and the stationary phase and values for the physical parameters such as temperature and pH, a separation can be optimized by varying the so-calledchromatographic parameters. These include the column dimensions, particle size, operating conditions (e.g. flow rate, attenuation) and instrumentation (e.g. detector cell, time constant). Optimization of the chromatographic parameters implies finding the best possible set of values, which we define as yielding (i) sufficient separation and (ii) sufficient sensitivity in (iii) the shortest possible time. Finding the best possible conditions (the global optimum) is very difficult for chromatographers in practice.An expert system is described that allows chromatographic optimization to be performed for isocratic separations. An initial chromatogram is required to consult the system. In return, the system provides a complete set of chromatographic parameters, which represents the global optimum within the limits set by the required resolution and signal-to-noise ratio specified by the user. The tolerated flow and pressure ranges, the volume of the available detector cells and the time constant of the detection system are constraints during the optimization. A separate module of the system concerns the sample preparation for pharmaceutical formulations in solid dosages and aqueous solutions.Prototype expert systems have been successfully implemented in the expert-system shell Knowledge Craft on a MicroVAX workstation.

Expert system for pharmaceutical analysis. II: Relative contribution of and rule validation for amperometric detection (oxidation mode)

Abstract The expert system predicted correctly whether a drug could be detected with an amperometric detector (oxidation mode) in 93% of the compounds investigated. The validation was performed for drugs possessing a low molar extinction coefficient and for pharmaceuticals containing only small amounts of drugs. For 50% of this group of drugs, the amperometric detector could be used and the sensitivity was significantly increased in comparison with UV detection. The remaining groups of drugs, i.e. , for those for which neither UV detection nor the amperometric detector offered a solution, are also reported, together with some UV-inactive drugs that could be determined only by amperometric detection.

Expert system for the selection of high-performance liquid chromatographic methods for the analysis of drugs

Abstract An expert system for the selection of high-performance liquid chromatographic methods is described for the label claim analysis of drugs in pharmaceutical formulations. The system contains knowledge for the selection of a suitable detection mode (UV detection or electrochemical detection in the oxidative nmode), an appropriate chromatographic mode (reversed-phase with water, reversed-phase with buffers or normal phase) and the starting mobile phase compositions in each chromatographic mode. The chromatography is performed on a single type of column, namely a cyanopropyl column. The implementation of the knowledge in the commercially available expert system shell (KES) is also described. As a knowledge representation method, production rules are used.

Feasibility study concerning the use of expert systems for the development of procedures in pharmaceutical analysis

The feasibility of using expert systems for the development of analytical procedures is investigated. A system for the computer generation of procedures to determine active drug substances in commercial formulations is proposed. It is shown that in nearly 85% of the cases investigated the present system immediately yields a correct procedure or conclusion. It is concluded that selecting methods and developing procedures with the use of expert systems is difficult but feasible.

Integration of optimization methodology with expert systems

Abstract An expert system for ion-pair liquid chromatography of basic drugs is described. Integration of experimental optimization methodology into the expert system is shown to be feasible. The system consists mainly of four modules: an introductory module, and initial guess module, a formal optimization module and an adaptation module. The formal optimization module, based on a simple 2 × 2 factorial design and an overlapping resolution map, is integrated with the expert system. The expert system was validated on 20 basic drugs and their 60 synthetic mixtures combined by using a random method. The rate of succes was satisfactory.

Determination of pentoxifylline and its 5-hydroxy metabolite in human plasma by solid-phase extraction and high-performance liquid chromatography with ultraviolet detection

The simultaneous determination of pentoxifylline and its 5-hydroxy metabolite in human plasma was performed: 10 ng/ml pentoxifylline and 15 ng/ml metabolite were determined at a signal-to-noise ratio of 3. The recoveries from plasma at a 100 ng/ml level were 98.0 and 86.9% for pentoxifylline and the metabolite, respectively. The intra- and inter-assay coefficients of variation were less than 5% for both pentoxifylline and the metabolite. This method shows advantages over many other published extraction procedures prior to high-performance liquid chromatographic analysis in terms of its speed and ease of manipulation.