Automated wet chemical analysers and their applications

Tolonta, Vol. 20, pp. 1045-1075.

Per$amon

Press, 1973. Printed in Gr+at Britain

TALANTA AUTOMATED

WET CHEMICAL ANALYSERS APPLICATIONS J. T.

Research Laboratory,

REVIEW*

VAN

AND THEIR

GEMERT

Kodak (Australasia) Pty. Ltd., P.O. Box 90. Coburg, Vie. 3058, Australia

(Received 7 May 1973. Accepted 3 June 1973)

Summary-A applications.

review is presented

of automated

analysis,

including

instrumentation

and

The trend towards mechanization in analytical chemistry was initially characterized by the development and increasing use of instruments in which the measurement of a physical or physic+chemical parameter replaced the manipulative processes of classical analysis. Subsequently, the need for a greater rate of analytical throughput was met by automating both the instrumen~l methods and the various techniques used in classical wet chemistry, such as sampling, dilution, reagent addition, titration, phase separation and measurement. A further development which has already reached an advanced stage, involves the use of computers for data processing, report writing and ultimately for control of the various analytical parameters. In this review of automatic analysers, it is proposed to restrict the field to those types of instrument which may be programmed to perform a variety of deter~na~ons with analytically acceptable accuracy and precision with minimum intervention by the analyst between the receipt of the sample and the reporting of the result. The emphasis will therefore be on automated wet chemistry. Instrumental techniques such as automated chromatography and spectrometry are more appropriately considered in reviews of the particularchromatographic, spectrophotometric or other techniques since they basically involve the addition of an automatic sampl~handling facility to an existing technique restricted to a range of materials with a specific property such as volatility, adsorptive power or spectral absorptivity. A wide variety of continuous monitors for on-stream analysis is available. Only those instruments which meet the criteria of wet chemistry and analytical versatility will be referred to. -A number of instruments will be mentioned which have been custom-built for a particular analysis and which are not generally commercially available. The applications of automatic analysers will be dealt with under a number of headings which represent a somewhat subjective choice but also reflect the most frequent uses to which such devices have been put. Previous reviews have tended to emphasize the instrumental aspects of automated analysis. The well-known text by Siggia’ devoted one chapter to equipment and in this he covered several automatic titrators and calorimeters. This book appeared two years after the * For reprints of this Review, see Publisher’s announcement 1045

near end of this issue.

1046

J. T. VANGEMERT

commercial development of the continuous-flow type analyser by Skeggs,* the Technicon “ AutoAnalyzer “. This unit has made the largest single contribution to the technology and applications of automatic analysers up to the present time. At a 1959 Symposium on Automatic Chemical Analysis,3 thirty papers were presented of which more than half involved the use of the Technicon “AutoAnalyzer”. The symposium also illustrated the fact that clinical chemists were largely responsible for the early development and utilization of automated techniques. It was noted4 that lack of specificity of existing methods and problems of sample-handling often made successful industrial uses more difficult to achieve. However, at two subsequent symposia5V6 on the subject of “Automation in Industrial Pharmaceutical Process and Quality Control ” a variety of methods and devices was presented, some representing adaptations of existing manual procedures and some consisting of entirely new techniques. Many extensive reviews have been published on automated instruments and methods in specialized areas, such as pharmaceuticals,’ clinical chemistry,*-‘3 the petroleum industry i4*15and water analysis. ‘w’ The annual Analytical Chemistry Reviews do not incorporate automated wet chemistry as a separate heading but many of the subjects in both the Fundamental and Application sections contain specific references to automation. Some reviews have appeared in which automated classical chemistry is discussed together with other instrumental techniques.1*-z2 The general philosophy and methodology of automation in analytical chemistry has been discussed by a number of authors.8*23-30 Malissa23 considered the physical aspects of mechanization, the chemistry and physics of instrumentation and the cybernetics of the measurement and output of results. Examples of open, closed and computer-controlled systems were given. To enable the concepts to be communicated more readily, a symbolic sign language was developed,24 which was subsequently extended for use with high-level computer languages. r5 A group of German, Austrian and Swiss workers is formulating a set of definitions for the various concepts in analytical automation (see Talanta, 1973,20,811). INSTRUMENTATION

A recent report3’ predicts that the market for automated wet chemistry instruments will achieve an annual growth rate in excess of 15 % for the period between 1970 and 1980 compared with an average growth rate of 9 y0 per year for all laboratory analytical instruments (excluding computers). This indicates that a list of manufacturers and models at any one time is rapidly outdated since changes are frequent. Furthermore, availability, price and service‘vary considerably between countries. It is more meaningful to discuss types of instruments and illustrate these with reported applications. Some publications comparing commercially available analysers should be mentioned, however.‘0-‘2V32-34 The classification of automated wet chemical instruments which is most commonly used and which will be followed here is based on the method of transporting samples and reagents, i.e., continuous-flow or batchwise processing. A new type of fast parallel-flow analyser and some automatic titrators will also be discussed. The many special-purpose instruments which have been reported and which may not readily fit these categories will be mentioned under the appropriate applications. Continuous-flow instruments The widespread use of the Technicon “AutoAnalyzer ‘* testifies to the versatility of the continuous-flow system. It is assumed that the reader is familiar with the principle of operation and the range of modules which is available. A general description has been given by

Automated

wet chemical analysers

1047

Siggia’ and others. 2*7 Originally developed for clinical use, Technicon equipment is now finding an increasing number of industrial applications. The original single-channel instrument with calorimeter read-out has been supplemented by later models and analytical systems with two, three, six and twelve channels. Also, versatile accessories have been developed, a continuous digestor for temperatures above lOO”, a solid sampler, a microdistillation unit, a tape filter and alternative measurement facilities such as a spectrophotometer or a flame photometer. A variety of integrated systems for multiple determinations in clinical and environmental chemistry will be mentioned under the relevant applications. Regular Technicon Symposia have been held since 1964 and the proceedings have been published in book form. At these symposia a considerable number of applications and new instrumental developments have been reported. It is considered more useful for the purpose of this review to concentrate on publications in the general analytical literature. An excellent bibliography3’ containing 1825 references up to November 1967 has been published by Technicon. However, approximately half of the papers cited originate from Technicon Symposia. The dialyser has proved to be one of the most useful accessories, particularly in the analysis of biological materials, to effect separations between the analyte and other diffusable materials and macromolecules such as proteins which may interfere with the calorimetric measurement. The original application of the dialyser for urea nitrogen determination2.36 has been followed by others which will be referred to below. The need for a rapid and automatic Kjeldahl determination led to the development of a continuous digestor3’ in which heating for a few minutes at a temperature of 400” or higher replaces the prolonged boiling required in the manual procedure. The versatility and validity of the automated technique were demonstrated in later publications.38P3g Other workers4’ have noted that the recovery of nitrogen when compared with the manual Kjeldahl method varies with the type of compound and could be as low as 70 %. Uhl ef aI.,41 however, using standard compounds, found that the automated procedure frequently produced a better accuracy at a relative standard deviation of 2-3 % for both methods. The continuous digestor has also been used for distillation42 and evaporation of an organic solvent.43 A solid-sampling device44 was specifically developed for pharmaceutical quality control of tablets. The commercial unit manufactured by Technicon is also able to handle preweighed samples of powders. The large number of applications of the solid sampler which have been reported were reviewed by Kuzel et al.’ Liquid-liquid extraction is one of the most important unit operations in clinical as well as general analytical chemistry, and consequently many workers have attempted to devise automated techniques. Because of the extent of mechanization of continuous-flow systems it is possible to achieve an acceptable precision under conditions of incomplete or nonequilibrium extractions. Two major problems have been attack on the tubing by organic solvents and insufficient mixing of the phases. Although various grades of acid- and solventresistant tubing are now available, special precautions must be taken. A displacement technique in which water is pumped into a vessel containing the immiscible solvent was first presented by Taylor and Marsh. 45V46The same technique was applied by Roudebush4’ in the determination of an antibiotic by an absorbance measurement at 283 nm on a chloroform extract. Thus the possibility of ultraviolet-absorbing materials being leached from the pump tubing is eliminated. Mixing of two phases is usually allowed to take place by passing the air-segmented mixture through glass coils of varying lengths. To increase extraction

1048

J. T. VANGEMERT

efficiency coils filled with glass beads,47 or long spirals4s have been used. However, they suffer from a large dead volume, resulting in greater sample interaction and loss of precision. An interesting modification was used by Carter and Nickless. Each of four mixing coils in series was shaken mechanically with an amplitude of approximately 1 cm. The degree of extraction increased with the speed of vibration. At 45 Hz, extraction was essentially complete without a significant increase in diffusion. For the determination of barbiturate in serum a double extraction has been used in which a small magnetically-stirred vessel” of 5 ml capacity replaced the conventionalmixingcoil. A magnetic stirrer has also been incorporated in a flowing stream to smooth the recorded response.‘l Other techniques reported for phase separations include filtration and distillation, both of which are more difficult to automate than extraction in a continuous-flow system. A Iilter has been used in tablet assayss* to clarify solutions before measurement on a spectrophotometer. A heated in-line gas filter was constructed by Knowles and Hodgkinson to remove aerosols from an air stream containing carbon dioxide, which formed part of an enzymatic method for the determination of oxalic acid in serum. A modified Technicon microdistillation unit was used by Friestad et al. 54 for the calorimetric determination of phenols. A more elaborate unit was described by Keay and Menage5s*56 for the determination of ammonium ion and nitrate in soil extracts. It will be evident from the examples above that many authors have devised modifications or additions to standard Technicon “AutoAnalyzer” modules to solve a specific analytical problem. The usefulness of such modifications is often enhanced by other workers adapting them to different applications. A lot of effort has been spent on developing alternative readout modules replacing the standard colourimeter. Examples of new detectors are ultraviolet and visible spectrophotometers, spectrofluorimeters, atomic absorption, flame emission, potentiometric and coulometric devices, including polarographic cells and flow-through liquid scintillation counters. A series of papers by RtUiEka et a1.57-62 demonstrated the feasibility of performing substoichiometric analysis in a continuous system by a radioactive isotope-dilution technique. Mercury’* could be determined down to 5 x IO-* g by the addition of a labehed standard and zinc dithizonate followed by extraction with carbon tetrachloride, phase separation and counting of gamma-ray emission from the organic phase. Subsequently,” phase separation was found to be not necessary and a solvent displacement technique was used to avoid problems with adsorption of the zinc dithizonate reagent on the pump tubing. An increased reliability was obtained with a two-detector method.61 Not all of the modifications and special techniques reported in the literature will be commented on in detail. In Table I an attempt has been made to list these references under a number of broad headings. All have in common that at least one standard Technicon “AutoAnalyzer” component has been used. The limitations of the continuous-flow method are illustrated by the number of papers on techniques to correct errors arising from sample interaction and instrument drift. The use of a continuously flowing air-segmented stream of sample and reagents causes problems of mixing and carry-over which adversely affect the precision and accuracy of automated determinations in comparison with the corresponding manual procedure. Thiers and Oglesby’ were the first of many workers to examine the effect of instrumental parameters such as sample volume and sampling rate. They considered the errors in six determinations of clinical interest: sodium, potassium, chloride, carbon dioxide, urea and glucose. The sample interaction was quantified and found to vary from 1% (for glucose) to 10% (for carbon dioxide). They also demonstrated that errors can arise from differences in volumes

Automated Table

1. References

to accessories,

wet chemical analysers

modifications or special techniques “AutoAnalyzer ”

1049 for use with the Technicon

Sampling devices solid sampler (standard type) solid sampler (bead and chain) dual sampling suspension sampler micro sampler pneumatic sampler plastic sample covers anodic sample dissolution timing and programming modified sampler modified fraction collector

43,44,52,87,88,90,91,93,104,117,131,186 65 72 94 97 69 80 67179144147 73:80:96 ’ 92,118

Phase separations continuous filter special purpose filters distillation units solvent displacement technique shaking and magnetic stirring improved separators

43,51,52,87,88,91,95,111,131,134,151,166.186 5390 54--56,82,99,109,136,137,151,154,184 45-49,59,86,121,176 49-51 86,132.133

Detection devices ultraviolet-visible spectrophotometer multichannel photometer repetitive scanning infrared spectrophotometer flame photometer atomic-absorption spectrophotometer fluorometer luminescence scintillation counter thermometric coulometric and polarographic potentiometric testing device Coulter counter

43,47,50-52,84-88,91,94,129,131,155,188 74,75 87 135,165,186 63-65,124,125,138,174 68,70,120,124,125,167-170 66,72,100,113-116,131,149,158-1~,173,176,179,181 157 57-62,110 76 140.141,153 89,145 142 182

Miscellaneous continuous digestor chromatographic column reductor column ion-exchange column thin-layer chromatography ultraviolet irradiation and photolysis modified flow cells multicomponent determination ultrasonic bath special mixing device medical isotope production batchwise incubation interference testing modified flow system chart reading device fragile incubation coil gas absorber countercurrent dialysis air-rinsing technique

37-43,82,102,103,106,108,1~,117,123,126,139,156,175,183 74.75,78,84,130,150,181 81 131,134 71 66.94.184 85,119,127,128,152 70,74,75,80,89,102,105,107,112,131,164,166,170-173,178,182,189 51 131 98 92 143 148 177 180 184 185 187

1050

J. T. VANGEMERT

of samples placed in the sample cups. A redesigned sampler” in which the aspirator tube moved more rapidly in and out of the sample cups was shown to decrease the variability from this cause. A similar modification was used by Kuzelg6 and a subsequent model of the Technicon Sampler incorporated these changes. Two approaches may be used to minimize sample interaction. One is to change the sampling parameters until the desired precision is obtained. It has been shownlgz* rg3 that interaction can be significantly reduced by increasing the time of sample pick-up and the ratio of sampling to washing periods. However, a larger volume of sample is required and sample peaks may become difficult to read when the valleys between them become less pronounced. It can be demonstrated that the frequent objective of producing sharp peaks with deep valleys is directly opposed to obtaining optimum precision and minimum interaction. Short-term fluctuations due to electronic noise, mechanical problems, bubbles in the optical path or insufficient sample are less likely to be detected under conditions producing sharp sample peaks. The other and more frequently used procedure involves the application of an appropriate correction factor.lgl* 1g4-1g7 This factor depends on the concentration of the preceding sample, the sample and wash timing and the type of analysis being performed. The improvement in precision resulting from this correction has been up to twofold.‘g’ Several authors’g5-1g7 have applied the correction by means of a computer programme which generally performs several other functions, including drift correction, curve fitting, converting peak height into concentration and reporting in an appropriate format. The nature of the correction factor is derived from studies of the kinetic parameters in continuous-flow analysis. 1gs-zo2 Similar conclusions were reached by Thiers et a1.l” and Walker et ~1.‘~~ from a consideration of the “ lag time “, the effect of overlapping rise and fall curves and the steady-state conditions. These parameters are incorporated in the exponential correction equation for carry-over. An empirical equation was presented by Stickler et al.“’ and applied to four clinical determinations of varying degrees of complexity. It was shown that application of the correction would allow a twofold increase in the assay rate without deterioration of the reproducibility. In two recent papers, Begg201’202 derived a linear model in which the leakage between successive slugs of solution depended only on the slugvolume and distance travelled, and a non-linear model in which the leakage rate also varied (linearly) with concentration. By comparison of experimentally found rise curves with calculated concentration distributions it was found that the linear model holds for the simple systems examined. Walker203 showed that sampling rates up to 180/hr became possible by applying an exponential correction to the sloping sections of the recorder trace and generating a new curve. The calculations involved become practical only if a computer is used. No information was supplied on the precision obtainable at the higher sampling rate. It has been recognized that sample interaction is in part a result of the debubbling process which occurs just before the flowing stream enters the colourimeter cell. Habig et aL204 have devised a system in which the air-segmentation is retained but the recorder is inactivated when an air-bubble is in the cell, as detected by a conductivity measurement. The bubblegating system requires careful control over the regularity of the bubble pattern, a flowthrough cell of reduced volume, and increased flow-rate. The authors consider these factors mitigate against its routine use. An interesting application arises when more than one measurement is to be made on the one stream as in kinetic analysis. Variations in the sample time have been shown’92 to affect sample interaction and therefore precision in continuous-flow analysis. Friedman ” has shown that such variations can

Automated wet chemicalanalysers

1051

be caused by large tolerances in the mechanical specifications of sampling cams. Jansen et a1.14’ designed a new instrument around a sampling system which is based on volume rather than time. This was achieved by a pair of platinum electrodes inserted in the sample line, which activate the sample-changing mechanism when the passage of an air-bubble is detected. An improvement in the relative standard deviation from 2.0 to 1.2 % was claimed for the determination of urea. Faithfullzo5 has recently shown that a “ warm-up” time as long as 40 min may be required in order to stabilize the tubing in the peristaltic pump. Histograms of the results of nitrogen and potassium determinations demonstrated that a normal distribution and acceptably low standard deviation could be obtained after an equilibrium period which was considerably longer than the time required to stabilize the flame photometer or other measuring modules. A scheme has been recommended ‘06 for the evaluation of automatic analysers. It includes specifications for the measurement of accuracy, precision, cross-contamination, overall performance and running costs. Although the scheme is designed for clinical and biochemical analysis it should be equally useful in other fields. An assessment of the precision of five clinical determinations on the Technicon “ AutoAnalyzer” has been made.“’ An unconscious bias introduced in the manual reading of “ AutoAnalyzer” charts has been discussed by Corns and Coms.2o8 Only relatively few continuous-flow analysers of other makes are available. The Italianmade Carlo Erba instrument also utilizes a peristaltic pump for transport of samples, standards and reagents. However, it does not use air-segmentation and appears to have only a limited number of accessories. Blaedel and Olsen lz6 have reviewed (in 1963) several commercially available continuous single-purpose analysers principally used for water analysis. The continuous flow of reagent and samples by a combination of gravity and a peristalticpump feed was used by Blaedel and Hickszoq in an instrument for enzyme assay and the measurement of enzyme-catalysed reactions. To decrease the response time and prevent laminar flow the reagent line is mechanically pulsed at a frequency of 5 Hz and an amplitude which may be varied to optimize the response. Up to thirty determinations per hour may be performed. The instrument as described is only partly automated since sample change-over is performed manually. A different type of continuous analyser has been described by Natelson” and has been the subject of several patent applications2’0-2’3 assigned to Scientific Industries Inc. The instrument is claimed to be especially suitable for clinical analysis. It consists of a tape to which samples are applied from capillaries. This tape is brought into contact with another containing a reagent capable of producing a colour. The spots are then read densitometritally. The system is limited to simple chemistries and does not appear to be used to any great extent. Automatic titrations are commonly discontinuous operations. One continuous device has been described by Pauschmann2r4 in which a stream of sample to which an indicator has been added flows through a transparent channel containing a series of narrow holes. A titrant solution is pumped into the sample stream through these holes. The sample concentration can be obtained from the distance at which the indicator undergoes a change of colour. Various modifications of this principle are discussed, including alternative methods of end-point detection, such as a change in pH, temperature, conductivity and absorption of light. A similar system of flowing sample and titrant streams was patented,215 but the titrant was delivered by a variable-speed pump. The speed of the pump was servo-controlled

1052

J.T. VANGEMERT

by the difference between an electrode signal and a preset potential indicating the endpoint. The desired concentration is then obtained from the generator which feeds the variable-speed motor. A large number of special purpose instruments is now commercially available for continuous monitoring or on-line analysis of liquid and gaseous process streams. Many of these devices are purely instrumental rather than wet chemical and are capable of achieving a precision which may be sufficient for their intended purpose but which would usually be unacceptable for general analytical work. However, some involve the transfer of reagent solutions and are adaptable to the measurement of several parameters. Simpson2163217 has described the types of analysers available for the continuous monitoring of gaseous pollutants. He has indicated the limitations on selectivity and sensitivity of wet chemical techniques for some of the common gases of interest in pollution control. McWilliam*‘* has provided a listing of 41 specific and non-specific techniques, mostly continuous, for on-line analysis in the chemical and petroleum industries. He has also reviewed the factors to be considered in the justification of purchasing or developing an automated system. LGrinc219 has presented a review of automatic instruments suitable for the analysis of flowing streams. Some special problems arising in the sampling of aqueous process streams have been discussed by Babcock**’ and a guide to the selection, installation and operation of air monitoring equipment has been given by Elfers.**l Discrete-sample processers

The essential feature of discrete-sample analysers is the fact that samples are processed and conveyed in individual containers from the initial sampling up to and sometimes including the final read-out stage. Such instruments are also referred to as discontinuous, repetitive or batch analysers. The techniques used more closely approximate those in conventional wet chemistry and as a result a manual procedure is usually more readily converted into an automated version. However, the problems involved in automating phase-separation techniques (distillation, filtration, extraction) on a discrete basis are probably responsible for the greater popularity of continuous-flow methods. There are some distinct advantages in discrete-sample processing. Since each step in the procedure is independent, trouble-shooting is greatly facilitated. Individual samples retain their identification without ambiguity, and interaction or cross-contamination may readily be eliminated. An inherently greater sensitivity may be expected because the measurement in the static system requires less solution than in a flowing system. In general, the consumption of samples and reagents is considerably less. One might also expect an easier adaptation of alternative read-out techniques. However, this is not borne out by published work in this area. The distinction between continuous and discontinuous processing is not always clear, since each uses some features of the other. Sample presentation in a continuous system is usually performed on a discrete basis by means of a turntable with individual containers. On the other hand, the measurement stage of a discrete-type instrument generally involves the transfer of the reaction mixture into the flow-through cell of a colourimeter or spectrophotometer. It is known that many commercial instruments have been produced from time to time and an even larger number of special purpose analysers have been constructed. In spite of this, relatively few publications have appeared in which such instruments have been evaluated or compared with manual or continuous techniques. A large proportion of the papers

Automated wet chemical analysers

1053

published has in fact been written by those involved in the building and development of analysers rather than by the users. Kuzel, Roudebush and Stevenson’ have reviewed the literature on automated techniques in phar.maceutical analysis up to July 1968. Their paper covers a number of batch analysers from the very simple automated colourimeters to the very elaborate systems capable of 3000 determinations per hour, with data-processing facilities. Therefore, mainly the more recent work will be reviewed here. Many of the commercial and special instruments have been designed for clinical analysis. 1o*34Five instruments of British manufacture have been reviewed by Rose.‘? Trotman has described an apparatus consisting of a sample turntable and four syringe-dispensers for the reagents in the Wassermann test. Sampling is performed manually and the test result is assessed visually. An instrument was developed by Westlake et ~1.~~~in which each sample is accompanied by an IBM card containing the relevant information. Sampling and reagent dispensing is performed by pipettes and syringes at a rate of 120 samples per hour. Carryover in the calorimeter cell is about 2 % and after correction for this the relative standard deviation for aqueous glucose standards varies from 0.2 to 0.7%. The photometer signal and the information on the card are simultaneously processed by a computer. Three analysers performing seven different tests with varying degrees of automation are linked to the central data-logging system. A relatively new instrument, the “Autolab,” made by A. B. Lars Ljungberg & Co., Sweden, has been described by Aberg. 224 It is modular in construction and comprises sampling and reagent units, an incubator and a calorimeter with digital display or print-out. Samples are transported in tubes held in chain holders of unlimited length. Carry-over is minimized by the application of wash-water followed by suction to the outside of the sampling probe. A suction device for the removal of gases has been described by Hulthe et aZ.225Again, the “Autolab” is principally designed for clinical analysis. It can handle 240 samples per hour and reproducibilities between 1.O and 3.8 % have been claimed for a variety of determinations. An apparatus for enzyme assay was constructed by Cove226 from a Unicam SP800 spectrophotometer with a cell-changer and programme-controller. Eight Hook and Tucker diluter units were used to dispense the sample enzyme with and without the substrate materials in four sample and four reference cells respectively. The sequence of operations was controlled by a Londex Rotaset Program Timer at an analysis rate of .48 assays per hour. It was claimed that the reproducibility of 10 % was accounted for by dispensing inaccuracies. Enzyme analysis was also performed with a Unicam AC60 system.227 This instrument also consists of a chain of tubes which passes a number of reagent stations before the solution is finally transferred to a spectrophotometer. A coefficient of variation of 2.7 y0 was claimed for eleven determinations on each of two serum samples and excellent agreement between the automated and manual methods was demonstrated. Several specially built automatic stopped-flow instruments have been described for kinetic determinations, utilizing motordriven syringes228 and valves or pneumatically-actuated components.22g The latter system was shown to produce faster mixing and reduced dead time. Approximately 1000 phosphate determinations per hour could be handled at relative standard deviations of l-3%. Potentiometric measurements by selective ion-sensitive electrodes have been automated on a discontinuous basis. A system for the determination of pH of soil was presented by Baker230 in which containers move on an endless belt. Addition of water, stirring, pHmeasurement and rinsing are performed automatically at a rate of 100 samples per hour. A

J. T. VANGEMERT

1054

more elaborate device for the determination of sodium, potassium, chloride and pH in blood was constructed by Dahms. 231 The system incorporates a peristaltic pump, a pneumatic timer, a rotary valve and specially made glass capillary flow-through electrodes for the alkali metals and pH. A pH-meter with an automatic probe-selector is connected through a data-transfer system to a card punch for data logging. Each cycle of measurements requires 65 set and calibration is performed after each tenth sample. The speed of analysis is limited by the electrode response. This parameter and its effect on the precision of automated measurements with selective ion-sensitive electrodes has been discussed by Malissa and JtIlintk.232 Solvent extractions have been automated by several workers233-236 and applied to the determination of dttergents23”*Z34 and an oil-additive. 234 A typical discrete system consists of commercially available syringe-dispensers and a beaded coil, followed by a phaseseparator and a flow-through cell in a spectrophotometer. Later, a continuous-flow method was developed r3’ which could extract trace amounts with equal efficiency and greater versatility. Two di&rent systems based on the timed flow of reagents through precision-bore tubing and a centrifugal separator were described by Trowe11.236 An apparatus for the automated determination of mercury was constructed by Lindstedt and Skare.237-z39 It consists of a peristaltic pump for the batchwise addition of reagents to predigested samples and transfer to a tower for scrubbing with nitrogen. The gas, containing the mercury vapour, is then passed through a flow-through gas cell in a spectrophotometer. An elaborate instrument for the evaluation of antibiotics and vitamins has been constructed by Kuzel and Kavanagh. 240*241It is based on a turbidimetric determination on an incubated sample to which a nutrient broth has been added. The equipment comprises a sampling and reagent module, an incubator and a measurement module. Data can be printed out or processed by an on-line computer. Table 2 lists the majority of currently available automatic analysers utilizing discontinuous processing. Some instruments used exclusively for clinical applications have been included for comparative purposes. Where general use is indicated the instrument has frequently been designed for clinical laboratories but has sufficient versatility to be programmed for a variety of determinations. A filtration, or in biochemical terms a deproteinization step, is of importance in many clinical methods and several of the instruments shown in the table have this capability. One model, the “ Mecolab,” combines the advantages of automation with the versatility of batch processing. Samples are treated in groups of fifteen on each module (dilution, centrifugation, measurement) for 3-min periods. Transfer from one module to another is performed manually. An automatic microcentrifuge is available on one instrument, the Quickfit 617 Automatic Analyser, but no information is available on its performance. Fast parallel

analysers

A new approach towards high-speed automated analysis was taken at the Oak Ridge National Laboratory by Anderson with the development of a fast analyser based on the transfer of samples and reagents by centrifugal force. z67-277 The prototype of this instrument was given the name of GeMSAEC (General Medical Sciences, Atomic Energy Commission). It employs a “Teflon ” rotor containing cavities to hold samples and reagents. By spinning at speeds of about 1200 rev/min the solutions art mixed and transferred into a

Automated

wet chemical analysers

Table 2. Commercially Manufacturer,

instrument country

and

AB Lars Ljungberg, Autolab, Sweden AGA Corporation, AutoChemist, Sweden Amer. Instr. Co., Assayomat, U.S.A. Amer. Opt. Instr. Co., Robot Chemist, U.S.A. Baird & Tatlock, Analmatic Clinical System, U.K. Bausch & Lomb, Automatic Sample Processor, U.S.A. Beckman, Discrete Sample Analyzer, DSA-560, U.S.A. Du Pont, Automatic Clinical Analyzer, U.S.A. Electra-Nucleonics GeMSAEC Systems, U.S.A. Gilford, Automatic Enzyme Analyzer, Model 3400, U.S.A. Griffin & George, Bioanalyst, U.K. Hycel inc., Mark X, U.S.A. Joyce Loebl, Mecolab, U.K. Lab-Line, Clinomak, Mark II, U.S.A. LKB, Ultrolab System, Sweden Perkin-Elmer, C4 Automatic Analyzer, U.S.A. Quickfit & Quartz, 617 Automatic Analyser, U.K. Radiometer, ATSl Autopipetting Titration System, Denmark Unicam, AC60 Chemical Processing Unit, U.K. Union Carbide, Centrifichem, U.S.A. Vickers, Multi-channel 300,

Use@)

1055

available discrete analysers

Detection system(2)

Presentation of results’“)

Max. No. of samples/hr

References

C,G

co

DD,DP

240

224,225

C

co

DD,DP,CM

135

242

P

SP

R

C,G,P

SP

DD,DP

120

244-248’

C

CO,FP

DP

300

12

G

CO,SP

DD,DP

300

C,G

co

R,DD,DP,TY

160

34,249,250

C

co

DP

loo

34,251,252

C

CO,SP

R,OD,TY,CM

300

253,254

C

SP

DP

C,G

COC4’

DP

120

12

co co

R R,DP R

400 240 300

255 12 34

C,G C,G

CO’“’ SP

DD,DP R,DP

400 120

256 34,257-259

C,G

CO’6’

DP

100

12

G

P

DP

G

SP

R,DD,DP

120

C

co

DP

600

34,227 260-264 34,265

C

CO,SP,FP

DP,TY,CM

300

12,34,266

: C

243

(I) C: clinical, G: general, P: pharmaceutical. w CO: colourimetric, SP: spectrophotometric, FP: flame photometric, P: potentiometric. c3) R: recorder, DD: digital display, DP: digital print-out, OD: oscillographic display, TY: typewriter, CM: computer. (*) EEL model 171 Automatic Colorimeter.

w LKB Calculating Absorptiometer or LKB Reaction Rate Analyscr. t6) EEL model 171 Automatic Colorimeter or Joyce Loebl Auto-Colourimeter. set of fifteen or more cuvettes arranged radially around the rotor. The cuvettes spin past the stationary beam of light of a photometer. The absorbanccs of all samples are displayed simultaneously as a series of peaks on the screen of an oscilloscope. Analysis is therefore parallel rather than sequential. Volumetric measurement of samples267 and phase separations274 are also accomplished by centrifugation and the appropriate choice of transfer disc and sequence of rotation.

Fig. 1. Operating sequence of the rotor for the separation of precipitates (GeMSAEC Fast Analyserj. In (A), the sample and precipitating reagent are placed in the upper we% and remain unmixed at rest. During rotation (3) the two solutions mix, precipitation occurs, and the precipitate is centrifuged against the wail (Ct. During deceieration, the supernatant liquid is decanted into the lower holding chamber (D), and the precipitate is left in the upper sedimentationchamber. On reacceleration (E), the supematant liquid is transferred centrifugally into a cuvette or into a plastic measuring chamber. (Reproduced by permission of the copyright holders from N. G. Anderson, AYZU~. Biocltem., 1969.31, 272.)

Figure 1 illustrates the procedure for the removal of a precipitate.368 The major advantage of such a system is that the total time for ane analysis is the same as for 15 or more determinations regardless of the complexity. Turn-round time for one set of samples may be as little as a minute. It is obvious that analytical data produced at this speed are ideally suited for computer processing Hatcher and Andersona’l have compared the results of the dete~in~tion of serum protein on the GeMSAEC system with the results obtained by the Kjeldahf. method and by the Technicon “AutoAnalyzer “. Levels of precision were comparable but the GeMSAEC system proved slightly more accurate, was faster and required considerably less sample and reagents. Up to thirty different cfinical analyses were claimed by Hatcher27J to have been automated, but few details were provided. He also introduced a new concept of absorbance easement invotving a common source and detector and various bundles of optical sbres for the simultaneous display of the signal from a number of probes. Burtis et ~1.“~ have described the development of a 42-place fast analyser and have presented results for a number of chemical and enzymatic analyses. Determinations for ten blood constituents were performed with reiative standard deviations mostly less than 2%. Although only 2 min were required to obtain 40 resufts, the actual time taken from the start of reagent preparation of the final washing of the absorption cells ranged from 16 to 20 min per transfer disc. This corresponds to 320-160 samples per hour and the authors daim that this could be increased by replacing the manual sample and reagent loading with an automated procedure. More recently a miniature fast analyser was described.277 Three commercial versions278 of the system were first announced in 1970. Two of these, by Efectro-Nucieonics and Union Carbide, have been inchided in Table 2, Litte information is available on the performance of these instruments under routine laboratory conditions. Maclinzs3 has discussed the theoretical basis of kinetic enzyme determinations with the

Automated wet chemicalanalysers

1057

Electra-Nucleonics GeMSAEC instrument and the effect of changing the variable parameters on the precision which may be expected. Tiffany et ~11.~~~ obtained relative standard determinations of 2.2-4.8 % on some clinical analyses. The programming of a minicomputer for use with this system was described by Kelly and Jansen.27g The Union Carbide system, known as “ Centrifichem”, utilizes a 30-cuvette rotor. Its performance on the determination of serum creatinine was presented by Fabiny and Ertingshausen.263 Relative standard deviations from 3 to 7 % were obtained by a method which involved two sets of absorbance readings, taken 20 and 80 set respectively after starting the rotor. It would seem that fast parallel analysers have considerable potential in general analytical chemistry, particularly for those applications in which a fast result is required on a relatively small number of samples. Obviously, many technical improvements are required before the more complex procedures may be handled by this system. A variety of rotors could be made for different types of analyses and one could visualize such rotors being automatically preloaded with the appropriate reagents so that the user need only introduce the samples. One factor which will prevent the widespread use of the commercial versions is the high cost, at present around $20,000 excluding the computer. Automatic titrators Titrimetric procedures have been automated 2*o for many years to various extents. This is presumably due to the repetitive and therefore tedious nature of the operations involved in carrying out a titration. Automatic titrators have been based on one of two principles. In one type, a reagent is added at a controlled rate and the variable measured (electrode potential, absorbance, etc.) is continuously monitored and displayed as a function of the volume of titrant. Thus the full titration curve is displayed from which the equivalence point is obtained and the calculation made. In the other type, addition of titrant is automatically stopped at the equivalence point, generally because a preset potential has been reached, and the equivalence volume may then be read from the titrant-dispensing mechanism. In both instances sample presentation, pretreatment, emptying and washing of the titration vessel, resetting of the instrument and calculation of the result has to be performed manually for each analysis. In an on-stream automatic titrator, such as the “ Titromatic Analyzer ” described in Squirrell’s book,280 most of these functions are automated. However, such instruments require considerable maintenance and results are subject to errors when electrode potentials tend to drift or when the inflection at the equivalence point becomes less pronounced. One system for automatic titrations was recently described by Johansson.281*282 It utilizes the graphical method of Gran for the calculation of the equivalence point. The titrant is added in equal increments and the electrode potential obtained after each addition. The sample is taken by an automatic syringe and reagents or diluents may be added before the titration. Sample carry-over is minimized by a water rinse between samples. The precision of the delivery is better than ItO*1 %. Electrode potentials are measured and printed out at a preset interval after each addition. Relative standard deviations for the titration of a strong and a weak acid with sodium hydroxide were 0.3 and 0*4’%respectively at an analysis rate of 30 samples per hour. The desirability of computer calculation was mentioned but not discussed in any detail. A semi-automatic computer-based system for titrations was described by Jagner.283 It comprises a series of motor-driven syringes and also uses Gran’s method for the deter-

1058

J. T. VANGEMERT

mination of the equivalence point. The emphasis in this instrument is on high precision. Jagner claims that weighing of samples is inherently more precise than volumetric measurement. Since weighing has not been satisfactorily automated, samples are weighed and presented manually. The electrode potential is measured with a digital voltmeter which is interfaced to a “ Teletype ” paper-tape punch. A scanner enables the progress of up to 45 titrations to be followed simultaneously. The data on punched tape are processed by the computer in an off-line mode although on-line data-logging and calculations are also possible. The system was used by Jagner and Ar&i ra4 for the potentiometric determination of total halides in sea-water. Graphical evaluation was compared with computer calculations. The latter method produced a better precision (@02 “/,>,In a subsequent paper by Anfalt and Jagnerza5 a fully computer-controlled system was described. Both of the Swedish groups of workers mentioned above base their determination of the equivalence point on the extrapolation method described by Gran.286 Extensions of these equations have been developed 2*772*8for titrations involving weak acids or bases. The precision and accuracy obtainable from various methods of equivalence-point determination has been recently reviewed by Anfiilt and Jagner. 28g It was shown that a modified Gran procedure was superior to any other method. However, the calculations involved are of a certain complexity so that a computer becomes almost an essential component of the system. Several approaches to the computation of titration curves have been described.2g0-rg3 Both the principle of Gran’s method2g”2g6 and the advantages of computer evaluation2” have been receiving renewed interest recently and further developments in their utilization in automated analysis can be confidently predicted. An automatic titrator with thermometric sensing has been described by Guillot.29* Sample and reagent are measured by pneumatically operated syringes into a cell equipped with a thermistor and stirrer. Determinations by neutralization, redox and complexation reactions were performed with a precision of about 1%. Mueller and Burke2” have constructed a computer-controlled reagent-addition system incorporating a syringe microburette and a spectrophotometer. An acid-base titration with photometric end-point detection provided an accuracy and precision of better than 05 %. A novel method of digitizing the titrant delivery in an automatic titrationapparatus has been developed by Hieftje and Mandarano.300 Uniform droplets of the titrant are produced and counted. The rate of delivery may be varied near the end-point. The system is suited for the production of derivative titration curves. A simpler drop-counting mechanism was described by Olsen and Foreback301 for the partial automation of spectrophotometric titrations. Several other titrators with fully automatic sample-changing facility have been described302-304 and one commercial unit has been included in Table 2. APPLICATIONS

The uses to which automatic analysers are now being put cover every field of analytical chemistry. The unique requirements of clinical laboratories, i.e., a large number of determinations for a small number of sample constituents with a relatively wide tolerance on accuracy and precision, together with the introduction of the Technicon “AutoAnalyzer”, were initially responsible for the widespread application in this field. Subsequent improvements in instrumentation and development of a greater variety of methods resulted in automatic analysers being used also in other areas, particularly in pharmaceutical quality control, agricultural chemistry and food analysis. More recently, the demand for more data in environmental studies has led to a greater use of automated techniques in this field.

Automated

wet chemical analysers

1059

The literature on applications has by now grown so voluminous that a comprehensive coverage is difficult to achieve and becomes rapidly outdated. In this review particular emphasis will be given to those types of applications which have not been dealt with elsewhere. Clinical chemistry

Methods and techniques in clinical chemistry are periodically reviewed305V306 in the Applications Section of Analytical Chemistry Reviews, including a section on automation. There is therefore no need to provide a detailed catalogue of applications here. The needs, both satisfied and unsatisfied, of automated clinical laboratories have been discussed by Gambino.g The trend to multi-component methods and instruments has been reviewed by Laessig” with particular reference to the costs of large-scale health-screening programmes. The economics of laboratory automation have also been analysed in a recent book.” Several other reviews have appeared on automation in clinical chemistry.‘2*34*307-310 A system for performing eight different determinations sequentially was first described by Skeggs and Hochstrasser. 311 Precalibrated recorder charts serve as the analysis report. A parallel multichannel analyser was constructed by Thiers et al.” from standard Technicon components, including seven colourimeters, one flame photometer and one fluorometer. Technicon eventually developed the SMA 12-30, a sequential multiple analyser capable of determining 12 components on each sample at the rate of 30 samples per hour. Evaluations of this instrument have been made by Broughton et aL312 and Hoffmeister and Junge.313V314 The latter workers studied the effect of storage time and temperature on the stability of serum samples and improved the reliability of the system by a new method of control and standardization. A subsequent model, the SMA 12-60, was evaluated by Finley et aL315 In spite of some excellent results reported, Laessig” still considers that in general less accurate data are produced by multichannel systems than by the older single- and dualchannel analysers. A computer-based system with 12 test channels assembled from standard Technicon components has been described by Abernethy et a1.1g7v316 The use of an offline computer was shown by Flynn317 to increase the speed of presentation with a reduction in the frequency and magnitude of laboratory errors. Some of the techniques developed especially for clinical work could have a wider application, but by being published in specialist journals escape general attention. An automated method for the determination of protein-bound iodine has been described by Knapp and Spitzy. 31* They combine a continuously operating ashing oven with an “ AutoAnalyzer” for iodide. An automated procedure for iodine at low concentrations in biological materials was evaluated and compared with a neutron-activation method.31g Both methods were found to have comparable precision and accuracy. Blood-cell counting has been automated by interfacing a standard “ Coulter Counter ” with an “AutoAnalyzer” which also performs haemoglobin determinations.lE2 Cell sedimentation in the samples is prevented by magnetic stirring. The Technicon method for glucose determination has been the subject of a lot of attention mainly because of its lack of specificity. Edwards and Freier 320 have determined the extent to which disaccharides and other reducing substances dialyse across the membrane. They also determined the effect of temperature and analysis rate on the dialysis efficiency of glucose and found that interaction between samples was up to 4.7 %. Hinton and Norris321 found that the presence of sucrose affected the performance of continuous-flow systems for protein determination. A twofold increase in cross-contamination occurred when the sample was 1*8M in sucrose.

1060

J.

T.VANGEMERT

Elimination of the dialysis step to simplify the simultaneous microdetermination of urea and glucose in serum was reported by Caron et al.322 The reliability of the o-toluidine method for blood-sugar determination was found by Sommer and Herbinger3” to depend critically on the concentration and speed of analysis. Sudduth et al. 324compared this method with a ferricyanide and a specific enzymatic procedure. The u-toluidine method produced the best accuracy and a relative standard deviation of I.2 %. Other hexoses were found to interfere. A modified enzymatic procedure for glucose in blood was described by van der Silk et al.325 Homby et al.326 have reported a novel method for glucose in which glucose oxidase is chemically attached to the inner surface of a polystyrene coil in a continuousflow system. Electrolytes of clinical interest include sodium, potassium, calcium, magnesium, iron, certain other metals and halides. A procedure for serum sodium and potassium determination, utilizing a Technicon sampler, an on-line diluter and a flame photometer, has been presented by Pennacchia et al.1’4 The simultaneous determination of sodium, potassium and chloride has been performed by Haeckel”’ on a Perkin-Elmer C4 analyser. The usable range for potassium was limited and other halide ions interfered. A simplified system for the two alkali metals with carbon dioxide and urea has been described by Kind et a1.327 Calcium and magnesium determinations in serum and other biological materials have been performed by atomic-absorption spectrophotometry.‘62*163 Lott and HermanJza have shown that the presence of proteins can be a source of error by increasing the rate of dialysis of calcium and magnesium ions. Calorimetric procedures have been used for iron and iron-binding capacity in serum, with continuous-flow systems. 32g*330The simultaneous determination of copper and iron has been described by Kattermann and Koehring.“i Fluoride in urine has been determined by Hargreaves et al.’ 54 with a lanthanum-alizarin complexone reagent after a distillation. Chloride and carbon dioxide in plasma have been simultaneously determined with the ” AutoAnalyzer “.172 A turbidimetric method for sulphate determination was automated by Dieu. ‘*’ Coating of the flow-cell with barium sulphate was prevented by an air-rinse between samples. Deuterium oxide in water and biological fluids was determined“j5 by coupling an infrared spectrophotometer to an “ AutoAnalyzer “. Concentrations between O-1 and 1% D,O could be determined with a relative standard deviation of l-4%. Knowles and Hodgkinsons3 described an enzymatic method for the determination of oxalic acid in serum. The specific enzyme decarboxylates oxalic acid to produce carbon dioxide which is then determined calorimetrically. A heated gas l3lter is used to remove any aerosol from the gas phase. The metabolic activity of collagen has been assessed by the determination of hydroxyproline in plasma and urine by an “AutoAnalyzer” procedure.33’ In the concentration range of 2.5-15 pg/ml, the relative standard deviation was 2.6 % and excellent agreement was obtained with an isotope-dilution method. Grant and Ha11332have reviewed automated methods for steroid analysis. An interesting application of a continuous-flow dialysis technique has been reported by Stein.333 The binding of dialysable compounds to macromolecules was studied by a dynamic method utilizing an “ AutoAnalyzer “. The information was obtained faster than by the conventional equilibrium procedures. The procedures of clinical interest which may be performed on parallel fast analysers (GeMSAEC) have already been referred to.

Automated

wet chemical analysers

1061

Pharmaceutical chemistry Two symposia5*6 and a review’ with 293 references have dealt with the use of automated techniques in pharmaceutical analysis up to 1968. Some of the special requirements of pharmaceutical quality control include the need to determine one or more active components in a single determination, the ability to handle solid samples such as tablets, and the use of turbidimetric procedures for biological assays. The construction and operation of an automatic dispensing analyser for the assay of individual tablets has been described by Beyer and Smith 334. It incorporates a Technicon pump and continuous filter. The simultaneous determination of several components in single tablets has been described recently by Urbinyi and O’Connell.13’ Reserpine, hydralazine hydrochloride and hydrochlorothiazide were assayed respectively by fluorometric, calorimetric and ultraviolet spectrophotometric measurements. Murfin166 has reported “ AutoAnalyzer ” methods for the determination of two or three components of commercial analgesic tablet formulations. Urbinyi and Lirnla6 used an infrared spectrophotometer coupled to an “AutoAnalyzer” with solid sampler to determine methylphenidate hydrochloride in tablets after extraction. Although the method is not specific and less precise than the official procedure, it is adequate for uniformity testing. A similar technique has been employed by Ryan et al. 135 for the determination of meprobamate. A dual extraction procedure for tablet assay has been described by Ahuja et af.43 Single tablets of chloral betaine have been assayed by Bryant et a1.335 after double dialysis. A variety of amine drugs has been analysed by Robertson et a1.336 by the acid dye technique. Bromothymol Blue at pH 6 is used for all polar, primary and quaternary amines while Bromocresol Purple at pH 2 is the indicator for non-polar compounds. The determination of phenylephrine hydrochloride has been automated by Lane.‘32 This method has been the subject of a collaborative study 133 showing a maximum coefficient of variation of 4.5 %. Cyclohexylamine in cyclamates has been determined by Berry and Crossland at concentrations as low as 5 ppm, using a calorimetric “ AutoAnalyzer” method. Multivitamin preparations have been analysed by Cavalli and Rurali,33* Geller et a1.33Qand Bryant et al.34o Penicillin determination by a calorimetric “ AutoAnalyzer ” method has been described recently by Holm. ‘*’ A high degree of sensitivity, accuracy and precision is claimed. The assay of a variety of commercial penicillin preparations has been reported by Mills.260 An automated apparatus for the turbidimetric determination of antibiotics has been constructed by Kuzel and Kavanagh. 240V241The calculation of potencies may be performed by computer.341 More recently a similar apparatus has been built by Rippere and Arret342 from commercially available components. Several other procedures for automated microbiological analysis have been described.343-345 Some additional recent papers have been included in Table 3 under a number of broad headings. Agricultural and food chemistry The use of a Technicon “AutoAnalyzer” for chemical analysis in agricultural research has been discussed by Skokan. 356 The determination of total nitrogen in fertilizers has been automated by Gehrke et a1.13’ This involves the manual reduction of all nitrogen compounds to ammonia followed by automated digestion and reaction with hypochlorite and alkaline phenol. In a later paper lE3 the reduction step was also automated. Potassium in

J. T.

1062

Table

3. References

VAN&ISERT

to automated ZWalYseS

amphetamines aotibiotica &ofourimetric~ ar3tibiotic.s~~r~~~c~ barbiuratea chlomJ betaine codeim CyCl~;irtcs

digitoxin mzymes epkdrines hydralazine hydr~b~o~da Rlep~obaolate methylpheeidate hydrochloride pi%m&amol phenacatin phenmetmzine me&e revitws steroids tablets vitamins

phamaceuticai

336 189,250,353 2~~241,34~_34~ 50 335 336 337 350,351 226,261 I35133,336 131 135 186 166 166 43,336 131,34&349,354 S-7,346 352 43,131,186,334,339,350 338-340,347,355

fertilizers has been determined by automated tIame photometry and the resulrs of a co&&orative study were presented by Hambleton.“‘8*35f The d~te~inat~on of manganese in fertilizers containing trace elements has been described by HoIz.~~~Phosphorus has been determined in rock,3s9 fertilimrs360 and superphosphoric acid.361 One of the earliest non-clinical applications of the Technicon “AutoAnalyzer” was the determination of zinc and other trace metals in soil extracts by Stanton and McDonafd.‘21-‘t2 The sirn~~neo~s analysis of soils for calcium, potassium, magn~ium and phosphorus has been performed by Lacy. 12*The first two elements are determined by Same photometry, magnesium by atomic absorption and phosphorus by the molybdenum blue method. Up to 40 samples per hour may be handled. In a study of American soils similar procedures have been followed by Flannery and Markus,362 using different extractants. It was noted that tow caicium values were obtained in the presence of sulphate. Automated methods for the determination ofnitro~n in soil extracts have been devefoped by Keay and Menage35756and Henrikscn and Seimer-Olsen.‘* The latter reduce nitrate to nitrite by passing the solution through 8 coppered cadmium reductor-column interfaced with an “AutoAnalyzer ” manifold. Nitrite is then determined colorimetricaity with sulphanilic acid and l-naphthy~ethylenediamine dihydrochloride. The exchange capacity of a large number of African soil samples has been determined by Burdin et a&$” The results from the automated method were siightly higher than from the manual dissipation procedure. The dete~ination of pH of soils has been automated by Baker.230Up to 100samples per hour can be measured with automatic temperature compensation, magnetic stirring, washing of electrodes and rinsing of containers. A high degree of correlation with manual pH determination was found. Varley and Baker” have described an eiectronic timer to increase the speed of anaiysis of plant and soil samples. Plant tissues and extracts have been analysed for a variety of elements, Boron has been determined by WiIiis,364using quinalizarin, and by Basson et a1.365 with the condensation

Automated wet chemicalanalysers

1063

product of salicylaldehyde and H-acid. Nitrogen in plant tissue has been determined by the indophenol method after manua1’25~366 or automatic’23 digestion. An acid digestion has also been performed on plant extracts for fluoride determination.42 Hydrofluoric acid is distilled in the digestor helix and collected in lanthanum-alizarin complexone reagent for colourimetric estimation. Plant growth has been studied by automated starch determination on the “AutoAnalyzer”, by means of the blue colour obtained with iodine. Good precision and recovery were also obtained in the estimation of starch in tobacco leaves.36* The automation of sugar analysis has been discussed by de Boos,~~’ including a number of physical measurement and data-processing techniques. Floridi13’ has developed a method for the separation of mono-, di- and trisaccharides by ion-exchange chromatography followed by a calorimetric determination on an “ AutoAnalyzer”. A continuous method for the measurement of periodate uptake in oxidized sugars by determination of iodate has been described by Barker et al. 370 Sawyer and Dixon have developed an automated procedure for the determination of the “ original gravity of beer, ” involving analysis for reducing sugars3’l and alcoho1.136 A special distillation unit was developed for use with an “AutoAnalyzer “. A system for peak detection and data processing has also been given. 372 A review of electrometric methods including the determination of sugars in beer has been made by Sawyer and Foreman.14’ Table 4 provides a summary of the applications in agricultural and food analysis. Environmental chemistry This field is inherently very large, particularly when one includes the automated determination of naturally occurring substances as well as those which have been introduced by man into the environment. Frequently, the concentration range of interest is considerably lower than in other types of applications. As legislative control over the type and concentration of wastes being discharged into the environment is becoming more prevalent, the use of automated techniques is expected to increase. Many single-purpcse monitors are available but these are generally based on instrumental rather than wet chemical principles and will therefore not be dealt with here. Automated methods are reviewed annually’*5~3*6 with the emphasis on inorganic constituents in waters and waste waters. In the Applications Section of Analytical Chemistry Reviews a part of the review on water analysis is usually devoted to automated techniques.“’ The instrumentation for water analysis has been discussed by Sprenger,16 and King3** has listed some methods for use with the Technicon “AutoAnalyzer “. An elaborate instrument for the determination of oxygen-demand, phenol, cyanide, oil and turbidity in environmental water and industrial discharges has been presented by Sunahara et al.‘*’ It is a discrete system in which most of the parameters are determined by wet chemical means. An evaluation of the Technicon CSM-12 for the continuous determination of twelve water-quality parameters has been made by O’Brien and Olsen.3g0 They found poor agreement with manual procedures and experienced a number of mechanical difficulties. Hey and HarknessJgl have discussed some of the problems involved in automating existing methods for the analysis of sewage and effluents. They divide waste water determinations broadly into three categories : organic matter, nitrogenous substances and miscellaneous inorganic elements and ions. StackJg2 has reviewed the water-quality surveillance programmes used by the Environmental Protection Agency, geologists and industry generally. He emphasizes the need for “real-time ” analytical information. A system for data collection from automatic water-pollution monitoring stations has been described by Manczak.3g3 The use of

1064

Table 4, References to automated analysis in agricuiturai and food chemistry Review Fe&ii: nisrosn

phssphoru~ paw&m tract met& Soils : exchange capacity herbicides %Ca*M&P nitrogen PR trace metals

Plants, fwds, beverages: alcohol animal feeds beer boron co&e beans enzymes fluoride fruit juice grain, flour K Ca, Mg z&en pesticides phosphorus starch sugan tobacco vitamins

356 139,183

359-361 138,357 358 363 383 124362 ~5~~6,~7~8~,3~

230 121,122 f 36,376 353,355 ~36*137,14~~3~~~3~*376 364,365 E,377,384 42 347 41,375,380 125,373 384,382 41,123,125,173,3fi6,374,375J%o38I 109,378,3X$384 123,125,373,382 367,368 134145,36!9-372 367,368 347,355

selective ion-electrodes in the monitoring of water-treatment processes for a variety of added chemicals has been discussed by Rivers and Schweitzer.“* A guide to the selection of methods and equipment for automatic air-monitoring has been given by Effersz2 A brief description of the Technicon CSMS Air Monitor has appeared3’s and Zaleikosg6 has presented a general review of coforimetric procedures for use on the Technicon I‘ AutoAnalyzer ‘* in air-pollution measurement programmes. The tedious nature of the manual determination of chemical oxygen demand (C.O.D.) in waters, coupled with the importance of such data, has produced a variety of automated techniques The principle of oxidation with potassium dichromate has been used by Hey ei &3g7 using a specially built apparatus, and by Haines and Ansefm3’a on a Technicon ~~ AutoAna~yzer “. The reaction time has been shortened from several hours under r&M to approximately 10 min by heating to 150”. Hey ei at. designed their system around commercial syringe-dispensers because of attack by concentrated sulphuric acid on the peristalticpump tubing. Some of the auxihary equipment for this instrument has been described by PhiUips.3g*~400A method for organically bound carbon, involving a silver-cataiysed oxida&n by perstiphate, has been automated by Popp and EngelhardL401 Recentfy, Fleet et dz4’ have used a novel system based on a Technicon “AutoAnalyzer” with potassium dichromate or permanganate as the oxidant. The excess of oxidant is reacted with hydrogen

Automated wet chemical analysers

1065

Table 5. References to automated analysis in environmentalchemistry air monitoring chloride C.O.D. cyanide detergents effluents

48,216,217.221,395,3% 225,402 403 141.397-401404 184,405 153,233,235 153,388,389,391,402,405

fluoride mercury metals nitrogen pesticides phenols reviews sea-water sulphate sulphide water monitoring

406,407 60,68,120.237-239 48,101,152 81,82,108,408-411 109 54 17,385-387,392 225,408-410,412 134 99,412,413 16,385,386,389,390,392-394,407

boron

peroxide and the oxygen produced is measured coulometrically by a porous catalytic silver electrode. Satisfactory agreement is obtained for a number of organic compounds with the standard manual procedure and with theoretical C.O.D. values. A summary of these and some additional references is presented in Table 5. Miscellaneous applications

The increasing use of automated techniques in general and industrial analysis is shown by the number of recent papers which do not fall into any of the categories used so far. One area in which considerable development is occurring at the present time is that of reaction-rate techniques in analytical chemistry. Such methods frequently have advantages of sensitivity and selectivity and are becoming of practical significance with the introduction and improvement of automated instrumentation. Reviews on the use of enzymes and kinetic aspects have generally incorporated a section on automated techniques414*415 and the use of computers. 416 A detailed discussion here is not warranted because a number of review papers have appeared recently.417420 The automation of the analysis of heterogeneous and bulk materials such as rocks and alloys is limited by the difficulty in obtaining a representative sample without manual intervention. An anodic dissolution technique has been described” for the determination of phosphorus in copper in which the manual operation is reduced to inserting the sample into an electrolytic cell. It is doubtful whether such a technique would be generally suitable for alloys. Steel samples421*422 are usually brought into solution in the conventional manner so that the time-saving achieved by automating the colourimetric measurement is minimal. However Atherton et al.4z3 have found that rock analysis can be done three times as fast by automated methods as by manual methods, without any loss in precision. Corrosion problems have been studied by the automatic determination of trace metals in water424 and chloride in industrial liquors. 42s Sebbom426 has applied automated techniques for metals in the range up to 10 ppm in several hundred chemicals used in the photographic industry. Fleet et a1.14’ have described a method for the determination of sodium hypochlorite in bleaching solutions. It is based on a Technicon “ AutoAnalyzer” and uses a

J. T. VAN GEMERT Table 6. Miscellaneous applications automated techniques aluminium amino-acids bleaching agents boron carbohydrates chloride corrosion studies formaldehyde geological materials kinetic methods metals, alloys molybdenum petroleum products phosphates silicon thorium trace metals uranium urea

of

427,428 100,146 140 429 100,107 425 424,425 100 129,421,423 155,209,250,414-420 77,421,422,428,429 129 15,234 78,107,431-434 421 435 424.426,431 151,436,437 430

hydrogen peroxide reagent and a coulometric oxygen sensor consisting of a porous catalytic silver electrode. The same procedure may be used for hydrogen peroxide determinations with a potassium periodate reagent. These and other applications are summarized in Table 6. Recently, a standard format has been recommended43s for the publication of automated analytical methods. The format provides for description of apparatus, analytical principles involved, calibration and performance checks, maintenance of the system and experimental procedure. COMPUTERS

No review on automated analysis would be complete without some reference being made to the use of digital computers. The type and volume of data produced by automatic analysers are ideally suited to computer processing, particularly if the calculations include the application of corrections for sample interaction and instrument drift. There are three basic modes in which computers are utilized. In the first, the instrument signal is recorded on chart paper, punched tape or in any other suitable form and the computer calculations are performed later. This method is generally referred to as “ off-line ‘* or “ batch-processing. ” It is generally the most economical technique and is suitable for automatic analysers where the rate of data production is relatively slow when compared with chromatographs or scanning spectrophotometers. In the second method, the computer acquires and processes the data from the analyser as they are being generated. Since this “on-line method” may be an inefficient use of computer capability, time-shared systems are frequently used in which the output from several instruments is processed by a common computer. In the third mode, which may be on a “ stand-alone ” or time-shared basis, the computer controls all of the operations of the automatic analyser as well as carrying out data processing. Such a system has inherent advantages and is desirable whenever the analytical information is used for automatic control of a plant or a process. During the discussion of instrumentation and applications, examples of the three methods have been mentioned. Many of the modem instruments, including the specially built automatic titrators, produce data in a

Automated wet chemical analysers format such that a computer

1067

is either an integral component of the system or a desirable accessory. A detailed review of the literature is not necessary since a number of comprehensive review papers have appeared in the last few years. Childs el al.4393440 have surveyed the applications of computers in analytical chemistry with emphasis on spectroscopic, electroanalytical and chromatographic techniques and the calculations of ionic equilibria and kinetic parameters. No references were given to automatic wet chemical analysers. Frazer441 discusses digital control computers and specifically mentions a commercially available 24channel discrete-sample analyser which incorporates a computer. More recently, Perone has reviewed computer applications in the chemistry laboratory, including a discussion of the historical development and possible future applications. Useful sections on computers may also be found in the review by Kuzel et aZ.’ and in the Technicon Bibliography.35 General criteria for on-line computerization of analytical instruments have been described.443Y444 A growth rate of 18 % per annum has been predicted3i in the use of computers with analytical instruments and by 1980, 30 y0 of all such instruments capable of being computerized will be. Economic considerations in the installation of on-line computers with time sharing have been discussed by Munson and Schneider.445*446 They have approached the subject from the position of both laboratory personnel and laboratory management. Clinical applications account for the majority of publications on computerized automatic analysers. A system in which up to twelve test channels from six standard “AutoAnalyzers” are coupled to a PDP8IS computer has been’described by Abernethy et aZ.1g7*316y447The analytical signal is obtained from retransmitting slidewires on the recorders. The programme functions include peak detection, data smoothing, drift correction, third-order polynomial curve-fitting, correction for specimen interaction and collation and print-out of results. The computer has a memory core of 8K and a 32K disc file is used for programme storage. Several other clinical systems have been described44*V44g and Whitby4” has reviewed the suitability of on-line and off-line methods for large and small hospital laboratories. An offline system has been described451 incorporating a peak-reading device for use with a data terminal to a remote computer. It has also been shown 452 how a relatively inexpensive programmable calculator can be used for calculations of concentrations from absorbance values. Four different methods for calculating concentrations from “ AutoAnalyzer ” results were compared by Torud. 453 Two involved computer programmes of differing complexities, one used a programmable calculator and one method was largely manual, using a transparent chart-reading device. It was shown that the corrections for drift in baseline and standards which the computer programmes apply resulted in a slight but significant improvement in both accuracy and precision. Keay 454 has discussed the application of a computer in the automated analysis of soils. The equipment required to interface the colourimeter of the analyser to either a paper-tape punch or a computer is described. A recent paper by Mueller and Burke 2gg describes a reagent-addition system and spectrophotometer under closed-loop control by a Hewlett-Packard computer. A photometric titration is performed in which the titrant addition rate is varied by programme control to meet the requirements of the solution being titrated. Some of the other computerized automatic titrators2*‘-285~300 h ave already been mentioned. A miniature on-line digital computer has been developed by Parker and Pardue in which several programmes for various applications are stored. The system incorporates a numerical data display and has been used for the kinetic analysis of organic and inorganic compounds.

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265. D. Ll Fabiny and G. Ertingshauscn, Cfin. Chem., 1971, 17, 696. 266. T. Home, Z. Anal. Ckm., 1970,252,241. 267. N. G. Anderson, Anal. Biochem., 1968,23,207. 268. Zdem, Science, 1%9, 166,317. 269. Zdem. Anal. B&hem.. 1969.28. 545. 270. N. G. Anderson, CZin. Chim. Acta, 1969, 25, 321. 271. D. W. Hatcher and N. G. Anderson, Am. J. Clin. Pathol.. 1969, 52, 645. 272. N. G. Anderson, Anal. B&hem., 1969,32. 59. 273. D. N. Mashbum. R. H. Stevens, D. D. Willis, L. H. Elrod and N. G. Anderson, ibid., 1970, 35, 98. 274. N. G. Anderson, Am. J. Clin. Pathol., 1970, 53, 778. 275. D. W. Hatcher, Ciin. Chem., 1971,17,475. 276. C. A. Burtis, W. F. Johnson, J. E. Attrill, C. D. Scott, N. Cho and N. G. Anderson, ibid., 1971,17.686. 277. N. G. Anderson, C. A. Burtis. J. C. Mailen, C. D. Scott and D. D. Willis, Anal. Lett., 1972, 5, 153. 278. Ckm. Eng. News, 1970,48(32). 45. 279. M. T. Kellcy and J. M. Janscn, Clin. Ckm., 1971, 17, 701. 280. D. C. M. Squimll. Automatic Met& in Volumetric Analysis, Hilger and Watts, London, 1964. 281. A. Johansson, Analyst, 1970,%,535. 282. A. Johansson and L. Pehrsson, ibid., 1970,%, 652. 283. D. Jagner. Anal. Chim. Actu, 1970.50, 15. 284. D. Jagner and K. A&n, ibid., 1970.52,491. 285. T. Anffilt and D. Jagncr, ibid., 1971, 57, 177. 286. G. Gran, Analyst, 1952.77, 661. 287. F. Ingman and E. Still, Tahzntu, 1966, 13, 1431. 288. F. J. C. Rouotti and H. Rossotti, J. C’bem. Educ., 1965, 42, 375. 289. T. Anf8lt and D. Jagner, Anal. Chim. Acta, 1971. S7, 165. 290. N. Ingri, W. Kakolowicz, L. G. Sill&n and B. Wamqvist, TaZuntu, 1967, 14, 1261. 291. B. Elgquist. ibid., 1969, 16. 1502. 292. S. E&i-, Z. -Anal. Ckm., 1%9, 245, 353. 293. T. Anf8lt and D. Jaaner. Anal. Chim. Acta. 1%9.47. 57. 294. A. Liberti and M. &s&i. AMI. Chem.. 1%9,4i, 676. 295. F. A. Schultz, ibid., 1972.43. 1523. 296. P. W. Carr, ibid., 1972. 44, 452. 297. T. J. MacDonald, B. J. Barker and J. A. Caruso, J. Ckm. Educ.. 1972,49,200. 298. P. Guillot, Anal. Chim. Acta, 1970. SO, 499.

Automated

wet chemical analysers

1073

299. K. A. Mueller and M. F. Burke, Anal. Chem., 1971,43, 641. 300. G. M. Hieftje and B. M. Mandarano, ibid., 1972,44, 1616. 301. E. D. Olsen and C. C. Foreback, J. Chem. E&c., 1972,49,206. 302. U. Fritz and K. Gussow, Chem.-Zag. Tech., 1%3,35, 577; Anal. Absfr., 1964, 11,5217. 303. G. Berthelot, L. Bisson and A. Martin, Ind. Chim. Paris, 1970, 57, 39; Anal. Abstr., 1971, 20, 2156. 304. W. Batter, G. I. T. Fachz. Lab., 1971,15, 1249; Chem. Abstr., 1972,76, 107517~. 305. G. R. Kingsley, Anal. C/rem., 1969,41, 14R. 306. Idem, ibid., 1971,43, 15R. 307. J. Krawczynski, Postepy B&hem., 1970,16, 559;Chem. Abstr., 1971,74,95151q. 308. F. L. Mitchell, Bio-Med. Eng., 1970, 5, 534. 309. Idem, ibid., 1970, 5, 589. 310. B. M. Kotenev and A. K. Puzyrevskii, Lab. Delo, 1971, (l), 3; Chem. Abstr., 1971, 74, 95153s. 311. L. T. Skeggs and H. Hochstrasser, Cfin. Chem., 1964,10, 918. 312. P. M. G. Broughton, D. Simpson, F. L. Mitchell, C. Toothill and L. G. Whitby, Clin. Chim. Aeta. 1968, 19, 297. 313. H. Hoffmeister and B. Junge, Z. Klin. Gem. Klin. Biochem., 1970, 8, 613. 314. Zdem, ibid., 1970, 8, 116. 315. P. R. Finley, L. Gillott, D. Peterson, F. Anderson and E. Boxman, Adtnm. Automat. Anal., Technicon Int. Congr., 1970, 1, 145. 316. M. H. Abemethy, G. T. Bentley, D. Gartelmann, P. Gray, J. A. Owen and G. D. Quan Sing, Biochem. J.. 1971. 121.(11.4P. 317. F: V. Fjynn,‘&chem. J., 1971, 121, (l), 2P. 318. G. Knapp and H. Spitzy, Clin. Chim. Acta, 1970,30, 119. 319. R. Malvano, G. Buzzigoli, M. Scarlattini, G. Cenderelli, C. Gandolfi and P. Grosso, Anal. Chim. Acta, 1972, 61, 201. 320. H. Edwards and E. Freier, Am. J. Med. Technol., 1971,37, 9. 321. R. H. Hinton and K. A. Norris, Anal. Biochem., 1972,48,247. 322. M. Caron, M. Aufrere, J. L. Barbier and E. Beranger, Feuill. Biol., 1971, 12, 51; Chem. Abstr.. 1972. 76,2269ow. 323. R. Sommer and W. Herbinger, Aerztl. Lab., 1970, 16,337; Chem. Abstr., 1971, 74, 28645r. 324. N. C. Sudduth, J. R. Widish and J. L. Moore, Am. J. C/in. Pathol., 1970,53, 181. 325. W. van der Silk, A. L. Koevoet, B. R. van Neerbos, G. M. Alkemade and P. van der Harst, Clin. Chim. Acta, 1970, 27, 325. 326. W. E. Homby, H. Filippusson and A. McDonald, FEBSLett., 1970,9,8; Chem. Abstr., 1971,74,9&j. 327. P. R. N. Kind, E. A. Morgan, A. H. C. Bignall and I. J. L. Goldberg, Proc. 7th Intern. Congr. Clin. Gem., 1969,1, 250; Chem. Abstr., 1971,75, 1036b. 328. J. A. Lott and T. S. Herman, Clin. Chem., 1971, 17, 614. 329. J. Fuehr and E. Stary, Aerztl. Lab., 1970, 16, 244; Chem. Abstr., 1971, 74, 72701e. 330. H. Y. Yee and A. Zin, Clin. Chem., 1971,17, 950. 331. D. W. Bannister and A. B. Bums, Analyst, 1970,%, 596. 332. J. K. Hall and P. E. Hall, Aduan. Sreroid Biochem. Pharmacol., 1971, 1, 419; Chem. Abstr., 1972,76. 96475c. 333. H. H. Stein, Anal. Biochem., 1965, 13,305. 334. W. F. Bever and E. W. Smith. J. Pharm. Sci.. 1970.59.248. 335. R. H. Bryant, F. J. Burger and F. B. Trenk, ibid., i971, 60, 1721. 336. D. L. Robertson, F. Matsui and W. N. French, Can. J. Pharm. Sci., 1972, 7,47. 337. C. T. Berry and R. J. Crossland, Analyst, 1970,95,291. 338. R. Cavalli and C. Rurali, Boll. Chim. Farm., 1971, 110,438;Chem. Abstr., 1972,76,49982e. 339. M. Geller, 0. W. A. Weber and B. Z. Senkowski, J. Pharm. Sci., 1%9,58,477. 340. R. H. Bryant, F. J. Burger, R. L. Henry and F. B. Trenk, ibid., 1971, 60, 1717. 341. F. Kavanagh, ibid., 1971, 60, 1858. 342. R. A. Rippere and B. Arret, ibid., 1972, 61, 449. 343. F. Simoncini, R. Rangone and C. Calanni, Farmaco, Ed. Prat., 1968, 23, 559; Anal. Abstr., 1970, 18, 1212. 344. K. Heil and V. Beitz, Pharm. Ind., 1972,34,37; Chem. Abstr., 1972,76,158386j. 345. K. H. Wallhaeusser, ibid., 1972, 34, 23; Chem. Abstr., 1972,76, 158387k. 346. H. Siedlanowska-Krowczynska, Farm. Pol., 1971,27,49; Chem. Abstr., 1971,75,67506m. 347. M. Hoffman, A. Bar-Akiva, L. Tanhum and Y. Berkenstadt, Anal. Biochem., 1970,38,35. 348. B. N. Kabadi, A. T. Warren and C. H. Newman, J. Pharm. Sci., 1%9,58, 1127. 349. D. P. Page,J. Ass. Ofic. Anal. Chem., 1970, 53, 815. 350. L. F. Cullen, D. L. Packman and G. J. Papariello, J. Pharm. Sci., 1970,59, 697. 351. J. W. Myrick, ibid., 1969, 58, 1018.

1074 352. 353. 354. 355. 356. 357. 358. 359. 360. 361. 362. 363. 364. 365. 366. 367. 368. 369. 370. 371. 372. 373. 374. 375. 376. 377. 378. 379. 380. 381. 382. 383. 384. 385. 386. 387. 388. 389. 390. 391. 392. 393. 394. 395. 3%. 397. 398. 399. 400. 401. :: 404: 2:

J. T. VANGEMERT J. F. Brower, J. Ass. Ofic. Anal. Chem., 1969, 52, 842. J. B. Zasgr, P. P. Ascione and G. P. Chrekian, ibid., 1971, 54, 1272. T. Urbanyi and H. Stoher. ibid., 1972.55, 180. A. Weil and J. M. Regnier, Ind. Aliment. Agric. (P&s), 1971,88,1539; Anal. Abstr., 1972.23, 1990. E. Skokan. Vestn. Cesk. Akad. Zemed., 1970.17, 544; Chem. Abstr., 1971,74,121122c. L. G. Hamhleton, J. Ass. Ofic. Anal. Cbem., 1970,53,456. F. Holx,Lundwirt. Forsch., Son&h., 1971,26, 294; Chem. Abstr., 1972, 76, 33126t. J. L. Hoyt and D. E. Jordan, J. Ass. Ofic. Anal. Chem., 1969,52. 1121. F. J. Johnson, ibid, 1972.55.979. A. B. Care1 and D. E. Jordan, ibid., 1%9,52, 577. R. L. Flannery and D. K. Markus, Proc. Symp. Instrum. Methods Anal. So& Plant Tissue, 1970, Ed. L. M. Walsh, p. 97. Soil Sci. Sot. Amer.. Madison, Wis., 1971. S. Burdin, M. Fortier and M. Richard, Agron. Trop. (Paris), 1971, 26, 392; Chem. Abstr., 1971, 75, 97631r. A. L. Willis, Commun. Soil Sci. Plant Anal., 1970, 1, 205; Chem. Abstr., 1971.74, 95248b. W. D. Basson, R. G. Bohmer and D. A. Stanton, Anulyst, 1969,94,1135. F. Holxand H. Kremers, LMhvirt. Forsch., Son&h., 1971,26, 177; Chem. Abstr., 1972,76,58119f. N. Rosa, Tob. Sci., 1971,lS. 63; Chem. Abstr., 1971,75, 72304~. T. P. Gaines, ibid., 1970,14, 164, Chem. Abstr., 1971,74,61522w. B. W. de Boos, Control Systems, 1969, 2(3). 26. S. A. Barker, P. V. Peplow and P. J. Somers, Carbohyd. Res., 1972,22,201. R. Sawyer and E. J. Dixon, Analyst, 1968.93, 669. R. Sawyer, E. J. Dixon and E. Johnston, ibid., 1969,94, 1010. J. E. Steckel and R. L. Flannerv. Proc. Svmo. Instrum. Meth& Anal. Soils Plant Tissue., 1970., Ed. L. M. Walsh, p. 83. Soil Sci. Soc.‘Amer., Madison, Wis., 1971. W. M. Crooke and W. E. Simpson, J. Sci. Food Agr., 1971,22,9; Cbem. Abstr., 1971,74, 14013Or. A. R. Des&eider and E. C. Maes, Ser. Getrei&chem.-Tag.. Dermoid, 1968, 19; Chem. Abstr., 1971, 74,98318k. R. G. Lidzey, R. Sawyer and P. B. Stockwell, Lub. Pruct., 1971,20,213. B. Rotenhei-8 and A. Iachan, Recta Bras. Tecnol., 1971,2,67; Anal. Abstr., 1972,23, 1953. G. Voss, J. Ass. Ofic. Anal. Chem., 1969, St, 1027. D. E. Ott, M. Ittip and H. 0. Friestad. ibid., 1971, H, 160. C. W. Gehrke and L. L. Wall, ibid., 1971,54, 187. J. E. McNeal, A. Karasx and E. George, ibid., 1970,53,907. Idem. ibid.., 1970,53,911. W. D. Hotmann, G. Formica, K. Ramsteiner and D. 0. Eherle, ibid., 1972,55,1031. G. D. Winter, Ann. N. Y. Acad. Sci., 1960,87,629. L. E. Doughty, J. Water Poll. Contr. Fed., 1971,43. 937. Idem, ibid., 1972,44,903. M. J. Fishman and B. P. Robinson, Atml. Cbem., l969,41,323R. G. H. King, Process Biochem., 1972,7(l), 16. H. Sunahara, Y. Ishihara, T. Ishizuka, K. Nakashima and K. Tanaka, C/tern. &on. Eng. Rev., 1970, 2(11), 34. J. E. O’Brien and R. A. Olsen, J. Water Poll. Contr. Fed., 1970,42, 380. A. E. Hey and N. Harkness. Mea. Contr., 1971,4(3). T45. V. T. Stack, Anal. Chem., 1972,44(8), 32A. H. Manczak, Pr. Nauk. Inst. Inz. Sunit. Wodmj Politech. Wroclaw, 1971, (11). 91; Chem. Abstr.. 1972, 76,49512b. H. M. Rivers and G. W. Schweitzer, J. Am. Water Works Ass., 1971,63, 533. Anal. Chem., 1970,42(9), 69A. N. S. Zaleiko, J. Air Poll. Contr. Ass., 1963, 13, 531. A. E. Hey, A. Green and N. Harkness. Water Res.. 1969.3. 873. G. D. Haines and C. D. Anselm, Ada. in Autom. Anal., Technicon Intern. Congress 1969. Vol. II, Industrial Amlysis, p. 159. Mediad Inc.. New York. 1970. J. Phillips, Water Res., 1959, 3, 907. Idem, ibid., 1%9,3. 911. K. H. Popp and H. Engelhardt, Cbem. Ztg., Chem. App., 1971.95.461; Chem. Abstr., 1971,75,80031x. L. J. Lionnel, Analyst, 1970,%, 194. J. Dojlido and H. Bierwagen, Chem. Amalit. Wursow. 1969,14,91. G. L. Baughman, B. T. Butler and W. M. Sanders, Wuter Sew. Works, 1969,116, 359. P. Campieri, R. Scott and E. A. Simpson, Anal. Chim. Arta, 1970.49, 188. K. M. Ghan and J. P. Riley, ibid., 1966, 35. 365.

Automated 407. 408. 409. 410. 411. 412. 413. 414. 415. 416. 417. 418. 419. 420. 421. 422. 423. 424. 425. 426. 427. 428. 429. 430. 431. 432. 433. 434. 43s. 436. 437. 438. 439. 440. 441. 442. 443. 444. 445. 446. 447. 448. 449. 450. 451. 452. 453. 454. 455.

1075

wet chemical analysers

R. J. Walker and R. R. Smith, J. Am. Water Works Ass., 1971,63, 246. J. J. Maclsaac and R. K. Olund, Invest. Pesq., 1971,X( 221; C/rem. Abstr., 1971. 75, 121231h. P. C. Head, Deep-Sea Res. Oceanogr. Abstr., 1971, 18, 531; Chem. Abstr., 1972,76,49738e. E. L. Atlas, S. W. Hager, L. I. Gordon and P. K. Park, U.S. Nat. Terh. Inf Serv., A. D. Rept., 19’71, No. 730482; Chem. Abstr., 1972, 76,49734a. W. F. McDiffett, H. Veening and R. F. Comte, J. Chem. Educ., 1972, 49, 510. K. M. Grasshoff and K. M. Chan. Anal. Chim. Acta. 1971.53.442. ’ ’ N. J. Bethea and R. M. Bethea, ibid., 1972, 61, 311. . G. G. Guilhault, Anal. Chem., 1966,38, 527R. Idem, ibid., 1970,42, 334R. R. A. Greinke and H. B. Mark, ibid., 1972,44, 29SR. H. B. Mark, Talanta, 1972, 19, 717. H. V. Malmstadt, C. J. Delaney and E. A. Cordos, CRC Crit. Rev. Anal. Chem., 1972,2, 559. I&m, Anal. Chem., 1972,44(12), 26A. I&m, ibid., 1972, 44(12), 79A. 0. P. Bhargava, G. F. Pitt and W. G. Hines, Tafanta, 1971, 18, 793. C. A. Clapham, G. D. Hall and P. H. Scholes, BISRA Open Rept., 1970, MG/D/647/70; Chem. Abstr., 1971.75. 10476On. M. P. Atherton, M. S. Brotherton and R. Raiswell, Chem. Geol., 1971,7, 285. H. W. Holy, Ind. Chim. Belge, 1967, 32, 451. H. Spitxer, Erzmetall, 1972,25, 51; Chem. Abstr., 1972,76, 16182Sg. W. S. Sebhom. Analvst. 1969. 94. 324. A. Dodson and V. J: Jennings, Thlanta, 1972,19, 801. R. R. Willis, Metallurgia, 1968, 78, 213. Idem, U.S. Nat. Tech. inform. Serv., PB Rept., 1971, No. 205104; Chem. Abstr., 1972, 76, 161923~. C. Liteanu, E. Cordos and L. N. Kekedy, Lucr. Conf. Nat. Chim. AnaI., 1971, 3, 289; Chem. Abstr., 1972,76, 148539x. L. G. Andren, Mod. Kemi, 1970, (4), 34; Chem. Abstr., 1971,74, 13460d. D. P. Lundgren, Ann. N. Y. Acad. Sci., 1960,87, 904. Idem, Anal. Chem., 1960,32,824. D. E. Jordan, J. Ass. Ofic. Anal. Chem., 1969,52, 581. J. R. Prall, U.S. At. Energy Comm., 1970, NCLO-1072; Chem. Abstr., 1971, 75, 583538. Z&m, ibid., 1970, NCLO-1962; Chem. Abstr., 1971, 75, 44573s. Fremeaux and G. Cattin, Chim. Anal. Paris, 1968, 50, 34. R. F. Heuermann, R. C. Kroner, V. C. Midkiff, G. Schwartzman and H. P. Eiduson, J. Ass. Ofic. Anal. Chem., 1972,55,368. C. W. Childs, P. S. Hallman and D. D. Perrin, Tafanta, 1969, 16, 629. Z&m, ibid., 1969,16, 1119. J. W. Frazer, Anal. Chem., 1968,40(8), 26A. S. P. Perone, ibid., 1971,43, 1288. K. Jones and A. Fozard, Chem. in Britain, 1969,5, 552. E. Blatt and H. Fleissner, G.Z.T. Fachz. Lab., 1971, 15, 1444; Anal. Abstr., 1972, 23, 19. E. L. Schneider and A. W. Munson, J. Am. Oil Chem. Sot.. 1971,48,217. Idem, ibid., 1971,48, 220. P. Gray and J. A. Owen, Clin. Chim. Acta, 1969,24, 389. P. D. Griffiths and N. W. Carter, J. Clin. Pathol., 1%9, 22, 609. E. L. Cohen, G. Hermarm and H. T. Sugiura, C/in. Cbem., 1970,16,305. L. G. Whitby, Lab. Pratt., 1970, 19, 170. H. Christiansen, S. Grimnes, F. R. Kulas and T. Waaler, Pharm. Acta Helv.. 1971,46, 677. J. R. Pemherton and P. W. Woodward, Comput. Bkwned. Res., 1972,5, 59. Y. Torud, Pharm. Acta Helv., 1971, 46, 248. J. Keay, An&St, 1969, 94, 690. R. A. Parker and H. L. Pardue, AM!. Chem., 1972,44, 1622. R&aurnUn presente les applications.

une revue de I’analyse automati&,

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Zmannnenfassnng-Es wird eine Uhersicht titer die automatisierte schliel3lich instrumenteller Ausriistung und Anwendungen.

I’instrumentation

Analyse

gegehen,

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ein-