Pharmaceuticals and related drugs - Analytical ... - ACS Publications

Anal. Chem. lQ85, 57,29R-46R (28) Taiwan Central Bureau of Standards, CNS K6717, 1982 BSI Worldwide List Stand. 1983, Jan, 39. (29) Varadarajan, K. J . Coathgs Techno/. 1983, 55, 95-104. (30) Verkholantsev, V. V.: Gul’, T. I.; Karyaklna, M. I.: Malorova, N. V.

Lakokras. Mat. 1981, 45-7. (31) Vltovtova, 0. G.; Zimon, A. D.; Serebryakov, G. A. Lakokras. Mat. 1981, 29-36. (32) Wahl, G. P. Mappe 1982, 192, 494-7.

Pharmaceuticals and Related Drugs R. K. Gilpin* Department of Chemistry, Kent State University, Kent, Ohio 44242

L. A. Pachla Warner-LambertlPurke-Davis, Pharmaceutical Research, PharmacokineticslDrug Metabolism, Ann Arbor, Michigan 48105

The current review surveys pharmaceutical analysis and related methodology that has appeared in Analytical Abstracts or Chemical Abstracts between July 1982 and Jufie 1984. The article is directed exclusively toward the analysis of pharmaceuticalsin unformulated m d dosage form and does not deal with biochemical or clinical aspects of the subject. Because of the extremely large number of references published during each review period, it is possible to cite only a representative sampling of the works published. In doing this an emphasis has been laced on references that have appeared to be significant an{ have been published in easily accessible journals. As in the past, the review is divided into 10 major sections: General, Alkaloids, Antibiotics, Inorganics, Nitrogen and Oxygen Containing Compounds, Steroids, Sulfur Containing Compounds,Vitamins, Techniques, and Miscellaneous. Most of the major sections are divided further into subsections. Because of space limitations and the desire to cite as many individual works as possible, a reference generally appears only as a single entry in the text.

GENERAL During the current review period a new Journal dealing with pharmaceutical analysis was introduced (1)and several books published including: “A Textbook of Pharmaceutical Analysis” (4),“Progress in the Quality Control of Medicines* (6),“Modern Methods of Pharmaceutical Analysis”, volumes 1and 2 (17,18),“Instrumental Data for Drug Analysis” ( I I ) , and Volume 11of a collective series concerned with individual compounds and their analytical profiles (8). A comprehensive review of the analysis of pharmaceuticalcompounds appeared. More than 800 references were cited (9). General aspects of chromatography as applied to the development of new drugs (2, 19,21) as well1 as specific aspects of compound analysis by capillary as chromatography (12),microbore (20) and conventional ?7,22) high-performance liquid chromatography, and high-performance(14) and reversed-phase (15)thin-layer chromatography were discussed. Likewise, a manuscript concerned with the chromatographic identification of major drugs of abuse was published (10). Other topical review dealt with electroanalytical (13)and membrane electrode (5) systems applied to drug analysis, computerization ( 3 )and data management (24)in the pharmaceutical laboratory, and various methods of stability testing (23). Finally, the determination of aromatic amines spectrophotometricallywas discussed (16). ALKALOIDS General. As has been the trend in the past, the chromatographic techniques continue to be employed most often for the analysis of alkaloids as well as pharmaceuticals in general. A book has appeared which discusses various aspects of thin-layer chromatography applied to the determination bf alkaloids ( I A ) . A number of compounds from the different classes have been separated by thin-layer (3A, 8A) and 0003-2700/85/0357-29R$06.50/0

high-performance liquid (6A)chromatographyin combination with ion-pairing techniques. Use of organic modifiers has been found to improve the selectivity in the ion-exchange separation of morphine, dihydromorphine, cocaifie, ephedrine, and dihydrocodeine when chromatographed on alumina (5A). A number of opium, tropdne, and xanthine alkaloids have been measured simultaneously in street samples by a GC temperature-programmingmethod on a capillary column of SE-54 (2A). Additionally, several different alkaloids have been determined spectrophotometrically as their cobaltothiocyanates (7A). Ergotamine and codeine have been chromatographed and then quantitated as their 4-(dimethylamin0)benzaldehyde and molybdenum blue complexes, respectively (4A). Cinchona. Mostly, high-performance liquid chromatoaphic methods have been used to analyze cinchona alkaloids. or example, separations have been obtained on silica (11A, 12A, 14A), cyano (IOA),and octadecyl(13A) columns. The analysis of quinine which is a bacteriostatic agent in hair preparations is possible under reversed phase conditionsusing an ODS column and an ion-pairing mobile phase system (9A). Ergot. Collisionally activated dissociation mass spectrometric experiments have been carried out on 12 ergot peptide alkaloids. The procedure reportedly required less sample cleanup than with other methods (19A). Similarly LC-MS and MS-MS have been utilized in the analysis of several ergot alkaloids (15A, 16A). Liquid chromatographicconditionshave been described for the analysis of ergocornine and a-and @-ergocryptineon an octadecyl column. Er ocornine and 6-ergocryptine were found to coelute except u n k r extremely high pH conditions (17A). An HPLC method for determining ergometrine in combination with oxytocin has been found to give assay results similar to those obtained by an approved colorimetric procedure (18A). Opium. In the current review period analytical methodologies and data have appeared for codeine (21A, 30A) and codeine in combination with other major opium alkaloids such as morphine, papaverine, and thebaine (24A,25A, 29A, 33A, 37A). Separations are possible either by HPLC on octadecyl (29A,33A) and amino (24A)columns or by GC after formation of the perfluoroacylated (25A) and TMS (37A) derivatives. The rate of degradation of codeine phosphate has been studied. The presence of citric acid or thiourea increases stability whereas the effect of pH ie greater under UV radiation (30A). Numerous procedures have been described for the analysis of diamorphine in illicit preparations and include the utilization of capillary gas chromatography (22A, 39A), highperformance liquid chromatography (28A, 36A), and a combination of GC and LC (35A). When a statistical evaluation of data obtained by several chromatographic methods was made, all were found to give satisfactory results (23A). TLC and HPLC have been used to detect and quantitative 03-monoacetylmorphine in diamorphine (31A). Minimum

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PHARMACEUTICALS AND RELATED DRUGS

levels of 0.02% and 0.05% were reported for the respective techniques. TLC also has been employed to rapidly check illicit heroin for the presence of various extenders (40A). Both diamorphine and caffeine will depress the HgCl2/NaNO2 colormetric reaction used for the determination of strychnine in heroin (32A). The stability of aqueous solutions of diamorphine and morphine has been evaluated using a reversed-phase HPLC procedure. Morphine hydrochloride was found to have greater stability (20A). Both morphine and morphine-6-nicotinate have been determined in the nanogram range by an in situ TLC technique (45A). Additionally, several important experimental considerations have been discussed in relation to the quantitation of morphine by GC (43A),HPLC (27A),and voltammetry (41A). Finally, the oxidative dimerization of morphine to psedudomorphine has been studied using a spectroelectrochemical method. Experimental details for construction of the microflow cell were given (38A). Procedures for the analysis of thebaine in Papaver bracteatum (26A,46A),and papaverine and noscapine in mixtures (34A)have been developed. Reversed phase chromatography has been used to determine naloxone hydrochloridein dosage form (42A)and the simultaneous assay of hydrocodone tartrate and acetaminophen in tablets (44A). Rauwolfia. Reserpine has been extracted from tablets with chloroform, and the methylated derivative quantitated by gas chromatography using an OV-101 column (47A). An improved version of a postcolumn reactor for the HPLC-fluorometric measurement of reserpine has been described (48A). Tropane. A gas chromatographicassay has been developed for the separation and quantitation of atropine in the presence of cholinesterase-reactivating oximes and their degradation products (50A). Likewise, atropine has been determined by GC following acylation (54A)and methylation (60A)and has been separated by HPLC from other belladonna alkaloids on ODS (61A) and diol (59A) columns (detection was at 220 nm and at 1.2 V vs. a Ag-AgC1 electrode, respectively). In the case of the latter mode of detection, a limit of 10 ng was reported. Benzotropine has been separated from its degradation product benzophenone on a octyl column (49A). Spectrometric methods also have been described for atropine and include utilization of colorimetric (52A),UV (64A), and fluorescence and phosphorescence (55A) techniques. Finally, a radio-immunoassay for the quantitation of hyoscyamine in plant material has been described (58A). The procedure involves development of an antiserum which is formed by coupling to human serum albumin the carboxy derivative of an immunogen prepared by treating rabbits the with reaction product of atropine and diazotized 4-aminobenzoic acid. Problems in the stability of atropine and scopolamine when stored in plastic containers have been examined (57A, 62A). Unbuffered solutions were reported to contain 90% of the initial drugs after 18 months at 20 "C. Likewise, the stability of aqueous solutions of cocaine and benzoylecgonine have been studied using a reversed-phase HPLC system (53A). A semiscreening test for cocaine involving formation of a colored complex with CU2+ in the presence of SCN- has been described (63A). Densitometric determination of scopolamine in plant material following treatment of the TLC plate with l % 4-(dimethy1amino)benzaldehyde in 5 % HzS04has been reported (51A). Scopolamine hydrobromide and N-butylscopolammonium bromide have been measured potentiometrically using liquid-membrane electrodes (56A). Vinca. Eight optical isomers of vincamine have been separated on a cyano column using the (+) and (-)-isomers of camphor-10-sulfonicacid as mobile phase additives (65A). An HPLC method involving dual-wavelength UV detection has been reported for the analysis of vincamine in commercial pharmaceutical preparations (71A). Xanthine. The concentration dependency of retention for caffeine and a number of other compounds has been studied for splitless injection capillary gas chromatography(67A). The technique is reported to be limited for toxicological screening due to significant dependency of retention on sample size. Several different techniques which include proton nuclear magnetic resonance spectrometry (68A),room-temperature phosphorescence measurements (#A), and titrimetric procedures (70A) have been employed in the analysis of theo30R

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phylline. An enzyme immuno-electrode formed by covalently immobilized antitheophylline antibodies to a nylon net has been developed (69A). The sensitivity of the electrode has ben reported to be in the 9.0-90 ng/mL range. Miscellaneous. In the last 2 years several procedures have been described for the analysis of ephedrine (72A, 74A, 80A82A, 87A, 88A). Most have involved the utilization of liquid chromatography (81A, 82A, 88A),or colorimetric (72A)and UV (74A)spectrophotometry. Separation of the enatiomer of norephedrine has been attempted by rotation locular countercurrent chromatography using aqueous 0.3 M sodium hexafluorophosphate as the stationary phase and 0.3 M (RR)-di-5-nonyltartrate in 1,2-dichloroethaneas the mobile phase (76A). Improvements in enantiomer purity were reported. High-performance liquid chroamtography has been used to measure pilocarpine in formulated products (77A,78A) and the degradation characteristics of salsoline and tetrahydropapaveroline (83A). Also HPLC has been utilized for the separation of various glycoalkaloids (79A) and macrocyclic pyrrolizidine alkaloids (84A). An improved TLC system for evaluation of (-)-tubocurarinechloride and commercial curare has been described (73A). The detection of quaternary candicine chloride in dried ethanolic extracts of cactus using laser desorption techniques has been reported (75A). Spectrometric procedures for berberine and brucine have appeared. These respectively involve an ion-pair extraction with bromophenol blue and quinine (86A) and the oxidation with Cr6+ in HzS04-oxalicacid medium (89A). In the latter case analogues of brucine (e.g., strycinine) do not interfere. A revised official method for strychnine has been examined (85A).

ANTIBIOTICS General. Several reviews of liquid chromatographic methods for antibiotics have appeared ( I B ,4B). Antibiotics that were discussed in the first review included the analysis of bleomycin in injectable preparations, doxorubicin and daunorubicin in fermentation broths, bulk amphotericin, tetracyclines, and fredericamycin A (1B). Another review discussed LC and other nonbiological methods for the quantification of antifungal agents (4B). The advantages and disadvantagesof isothermal differential microcalorimetry and thermometric titrimetry for the analysis of antibiotic agents were the subject of an excellent review article (2B). This review contained 117 references. Improved separations of cephalosporins, penicillin, aminoglycoside, and anthracycline antibiotics have been achieved with ultra-high-performance columns using ion-pairing techniques (5B). Ten anthracycline antibiotics have been characterized by desorption chemical ionization mass spectrometry (3B). As little as 1 ng of antibiotic could provide useful negative ion mass spectra, whereas positive spectra were shown to provide useful information only for the glycosidic moiety. Cephalosporins. Silica gel 60 has been suggested as an excellent stationary phase for TLC and LC separation of cephalosporin C and its deacetoxy and deacetyl analogues (12B). Alternatively, polystyrene resins containing copper complexes of lysine derivatives have been shown useful for producing pure cephalosporin C (15B). A microprocessorcontrolled scanning polarograph has developed for the quantification of labile compounds (8B). This unit automatically dissolves cephalosporin samples in removable glass weighing vials just prior to polarographic analysis, thus reducing degradation. A precision of 0.58% was reported. A selective spectrophotometric determination of eight cephalosporins has been described that is based on alkaline degradation to HzS (6B). A thermal gravimetric and microcalorimic method has been recommended for the determination of the sodium content of cephalosporins (7B). A reversed-phase chromatographic method has been compared to the hydroxylamine and microbiological methods for cefsulodin (9B). The chromatographic method agreed well with the reference methods and as little as 0.10 wg/mL could be detected at 261 nm. Traces of cefotaxime and five degradation products have been quantified by TLC with fluorometric detection (IOB). The method was linear between 5 and 25 wg and a detection limit of 0.15 ng was reported. A method for cephalexin and cefadroxil has been reported using differential pulse polarography and linear sweep voltammetry (11B). Thermoanalytical methods have been characterized

PHARMACEUTICALS AND RELATED DRUQS

over Tu:and speetmmpic methods were discussed. Another liquid chromatographic method was presented for the determination of isoniazid and amindevlate in hulk drUp and

for the determination of aodium and potassium salta of three cephaloeporins and penicillins. Decomposition of the cephalosporins began at 135-170 "C while K-benzylpenicillin began at 16C-240 "C. NMR spectmscopy was shown to be a useful analytic@ tool for the quantification of cephalothin sodium, cephaloridine, cephadrine. and cefoxitinan cefoxatime in parenteral and capsule formulations (138). A colorimetric method has been p r o p e d for the estimation of cephaloridine in solutions and tablets. The method is based on acid hydrolysis followed hy the formation of a highly colored Schiff base which has an absorbance maximum of 485 nm. Normal excipients did not interfere, and recoveries greater than 99.5% were reported. Chloramphenicol. Two reversed-phase chromatoqaphic procedures have been published for the determination of chloramphenicol (178. 20H). The first method is based on UV detertion at 278 nm and utilizes a C8 column to monitor the stability of eye.drop formulations. The second method is based on reductive amperometric detection at a hanging mercury drop electrode. This method was rectilinear from 2 ng to 20 pg and could monitor the presence of degradation productn. A titrimetric procedure has also appeared for the determination of chloramphenicol in a variety of pharmaceutical preparations (188). A manuscript comparing polarogra hic. spectroscopic. and liquid chromatographic m e t h d of analysis has appeared (198). The authors concluded that only the chromatographic method was specific for the determination of chloramphenicol in photolyzed and heated solutions. Isoniazid. An improved liquid chromatographic method for tabletrt has been recommended for the determination of isoniazid impurities (228). The advantages of this method

' GLC separation and FID detection. Several spectroscopic methods have been published during .the last 2 years for the determination of isoniazid or its degradation products (238,248,27B, 308). The absorbance produced at 430 nm after reaction between isoniazid and vanadophosphoric acid was the basis of a method for tahlets (278). Another method relied on the colorimetric reaction between isoniazid and 2,5-diphenyl-3-(2-thiazolyl)-ZH-tetrazolium chloride (248). The method is rectilinear between 0.025 and 2.5 pg and other substances coformulated with isoniazid did not interfere. Chloranil has also been reported to be a useful reagent (308). Low levels of hydralazine in hydrolyzates of isoniazid formulations were determined using difference spectrophotometry (238). The absorbance difference was proportional to the original hydralazine concentration and was unaffected by excess isoniazid. Flow-injection analysis using a vitreous-carbon electrode has been proposed as a specific method for the quantification of isoniazid (298). The method was linear between 0.05 and 6 pg/mL with a detection limit of 0.5 ng. A titrimetric microdetermination has been reported for isoniazid (218). The method is based upon an in situ amplification reaction and has a precision of 3.6% for 10 pg of isoniazid. Two other titrimetric methods have appeared that use KMNO, (26B) and 2-(iodoxy)henzoate (318). Penicillins. A variety of methods have been developed for penicillins during this review period. A reversed-phase method has been described for ampicillin on a ODS column (438). This method has a linearity range from 0.7 to 36 pg with a precision of 2%. Ampicillin polymers have been separated and measured in bulk material after TLC on silica gel (4IB). Ampicillin and cloxacillin have been analyzed by NMR spectroscopy (528). Integration of the signals at 4.57 ppm and 2.68 ppm was proportional to the amount of ampicillin and cloxacillin, respectively. A selective method based on the conversion of ampicillin, amoxicillin, and cyclacillin to 2,5piperatinedione derivatives has also appeared (348). This method has been applied to stability testing of these aminopenicillins. A liquid chromatographic procedure has been described for monitoring the titrimetric reaction kinetics between hydroxylamine and ampicillin, cyclacillin, and 6aminopenicilloic acid (548). This method was superior when compared to conventional titrimetric stoichiometric methods. A colorimetric amoxicillin method gave comparable results with the 1980 British Pharmacopeia1 method (SOB). A collaborative study has appeared that compares four methods of analysis for benzylpenicillin (55B). The methods which were evaluated included (i) an iodimetric titration, (ii) spectrophotometry with HgCL-imidazole reagent, (iii) Hg(NO,), titration in acetate buffer, and (iv) Hg(CIO,), titration in pyridine. All methods were found to give similar results hut method (iii) was preferred since it needed no reference agent. Formation of a Cu(I1) complex with benzylpenicillin was the basis of a spectroscopic method (518). The absorbance at 750 nm of the green complex was used to construct ah e a r calibration graph between 1and 300 pg. This method gave similar results with a pharmacopoeial method. An orthogonal polynomial method has been described for the determination of benzylpenicillin and ampicillin (568). The method is based on the computation of a combined polynomial coefficient from absorbance data obtained at 2-nm intervals from 247 to 269 nm for benzylpenicillin and from 249 to 271 nm for ampicillin. The coefficient was independent of the presence of degradation products and gave similar results when compared to an official iodimetric method. A spectrophotometric procedure has been reported for the reaction of benzylpenicillin with Azure B (74B). A cathodic stripping voltammetric determination for benzylpenicilloic acid has been described (35B). An ion-pair reversed-phase chromatographic method has been reported for the determination of henzylpenicillin and ita degradation products (388). Ac polarography has been evaluated for the analysis of cloxacillin (468). An electroactive product is formed when cloxacillin is hydrolyzed at pH 4. This product can he monANALYTICAL CHEMISTRY. VOL. 57, NO. 5. APRIL 1985

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itored at either -0.23 or -0.13 V and a linear relationship was M. A reestablished between 2.2 X lo4 and 2.2 X versed-phase procedure that is linear between 0.11 and 0.61 mg/mL has also been described for cloxacillin (42B). Liquid chromatography has been applied to separate the side-chain diastereoisomers of carbenicillin, ticarcillin, amoxicillin, ampicillin, phenethicillin, azidocillin, propicillin, and clometocillin (39B). A densitometric TLC procedure has been evaluated for the determination of carbapenem antibiotics in fermentation broths (47B). A flow-injection method with electrochemical detection was applied to the measurement of penicilloic acid in penicillin preparations (36B). This rapid, sensitive technique gave good agreement with two titrimetric methods. The reaction between sodium nitroprusside and penicillamine was evaluated for the colorimetric analysis of pharmaceutical preparations (49B). This method reported a recovery of 99.8% and a precision of 0.67%. Another colorimetric procedure was based on the oxidation of penicillamine with Fe(II1) has been used for the analysis of pharmaceutical preparations (48B). Two liquid chromatographic methods were published for the determination of penicillin V (33B,40B). The f i i t method involved cleavage by penicillin V-amidase to 6-aminopenicillanic acid which was then derivatized postcolumn with o-pthalaldehyde and detected by fluorometry (33B). The second method involved direct detection at 220 nm (40B). The hydroxy analogue of penicillin V was simultaneously measured in this method using an electrochemical detector. A chromatographic method has been reported for the analysis of vermiculin (37B). Several other techniques have been described over the last 2 years for the analysis of penicillins ( 5 3 4 44B, 32B). For example, thermal analytical methods have been preferred over flame photometry for the determination of sodium in penicillins (53B). Mass spectral and liquid chromatographic/mass spectrometricstudies of several antibiotics have been described (44B). Tandem mass spectrometry has been shown useful for the identification of penicillins and analogues (32B). Streptomycin and Related Antibiotics. A review article has appeared that describes LC methods for antitumor antibiotics (58B). This report contained 106 references and covered the analysis of actinomycins, vincaalkaloids, bleomycins, and anthracyclines. Distamycin A has been separated from its synthetic analogues using a C18 column and a mobile phase containing phosphate buffer/ethanol (66B).Several chromatographic methods have been reported for erythromycin (80B, 75B, 69B). An improved LC method for the measurement of erythromycin in solid dosage forms has been reported using reversed-phased chromatography with detection at 215 nm. Results from this method were expressed in terms of antimicrobial bioequivalency against staphylococcus. No statistically significant differences were observed from those of a microbiological assay. A similar chromatographic method has appeared for the analysis of erythromycinsA and B in fermentation broths (75B). Thin-layer chromatography on silica gel has been evaluated for the separation of erythromycin and its esters (69B). A reported detection limit of 0.5 pg was adequate for the identification and purity testing. Complex formation between erythromycin and bromophenol blue has also been investigated as a colorimetric method for pharmaceutical preparations (76B). Chelation with aluminum has been used as the basis of a spectrophotometric method for efrotomycin (65B).Efrotomycin functioned as a bidentate ligand, and the method was based upon the red shift observed in its absorbance spectrum. Optimal chelation conditions such as time, temperature, and reagent conditions were evaluated. Two reversed-phase LC methods have been published for the chromatographic determination of gentamycin that uses o-phthalaldehyde as the derivatization reagent (71B,81B). One method relied on UV detection at 330 nm (81B) while the second was based on fluorescence detection at 430 nm (71B). NMR spectroscopy has also been investigated as an analytical tool for the determination of gentamycin (70B, 77B). A method based on the 90-MHz spectrum of a 20% solution containing 0.05% of sodium 3-(trimethylsilyl) ropanesulfonate as a zero frequency reference was reportef(77~).The gentamycin content was calculated from the signals from the N-methyl protons. Another method was based on the carbon-13 NMR spectra of the free base of gentamycin (70B). Calibration curves were 32R


obtained using peak height ratios of analyte to a dioxan reference under conditions of full relaxation. Alternatively, a steady-state procedure was found to give quicker and simpler results. A potentiometric microbiological assay employing a carbon dioxide gas sensing electrode has been reported for gentamycin, streptomycin, and neomycin (78B). Liquid chromatographyand MS have been investigated for the identification of mitomycin C, 2 mitosane, and 12 mitosene derivatives (5723). Only two compounds were found to coelute on a Radial-PAK CI8cartridge. Mass spectra and fragmentation patterns were presented for six acetyl derivatives. Several chromatographic methods for neomycin have been reported since the last review (614 64B, 67B, 73B). Column chromatographyon Bio-Rad anion exchange resins was found useful for the measurement of 7-70 mg of the free base of neomycin B and C in neomycin sulfate powders (64B). Neomycin has been quantified in etroleum-based ointments and in veterinary formulations gy normal-phase LC with detection at 254 nm (61B).An improved LC method for the simultaneous determination of neomycins A, B, and C has been reported (67B). This method required derivatization with l-fluorc-2,4-dinitrobenzeneand gave similar results when compared to a microbiological assay. Lastly, a descending paper chromatographic assay was published for the measurement of neomycin C in cream, ocular, and skin ointments ( 73B). Paired-ion liquid chromatography has been used to determine the stability of novobiocin in mastitis products sterilized by cobalt-60 irradiation (68B). Nystatin has been quantified by a colorimetric method (63B) and by a microbiological assay (79B). Chromatographic assays have been reported for the reversed-phase separation of propionylmaridomycin (59B)and the normal-phase determination of turimycin and spiramycin (60B). The first international reference preparation has been published for tobramycin (72B),and vanomycin has been measured by continuous-flow hydrodynamic amperometry (62B). Sulfonamides. Several chromatographic methods have been published for a variety of sulfonamides (83B,84B, 91B). N'-acetylsulphisoxazole and related impurities have been quantified by TLC and LC (84B). A collaborative study on the LC quantification of sulfisoxazole has been reported (91B). The LC method was tested in seven laboratories and recoveries between 99.9 and 104.5% were obtained for synthetic samples. The utility of microbore LC was investigated for the analysis of sulfadiazine, sulfafurazole, and sulfadimethoxine(83B). As little as 16.5 pg of each drug was detectable at 254 nm. Spectroscopic methods continue to provide rapid simple methods for sulfa drug analysis (85B,8 6 4 94B). For example, sulfaguanidine and sulfadimidine can be quantified within 5 min after reaction with NH4V03(94B). Beers law is obeyed between 400 and 1100 pg for sulfaguanidine and 100 and 900 pg for sulfadimidine. A method for trimethoprim based on its reaction with chloranil has been evaluated for solid dosage forms (85B). A simple ultraviolet method has been described for the measurement of trimethoprim and sulfamethoxazole in alkaline solutions (86B). Since this class of compounds is electroactive, an increase in electroanalytical methods can be anticipated in the future. Polarographicmethods have been reported for sulfadimidine, sulfafurazole, sulfadimethoxine, sulfaguanidine, sulfamethoxypyridazine (92B),and trimethoprim (82B). Cyclic voltammetry at a platinum electrode has also been proposed as an alternate method for the quantification of trimethoprim and sulphamethoxazole (82B). An ammonia gas sensing electrode has been employed for the determination of ethionamide and prothionamide after acidic degradation (93B). A silver sulfide electrode has been investigated for the potentiometric measurement of sulfacetamide and sulfadimethoxine (89B). A linear relationship was observed between EMF and log concentration. As noted for the other antibiotic classes, thermal analytical methods offer a straightforward means to measure sulfonamides (87B,88B). The thermal behavior of 14 sulfonamides have been evaluated by thermogravimetry, derivative thermogravity, and differential thermal analysis (87B). Sulphathiazole, salfasomidine, sulfaguanidine,and sulfacetamide have been measured after both endo- and exothermic DTA. An in vitro and in vivo evaluation has been reported for dosage forms containing trimethoprim and sulfamethoxazole (90B).


Tetracycline. As in the past, chromatography continues to be an important means of analyzing tetracyclines. Thirteen commercial preparations containing tetracycline, oxytetracycline, methacycline, and doxycycline have been assayed using column chromatography (103B). A stability-indicating assay has been developed for 4-epitetracycline and anhydrotetracycline using a pBondapak Phenyl column with detection at 280 nm (95B). A reversed phase assay was useful in achieving separations of anhydro- or epianhydrotetracycline, tetracycline, and epitetracycline in bulk drug (99B). Tetracycline and its impurities can be simultaneously determined using reversed-phase chromatography (97B). Likewise, separation on reversed-phase TLC plates has been recommended as a viable alternative to liquid chromatography (IOIB). Alternatively, densitometric detection to liquid chromatography (IOIB). Alternatively, densitometric detection on silica gel plates has been studied for tetracycline (102B) or tetracycline, oxytetracycline, and chlortetracycline (96B). Miscellaneous methods that have appeared include a voltammetric assay (IOOB)or a lanthanide-sensitized luminescence assay (98B),for tetracycline, chlortetracycline, doxycycline, and anhydrotetracycline. Miscellaneous. A LC determination has been published for anthralin in ointments (104B). Chloroquine has been measured spectrophotometrically after formation of a thiocyanatochromium(II1)complex (107B). A variety of reagents have been investi ated and proposed for the colorimetric determination of japsone. Doxycline has been determined in pharmaceutical preparations by several colorimetric procedures (II3B). A tablet assay method for ethambutol has appeared using GLC with FID detection (IIOB). In this method, the analyte was converted to a silyl derivative prior to analysis. The identity of the derivative was confirmed by GC/MS. Fusidic acid has been measured by LC and gave comparable results when compared to a microbiological method (108B).Methods have been published for methenamine ( I I I B ) , polymixins (105B, 106B), and taurolidine (109B).

INORGANICS Single Element Analysis. The release of ammonia from rubber caps manufactured from natural, chlorobutyl, and bromobutyl rubbers has been studied by an ion selective electrode technique (9C). Similarly, ion selective electrodes have been employed in the measurement of bromide activity in solutions of cetrimide between pH 6 and 10 ( I C ) ;quantitation of fluoride in dentrifrices, dental gel, tablets, and injections (3C);and establishing equilibrium concentrations of free and complexed iodine in aqueous solutions of poly(vinylpyrro1idione)-iodine (5C). Also a tetraphenylborate-selective electrode has been constructed for the potentiometric titration of potassium with sodium tetraphenylborate ( I I C ) . Data generated by using the new electrode were nearly eqivalent to those obtained with a valinomycin-typeK+ selective electrode. Spectrophotometric procedures have been developed for the analysis of bismuth as tetrabutylammonium tetraiodobismuthate (6C), iron as either the 3‘,5‘-dibromo-2’,4’-dihydroxyacetophenone oxime (2C) or the 5’-chloro-2’,4’-dihydropropionphenone complex, and lithium as a “crowned” dinitrophenylazo henol (IOC). Likewise, trace amounts of palladium have Eeen measured colorimetrically following treatment of the sample with solutions of dimethylforamide, thio-Michler’s ketone, and hydroxylammonium chloride (I3C). Both atomic absorption spectrometric (8C) and titrimetric (4C) methods have been used to determine mercury in products containing phenylmercury borate and related compounds. A previously developed differential pulse polarographic method for the analysis of iodine in thyroid tablets has been evaluated and results from the collaborative studv published (7C). Multiple Element Analysis. Over the course of the current review period the determination of various heavy metals in active materials and formulated products has been carried out by several methods (15C, 16C, 21C, 25C). Additionally, the limit test for heavy metals according to the European Pharmacopoeia I and I1 (24C) has been evaluated and reported to be unsuitable for the analysis of Cd, Cr3+,Fe3+, and Zn. Likewise, iron and zinc as well as calcium, cop er, magnesium, and phosphorus have been analyzed by in uctively coupled plasma emission spectrometry (19C). In the

B

study two methods of sample introduction were compared. Vaporization of a slurry of the sample from a heated graphite rod gave equivalent results to those obtained by conventional pneumatic nebulization of aqueous solution with an added advantage of a significant time savings in sample preparation. A method employing californium-252 thermal-neutron activation has been developed for the determination of aluminium and magnesium in antacids (ISC). The method gave poor precision when compared to standard titration methods. However, it is possible that these shortcomings can be minimized with a more intense 252Cfsource. The titration methods of the Swiss Pharmacopoeia, for determination of bromide and chloride, have been reported to be unsuitable (20C). Similarly, methods of the Ph. Eur. and D.A.B. VI1 have been found to be unsatisfactory in several solvents (22C). Sulfate and halide (17C)and sulfate and sulfite (23C) ions have been determinated for various compounds using titrimetric and isotachophoretic methods, respectively. Radiopharmaceuticals. General aspects of the analysis and quality assurance of radiopharmaceuticals have been reviewed (28C, 30C, 36C). Likewise, specific aspects of the utilization of HPLC for determining purity of labeled compounds have been examined using tritiated prednisolone as a model system (37C). A major pitfall is possible isotopic fractionation. Liquid and thin-layer chromatography, respectively, have been employed to assess the specific activity of radiohalide preparations as their corresponding l-halo-2naphthol derivatives (33C) and for quantitation of carbon14-labeled cyclophosphamide (29C). Within the review period various aspects of the chromatographic analysis of technetium-99m products have been considered (27C, 34C, 38C, 39C). A small volume cadmium telluride y-ray HPLC detector has been described (35C)with a sensitivity of 100 nCi of &Tc as a result of better detection efficiency and lower background radiation. Large differences in extraction efficiency of technetium from several different carrier solutions have been observed using 0.4 M quinolin-8-01 in chloroform (3IC). Other reported procedures for radiopharmaceuticals include the quantitation of tin(I1) in technetium preparations (26C, 32C).

NITROGEN-OXYGEN CONTAINING COMPOUNDS General. A handbook which contains basic data and analytical metholodogy for benzodiazepines has been published (40). Likewise, various aspects of a general nature have been considered for the following compound amitriptyline hydrochloride (50),calcium cyclobarbitone and hexobarbitone ( 3 0 ) ,fendiline and prenylamine ( 2 0 ) ,nitroglycerin ( I D ) ,and zomepirac ( 6 0 ) . Chromatography (General). Gas, liquid, and thin-layer chromatographicmethods have been reported for the analysis of the calcium antagonists, nifedipine, and niludipine ( 7 0 ) . Similarly, phencyclidine and eight related analogues have been separated by TLC using silica plates and two different developing solventa, HPLC on an octydecyl column, and GC on either a 2% OV-101 or 3% OV-1 column (80). Gas Chromatography. Several different derivatization procedures have been published for nitrogen-oxygen containing compounds prior to their gas chromatographic analysis. An investigation of iodoalkanes as alkylation reagents for phenytoin, mephenytion, and primidone has been carried out (150). Also various barbiturates have been determined after treatment with N-methylbis(trifluoroacetamide) (100) or N-trifluoroacetyl-L-prolyl chloride (190,200). A method for the rapid analysis of various barbiturates available in Canada has been described ( 9 0 ) . The procedure is useful for amobarbital, butabarbital, heptabarbital, mephobarbital, pentobarbital, phenobarbital, and secobarbital. A study has been made of methylamphetamine hydrochloride prepared under varying reaction conditions (240)using a fused-silica column. Since the levels of impurities were dependent on the synthesis route, chromatographic profiles potentially are useful for identification of a common origin for illicit materials. The effect of split and splitless injection modes of sample introduction of hexobarbitone and related materials has been examined (140). Statistical analyses of the data demonstrate that the latter technique is best. Various topical anesthetics and antiinfective have been analyzed singly or in combination. Published GC procedures ANALYTICAL CHEMISTRY, VOL. 57, NO. 5, APRIL 1985

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have included analysis of benzethonium chloride in solution (180), cetylpyridinium chloride in five different pharmaceuticals (120), chlorhexidine in creams (220), benzocaine in liquid and ointment form (16D),and benzocaine and lidocaine in isopropyl myristate (110). Although chloroform as an injection solvent has been found to produce artifacts with certain amines, the problem is not present with lignocaine (170). Methyl silicone stationary hases have been used to assay bromperidol (210), nadolol &3D), and phenacemide (130) in tablets as well as to study the photodecomposition of doxepin in aqueous solutions (250).In the latter investigation decomposition was accelerated in dilute HCl compared to phosphate buffer solution. Liquid Chromatography. As has been the case for several years liquid chromatography continues to be the most important means of analyzing nitrogen-oxygen containing compounds. A number of methods for various analgesics (340, 380, 450, 520, 750, 760, 1140) and cou h-cold products (340,540, 600, 660, 970) have appearecfover the review period. Trace levels of salicylic acid in aspirin (750,760) have been analyzed by high-performance chromatography. Likewise, HPLC has been used to determine acetaminophen in several dosage forms using a totally aqueous mobile phase (520). After sample preparation which is a simple dissolution step, the chromatographicanalysis takes approximately 2 min per sample. Reversed-phasesystems employing octydecyl columns have been developed for the analysis of the dental analgesic chlorbutol (440), the antiinflammatories indomethacin and related impurities (670), and phenylbutazone and its decomposition products (470) as well as to access the stability of the local anesthetic procaine in aqueous solutions (1100). In the cases of antiinflammatoryagents fentiazac and mefenamic acid analysis have been carried out using an octyl column and a methanol-phosphate buffer mobile phase (350) and by ion-pair partition chromato aphy (270), respectively. Cyano columns have been utilize to simultaneously measure hexylcaine hydrochloride,and methyl and propyl parabens (330) as well as to determine benzalkonium chloride in the presence of intefering alkaloids and polymeric substances (720). Procedures for phencyclidine (320) and tetracaine and chlorhexidine (310) also have been published. Phenylpropanolamine has been determined in ap etitesuppressant formulations after conversion to benzal ehyde (1030). Additionally, a chiral separation has been reported for this same amine following a condensation reaction with COClz (1080)and for amide derivatives of amphetamine using an optically active mobile phase additive and an aminopropyl column (1070). Miscellaneous adrenergic compounds studied over the time of this review include epinephrine (460,610, 1110),naphazoline (300), and terbutaline (1130). An assay has been described for quantitation of nadolol in tablet formulations (860). Likewise, several different procedures have been described for other p-adrener ic blocking agents such as propranolol, related compounds, an impurities. Two of these have determined the active directly using octyldecyl columns to se arate propranolol and hydralazine hydrochlorides from ta&et formulations (91D), and propranolol from peritoneal dialysis fluid (840). A third method also utilizes an octydecyl column to resolve the enantiomers of propranolol and 10 related compounds following derivaisothiotization with 2,3,4-tri-O-acetyl-a-~-arabinopyranosyl cyanate or (preferably) 2,3,4,6-tetra-O-acetyl-/3-~-glucopyranosylisothiocyanate (990).Likewise, the chiral resolution of propranolol,alprenolol, and oxprenolol has been attempted using a diol surface and (+)-camphor-10-sulfonic acid as a mobile phase additive (870). A final method for propranolol and five related impurities has employed a silica surface which was dynamicall modified with hexadecyltrimethylammonium bromide addegto the mobile hase (570). This latter procedure has been suggested to e! column manufacture independent. Specific analytical procedures have been described for the vasodilators nitroglycerin (830) and oxprenolol (740). Likewise, the amounts of partially nitrated glycerins in crude glyceryl trinitrate have been determined on a phenyl column with an acetonitrile-water mobile phase (280). It has been noted that acetonitrile is more effective in extracting nitroglycerin as well as isosorbide dinitrate and pentaerythritol

cr

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tetranitrate from tablets and capsules than dimethyl sulfoxide (510). In the case of the diuretic isosorbide dinitrate, results from a stability study also have appeared (780). Other cardiovascular agents which have been studied include acetyldigoxin (260), digoxin (410,420), heptaminol(790) in formulated form, as well as numerous other naturally ocurring glycosides (400,490,620, 640,820,850). The tranquilizers oxazepam (290,920) and chlordiazepoxide (960)have been separated from excipients and related impurities using octadecyl columns and aqueous-methanol mobile phases. The neuroleptic haloperidol has been assayed under similar conditionsin an interlaboratory study involving 13 participants (690). Other reported methods for the analysis of tranquilizers in dosage form include the determination of diazepam (1020) and fluspirilene (580)under reversed-phase and normal-phase conditions, respectively. Allantoin has been quantitated in a number of products on either an NH2surface (1160)or a strong cation-exchangeresin (630). Both amitriptyline (1090) and amygdaline (1010) have been measured in tablets and injectables on cyano columns. Octadecyl columns have been utilized in conjunction with acetonitrile-water mobile phases to analyze capsaicin (680), orphenadrine (IOOD), and pralidoxime and decomposition impurities (890). Pralidoxime and major degradation products have been resolved with a methanol-aqueous buffer as well (730). The diuretic ethacrynic acid (390),the antinauseant meclozine @OD),and the barbiturate secbutobarbitone (980)have been separated under similar conditions. In the latter method, a postcolumn change in pH was used to enhance detection. Reversed phase methods also have been described for cyclobenzaprine (56D),primidone, (95D), propantheline (360), levodopa and carbidopa (500, 940),and thyroxine (530,930). In two cases electrochemical detection was used (530,940). Additionally,the temperature dependence of electrochemical detection has been examined (770). Normal-phase methods have been developed for bisacodyl and its deaceyl and dideaceyl derivatives (430), and alprazolam and related compounds (1040,1170). Both normal and reversed-phase systems have been described for podophyllotoxin (710). A combined procedure has been published for tiodazosin and lavevulic acid (880). The assays respectively are carried out on octyldecyl and phenyl surfaces. Other compounds which have been investigated over the course of the review period include cis- trans-fl-carotenes (1050),chlorazepate (370), dauorubician doxorubicin (550), insdin (1060,1120,1150), methotrexate (480,GO),oxytocin (7OD), platinum(I1) complexes of cyclohexane-lR,2R-diamine (NO), tiodazosin (880), 1-(3-hydroxy-a-phenylphenethyl4-(3-methylbut-2-enyl)piperazine@OD), and l-(5-tetradecyloxy-2-fury1)ethanone and 5-(tetradecyloxy)furan-2carboxylic acid and esters (590). For the latter compounds electrochemical detection was employed. Thin-LayerChromatography. Thin-layer methods have been used to identify the active constituents of analagesic preparations (1190), to identify and study mechanisms of reactions of barbiturates (1250),and to monitor the synthesis of the antiinflammatory 2-(4-benzoylphenyl)-2-methylpropionic acid (1180). Additionally, the stability of a number of pharmaceutical compounds in various forms have been studied by thin-layer chromatographic procedures. Cited compounds with related degradation products include cadralazine (1210), denaverine hydrochloride (1260), dipyrone (1240), meprobamate (1220), niclosamide (1340), suxamethonium chloride (1230), and tropicamide (1280). The separation of seven antihistamines has been carried out on silica gel plates which were impregnated with 1%zinc acetate (1300). In this same study other sal& were examined and found to give poor results. Biphenyl modified plates and an aqueous methanol mobile phase have been used in the analysis of epinephrine,norepinephrine, and dopamine (1290). The reversed phase mode also has been utilized in the HPTLC determination of three possible contaminants in metoprolol tablets at concentrations below 1% (1200). Both HPTLC and TLC methods have been evaluated for use in the analysis of acetyl derivatives of tyramine (1310). It was reported that the conventional procedure was preferred. Other compounds which have been studied by thin-layer methods include aspirin and diazepam (1320), tolazoline and demelverine (1270), and ibuprofen (2310). In the latter two

d


citations specific spray reagents were also listed. Spectroscopy (Colorimetric). During the 2-year period various colorimetric methods have been developed for the analysis of several analgesics, antipyretics, and antiinflammatories. Carbamazepine (1660), and dextropropoxyphene (1360) have been determined after oxidation with NaI04 and acidification and treatment with Co(SCNI2, respectively. Three separate methods have been evaluated for acetarninophen, phenacetin, as well as several other compounds (1750). The methods were applied to 12 different formulations. The antiinflammatories oxyphenbutazone and phenylbutazone (1420) have been reacted with 4-(dimethy1amino)cinnamaldehyde to yield products which are read at 525 nm and 540 nm, respectively. Likewise, treatment of phenylbutazone as well as aminopyrine with a mixture of nitric and sulfuric acids produces orange and green to reddish orange colors (1500). Other methods have been published for oxypenbutazone (1350) and indomethacin (1640). Several colormetric assays have been developed for various cough-cold aids and include the analysis of the expectorant bromhexine camsylate (1400), the antitussive oxeladin citrate (1590), and the antihistamine chlorpheniramine maleate (1480,1680). Analytical procedures have been published for phenylephrine (1720) and other adrenergic agents such as oxymetazoline (1550, 1740, 1850) and terbutaline (1440, 1520,1550,1790,1830). Terbutaline also has been quantitated (1900) as well as isoprenaline (1370) by a mircoprocessor-controlled flow-injection analysis based around the reaction of K,Fe(CN), with the active. Likewise, flow injection has been useful for determining diphenhydramine although measurement was in the UV region (1460). Powers, injections, and ophthalmic solutions containing tetracaine have been evaluated using 4-(dimethylamino)cinnamaldehyde (1430). The colored product has been reported to be stable up to 12 h and to observe Beer's law from 0.5 to 20 hg/mL. The analyses of other locally acting compounds include topical preparations of the anesthetic benzocaine (1580, 1700) and the antiinfective agents benzethonium (1690),chlorhexidme (1650),and clioquinol(1510). Methods for the analysis of the antiarrhythmic procaine hydrochloride (1450), the cardiotonic dobutamine hydrochloride (1410), and hydralizine hydrochloride (1890) have been described recently. Of the drugs commonly formulated with hydralazine, only reserpine showed some degree of interference. Procedures for general as well as specific vasodilators have been described recently. For example, isoxsuprine hydrochloride has been estimated in injections and tablets by treatment with a variety of acid-base indicators (1730) and by reaction with 4-nitroaniline under basic conditions (1800). Likewise, 4-nitroaniline (1570) as well as 4-aminophenazone (1560)have been employed in the analysis of nylidrin in dosage form. The detection of various benzodiazepines by five different color forming reactions has been reported (1600). One of the procedures involves treatment with HC1. Similarly, a HC1 hydrolysis has been used to estimate nitrazepam in tables and capsules (1780). Treatment with l-fluoro-2,4-dinitrobenzene also has been employed (1810). Other colorimetric procedures have been published for the antiamebic compounds diloxanide (1760) and diiodohydroxyquinoline (16201, the antidepressant doxepin (163D), and antimalarial agents amodiaquine (1670), pyrimethamine (1710), and primaquine (1490), the antiemetic metoclopramide (1530,1540), the central stimulant piperazine (1860), and the cholinergic paraoxon (1460). The tuberculostatic agents ethionamide and ethambutol have been determined respectively in tablets after conversion into 2ethylpyridine-4-thiohydroxamicacid (1770) and reaction with 2,4-dinitro-l-fluorobenzene(1840). Additionally, complexation methods employing palladium (1870) for ethionamide and copper, nickel, and cobalt (1380) for ethambutol have been utilized. All methods have been reported to be free from possible interferences from various excipients. Reactive procedures also have been described for 4-(4-nitrobenzyl)pyridine (1390)and prenalterol(1610,1910). For the latter compound methods employing other techniques are discussed in the listed references as well. Spectrometric,separation, and voltammetric techniques have been utilized to examine the complexation of bromazepam with iron, copper and cobalt (1880).

Spectroscopy (Other). A second-derivative ultraviolet spectrometric method has been developed for accessing the salicylic acid content of bulk aspirin (2150). Likewise, a UV procedure for determining aspirin in coated tablets and suppository formulationshas been utilized to measure dissolution rates (2140). Finally, diffuse reflectance infrared spectra acquired from KBr have been reported for aspirin as well as for phenacetin (2090). The physicochemical and analytical characteristics of piroxicam have been published (2200). UV, IR, and NMR data are given. Nuclear magnetic resonance spectrometry has been used to assay dipyrone in solution (2010). The analysis of other analgesics, antiinflamatory agents, as well as stimulants and sedatives include the fluorometric determination of acetaminophen as its dansyl derivative (2240), the reaction of antipyrine with N-bromosuccinimideand measurement of the absorbance a t 290 nm (2250), the identification of amphetamine and related illicit drugs by second-derivative ultraviolet techniques (2180),a nonspecific UV method for indomethacin (2110), and the application of chiral lanthanoid shift reagents and NMR to establish purity of ibuprofen, naproxen, and related compounds (1990), as well as glutethimide (2000) and amphetamine enantiomers (2190). NMR also has been employed in the quantitaion of the sedative ethchlorvynol (2060). Likewise, ethchlorvynol, the related compound ethinamate and the tranquilizer methylpentynol carbamate have been measured in the ultraviolet region following derivitization (2300). Methylphenobarbitone has been determined by both UV (2280) and FT-IR photoacoustic spectrometric (2260) methods. A number of @-adrenergicblocking compounds and coronary agents have been assayed by several different techniques. Dipyridamolein combination with the tranquilizer oxazepam has been measured by acquiring UV spectra in both 0.1 M HzSO and 0.05 M Na2B40, and solving simultaneous equations 42160). Isosorbide dinitrate has been determined by NMR alone or in combination with alprenolol and propranolol (1960). Analytical results for synthetic mixtures and commercial formulations were comparable to those obtained by other procedures. Additionally, propranolol has been quantitated in commercial preparations via measurement of room-temperature hosphorescence (1940). The related @-blockerscarazolol&220) and carazolol, metoprolol, pindolol, and timolol (2230) have been evaluated by fluorometric and UV methods. These same techniques have been applied respectively to the determination of hydralazine in tablets (1970) and ephedrine and norephedrine following treatment with brominating agents (2290). In the same report methyldopa was measured in the visible region. The antidepressant imipramine (2030) and the antineoplastic compounds chlorambucil (2020) and methotrexate (2040) have been studied by UV procedures. In the latter case results were compared with those obtained colorimetrically and electrochemically. Other UV methods have appeared for diazepam and nitrazepam (2050), diphenhydramine (198,2070,2080),and thyroxine (2120). Miscellaneous reports include fluorometric procedures applied to flubendazole and mebendazole (1930) and primaquine (1920);NMR assays for camphor and p-chlorophenol (2100), midazolam (1950), nadolol (2210), and rutin (2130); and the utilization of IR spectrometry for benzodiazepines (2270). Finally, polymorphism has been studied for several compounds (2170). Electrochemical Analysis. Ion-selective electrodes have been prepared for use in protein binding studies involving flufenamic acid (2360) and in the analysis of aspirin (2320) and naproxen (2340) in formulated form. Likewise, differential-pulse polarographic (DPP) procedures have been applied to the analysis of various compounds in tablet or capsule formulations which include chlorhexidine (2430), metronidazole (2390), pipemidic acid (2330), and zomepirac (2310). Similarly, injectable forms of ketamine (2380), hospital-formulated suspensions with clonazepam and nitrazepam (2370), and both tablets and in'ectables containing flunitrazepam (2410) have been assayed by DDP methods. A DPP method also has been developed for the quantitation of 2,g-diaminopurine in the presence of its metabolite 2,6-diainopurin-8-01 (2420). A direct current technique has been reported for mebendazole (2400). The electrochemistry of several pharmaceuticals has been studied. The redox properities of the neuroleptic agents loxapine (2350, 2450) and several buANALYTICAL CHEMISTRY, VOL. 57, NO. 5, APRIL 1985

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tyrophenones (Le., benperidol, droperidol, haloperidol, spiperone,. and azaperone) (2440)have been examined. In the latter citation dc, ac, and differential pulse polarography as well as cyclic voltammetry were used. Miscellaneous. Since the last review, two papers have appeared reporting on the mass spectrometric analysis of benzalkonium chloride. These have involved the utilization of chemical (2550) and laser (2490) ionization techniques. A number of titrimetric methods have been reported for antiinflammatories(2470,2590),barbiturates (2530,%40), and local anesthetics (2580) as well as carazolol (2600),esculin (2560),and propranolol (2460,2620). Immunoassays have been developed for aprotinin (2650),di oxin (2480,2500), insulin (26701,meclofenoxate (2520),anf vasopressin (2510). Capillary isotachophoresis has been used in the analysis of the peptide drugs gonadorelin, profirelin, and saralasim (2570). Miscellaneous papers have dealt with use of thermochromism of associates for the determination of antihistamines (2640),photolysis products in aqueous amidopyrine solutions (2630), acetylation of sympathomimetic amines ( 2 6 6 0 , and various factors influencing the pharmacopoeial assay of ethambutol HCl in tablets (2610).

STEROIDS General and Gas Chromatography. A compendia1 monograph has been published for prednisolone (1E).This report contains recommended revisions for identification and content uniformity tests. A study has reported on the solidphase extraction of steroid samples (3E). Steroid polarity was correlated with adsorption on silica and various bonded phase columns. For example, hydrocortisone was retained on all columns whereas hydrocortisone acetate and 170-estradiol were absorbed only on silica and prednisolone and cortisone were retained on CISand CN columns. The application of fused-silica capillary gas chromatography has been applied to the analysis of conjugated estrogens in tablets (2E). Liquid Chromatography. A variety of LC procedures have appeared over the last 2 years for steroid analysis. One study has described the measurement of 25 corticosteroids in 69 topical preparations (13E). These corticosteroids were separated on a Nucleosil CIScolumn using an isocratic mobile phase composition of acetonitrile-dilute phosphoric acid with detection at 240 nm. Dexamethasone and betamethasonehave been quantified by LC/MS (5E). The eluate was monitored a t 254 nm and then introduced into a Finnigan 3300 quadropole instrument. Thermal degradation which was concentration dependent occurred on the moving-belt interface. Another report has described LC procedures for the determination of the phosphate esters of dexamethasone and prednisolone (7E). Recently, two procedures have been published for the determination of ethinyl estradiol (4E,1423). The first method was based on liquid chromatography with electrochemical detection (4E) and the second method consisted of an extraction of solid dosage forms followed by fluorometric detection at 330 nm (14E). A precision for the fluorometric method of 0.4 to 2.2% was reported with recoveries that ranged from 97.3 to 101.5%. A simple and rapid method has been developed for the determination of ethynodiol diacetate in the presence of ethinyl estradiol or mestranol (6E).A method has been published that is capable of detecting as little as 0.5 ng of fluorometholone (1OE).This method was applicable to quality control studies for drug formulations or commercial products and required only 6.5 min per sample. An interlaboratory study has been conducted for the analysis of hydrocortisone acetate in ointments (9E). The evaluated LC method was found acceptable as an alternative to the time-consuming 1973 British Pharmacopieal method. Other methods for hydrocortisone include normal phase (15E) and reversed phase (12E) procedures. The determination of clioquinol and hydrocortisone has been the subject of two publications (8E, 11E). Thin-Layer Chromatography. A thin-layer chromatographic procedure has been evaluated for the analysis of betamethasone dipropionate in semisolid pharmaceutical preparations (17E). Thin-layer chromatography was performed on silica plates using a mobile phase composition of CHC13-(CH3)2C0(7:3). Detection was at 240 nm using a reflectance scanning spectrophotometry and the method was acceptable for quality control and stability studies. In ad36R

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dition, densitometric detection was the subject of an investigation concerning the TLC determination of ethinyl estradiol (16E).This procedure involved CHC& extraction followed by TLC separation on silica gel using a chloroform-hexaneethyl acetate-methanol (95:205:3) mobile phase. Electrochemical Analysis. The renaissance in practical electroanalytical chemistry has finally been recognized as a useful tool for steroid analysis. For example, the ac polarographic behavior of several steroids has been elucidated in aprotic solvents (19E). Testosterone, methyltestosterone,and progesterone gave nearly ideal ac responses in acetonitrile and Nfl-dimethylformamide. These compounds were characterized as a facile one-electron heterogenous charge transfer process that produced a stable radical anion. Assay sensitivities in aprotic media increased 7.4 to 14.6 times when compared to protic media. However, prednisolone and hydrocortisone gave nonlinear calibration curves in these solvents which indicates that a second-orderchemical reaction follows the initial electrochemical reaction. Nevertheless, linear calibration curves could be obtained by the addition of water but a loss in sensitivity was observed. Satisfactory assay results were comparable to the USP procedure for prednisolone. A cholate liquid membrane ion-selective electrode has been developed for deoxy-, chenodeoxy-,ursodeoxy-, and lithocholic acids (18E).The electrode contained benzylhexadecyldimethylammonium cholate as the sensor and the results obtained from this electrode were compared to a benzoate liquid membrane electrode and an enzymatic method. The cholate electrode gave greater precision, an increased linearity range, and a lower detection limit when compared to the benzoate electrode. However, the cholate electrode method was less precise but more rapid and less expensive when compared to the enzymatic method. Spectroscopy. A differential kinetic model has been introduced for the determination of betamethasone 17-valerate in the presence of its degradationproducts (25E). The method involves oxidation of the 21-hydroxy group followed. by condensation of the aldehyde with 3-methyl-2(3H)-benzothiazolone hydrazone (MBTH). The absorbance was monitored at 394 nm and the assay's selectivity was based on the differential reaction rates of oxidized analyte and betamethasone with MBTH. The tetrazolium blue reduction method for corticosteroids has been assessed for potential interference by 19 compounds (21E). The following compounds were found to interfere: dipyrone, aminophylline, chloramphenicol, chlorzoxazone, diazepam, methapyrilene, meprobamate, papaverine, paracetomol, phenobarbital, phenylbutazone, and theophylline. An ultraviolet spectroscopic method has been introduced for the analysis of various steroids that have undergone allylic oxidation with CrOs (22E). A colorimetric method has also appeared for several ethinyl steroids (20E). A prednisolone colorimetric method has been adapted for dissolution studies (24E). In this method, prednisolone was reacted with phenylhydrazine for 30 min at 50 "C and the absorbance at 410 nm was proportional to the original prednisolone concentration. The method was rectilinear between 10 and 300 Mg/mL with an average RSD of 3.7%. Titrimetry. A potentiometricand thermometrictitrimetric procedure has been reported for several steroids containing the pyridine and androst-5-enemoieties (25E). Samples were dissolved in acetic acid and titrated with 0.1 M HCIOI in acetic acid and pK values were calculated. This report also discussed the relationship between pK,, structure, and basicity.

SULFUR-CONTAINING COMPOUNDS General and Gas Chromatography. A recent study has investigated the usefulness of solubility data for phase-sohbility determination of azathioprine (IF). Solubilities of azathioprine and related thiopurines were determined at equilibrium for 28 h in 12 organic solvents. Ethanol and CHC1, were found to be inadequate solvents. A low correlation was found between log solubility and log dipole moment. The phase solubility of azathioprine in pyridine ethanol (1:l)was recommended as the solvent of choice when mercaptopurine was present. A GLC method for promethazine has been developed using the Hall electrolytic-conductivity detector (287. A promethazine recovery of 100% was reported from polyoxy-


ethylene suppositories. Factors affecting aealysis and experimental parameters were discussed. A GLC stability-indicatin assay has also appeared for promethazine (3F). The metho! was linear from 120 to 600 pg/mL and was applied to thermal and photolytic degradation studies. Liquid Chromatography. Liquid chromatography continues to be an important tool for the separation and quantification of sulfur-containingcompounds. A recent study has shown that liquid chromatographic procedure gave more accurate results than the USP spectrophotometric assay for chlorthalidone (4F). This study established that chlorthalidone underwent partial acidic degradation during the USP procedure. Two degradation products were formed which had a greater molar absorptivity than chlorthalidone in the USP method. The LC method could separate the analyte from these degradation products. A recovery of 98.4% to 99.2% was reported and the LC method was stability-indicating. A method has been reported for chlorthalidone and clonidine in tablets (1OF). The experimental procedure entailed homogenizing tablets with methanol followed by LC separation. Chlorthalidone was separated and quantified on an octadecyl silica column, whereas clonidine was quantified on a chlorotrimethylsilane-bondedsilica column. Sulindac has been separated from six analogues using an optimal fadorial experimentaldesign and computer simulation ( 5 0 . A stability-indicating assay has been proposed for bendrofluazide in bulk powder (SF).The drug was extracted from bulk supplies using methanol. Separation was achieved with a Hypersil ODs column and a mobile phase consisting of 50% aqueous methanol. Statistical comparison showed that the chromatographic procedure was superior to two official methods. An assay has appeared for the quantification of triamterene and hydrochlorothiazide (7F).A Cz column was employed for separation with detection a t 266 nm. Both compounds could be separated from their degradation products. A LC method using a Radical-PAK column has been developed for the measurement of thiomersal in ophthalmic solutions (SF). The assay was specific for thiomersal in the presence of degradation products. The optical isomers of diltiazem have been quantified after hydrolysis and esterification with the chiral rea ent d-242naphthy1)propionyl chloride (SF). Acidic hy8olysis was complete in 50 min and esterification proceeded within 5 min without the formation of side products. Both isomers were separated from each other by reversed-phasechromatography using 0.01 M pH 6.6 NH40AcMeCN (1:9) as the mobile phase and detection at 254 nm. Thin-Layer Chromatography. A study has been conducted to determine the TLC behavior of hydrochlorothiazide, methylclothiazide, trichloromethiazide, buthiazide, and cyclothiazide on silica gel and alumina plates (11F). A report has appeared that recommends four solvent systems be used for the identification of 20 phenothiazines (12F). A modification of the British Pharmacopeialmethod has been proposed for glibenclamide (13F). The proposed method was also applicable for chloropropamide and tolbutamide. This method consisted of (i) CHzC12-acetoneextraction, (ii)TLC separation, and (iii) quantification by UV spectroscopy. Degradation products could also be identified. Electrochemical Analysis. The polarographic, cyclic voltammetric, and cathodic-stripping voltammetric behavior have been characterizedfor four potential thioamide antiulcer drugs (14F).Primary and secondary thioamides underwent anodic oxidation and cathodic stripping with formation of HgS. The electrochemicalbehavior was described for several primary thioamides. Dc polarography provided a detection limit of 0.5 pM while cathodic-stripping voltammetry had a reported detection limit of 20 pM. Tertiary thioamides were found electroinactive. A polarographic method has been reported for benzthiazide or bendrofluazide (17F').The assay consisted of dissolution of sample in DMF (buffered at pH 7.8 or 8.1) followed by quantification by differential-pulse polarography. The effect of immersion of a wax-impregnated graphite electrode in an aqueous solution of chlorpromazine was examined by differential-pulse voltammetry and chronocoulometry (15F). Both extraction of chlorpromazine into the electrode and adsorption a t the interface occurred. The extraction phenomena of chlorpromazine into the electrode was

proposed as a preconcentration step that could lower the detection limit to 5 nM for differential-pulse voltammetric methods. A titrimetric-polarographic procedure has been reported for the determination of trifluoperazine (16F). This procedure consisted of titrating trifluoperazine with tungstosilic acid. When precipitation of trifluoperazine was complete, a polarographic wave appeared for excess tungstosilic acid. The wave height at -0.56 V for tungstosilic acid was plotted against the titrant volume. The equivalence point was obtained via extrapolation to zero wave height. Spectroscopy. Synchronous luminescence s ectroscopy has been evaluated for phenothiazines analysis of losage forms (19F). Phenothiazine sulfoxides generated emission peaks at 360 nm in pH 3.0 phosphate buffer, whereas phenothiazines gave an emission peak at 430 nm. This technique was applied to the determination of promethazine in injections and elixirs. Emission peak intensively was rectilineary up to 10 pg mL for promethazine and up to 1pg/mL for its sulfoxide. &his technique was applied to the determination of chlorpromazine, trimeprazine, and dimethothiazine in dosage forms. A rapid spectrophotometric determination has been proposed for the determination of ten phenothiazines in bulk-drug and formulations (24F). The proposed method is based on the formation of pink or violet colored products with N bromosuccinimide in strong HzS04. The stable products have absorption maxima between 512 and 565 nm with apparent t values of 6000 to 20000. The proposed method agreed favorably with the 1980 British Pharmacopeial and USP XX methods. A spectrophotometric method applicable to solubility studies has appeared for the following benzothiazides: bendrofluazide, chlorthiazide, cyclopenthiazide, flumethiazide, hydrochlorothiazide, and methylcyclothiazide (188'). Several colorimetric methods have been published for cimetidine since the last review (2OF-22F). Cimetidine has been determined in capsules after reaction with ninhydrin at pH 7 (20F). The purple chromogen that was formed had an absorption maximum at 570 nm and the absorbance was rectilinearly related to concentration from 10 to 200 pg/mL. Another method employed CofSCN), or 1,2-dihydro-1,2-dioxo-4-naphthalenesdfonic acid as chromogenic reagents (2187. Finally, a method has been developed which involves formation of an insoluble cimetidine reineckate complex (22F). After precipitation, the residue is dissolved in acetone and the absorbance is monitored at 525 nm. Beers law is obeyed from 400 to 2000 pg/mL. A method has been published for methdilazine and dipyrimadole in pharmaceutical preparations (23F). In addition, picric and flavianic acids have been evaluated for the development of an extractive spectrophotometric analysis of thioproperazine (25F). This method is based on the ability of picric and flavianic acids to precipitate thioproperazine. After extraction, the absorbance is monitored at 406 nm or 390 nm for picrate and flavinate, respectively. Miscellaneous. A direct-probe MS method has been reported for the measurement of 3-methoxydiphenylamine in the presence of the analgesic methotrimeprazine maleate (26F). An NMR method based on the use of lanthanoid shift reagent has been proposed for the determination of the enantiometric purity of levamisole and dexamisole (27F). A titrimetric method for oxfendazole has also appeared (28F). An iodimetric titrimetric method has been reported for several N-substituted phenothiazines (29F). For this method, the test solution was treated with an excess of either 5 mM 1,3-dibromo-5,5-dimethylhydantoinor 0.01 M N-bromosuccinimide. After 15-30 min, excess reagent was determined iodimetrically. Reaction mechanisms were elucidated by UV, TLC, MS, IR, and NMR. Stoichiometries were reported for chlorpromazine, promazine, methotrimeprazine, trifluoperazine, prochlorperazine, perphenazine, and mesoridazine.

VITAMINS Fat Soluble. A LC method has been described for vitamin A palmitate determination in liquid multivitamin preparations (7G). Water-dispersed formulations containing DMSO were extracted with hexane. The supernatant was diluted with fluoranthene and analyzed by LC on several silica columns. The best separation of 13-cis, all trans, g-cis, and 9,13-di-cis isomers was accomplished on a 5 pm Lichrosorb column. A two dimensional HPTLC method has also been reported for the all-trans and 13-cis vitamin A (1G). For gel formulation, ANALYTICAL CHEMISTRY, VOL. 57, NO. 5, APRIL 1985

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samples were extracted with methanol and applied to silica HPTLC plates. Visualization was accomplished at 365 nm before and after sprayingwith EtOH-H2S04and heating. For cream formulations HPTLC plates containing silica gel and C18 layer were required to remove interferences. A method for the simultaneous determination of vitamin A and vitamin D has been reported for oily solutions, ointments, and elixirs (5G). This method was not applicable to vitamin A determinations in capsules. A nonaqueous reversed-phase assay has been published for vitamin Dz in multivitamin D3 preparation (2G). DMSO solutions containing the vitamin, and methanol-H20 (1:l) were extracted with hexane. The extract was concentrated, passed through a Sep-PAK silica cartridge, and then quantified by LC. A method has also appeared for the measurement of vitamin D3 in codliver oil (4G). This method also consisted of a hexane extraction followed by a Sep-PAK silica cleanup. Final quantification occurred on either a Hypersil ODS or Spherisorb S5 ODS column. Calibration curves were linear from 0.5 to 3.0 pg/mL. A spectrophotometricdetermination has been described for menadione and its bisulfite analogue (6G). Menadione bisulfite was first converted to menadione as described in the USP XX assay. Alkalinized thiosemicarbide was then added and the absorbance was measured at 540 nm. Beers law was obeyed between 4 and 40 pg mL. Differential scanning calorimetry has been evaluate to determine naphthalene, and 1-and 2-methylnaphthalenes and tetracosane in menadione (3G). Results indicated that the measurement of each impurity is concentration dependent. NMR measurements were recommended as more precise measurements of purity. Water Soluble. Ascorbic acid has been determined in tablets by differential pulse voltammetry (17G). A PAR Model 174A analyzer and a carbon-paste working electrode were employed for analysis. The supporting electroyte consisted of pH 4.7 acetate buffer. A detection limit of 0.15 pM was reported for tablets. Titrimetric methods using 2,6-dichloroindophenol (14G),2-iodosobenzoate (27G),and chloramine T (23G) have been published during the last 2 years. A recent study has evaluated kinetic, titrimetric, and spectrophotometric bromine methods for ascorbic acid (8G). Another comparitive study has evaluated the ascorbate content in rose-hip tablets (12G). This study established that an enzymic method using ascorbate oxidase was more specific than an iodimetric titration or 2,6-dichloroindophenolspectrophotometric method. A new spectrophotometric method for cyanocobalmin has appeared (9G). The method consists of boiling cyanocobalmin in aqua regia until a colorless solution is obtained. Thiocyanate and hexamethylphosphoramide are added and the absorbance a t 317 nm is measured. A rapid and specific reversed-phase method has been proposed for folic acid in multivitamin preparations (25G). Recoveries of 99.1-100.3 % were reported. The method was applied to tablets and soft-elastic capsules and no interferences from other ingredients were reported. 0 timal separation conditions have been reported for folic aci$ methotrexate, and calcium folinate from impurities ( 1 l G ) . A reversed-phase method has appeared for the determination of panthothenic acid in multivitamins containing calcium panthothenate, yeast, and vitamin premixes (13G). Bulk material was dissolved in pH 4.5 phosphate buffer and then applied to a Lichrosorb-NH2column. Comparable results were found with the official USP microbiological method. A postcolumn derivatization method had been published for (15G). vitamin B6using 3,5-dibromo-p-benzoquinochlorimine A Zorbax C8 column was used to separate pyridoxamine, pyridoxal, and pyridoxic acid with detection of the derivatized products at 650 nm. A colorimetric method based on a modification of the 1975 USP method has been proposed (20G). The method provided increased color stability, rapidity, and specificity. A simple gravimetric analysis of thiamine has been reported that uses Na tetraphenylborate as the gravimetric reagent (29G). A study has appeared that compares the fluorometric thiochrome method with a LC method (24G). Both methods were compared for the analysis of nine oral and eight parenteral formulations. Results indicate that the LC method was more accurate and precise than the fluorometric method. Two publications have appeared for the separation of thiamine

d

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from its phosphate esters (16G) or its degradation products (21G). Both methods were specific and precise. A differential-pulse polarographic method has also been described for the determination of thiamine in the presence of thiourea (26G). A titrimetric method has been published for the determination of thiamine (22G). A method based on the synergistic combination of TLC with pyrolysis gas chromatography has been evaluated for the determination of water-soluble vitamins (18G). Nicotinamide, thiamine, pyridoxine, and riboflavin have been determined in nine multivitamin preparations (IOG). Sample preparation involved automated (i) homogenization at 70 "C, (ii) dialysis at 37 "C, and (iii) analysis by reversed-phasechromatography. The analysis rate was 5-10 samples/h and linear calibration curves were obtained for each vitamin.

TECHNIQUES Chromatography. Several articles dealing with new

technology chromatography have appeared during the last 2 years (2H, 3H, 13H). Recently, Tsusi reported on the application of microbore LC to the analysis of pharmaceuticals (13H). This article described a 16-fold increase in sensitivity when compared to conventional LC systems. The technique was applicable for the separation of antibiotics, steroids, and ibuprofen. Automated column-switching was reported useful for the on-line cleanup and analysis of drugs in topical cream formulations (3H). This technique assured the successful analysis of sulconazole and fluocinonide and its analogues. Rapid-scanning UV spectrophotometry has been reported to be capable of detecting 0.1% impurities in carbamazepine, desipramine, and estrone (2H). A deferred-standard method has been introduced by Guillemin for process analysis (5H). The cited method involves injection of a known amount of pure compound with each sample. Injection of pure drug is delayed relative to sample injection to avoid interference with sample components. This method was compared with the internal standard method for the analysis of chlorpromazine and promethazine and gave excellent results. Formation of ternary nickel dithiocarbamate complexes of sympathomimeticdrugs has been useful for screening of structurally related contaminants (8H). Two articles have appeared that concern the separation of enantiomers on chiral stationary phases (7H, 14H). The enantiomers of mepenzolate, propiomazine, disopyramide, promethazine, bupivacaine, mepivacaine, prilocaine, and oxyphencyclimine have been resolved on silica particles containing immobilized al-acid-glycoprotein (7H). Four a-methylarylacetic acids have been resolved as enatiomeric amide derivatives on a stationary phase consisting of covalently bound (R)-N-[ (3,5-dinitrobenzoyl)amino]benzeneacetic acid (14H). A review with 75 references has been presented on ion-pair extraction and LC in pharmaceutical and biomedical analysis (12H). A standardized analysis strategy for basic drugs has appeared that uses ion-pair extraction (6H). No internal standard was necessary using this technique because of the excellent precision and recovery. The effects of Li+, Na+, K+, Mg2+,and Ca2+,as counterions were studied on the retention of polar organic compounds by cation exchange chromatography (4H). This article proposed a theory based on ionic hydration to account for the counterion effects on retention behavior. A scheme has been reported for the rapid identification of at least 34 drugs in illicit pharmaceutical or biological samples (15H). The method involves liquid-liquid extraction followed by TLC separation. Sensitivity limits in the submicrogram range were reported. Thin-layer chromatography minifilms have been described as an effective method for purity testing (11H).

An article has appeared that deals with the performance and chemical durability of fused-silica columns coated with SE-54 for the determination of 32 underivatized drugs (10H). Characteristics of cyanosilicone fused-silica columns have been tabulated by Markidas et al. (9H). In addition, two fused-silica columns of different polarities were connected to FID and N-P detectors in order to simultaneously determine drugs of abuse UH).

Electrochemical Analysis. Recent developments in polarographic and voltammetric methods have been reviewed for pharmaceutical chemistry and pharmacology (20H). This


review contained 30 references and includes topics on automation of polarographic measurements, derivatization of electroinactive compounds, new electrodes, ac polarography, and chromatographic detectors. An article has also appeared on the polarographic analysis of psychotropic drugs (18H). The on-line voltammetric analysis has been reported for biologically important molecules (19H). This report evaluated detection limits and linearity ranges for vitreous-carbon electrodes and mercury-coated vitreous-carbon electrodes. Miniaturized semiconductor chemical sensors have been prepared by depositing a selective membrane on a field-effect transistor (17H). This report described two types of electrodes, the ISFET (ion selective) and the GASFET (selective for H2S, NH3, and HJ. These electrodes have all the electrochemical properties of conventional electrodes but are smaller and cheaper and have greater response times. Recently, Cunningham and Freiser reported on the development of ionselective electrodes for the analysis of methadone, cocaine, protriptylene, and methamphetamine (16H). Mass Spectrometry. A review has been published on the origins and aspects of fast-atom bombardment (25H). This report has described the application of the technique to the sequencing of peptides and examination of antibiotics. Another article characterized secondary-ion emissions from mixtures of stimulants, barbituates, opiates, and amino acids WH). The combination of mass spectrometry and liquid chromatography continues to be a productive research area in pharmaceutical analysis (22H-24H). For example, spectra for cyanocobalamin and erythromycinA have been obtained after direct introduction of LC effluent into a quadropole (23H). The design of a californium-252 fission fragment induced desorption mass spectrometer was evaluated for sensitive drug determinations (22H, 24H). Reagents. Although instrumentation advances aid in the determination of drugs, the application of classical organic chemistry will always aid in the selective and sensitive determination of difficult-to-analyze drugs. For example, a review of several specific fluorogenic reactions has appeared for pharmaceuticals (27H). Several examples of ring-closing and dehydration reactions and aromitazation of diphatics and conjugation of ring systems were described for nonfluorescent compounds. Several reagents have been evaluated for the sensitive derivatization of thiols and their subsequent analysis by LCEC (30H). Iodic acid has been identified as a useful visualization reagent for determining 163 drugs by TLC (26H). Other reagents that have appeared included 9-chloracridine for amines (29H) and a review of reaction pathways for xanthydrol (28H). Spectroscopy. A review with 77 references was presented on the use of diffuse reflectance for the determination of pharmaceuticalsin formulationsand biological samples (33H). This article also reported on the use of photoacoustic spectroscopy after TLC or LC and FTIR photoacoustic spectroscopy. A quantitative assay for propranolol has been described using photoacoustic spectroscopy (32H). An article describing OPTIMATE, an automated fluorometric photometer, has been described for homogenous immunoassays (36H). This instrument is a fully automated bench-top analyzer that can be used for homogenous fluorescent immunoassays and colorimetric assays. This instrument features a combination fluorescence-absorbance aspirating thermo-cell, a photoncounting fluorometer-photometer, a multidistribution valve for dispensing three reagents and a user-replaceable programmable memory cartridge. The phosphorescence of five drugs has been characterized on filter paper at ambient temperature and 90 K (37H). This technique was applicable for the selective determination of drugs in pharmaceutical formulations (31H). The effects of substituents groups of chromophores containing the benzene ring and solvents have been evaluated by UV spectrophotometry (34H). The absorption spectrum, melting point, refractive index, and eutectic temperature of 32 drugs have been characterized as a means of identification of pure substances (35H). Thermal Analysis. Two review articles on thermal analysis have appeared since the last review (39H,43H). The first review contained 92 references and described the use of DTA and differential scanning colorimetryin pharmaceutical analysis (39H). The second review contained 241 references

and reviewed the application of DTA to identifyin , purity testing, quantitative analysis, polymorphism,phase gagrams, compatability testing, and decomposition studies in pharmaceutical research (43H). A recent report has employed thermoanalytical methods for checking the composition of 27 commercially available suppositories (42H). The various polymorphic forms of anilamate have been characterized by differential scanning colorimetry and IR spectroscopy (4123. A method based on the coupling of thermometric titrimetry and constant current coulometry has been described for the analysis of ascorbic acid and as irin mixtures (38H). Dynamic purity determinationsof menagone and phenacetin have been developed using DSC and DTA (40H). Miscellaneous. A recent review was presented on the role of microcomputers in pharmaceutical and clinical analysis ( 5 0 . A universal data system for chromatographic analysis of drug has also appeared (51H). A membrane filtration unit has been described for the filtration of fermentation samples (48H). Fluorine-19nuclear magnetic resonance spectrometry was useful for the measurement of pentafluoropropronioanhydride derivatives (52H). Chiral lanthanide shift reagents have also been the subject of NMR determinations of drugs (46H). Tensammetric detection was reported as a useful technique for the LC determination of lynoestrenol and several cardiac glycosides (45H). A paper describing present and future developments for continuous flow analysis has also appeared (49H). Finally, the potentiometric titration for pharmaceutical compounds using sodium tetraphenylborate has been described (44H, 47H).

MISCELLANEOUS A series of papers which deals with various aspects of the analysis of creams has appeared during the 2-year period of the current review. The following techniques have been considered titrations in nonaqueous solvents (250,GC (12I), HPLC (131), and TLC (261). Topics of a general nature include the utilization of thermal methods to evaluate drugexipient interactions (71,81,151,221) and the development of a microcomputer-based system for identification of solid formulations (SI). A number of procedures have been published for the analysis of the various parabens (181,191,211, 231) and oil bases and mixtures (101, 111, 161) used as pharmaceutical additives. Gas chromatographic assays have appeared for acetone in (hydroxyethy1)starches(141), methanol and methylene residues in coated tablets (271), and chlorbromuron herbicide residues in drugs (241). Also problems associated with USP XX GC determination of ethanol in drug formulations also have been discussed (31). HPLC has been utilized in the measurement of viral RNA inactivators (51) and toluene-o-sulfonamidein saccharin (171). Likewise, the saccharin content of pharmaceuticalshas been determined (201) by a liquid chromatographic method. Other miscellaneous papers have dealt with the analysis of poly(oxyethy1ene glycol) (41), halothane (In,moisture content (24, and the effect of counterion size on retention in ion-pair adsorption TLC (61).

ACKNOWLEDGMENT We thank B. A. DeCastro, C. Gilpin, and B. Vicini for their valuable assistance in the preparation of this manuscript. LITERATURE CITED GENERAL

(1) Journal of fharmaceut/cal and Biomedical Analysis ; Pergamon Press: Oxford, 1983; Vol. 1 No. I. (2) Bailey, F. Anal. R o c . (London) 1082, 79 (4), 189. (3) Berthrong, P. G. Am. Lab. 1084, 16 (2), 118. (4) Connors, K. A. "A Textbook of Pharmaceutical Analysls", 3rd ed.;WileyIntersclence: New York, 1982; 608 pp. (5) Cosofret, V. V. "Membrane Electrodes In Drug-Substances Analysis"; Pergamon Press: Oxford, 1982; 362 pp. (6) Deasy. P. B.; Tlmoney. R. F.: Eds. "Progress In the Quallty Control of Medlclnes"; Elsevler Blomed. Press: Amsterdam, 1981; 297 pp. (7) Debesls, E.; Boehlert, J. P.; Givand, T. E.; Sherldan, J. C. fharm. Techno/. 1982, 6 (9), 120. (8) Florey. K., Ed. "Analytical Profiles of Drug Substances"; Academlc Press: New York, 1982; Vol. 11. 665 pp. (9) Gilpln, R. K.; Pachla. L. A.; Ranweller, J. S. Anal. Chem. 1983, 55, 7013. (IO) %ugh, T. A.; Baker, P. 8. J . Chromatogr. Sci. 1083, 27 (4), 145. (11) Mills. T., 111; Prlce, W. N.; Prlce, P. T.; Roberson, J. C. "Instrumental Data for Drug Analysls"; Elsevler: New York, 1982; Vol. 1, 640 pp. (12) Novotny, M. Drug Metab. Rev. 1081, 72 (2), 279.


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PHARMACEUTICALS AND RELATED DRUGS (13) Pungor, E.; Feher. 2 . ; Nagy, G.; Lindner, E.; Toth, K. Anal. Proc. (London) 1982, 79 (2), 79. (14) Sancilio, F. D. Proc, Int , Symp , Instrum. High Perform, Thln -Layer Chromatoar.. _ .2nd~1982. - 314. (15) Sander, L. C.; Sturgeon, R. L.; Field, L. R. J. Ll9. Chromatogr. 1981, 4 (Suppl. I), 63. (16) Sastry, C. S.;Prakasa, R. B. G.; Murthy, K. V. S. S. J. Indian Chem. SOC. 1982. 59 (9). 1107. (17) Schirmer, R: ‘“Modern Methods of Pharmaceutical Analysis”; CRC Press: Boca Raton, FL, 1982; Vol. 1, 274 pp. (18) Schlrmer, R. “Modern Methods of Pharmaceutical Analysis”; CRC Press: Boca Raton, FL, 1982; Vol. 2, 252 pp. (19) Tillman, J. Anal. Proc. (London) 1982, 19 (4), 191. (20) Tsujl, K.; Blnns, R. B. J. Chromatogr. 1982, 253 (2), 227. (21) Van de Vaart, F. J.; Indemans, A. W. M.; Hulshoff, A.; Lake, 0. A. Chromatographla 1982, 76, 247. (22) Van Rooij, H. H.; Tomlinson, E. Anal. Proc. (London) 1982, 79 (4), 174. (23) Wolff, A. Krankenhauspharmazle 1983, 4 (a), 49. (24) Woodruff, H. 6.; Tway, P. C.; Downlng, G. V.; Gilbert, J. P. J. Autom. Chem. 1982, 4 (4), 161. ~

ALKALOIDS General (1A) Baerheim, S. A.; Verpoorte, R. “Chromatography of Alkaloids”; Elsevier Scientific Publishing: Amsterdam, 1983; 536 pp. (2A) Barni, C. I.; Centlnl, F.; Pariall, A. J. Chromatogr. 1983, 279, 609. (3A) Jost, W.; Hauck, H. E. J. Chromatogr. 1983, 264(1), 91. (4A) Kubln, H.; Brehm, M.; Ulmen, J. Pharm. Ind. 1982, 44 (12), 1269. (5A) Laurent, C. J. C. M.; Bliiiet, H. A. H.; De Galan, L. Chromatographla 1983, 17 (7), 394. (6A) Low, G. K. C.; Haddad, P. R.; Duffleld, A. M. J. Chromatogr. 1983, 267 (3), 345. (7A) Shahine, S.;Khamis, S. Microchem. J. 1983, 28(1), 26. (EA) Volkmann, D. High. Resolut. Chromatogr Chromatogr Commun. 1983, 6 (7), 378.

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PHARMACEUTICALS AND RELATED DRUGS INORGANIC Slngle Element Analyols (IC) Beg, A. E.; Meakln, B. J.; Davies, D. J. G. Pharmazie 1082, 3 7 (12), 841. (2C) Bhuee, G. S.; Rastogl, S. N.; Singh, J. East. Pharm. 1082, 25 (292). 113. (3C) Compagnon, P. A. Sci. Tech. Pharm. 1083. 12 (lo), 495. (4C) Gaal, F. F.; Abramovlc, B. F. Mlkrochlm. Acta 1082, 1 (5-6), 465. (5C) Gottardi, W. fresenlus‘ 2.Anal. Chem. 1083, 314 (6), 582. (6C) Hasebe, K.; Taga, M. Talanfa 1082, 29 (12), 1135. (7C) Holak, W. J . Assoc. Off. Anal. Chem. 1082, 65(5), 1059. (8C) Holak, W. J . Assoc. Off. Anal. Chem. 1083, 66(5),1203. (9C) Kovacs, P.; Takacsl-Nagy, G.; Trischler, F. Pharmazie 1082, 3 7 (a), 187. (1OC) Nakashlma, K.; Nakatsujl, S.; Akiyama, S.; Kaneda, T.; Misuml, S. Chem. Len. 1082. 11, 1781. (1 IC) Peinhardt, G.; Siemroth, J. Pharmazle 1083, 38 (I), 33. (12C) Sharma, K. N.; Bhuee, G. S.; Rastogl, S. N.; Singh, J. Chem. Era 1082, 18 (4), 85. (13C) Tsurubou, S.; Sakai, T.; Shibata, S. Chem. Pharm. Bull. 1083, 31(E), 2905. (14C) Van den Winkel, P.; Mertens, J. Bull. SOC. Chlm. Be@. 1081, 90 (4), 381. Multlple Element Analyols (15C) Akguen, E.; Pindur, U. Pharm. Acta Helv. 1083, 58 (5-6), 130. ( 1 6 0 Frahne, D.; Geil, J. V.; Geng, K.; Schrader, U. Dtsch. Apoth.-Ztg. 1083, 123 (12), 563. (17C) Kovar, K. A.; Zakhari, N.; Pleper, R. Dtsch. Apofh.-Ztg. 1982, 122 (47), 2421. (18C) Landolt, R. R.; Hem, S. L. J . Pharm. Sci. 1083, 72(5), 561. (19C) Long, S. E.; Snook, R. D. At. Spectrosc. 1082, 3(6), 171. (20C) Ochsner, M. Pharm. Acta Hehr. 1083, 58 (E),227. (21C) Rohdewald, P.; Vlachos, A. Pharm. Zfg. 1082, 127(3), 171. (22C) Surmann, P.; Dietz. C.; Wiik, H.; Nassauer, T. Dtsch. Apoth.-Ztg. 1983. 123 123). 1110. _.,...... (23‘2) Tatsuharu, T.; Tabuchi, F.;Nlshimura, I.; Muro, H.; Ozoe, F. Chem. Pharm. Bull. 1082, 30 (4), 1347. (24C) Veeman, G. E.; Bult, A.; Franke, J. P.; Faber, J. S. Pharm. Weekbl. 1082. 117(1). 6. (25C) virang, ii’Dewald, H. D. Anal. Len. 1083, 16 (B12), 925 ~

Radlopharmaceutlcals (26C) Chervu, L. R.; Vallabhajosyula, B.; Manl, J.; Chun, S. B.; Blaufox, M. D. Eur. J. Nucl. Med. 1082, 7(7), 291. (27C) Cioutet, W. E. J. Nucl. Med. Technol. 1082, 10 (I), 20. (28C) Dorner, W. G. Laborpraxis 1082, 6 (9),978. (29C) Gattavecchia, E.; Tonelli, D.; Ghlna, S.; Breccla. A. Anal. Left. 1083, 16 (SI), 57. (30C) Heide, L.; Stamm, A,; Boegi, W. STH-Ber. 1083, Part 5, (1) 349 pp. (31C) Hwang, L. L.-Y.; Ronca, N.; Solomon, N. A,; Stelgman, J. J . Labelled Compd. Radlopharm. 1082, 19 (11-12), 1560. (32C) Kato-Azuma, M.; and Hazue, M. J. Labelled Compd. Radiopharm. 1082, 19 (11-12), 1542. (33’2) Kloster, 0.; Laufer, P. J. Labelled Compd. Radioopharm. 1083, 20 (11). 1305. (34C) Kowalsky, R. J.; Creekmore, J. R. J. Nucl. Med. Technol. 1082, 10 (1)- 15. (35‘2) Needham, R. E.; Delaney, M. F. Anal. Chem. 1083, 55(1), 148. (36C) Pfelffer, G. Dev. Nucl. Med. 1084, 4 . 66. (37C) Unadkat, J. D.; Rowland, M. J . Chromatogr. 1083, 261 (2), 298. (38C) Vallabhajosula, S.; Goldsmlth, S. J.; Lipszyc. H. J. Labelled Compd. Radiopharm. 1082, 19 (11-12), 1565. (39C) Vilcek, S.; Kalincak, M.; Machan, V. Radiochem. Radioanal. Left. 1082, 52 (1). 55. NITROGEN-OXYQEN CONTAINING COMPOUNDS General f1D) Avraham, Y.: Amann, A. H.; Baaske, D. M. Drug. Infeli. Clln. Pharm. . 1083, 17(4), 255. (2D) Eiden, F.; Braatz-Greeske, K. Dtsch. A p o t h J t g . 1983, 123 (20), 958. (3D) Goerlitzer, K.; Hoebbel, G. Arch. Pharm. (Welnheim, Ger.) 1083, 316 (IO), 866. (4D) Schuetz, H. “Benzodiazepines”; Springer-Verlag: Berlin 1082, 439 pp. (5D) Walker, S. T. Pharmacopeia/ forum. 1083, 9 (5),3562. (6D) Zlnic, M.; Kuftinec, J.; Hofman, H.; Belln, B.; KaJfez, F.; Blazevic, N.; Melc, 2. Acta Pharm. Jugosl 1082, 32 (4), 281. Chromatography (General) (70) M e n , F.; BraatzGreeske, K. Msch. Apofh.-Zfg. 1083. 123 (42), 2003. (ED) Rao. K. 0.; Soni, S. K. J . Assoc. Off. Anal. Chem. 1083, 66(5), 1186. Gas Chromatography (SD) Black, D. B.; Kolasinski, H.; Lovering, E. G.; Watson, J. R. J . Assoc. Off. Anal. Chem. 1082, 65 (5),1054. (10D) Brettel, T. A. J . Chromatogr. 1083, 257(1), 45. (11D) Chen-Chow, P.-C.; Frank, S. G. I n f . J . Pharm. 1081. 8(2), 81. (120) Christofides, A.; Crlddle, W. J. J. Anal. Appl. pVro/ysls 1082, 4 (3), 211. (13D) COnnOlly, P.; Slrmans, S.; Belmonte. A. A.; Darling, C. M. J . Pharm. Sci. 1082, 71 (1 I), 1267.

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(14D) Desage, M.; Brazler, J. L.; Comet, F.; Guiiluy, R. Analusis 1083, 11(3), 1IS. (15D) Hulshoff, A.; Renema, J.; Roseboom, H.; Loriaux, B.; Rook, B. J . Pharm. Biomed. Anal. 1083, 1 (2), 169. (16D) Jun, H. W. Pharm. Acta Helv. 1082, 57(10-ll), 290. (17D) Kacprowicz, A. T. J . Chromatogr. 1083, 269 (2), 61. (l8D) Kawase, S.; Kanno, S.; Ukal, S. J . Chromatogr. 1082, 247 (2), 273. (19D) Liu, J. H.; Ku, W. W. Anal. Chem. 1981, 53(14), 2180. (20D) Liu, J. H.; Ku, W. W.; Tsay, J. T.; Fltzgerald, M. P.; Kim, S. J. forenslc SCi. 1082, 2 7 (I), 39. (21D) Martln, R. P.; Lum, S. W. K.; McGonigle, E. J.; Gubler, H. R. J. Pharm. 112. Sci. 1082, 71 (I), (22D) Miribel, L.; Brazier, J. L.; Comet, F.; Lecompte, D. J. Chromatogr. 1083, 268 (2), 321. (23D) Mohamed, M. E.; Tawakkol, M. S.; AbouCEnein, H. Y. Anal. Len. 1082, 15 (B2), 205. (24D) Stromberg, L.; Bergkvlst, H.; Edirlsinghe, A. M. K. J. Chromafogr. 1083, 258, 65. (25D) Tammilehto, S.; Helkkinen, L.; Jarvela, P. J . 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R.; Dockens, R.; Barksdaie, J. M.; Arrlngton, H. S.; D’andrea, G. H. J. Chromatogr. 1082, 240(1), 196. (38D) Das Gupta, V. J . Pharm. Sci. 1083, 72 (6), 695. (39D) Das Gupta, V. Drug Dev. Ind. Pharm. 1082, 8 (6), 869. (40D) Davydov, V. Y.; Gonzalez. M. E.; Kiselev, A. V. J . Chromatogr. 1082, 248 (I), 49. (41D) Desta, 8.; McErlane, K. M. J . Pharm. Sci. 1082, 71 (7), 777. (42D) Desta, B.; McErlane. K. M. J. Pharm. Sci. 1082, 71 (9),1018. (43D) Doorenbos, H. J.; Van Duljn, J. W.; Nlenhuls, J.; Smits, H. M.; Teigeler, C. A. Pharm. Weekbl. 1083, 118 (15), 305. (44D) Dunn, D. L.; Jones, W. J.; Dorsey, E. D. J. Pharm. Sci. 1083, 72(3), 277. (45D) Eddine, N. H.; Bressolle, F.; Mandrou, B.; Fabre, H. Analyst (London) 1082, 107 (1270), 67. (46D) Ermer, E. Pharm. Zfg. 1082, 127(41), 2219. (47D) Fabre, H.; Mandrou, B.; Eddine, H. J . Pharm. Sci. 1082, 71 (l), 120. (48D) Feyns, L. V.; Thakker, K. D.; Reif, V. D.; Grady, L. T. J. Pharm. Sci. 1082, 71 ( l l ) , 1242. (49D) Fujil, Y.; Fujil, H.; Yamazaki, M. J . Chromatogr. 1083, 258, 147. (50D) Gelber, L. R.; Neumeyer, J. L. J. Chromatogr. 1083, 257 (2), 317. (51D) Gelber, L.; Papas, A. N. J . Pharm. Sci. 1083, 72(2), 124. (52D) Gilpln, R. K.; Gaudet, M. H. J . Chromatogr. 1082, 248 (I), 160. (53D) Hadl-Mohammadi, M. R.; Ward, J. L.; Dorsey, J. G. J. Liq. Chroma’ togr. 1083, 6 (3), 51 1. (54D) Halstead, G. W. J . Pharm. Sci. 1082, 71 (IO), 1108. (55D) Haneke, A. C.; Crawford, J.; Aszalos, A. J. Pharm. Sci. 1081, 70 (lo), 1112. (56D) Heinitz, M. L. J. Pharm. Sci. 1082, 71 (6), 656. (57D) Helboe, P. J . Chromafogr. 1082, 245 (2), 229. (58D) Hikal, A. H.; Ai-Shoura, H. I . J. Liq. Chromatogr. 1082, 5(11), 2205. (59D) Housmyer, C. L.; Lewis, R. L., Jr.; Keily, H. J. Anal. Chlm. Acta 1083, 146, 117. (BOD) Hughes, D. E. J. Chromatogr. 1083, 262, 404. (6lD) Juenge, E. C.; Flinn, P. E.; Furman, W. B. J . Chromafogr. 1082, 248 (2), 297. (62D) Kaizuka, H.; Takahashl, K. J . Chromatogr. 1083, 258, 135. (63D) Kawase, J.; Ueno, H.; TsuJI, K. J . Chromafogr. 1082, 253 (2), 237. (64D) Kopp, B.; Jurenitsch, J.; Czernia, B.; Kubelka, W. J. Chromafogr. 1083, 257 ( I ) , 137. (65D) Kumar, A. A,; Kempton, R. J.; Anstead, 0 . M.; Price, E. M.; Frelsheim, J. H. Anal. Blochem. 1083, 128 (I), 191. (66D) Kumar, J. L.; Mann, W. C.; Rozanski, A. J. Chromatogr. 1082, 249 (2), 373. (67D) Kwong, E.; Pillai, G. K.; McErlane, K. M. J . Pharm. Sci. 1082, 71 (7), 828. (68D) Law, M. W. J. Assoc. Off. Anal. Chem. 1083, 66 (5),1304. (690) Lea, A. R.; Hailey, D. M.; Duguld, P. R. J . Chromatogr. 1082, 250, 35. (70D) Lebl, M. J . Chromatogr. 1083, 264 (3), 459. (71D) Lim, C. K.; Ayres, D. C. J . Chromafogr. 1083, 225, 247. (72D) Marsh, D. F.; Takahashl, L. T. J . Pharm. Scl. 1083, 72 (5),521. (73D) May, E. M.; Pearse, J. E. Anal. Proc. (London) 1083, 20 (4), 178. (74D) Mehta, A. C. Analyst (London) 1082, 107 (1280), 1379. (75D) Menouer, M.; Bouabdellah, F.; Ghernati, H. M.; Guermouche, M. H. J. High Resoiut. Chromatogr. Commun. 1982, 5 (5),267. (76D) Menouer, M.; Ghernatl, H. M.; Bouabdeilah, F.; Guermouche, M. H. Analysus 1082, 10 (4). 172. (77D) Miner, D. J. Anal. Chim. Acta 1082, 134, 101.

PHARMACEUTICALS AND RELATED DRUGS (780) Mizuno, N.; Shlmizu, C.; Morita, E.; Shinkuma, D.; Yamanaka, Y. J. Chromatogr. 1983, 264 (l), 159. (79D) Nicoias, A,; Leroy, P.; Moreau, A.; Mirjolet, M. J. Chromatogr. 1982, 244 (l), 148. @OD) Nobuhara, Y.; Hirano, S.;Nakanishi, Y. J. Chromatogr. 1983, 258, 276. (81D) Noji, M.; Achiwa, K.; Kondo, A,; Kidani, Y. Chem. Lett. 1982, 11, 1757. (82D) Ohshima, Y.; Takahashi, K. J. Chromatogr. 1983, 258, 292. (83D) Olsen, C. S.;Scroggins, H. S. J. Pharm. Sci. 1983, 72 (E), 963. (84D) Parrott, K. A. J. Chromatogr. 1983, 274; Biomed. Appl. 25, 171. (85D) Pekic, B.; Petrovic, S.M.; Slavica, B. J. Chromatogr. 1983, 268 (2), 237. (86D) Perlman, S.;Szyper, M.; Kirschbaum, J. J. J. Pharm. Sci. 1984, 73, (2), 259. (870) Pettersson, C.; Schili, G. Chromatographia 1982, 16, 192. (88D) Prosser, 8. C.; Floor, B. J.; Klein, A. E.; Muhammad, N. J. Pharm. Sci. 1983, 72 (lo), 1168. (89D) Prue, D. 0.; Johnson, R. N.; Kho, B. T. J. Pharm. Sci. 1983, 72 (7), 751. (90D) Rao, G. R.; Murty, S.S.N.; Mohan, K. R. Indian Drugs 1982, 19 (1l), 451. (91D) Rao, G. R.; Raghuveer, S.; Pullarao, Y. Mohan, K. R. Indian Drugs 1983, 20 (7), 285. (92D) Reif, V. D.; DeAngeiis, N. J. J. Pharm. Sci. 1983, 72 ( i l ) , 1330. (93D) Richheimer, S. L.; Amer, T. M. J. Pharm. Sci. 1983, 72(11), 1349. (94D) Rihbany, L. A.; Delaney, M. F. J. Chromafogr. 1982, 248 (l), 125. (95D) Roberts, S.E. J. Assoc. Off. Anal. Chem. 1982, 65(5), 1063. (96D) Roberts, S.E.; Delaney, M. F. J. Chromatogr. 1984, 283, 265. (970) Schieffer, G. W.; Hughes, D. E. J. Pharm. Sci. 1983, 72 (I), 55. (98D) Scott, E. P. J. Pharm. Sci. 1983, 72(9), 1089. (99D) Sedman, A. J.; Gal, J. J. Chromatogr. 1983, 278; Biomed. Appl. 29, 199. (1OOD) Seikirk, S. M.; Miller, J. H. McB.; Smith, G.; Fell, A. F. J. Pharm. Pharmacol. 1983, 35 (Suppl.), 23P. (101D) Smith, D. J.; Weber, J. D. J. Chromatogr. Sci. 1984, 22 (3), 94. (102D) Smith, F. M.; Nuessle, N. 0. Anal. Lett. 1982, 15(B4), 363. (103D) Tan, H. S. I.; Salvador, G. S. J. Chromatogr. 1983, 261 (1). 111. (104D) Theis, D. L.; Bowman, P. 8. J. Chromatogr. 1983, 268(1), 92. (105D) Tsuklda, K.; Saiki, K.; Takii, T.; Koyama, Y. J. Chromatogr. 1982, 245 (3), 359. (106D) Vigh, G.; Varga-Puchony, 2.; Hlavay, J.; Papp-Hites, E. J. Chromatogr. 1982, 236(1),51. (107D) Wainer. 1. W.; Doyle, T. D. J. Chromatogr. 1983, 259 (3), 465. (108D) Wainer, I . W.; Doyle, T. D.; Hamidzadeh, 2.; Aidridge. M. J. Chromatogr. 1983, 268 (l), 107. (109D) Walker, S.T. J . Assoc. Off. Anal. Chem. 1983, 66 (5), 1196. (IlOD) Wang, D.-P. Analyst (London) 1983, 108 (1288), 851. (111D) Waraszkiewicz, S. M.; Milano, E. A.; DiRubio, R. J. Pharm. Sci. 1981, 70(11), 1215. (112D) Weliner, B. S.;Llnde, S.;Brush, J. S. J. Chromatogr. 1983, 257(1), 162. (113D) Williams, D. A.; Fung, E. Y. Y.; Newton, D. W. J. Pharm. Sci. 1982, 71 (E), 956. (114D) Wilson, T. D. J. Chromatogr. 1982, 243 (1). 99. (115D) Yamaguchi, Y.; Hayashi, C.; Miyai, K. Anal. Lett. 1982, 15(88),731. (Il8D) Zaidi, 2. R.; Sena, F. J.; Basilio, C. P. J. Pharm. Sci. 1982, 71 (9), 997. (117D) Zoutendam, P. H.; Bowman, P. B.; Ryan, T. M.; Rumph, J. L. J. Chromatogr. 1984, 283, 273. Thln-Layer Chromatography (1 18D) Banjanin, 6.; Budimir, J.; Djonlagic, N.; Hadzisce, A,; Mazalovic, M.; Stancic, 8. Chromatographia 1982, 16, 294. ( l l 9 D ) Chawla, H. M.; Chibber, S.S. Sci. Cult. 1982, 48 (3), 105. (120D) Cheng, M.-L.; Poole, C. F. J. Chromatogr. 1983, 257(1), 140. (121D) Crolla, T.; Citerio, L.; Visconti, M.; Plfferi, G. J. High Resolut. Chromatogr. Chromatogr. Common. 1983, 6 (E),445. (1220) Dreijer Van der Gias, S. M.; Dingjan, H. A. Pharm. Weekbl., Sci. Ed. 1983, 5 (4), 188. (123D) Doege, G.; Pohloudsk-Fabini, R.; Kottke, D. Pharmazie 1982, 3 7 (lo), 708. (124D) Fabre, H.; Eddine, N. H.; Bressolle, F.; Mandrou, B. Analyst (London) 1982, 107(1270), 61. (125D) Fiorese, F.; Vermueien, G.; Turcotte, C. Subst. Alcohol Actions lMisuse 1982, 3 (1-2), 61. (126D) Goeber, 8.; Lisowski, H.; Franke, P. Pharmazie 1981, 36 (12), 812. (127D) Papke, E. Pharmazie 1982, 37 (IO), 737. (128D) Pohloudek-Fabini, R.; Martin, E.; Gailasch, V. Pharmazle 1982, 37 (3), 184. (129D) Sleckman, B. P.; Sherma, J. J. High. Resolut. Chromatogr. Chrom t o g r . Commun. 1983, 6 (3), 156. (130D) Srivastava, S.P.; Reena Anal. Lett. 1982, 15 (5A), 451. (131D) Sysmalainen, M.; Halmekoski, J. Acta Pharm. Fenn. 1983, 92 (3), 165.

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Spectroscopy (Mher) (192D) Aaron, J. J.; Ndiaye, S. A.; Fidanza. J. Analusis 1982, 10 (9), 433. (193D) Abdei, F. F.; Baeyens, W.; De Moerioose, P. Anal. Chim. Acta 1983, 154, 351. (194D) Bateh, R. P.; Winefordner, J. D. J. Pharm. Sci. 1983, 72 (5), 559. (195D) Bhattacharyya, P. K.; Grant, A. Anal. Chim. Acta 1982, 142, 249. (196D) Chiareiii, S. N.; Rossi, M. T.; Pizzorno, M. T.; Aibonico, S. M. J. Pharm. Sci. 1982, 71 (lo), 1178. (197D) Danieison, N. D.; Bartolo, R. G. Anal. Lett. 1983, 16 (B5), 343. (198D) Davidson, A. G. Analyst (London) 1983, 108 (1287), 728. ANALYTICAL CHEMISTRY, VOL. 57, NO. 5, APRIL 1985

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PHARMACEUTICALS AND RELATED DRUGS (199D) Dewar, G. H.; Kwakye, J. K.; Parfitt, R. T.; Sibson, R. J . Pharm. Sci. 1082, 77 (7), 802. (200D) Eberhart, S.;Rothchild, R. Appl. Spectrosc. 1083, 37 (3), 292. (201D) El-Fatatry, H. M. Pharmazie 1083, 38 (4), 227. (202D) El-Tarras, M. F.; Ellalthy, M. M.; Tadros, N. 8. Acta Pharm. fenn. 1083, 92 (I), 31. (203D) Ellaithy, M. M. Egypt. J . Chem. 1083, 25(3), 205. (204D) Ellaithy, M. M.; El-Tarras, M. F.; Tadros, N. 6.; Amer, M. M. Anal. Lett. 1982, 75(B11), 981. (205D) Feher, 2.; Horvai, G.; Nagy, G.; Nelgreisz, 2.; Toth, K.; Pungor, E. Anal. Chim. Acta 1083, 745, 41. (206D) Fekety, K. 6.; Medwick, T. J . Pharm. Sci. 1083, 72 ( l l ) , 1358. (207D) Fell, A. F.; Scott, H. P.; Gill, R.; Moffat, A. C. Anal. Proc. (London) 1083, 20 (4), 173. (208D) Fell, A. F.; Scott, H. P.; Gill, R.; Moffat, A. C. J . Pharm. Pharmacoi. 1082, 34 (Suppl.), 99P. (209D) Hannah, R. W.; and Anacreon, R. E. Appi. Specfrosc. 1083, 37(1), 75. (210D) Hassan, M. M. A.; Loutfy, M. A.; Madani, A.-A. E. Spectrosc. Lett. 1082, 75 (9), 679. (211D) Hassan, S.M.; Shaaban, S. A. M. Anal. Lett. 1082, 75 (B21-22), 1693. (212D) Heintz, 8.; Hamacher, H. Dtsch. Apoth.-Ztg. 1083, 723 (9), 417. (2130) Khallfa, T. I.; Muhtadi, F. J.; Hassan, M. M. A. Zentralbl. Pharm., Pharmakother , Laboratorlumsdiagn 1083, 722 (8). 809. (214D) Klrchhoefer, R. D.; Jefferson, E.; Flinn, P. E. J . Pharm. Sci. 1082, 77 (9), 1049. (215D) Kltamura. K.; Majima, R. Anal. Chem. 1083, 55(1), 54. (216D) Korany, M. A.; Haller. R. J . Assoc. Off. Anal. Chem. 1082, 65(1), 144. (217D) Kuhnert-Brandstaetter, M.; Geiler, M.; Wurlan, I. Mlkrochim. Acta 1083, I (3-4), 221. (218D) Lawrence, A. H.; MacNeil, J. D. Anal. Chem. 1082, 54 (3), 2385. (219D) Liu, J. H.; and Tsay, J. T. Analyst (London) 1082, 707 (1274), 544. (220D) Mlhalic, M.; Hofman, H.; Kajfez, F.; Kuftinec, J.; Blazevic, N.; Zinic, M. Act8 Pharm. Jugosl. 1082, 32 (I), 13. (2210) Mohamed, M. E.; Tawakkol. M. S. Pharmazie 1081, 36 (12), 856. (222D) Mohamed, M. E.; Tawakkol, M. S.; Aboul-Enein, H. Y. Spectrosc. Lett. 1082, 75 (2), 73. (223D) Mohamed, M. E.; Tawakkol, M. S.;Aboul-Enein, H. Y. Spectrosc. Lett. 1082, 75 (8). 609. (2240) Oztunc, A. Analyst (London) 1082, 707(1274), 585. (225D) Pathak, V. N.; Shukla, I. J . Indbn Chem. SOC. 1083, 60 (2), 206. (226D) Rockley, M. G.; Woodard, M.;Richardson, H. H.; Davls, D. M.; Purdie, N.; Bowen, J. M. Anal. Chem. 1083, 55(1),32. (22711) Schutz, H.; Suphachearabhan, S. Mikrochim. Acta 1083, I I (1-2), 109. (228D) Wahbi, A. A. M.; Belal, S.;Abdlne, H.; Bedair, M. Tabnta 1082, 29 (lIA), 931. (229D) Walash, M. I.; Ouf, A. A.; Salem, F. B. J . Assoc. Off. Anal. Chem. 1082, 65 (6), 1445. (230D) Walash, M. I.; Rlzk, M. S.; El-Brashy, A. Anal. Lett. 1082, 75 (61 1). 963.

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Electrochemlcal Analyrls (231D) Chatten, L. G.; Pons, S.; Amankwa, L. Analyst (London) 1083, 708 (1289), 997. (232D) Choi. K. K.; Fung, K. W. Anal. Chim. Acta 1082, 738,385. (233D) Hoffmann, H.; Dybowskl, M. fresenipus' 2.Anal. Chem. 1082, 372 (7), 625. (234D) Hogue, E. R.; Landgraf, W. C. Anal. Lett. 1081, 74 (B20), 1757. (235D) Kauffmann, J.-M.; Laudet, A.; Vlre, J.-C.; Patrlarche, 0. J.; Christian, 0. D. Microchem. J . 1083, 28 (3), 357. (236D) Klryu, s.; Oda, Y.; Sasakl, M. Chem. Pharm. Bull. 1083, 37 (3), 1089. (237D) Lannigan, N. A.; PryceJones, R. H.; Johnson, J. R. J . Pharm. Pharmacol. 1082, 34 (Suppl.), 11P. (238D) Oelschlaeger. H.; El-Hossny. T. Arch. Pharm (Welnhehn, Ger .) 1083, 376 (5),i 1 2 . (239D) Papas, A. N.; Delaney, M. F. Anal. Lett. 1082, 75(B8), 739. (240D) Pinzautl, S.; La Porta, E.; Papeschi, G. J . Pharm. Biomed. Anal. 1083, 7 (2), 223. (241D) Sengum, F. I.; Caliskan, 2. Sci. Pharm. 1083, 57 (3), 297. (2420) Szurley, E.; Brajter-Toth, A. Anal. Chim. Acta 1083, 754, 323. (243D) Tomas Vert, F.; Vicente Pedros, F.; Martlnez Calatayud, J.; Peris Martlnez, V. Talanta 1083, 30 (12), 977. (244D) Vlre, J. C.; Fischer. M.; Patriarche, G. J. Analusls 1082, 70 (I), 19. (2450) Vire, J. C.; Kauffmann, J. M.; Patriarche, G. J. Anal. Lett. 1082, 75 (Ble), 1331. I

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(2550) Daoud, N. N.; Crooks, P. A.; Speak, R.; Gilbert, P. J . Pharm. Scl. 1083, 72 (3), 290. (256D) Doulakas, J.; Kis, G. Fresenius' 2.Anal. Chem. 1082, 732(4), 353. (257D) Jannasch, R. Pharmazle 1083, 38 (6), 379. (258D) Johansson, P.-A.; Hoffmann, 0.; Stefansson, U. Anal. Chim. Acta iosa, 140 (I), 77. (259D) Kanoute, G.; Nivaud, E.; Paulet, B.; Boucly, P. Taianta 1084, 31 (2), 144. (260D) Mohamed. M. E.;Tawakkol, M. S.;Aboul-Enein, H. Y. Pharmazie 1082, 37 (9), 670. (261D) Ng, T. L. Analyst (London) 1082, 707 (1275), 695. (262D) Pathak, V. N.; Shukla, S. R.; Shukla, I. C. Analyst (London) 1082, 707 (1278), 1086. (263D) Reisch, J.; AbdeCKhalek, M. Pharmazie 1083, 38 (3), 199. (264D) Sakai. T.; Ohno, H. Analyst (London) 1082, 707 (1275), 634. (265D) Shlkimi, T. J . Pharmacoblo-Dyn. 1082, 5 (g), 708. (266D) Sysmalalnen, M.; Halmekoski, J. Acta Pharm. Fenn. 1083, 92 (3),

155.

(267D) Yamaguchl, Y.; Hayashi, C.; Miyai, K. Anal. Lett. 1082, 75(B8), 731. STEROIDS

General and Gas Chromatogrgphy (IE) Brower, J. F. Pharmacopeia/ forum 1083, 9 ,3566-3570. (2E) Lyman, 0. W.; Johnson, R. N. J . Chromatogr. 1082, 234,234-239. (3E) Zelf, M.; Crane, L. J.; Horvath, J. Int. Lab. 1082, 12, 102-111. Llquld Chromatography (4E) Bond, A. M.; Heritage, I. D.; Brlggs, M. H. Anal. Chim. Acta 1082, 738, 35-45. (5E) Cairns, T.; Siegmund, E. G.; Stamp, J. J.; Skelly, J. P. Biomed. Mass Spectrom. 1083, 70, 203-208. (6E) Carlgnan, G.; Lodge, B. A.; Skakum, W. J . Pharm. Sci. 1082, 77, 264-266. (7E) Dijkstra, J.; Dekker, D. J . Chromatogr. 1082, 238,247-249. (8E) Ezzedeen, F. W.; Stohs, S.J.; Masoud, A. N. J . Pharm. Sci. 1083, 72, 1036-1 039. (9E) Hailey, D. M.; Lea, A. R. J . Assoc. Off. Anal. Chem. 1081, 64, 870-874. (10E) Jonvel, P.; Andermann, G. Analyst (London) 1083, 708,411-414. (11E) Phoon, K.; Stubby, D. J. Chromatogr. 1082, 246,297-303. (12E) Rego, A.; Nelson, B. J . Pharm. Sci. 1082, 77, 1219-1223. (13E) Rehm, K. D.; Stelnigen, M. Pharm. Ztg. 1082, 727,888-892. (14E) Struslak, S. H.; Hoogerheide, J. G.; Gardener, M. S. J . Pharm. Sci. 1082, 77,636-640. (15E) Walters, M. J.; Dunbar, W. E. J . Pharm. Sci. 1082, 77,446-451. Thln-Layer Chromatography (16E) Molnar, J.; Gazdag, M.; Szepesl, T. Pharmazie 1082, 37, 836-838. (17E) Vukusic, I.J . Chromatogr. 1082, 243, 131-138. Electrochernlcal Analysis (18E) Campanella, L.; Sorrentlno, L.; Tomassettl, M. Analyst (London)1083, 708, 1490-1494. (l9E) Schaar, J. C.; Smith, D. E. Anal. Chem. 1082, 54, 1589-1594. Spectroscopy (20E) Belal, S.;Issa, N. Pharmazie 1082, 37,297-298. (21E) Chatterjee, S. K.; Sharma, S. C.; Roy, S. K. J . Inst. Chem. (Indla) 1082, 54, 184-186. (22E) Grignard, R.; Kgrboul, A. Anaiusis 1082, IO, 423-425. (23E) Hansen, J.; Bundgaard. H. Int. J . Pharm. 1081, 8 , 121-129. (24E) Kawn, L. C.; Schott, H. J . Pharm. Scl. 1084, 73, 157-161. Tltrlmetry (25E) Gall, F. F.; Miljkovic, D. A.; Gad, K. M.; Kuzmic, D. L. Fresenius' 2. Anal. Chem. 1082, 372, 618-621. SULFUR-CONTAINING COMPOUNDS

General and Gas Chromatography (1F) Newton, D. W.; Murray, W. J.; Ratanamaneichatgra, S. Anal. Chim. Acta 1082, 735,343-346. (2F) Stavchansky, S.; Wallace, J. E.; Chue, M.; Wu, P. Anal. Lett. 1082, 15. 1361- 1372. (3F) Stavchansky, S.;Wallace, J. E.; Wu, P. J . Pharm. Sci. 1083, 72, 546-548. Llquld Chromatography (4F) Bauer, J.; Qulck, J.; Krogh, S.; Shada, D. J . Pharm. Sci. 1083, 72, 924-928. (5F) Cotton, M. L.; Down, 0. R. B. J . Chromatogr. 1083, 259, 17-36. (6F) Hassan, S. M. Chjomatographb 1083, 77,101-103. (7F) Korany, M. A.; Franzky, H. J . Sci. Pharm. 1083, 57, 291-297. (8F) Lam, S. W.; Meyer, R. C.; Takahashl, L. T. J . Parenter. Sci. Techno/. 1081, 35,262-265. (9F) Shimizu, R.; Ishii, K.; Tsumagari, N.; Tanigawa, M.; Matsumoto. M.; Harrlson, I. T. J . ChfOm8tOq. 1082, 253, 101-108. (IOF) Walters, S.;Stonys, D. J . Chromatogr. Sci. 1083, 27, 43-45. Thln-Layer Chromatography (1 1F) Misztal, G.; Przyborowska, M.; Przyborowska, L. Pharmazle 1083, 38,

67-69.

PHARMACEUTICALS AND RELATED DRUGS (12F) Steinbrecher, K. J. Chromafogr. 1983, 260, 463-470. (13F) Takla, P. G.; Joshi, S. R. J. Pharm. Bbmed. Anal. 1983, 7 , 189-193. Electrochemical Analysls (14F) Davidson, 1. E.; Smyth, W. F. Anal. Chlm. Acta 1983, 747, 53-64. (15F) Jarbawi, T. B.; Heineman, W. R. Anal. Chim. Acta 1982, 735, 359-362. (16F) Kala, H.; Fahr. F. Pharmazie 1983, 3 8 , 419-420. (17F) Van Kerchove, C.; Bontemps, R.; Schoenmakers, A. J. Pharm. PharmaCOl1982, 34, 420-424. Spectroscopy (18F) Agrawai, D. K.; Deshpande, A. V. Pharmazle 1982, 3 7 , 150. (19F) Clark, B. J.; Feii, A. F. J. Pharm. Pharmacol. 1983, 3 5 , (Suppi.), 22 P. (20F) Rao, 0. R.; Raghuveer, S. Indian Drugs 1981, 78, 408-409. (21F) Rao, G. R.; Raghuveer, S.;Rao, Y. P. J. Insf. Chem. (India) 1982, 5 4 , 148-148. (22F) Sabins, D. S.; Kunde, S. U. S. Indlan Drugs 1982, 79, 410-411. (23F) Sane, R. T.; Nayak, V. G.; Naik, N. R.; Gupte, D. D. Indian Drugs 1983, 2 0 , 334-336. (24F) Taha, A. M.; El-Rabbat, N. A.; El-Kommos, M. E.; Refat, I. H. Analyst (London) 1983, 708. 1500-1505. (25F) Tarasiewicz, M.; Staniszewska, E.; Puzanowska-Tarasiewicz, H. Pharmazie 1983, 38, 203-204. Mlscellaneous (26F) Balia, J.; Brllk, J. Int. J. Mass Specfrom. Ion. P h p . 1983, 48, 269-272. (27F) Buyuktimkin, N.; Schunack, W. Arch. Pharm. 1983, 376, 1042-1045. (28F) Drewry, P. C. Analyst (London) 1982, 707, 689-691. (29F) Walash, M.; Rizk, M.; Abou-Ouf. A.; Belal, F. Analyst (London) 1983, 708, 626-632. VITAMINS Fat Soluble (1G) DePaolis, A. J. Chromatogr. 1983, 258, 314-319. (2G) Fong, G. W. K.; Johnson, R. N.; Kho, B. T. J. Assoc. Off. Anal. Chem. 1983, 66,939-945. (3G) Habash, T. F.; Houser, J. J.; Garn, P. D. J. Therm. Anal. 1982, 2 5 , 271-277. (46) Pask-Hughes, R. A.; Caiam, D. H. J. Chromafogr. 1982, 246, 95-104. (5G) Santoro, M.; Magalhaes, J. F.; Hackmann, E. R. M. J . Assoc. Off. Anal. Chem. 1982, 6 5 , $19-23. (6G) Sihom, M. B.; El-Kommos, M. E. J. Assoc. Off. Anal. Chem. 1982, 65, 141-143. (7G) Van Antwerp, J.; Lepore, J. J. Liq. Chromafogr. 1982, 5 , 571-584. Water Soluble (8G) AbdeCSalam, M. A.; Abdei-Hamid, M. E.; AbdeCHady, E. M. Scl. Pharm. 1982. 50. 11-16. (9G) Bruno, P. Anal. Left. 1981, 74. 1493-1500. (100) Coverly, S. C. J. Aufom. Chem. 1983, 5 , 89-93. (1 1G) Feyns, L. V.; Thakker, K. D.; Reif, V. D.; Grady, L. T. J. Pharm. Scl. 1982, 77, 1242-1246. (126) Gllniecki, K.; Hagemann, U.; Kuhne, W.; Carola, L. Pharm. Zig. 1982, 127, 823-826. (13G) Hudson, T. J.; Allen, R. J. J. Pharm. Scl. 1984, 73, 113-15. (140) Hughes, D. J. Pharm. Scl. 1983. 72, 126-129. (15G) Kawamoto, T.; Okada, E.; Fujita, T. J. Chromafogr. 1983, 267, 4 14-4 19. (16G) Kimura, M.; Panijpan, B.; Itokawa, Y. J. Chromafogr. 1982, 245, 141-143. (17G) Lechien, A.; Valenta, P.; Nuernberg, H. W.; Patrlarche, G. J. Fresenius' Z . Anal. Chem. 1982, 377, 105-108. (18G) Lyle, S. J.; Tehrani, M. S. J. Chromatogr. 1982, 236, 31-38. (190) Mehta, A. K.; Wadodkar, S. G.; Kasture, A. V. Ind/an Drugs 1982, 798 165- 166. (20G) Moussa, A. A. Mikrochlm. Acta 1982, 7 , 169-174. (210) Panijpan, B.; Kimura, M.; Itokawa, Y. J. Chomatogr. 1982, 245, 144-147. (22G) Rao, G. R.; Rao, Y. P.; Raju. I.R. K. Scl. Cult. 1982, 48, 137-139. (23G) Rao. N.; Rao, K. J. Indian Chem. Soc.1981, 5 8 , 1127-1128. (24G) Rehm, K. D. Pharm. Zfg. 1981, 726, 1859-1861. (25G) Tafolla, W. H.; Sarapu, A. C.; Dukes, G. R. J. Pharm. Sci. 1981, 70, 1273-1276. (26G) Van Kerchove, C.; Bontemps, R. J. Pharm. Belg. 1982, 3 7 , 169- 176. (27G) Verma, K. K. Talanfa 1982, 2 9 , 41-45.

(7H) Hermansson, J. J. Chromatogr. 1983, 269, 71-80. (6H) Low, G. K. C.; Haddad, P. R.; Duffield, A. M. Chromafographia 1983, 77, 16-22. (9H) Markides, K.; Biomberg, L.; Buijten, J.; Wannman, T. J. Chromafogr. 1983, 267, 29-38. (10H) Piotczyk, L. L.; Larson, P. J. Chromatogr. 1983, 257, 211-228. (11H) Rohdewald, P. Pharm. Zfg. 1982, 727, 327-330. (12H) Tomiinson, E. J. Pharm. Biomed. Anal. 1983, 7 , 11-27. (13H) Tsuji, K.; Binns, R. B. J. Chromatogr. 1982, 253, 227-236. (14H) Wainer, W.; Doyle, D. J. Chromafogr. 1984, 284, 117-124. (15H) Warfield, R. W.; Maickel, R. P. J . Appi. Toxicol. t983, 3 , 51-57. (16H) Cunningham, L.; Freiser, H. Anal. Chhn. Acta 1982, 739, 97-103. (17H) Leroy, F.; Gareil, P.; Rosset, R. Analusis 1982, 70, 351-366. Electrochemlcal Analysls

.

(18H) Oeischiaeger, H. Bioelechochem, Bloenerg 1983, 70, 25-36. (19H) Smyth, W.; Ivaska, A.; Burmicz, J. S.; Davidson, I. E.; Vaneesorn, Y. Bbelecfrochem. Bloenerg. 1981, 8 , 459-467. (20H) Voike, J. Bloelecfrochem. Bioenerg 1983, 70, 7-23.

.

Mass Spectrometry (21H) Benninghoven, A.; Sichtermann, W. I n f . J. Mass Specfrom. Ion PhyS. 1981, 3 8 , 351-380. (22H) Danigei, H.; Junglcas, H.; Schmidt, L. I n f . J. Mass Specfrom. Ion P h y ~ 1983, . 5 2 , 223-240. (23H) Dedieu, M.; Juin, C.; Arpino, P. J.; Guiochnon, G. Anal. Chem. 1982, 54, 2372-2375. (24H) Jungcias, H.; Danigei, H.; Schmidt, L.; Dellbruegge, J. J. Org. Mass Specfrom. 1982, 77, 499-502. (25H) Rinehart, L. Trends Anal. Chem. (Pers. Ed.) 1983, 2 , 10-14. Reagents (26H) Cavazzutti, G.; Gagliardi, L.; Amato, A.; Profili, M.; Zagarese, V.; Tonelii, D.; Gattavecchia, E. J. Chromafogr. 1983, 268, 528-534. (27H) Fink, D. W. Trends Anal. Chem. (Pers. Ed.) 1982, 7 , 254-258. (26H) Pindur, U.; Deechner, R. Dfsch. Apofh.-Zfg. 1983, 723, 1035-1037. (29H) Sanghavl. N. M.; Sathe, V. H.; Padki, M. M. Drugs 1983, 2 0 , 341-342. (30H) Shimanda, K.; Tanaka, M.; Nambara, T. Anal. Chlm. Acta 1983, 747, 375-380. Spedroscopy (31H) Bateh, R. P.; Winefordner, J. D. J. Pharm. Biomed. Anal. 1983, 7 , 113-1 19. (32H) Castieden, S. L.; Kirkbright, G. F.; Long, S. E. Can. J . Specfrosc. 1981, 2 6 , 244-246. (33H) Fairbrother, J. E. Pharm. J., 1983, 230, 926-329. (341.1) Kracmar, J.; Kracmarova, J. Pharmazie 1983, 3 8 , 524-527. (35H) Kuhnert-Brandstaetter, M.; Geiler, M.; Wurian, I. Scl. Pharm. 1983, 57, 34-41. (36H) Li, T. M.; Robertson, S. P.; Crouch, T. H.; Pahuski, E. E.; Bush, 0. A,; Hydo, S. J. Clin. Chem. 1983. 2 9 , 1628-1634. (37H) McCall, S. L.; Winefordner, J. D. Anal. Chem. 1983, 5 5 , 391-393. Thermal (38H) Boudeviiie, P.; Burgot, J. L.; Chauvei, Y. Analusls 1983, 7 7 . 406-408. (39H) Fairbrother, J. E. Pharm. J. 1883, 230, 730-734. (40H) Habash, T. F.; Houser, J. J.; Garn, P. D. J. Therm. Anal. 1982, 2 5 , 271-277. (41H) Kuhnert-Brandstaetter, M.; Wurian, I.; Geiler, M. Sci. Pharm. 1982, 50, 208-216. (42H) Wesoiwoski, M. Int. J. Pharm. 1982, 7 7 , 35-44. (43H) Wollmann, H.; Braun, V. Pharmade 1983, 3 8 , 5-21. Mlscellaneous (441-1) Christopoulos, T. K.; Diamandis, E. P.; Hadjiioannou, T. P. Anal. Chlm. Acfa 1982, 143, 143-151. (45H) De Jong. H. G.; Voogt, W. H.; BOS,P.; Frei, R. W. J . Liq. Chromafogr. 1983, 6,1745-1758. (46H) Dewar, G. H.; Kwakye, J. K.; Parfitt, R. T.; Sibson, R. J. Pharm. Scl. 1982, 71, 602-806. (47H) Diamandis, E. P.; Christopouios, T. K. Anal. Chim. Acta 1983, 752, 281-284. (48H) Geppert. G.; Thieiemann, H. Chem. Tech. 1983, 35, 517-519. (49H) Mace, A. W. Anal. Proc. (London) 1983, 2 0 , 427-429. (50H) O'Haver, T. C. J. Pharm. Blomed. Anal. 1983, 7 , 3-9, (51H) Pfandl, A.; Kuehn, N.; Vreven, F. GIT Fachz. Lab. 1983, 2 7 , 646-853. (52H) Zuber, G. E.; Staiger. D. B.; Warren, R. J. Anal. Chem. 1983, 55, 64-67.

TECHNIOUES

MISCELLANEOUS

Chromatography

(11) Albery, W. J.; Hahn, C. E. W.; Brooks. W. N. Br. J. Anaesth. 1981, 53 (5), 447. (21) Bremecker, K. D. Pharm. Ind. 1983, 45(1), 78. (31) Bunch, E. A. J. Pharm. Scl. 1982, 77(12), 1424. (41) Cole, S. C.; Christensen, 0. A.; Olson, W. P. Anal. Biochem. 1983, 734 (2), 368. (51) Dubes, G. R.; Masoud, A. N.; AI-MosW, M. I. J. Pharm. Sci. 1983, 72 (3), 300. (61) Giebelmann, R. Pharmazie 1982, 37 (lo), 737. (71) Grant, D. J. W.; Abougela, I. K. A. A m / . Proc. (London)1982, 79(12), 545. (81) Hardy, M. J. Anal. Proc. (London) 1982, 79 (12), 556

(1H) Alm, S.; Jonson. S.; Karlsson, H.; Sundhoim, E. G. J. Chromafogr. 1983. 254. 179-186. (21-1) Carter, G. T.; Schlesswohl, R. E.; Burke, H.; Yang, R. J. Pharm. S d . 1982. 77, 317-321. (3H) Conley, D. L.; Benjamin, E. J. J. Chormafogr. 1982, 257, 337-344. (4H) Dieter, D. S.; Walton, H. F. Anal. Chem. 1983, 55. 2109-2112. (5H) Guiiiemin, C. L.; Gressin, J. C.; Caude, M. C. J. Hlgh Resoluf. Chromatogr. Chromafogr. Commun. 1982, 5 , 128-133. (6H) Hoogewijs, G.; Massart, D. L. J. Liq. Chromafogr. 1983, 6 , 2521-2541,


45R

Anal. Chem. 1905, 57,46 13-88 R (91) Kotecha, J.; Morgan, R. M. J. Pharm. fharmacoi. 1982, 34 (Suppl.), 113P.

(101) Kovar, K. A.; Langlouis, H.; Auterhoff, H. Pharm. Weekbl. Sci. Ed. 1983, 5(4),134. (111) Kovar, K. A.; Sakmann, A. J. Chromafogr 1982, 247(2),356. (121) Lake, 0.A.; Hulshoff, A.; Indemans, A. W. M. Pharm. Weekbl., Sci. Ed. 1982, 4 (2),43. (131) Lake, 0.A.; Hulshoff, A.; Van de Vaart, F. J.; Indernans, A. W. M. Pharm. Weekbl., Sci. Ed. 1983, 5 (I),15. (141) Lee, Y.-C.; Karnatz, N. N.; Baaske, D. M.; Ellason, M. S.; Alam, A. S. J. Chromatogr. 1983, 269 (l),28. (151) Liversidge, G. G.; Grant, D. J. W.; Padfield, J. M. Anal. Proc. (London) 1982, 19 (12),549. (161)Luedde, K. H.; Melson, F.; Wedei, R. Zenfralbl. Pharm., Pharmakofher, Laboratoriumsdiagn. 1982, 121 (9),891. (171) Nondek, L.; Chvaiovsky, V. J. Chromafogr. 1983, 268 (3),395.

(181) Padmanabhan, G. R.; Smith, J.; Mellish, N.; Fogel, G. J. Liq. Chromafogr. 1982, 5 (7),1357. (191) Radus, T. P.; Gyr, G. J. Pharm. Sci. 1983, 72(3),221. (201) Ramappa, P. G.; Nayak, A. N. Analysf (London) 1983, 108 (1289), 966. (211) Schieffer, G. W.; Palerrno, P. J.; Pollard-Walker, S. J. Pharm. Sci. 1984, 73 (l),128. (221) Smith, A. Anal. f r o c . (London) 1982, 19 (12),559. (231) Such, V.; Traveset, J.; Gonzalo, R.; Gelpl, E. J. Chromafogr. 1982, 234 (I),77. (241) Thieme, H.; Kurzik-Durnke, U. Pharmazie 1982, 37 (5),370. (251) Van de Vaart, F. J.; Hulshoff, A.; Indemans, A. W. M. Pharm. Weekbl., Sci. Ed. 1982, 4 (I), 16. (261) Van de Vaart, F. J.; Hulshoff, A,; Indemans, A. W. M. Pharm. Weekbl., Sci. Ed. 1983, 5 (3), 109. (27D) Winkel, D. R.; Hendrick, S. A. J . Pharm. Sci. 1984, 73 (l),115.

Water Analysis J. R. Garbarino,* T. R. Steinheimer, and H. E. Taylor

U.S. Geological Survey, M S 407, P.O. Box 25046, Denver Federal Center, Denver, Colorado 80225

This is the twenty-first biennial review of the inorganic and organic analytical chemistry of water. The format of this review differs somewhat from previous reviews in this series-the most recent of which appeared in Analytical Chemistry in April 1983 (1). Changes in format have occurred in the presentation of material concerning review articles and the inorganic analysis of water sections. Organic analysis of water sections are organized as in previous reviews. Review articles have been compiled and tabulated in an Appendix with respect to subject, title, author(s), citation, and number of references cited. The inorganic water analysis sections are now grouped by constituent using the periodic chart; for example, alkali, alkaline earth, 1st series transition metals, etc. Within these groupings the references are roughly grouped by instrumental technique; for example, spectrophotometry, atomic absorption spectrometry, etc. Multiconstituent methods for determining analytes that cannot be grouped in this manner are compiled into a separate section sorted by instrumental technique. References used in preparing this review were compiled from nearly 60 major journals published during the period from October 1982 through September 1984. Conference proceedings, most foreign journals, most trade journals, and most government publications are excluded. References cited were obtained using the American Chemical Society's Chemical Abstracts for sections on inorganic analytical chemistry, organic analytical chemistry, water, and sewage and waste. Cross-references of these sections were also included.

INORGANIC ANALYSIS ALKALI AND ALKALINE-EARTH METALS

Barium. Rollemberg and Curtius (IIA) have described a method for the determination of barium in lake water and seawater using a carbon rod atomizer-atomic absorption technique. They used Dowex 50W eluted with ethylenediaminetetraacetic acid to separate interfering ions. A detection limit of 9 pg/FL is reported. Barium was determined in the presence of calcium by Johnson et al. (6A), using a flame atomic emission procedure. They used an ion exchange procedure to separate the calcium at a 1OOO-foldconcentration excess. Detection limits of 5 ng/mL were easily achieved. Sugiyama, Fujino, and Matsui (15A) determined barium in seawater by graphite furnace atomic absorption spectrometry after proconcentration and separation by solvent extraction. After the pH was adjusted to 5 with acetic acid, the sample was extracted with benzene containing l-phenyl-3-methyl-4benzoylpyrazoi-5-one and trioctylphosphine oxide. The aqueous phase was adjusted to pH 6.4 with ammonium hy46 R

This article not subject to

U S . Copyright.

droxide and the barium was extractd with the benzene solution of complexing agents. The benzene was back extracted into dilute nitric acid and analyzed by Zeeman background corrected graphite-furnace atomic absorption, using a pyrolytically coated tube. Beryllium. Kuo et al. (8A) have reported a gas chromatonrar,hic method for the determination of bervllium in tar, wa'tei. A complex with trifluoroacetylacetone was formed cn ethanol and subsequently extracted into cyclohexane,followed by a wash with 0.1 M sodium bicarbonate solution. They reported that fluoride ion interferes to some degree. A polarographic determination of beryllium in water is described by Chen and He (3A). Wave form symmetry and sensitivity is improved by adding tetraethylnickel to the ammonium chloride, ammonium hydroxide, ethylenediaminetetraacetic acid, and Be-reagent supporting electrolyte. They report a linear calibration curve over the range of 0.0002-1.0 Fg/L and a recovery of 99% with a relative standard deviation of 1.69. Finally, an atomic absorption procedure is described by Burba et al. (2A), using an enrichment step cellulose ion exchanger. They show that nanogram quantities of beryllium can be enriched by a factor of 100 to 200 from tap water, river water, and seawater. Although calcium ion causes signal depression, detection limits for the complete procedure are 50 ng/L and 1ng/L, respectively, for flame atomic absorption and graphite furnace atomic absorption. Calcium. Bramall and Thompson (IA) reported a method for reducing the atomic absorption sensitivity for the determination of calcium, by using the 430.3-nm nonresonance spectral line. A nitrous oxide-acetylene flame was used and linear calibration curves up to 10.0 absorbance units were obtained, indicating that little self-absorption occurs. Recovery experiments were satisfactorally performed on sewage sludges. Calcium was determined in raw and potable water by Frend et al. (5A)using flow injection analysis and a tubular membrane flow-throu h potentiometric electrode. The calcium selective electrole was based on calcium bis(4-(1,1,3,3tetramethylbuty1)phenyl)phosphate with trioctyl phosphate in poly(viny1chloride). This electrode has improved resistance to interferences by anionic surfactants. They specified that M free calcium can be determined in the presence of moderate amounts of background detergents. Nakagawa, Wada, and Wei (9A) have reported the indirect determination of calcium in the range of 0.8-7.2 mg/L by a flow-injection spectrophotometric method. The procedure is based upon the exchange reaction between calcium and the zinc complex of ethylene glycol bis(2-aminoethyl ether)tetraacetic acid in the presence of 4-(2-pyridylazo)resorcinol (PAR). A sample analysis rate of 80 per hour was achieved. A spectrophoto-

Published 1985 by the American Chemical Society

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