Anal. Chem. 1901, 63,130R-148R (L13) Qeve, P. A.; Hogendoorn, E. A. Msdsd. Fac. Landbouwwet., RI#ksuniv. Oent 1988. 53, 1531-1533. (L14) Xho, Y.; Fan, D.; Chon, H. J. Assoc. Off. AMI. chem.1990, 73, 761-783. (L15) MndeS, M. C. S. J . A@. Foodchem. 1990, 38, 174-178. (L16) Calms, T.; Slegmund, E. 0.;Chlu, K. S.; Nelson, R. B&med. fnvkon. AASU Spscbwn. 1989. 18, 110-115. (L17) Jamleson, J. A.; Duncan, H. J. Potato Res. 1989, 32, 123-126. (Ll8) R d k , S. D.; De C a m , L. J. A m . Food 1989, 37,975-978. 1990, 35, (L19) Bushway, R. J.; Savage, S. A.; Ferguson, B. S. Food-. 51-58. (L20) Vulk, J.; Brouwer. W.; Krlshnadath. G. J. N.; Van de Lagemaat, D. J. A@. Food chem.1989, 37, 88-90. (L21) MaasfekJ, W. ptlanzenschuk-Nachr. Eayof(Eng1. Ed.) 1987, 40, 2948; Chem. Abstr. 1989, 110, 207600k. (L22) Van den Broek, H. H.; Hermes, 0. B. M.; Goewle, C. E. Ana/yst (London) 1988, 113, 1237-1239. (L23) Sanchezdasero, F.; Romero, T. E.; Dlos, C. 0. J. Chromatogr. 1980, 479, 424-429. (L24) Jung, F.; Meyer, H. H. D.; Ha”, R. T. J. Agric. Food Chem. 1989, 3 7 , 1183-1187. (L25) GWvydls, D. M.; Welters, S. M. J. Agrlc. Food Chem. 1988, 3 6 , 957-961. (L26) El-Nabarawy, I.M.; Carey, W. F. J. Assoc. Off. Anal. Chem. 1988, 71, 356-360. (L27) Brennecke, R. Ptlenz~nscbutr-NadK.Eayef (fngl. Ed.) 1088, 4 1 , 137-174; Chem. Abstr. 1990, 112, 1174482. (L28) Wallszewskl, S. M.; Wallszewskl, K. N. Fresenlus’ 2. Anal. Chem. 1988. 331, 528-520. (L29) Losade, P. P.; Lozano, J. S.; Gandara, J. S. J. Assoc. Off. Anal. Chem. 1990, 73, 632-637. (L30) Llu, C. H.; Mattern, G. C.; Yu, X.; Rosen, J. D. J. Aplc. Food Chem. 1990. 38. 167-171. (L31) Brennecke, R. ptlanzenschutz-Nachr. &yef (Engl. Ed.) 1988, 4 1 , 113-136 chsm.Abstr. 1990, 112, 156811g. (132) &andsteterova, E.; Lehotay, J.; Geraj, J.; Leclercq, P. A. J. Chromat w . 1990, 502, 214-220.
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PYRETHRINS AND PYRETHROIDS
(Ml) Bdygo, E.; HadReld, S. T. J. H@h Resdut. Chrometogr. 1990, 13, 457-460. (M2) Debon, A.; Segalen, J. L. Pyrethrum Post. 1989, 17, 43-46. m,P. R.; Brayan, J. G.; Sharp, G. J.; MIII, S.; Desmarcheller, J. M. J . Chfnaw1989, . 461, 337-346. (M4) Padadopoulou-Mourkldou, E. Anal. Chem. 81, 1149-1158. (M5) Hale. J. R.; Walk, M. D.; Bryson. T. A. J. Agrfc. Food Chem. 1980, 3 7 , 70-74. (Me) Sundaram, K. M. S. J. Envkon. Scl. Health, Part 8 1900, B25, 357-378. (M7) Stanker, L. H.; Bigbee, C.; Van Emon, J.; Watklns, 6.; Jensen, R. H.; Monb, C.; Venderlaan, M. J. A@. Food Chem. 1980. 3 7 , 834-839. (M8) Ywng, J. M.; Shemanchuk. J. A.; Spooner, ‘R. W. J. Aglc. Food chem. 1988, 36. 1287-1200. (M9) Mdnard, C.; Bruneau. P. J. Chrometom. 1988. 450. 169-174. (M10) Hernandez, P.; Vlcente, J.; Hefnande;, L. Fresenlus’ 2.Anal. Chem. 1989, 334, 550-553. ( M l l ) Berblna, M. T.; De Paoll, M.; Valentlno, A. Pesffc. Sei. 1090, 2 8 , 107-202.
(m)
FUMIQANTS
(NI) Dan, J. L. J. APIC. ~ o o d ” . 1989. 3 7 , 560-564. (N2) Van Rlllaer, W. Q.; Beemaert, H.; Dejonckheere, W. 2.Lebensmdntm. F m c h . 1988, 187, 97-101. (N3) Rangaswamy, J. R. J. Assoc. Off. Anal. Chem. 1988, 71, 557-559. (N4) Rangaswamy, J. R. J. FoodScl. Technd. 1990, 2 7 , 33-37. (N5) Russo, M. V. Chrometographla 1989, 2 7 , 469-471. (N6) Suzuki, T.; Ishlzaka, T.; Sasakl, K.; Salto, Y. J. AgflC. Food Chem. 1089, 3 7 , 564-567.
(N7) Nakamura. Y.; Hasagawa, Y.; Tonogal, Y.; Hanafusa, M.; Hkose, H.; Taharasako, Y.; Ito, Y. J. F o o d h t . 1988, 5 1 , 727-730. (Ne) Jensen, K. 0. 2.Lebensm.-~ters.Forad,. 1988, 187, 535-540. (N9) Altkenhead, P.; VMnes, A. J. Assoc. Off. AMI. chem. 1988, 7 1 , 729-731. MISCELLANEOUS PESTICIDES
(01) Houglum. J. E.; Larson, R. D.; Neal, R. M. J . Chromatogr. 1989, 481, 458-460. (02) Felice, L. J.; Murphy, M. J. J. Anal. T o x W . 1989. 13, 229-231. (03) Stricker. 0.; Olersdmer, K.; Vorwohl. 0. Dtsch. Lebensm.-Rundsch. 1980, 85, 72-75; Chem. Absb. 1989, 1 1 1 , 55920r. (04) Olek, M. J. Chfomatogr. 1988, 447, 421-425. ( 0 5 ) McGhle, T. K.; Holland, P. T.; Malcolm, C. P. Blomed. Envkon. Mss SpeCtrO” 1990, 19, 267-272. (06) Knuth, M. L. Chemosphere 1989, 18, 2275-2281. (07) Allen, C. R.; Dlcklnson, C. M. J. Liq. Cbfomatoq. 1990, 13, 371-381. ( 0 8 ) Oulmette, D. G.; Coffey, M. D. phviopethologv 1988, 78, 1150-1155. (09) Dawson, V. K.; Allen. J. L. J. Assoc. Off. Anal. Chem. 1988, 71, 1094-1096. (010) Ozawa, H.; Tsukioka. T. J. chromafogr. 1989, 473, 251-259. (011) Booth, M. C.; Campldonica, M. J.; Fujino. D. W.: Sachs. R. M. J . Rlanf Growth RwuI. 1989, 8 , 293-300. (012) Cabras, P.; Spanedda. L; Tuberoso, C.; Gennarl. M. J. Chromaw. 1989, 478, 250-254. (013) Dan. J. L. J. chromatogr. SCI. 1989, 27, 75-78. (014) Contos, D. A.; Slivon, L. E. SrJShtonCrop Prof. C o n f . - W d 1989, (I), 273-275; Chem. Abstr. 1990, 112, 134315~. (015) Cheung, M. W.; Khars, R. A.; Nlxon, W. B.; Ross, J. A.; Tweedy, 8. G. ACS S w p . Ser. 1089, 382. 231-239. (016) Weisskopf, C. P.; Selber, J. N. ACS Symp. Ser. 1989, 382, 206-214. INDUSTRIAL CHEMICALS RELATED TO PESTICIDES (Pl) Clement, R. E.; Toslne, H. M. Mass Specbom. Rev. 1 9 0 , 7 . 593-636. (P2) Alford-Stevens, A. L.; Budde, W. L. ASTM Spec. Tech. fubl. 1988. 976, 204-212. (P3) Creaser, C. S.; Al-Haddad, A. AMI. Chem. 1989, 61, 1300-1302. (P4) BHlets, S.; Ballard, J. M.; Vonnahme. T. L.; Nunn, N. J.; Youngman, D. R. ASTM Spec. Tech. PUbl. 1088, 999, 1-13. (P5) Jaslnski, J. S. J. C h f m t o g r . 1989. 478, 349-367. (P6) eainger, J.; Reddy, V. V.; Patterson, D. G.. Jr. Appl. Spectrosc. 1988, 42. 800-806. (P7) Thielen, D. R.; Olsen, 0. AMI. Chem. 1988, 60, 1332-1336. (P8) Fehrlnger, N. V.; Walters, S. M.; Nlemann, R. A. J. Assoc. Off. AMI. Chem. Ig80, 72, 394-398. (P9) Stanley, J. S.; Sack, T. M.; Tondeur, Y.; Beckert, W. F. B&med. En& ron. Mess Spectrom. 1088, 17, 27-35. (P10) Mossoba, M. M.; Niamann, R. A.; Chen. J. Y. T. Anal. Chem. 1989, 61, 1678-1685. (P11) Robards, K. FoodAWlt. Contam. 1090, 7 , 143-174. (P12) Oliver. B. G.; Baxter, R. M.; Lee, H. B. In Anal. Trace Org. Aquat. En&n.; Afghan, B. K.. Chau, A. Y. S., Eds.; CRC Ress: Boca Raton, FL 1989, 31-68. (P13) Czuczwa, J. M.; Alford-Stevens, A. J. Assoc. Off. AMI. Chem. 1989, 72, 752-759. (P14) Sutcllffe, C. R.; Oladney, E. S.; Sek, D. M.; Brooks, G. H. AMI. Chem. 1089, 67, 2682-2686. (P15) Burse, V. W.; Groce,D. F.; Korver. M. P.; McClure, P. C.; Head, S. L.; Needham, L. L.; Lapaza, C. R., Jr.; Smrek. A. L. AM&st (London) 1990, 115, 243-251. (P16) Wells, D. E.; De Boer, J.; Tulnstra, L. 0. M. T.; Reutergardh, L.; Wepink, B. Fresenlus’ 2.Anal. Chem. 1988, 332, 591-597. (P17) Tulnstra, L. G. M. T.; Roos, A. H.; Wells, D. E.; Wepink, B. Mkrocblm. Acta 1080, 1 , 1-7. (Pl8) Bwse, V. W.; Korver, M. P.; Needham, L. L; Lapeza. C. R., Jr.; Boozer, E. L.; Mad, S. L.; Liddle, J. A.; Bayse, D. D. J. Assoc. Off. AMI. Chem. 1989, 72, 649-659. (P19) Eganhouse, R. P.; Gould, B. R.; Olaguer, D. M.; Phlnney, C. S.; Sherblom, P. M. I n f . J. fnvlron. AMI. Chem. 1080, 35, 175-198.
Pharmaceuticals and Related Drugs R.K.Gilpin* Department of Chemistry, Kent State University, Kent, Ohio 44242
L.A. Pachla Sterling Drug, Inc., 9 Great Valley Parkway, Malvern, Pennsylvania 19355
The current review is a survey of the methods and proced u m used to analyze pharmaceuticals and related compounds 190 R
0003-270019 110363-130R$09.5010
that have a peared in either Anal tical Abstracts or Chemical Abstracts Between Nov 1988 a n f 0 c t 1990. As has been the @ 199 1 Amerlcan Chemical Society
PHARMACEUTICALSAND RELATEO DRUGIS Rogw K. Gllpln Is Professor and Chatman of the Deparhnent of Chemktry at Kent State University. He received his B.S. degree in chemistry from Indiana State Universlty in 1969 and his Ph.D. degree in a n a w l chemistry from the Unhrersity of Arizona in 1973. From 1973 to 1975 he was empbyed as Senlor Scientist and from 1975 to 1978 as Group Leader of Analytical Chemistry in the Research Division of McNeli Laboratories. In 1978 Dr. Gilpin joined the faculty of Kent State University. Between 1981 and 1983 he also served as a Senior Technical Advisor for IBM Instruments. Hls research interests are in fundamental and applied gas, liquid, and thin-layer chromatography, chromatographic, ESR, IR, and NMR studies of chemkally modified surfaces, and pharmaceutical and related analysis. He has numerous publications in the areas of organometallic surface reactions. synthesis of organosilane and labeled reagents, pharmaceutical analysis, the development of chemically modified surfaces for TLC. GC.and HPLC. physicochemical studies by chromatographic techniques, electron spin resonance, nuclear magnetic resonance, and infrared invesytlons of immobilized ligands. liquld crystals, and related media, and metal, %, and wide-line 2H NMR. Dr. Giipin has organized or been invoked in several symposia and short courses in the area of chromatographic analysk. Likewise, he has held offices in local chromatography and ACS groups. He is also a member of the American Chemical Society. Society of Applied Spectroscopy, American Association for the Advancement of Sciences, and Sigma Xi and serves on the Editorial Advisory Board of the Joumel of c h r o m a t q a m Sdence Or. Gllphr served as 1988 Program Chairman of FACSS.
.
Lawrence A. Pachle k Asslstant Research Dlrector of the Analytical Bbchemlstry Department within the worldwide Analytical Sciences organization of the Sterling Research Group. He received a B.Sc. in chemistry (1973) from Lawrence Instftute of Technology and a Ph.D. in analytical chemistry (1978) from Purdue University. He has been employed as a Research Chemist (1975-1978) at Bioana~icaiSystems Inc. and as a Research Scientist (1978-1979) and a Senior Scientisl (1979-1981) at McNeil Pharmaceutical. AI Parke-Davis, he held the positions of Senior Scientkt (1981-1982). Research Associate (1983-1984), Sentor Research Associate (1985-1987). and Sectkm Director (1987-1989) of the Bioanalytlcal/PDM Research Section and served as development chak (1985-1989) for allergy clinical candidates. He has also lectured at Lawrence Institute of Technology. His research Interests lie in the areas of robotics, electroana)ytfcal chemistry, chromatography, pharmacokinetics, drug metabolism. and the analytical chemistry of proteinaceous drugs. He has published more than 45 papers and is a member of the American Chemical Society, Academy of Pharmaceutical Sciences, American Assoclatlon of Pharmaceutical Sciences, Association of Official Analytical Chemists. and the American Association for the Advancement of Science. He serves on the Editorial Board of An~m&r&/ Agents and Chmofherapy, has served on the Advisory Board of Anatytilcal Cbmkfry, and served as Assktant Program Chair for FACSS (1988-1990).
j
case in past reviews, the article does not consider biochemical or clinical aspects of the subject and represents only a samplin of the very large volume of work published. T t e review continues to be divided into 10 major sections: General, Alkaloids, Antibiotics, Inorganics, Nitrogen- and Oxygen-Containing Compounds, Steroids, Sulfur-Containing Compounds, Vitamins, Techniques, and Miscellaneous. In many cases, these major divisions are divided into subsections. In order to conserve space, a cited work generally appears only in a single section.
GENERAL Books and reviews of a comprehensive nature published were Analytical Profiles of Drug Substances ( I ) , "Pharmaceuticals and Related Drugs" (2),and Chromatographic Analysis of Pharmaceuticals (3). Other topics considered included an overview of the impact of various chromatographic techniques on product purity evaluation (4), procedures used to maximize accuracy in trace analysis (5), and identification reactions and purity tests (6).
ALKALOIDS As has been the trend in past reviews, chromatographic methods continue to be utilized most often for alkaloid analysis. A review has been published that considers the
thin-layer chromatography (TLC) of eight groups of alkaloids ( A I ) . Similarly, a comprehensive TLC study of 31 alkaloids has been carried out to examine the feasibility of using densitometric absorbance ratios as a means of identification (A2). The method is based on an initial identification using R,values and the 254-nm/220-nm peak area ratio followed by final confirmation using the absorbance maximum/220-nm ratio. The retention of 10 different alkaloids has been measured under reversed-phase liquid chromatographic conditions using bis(2-ethylhexy1)hydrogenphosphate as a mobile-phase additive (A3). Solute retention was attributed to a dynamic ion-exchan e mechanism. Reverse2phase liquid chromatography (RPLC)has been used to analyze chinchona (A4),ergot (A5),opium (A6, A n , rauwolfia (A8),tropane (A9),and xanthine (AIO) alkaloids. In all cases, ion-pairing reagents or related mobile-phase additives were used to enhance the chromatographic performance. Similarly, RPLC methods have been described for various miscellaneous compounds, which include Areca catechu alkaloids ( A l l ) ,Camptotheca acuminuta extracts (AI2), indole compounds from Catharanthus roseus (A13), pilocarpine and related impurities degradation products (A14, A15), and isoquinoline alkaloi s (A16, A17). The latter citation (A17)also reviewed other chromatographic techniques as well as immunoassay methods, and in another of the published works (Al3),thermospray mass spectrometer was used for on-line detection. Results from singleion monitoring were found to compare favorably with those obtained from UV detection. Field desorption and desorption chemical ionization have been utilized to study the degradation products of the antitumor alkaloids,vinblastine and vincristine (A18). In both cases, the dominant signals were the protonated molecular ions of the free bases. Other papers published during the review period that used chromatographic procedures to analyze specific classes of alkaloids included the quantitative determination of theophylline in tablet samples (AI9) as well as the application of conventional TLC, high-performance TLC, and overpressured layer chromatography (OPLC) to the separation of tropane alkaloids (A20). An optimization model was utilized in selecting an appropriate solvent system. The OPLC technique was found to increase the speed of the analysis by a factor of 5 for a similar resolution of the eight solutes studied. Several spectrometric methods have been developed for various alkaloids. Colorimetric (A21, A22) and luminescence (A23-A26) techniques have been employed most often. Both room-temperature hosphorimetric and stopped-flow fluorimetric assays have L n reported for theophylline ( A B ,A26). The latter procedure has a through-put rate of approximately 100 samples/h. Methods using NMR spectrometry (A27, A B ) , capillary zone electrophoresis (A29),titrimetry (A30), and radioimmunoassays (A31) also have been published. Lastly, the analytical profile of nalorphine hydro1 has been considered (A32).
ANTIBIOTICS General. This major section includes drugs that are derived from both natural and synthetic sources. This section discusses methods for antibacterials, antiinfectives, antifungals, antiparisitics, and antimicrobials. Anticancer drugs are included if they were originally discovered in fermentation broths. Cephalosporins. A variety of methods were introduced for @-lactamantibioticsduring the current review period. The compounds in this subsection will appear in alphabetical order. A LC method was introduced for cefadroxil in dosage forms (BI). A variety of inactive ingredients were found not to interfere because of the specific isolation procedure and the analytic chromatographic separation. T w o spectrophotometric methods based on the oxidation of cefadroxil and other cephalosporins have been described (B2, B3). The first method involves oxidation of cefadroxil and cephalexin with ammonium vanadate in concentrated sulfuric acid media followed by subsequent monitoring of the absorbance at 760 nm. The method was linear from 0.2 to 2.5 mg and was ANALYTICAL CHEMISTRY, VOL. 63, NO. 12, JUNE 15, 1991 131R
PHARMACEUTICALS AND RELATED DRUGS
applied to determining the seudo-first-order kinetics of the drugs. The second metho$involves the oxidative spectrophotometric determination of cefadrod, cefapirin, ceforanide, and cefuroxime after reaction with molybdophos horic acid. Calibration curves were linear up to 100, Sp, an ppg/mL, res ectivel ,and recoveries were quantitative for in ectable anihard fited capsules. Results agreed with those obtained by the USP method. A spectrophotometricmethod based on zero crossing derivative spectroscopy was described for the determination of mixtures containing cefapirin and cefuroxime (B4). The method was linear up to 40 pg/mL with detection limits of 0.37 and 0.64 p /mL, respectively. The electrochemical parameters for t e cyclic and linear swee voltammetric determination of cefazolin and cefmetazole lave been described (B5).The authors found electroanalysis of these compounds at high sweep rates and low concentrations was primarily due to reduction of adsorbed molecules at the electrode surface. Peak currents for cefamlin and cefmetazole varied linearly between 10-E9 to 10-E7 and 10-E8 to 10-E7 M, respectively. A purity and stability method has been described for cefonicid (B6). The method was found to be rapid, precise, and selective for the determinationof cefonicid in the presence of synthetic impurities. Two other zero E8)for crossing derivative methods have also appeared (B7, cefoperazone and cefamandole, and ce haloridine and cephalothin, respectively. The fmt methdwas applied to PRlg substance and dosage forms and was found to have coefficlenta of variation as low as 0.35 and 0.41% for first- and secondderivative spectra. The second monograph was found to be linear up to 28 and 36 pg/mL for first- and second-derivative modes. Detection limits were 0.13 and 0.37 pg/mL for cephaloridine and cephalothin in the first-derivative mode and 0.25 and 0.29 pg/mL in the second-derivative mode. Charge transfer complexation between cephalothin/cephradine and iodine or 2 , 3 - d i c h l o r o - 5 , 6 - d i c y a n o - ~ ~ ~ .(DDQ) ~ o n e was the basis of spectroscopic and s ctrodensitometric methods (B9). The spectroscopic proceEes were linear in the range of 2-30 and 2-16 p /mL, res ctively! for iodine and 10-120 and 30-270 pg/mf for D D r If excipients or degradation products are present, the HPTLC spectrodensitometricmethod is recommended. A recent report has focused on the and construction of a cephalothin selective electrode (BIO), the parameters that effect linearity, slope, detection limit, selectivity, and electrode lifetime were investigated. This report also describes the effect of side chain substituents for the above electroanalytic pro rties. With proper adaptation and validation, this method sEuld rove useful for the rapid analysis of the dru and could also useful as an in-process manufacturing toof A variety of methods have a peared for the determination of multiple cephalosporins. &ese publications include the spectroscopic investi ation of the utility of paramolybdate for cephalosporin, ce aclor, cefazolin, cefotaxime, cefoxitin, and cefamandole 0311);the RpLC analpis of 13 cephalosporins (BIZ);the utility of LC for drug stab!hty testin and monitoring (B13);the analysis of cephradine, cephafexin, cephalosporin C, cefadroxil, cephapirin, and cephalothin by continuous flow molecular emission cavity analysis (B14);the determination of cefadroxil, cephalexin, and cephradme by mathematical application of a Fourier series and the utilization of LCto fluorescence quenching (B15); photolysis-electrochemical detection for (L-658,758) a novel cephalosporin (B16). During the current review period, several articles appeared that describe the methodology applicable to simultaneously determining several cephalosporins and penicillins (B! 7-B22). One analytical investigation described a complexation spectrophotometric a proach for determining cephalexin, cehradine, am icilin, and amoxycillin in doeage forms (B17). !his approac! consisted of complexing these &lactams with co per acetate and monitoring the absorbance at 675 nm in ~ 8 6 . 7 buffer. 5 Color formation was stable for at least 20 min, and Beer’s law was obeyed between 0.25 and 3 mg/mL for these antibiotics. The method offers marginal advantages in accuracy and precision when compared to the BP and USP methods. Another method involved reaction with 2-nitrophen lh drazine in the presence of dicyclohex lcarbodiimide (BIB; *his general method is applicable to goth classes of antibiotics in bulk and dosage forms and had coefficients of variations less than 2%. Another eneral method applicable to @-lactamsinvolved reaction wit%haematoxylin and chlo-
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ANALYTICAL CHEMISTRY, VOL. 63, NO. 12, JUNE 15, 199
separation over conventional chromatographic methods. Typical run times are less than 15 min. Penicillins. Since the last review, a variety of papers were ublished describing analytical methodology for penicillins. !his subsection is subdivided by technique. A review with 107 references for the LC determination of nicillins has been published (B23). Two methods appeareghat describe the chromatographic determination of ampicillin in the presence of another penicillin (824, B25). The first method involved the quantitation of ampicillin embonate and amoxycillin embonate (B24). The method utilized a RP-8separation at pH 7 with detection at 240 nm and amoxycillin was used as the internal standard for ampicillin and phenoxymeth lpenicillin was used as the interna~standard for amoxycillin. Loxycillin and embonic acid were determined simultaneously; however, ampicillin and embonic acid required separate analyses. Calibration aphs were linear over the range 1.5-21 pg/mL embonic aci$l&llO pg/mL amoxycillin, and 50-500 &mL ampicillin. Another method involved the RP-18 determination of ampicillin and cloxacillin in ca sules (B25). Sample preparation consisted of a sim le dxution with methanolic sulphamethoxazole solution folrowed by direct injection and subsequent monitoring at 254 nm. Calibration curves were linear between 0.05 and 0.6 mg/mL with quantitative recoveries and precision of leas than 1.1% RSD. Other methods for chromatographically determining a s le nicillin include the determination and monitoring of az oci in during bulk dru synthesis (B26),the determination of benzylpenicillin in %armaceuticalsby ca illary zone electrophoresis (B27), a n i a collaborative AOA stud for determining V in tablets (BB).A method gas appeared for t r : : ; : mination of carbenicillin and ticarcillin in injedables (B29). The method was linear over the ranges 4G130 and 20-90 pg mL, respectively. Other chromato aphic methods publis ed include the simultaneous r e c o k n derivatization of 6-aminopenicillanic acid, benz Genicillin, phenoxymethylpenicillin, penicillin X, penicihn K, benzylpenicillin, and penicilloic acid using 1-hydroxybenzotriazole (B30);the LC se aration with laser based polarimetric detection of benzyy enicillin, ampicillin, carbenicillin, and ticarcillin (B31); an! a study outlining the effect of temperature on the LC separation of amoxycillin, ampicillin, piperacillin, benzylpenicillin, phenoxymethylpenicillin, and cloxacillin (832). Several papers have reported the use of enzyme selective electrodes for determining penicillins ( B 3 3 4 3 6 ) . The first paper investigated the effeds of pH and buffer concentration on the res nse of an enzyme membrane coated wire electrode (B33). T E enzymatic sensor was constructed by coating a silver wire with a membrane consisting of 31% carboxy substituted PVC, 63% 2-nitrooctyl ether, 5.5% tridode lamine, 0.5% sodium tetraphenylborate and membrane mxfication with penicillinase. The authors reported that the optimal pH ran e was 6.5-8.5 and response decreased with increasing b d e r concentration. Penicdlin sensors have also found utility in flow injection analysis (FIA). One techni ue has utilized the enzymatic hydrolysis of penicillin to penicil loic acid. This process results in a H change that is monitored usin a colored acid-base inJcator and bundled fiber optics for etection (B34). Another FIA-enzyme sensor was based on immobilized penicillinase and a glass H electrode for detection (B35). This method reported fnearity between 0.1 and 15 mM with a recision of approximately 1% RSD. The method should finaapplicability for K salts for penicillins in
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PHARMACEUTICALS AND RELATED DRUGS
pharmaceutical preparations. Other methodology involves a potentiometric determinationof benzylpenicillin, ampicillin, and oxacillin (B36) and the iodimetric titrimetric determination of penicillin (B37). Spectrophotometricmethods continue to enjoy popularity for the determinations of a variety of penicillins. The firstderivative mode of operation was found to be simple, accurate, and precise for the determination of am0 cillin and clavulanic Second-derivative acid in pharmaceutical preparations spectroscopy has been applied to uantitation of ampicillin and dicloxacillin (B39)and ampicllin and cloxacillin (B40). Both methods by Morelli are sutable for the analysis of these &lactams in pharmaceutical preparations. Finally, a fourth-derivative spectroscopic approach has been described for the determination of 4-hydroxyphenoxymeth lpenicillin in phenoxymethycillin samples (B41). Since the rast review, several colorimetric procedures have appeared in the literature. These methods describe the use of nitrobenzene for isolation reduction with of benzyl nicillin and pheno nicillin (B42), Cu(I1) forowed b color p r o g t i o n with neocuprine (B43), reaction with F e h with subsequent spectrophotometric determination of the iron-isothiocyanate complex for cloxacillin levels in pharmaceutical preparations (B44),reaction and a FIA meof cloxacillin w t h 2,6-dichloroquinone (W), thod based on reaction of penicillamine with Co(I1) (B46). Finally, a publication recommends that near-infrared reflectance spectroscopy is superior to IR or potentiometric methodology (B47). Chloramphenicol. Since the last review, several articles were published for the quantification of chloramphenicol and isoniazid. T w o reversed-phase methods appeared for the determination of chloramphenicol and analogues (B48,2350). The first paper described a rapid, specific, accurate, and precise method for the determination of chloramphenicol in ophthalmic solutions (B48).This paper reported that the linearity for chloramphenicol was 0.084.13 mg/mL and that the method was a plicable for the determination of chloramphenicol in oprlthalmic preparations on the Canadian market. Another paper has a eared that describes the separation of enantiomeric an iastereomeric derivatized producte of chloramphenicol and thiamphenicol (B49). T w o other spectroscopic methods were ublished for the spectroscopic determination of chloram [enicol (B50)and thiamphenicol (B51).The first methoainvolved the UV spectroscopic determination of chloramphenicol ( B O ) , and the second Results for method was based on PMR s ectroscopy (MI). both methods agreed with piarmacopoeial methodology. Isoniazid. A simple, sensitive, selective, and rapid RP-18 chromatographic procedure has been employed for the quantification of isoniazid and rifampicin in pharmaceutical preparations (B52).The procedure was linear for 0.2-10 p of isoniazid and 0.125-5 rg of rifampicin, and excipients di not interfere. Several Spectroscopic methods a peared for the determination of isoniazid. These methods ave em loyed the following oxidative chromogenic reagents: moly d n u m (VI) (B53), benzoquinone (B541,and 6,7-dichloroquinoline-5,&one (B55).Fluorescence detection was suggested as the basis for the determination of isoniazid after reaction with hydrogen peroxide and FIA analyses (B56) or for h drazine after reaction with 2-hydrox 1-naphthaldehyde (858.Other methods that have been Jicussed in the literature involve the titrimetric determination of isoniazid with Pb(1V) acetate (B58)or with N-bromosuccinimide (B59). Polyenes. A LC rocedure has been ex lored for the deThe termination of lysooelln from fermentation trot, (~60). method consisted of a simple dilution with ethanol, filtration, and separation and quantitation using an ODS column. Monensin and 1.asalocid did not interfere. Another report described the solid-phase isolation of amphotericin in the reaence of other li ids in pharmaceutical pre ations (B61). gourier transformfhman spectroscopy has E n studied as a possible technique to quantify impurities in the presence of nystatin and amphotericins A and B (B62). Quinolones. A variety of methods have appeared since the last review that focus either on the chromatographic, spectroscopic, or electroanalytic determination of quinoline antibiotics. These publications include the spectrosco ic determination of ciprofloxacin (B63),the chromatograpEic determination of norfloxacin (B64-E66), the s ectrophotometric determination of norfloxacin (B67),and tEe adsorptive
(my.
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stri ping voltammetric determination of ofloxacin (B68). $)treptomyoes and Related Analogues. As has been the case for the last several reviews, chromatographic techniques continue to be employed for the selective determination of Streptom ces and related analogues. Reversed-phase chrom a T p i y was investigated as a potential tool for evaluating the c romatogra hic separation of the antimycin A complex (B69).The cite{ report has illustrated that gradient LC is capable of resolving the four major components of the drug into a subset containing eight entities. The separation of theae com nenta was extreme1 dependent upon organic modifiers, b& type, and electro&t.es, which impacted on capacity factors, separation factors, and resolution. Another publication reported on the direct LC/NMR analyses of the antymicin complex (B70).This report also evaluated methylation procedurea and concluded that the antimycin A com lex consisted of at least 10 subcomponents. The use of LC-EC with dual electrodes was the subject of a manuscript describin the quantification of clindamycin and its phosphate anafbgue (B71).The detection limit was found to be 100 p injected on column and compared favorably to ultraviolet jetection. A recent report has investigated the previous observations that concern improved separation and uantification of erythromycin achieved on older reversed-pLe columns (B72).The authors conclude that the increased separation of erythrom cin on reversed-phase packinp was due to an increased s i L o l interaction due to stationary-phase degradation. Several reports were published that describe the chromatographic determination of gentamycin. These reports include the evaluation of column pac and effect of in0 anic ions on the separation of phthalde yde derivatives ( 73), the correlation of LC data with microbiological potency (B74),and the isolation of entamycin C from culture filtratm and broths (B75).The idrentification, characterization, and ultimate uantification of a variet of Streptom ces derivatives in bulk 8rug/fermentation brotL was the sugject of several reports (B76-B78). Thee papers described the preparative separation B (B76)and the identification and quantification Of of eit er rifam icin (B77)or sparsomycin (B78) in fermentation broths. &her direct chromatographic reports recently appearing in the literature include the determination of spiram cm from its neospiramycin analogues (B79)and the use of EC-EC to quantify tobramycin (B80). LC/MS has been utilized to investigate the determination of several antibiotics in this class. The subject of one report investigated the direct liquid introduction of thermally unstable rifampicin antibiotics (B81).The authors found that negative ionization MS produced significant amounts of molecular ions that were proportional to the square of sample concentration. Another report described the separation of DNA adducts formed via the reaction with mitomycin C and porfiiomycin (B82).These adducts were quantifiable in the range 100-300 ng. Thin-layer and most recently electrophoretic separations of antibiotics continue to rovide optimal separation methodologg: Recent reports incide the analysis of aminoglycoside anti iotica (B83),the quantification of the bleom cin complex (B84),and the utilization of TLC for the pH/idntification of erythromycin estolate (B85). Since the last review, a variety of spectroscopic, electroanalytic, and flow injection methods have been applied to the compounds within this subclass. These re rts have included the determination of cycloserine after grivatization with 9-methoxyacridine (B86),the use of the xanthyrol test for a matrix manipulation program applier hromycin (B87), and the a ca le to different matrices for rifam icin (B88), plication of either co per sulfate (j89)or o-phthaldehyie fluomcamhe of dmsyLtion for qt+ifyhg tobramycin (BSO). Electroanalytic techniques continue to find applicability. Carbon paste, vitreous carbon, and com osite graphitepolymer electrodes provided the basis for t t e voltammetric estimation of carminomycin (B91), whereas differential pulse polarography served as the technique of choice for gentamycin (B92).Other reports have described the determination of the use of FIA with water in erythromycin formulations (B93), and the chemiluminescence detection for erythromycin (B94), utilization of fast atom bombardment mass spectroscopy for anthracyclines (B95). Sulfonamides. During the 2-year review period, a variety of new methods have appeared for sulfonamide antibiotics. Chromatographicmethods continue to be the most popular;
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PHARMACEUTICALS AND RELATED DRUGS
biotics was achieved in the presence of common impurities. however, electroanalytic and spectroscopic techni ues still Other chromatographic based methods include the LC-EC enjo popularity for routine use. A reversed-phase8method determination of oxytetrac cline, tetracycline, chlorhas &en shown to be useful for dissolution tes and quality tetracycline, and doxycycline (&15), the TLC determination control of sulfadiazine and tetroxoprim (B96) nother meand the identification and quantifiof tetracyclines (B116), thod involved ion-pairi chromatographyand was applicable cation of tetracyclines on cyano HPTLC plates (BI17). to a variety of dosage7orms of sulfadiazine and tetro rim A recent publication has explored the use of FIA with (B97).This procedure was linear from 0.1 to 200 pg/m for am erometric determination for the analysis of tetracycline both compounds with recisions of approximately 5% RSD. anfoxytetrac cline (B118). Linearity was observed between Acetoacetanilide was kund to be a suitable cou lin for the TLC determination of 12 sulfonamides & 9 8 ! . ~ ~ ~ 2-200 pM andr6-300 pM for the drugs, respectively, and data were in agreement with those obtained by a microbiological procedure involved in situ couplin of the reagent with the method. Adsorptive stripping voltammetry at a hanging H diazonium salts of the sulfa drugs kllowed by normal-phase drop electrode was the basis of a recent procedure re orted separation and detection via iodine va r treatment. Another for oxytetracycline (B119).Other methods reportedr!t tetreported TLC method involves the Etermination of sulfaracyclines include the spectrophotometric determination of methoxazole and trimethoprim using densitometric detection tetracycline by FIA with chemiluminescencedetection (B120), (B99).Two GLC methods have been proposed (BlOO,B10I). the application of derivative spectroscopy for anhydroThe first method involves direct quantification of sulfa. tetrac clines (B121)and oxytetracycline and doxycycline methopyrazine and pyrimethamine on an OV-1 column (BI 123: and the development of colorimetric methods using (B100).Calibration curves were linear for 2.5-20 and 0.125-1.0 the followin oxidative reagents alkaline Cu(I1) (B123), rg/mL for the two compounds, respectively, and the results mol bdate (1124), and tungstate (B125,8126). agreed well with official methods. The other GC method dscellaneous. A variety of methods have appeared since involves quantification of sulfamethazine (BIOI). the last review which include a general review on clofazimine One recent report has described the use of differential pulse (B127),chromatographicmethods for chlor uinadol ( B I B ) , polarography and strip ing voltammetry for the potential ethambutol (B129),diloxanide and tinidazge (B130),micodetermination of sulfatkazole, sulfamidine, sulfamethoxypyrithione (B1321,ticonazole (BI33);electronazole (B131), diazine, sulfamethoxypyridine, and phthazol (B102). The a titrimetric meanal ic methods for bitrofurazone (B134); authors conclude that fast sweep differential pulse olarogtho for pyrimethamine (B135); and spectroscopicmethods raphy was not a plicable for sulfathiazole and p thazol, for fusidate (B136), ketoconazole (B137,B138),nalidixic acid whereas phthazofcould be assayed by using stripping vol(B139), niclosamide (B1402,B141),prima uine (B142-B144), tammetry. Both cited techniques were not applicable to pyrimethamine (B145-B147), aminoquinolones(B148,B149), sulfathiazole in the presence of the other antibiotics. Difclotrimazole (B150),dilozanide and tinidazole (B151), furaferential ulse voltammetry at a vitreous carbon electrode was zolidine (B1521,miconazole and econazole (B153),pyrimep r e s e n J a s a viable technique for the analysis of sulfadiazine thamine and sulfadoxine (B154),and dapsone (B155). in pharmaceutical preparations (BI03). Linearity was achieved over the range 15-60 r M with precisions less than INORGANICS 2.4% RSD. A variety of s ectroscopic procedures have appeared for sulfonamides. Fhese procedures include the use Single Element Analysis. Potassium has been deterof first-derivative s ectroscopy for the determination of mined both fluorometrically ( C I ) and photometrically ((72) sulfacetamide, sulfatimidine, and sulfathiourea (B104)and as 18-crown-6eosin and picrate complexes, respectively. The the application of a Kalman filter for the harmaceutical latter method was used to analyze otassium aspartate and determination of sulfamethoxypyrazine a n t trimetho rim canrenoate, which also have been fetermined by an ion-se(B105).In addition, the following spectroscopicreagentaLve lective electrode method (C3).A rapid aper chromatographic found utility in new methods: sodium tungstate for sulfaprocedure has been described for the Ietection of potassium methoxypyridazine (B106), o-chloranil for sulfadoxine and cyanide in various medical preparations (C4).Methanol exsulfalene (BI07);-benzoquinonefor studying the kinetics of tracted samples are applied to a strip of Whatman No. 3 per, eight sulfa drugs 6108) and metol-periodate for sulfadioxine developed with acetone-water-1.5 % EDTA (8:1l:lrand and sulfalene (B109). visualized using an a ueous mixture of 2-(iodophenyl)-3-(4Tetracyclines. In the current review period, many new nitrophenyl)-5-pheny?tetrazoliumchloride and phenazonium articles describing the determination of tetracycline antibiotics methosulfate. Colorimetric methods have been reported for cobalt (C5), were proposed for routine analysis. The majori of published copper (C6), selenium (C7),and titanium (C8). Two of these chromatographic methods involve either col aborative ininvolved the analysis of vitamin preparations (C5, C7). Advestigations or improvements on standard methods of analditionally, selenium has been determined in nutritional supyses. Reversed-phasechromatography was explored for the plements and yeast preparations by Zeeman-effect graphitedetermination of chlortetracycline in capsules, tablets, ointmenta, and aerosols (B110).Solid dosage forms re uired furnace atomic absorption spectrometry (C9).Results from simple dilution with HCl, ointments were extractel with the latter method have been found to agree well with those hexane in the presence of dilute HCl, and pressurized spray obtained by NAA and spectrofluorometry with a reported day-to-day variation of 4.2%. A combined automated predosage forms were cooled with butanol/solidified carbon concentration-inductively coupled plasma atomic emission dioxide and the volatiles were allowed to evaporate overnight. technique has been used to assay aluminum in calcium gluSe aration quantification was achieved on a Zorbax C8 co umn wit detection at 280 nm. Calibration curves were conate pharmaceuticals (ClO).Optimum results were obtained using a quinolin-8-01cellulose resin in the initial preconcenlinear, and detection limits were less than 0.05% of the label tration step. claim. A collaborative study was conducted to evaluate the applicability of a recent method using polystyrene-divinylTitrimetric methods have been published for antimony ( C l l ) ,gold (ClZ),mercury (C13), and bicarbonate (C14). In benzene stationary phases for the d e t e m t i o n of doxycycline (B111).This study investigated the reproducibility and actwo cases, the end points were determined electrochemicall curacy across 5 laboratories and the utilization of 11different ( C l l , C12)and the remainin colorimetrically (C13,C14). bromide selective electrode %as been fabricated based on a columns and 4 discrete samples. Analysis of variance showed an absence of laboratory bias and laboratoryaple bias when methacrylate membrane and an internal solid contact (C15). com ared to recently published methods. Another similar The electrode was used to measure titrimetrically bromine colla%orative report has appeared that gives reproducibilities levels in biologically active substances following combustion of the sample. at precision levels of less than 0.6% RSD (B112). The Other reported assay rocedures include the quantitation quantification of seven tetrac clines on a C2 column with comparison to a microbiologicalfassay usin Bacillus pumilus of sodium hydrogen sul#te in parenteral samples by flow-injection analysis (C16)and the determination of fluoride in was described in another paper (B113).T t e LC method was found to be more rapid than the microbiological method. The multiple anion containin pharmaceutical preparations via final reported method also utilized a polymeric support for isotachophoresis (C17). n the latter instance, fluoride was quantitated in the presence of citrate, phosphate, sulfate, and the determination of tetracycline, oxytetracycline, chlorsulfite ions at a level of detection of 5 mM. tetracycline, 6-demeth lchlortetracycline, methacycline, and minocycline (~114).eparation of these tetracycline antiMultiple Element Analysis. A review has appeared that
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PHARMACEUTICALS AND RELATED DRUGS
diecussed the analysis of aluminum, calcium, lead, magnesium, and mercury by direct and indirect EDTA titration methods (C18). The use of different metallochromic indicators described in 12 different pharmacopeia5 was considered. Neutron activation analysis has been used to detect the resence of 39 trace metals in dialysis fluid ingredients (C19). !‘he metal concentrations were found to vary from less than 1ng/g to several mg(g in the nine salts examined. Likewise, the trace contamination of heavy metals in other sample has been investigated. Studies have been carried out on b ood sampling devices (C20),antifungal dyes (C211,human albumin solutions (C22),and infusion solutions (C23). Other published works have appeared that considered the analysis of rubidium, sodium, and calcium by ca illary isotachophoresis (C24),the microdetermination of a l h metals gravimetrically (C25),and the influence of the acid selected on the quantitation of halides via argenitimetric titrimetry (C26). Labeled and Miscellaneous Compound Analysis. As has been the general trend in the past, the quality control of technetium-99m products has received the most attention (C27-C36).A compendial monograph has appeared that deals with the radiochemical purity of sodium pertechnetate technetium-99m (C27).High-performanceliquid chromatographic procedures have been developed for the separation of technetium-99m cationic amine complexes (C28),labeled hosphonoacetic acid skeletal imaging agents (C29),and Eexamethylpropyleneamine oxime (C30). Similarly, thin-layer chromatographic (C32-C34),electrophoresis (C35),and membrane filtration (C31)methods have been used to assess the purity of various technetium-99m containing pharmaceuticals. In the latter case, combined olycarbonate and mixed celluloseester disks were used in tEe analysis. Lastly, technetium in molybdenum-99m-technetium-99m generators has been detected down to 3 ng- via a neutron activation anal sis (C36). Tile radiochemical Duritv of reductant-free iodine-123has been evaluated by HPLClwith an octadecyl column and a flow-through NaI (Tl) detector (C37). The liquid chromato aphic results were com ared with those obtained by two direrent TLC procedures; Rowever, good agreement was obtained in only one case. Spectrometric methods have been described for quantitatin6 tin (C38)and diphosphonates (C39) in commercial bone scintigraphy kits, and an anodic-strip ing voltammetric analysis has been developed for assayin tRallium and copper in thallium-201 solutions (C40). Alttou h interferences between T1 and Cu were insignificant, t&le presence of Pb presented a problem.
r””
NITROGEN- AND OXYGEN-CONTAINING COMPOUNDS General. The chemistry and related analytical methoetoposide (02),nifedipine (031, dology for clin uinol (Dl), physosti mineq(b4), razosin hydrochloride (051,and tetracaine hyfrochloride (66)were reviewed in Analytical Profiles of Drug Substances. These cha ters contain a comprehensive treatment of the physical and cRemical properties of the cited compounds as well as analytical methodology, stabilit ,to;icity, and related pharmaceutical data. A minor modiLation to the analytical procedure described in the mono raph on b y using indomethacin sup ositories has been issued (07). this modification,tetter recoveries and analytical precision have been obtained. Gas Chromatography. Several different procedures have been employed prior to the gas chromatographicdetermination of nitrogen- and oxygen-containin pharmaceuticals (08-012).The detection lunita for the &bfockers,oxprenolol, nadolol, and propranolol, have been found to be improved from 8 to 60 times followin conversion to their trimeth lsilane derivatives compared to t e underivatized compounc6 (08). Similar1 derivatization procedures have been used to assay indometgacin in capsules (09)and the Cl2-Cl8benzalkonium chlorides (010).In the first instance, the antiinflammatory was converted to its methyl ester via treatment with diazomethane, and in the latter case, potassium tert-butoxide was the re ent of choice. The gas chromatogra hic separation of thexastereoisomeric (R)-phenylethylamig derivatives of ibuprofen, flurbiprofen, ketoprofen, and related compounds (01 1) as well as that of the heptafluorobutyryl-L-pro1 1 derivatives of racemic amphetamineshave been reported $12).
E
For the first rou of compounds, better resolution was obtained on a SbE 8P-1column compared to that obtained on an OV-1 column. A stability-indicating assay that uses phenacetin as the internal standard has been develo ed to investigate formulations containing dicyclomine hygochloride (013).An average overall recovery of 99.9% and a relative standard deviation of 1.7% were reported for capsules, injectables, and tablets that contained 5-25 mg of the active ingredient. Other GC assa s appearing during the time of the current review includedr the estimation of timolol maleate in ophthalmic solutions (014), the quantitation of diclofenac sodium in tablets (015), and the determination of cresol isomers in antiseptic soap solutions (016). The sensitivity of the surface ionization detector has been measured for a variety of pharmaceuticals and related compounds including lignocaine and clomipramine (017). Coefficients of variation for results were approximately 2.5% at the 0.1-3 bg/mL level. In addition, the influence of methanol as a supercritical fluid mobile-phasemodifier on the resolution of 11 benzodiazepines has been studied (018). Separationswere carried out on three different column types, a prolylst ene polymer support and octadecyl- and cyanobonded pgses. Liquid Chromatography. As has been the general trend for a number of years, liquid chromatography continues to be the preferred technique for the analysis of nitrogen- and oxygen-containing pharmaceuticals. Most of the reported separations have been carried out under reversed-phase conditions on octadecyl-bondedphases (019-061).In several of these, an ion-pairing reagent was added to the mobile phase to improve chromato aphic performance (019-030).In one instance, an a-phenyginnamonitrile quaternary ammonium salt was utilized as a postcolumn fluorescent ion-pair reagent to enhance detection (022).The procedure was applied to the quantitativedetermination of ketoprofen and val roic acid in dosage form. A column switching method was &eloped for derivatized 5-fluorouracil where the final analysis was carried out on an ODS column following initial separation on a phenyl phase (031).Besides ODS columns, octyl-bonded phases (062-072)and silica (073-081)have been the most often used column materials followed by other common phasea such as those containing cyano, phenyl, and amino groups (082-086).Multiple column studies were described in several In one case the rate published accounts (032-034,078,084). of column degradation was examined as a function of mobile-phase composition and brand of the octadecylsilane packing (034).As a result of this study, a stability-indicating assay was developed for atenolol and nitrendipine in the reaence of their degradation products. In two other instances, Fl0th normal- and reversed-phase techniques were used to study dithranol and its degradation products (033)and to analyze spiperone and four of its derivatives (032). There have been several instances where speciality phases have been developed or employed in the harmaceutical analysis of N- and O-containing compounds b87-098). For example, the preparation of an adamantyl-bonded silica has been described, and the resulting material has been used to separate antihistimes and related cough-cold pharmaceuticals (087).Excellent peak symmetry was obtained for strong1 adsorbin solutes without the presence of mobile-phase adr ditives. 4his improvement in erformance was attributed to the spherical sha e of the bonfed adamantyl molecule which effectively shielfs unreacted surface silanols. Similarly, a commercially available short-chain silanol-deactivatedcolumn has been selected to analyze a variety of common basic drugs including the antidepressant drug, amitriptyline, under isocratic eluent conditions (096).Amitriptyline also has been quantitated on a standard octadecyl column with sodium octanesulfonate in the mobile phase (038).Other examples of speciality phases include the use of immobilized albumin to carry out the chiral separation of DL-thyroxine (088)and to estimate the amount of the l-threo impurity in an intermediate of d-threohydroxyacid (092).Likewise, enantiomeric assays have been reported for meto rolol using an a-acid lycoprotein bonded phase (D89),am Retamines on covalently %ound D- henylglycine (0901, a n 8 bextaxolol (091)and celiprolol b93) on cellulose tris-3,5-dimethylphenylcarbamate columns. The dextran ester prodrugs of naproxen have been investigated chromatographically. The separations were ANALYTICAL CHEMISTRY, VOL. 63, NO. 12, JUNE 15, 1991
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PHARMACEUTICALS AND RELATED DRUQS
Table I. Additional References Not Specifically Discussed in Text compound alprazolam 5-aminosalicylate anthraquinone astemizole bacterial collagenase bepridil HCl
method'
ref
RPLC
056 0157 RPLC, TLC 058 053 RPLC I1 RPLC RPLC 024 I2 tert-butyl-4-methoxyhenol RPLC 083 RPLC clenbuterol RPLC 039 clioquinol NPLC 086 dequalinium chloride RPLC 026,030 CA 0154 diphenhydramine RPLC 026 disodium edetate RPLC I3 fentanyl citrate RPLC 061 GC I4 glycerol RPLC I5 glycyrrhizin gallamine triethiodide RPLC 051 RPLC 068 halazepam RPLC 072 halothane 5-hydroxymethyl-2-furaldehyde RPLC 043,047 imazodan RPLC 046 isoetharine hydrochloride CA 0162 isosorbide dinitrate RPLC 041 loperamide hydrochloride NPLC 076 meclozine RPLC 066 6-mercaptopurine CA 0153 metronidazole CA 0152 EA I6 povidone thyroxine sodium CA 0148,0149 tax01 RPLC 084 CA
a CA, colorimetric analysis; ECA, electrochemical analysis; RPLC, NPLC, and TLC, reversed-phase, normal-phase, and thinlayer chromatography, respectively.
carried out on a bonded diol hase in combination with fluorometric detection (094). {he assay was useful in the 2-120 ppm range; however, reported recoveries were not quantitative. Miscellaneous studies of barbiturates (095)and have been carried out respectively using 2-imidazolines (098) ion exchange and alumina column packings. In terms of the various thera eutic areas, analgesics and attention. The antiinflammatones again receivet!considerable compounda studied included acetaminophen (045,063, 073), aspirin (D63),fluribi rofen (054), ibuprofen (022, 075), indomethacin (097), Eeto rofen (022, 064, 074), phenylbutazone (042), propox &ne hydrochloride (063,073), and , Several other related compounds tolmetin sodium (025#5). were investigated in three of the above citations (022,045, 075). In one paper, nine common non-steroidal antiinflammatories were separated on an underivatized silica column using an aqueous mobile phase that contained &lo% acetonitrile (075). High to totally aqueous mobile phases also have been used to separate cough-cold compounds such as dextromethorphan hydrobromide, henyl ropanolamine, seudoephedrine, and triprolidine \ydroc!lorides (087). Eikewise, these or related compounds have been assayed utilizing either an ion-pair (020) or an amine additive (082) in the mobile phase. A compendial monograph has been issued on the antihistamine cyproheptadine hydrochloride (085). Additional important classes of pharmaceuticals that have been studied often are antineoplastic compounds (028,048, 052), benzodiaze ines (050, 060,074, D78), blocking ents (034,D69,070, B77, D89, 091, 093), vasoconstrictingaPb23) and dilating (021,040,044,049,059,067) drugs, prostaglandine (019,037, 057), and tranquilizers (055,062). Other miscellaneous compounds that have been assa ed by using liquid chromatogra hy during the review periodlare listed in Table I. Includefin this table is a short notation of the techniques used and the literature citations where the original information may be found. The optical purity of the 8-blockers, betaxolol, celiprolol, and metoprolol, have been examined respectively in three 136R
ANALYTICAL CHEMISTRY, VOL. 63, NO. 12, JUNE 15, 199 1
different studies (089, 091,093). In the latter instance, the effect of various mobile- hase conditions on enantiomeric resolution was investigated!' Likewise, procedures of assess' the optical purity of a new D-2 dopamine agonist (035)an epinephrine hydrochloride (036)have been published. Chiral reagents were used in both procedures. Two methods have been reported for the determination of tamoxifen and ita , Both of these also related isomer impurities (028048). employed mobile-phase additives to enhance resolution. A comparison has been carried out to evaluate the performance of the hanging mercury drop electrode vs the @"lacy carbon based electrode for the electrochemical detection of cisplatin (052). Better sensitivity was reported for the latter electrode type. Further improvements were obtained with a dual vitreous carbon electrode arranged in parallel fashion. In the caae of di yridamole, a coronary vaeoddator, a rotating disk Pt electrofe system was used to measure the analyte down to a level of 400 pg (044). Electrochemical detection as well as thermos ray MS detection has been utilized to analyze bambuteror hydrochloride (027). The detection of carnitine has been improved via addition of the fluorometric reagent 9-anthryldiazomethane (081). The working range of the standard curve was reported to be 0.02-100 ng with a coefficient of variation of 1.6% for 10-ng sam les. Fluorometric detection also haa been employed in the Betermination of a leukotriene D, antagonist in formulations (065). Stability-indicating assays have been re ortad for atenolol (034, 070), metoclopramide hydrochlorife (071), and physostigmine (029) in the presence of related compounds and Likewise, a reversed-phase degradation produds (034,070). stability-indicating method has been developed for the adrenergic blocker propranolol hydrochloride (D69). The results obtained by the new method were similar to those obtained by using the USP XXI method. Timolol and three of ita degradation roducts (077) as well as pralidoxime chloride (079) have 8,en resolved on dynamically modified silica columns. In the first case, when hexadecyltrimethylammonium bromide was added as the surface modifyin reagent, better chromatographic performance was obwned than with a bonded-phase column. Other miscellaneous assays that were developed include the determination of the coronary vasodilator, amiodarone (059), the bronchodilator, terbutaline sulfate (049), and the vasodilator, pentaerythritol tetranitrate (040). The nasal decongestant, oxymetazoline hydrochloride, was analyzed by ion-pairing reversed-phase chromatography (023). Similarly the vasodilator, buflomedial h drochloride, was quantitated by an ion- airin procedure (d21) as well as non-ion-pairing method (867). $inally, the tranquilizers, lorazepam (0551, diazepam, and oxazepam (062), were studied by reversedphase liquid chromatography. Fourth-derivative spectrophotometry also was used to examine the latter two compounds. Thin-Layer Chromato raphy. Quantitative TLC-UV densitometry has been appf ed to the simultaneous analysis of the active ingredienta in cough-cold mixtures and related compounds ( D S D l O l ) and antiseptic qenta (0102,1030). In the latter citation, benzalkonium chloride was determined in' ita liquid formulations by using both normal-phase and reversed-phase TLC and an ion-pauing reagent. In addition, quantitative TLC-fluorodensitometr has been used to measure several purine drugs (0104). $he separations were carried out on either starch or cellulose plates. A TLC assay has been reported for the determination of @-blockerssuch as acebutolol and atenolol following conversion of the actives to their respective dabs 1derivatives (0105). A compendial report to the monograpc on phentermine hydrochloride has been issued that considers both the thin-layer and infrared analyses of the com ound (0106). Similarly, a comparison between as= resuka for 5-fluorouracil in 5fluorocytosine obtained i y high-performance TLC and fourth-derivative UV s ectrophotometry was carried out (0107). Other publishefaccounta which appeared in the last 2 years include a mathematical treatment of the retention behavior of nine isosorbide esters (0108)and a study of the retention behavior of 2-bromo-2-nitropropae (0109). Spectroscopy (Colorimetric). A variety of colorimetric methode have been developed for analgesics, antipyretics, and antiinflammatories (0110-0122). Multiple procedures have been reported for aspirin (0110, D l l l ) , acetaminophen
7
PHARMACEUTICALS AND RELATED DRUGS
0112-D114), di yrone (0115, 0116), oxyphenbutazone 10114, D122), anfnaproxen (0120,0121). A general colorimetric m y was described based on the formation an ionassociation complex between methylene violet and various antiinflammatones such as ibuprofen, piroxicam, ketoprofen, dichlofenac sodium, and mefanamic and enfenamic acids (0118). Likewise, the last three compounds were quantitated by an alternate spectrophotometric procedure (0119). The local analgesic pentazocine has been measured in powder, tablet, and injectable form following treatment with 3methylbenzothiazolin-2-onehydrazone (Dl17). The vasodilators, nifedipine, isoxsurpine, indolol, and prenylamine, were determined respectively fo lowin treatment with ammonium vanidate, p-aminophenof 4-dimethylaminobenzaldehyde,and chloranilic acid (DlPD126). One of these procedures was used to determine nylidrin and other adrenergic such as noradrenaline (0124). Several adrener ic blockers ave been examined colorimetrically during t i e review period (0127-0130). Propranolol (01270130) and salbutamol(0131,0132,0135) have been studied most often (0127-0129). The latter method, which is based on the formation of an iron com lex, was applied to eight other adrenergic drugs includin agenaline, noradrenaline, and tebutaline. Methods for a i renaline based around oxidation (0134) and formation of a co er complex (0133)also have been suggested. Simiily, acif!ydrolysB followed b reaction of the resulting de radation roduct with s d u m 1,2naphthoquinone-4-subonatehasLen useful for determining acebutolol (0130). Other therapeutic areas studied by colorimetric methods include antihypertensives (0136,0138,antidepressants sedatives and tranquilizers (0138-0141), neurotransmitters (0142,0143),chohsterws (0144,0145),antiemetics (0146, 0147) hormones (0148,0149),muscle relaxants (0150,0151) and a variety of other miscellaneous com unda (0152-0167). Com ounds not s ecificall discussed g l o w in the text are listefalphabetic8ly in Tabe I. Carbidopa and methyldo a have been assayed by formin colored complexes with morydbdatophosphoricacid (01367 and tetrazolium blue (0137). The methods are suitable for dosage form analysis. A molybdenum complex also has been used to analyze 5,7-diiodoquiolin-8-01 in the presence of common excipients and metronidazole (0161). Similarly, metal complexes have been used to quantitate several other nitrogen- and oxy en-containin pharmaceuticals including allopurinol (D156f diodoquin 0 1 5 9 , 01601, do amine hydrochloride (0142), flurazepam hydrochloride (%140), and pralidoxime chloride (0144,0145). In these procedures, Fe and Pd were the cations used most often. An alternate rocedure has been developed for dopamine HC1 which invoyves treatment of the active with thiosemicarbazide (0143). The colored roduct formed has a listed molar absorptivity of 24000. Likewise, highly sensitive methods in the low microgram/milliliter ran e have been reported for baclofen (D150),brox uinoline b l 5 8 ) ,metoclopramideh drochloride (0146,Dllqmephenesin (01511, metformin (d155),mianserin hydrochloride (01651, and diosmine (0163). Spectroscopy (Fluorometric). A sensitive fluorometric assay has been developed for amiloride h drochloride in its pure form and as a formulated product (8167). Excipients and other compounds such as benzthiazide and hydrochlorothiazidedo not interfer. In the case of procaine, &cyclodextrin has been used to enhance its fluorescence,resulting in a highly sensitive method with detection limits in the 2-6 ng/mL range (Dl68). A continuous-flow chemiluminescence technique has been utilized to analyze acetaminophen (0169). Similarly, the chemiluminescence of seven different benzodiazepines has been investigated (0170). Only one of these, lopramlam, gave an adequate emission. The level of detection for loprazolam was approximately 160 ng. Spectmcopy (W).UV derivative procedures have been described for a wide variet of compounds (0171-0180). In most of these, the second-Jrivative spectrum has been used to determine antihistaminesand related cough-cold produds such as clemastine (Dl 711, pseudoephedrine hydrochloride, chlorpheniramine maleate, and dextromethorphan hydrobromide ( 0 172), otassium paiacolsulfonate (D173), naphazoliie, and diptenhydramine hydrochlorides (Dl74). In one account, 23 benzodiazepinea and/or their metabolite were examined by second-derivativespectrometry (0175). From
P
7
the spectra obtained between 260 and 680 nm, 15 out of 19 of the parent compounds could be identified. T w o other UV methods also have been developed for the quantitation of benzodiazepines (0181,0182). The first of these involved an initial conversion of the analyte to its correspondin benzophenoneand addition of a surfactant to enhance resolution for combined mixtures. In one report, both the second-derivativeand first-derivative spectra were used to assay amiodarone hydrochloride in formulations (0176). The UV results were compared with those obtained by HPLC. Other compounds analyzed by derivative spectrometry were triprolidine, pseudoephedrine, and dextromethorphan by a combined second- and fourth-derivative method (Dl 77), tranylcypromine sulfate and trifluoperazine hydrochloride from the first- and fourth-derivative spectra (D178), and ephedrine and na hazoline hydrochlorides via a third-derivative r d u r e 79). The decomposition of aminoealicylic acid [as been investigated by both derivative (0180) and nonderivative (0183,0184) UV techniques. A stability-indicatingmethod for methenamine mandelate in tablets has been developed that utilizes an initial clean-up step on an octyl solid-phase extraction column followed by a hydrolysis ste (0185). A chemical procedure followed by W analysis h a s k n reported for ethacrynic acid (0186). The analyte is converted to its N-acet lcysteine derivative prior to measuring its spectrum absoriance at 244 and 270 nm. Other UV assay procedures that have appeared over the last 2 years involve the simultaneous determination of acetaminophen in combination with codeine phosphate (0187) and with chlorzoxazone (0188). Other topics considered were the influence of acid-base equilibria on the spectra of imidazobenzodiazepine and midazolam (0189)as well as a collaborative study carried out between five laboratories involving the determination of hydralazine hydrochloride in tablets (0190). The pooled mean recovery for synthetic 10- and 100-mg formulations was 101.2%. Spectroscopy (Other). Of the other types of spectrometric techni ues utilized to examine various as ecta of pharmaceutic& nuclear magnetic resonance (NM ) spectrQmetryhas been employed most frequently (0191-0203). 'H measurements have been split about equally between optical purity determinations (0191-0197) and quantitation of the active ingredient in dosage form (0198-2030). The enantiomeric purity of carnitine (0191),carprofen (D192),ketazolam (0193),lofexidine (0194),tranylcypromine sulfate (0195,D l H ) ,and tocainide (0197) has been investigated by NMR. Similarly,methods for the quantitation of carbachol (D198),diclofenac sodium (D199),halo eridol (0200),primidone (2011, tolmetin sodium (02027, and methyldopa (0203)have been develo . In the latter case,fenfluramine, diethylpropion hydroch orides, and triflusal also were measured. Mass s ectrometry (0204-0207) and near-infrared speca l s have ~ been used to examine vmow trometry aspects of pharmaceuticals. Contact len solutions containing benzalkonium chloride have been studied by positive-ion fast atom bombardment (FAB) mass spectrometry (0204). The FAB matrix thioglycerol 'elded intense peaks for the intact cations M - Cl] of the and C14homolo es. Similarly, FAB-M in combination wth laser microprog MS has been used to characterize analogues of cisplatin (0205). A comparison of the two techniques was presented in terms of advantages and limitations. In some cases, the laser techni ue was found to provide more structural information. Ot%er reported research included a study of the decomposition of phenylbutazone (0207),the development of a flow injection technique for acetaminophen which used a combined electrochemical-thermospray MS detection system (0206),and the use of near-infrared spectrometry to quantitate aminodarone in tablets (0209). Electrochemical Analysis. As in the past, ion-selective poly(viny1 chloride) (PVC) electrodes have received the most attention (0210-0212). These have been developed respectively for hydralazine, trazodone hydrochloride, and local anesthetics. Similarly, liquid membrane electrodes have been constructed for naproxen, salicylate, and metoclopramide (021%0215). In the latter case a double-membrane was used that consisted of an internal Bu,N+Br- system and p external ion-pair complex of metoclopramide with sodium tetra-
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ANALYTICAL CHEMISTRY, VOL. 63, NO. 12, JUNE 15, 1991
137R
PHARMACEUTICALS AND RELATED DRUGS
The electrode was Nerstian in the 10-1-10-5 EIhenylborate. range. An amperometric enzyme-amplified receptor assay for
tricyclic antidepressants has been described that measures the competitive binding of the analyte and a glucose-6phosphate dehydrogenase-desipramine conjugate to acetylcholine receptors (0126).Results obtained by this procedure were found to compare favorably with those obtained spectro hotometrically. Other reported electrochemical assays inckde the quantitation of clozapine (0217)and flunitrazepam (0218)by voltammetric measurements. Modified carbon paste electrodes were employed in both cases. The photode radation of calcium antagonists such as nicardipine, nitrefiipine, and nifedipine have been examined to evaluate changes in the drugs' activities (0219).The o-nitro analogues were found to be more stable than the corresponding m-nitro analo ues. The electrochemical behavior of indomethanacin (b220)and acemetacin (0221)also have been investigated in order to optimize the condition used for the differential pulse polarographic determination of these comunds. Similarly, polarographic methods have been reported r r clioquinol (0222),cloxazolam (0223),Isosorbide 5mononitrate (0224),proquazone (0225),loprazolam (0226), and triprolidine (0227). Other miscellaneous electrochemical methodologies have involved typically used potentiometric titrations (0228-0232). The compounds analyzed by this technique were acetaminophen, bromhexine, me henoxalone, 6-mercaptopurine, and verapamil hydrochlorig. Flow Injection Analysis and Miscellaneous Methods. Several procedures have been published for acetaminophen based on flow injection analysis (FIA) (0233-0236). In one instance, the method was useful for other ara- and metasubstituted phenols (0236).Likewise, FIA {as been utilized to measure all0 urinol (0237),nicardi ine (0238),and lovastatin (0239)Por"ations. Additiondy, the disolution rate of felodipine tablets has been evaluated by FIA with a precision similar to that obtained by liquid chromatography (0240). Miscellaneous studies of pharmaceuticals reported in the last 2 years included a kinetic procedure to determine the level of phenol in acetaminophen (0241)and nitroglycerin in ointment (0242)as well as titration methods for quantitating ibu rofen and acetaminophen (02431,metronidazole (0244), antvarious common benzodiaze ines (0245).In the latter study, the dissociation constants ofdiazepam, nitrazepam, and oxazepam were determined in acetonitrile.
STEROIDS General. Since the last review, a variety of methods appeared for the quantification of steroids in pharmaceutical re arations. A recent monograph focuses on steroid analysis e!t harmaceutical industry ( E l ) . Coulometric analyses of anagolic steroids was explored for the determination of anabolic steroids (E2). These investigators focused on the bromo or chloro coulometric detection of the steroids and used methyl orange as an indicator. The authors found that the reaction with bromine proceeded at a slower rate than chlorine, and they recommend that the chloro coulometric procedure be used. Common excipients in formulations did not interfere. A recent harmaco oeial forum report has focused on a monograpg for LC &termination of dexamethasone or dexamethasone elixirs (E3).This report indicates that recoveries of greater than 98.9% were obtainable in the presence of benzoic acid or alkyl hydroxybenzoates, whereas a slight drop in recovery (96.5%) was observed for formulations not containing these additives. Another manuscript has overviewed a variety of hyphenated chromatographictechniques and their application to estimating the impurity profiles of steroidal drugs (E4). The authors have reviewed the applicability of flumecinol anal sis by GC/MS, the determination of 17pethynyl-17a-hyd7roxyimpurities in l7a-ethyn 1-17p-hydroxy steroids, the analysis of hexoestrol or dehyd;oxymestranol using photodiode array detection, and the determination of chiral purity using chiral stationary phases. Chromato raphic. As noted for other drug classes, chromatogra ic techniques continue to be popular for the selective anzsensitive determination of steroids. A recent publication has explored the utility of determining betamethasone for assay and content uniformity assays using
k
5
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ANALYTICAL CHEMISTRY, VOL. 63, NO. 12, JUNE 15, 1991
reversed-phase chromato aph (E5).No interferences were observed, and the pro&me&d was able to recover greater than 98% active with excellent precision. Another reversed-phase method involved an interlaboratory investigation for determining cortisone and dexamethasone in drug substance and dosage forms (E6).The precision of the proposed ,less than 2% for suspensions, method was 0.7% for bulk and less than 2.5% for tab ets. Other chromatogra hic methods include the determination of cyprotene acetate &7), the TLC determination of dehydroepiandrosterone and estradiol (E8),and the determination of conjugated estrogens (E9). The utility of liquid chromato aphy with electrochemical detection was recent1 ex lorerfor the determination of ethinyestradiol in tabLts &IO). This method consisted of a simple dilution and addition of internal standard followed by fitration and direct analysis. Calibration curves were linear between 0.5 and 2 pg/mL with recoveries in the range 98-102%. Another method reported the TLC-scanning densitometric determination of ethinyl steroids (El1). Reversed-phase chromatography with a cyclodextrin mobile phase was utilized for determining the chiral composition of levonor estrel (E12). As little as 0.1% norgestrel could be detectej in levonorgestrel. Other chromatographic methodologies reported since the last review include the LC determination of medroxypr esterone (E13),the determination of con'ugated oestrogens (%4), the determination of selenium in bulk prednisolone (E15),the densitometric determination the microdetermination of cardiac of prednisolone (E16), glycosides (El7), and a LC photolysis-electrochemical determination of spironolactone (EIS). Spectroscopic. Several spectroscopictechniques have been applied to the determination of steroids (E19-E23). They include the direct UV determination of clobetasol (E19),the application of first-derivative spectroscopy for several corticosteroids (E20),the fluorometric determination of prednisone (E21),the spectroscopic estimation of spironolactone (E22), and the colorimetric estimation of stanazol (E23).
9
SULFUR General. This major section is divided into five major sections: general, chromatographic, electroanalytic, s ectroscopic, and miscellaneous. A variety of Analytical Lofile monographs appeared since the last review. These monographs describe the preparation, physical pro erties, determination, metabolism, and stability of the folyowin sulfurcontaining drugs: chlorothiazide ( F I ) ,furosemide &'!& ketotifen (F3),thioridazine and ita HC1 salt (F4),and thiothixene (8'5). In addition, a review article on the determination of chlorpromazine,related impurities, and degradation products was published (Fs).The review cites 44 references, the related impurities, and degradation products in pharmaceutical preparations, and official methods of analysis are defined. Methods described include gravimetric, titrimetric, UV-visible spectrophotometric, chromato raphic, and electroanalytic techniques. A scheme for the isentification, determination, and quality control of enalapril maleate in formulations has also been described (M). The paper has evaluated TLC, TGA, NMR, UV, X-ray diffraction, and chromatogra hic methods. Chromatographic, As has been the t r e n i for the ast reviews, chromatogra hic techniques continue to be a &minant technique for tEe determination of sulfur-containing compounds. Thiolyte has been introduced as a viable precolumn derivatization reagent for the determination of acetylcysteine in harmaceutical preparations (I%). The method consisted of tEe addition of the re ent and dithioerythritol in the presence of penicillamine %),followed by a 2-h incubation period and analyses by C s chromatography with fluorometric determination. The determination of acetylcysteine for seven formulations yielded results over the range of 96-102% of the label claim. Other chromatographic methods appearing in the literature include the determination of azintamide in pharmaceutical preparations (F9) and chlorpropamide in dosage forms (F10). Several papers have appeared in the literature for the selective and quantitative determination of diltiazem (FII-FI3). Two of the methods are based upon LC, whereas the last method involves the GLC determination of the drug in pharmaceuticals. trans-Diltiazem and seven known and several unknown related compounds were separated by using
PHARMACEUTICALS AND RELATED DRUGS
a pBondapak C18column. The minimum detectable amounts for the compounds was less than 0.1% except for an early synthetic intermediate, which approximatea a 2% MQL. This paper has reported that the total amount of related compounds was
