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(J110) Steedman, W. P A C , Trends Anal. Chem. (fers. Ed.) 1988, 7(4), 121-2. (J111) Esteva, 0. R.; Ochoa, D.; Escobar, 0. Rev. Cubana Ouim. 1988, 2(3), 41-53. (J112) Todorovic, M. R. J. Serb. Chem. SOC. 1987, 52(9), 499-514. (J113) Gorelkinskaya, S. I.; Dalmatova, L. V.; Razdorskli, A. I. Khim. Tekhno/. Topl. h4asel 1986, (8), 38-9. (J114) Dale, L. S.;Matulls, C. E. Fuel 1988, 67(5), 733-4. (J115) Kocman. V. Adv. X-Ray Anal. 1987, 30, 243-9. (J116) Kaegler, S.H. Erdoel, Erdgas, Kohle 1988, 704(3), 131-8. (J117) Maruska, H. P.; Rao, B. M. L.; Enard, J. Prepr.-Am. Chem. Soc., Div. Pet. Chem. 1986, 37(3-4), 573-5. ( J l l 8 ) Alder, J. F.; Clegg, 1. M.;Drew, P. K. P. Analyst 1986, 777(7), 781-3. (J119) Zjawiony, I.; Pasciak, J. Nafta (Katowice, Pol.) 1987, 43(1), 22-8. (J120) Pappln, A. J.; Tytko, A. P.; Battle, K. D.; Taylor, N.; Mills, D. G. Fuel 1987, 66(8), 1050-9.
(J121) Malone, G. R.; Skursha, S.K.; Jost, R. M. US. US 4710474 A, 1 Dec 1987, 15 pp. Appi. 897115, 15 Aug 1986. (J122) Pawlak-Tymanska, A.; Stankiewicz, M. Pol. PL 136739 B1, 31 Mar 1987, 2 pp. Appl. 239752, 23 Dec 1982. (J123) Koreeda, R. Jpn. Kokai Tokkyo Koho JP 63/36144 A2 [88/36144], 16 Feb 1988, 5 pp. Appl. 83/177826, 30 Jul 1988. (J124) Altman, L. J.; Milliken, J. B. U S . US 4700562 A, 20 Oct 1987, 4 pp. Appl. 816939, 8 Jan 1986. (J125) Langmaier, J.; Polak, J.; Opekar, F. Analyst 1986, 773(3), 501-3. (J126) Vandenbroucke, M.; Behar, F.; Espitalie, J. Energy Fuels 1988, 2(3), 252-8. (J127) Nunes dos Santos, A. Braz. Pedido PI BR 84 05,986, 17 Jun 1986, 16 pp. Appl. 8415,988, 19 Nov 1984. (J128) Instrumental Methods for a Study of Petroleum (Instrumental’nye Metody Issledovaniys Nefti); Ivanov, G. V., Ed.; Nauka, Sibirskoe Otd.: Novosibirsk, USSR, 136 pp.
Pharmaceuticals and Related Drugs R. K. Gilpin* Department of Chemistry, Kent State University, Kent, Ohio 44242
L. A. Pachla
Warner-LambertlParke-Davis,Pharmaceutical Research, PharmacokineticslDrug Metabolism, Ann Arbor, Michigan 48105
As has been the case in past reviews, the current article represents a survey of pharmaceutical analysis and related methodolo appearing in Analytical Abstracts or Chemical Abstracts g t w e e n November 1986 and October 1988. The article does not deal with biochemical or clinical aspects of the subject but rather covers compounds in unformulated and dosage form. Because of space limitation the article is by no way meant as an exhaustive review and work cited is only a sampling of the total information published. The 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. These sections with the exception of Miscellaneous are divided further into subsections. As in the past to conserve space, a reference generally appears only in a single section.
GENERAL Books and reviews of a comprehensive nature published were Chemical Analysis, Vol. 85: Ultratrace Analysis of Pharmaceuticals and Other Compounds of Interest ( l ) , Modern Analysis of Antibiotics ( Z ) , Practical Protein Chemistry: A Handbook ( 3 ) )Pharmaceuticals and Related Drugs (4), Handbook of Pharmaceutical Excipients (5), Animal Drug Analytical Manual (6), T h e International Pharmacopeia, Vol. 3 Quality Specifications, 3rd ed. (7), and Basic Tests for Pharmaceutical Substances (8). Books that were published which deal with the chromatographic analysis of pharmaceutics include CRC Handbook of Chromatography. Peptides ( 9 ) ,Liquid Chromatography in Pharmaceutical Development: A n Introduction ( I O ) , and Analytical and Chromatographic Techniques in Radiopharmaceutical Chemistry (11). Likewise, a major review of the HPLC analysis of analgesics was written covering both alkaloid and nonalkaloid compounds (12). Other major works which contain information related to the topic being considered are listed elsewhere (13-16). As has been the general trend in past reviews, liquid chromatography continues to be the technique used most *To whom correspondence should
be addressed.
0003-2700/89/0361-191R$06.50/0
often. Three papers have been published that consider either the separation of chiral isomers (17))the biomedical usefulness of combined HPLC-amperometric detection (18), or “Chromatographic Methods in the Federal German Pharmacopeia 9” (19). Other general topics that have been reviewed are trends in techniques used in the analysis of pharmaceuticals (20),NDA analytical methodology (21),and stability testing procedures (22). Lastly, the application of near-infrared reflectance analysis for detecting capsule tampering has been evaluated (23).
ALKALOIDS General. As a major class, the opium alkaloids have been studied most often as has been the general trend in past reviews. Chromatographic techniques continue to be utilized most often for alkaloid analysis. A gas chromatographic method has been described for the separation of the polyhydroxy derivatives of pyrrolidine, piperidine, and indolizidine alkaloids (Al). A number of alkaloids also have been separated under normal-phase liquid chromatographic conditions on polyol-derivatized silica (A21and under reversed-phase conditions on cross-linked cyclodextrin (A3). In the latter case, the resolution of various enantiomers was studied as a function of the size of the cyclodextrin and pH of the mobile phase. The influence of pH and ion-pair formation on droplet counter-current chromatography of alkaloids also has been investigated (A4). Other studies of a general nature include the microdetermination of alkaloids by potentiometric titrations (A5)and spectrophotometric determination of alkaloids by using 2,6-dichlorophenolindophenol(A6). Chinchona. A variety of methods have been used to assay chinchona alkaloids. These include liquid chromatography (A7,A8), flow-injection analysis (A9),isotachophoresis (AIO), spectrophotometric (A11-Al3) and spectrofluorometric (A14) analysis, titrimetry (A15),and atomic absorption spectrometry (A16). In the latter method determination of several cinchona alkaloids including quinine and quinidine were made after first reacting the analytes with Mayer’s reagent and then measuring the Hg present in the complex which formed. Likewise, quinine (A9-All, A13) and quinidine (A8, AlO, A l l , A141 have been assayed by other procedures. In one account,
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quinidine was resolved from its dihydrox and demethoxy derivatives found in cinchona barks by liquid chromatography ( A 8 ) . In another case, a computer program was developed to display contour maps generated from the HPLC separation-UV diode array detection of alkaloids in cinchona bark extracts ( A 7 ) . Ergot. Tablets containing ergonovine maleate and ergotamine tartrate have been assayed respectively by flow-injection analysis ( A 1 3 and liquid chromatography (A18). In the former instance detection was made amperometrically by using a Kel-F-graphite composite electrode and in the latter instance a fluorescence detector was utilized. Both methods reported good coefficients of variations. Opium. Codeine has been determined singularly in dosage forms by reversed-phase liquid chromatography (A19) and kinetically by following changes in its absorbance after treatment with CoS04 and HZOz-ethanediol (A20). The colorimetric procedure is reported to suffer from problems of interferences from diamorphine, morphine, and papaverine. The reactions of chloramine T with codeine, papaverine, and quinine in pharmaceuticals also have been studied (A21). Codeine has been analyzed in the presence of other related alkaloids by RP-LC (A22, A23), thin-layer chromatography (A24),and differential pulse polarography (A25). Likewise, this same compound has been quantitated in combination with propylphenazone and caffeine by liquid chromatography using an octadecyl column (A26) and in combination with ephedrine by isotachophoresis in a 0.3 mm X 20 cm capillary (A27). General procedures for the separation of various opium alkaloids have been described during the review period (A28, A29). In one account, a HPLC method is reported based on the use of a dynamically modified silica stationary phase ( A B ) . With this method it is possible to separate and quantitate opiates ranging in polar from morphine to papaverine. Other methods have been based on the separation of the target compounds by supercritical fluid chromatography using packed columns containing either an aminopropyl-bonded stationary phase or bare silica in combination with COz as the primary mobile phase (A29). Small amounts of various modifiers were added to alter selectivity. The analysis of morphine was obtained by HPLC (A30), flow injection analysis (FIA) (A31),and near-IR reflectance spectrometry (A32). In the latter case, the analyte was determined in powdered samples of the seed heads. The results obtained were compared to those from GC and TLC and found to be in good agreement. Other reported procedures for opium alkaloids included the chromatographic isolation and infrared spectrometric identification of hydrocodone in cough syrups (A33),the determination of noscapine by both TLC (A34) and HPLC (A35),and the analysis of papaverine by colorimetric methods (A36) and by liquid chromatography (A37). Rauwolfia. Reserpine has been assayed in various pharmaceutical formulations by colorimetric means as the picrate complex (A38),by liquid chromatography (A39-A41), and by electrochemical means (A42). Fluorometric detection at 360 nm was used in two of the HPLC methods (A39, A40). Additionally, reserpine also has been determined in Rauwolfia vomitoria root bark by both thin-layer and liquid chromatographic methods (A43). Results obtained using high-performance TLC-densitometric detection with those obtained by HPLC were compared. A fluorometric method has been developed for determining reserpiline, a common contaminant in reserpine and rescinnamine (A44). A detection limit of 0.3 ng jmL was reported. The electrochemical behavior of rescinnamine has been studied and found to undergo a oneelectron reduction followed by a homogeneous reaction (A45). Based on these results a differential pulse procedure was developed. In the last two years an extensive review of the properties of yohimbine as well as methods for its determination have appeared (A46) and a radioimmunoassay for quantitating ajmaline has been described (A47). Tropane. Two procedures have been reported for the separation of enantiomers of tropane alkaloids by HPLC using a P-cyclodextrin bonded phase (A48, A49). Of the tropane alkaloids, atropine has been the one investigated most often. It has been determined singularly (A50, A51) or simultaneously in combination with other compounds such as diphenoxylate HCl (A52), cocaine (A48),philocarpine (A53),scopolamine ( A 4 8 , A53), and homatropine (A48, A.53). Other 192R
ANALYTICAL CHEMISTRY, VOL. 61, NO. 12, JUNE 15, 1989
methods also have been published for homatropine (A54,A53). PVC membrane electrodes have been developed for this compound as well as electrodes for N-butylscopolamine and anisodamine (A55). The electrode membranes were prepared via reacting the alkaloid of interest with sodium tetraphenylborate, dissolving the resulting complex in dibutyl phthalate, and mixing with 5% PVC which is dissolved in THF. Vinca. High-performance liquid chromatography has been used to separate vinblastine and vincristine from other indole alkaloid impurities (A56). Likewise, it has been used for vinblastine, vincristine, vindoline, and catharanthine in extracts of vinca rosea (A57). Xanthine. Two indirect methods have been developed for the determination of caffeine in pharmaceuticals (A58). Both of these involve the formation of the molybdophosphate complex and subsequently its analysis by either a voltammetric or an atomic absorption procedure. Other reported assays for caffeine involve oxidimetric titration (A59) and derivative spectrometric (A60) procedures. The luminescence characteristics of caffeine as well as theophylline have been characterized as a function of pH and the presence of a heavy atom such as iodine (A61). Alternately, theophylline has been quantitated in various dosage forms and combinations by HPLC (A62, A63), potentiometric methods (A64),stoppedflow fluorometry (A65),and TLC (A66). Both liquid chromatographic assays were carried out in the reversed-phase mode with octadecyl columns. By use of these methods theophylline was measured simultaneously with either etofylline (A63) or ephedrine and phenobarbitone (A62). The fluorometric method was based on measuring the kinetics of the reaction of theophylline with Ce(V1). Other xanthine alkaloids investigated were 8-chlorotheophylline (A67, A68) and diprophylline (A69). For the first compound measurements were made electrochemically and for the second compound colorimetrically. Miscellaneous. Pilocarpine has been determined in ophthalmic solutions by normal-phase (A70) and reversedphase (A71) liquid chromatography, thin-layer chromatography (A72), colorimetric analysis (A73), and atomic absorption spectrometry (AAS) (A74). The AAS procedure was based on the measurement of a mercury-pilocarpine complex. Results from the method were in good agreement with those obtained from official procedures. Proposed changes to the USP XXI monograph for pilocarpine have been considered (A75). One of the modification involves changes in the current HPLC assay. High-performance liquid chromatography has been used to resolve Chelidonium majus (A76),C19-diterpenoid ( A 7 3 , Ephedrae herba (A78),Tabernaemontana divaricata (A79), and Senecio vulgaris (A80) alkaloids. In the latter case, the HPLC method and an alternate NMR method were compared. This work was followed up by another NMR study (A81). Other reported uses of liquid chromatography have been its application to study skimmianine (A82),sanguinarine (A83), tetrahydroprotoberberine, corydaline, and tetrahydrojatrorrhizine (A84). For the last three compounds, partial resolution of their epimers was reported using a cellulose tris(pheny1carbamate) stationary phase. Other miscellaneous investigations of alkaloids have included the separation of carbazole and eight related alkaloids by TLC (A85),the identification of tubocurarine by thin-layer chromatography (A86),and the analysis of berberine electrochemically (A87, A88) and spectrofluorometrically (A89). Likewise, veratridine was determined spectrofluorometrically (A901 and catharanthine by a radioimmunoassay procedure (A91). The quantitative sensitivity of the RIA procedure is in the picomole range and as little as 196 fmol can be detected.
ANTIBIOTICS General. This major section includes drugs that are derived from both natural and synthetic sources. In the past many synthetic compounds were included in other sections. These compounds can now be found within this major classification. This section discusses methods for antibacterials, antiinfectives, antifungals, antiparisitics, and antimicrobials. Anticancer drugs are included if they were originally discovered in fermentation broths. Chloramphenicol/Isoniazid /Polyene jQuinolone. A spectrophotometric assay was developed for chloramphenicol
PHARMACEUTICALS AND RELATED DRUGS
t i v i t y and sensitivity were reported when the procedure was compared tu urdinary sput test m e t h d s . A simple and rapid flurrumetric methud was explored for the determination of isoniazid (86). T h e prucedure invulved reaction w i t h 2hydroxy-I-naphthaldehyde a t pH 1.1 w i t h reaction termination occurring at 10 s by the addition of pH 6.0 acetate huffer. T h e fluorescence was monitored at 510 nm and the minimum quantifiable l i m i t was 0.4 ng/mL. A n alternative equilihrium method was also described. A method based un using T L C for the isolation of five cumponents of amphotericin B fullowed hy quantification b y L C served as the basis of a method (87). Cinoxacin has been quantified h y GC after conversion t o its pentafluoruhenzyl derivative (88).A method has appeared for estimating norfluxacin b y titration with HCIO, in anhydrous acetic acid
R a w r K. Gllpin is Prole~sorand Chairman of the Depanment 01 Chemistry at Kent State university. He received his B.S.degree in chemistry from Indiana State Universlry in 1989 and his h.0. degree in analytical chemistry lrom the Universlly 01 Arizona in 1973. From 1973 to 1975 he was employed as Seniw Scientist and from 1975 to 1978 as Ooup Leader 01 Analflical Chemistry in the Research Division of MCNeil LabOTatwieS. In 1978 Dr. Gilpin joined the lacuily of Kent Stale University. Between 1981 and 1983 he also served as a Senior Technical Advisor lw IBM Instrument$. His research interests are in fundamental and applied g s . liquid and thin-layer chromatography. chromatographic. ESR. IR. and NMR studies of chemically mdified surlace~.and pharmaceutical and related analysis. He has numerous publicalionr in the areas of wganometsllic surface reactions. synmesis 01 organmilane and labeled reagents. pharmaCeUtical analysis. the development 01 chemically modified surlaces lor TLC. GC.and HF'LC. physicochemical studies by c h w matographic techniques. elernon Spin resonance. nuclear magnetic resnmce. and infrared investqalianr of immobilized ligands. liquid CryStais and related media. and metal. "C. and wae-line 'H NMR. Or. Gilpin has organized or been involved in several symposia and shon courses in the area 01 chromatographic analyvsls. Likewire, he has held ollices in local chromalog raphy and ACS groups. He is also a member 01 the American Chemical SocieR.. Society 01 Applied S p ~ t r o l ~ ~ American py. Association lor the Advancement of Science. and Sqma Xi, and the Editwial AdViSoq Board 01 the Journal 01 Chromatographic Science Dr. Gilpin served as 1988 Program Chairman 01 FACSS
(nsi).
~ a w r e m eA. ~ a e directs ~ s me activities 01 the Drug Disposnion and Bloanalytlcal Research Seclbn 81 P~lltBDavIsPtmrm~ceutical Research. He received a B.Sc. in chemiswy (1973) hom Lawrence ln~titute01 Technology and a Ph.D. in analyti~sl Chemistry (1978) lrom PurduB university. .C He has been employed as a ReSearCh Chemist (1975-1978) at BioanaWical Systems. Inc.. and as a Research Scientist (1978-1979) and Senior Scientist (1979-1981) a1 MCNeli Pharmaceutical. Whib at ParkB-Davis. he he5 held the positons 01 Senlor Scientist (1981-1982). Research Asroclate (1983-1984). Seniw Research AsSOCiate (1982-1987). and Section Directw (1987-1989) and has lectured at Lawrence Institule of TeChnOlOgy. His reSpOnSibilities at Park% Davis include directing all analytical. pharmacokinetic. and drug metabolism studies lor candidales emanating hom lour therapeutic areas a i d also chairman 01 a drug development team lor an allergy clinical candidate. His research interests lie in me areas 01 robolic% electmanaWical Chemistry. liqua chromatography. pharmacokinetics. and drug metabolism and has published more than 40 manuscripts. He is a100 on the Editorial Advisory Boards 01 Anstyiical Chemistry and AnfimlcrObial Agents and Chemofherspy. Dr. Pachla is SeNing as 1988 and 1989 Aeristant Program Chairman lw the Bioanalytlcai Section of FACSS.
and its succinatP and hase analngues (H1L Reaction hetweeii the alkaline hydrolytic products of the analytes and ammw n i u m molybdate served as the basis fnr the method. T h e effects of temperature, acidity. and reagent concentration on the overall effiriencv of the method were reported A dit'. ferential speclruphotometric method for rhloramphenicol in huth acidic and neutral media appenred and wns applied t o the analysis o i ear drnps tf32i. l'olarographic techniques fiirmed the basis of a method tu quantifv chhir.imphenind nnd p-nitruphenyl-2.amino-I..l-propanedwl in expired samples uf formulated drug IRJJ. In this method. r h l # w a m p h e n dQ X . hihited I wave at p H 2.4 and 4.1 while its degradation p r d t i c t shuwed two wave? at the lower p1i and n cmnpmite wave at pH .1 I T h e extent of degradation was equivalrnt 11, the extent of decrease of the reducti12 h and Beer’s law was obeyed between 10 and 120 pg/mL. Conditions have been evaluated for the mercurimetric determination of penicillins (B33). The method for penicillins involved alkaline hydrolysis followed by potentiometric titration at a platinum electrode with Hg(C104)? Quantitative hydrolysis was achieved within 10 min in 1 M NaOH for azlocillin, mezlocillin, ticarcillin, and piperacillin. The benzathine and procaine salts of benzylpenicillin and benzathine phenoxymethylpenicillin were dissolved in DMF prior to titration in acetate buffer. An acetate-formamide medium was used for the titration of ampicillin, amoxypenicillin, and azlocillin. Relative standard deviations were 72 h and precisions of the methods for dexamethasone acetate drug substance and suspensions were 0.9% and
