Anal. Chem. 1995, 67, 295R-313R
Pharmaceuticals and Related Drugs R. K. Oilpin* Department of Chemistry, Kent State Univetsity,Kent, Ohio 44242
L. A. Pachla Sanofi Winthrop, 3 1 Great Valley Parkway, Malvem, Pennsylvania 19355 Review Contents Alkaloids
Antibiotics Chloramphenicol and Isoniazid Cephalosporins
Penicillins Quinolines Streptomyces and Related Compounds Sulfonamides Tetracyclines Miscellaneous
Inorganics Single and Multiple-ElementAnalysis Labeled Compound Analysis Nitrogen- and Oxygen-Containing Compounds Chromatography
Spectroscopy Electrochemical Analysis Miscellaneous Methods
Proteins and Peptides Steroids Chromatography Spectroscopy
Electrochemical and Miscellaneous Analysis Sulfur Chromatography Spectroscopy Electrochemical Analysis Miscellaneous Vitamins Fat Soluble Water Soluble
Multivitamins Techniques Miscellaneous ~~~
~~
~~
295R 296R 296R 296R 296R 297R 297R 298R 298R 299R 299R 29913 299R 29913 299R 301R 302R 302R 302R 302R 302R 303R 303R 303R 303R 303R 304R 304R 304R 304R 304R 305R 305R 305R
~~
The current review surveys methodology developed to analyze pharmaceuticals and related compounds that appeared in either Analytical Abstracts or ChemicalAbstracts between November 1992 and November 1994. The selected materials represent only a fraction of the published work and do not include biochemical or clinical chemistry investigations. Books and reviews of a comprehensive nature that were published included Analytical Profiles of Drug Substances (1), Pharmaceuticals and Related Drugs (2),Bioanalytical Approaches for Drugs, Including Antiasthmatics and Metabolites (3), Drug Stereochemisty, Analytical Methods and Pharmacology (4, and Quantitative Calculations in Pharmaceutical Practice and Research (5). In addition, drug purity and pharmaceutical and biomedical analysis were the topics of two international meetings (6, 7). Other general subjects considered included chral drugs (3, automation 0003-2700/95/0367-0295$15.50/0 0 1995 American Chemical Society
of flow injection analysis procedures (9) and various aspects of chromatography as they relate to natural, synthetic, and recombinant products (IO, 1 4 , pharmaceutical development (12, 13), and hardware considerations (14,15). ALKALOIDS Chromatographic methods dominate the procedures used to analyze alkaloids (AI-AI9). Of these, reversed-phase methods were employed most often (AI-All) to evaluate a variety of cinchona ( A I ) , opium (AZ-A4), tropane (A5-A7), and vinca (AS) drugs. In one of the studies, both high-performance liquid chromatography (HPLC) and capillary gas chromatography (GC) were used to assay coca leaves and a comparison of the two techniques was made (An. Although the GC method was better for resolving cocaine and related compounds, the HPLC procedure was faster and more convenient. Other reports of a comparative nature included a study of the relative chiral resolving power of al-acid glycoprotein and human serum albumin columns for vinca alkaloids (All) and an evaluation of performance differences between HPLC and micellar electrokinetic capillary chromatography for determining caffeine and its analogs in tablet formulations (A22). Capillary electrophoretic (CE) methods also have been described for analyzing pilocarpine in the presence of its degradation products (A14), the determination of the active ingredients in theophylline tablets (AI@, and the measurement of codeine and related byproducts (AI$. In the latter instance, the CE method was used to assay Kodynal, Ipecarin, Spasmoveralgin, and Alnagon formulations. Other chromatographicmethodologies described during the review period were the GC analysis of pyrrolizidine alkaloids (A13 and TLC assays for protoberberine (A18) and indole (A29) compounds. In each of the latter two procedures, densitometric detection was used. Besides methods based on chromatography, a number of electrochemicaland spectrometric methods have been developed for cinchona (AZO,&'I), ergot W2,A23), opium (AZ4-A28), tropane (A29, A30), and xanthine (A31-A34) alkaloids. These have ranged from electrochemical and sensor procedures for determining %chlorotheophylline,quinidine, quinine hydrochloride, atropine, and scopolamine (AZO,A21, A29, A30, A33) to ultraviolet and colorimetric assays for papaverine hydrochloride (A25-AZ7) and theophylline (A34) to various mass spectrometric (AZZ), nuclear magnetic resonance (AZ3),infrared (A31), and luminescence (A32, A 3 9 methodologies for ergots and dihydroergots, methylxanthine stimulants, and berberine. Besides these procedures, an indirect atomic absorption assay has been developed for papaverine, strychnine, and cocaine (A28) and flow injection analysis PIA) in combination with chemiluminescence (CL) detection has been used to measure morphine in process Analytical Chemistry, Vol. 67, No. 12, June 15, 1995 295R
streams (AZ4). The first method is based on continuous precipitation with Dragendorff reagent, and the second assay is based on the measurement of the CL emission from the reaction of the analyte with potassium permanganate and tetraphosphoric acid. The linearity of both procedures is about 2 orders of magnitude. Finally, a general review of the analytical characteristics of vinblastine sulfate was published that contains 131references and deals with the synthesis, physical properties, stability, and analytical methodology for the compound (A36). ANTIBIOTICS
The antibiotics reviewed in this section are derived from either synthetic or natural sources and include antibacterials, antiiectives, antifungals, antiparisitics, and antimicrobial agents. In addition, anticancer pharmaceuticals are included if they fall into one of the subclasses. Since the last review, two papers of importance general to antibiotic analyses have appeared. One of these (BI),which deals with new column technology as applied to the analysis of antibiotics, discusses the advantages of sterically protected silane stationary phases in terms of enhanced separation reproducibilty and stability obtainable that surpass “fast column” LC techniques. The other paper details the physical, chemical, and analytical methodology for determining sulfathiazole (B2). Chloramphenicol and Isoniazid. Several methods have appeared for the analysis of either chloramphenicol or isoniazid (B3-B8). In the case of chloramphenicol, it has been determined using differential pulse polarography at -0.23 V vs a Ag/AgCl reference (B3). The method has a coefficient of variation of 2.3% with recoveries of ’99%. Additionally, the levels of isoniazid have been measured by flow injection analysis (B4)as well as photometrically using either Azoic Diazo component 36 (Bg,tetrazolium blue (BS),chlorpromazine ( B q ,or Fe(III) -phenanthroline (B8) as colorimetric reagents. Cephalosporins. As has been the trend in the past, chromatographic methods continue to be popular for this class of antibiotics. A multidimensional approach has been reported for determining impurities, degradation products, and formulation excipients in cefaclor and cephalexin (B9). The method involves a combination of gradient elution chromatography with either photodiode array detection or mass spectrometry to provide information on the impurities. Another gradient elution analysis, which is capable of determining 19 process-related impurities and degradation products in cefaclor, has been used to study the stability samples (B10). A variety of investigations have appeared that have been concerned with the analysis of cefadroxil (B11-BI6). In one of these, results from a new chromatographic method were compared with results obtained from a standard microbiological method (B11). Recoveries were greater than 97%with coefficients of variation below 0.7%. Another paper compared the results obtained using the methods described in the European Pharmacopeia and the USP (BIZ). The authors evaluated 18 different CISstationary phases and found that polystyrene-divinylbenzene columns gave elution profiles equivalent to silica-based bonded phases (B13). Other papers that have appeared include a multicenter trial to assess a chromatographic method (B14) and two colorimetric methods (B15, B16). The stability of ceftazidine in plastic syringes has been evaluated using an ultrasphere-0DS column following a simple 296R
Analytical Chemistry, Vol. 67,No. 12, June 15, 1995
aqueous dilution of the samples (B17). The reported recoveries were greater than 98%. Similarly, an LC method has been developed for cephamandole nafate and its hydrolysis product, cephamandole, in isotonic media (B18). No significant drug loss was observed for a 1-h period in PVC infusion bags or after 24 h at 4 “C. Two electrochemical methods have been described for ceftriaxone (B19, B20). One of these was a cathodic stripping voltammetric procedure and the other a differential pulse polarographic procedure. In the latter, the antibiotic can be determined in the presence of cefobid. A size exclusion liquid chromatographic assay has been reported for measuring high molecular weight impurities in ceftiofur (B21)following an initial ultra6ltration of a pH 7 solution of the antibiotic. Responses were linear from 0.005 to 9.25 pg of the high molecular weight impurities with a limit of detection of 0.03%. A reversed-phase method, which is capable of assaying as little as 7.5 pg/mL of cefuroxime in the presence of 16 pg/mL aminophylline and 13pg/mL theophylline has been described (B22). Several different types of assays have appeared for cephalexin (BZ3-BZ5). One of these was a simple specific method for cephalexin that was based on a production of a yellow chromphore via its reaction with acetylacetone-formaldehyde (B23). The chromophore was stable for up to 3 h and is specific for p-lactams. Another method involved degradation of the compound in alkaline media followed by adsorptive stripping voltammetry (BZ4). The latter work focused not only on quantitation but also on understanding the mechanisms of degradation and the electrode reaction processes. The last two assays that appeared were kinetic based and involved either the reaction alkaline Co(III) (B25) or imidazole (BZ6) with cephalexin. An investigation comparing the utility of spectral suppression, absorbance ratioing, and spectral overlay techniques for peak purity testing was the subject of one investigation (B27). Cefotaxime and theophylline were used as the model system. The authors concluded that although absorbance ratioing could be used to detect impurities, it was the least sensitive approach, whereas the other two techniques could detect as little as 0.3%of the impurity. A TLC approach was described for the multicomponent identification of up to 30 cephalosporins (B28). A combination of seven different solvent systems, selective visualization reagents, or both were used. In addition, a dynamic ratebased mathematical model was developed and validated to predict the breakthrough behavior of cephalosporin C on a reversed-phase column (B29). The model accurately predicated this behavior and also was used to evaluate particle size, bed depth, and velocity. Other methods reported include a comparison of LC methodology for cephalothin (B30) and cephradrine (B31),a multilaboratory comparison of a pharmacopeia bulk drug substance assay for cephradrine (B32),and chromatographic method development for cephradrine (B33) and loracarbef (B34). Penicillins. An interlaboratory validation of a LC method for amoxycillin was carried out (B33). Nine laboratories participated in this study which examined bulk drug substance, granule composites, and commercial formulations. The repeatability was -= 1%RSD and the reproducibility across sites was ~( L 6) , 311-318. S . ; Issa, Y.M.; Shoukry, A F.; Abdel-Aal, M. M.Ana1. 355-1065. J. Chromatogr. 1993,640 (1-2), 445-
Multivitamins
(H28) Villamil M. J. F.; Miranda prdieres, A. J.; Costa Garcia, A; Tunon blanco, P. Anal. Cham. Acta 1993,273(1-2), 377382. (H29) Huopalahti, R.; Sunell, J. J. Chromatogr. 1993,636 (l), 133-
Wii, W.; Hu, C.; Zhu, W.; Yao, S.Anal. Lett. 1993,26 ( l l ) , 2371 - - . - -2.183 -- - -. Conder, S.Proc. Int. Symp, Lab Autom. Rob. 1991,116-136. Clarke, G. S.J. Pharm. Bzomed. Anal. 1994,12 (5), 643-652. Ferenczi-Fodor, IC; Ve h, Z.; PapSziklay, Z. J. Planar Chromatogr.-Mod. TLC 1995,6 (3), 198-203.
1.15.
MlSCIELLANEOUS
Hewala, I. I. J. Pharm. Biomed. Anal. 1994,12 (l),73-79. Hewala, I. I. Talanta 1993 40 (6), 919-923. Ramstad, T.; Miller, L. S.;h o m a s , V. N.J. AOAC Int. 1993, 76 (2). 313-319. Deleted in proof. Destacamp, P.; Hos ital,X.; Comelou , S.; Du in, J.-P.;Dosque, J.-P. Pharm. Acta Jelv. 1994,68 (47, 221-f24 Cardeal, 2. L.; Pradeau, D.; Lejeune, B.; Hamon, M. Analysis 1994,22(1 , 23-26. ChernomorsL, S. J. AOAC Int. 1994,77 (3), 756-757. Snell, R. P. J. AOACZnt. 1993,76 (5), 1127-1132. Atkins, P. J.; Chen, N. N. R.; Gorman, W.; Hawkinson, R. W.; Kim, S. I.; Miller, N. C.; Rullo, G. Drug Dev. Ind. Pharm. 1993, 19 (6), 713-727. Cohen, H. P.; Tway, P. C.J. Liq. Chromatogr. 1993,16 (S),
Jegle, U.J. Chromatogr. 1993,652 (2), 495-501. TECHNIQUES
(11) Euro ean Pharmacopoeia Commission. Pharmeuropa 1993,5 (2), l%6-165 fI2] Kirchhoefer, R . D. J. AOAC Int. 1992,75 (3), 577-580. I3 Mazzo, D. J.; Engerer, R.; Egoville, J. J. Pharm. Biomed. Anal. 1993,11 (4-5), 313-321. (14) Lamparter, E.; Lunkenheimer, C. J. Pharm. Biomed. Anal. 1992,10 (10-12), 727-733. (15) Fabre, H.; Fell, A. F. J. Liq. Chromatogr. 1992,15 (17), 3031?OA?
---. ---_.
W ~ ~ o l o w s kM. i , Thermochim. Acta 1992 209,223-251. Barnes, A.F.; Hardy, M. J.; Lever, T. J.J. h e m Anal. 1993, 40 (2), 499-509. Altria, K. D. LC-GC Int. 1993,6 (10) 616-620. Ibrahim, H. Microchem. J. 1991,44 (2), 99-104. Ber lund, R. A; Graham, P. B.; Miller, R S.Spectroscopy 1993, 8 31-32, 34-36, 38 Plu ge, W.; Van der Vies, C. J. Pharm. Biomed. Anal. 1992, 10 $10-12), 797-803. Dem ster, M. A; Jones, J. A; Last, I. R; MacDonald, B. F.; Prebgle, K. A. J. Pharm. Biomed. Anal. 1993,11 (11-12), 1n87- 1092. 013) MacDo
