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Encyclopedia of Chromatography, Third Edition

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Nitrofurans: HPLC Analysis

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Mochammad Yuwono, Gunawan Indrayanto
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 Nitrofurans: HPLC Analysis
Mochammad Yuwono
Gunawan Indrayanto
Faculty of Pharmacy, Airlangga University, Surabaya, Indonesia
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INTRODUCTION
Nitrofurans are a class of synthetic, broad-spectrum anti-
biotics which have been widely used in the form of feed
additives for the prophylactic and therapeutic treatment
of infections caused by bacteria and protozoa in food-
producing animals, (e.g., cattle, pigs, poultry, cultured
fish, and shrimps). Nitrofurans have also been used as
animal growth stimulants, as well as for increasing egg
production in layers.[1–3] The most common nitrofurans are
furazolidone, furaltadone, nitrofurantoin, and nitrofura-
zone, which are characterized by the presence of a 5-nitro
group. These drugs are rapidly metabolized by animals
with in vivo half lives of a few hours, generating related
metabolites that are stable during weeks as residues bound
to tissue proteins. The metabolites of furazolidone, fural-
tadone, nitrofurantoin, and nitrofurazone are 3-amino-2-
oxazolidinone (AOZ), 3-amino-5-methylmorpholino-2-
oxazolidinone (AMOZ), 1-aminohydantoin (AH), and
semicarbazide (SC), respectively (Fig. 1).
Furazolidone and its related compounds are used in
human medicine for the treatment of urinary tract infec-
tions and gastrointestinal diseases. In veterinary practice,
the use of nitrofurans can leave drug residues that can be
found as contamination in foods of animal origin and in the
environment. Residues of these drugs can cause serious
health problems for humans, leading to increased drug
resistance of microorganisms. Several reports have indi-
cated that nitrofurans have a mutagenic effect, which has
been observed in fungi, bacteria, and in submammalian
systems. It has also been stated that furazolidone and
AOZ, which is the main metabolite of furazolidone, are
genotoxic and carcinogenic.[1,4] Therefore, nitrofurans
have been banned for food-producing animals by the
European Union, the United States, and some other coun-
tries. The EU Commission Decision of March 13, 2003 has
set minimum required performance limits (MRPLs) at
1 mg/kg for each nitrofuran metabolite.[5]
Numerous analytical methods have been developed for
the analysis of nitrofurans in various samples. These
Natural –
include microbiological,[6] thin-layer chromatography
Open
(TLC),[7,8] and high-performance liquid chromatography
(HPLC) techniques. HPLC is the most widely used techni-
que for determining nitrofurans of food sample origin, such
as shrimps,[9] fish,[10] milk,[11] egg and chicken
Encyclopedia of Chromatography, Third Edition DOI: 10.1081/E-ECHR3-120043024
1586
tissues,[12,13] honey,[14] plasma and urine,[15] and animal
feeds.[16] One difficulty in the analyses of nitrofurans in
biological samples is the complexities of the sample
matrices. In addition, the use of nitrofurans in veterinary
practice results in trace levels of the parent compound in
edible products, due to a rapid metabolism of the com-
pound in the animal. With HPLC techniques, it is possible
to reduce interfering background peaks on chromatograms
and increase specificity. The combination of HPLC separa-
tion and mass spectrometric (MS) detection is a valuable
analytical technique that is increasingly being applied to
identify nitrofuran in complex matrices, because it offers
high sensitivity and selectivity in the analysis of nitrofur-
ans based on its metabolites.
SAMPLE PREPARATION AND HPLC CONDITIONS
Several approaches to sample preparation for nitrofuran
analysis have been reported, including using a single solvent
to extract the analyte(s) from samples, followed by a single or
several clean-up steps. The drugs have been extracted from
samples primarily with acetonitrile, ethyl acetate, or dichlor-
methane. Liquid–liquid extraction using ethyl acetate, fol-
lowed by evaporation and reconstitution in the mobile phase
was reported by Muth et al.[15] for the determination of
nitrofurantoin in plasma and urine. The reported recovery
of nitrofurantoin was 84%–86% over the concentration range
of 0.12–0.24 mg/ml. Hormazabal et al.[17] used acetonitrile
for the extraction of furazolidone in meat tissues. The organic
layer was separated and evaporated to dryness and then
injected into the HPLC system. The recovery was reported
to range from 97 to 100%. Liquid–liquid partition procedures
are frequently applied as a clean-up step prior to solid–liquid
partition using a column or cartridge. Solid phase extraction
(SPE) with C18 cartridges is generally used in clean-up pro-
cedures, where they provide high recovery of the analyte(s).
Degroodt et al.[10] reported a method for simultaneous deter-
mination of the nitrofuran derivatives furazolidone, furalta-
done, nitrofurazone, and chloramphenicol residues in meat
and fish. The samples were extracted with ethyl acetate, then
purified with petroleum ether and n-pentane. The recoveries
were reported in the range of 69–88%. A two-stage SPE
clean-up was used by Cooper et al.[18] for the multi-residue
determination of some veterinary drugs, including nitrofuran
Copyright # 2010 by Taylor & Francis. All rights reserved.
 Nitrofurans: HPLC Analysis
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Fig. 1 Chemical structures of nitrofuran parent drug compounds, the metabolites, and their 2-NBA nitrophenyl derivatives.
derivatives, using C18 and silica cartridges. The proposed
method was applied for screening pig kidney samples,
achieving a limit detection of 2–18 mg/kg at recoveries of
40–70%. A one-step extraction/derivatization, followed by
SPE clean-up using polymeric cartridges, was described by
Edder et al.[9] for the analysis of nitrofuran metabolites in
food. Gel permeation chromatography (GPC) has also been
reported as the clean-up procedure for the determination of
nitrofurans and their cyanometabolites, after liquid–liquid
extraction with acetonitrile.[19]
The separations of nitrofurans have been carried out, in
most instances, with a reversed phase (RP) column. As
summarized in Table 1, C18 columns were selected as the
analytical column for LC in most reports; however, the use
of a C8, CN, and cyanopropyl-modified silica analytical
column has also been described. The parent compounds,
as well as their metabolites, are satisfactorily separated by
C18 columns with commonly used mobile phases, such as
mixtures of acetonitrile with phosphate buffer, acetate buf-
fer, or water. The mobile phase elution for HPLC analysis
can be isocratic or as a gradient system. Acetonitrile-0.1 M
aqueous solution of sodium perchlorate (28:72), with 0.5%
glacial acetic acid, was reported by Galeano Diaz[20] as an
optimum mobile phase for the separation of the three
nitrofuran derivatives: nitrofurantoin, furazolidone, and
furaltadone in milk. Lin et al.[16] used an acetonitrile gra-
dient with an initial hold time of 1 min at 0% acetonitrile,
1587
followed by an increase to 50% acetonitrile over 10 min for
the simultaneous separation of furazolidone, nitrofurazone,
carbadox, olaquindox, and nitrovin in feed.
UV detection and diode-array detection (DAD) have
been widely used, coupled to HPLC, for the analysis of the
parent compounds of nitrofurans. The detection wave-
lengths of nitrofurans have been set at 368 nm,[19]
365 nm,[21] 360 nm,[10,22] 270 nm,[23] or at 254 nm.[24] An
HPLC method, with electrochemical detection, has also
been described for the monitoring of furazolidone and fur-
altadone hydrochloride in chicken tissues and eggs.[11]
Typical HPLC chromatograms and UV-spectra,
obtained by injecting standard mixtures of nitrofurans (fur-
azolidone, furaltadone, nitrofurazone, and nitrofurantoin)
and standard mixtures of nitrofuran metabolites (AOZ,
AMOZ, AH, and SC), are presented in Figs. 2 and 3,
respectively. Fig. 4 shows a typical chromatogram and
UV-spectra of standard mixtures of nitrofuran and its meta-
bolites. Unfortunately, nitrofurantoin and furazolidone, as
seen in Fig. 4, cannot be well separated. The optimization
to separate the peaks at our laboratory is in progress.[25]
Natural –
Open
CONFIRMATION PROCEDURES
As described above, the nitrofurans used in veterinary
practice are quickly metabolized by the animal,
 1588 Nitrofurans: HPLC Analysis

Table 1 High-performance liquid chromatography (HPLC) conditions of the analysis of nitrofurans.

Column Mobile phase Detector Substance Refs.
Nova-Pak C18 MeCN-0.1 M NaClO4 þ 0.5% HOAc ELCD Nitrofurantoin, furazolidone, [11]
(28:72) furaltadone in milk
C18 MeCN–H2O (1 mM NH4OAc þ 1% UV–DAD and MS Nitrofurazone, furazolidone, [13]
HOAc (50:50) furaltadone in egg
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C18 MeCN–HOAc/NaOAc 0.1 M, pH 3.2 UV 360 nm Nitrofurantoin, furazolidone, [20]

(10:90) furaltadone in milk feed formulation
Zorbax CN Buffer 0.01 M NaOAc–MeOH (3:2) UV 365 nm Nitrofuran derivatives in animal [21]
substrates
C18 A: 0.1 M NH4OAc pH. 4.6; UV 360 nm Nitrofurazone, furazolidone, [22]
B: MeCN 100% A to 30% A in 8 min furaltadone in meat and lever poultry
Nova-Pak C18 MeCN–Phosphate buffer UV 254 nm Furazolidone, berberine HCl, [24]
carbenoxolone Na in tablets
Cyanopropyl- MeCN–Acetate buffer, pH 5 (20:30) UV spectrometry Nitrofurans derivatives from milk and [26]
modified silica meat
Luna C18 MeCN-0.05 M NaH2PO4 gradient UV DAD Furazolidone and other antibacterial [27]
elution substances in chicken and swine
C18 MeCN–Buffer pH 4.5 (15:85) UV 230 nm Furazolidone, metronidazole in tablets [28]
Bondapack C18 Water-MeCN-Triethyl amine UV 335 nm Nitrofurazone, furazolidine, [29]
(80:20:0.1) chloramphenicol in muscle, liver and
kidney
C18 Acetate buffer–MeCN (80:20) UV DAD Nitrofurans compounds [30]
C18 MeOH–Water–Buffer pH 3 (40:55:5) UV 350 nm Furazolidone, nefuroxime in dosage [31]
form
C18 5 mM Oxalic acid–MeCN (55:45) UV 265 nm Furazolidone and other antibacterials in [32]
fish
C18 H3PO4–MeCN (30:20) UV 365 and DAD Furazolidone in milk [33]
C18 Phosphate buffer (pH 4.5)- UV 265 nm Nitrofurantoin, nitrofurazone [34]
tetrahydrofuran (97:3)
C18 0.5 mol/L KH2PO4 pH 4.3–4.4- UV 260, 289 nm Salicylic acid, benzoic acid, resorcinol [35]
MeOH (50:50) and nitrofurazone in powder
C18 0.02 M sodium acetate buffer–MeCN 370 nm Nitrofurans, sulfonamides and [36]
(80:20) chloramphenicol in milk
C8 MeCN–H2O–HOAc (3:97:1) 340 nm Furazolidone, nitrofurantoin, carbadox, [37]
olaquindox, morantel in swine muscles

generating protein-bound metabolites that are detectable
for several weeks after administration. Consequently,
methods for the analysis of nitrofuran based on the parent
drugs are inappropriate. Recently, the analysis of nitro-
furan drug residues has been based on the detection of the
protein-bound metabolites of their nitrofuran parents.
Since the protein-bound metabolites cannot be separated
from the tissue protein by liquid–liquid extraction, a
hydrolysis step using aqueous hydrochloric acid is
Natural –
reagent is 2-nitrobenzaldehyde (2-NBA), which forms a
nitrophenyl derivative (Fig. 1).
Particularly, in a residue analysis, identification of
detected analytes is required to confirm a result. For nitro-
furans analysis, there are a few confirmatory methods
reported, including the use of the photodiode-array system
and MS detection. The use of a photodiode array detector
coupled to HPLC (HPLC–DAD) offers advantages that the
target peak can be identified by its retention time and

usually applied in the sample preparation to hydrolyze absorption spectrum. In this case, the continuous spectral
Open

the metabolites from the tissue protein. After hydrolysis, data generated during the analysis are collected to check for
it is also necessary to derivatize the nitrofuran metabo- interfering substances by comparing the spectra of samples
lites, owing to their small molecular weights. For with those of the standards. However, the specificity and the
this purpose, the most commonly used derivatizing limit of detection are not sufficient to determine or identify
 Nitrofurans: HPLC Analysis
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Fig. 2 High-performance liquid chromatography (HPLC) chromatograms (A) and UV-spectra (B) of standard mixtures of nitrofuran parent
drugs nitrofurantoin (1), nitrofurazone (2), furazolidone (3), and furaltadone (4).
trace levels of the nitrofuran metabolites in samples.
Considerable progress has been made recently in the
detection of nitrofuran metabolites by the use of MS tech-
niques[38] and tandem MS, owing to its high sensitivity and
specificity. Draisci et al.[39] presented HPLC–DAD and
HPLC–MS methods for the confirmation of the identities
of nitrofurazone, furazolidone, and furaltadone residues.
The HPLC–DAD limit of detection, based on a signal-to-
noise ratio (S/N) of 3, was estimated to be 2.5 mg/kg for
nitrofurazone and furazolidone and 5.0 mg/kg for furalta-
done, whilst the HPLC–MS limits of detection were
estimated to be 3.2, 1.6, and 1.0 mg/kg for nitrofurazone,
furazolidone, and furaltadone, respectively. Recently,
Leitner et al.[40] described a liquid chromatography-
electrospray ionization tandem mass spectrometry (LC–
ESIMS/MS) procedure for the simultaneous analysis of
four nitrofuran metabolites in animal muscle tissues, at
limit of detection of 0.5–5 ng/g. The bound metabolites are
released from samples by acidic hydrolysis and subse-
quently derivatized using 2-NBA freshly prepared in
DMSO. In this study, SC, as its 4-nitrobenzaldehyde deri-
vative, was used as internal standard. Further sample pre-
paration was improved by the use of SPE, leading to an
effective sample clean-up with recoveries of 92–105%.
1589
Finzi et al.[41] proposed a similar LC–ESIMS/MS method
that allows the simultaneous analysis of the metabolites of
four commonly used nitrofuran drugs (AOZ, AMOZ, AH,
and SC) in poultry muscle and eggs. The procedure involves
an acid-catalyzed release of protein-bound metabolites,
followed by their derivatization as described by Leitner
et al.[40] A single step liquid–liquid extraction was per-
formed for the sample clean-up before LC–MS/MS analysis.
Two deuterated internal standards (AOZ-d4 and AMOZ-d5)
were used during the study to mimic the analyte extraction.
Limits of quantification of 0.5 ng/g were achieved using
electrospray ionization in positive mode in an analytical run
of 5 min. Mottier et al.[42] developed a confirmatory and
quantitative method based on isotope dilution LC–ESIMS/
MS for the determination of four nitrofuran metabolites in
meat, e.g., furazolidone, furaltadone, nitrofurantoin, and
nitrofurazone. Four isotope-labeled internal standards were
used during this study. Liquid–liquid extraction and a poly-
meric SPE were carried out, after acid hydrolysis and deri-
Natural –
vatization into 2-NBA imine type derivatives. The method
Open
was fully validated following the European Union criteria
and applied for monitoring nitrofuran residues in food. The
author reported that the method is robust with decision limits
ranged between 0.11 and 0.21 mg/kg.
 1590
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Fig. 3 High-performance liquid chromatography (HPLC) chromatograms (A) and UV-spectra (B) of standard mixtures of nitrofuran
metabolites AOZ, AMOZ, SC, and AH after derivatization with 2-NBA.
CONCLUSIONS
High-performance liquid chromatography is the method of
choice for the analysis of nitrofuran antibiotics furazoli-
done, furaltadone, nitrofurantoin, and nitrofurazone in
food animal origin. The drugs are characterized by rapid
metabolism, leading to trace levels of parent drugs found in
samples. However, the metabolites (AOZ, AMOZ, AH,
and SC), bound to protein tissues, are toxic and more stable
within several weeks. Therefore, some authors have
recently focused on the detection of protein-bound meta-
bolites for the analysis of nitrofurans. For this purpose,
LC–MS/MS is presently the most modern and promising
method, due to its high sensitivity, reproducibility, and
specificity.
Natural –
ACKNOWLEDGMENTS
Open
The authors wish to thank Prof. Dr. Rainer Ebel and Mr.
Arnulf Diesel (Institute of Pharmaceutical Biology and
Biotechnology, University of Düsseldorf, Germany) for
Nitrofurans: HPLC Analysis
the providing of recent references; DAAD (Deutscher
Akademischer Austauschdienst), Bonn, Germany for the
financial support during our short visit at some German
universities in 2005; Ms. Nur Yanti S.Si, Apt and
Mr. Fadjar Zulkarnaen Lubis (Assessment Service Unit,
Faculty of Pharmacy Airlangga University, Surabaya-
Indonesia) for the valuable technical assistance.
Optimization of HPLC procedures for nitrofurans pre-
sented in this work is financed by the Indonesian
Ministry of Education, DP2M through the research grant
‘‘Penelitian Hibah Bersaing XIV.1/2006.’’
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 Nitrofurans: HPLC Analysis
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