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DOI 10.1007/s10311-004-0096-1
ORIGINAL PAPER
Received: 18 March 2004 / Accepted: 22 November 2004 / Published online: 21 January 2005
Springer-Verlag 2005
Abstract The photolytic decomposition of hydrochlorothiazide in water was investigated. Irradiation of the drug
was performed in pure water and sewage treatment plant
water with a solar simulator and by direct sunlight. Here
we show that three photoproducts were obtained. Two of
them were formed in yields much higher than 10%. An
environmental risk assessment of hydrochlorothiazide
should take into account also these photoproducts in a
complete analytical and ecotoxicological evaluation.
Keywords Hydrochlorothiazide Drug Photodegradation Phototransformation Water
Introduction
The occurrence of pharmaceutical chemicals in natural
waters has been extensively reported and a growing interest is addressed to their ecological impact (Daughton
and Ternes 1999; Halling-Sorensen et al. 1998; Kmmerer
2001). In 2001, the Scientific Committee on Toxicity,
Ecotoxicity and the Environment (CSTEE 2001) has
recommended that attention should also be paid to degradation and reaction products of pharmaceuticals.
Hydrochlorothiazide (6-chloro-3,4-dihydro-2H-1,2,4benzothiadiazine-7-sulfonamide1,1-dioxide) (1a) is a diuretic and antihypertensive and it is supplied as tablets for
oral use. It is a white, or practically white, crystalline
powder, which is slightly soluble in water, but freely
soluble in sodium hydroxide solution. It is well known
M. Brigante
Dipartimento di Scienze della Vita,
II Universit di Napoli,
Via Vivaldi 43, I-81100 Caserta, Italy
M. DellaGreca L. Previtera M. Rubino F. Temussi ())
Dipartimento di Chimica Organica e Biochimica,
Universit Federico II,
Via Cinthia 4, I-80126 Naples, Italy
e-mail: ftemussi@unina.it
Tel.: +39081674471
Fax: +39081674393
196
mation of 2c and a hydrochlorothiazide photodehydrogenation process that leaded to chlorothiazide (3a) and
derivatives 3b, 3c (Fig. 1). The different photoproduct
distribution for hydrochlorothiazide was attributed to the
UV-A lamps employed and the method of product detection and identification. 1b and 2a were the main
products obtained by Ulvi and Tammilehto (1989) when
hydrochlorothiazide was irradiated in ethanolic solution
with a high-pressure mercury lamp. This report describes
the photochemical transformation of hydrochlorothiazide
in water when irradiated by sunlight.
Experimental
Equipment and methods
High-performance liquid chromatography (HPLC) experiments were carried out on an Agilent 1100 HPLC
system equipped with an ultraviolet (UV) detector. Irradiations were performed using a 150-W solar simulator
equipped with a Xenon lamp with a spectral output 200
2,400 nm using a filter to simulate irradiation at the earth
surface (Oriel Instruments). Elemental analysis was performed on a 2400 Series II CHNS/O Analyzer (PerkinElmer). Mass spectra were recorded using a Finnigan
LCQ equipped with an electrospray ionisation (ESI)
probe operating in negative ion mode. The scan range was
802,000 m/z.
Nuclear magnetic resonance (NMR) spectra were
recorded at 500 MHz for [1H] and 125 MHz for [13C] on a
Fourier Transform NMR Varian 500 Unity Inova spectrometer. The carbons multiplicity was evidenced by
distortionless enhancement by polarisation transfer
(DEPT) experiments. The proton couplings were evidenced by 1H1H correlation spectroscopy (COSY) ex-
In a typical procedure a suspension of hydrochlorothiazide (1a) (100 mM) in distilled water was irradiated at
room temperature for 200 h by a 150-W solar simulator.
To follow the irradiation experiment, an aliquot was
withdrawn at various times, concentrated and the residue
dissolved in methanol, and injected in a HPLCUV system. The column used was a RP-18 column (Phenomenex
HYDRO RP-18, 4 m, 250 mm4.5 mm. The column was
eluted with a mixture of A (H2O containing 1% acetic
acid) B (MeOH containing 1% acetic acid) 90:10 (v/v),
detection was at 260 nm and the flow rate was 0.7 ml/min.
Experiments in the same irradiation conditions were
run also in distilled water under argon atmosphere, and in
water of a sewage treatment plant (STP). STP water was
obtained from Mercato S. Severino treatment plant
(Salerno, Italy).
Irradiation of hydrochlorothiazide in distilled water
(preparative scale)
A solution of hydrochlorothiazide (1a) (0.7 mM) in distilled water was irradiated at room temperature for 200 h
by a 150-W solar simulator. The water was evaporated to
dryness. The mixture (100 mg) separated by silica gel
flash column chromatography eluting with hexaneethylic etheracetone 3:3:4, yielded two fractions: A (70 mg)
and B (26 mg). Fraction A contained hydrochlorothiazide
and compound 2a. Compound 2a (29 mg) was separated
from hydrochlorothiazide on a preparative TLC plate
(0.5 mm) eluting with hexaneethylic etheracetone 3:3:4
(TLC: thin layer chromatography). Fraction B was purified from reverse phase (RP)HPLC (for experimental
conditions see above) and compounds 1d (20 mg) and 2d
(2 mg) were obtained.
Spectral data of photoproducts
Compound 2a: ESI-MS: m/z 278 [M-1]. 1H NMR
(CD3OD) d 8.34 (1H, s, H-2), 6.97 (1H, s, H-5). 13C NMR
(CD3OD) d 150.5 (C-4), 137.0 (C-1), 132.1 (C-2), 128.2
(C-6), 123.0 (C-3), 119.2 (C-5).
Compound 1d: Elemental analysis (found: C, 30.28; H,
3.44; N, 15.22; O, 28.70; S, 23.12; calcd: C, 30.24; H,
3.50; N, 15.18; O, 28.78; S, 23.06). ESI-MS: m/z 278 [M1]. 1H NMR (CD3OD) d 7.92 (1H, s, H-8), 6.24 (1H, s, H5), 4.70 (2H, s, H-3). 13C NMR (CD3OD) d 160.0 (C-6),
150.0 (C-40 ), 127.0 (C-8), 120.2 (C-7), 114.6 (C-80 ), 101.9
(C-5), 56.0 (C-3).
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Conclusion
Hydrochlorothiazide was irradiated in biomimetic conditions for 200 h leading to three photoproducts that were
isolated and characterised. Two of them were isolated in
percentage significantly higher than 10%. For an environmental risk assessment of hydrochlorothiazide, further
studies on the distribution of hydrochlorothiazide including its phototransformation products in the aquatic
environment as well as eco-toxicological data are needed.
Acknowledgements This work was supported by MIUR (Ministero
Istruzione Universit e Ricerca) in the frame of PRIN 2002 (Progetto Ricerca Interesse Nazionale). NMR experiments were performed at CIMCF (Centro Interdipartimentale di metodologie
chimico-fisiche) on a Varian 500 Inova spectrometer of Consortium
INCA (Interuniversitario Nazionale Consorzio Ambiente) (Cluster
11-A, Project P0, L.488). The authors wish also to thank Dr. G.
Giacometti.
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