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Degradation of Aqueous Pharmaceuticals by

Ozonation and Advanced Oxidation Processes: A
Review

Keisuke Ikehata , Naeimeh Jodeiri Naghashkar & Mohamed Gamal El-Din

To cite this article: Keisuke Ikehata , Naeimeh Jodeiri Naghashkar & Mohamed Gamal
El-Din (2006) Degradation of Aqueous Pharmaceuticals by Ozonation and Advanced
Oxidation Processes: A Review, Ozone: Science and Engineering, 28:6, 353-414, DOI:
10.1080/01919510600985937

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Ozone: Science and Engineering, 28: 353–414
Copyright # 2006 International Ozone Association
ISSN: 0191-9512 print / 1547–6545 online
DOI: 10.1080/01919510600985937
Degradation of Aqueous Pharmaceuticals by Ozonation
and Advanced Oxidation Processes: A Review
Keisuke Ikehata, Naeimeh Jodeiri Naghashkar, and Mohamed Gamal El-Din
Department of Civil and Environmental Engineering, CNRL Natural Resources Engineering Facility, University of Alberta,
Edmonton, Alberta, Canada
A vast number of pharmaceuticals have been detected in
surface water and drinking water around the world, which
indicates their ineffective removal from water and waste-
water using conventional treatment technologies. Concerns
have been raised over the potential adverse effects of phar-
maceuticals on public health and aquatic environment.
Among the different treatment options, ozonation and
advanced oxidation processes are likely promising for effi-
cient degradation of pharmaceuticals in water and waste-
water. Recent progress of advanced oxidation of aqueous
pharmaceuticals is reviewed in this paper. The pharmaceu-
ticals and non-therapeutic medical agent of interest include
antibiotics, anticonvulsants, antipyretics, beta-blockers,
cytostatic drugs, H2 antagonists, estrogenic hormone and
contraceptives, blood lipid regulators, and X-ray contrast
media.
Keywords Ozone, Advanced Oxidation Processes, Antibiotic,
Antipyretic, Anticonvulsants, Blood Lipid Regula-
tor, Beta-blocker, Cytostatic Drug, X-Ray Contrast
Media, Estrogens
INTRODUCTION
A large amount of numerous prescription and non-
prescription drugs of different classes are consumed
annually throughout the world. These pharmaceutical
compounds include antipyretics, analgesics, blood lipid
regulators, antibiotics, antidepressants, chemotherapy
agents, and contraceptive drugs. After the administration,
these compounds are partially metabolized and excreted
Received 03/28/2006; Accepted 06/05/2006
Address correspondence to Mohamed Gamal El-Din, Dept. of
Civil and Environmental Engineering, 3-093 Markin/CNRL
Natural Resources Engineering Facility, University of Alberta,
Edmonton, Alberta T6G 2W2, Canada. E-mail: mgamalel-din@
ualberta.ca
Ozonation and Advanced Oxidation of Pharmaceuticals
in the urine and feces, and subsequently enter into sewage
treatment plants where these compounds are treated,
along with other organic and inorganic constituents in
wastewater. However, it has been shown that some of
these pharmaceutical compounds are not completely
removed in sewage treatment plants (Halling-Sørensen
et al., 1998; Ternes, 1998; Ternes et al., 1999; Heberer,
2002; Boyd et al., 2003). As a result, they have been found
in some sewage treatment plant effluents as well as in
surface water and groundwater in many countries
(Ternes, 1998; Sacher et al., 2001; Soulet et al., 2002;
Miao et al., 2004). In addition, non-therapeutic medical
agents such as X-ray contrast agents (also known as
radiocontrasts) and some veterinary drugs have been
also found in the aquatic environment (Ternes and
Hirsch, 2000; Drewes et al., 2001; Kümmerer, 2001).
Although some of these pharmaceuticals and their meta-
bolites can be partially removed through sorption and
biotic or abiotic degradation in the environment, they
can eventually reach drinking water sources. Several
recent studies have revealed that conventional water
treatment processes cannot remove some prescription
and non-prescription drugs completely from source
waters (Ternes et al., 2002; Stackelberg et al., 2004;
Jones et al., 2005a).
The frequent occurrence of pharmaceuticals in the
aquatic environment as well as in finished drinking
water has raised a concern about their potential impact
on environmental and public health. Some of the adverse
effects caused by pharmaceutical pollution include aqua-
tic toxicity, resistant development in pathogenic bacteria,
genotoxicity, and endocrine disruption (Arcand-Hoy
et al., 1998; Halling-Sørensen et al., 1998; Sumpter,
1998; Kümmerer, 2004). The presence of trace pharma-
ceutical and other xenobiotic compounds in finished
drinking water is another public health concern, since
little is known about potential chronic health effects
December 2006 353
associated with long term ingestion of mixtures of these
compounds through drinking water (Kümmerer, 2001;
Stackelberg et al., 2004). Thus, it is an emerging issue in
environmental science and engineering to achieve effec-
tive removal of pharmaceutical compounds, along with
other priority pollutants, from the sources such as hospi-
tal and domestic wastewaters before their discharge.
As conventional water and wastewater treatment pro-
cesses are unable to act as a reliable barrier toward some
of recalcitrant pharmaceuticals, it is necessary to intro-
duce additional advanced treatment technologies in the
areas where a persistent pollution problem has been
recognized or is anticipated. Various advanced treatment
technologies have been evaluated for this purpose in
recent years, including chemical oxidation using ozone
and ozone/hydrogen peroxide (Zwiener and Frimmel,
2000; Ternes et al., 2002), membrane filtration such as
nanofiltration and reverse osmosis (Hartig et al., 2001;
Heberer et al., 2002; Nghiem et al., 2004; Nghiem et al.,
2005), and activated carbon adsorption (Hartig et al.,
2001; Ternes et al., 2002).
The latter two processes are highly energy and material
intensive (Larsen et al., 2004) and only suitable for the
treatment of relatively clean surface water and ground-
water with less background contamination such as natural
organic matter (NOM). These physical treatment processes
also require the disposal of wastes such as membrane
retentate and spent activated carbon generated during
the treatment. In addition, activated carbon adsorption
has a limited ability to remove polar organic compounds
due to its removal mechanism (i.e., hydrophobic inter-
actions), especially in the presence of competitive NOM
(Snyder et al., 2003), and many pharmaceutical com-
pounds and metabolites are indeed polar substances. On
the other hand, chemical oxidation such as ozonation and
advanced oxidation processes (AOPs) may be a more
appropriate treatment option for pharmaceutical com-
pounds in wastewater as well as in surface water and
groundwater.
In this review, recent literature concerning ozonation
and advanced oxidation treatment of a number of phar-
maceutical compounds in aqueous medium are reviewed
and discussed in terms of the degree of reaction (i.e.,
degradation), reaction kinetics, identity and characteris-
tics of oxidation by-products, and possible degradation
pathways. Nine major classes of pharmaceuticals listed in
Table 1 are covered, including antibiotics, anticonvul-
sants and antidepressants, antipyretics and non-steroidal
anti-inflammatory drugs, beta-blockers, cytostatic drugs,
histamin H2-receptor antagonists, hormones and oral
contraceptives, lipid regulators, and X-ray contrast
media. A brief review of pharmaceuticals and its metabo-
lism, their occurrence and fate in the environment, and
their potential impact on environmental and public health
is provided in the following section as well. Please also
refer to the comprehensive surveys published elsewhere
354 K. Ikehata et al.
for details of these issues (Halling-Sørensen et al., 1998;
Kümmerer, 2001; Heberer, 2002; Snyder et al., 2003;
Debska et al., 2004).
BACKGROUND
Pharmaceuticals and Their Metabolites
Pharmaceuticals, or medical drugs, are a group of
chemical substances that have medicinal properties.
These substances include both inorganic and organic
compounds, although most of the modern pharmaceuti-
cals are small organic compounds with a molecular
weight below 500 Daltons (Lipinski et al., 1997). These
chemicals are moderately water soluble as well as lipo-
philic to be bioavailable and biologically active.
Pharmaceuticals are either administered topically (e.g.,
inhalation and skin application), internally (e.g., oral
administration), or parenterally (e.g., injections and infu-
sions) in households or healthcare facilities such as hos-
pitals and clinics. After the administration, drug
molecules are absorbed, distributed, metabolized, and
finally excreted from the body. To be used safely most
of the modern pharmaceuticals are designed in a way to
undergo metabolism in organs such as liver and kidney
after they have achieved desired pharmacological effects.
Metabolisms detoxify excess drug molecules, as well as
other toxic xenobiotics, via a series of enzymatic biotrans-
formations and convert them to be more polar and
hydrophilic (Silverman, 1992). The drug metabolism
begins with various biochemical reactions including
hydroxylation, epoxidation, reduction, and hydrolysis,
in which functional groups are introduced or unmasked
(phase I transformation). Afterwards, highly polar endo-
genous molecules such as glucuronic acid, sulfate, and
amino acids are attached to drugs or metabolites of
phase I transformation to generate conjugates (phase II
transformation) that are water-soluble and can be readily
excreted in the urine or bile. There are certain drugs, non-
therapeutic medical agents, and xenobiotics that are non-
metabolizable because they are poor substrates for meta-
bolizing enzymes such as cytochrome P-450. These com-
pounds may be eliminated slowly from the body without
biotransformation.
Occurrence and Fate of Pharmaceuticals in the
Environment
Until recently pharmaceutical compounds in the envir-
onment have drawn very little attention. Although their
presence in sewage treatment plant effluents was reported
(Richardson and Bowron, 1985), it had been anticipated
that these compounds were easily biodegradable in
environment as most of them could be metabolized and
transformed to some extent in humans, as discussed
before (Kümmerer, 2001; Debska et al., 2004). However,
a large number of recent studies have demonstrated
persistence of these pharmaceuticals in the aquatic
December 2006
TABLE 1. Pharmaceuticals Reviewed
Class Sub-class
b-Lactam
Macrolide
Antibiotic Quinolone
Sulfonamide
Other
Anticonvulsant
and antidepressant
Antipyretic and NSAID*
b-blocker
Alkylating agent
Cytostatic drug Anthracycline
Anti-metabolite
Histamine H2-receptor
antagonist
Hormone and oral
contraceptive
Lipid regulator
X-ray contrast medium
Note: * non-steroidal anti-inflammatory drug.
environment. The occurrence of several pharmaceutical
compounds have been reported in sewage treatment plant
effluents as well as in surface waters in Germany (Ternes,
1998; Hirsch et al., 1999; Putschew et al., 2000), the
Netherlands (Belfroid et al., 1999), Switzerland (Soulet
et al., 2002), Canada (Ternes et al., 1999; Miao et al.,
2004), Brazil (Ternes et al., 1999), Italy (Castiglioni et al.,
2004), Spain (Rodrı́guez et al., 2003), and the United
States (Drewes et al., 2001; Kolpin et al., 2002). The
detected compounds included antibiotics, anticonvul-
sants, painkillers, cytostatic drugs, hormones, lipid regu-
lators, beta-blockers, antihistamines, and X-ray contrast
media. The concentrations of these pharmaceuticals were
in the range of ng/L to mg/L in sewage treatment plant
effluents and surface water. In addition, a number of
polar pharmaceutical compounds and metabolites, such
as diclofenac, carbamazepine, sulfamethoxazole, and
amidotrizoic acid, have been detected in groundwater
samples at concentrations up to 1 mg/L (Sacher et al.,
2001; Cahill et al., 2004; Clara et al., 2004).
There are several possible sources and routes for the
occurrence of pharmaceutical compounds in the aquatic
environment (Figure 1). For human pharmaceuticals,
non-prescription drugs and some prescription drugs are
consumed in households, and other prescription drugs are
consumed in healthcare facilities such as hospitals and
Ozonation and Advanced Oxidation of Pharmaceuticals
Pharmaceuticals covered
Amoxicillin, cefradine, ceftriaxone, penicillin, penicillin G,
penicillin VK, sultamicillin, MMTD, MMTD-Me
Azithromycin, clarithromycin, erythromycin,
roxithromycin, lincomycin
Ofloxacin, enrofloxacin
Sulfachlorpyridazine, sulfadiazine, sulfadimethoxine,
sulfamerazine, sulfamethazine, sulfamethizole, sulfamethoxazole,
sulfamoxole, sulfasulfapyridine, sulfathiazole, sulfisoxazole
Carbadox, spectinomycin, tetracycline, trimethoprim
Buspirone, carbamazepine, diazepam, primidone
Diclofenac, ibuprofen, indomethacin, naproxen, paracetamol,
salicylic acid
Atenolol, celiprolol, metoprolol, propranolol, sotalol
Cyclophophamide, ifosfamide, melphalan
Aclarubicin, daunorubicin, doxorubicin, epirubicin, idarubicin,
pirarubicin
Azathioprine, cytarabine, 5-fluorouracil, methotrexate
Cimetidine, ranitidine
17b-Estradiol, estrone, 17a-ethinylestradiol, diethylstilbestrol
Bezafibrate, clofibric acid, fenofibric acid, gemfibrozil
Diatrizoate, iomeprol, iopamidol, iopentol, iopromide
clinics. These drugs are partially metabolized and
excreted in the urine and feces and go into a wastewater
collection system (Heberer, 2002; Jones et al., 2005b).
Some unused, surplus, or expired drugs may be disposed
into toilets, although this kind of practice is not recom-
mended nowadays. Wastewater from the hospitals may
be treated separately or combined with municipal waste-
water and then treated at sewage treatment plants.
Some of the pharmaceuticals and (human) metabolites
in wastewater are degraded completely or partially, giving
rise to a mixture of parent compounds and a variety of
microbial metabolites (Ternes, 1998; Drewes et al., 2001;
Miao et al., 2002; Soulet et al., 2002; Jones et al., 2005b).
Some pharmaceuticals such as ibuprofen and bezafibrate
are relatively biodegradable, while others such as carba-
mazepine and diazepam are practically non-biodegradable
(Larsen et al., 2004). It is also known that some drug
conjugates such as glucoronides can be cleaved by micro-
bial degradation resulting in a release of parent com-
pounds (Heberer, 2002; Jones et al., 2005b). Effluent
from sewage treatment plants may be released to surface
water or be subjected to groundwater recharges, so that
the mixture of compounds enters the aquatic environment.
In some cases, biologically treated municipal wastewater
may be treated further to produce various reclaimed
waters for different purposes including portable re-use.
December 2006 355
 FIGURE 1. Routes of pharmaceutical contamination of the aquatic environment.
Sorption can also occur during the sewage treatment
processes and some of the pollutants can be transferred to
sewage sludge (Larsen et al., 2004). Sewage sludge may be
subjected to anaerobic or aerobic digestion, conditioning
and dewatering, and is subsequently landfilled, inciner-
ated, or applied to lands as a biosolid. Pharmaceutical
compounds in the sludge can be degraded further during
the digestion, although some of them may remain intact.
These compounds can be seeped into groundwater aqui-
fers or be flushed by surface water runoff after the land
application and can cause additional contamination pro-
blems in the aquatic environment. Therefore, the sorption
of pharmaceuticals during sewage treatment processes
cannot be counted as a removal process unless the sludge
was incinerated (Larsen et al., 2004).
In addition to the drugs and medical agents for human
use, a large amount of pharmaceutical compounds, espe-
cially antibiotics, are used for various agricultural pur-
poses, such as veterinary therapeutics, growth promotion
of livestock, and feed additives in fish farms (Halling-
Sørensen et al., 1998). As shown in Figure 1, these phar-
maceuticals can enter into the aquatic environment
directly (feed additives for fish) or indirectly through live-
stock manure (growth promoters and therapeutics). Land
356 K. Ikehata et al.
application of livestock manure is often practiced and
may cause contamination problems in surface water and
groundwater similar to the case of municipal sewage
sludge disposals described above. Additional sources of
pharmaceuticals in the aquatic environment include was-
tewater from pharmaceutical production/formulation
plants and waste disposal of unused drugs as a solid
waste.
ENVIRONMENTAL AND PUBLIC HEALTH IMPACTS
OF PHARMACEUTICALS IN THE ENVIRONMENT
After publication of the earlier occurrence data, the
risks associated with pharmaceutical contamination of
the aquatic environment have become a major issue of
concern for environmental scientists and engineers, as
well as among the public. Drugs are the chemicals that
are designed to give a certain therapeutic (= biological)
effect; therefore, certain environmental and public health
risks can be anticipated from the exposure to the envir-
onmental pharmaceuticals. Besides, there are a few
classes of pharmaceuticals that pose unambiguous
impacts on the aquatic organisms, including microorgan-
isms, phytoplankton, plants, crustaceans, fish, and
December 2006
insects, as well as on soil microorganisms and possibly
humans (Halling-Sørensen et al., 1998; Sumpter, 1998;
Kümmerer, 2001, 2004). These pharmaceutical classes
include:
 Cytostatic agents, immunosuppressive drugs,
and some genotoxic antibiotics because of
their evident cytotoxic, carcinogenic, muta-
genic, and/or embryotoxic properties;
 Human and veterinary antibiotics because of
their pronounced microbial toxicity and the
development of antibiotics resistance in envir-
onmental bacteria including human pathogens;
 Natural and synthetic hormones because of
their high efficiency, low effect thresholds and
potential for endocrine disruption;
 Halogenated compounds such as iodinated X-
ray contrast media because of their resistance
toward biodegradation and their mobility and
persistence in the environment and the food
web;
 Heavy-metal containing drugs and non-thera-
peutic medical agents because of the toxicity of
the metals in certain oxidation states.
In addition, the presence of other types of pharmaceu-
ticals, such as analgesics and anticonvulsants, in drinking
water is a potential public health issue. Although the
concentrations found in finished water is generally very
low, it is apparent that drinking water consumption is the
major route of human exposure to the environmental
pharmaceuticals (Figure 1). Since the long-term health
effects are still largely unknown for the exposure to the
trace pharmaceuticals and their metabolites, especially as
a mixture of biologically active compounds, the existence
of these compounds in drinking water should be avoided
on the basis of precautionary principle (Snyder et al.,
2003; Jones et al., 2005a). Similarly, long-term exposure
of aquatic organisms to trace pharmaceuticals in surface
water may have some as-yet-known ecological impacts.
Control Measures for Pharmaceutical Contamina-
tions in The Aquatic Environment
As shown in Figure 1, there are several routes of
pharmaceutical contamination of the environment. This
implies that a number of opportunities exist to control the
pollution problems. However, as suggested by several
groups of researchers (Larsen et al., 2004; Jones et al.,
2005b), the conventional end-of-pipe approach can be
very costly and may not be a feasible option, and it is
highly desired to treat and remove those potentially
hazardous pharmaceutical compounds in wastewater
and solid waste properly and as close as their primary
sources. In the view of the aquatic environment, waste-
water treatment is considered as the key step, at least to
keep out human pharmaceuticals. Because current sys-
tems cannot remove some of pharmaceuticals effectively,
Ozonation and Advanced Oxidation of Pharmaceuticals
some improvement and modification will be necessary to
account for this problem (Jones et al., 2005b). For exam-
ple, increasing solids retention time in biological treat-
ment processes will facilitate the development of
population of slower growing bacteria and may enable
them to be acclimated to the recalcitrant compounds.
Application of the advanced treatment technologies is
another option. Those advanced technologies include
membrane filtration (reverse osmosis and nanofiltration),
activated carbon adsorption, ozonation, and AOPs
(Petrovic et al., 2003). Although they are effective, nearly
all of these advanced technologies are energy and/or
material intensive to be applied to wastewater treatment,
especially membrane processes and activated carbon
adsorption. Introduction of ozonation or AOPs before
or after biological treatment process may be feasible
because the chemical/photochemical oxidation renders
recalcitrant xenobiotics more biodegradable and less
toxic and improves their degradation in the following
treatment process or in the environment (Alvares et al.,
2001).
Potable water treatment is the last line of defense
toward the contamination of water for human consump-
tion. Therefore, it is still necessary to ensure that finished
drinking water is free from any potentially hazardous
substances, including trace pharmaceuticals, to humans.
This is particularly important in such areas where: (1)
conventional drinking water sources are scarce and recla-
mation of wastewater is required to supplement the water
sources; (2) municipal sewage treatment facilities do not
provide effective removal of potentially toxic pharmaceu-
ticals; and (3) major pollution sources such as sewage
treatment plants, farmlands, and pharmaceuticals manu-
facturing/formulation plants, are located nearby. The
individual or a combination of advanced treatment tech-
nologies mentioned above can be applied to drinking
water treatment as well.
In addition, source separation is also an important
management strategy to alleviate the problem of pharma-
ceutical pollution of the environment. Some of the phar-
maceuticals are not usually consumed in households, but
mainly in healthcare facilities. Those compounds include
cytostatic agents, immunosuppressive drugs, some anti-
biotics, and contrast media. On the other hand, some
antibiotics, hormones, and many other prescription and
non-prescription drugs are widely consumed in the house-
holds. Separated treatment of highly contaminated and
potentially more toxic hospital wastewater is probably
desired. Separating human urine from the rest of domes-
tic wastewater is also considered as an attractive option
for improving the water pollution control with respect to
nutrients and micropollutants, including pharmaceuticals
(Larsen et al., 2004). Most of xenobiotic compounds,
including pharmaceuticals, are excreted by kidney as
polar, water-soluble metabolites. Treatment of pharma-
ceuticals and their metabolites in the urine prior to
December 2006 357
dilution can be cost effective owing to the simple water
matrix as compared with combined wastewater (i.e., the
absence of interferences such as suspended solids and
other dissolved organics). Chemical oxidation such as
ozonation and AOPs can be a viable treatment option
for the separated urine.
Ozonation and Advanced Oxidation Treatment of
Water and Wastewater
Ozonation and AOPs have recently emerged as an
important class of technologies for the oxidation and
destruction of a wide range of organic pollutants in
water and wastewater (Legrini et al., 1993; Alvares
et al., 2001; Zhou and Smith, 2001; Oppenländer, 2003).
The AOPs are characterized by a variety of radical reac-
tions that involve combinations of chemical agents (e.g.,
ozone (O3), hydrogen peroxide (H2O2), transition metals,
and metal oxides) and auxiliary energy sources (e.g.,
ultraviolet-visible (UV-Vis) radiation, electronic current,
g-radiation, and ultrasound). Examples of AOPs include
O3/H2O2, O3/UV, O3/H2O2/UV, H2O2/UV, Fenton
(Fe2+/H2O2), photo- and electro-Fenton, chelating
agent assisted Fenton/photo-Fenton, heterogeneous
photooxidation using titanium dioxide (TiO2/hn), g-radi-
olysis, and sonolysis (Oppenländer, 2003).
Hydroxyl radicals (OH) are the primary oxidant in
AOPs while other radical and active oxygen species such

as superoxide radical anions (O2 ); hydroperoxyl radi-

cals (HO2 ); triplet oxygen (3O2), and organic peroxyl

radicals (R-O-O ) are also involved (Oppenländer,
2003). Molecular ozone and hydroxyl radicals are
involved in ozone treatment of water and wastewater.
Ozonation at high pH (>8) is also considered as an
AOP because of the enhanced generation of hydroxyl
radicals under such conditions (Beltrán, 2003). The oxi-
dation potentials of molecular ozone and hydroxyl radi-
cals are 2.07 and 2.80 V, respectively, indicating that they
are very strong oxidants (Legrini et al., 1993). Whereas
molecular ozone reactions are selective to the organic
molecules having nucleophilic moieties such as carbon-
carbon double bonds, aromatic rings, and the functional
groups bearing sulfur, phosphorus, nitrogen and oxygen
atoms, hydroxyl radicals reactions are non-selective
toward various organic and inorganic compounds
through hydrogen abstraction, radical-radical reactions,
electrophillic addition, and electron transfer reactions,
and eventually lead to complete mineralization of organic
compounds (Legrini et al., 1993; Oppenländer, 2003).
Ozonation and AOPs are particularly appropriate for
municipal and industrial wastewaters containing
bio-refractory and/or toxic organic pollutants such as
pesticides (Reynolds et al., 1989; Ikehata and Gamal
El-Din, 2005; Ikehata and Gamal El-Din, 2006), surfac-
tants (Ikehata and Gamal El-Din, 2004), and many
other industrial chemicals (Legrini et al., 1993;
Andreozzi et al., 1999; Alvares et al., 2001). In addition,
358 K. Ikehata et al.
ozone treatment is often employed for pathogenic
microorganism reduction (i.e., disinfection) (Loeb,
2002; Paraskeva and Graham, 2002). Some of the
advantages of these processes include complete miner-
alization of organic contaminants, production of less
harmful and more biodegradable by-products, and abil-
ity to handle fluctuating flow rates and compositions
(Zhou and Smith, 2001). The performance of AOP is
also affected by the presence of other water and waste-
water constituents, such as natural organic matter,
dissolved and suspended solids, and alkalinity, as well
as by water pH and temperature (Oppenländer, 2003).
For example, suspended solids and color can hinder
photochemical reactions by light scattering and absorp-
tion and may impair the performance of photochemical
AOPs, such as O3/UV, H2O2/UV, photo-Fenton, and
TiO2/hn processes. Carbonate, bicarbonate, and chlor-
ide ions, as well as some natural organic compounds are
known to act as radical scavengers. These compounds
compete with target pollutants for hydroxyl radicals;
therefore their presence increases oxidant demands and
lowers the treatment efficiency. In addition, the costs of
materials and equipment, as well as energy requirements
and efficiency must be taken into account when asses-
sing the overall performance of AOPs (Legrini et al.,
1993; Oppenländer, 2003).
DEGRADATION OF PHARMACEUTICALS IN
AQUEOUS SOLUTION BY OZONATION AND
ADVANCED OXIDATION PROCESSES
Degradation of recalcitrant organic pollutants such as
pharmaceuticals in water and wastewater can be achieved
using ozonation or AOPs. These treatment processes can
either eliminate such pollutants completely through
mineralization or convert them to the products that are
less harmful to human health and the aquatic environ-
ment. As the partial degradation of organic compounds
generally enhance their biodegradability (Alvares et al.,
2001), the latter approach can be also used as a pretreat-
ment of wastewaters containing pharmaceuticals prior to
biological treatment such as activated sludge. However,
this approach may not be appropriate in the cases where
other organic matter is predominantly present, which is
often the case of municipal wastewater, because oxidant
requirement can be exceedingly high in order to achieve
effective degradation of trace target pollutants. Thus, it is
likely more feasible to install ozonation or an AOP as
tertiary treatment after biological (secondary) treatment
(see Figure 2), unless urinary sepacation is practiced as
suggested by Larsen et al. (2004). In this case, the level of
treatment depends on the destination of treated effluent.
Partial treatment may be sufficient if the effluent will be
discharged into surface water, although it is still needed
to eliminate aquatic toxicity and improve biodegradabil-
ity. However, if the effluent will supplement drinking
December 2006
 FIGURE 2. Possible points to apply ozonation and AOPs for the degradation of pharmaceuticals.
water sources, which is increasingly common in semi-arid
areas, complete removal or destruction of pharmaceuti-
cals may be desired. As shown in Figure 2, ozonation and
AOPs can be applied to water treatment as a part of pre-
oxidation and/or disinfection steps. Wastewater from
pharmaceutical production/formulation plants and hos-
pital wastewater can be treated in a similar manner to
domestic wastewater, with appropriate pretreatment such
as pH adjustment.
During the treatment by ozonation or advanced oxida-
tion, organic pollutants such as pharmaceutical com-
pounds undergo a series of oxidation and spontaneous
transformations. In other words, primary degradation
products are often degradated further in prolonged treat-
ment. In some cases, disappearance of parent pharmaceu-
tical compounds does not indicate successful treatment
because the degraded products may be as biologically
active as the parent compounds. Likewise, some conven-
tional water quality parameters can be used to evaluate
the effectiveness of the process, such as total organic
carbon (TOC), chemical oxygen demand (COD), dis-
solved organic carbon (DOC), absorbable organic halo-
gene (AOX), and aromaticity; however, they do not
provide direct information about the identity of degrada-
tion products and the safety of treated water.
Consequently, the analysis of pharmaceutical compounds
and their degradation products (by-products) using gas
chromatography (GC) or liquid chromatography (LC)
coupled with mass spectrometry (MS) has been increas-
ingly common and becoming an asset in recent studies
(Ternes, 2001; Debska et al., 2004).
In some cases, the rate constants for the reaction
between a pharmaceutical compound and oxidant (i.e.,
molecular ozone and hydroxyl radicals) has been deter-
mined. These rate constants indicate the reactivity of the
Ozonation and Advanced Oxidation of Pharmaceuticals
compounds toward ozonation and AOPs and can be use-
ful to model the treatment process (Beltrán, 2003;
Oppenländer, 2003). Typically, the reaction kinetics can
be described by a second order rate law:
rðMÞ ¼ d½Mt =dt ¼ koxidant;M ½M½oxidant
where r(M) represents the rate of diminution of the
concentration of M (organic substrate = pharmaceuti-
cals), and koxidant,M is the second order rate constant for
the reaction of oxidant (O3 or OH) and M. In addition to
molecular ozone and hydroxyl radical reactions, direct
photolysis also contribute to the degradation of pharma-
ceutical compounds during the AOPs in which UV-Vis
irradiation is involved. In such a case, the quantum yield
(F), defined by the amount of reactant consumed per
amount of photon absorbed, of the direct photolysis
may be determined. These three types of reactions can
occur simultaneously and competitively, depending on
the AOP combination used, the presence of other water
and wastewater constituents, and pH.
A tabulated summary is presented in the Appendix
with major reaction conditions such as initial pH and
temperature. It should be noted that in most of the ozo-
nation studies, only the amount of applied ozone has
been given, and there was not enough information
about the actual amount of ozone utilized during the
treatment.
Antibiotics
Antibiotics are a group of pharmaceuticals used for the
treatment of both human and animals with bacterial and
fungal infections. Many of the antibiotics are derived
from wholly or partially from certain microorganisms,
but some are synthetic (e.g., sulfonamides). A wide
December 2006 359
range of antibiotics with diverse structures have been
used and subsequently found in the environment.
Removal of some of these compounds has been studied
using ozonation and AOPs (Table 1). In this review, they
will be divided into four sub-classes, including b-lactam,
macrolide, quinolone, and tetracycline, as well as several
other types of antibiotics that do not belong to these
subclasses. The chemical structure and molecular weight
of these antibiotics are shown in Figures 3–7.
b-Lactam Antibiotics. b-Lactam antibiotics covered
in this review include amoxicillin, cefradine (cephradine),
ceftriaxone, penicillins G and VK, and sultamicillin (see
Figure 3). These b-lactam antibiotics have been originally
isolated from molds, such as Penicillium chrysogenum and
Cephalosporium acremonium, and been modified to gain
different physico-chemical and pharmacological proper-
ties (Merck & Co., 1999). These antibiotics generally have
a property to inhibit bacterial cell wall synthesis. Among
the b-lactam antibiotics here, cefradine and ceftriaxone
are the members of cephalosporins. It is known that most
of these penicillins and cephalosporins are excreted
mainly in urine without major metabolic modifications
(Merck & Co., 1999). Degradation of two intermediates
of cephalosporin antibiotics, including 5-methyl-1,3,4-
thiadiazole-2-thiol (MMTD) and 5-methyl-1,3,4-thiadia-
zole-2-methylthiol (MMTD-Me), have been also studied
and are included here.
Penicillins (including amoxicillin and sultamicillin).
Ozonation and advanced oxidation treatment of various
penicillin formulation effluents containing one of four
penicillin-type b-lactam antibiotics, including penicillins
G and VK, amoxicillin, and sultamicillin has been exten-
sively studied to improve the biodegradability of these
wastewaters. Akmehmet Balcioglu and Ötker (2003)
applied ozonation to synthetic penicillin VK formulation
wastewater. About 70%, 40%, and 30% of initial COD
(450 mg/L), TOC (162 mg/L), and aromaticity (0.456;
absorbance at 254 nm) were removed by ozonation in
one hour at an applied ozone dose of 2.96 g/L at pH 7
or 11 at 20  C. Biodegradability of the penicillin solution,
measured by a ratio of 5-day biochemical oxygen demand
(BOD5) and COD, was also improved considerably by
the ozone treatment from zero to 0.25. Removal of COD
was less at low pH, suggesting the importance of hydroxyl
radical reactions. Addition of 20 mM H2O2 (O3:H2O2
molar ratio = 3.08:1) improved the COD removal to
95% at pH 7 (Akmehmet Balcio glu and Ötker, 2003).
The feasibility of a number of AOPs was tested for the
degradation of penicillin formulation wash water (waste-
water) containing amoxicillin trihydrate and clavulanic
acid, a b-lactamase inhibitor (Arslan-Alaton and
Dogruel, 2004). The wastewater also contained other
inert substances such as additives, buffer, and flavors.
The concentrations of these active and inert ingredients
were unknown ([TOC]0 = 920 mg/L, [COD]0 = 1,395 mg/
L, alkalinity = 85 mg CaCO3/L, pH 6.95). Among the
360 K. Ikehata et al.
AOPs tested, ozonation at pH 11.5 and photo-Fenton/
photo-Fenton-like process were more promising than the
others, namely H2O2/UV, Fenton, and Fenton-like pro-
cesses (see Appendix). In addition to these AOPs, direct
photolysis was also studied by Arslan-Alaton and
Dogruel (2004); however, it was virtually ineffective.
About 50% of COD and 52% of TOC were removed
from the wastewater by ozonation at an applied ozone
dose of 2.76 g/L in 1 h at pH 11.5 (initial value). The pH
value decreased presumably due to the formation of
organic acids during the ozonation, which inhibited
further COD removal. It was also noted that the COD
removal by ozonation was improved from 49% to 86%
using phosphate buffer at pH 11.5. Photo-Fenton and
photo-Fenton-like processes [2 mM Fe2+ or Fe3+, 20
mM H2O2, a 21-W low pressure Hg lamp, l = 253.7 nm
(1.73 · 104 EinsteinL1s1)] are equally effective in
COD and TOC removals: 56 and 66% COD removal
and 51 and 42% TOC removal, respectively. Complete
conversion of 400 mg/L amoxicillin was also confirmed
using ozonation at pH 11.5 and photo-Fenton process
(Arslan-Alaton and Dogruel, 2004).
Biodegradability of the penicillin formulation (amox-
icillin + clavulanic acid) wastewater was improved
slightly from zero to 0.08, based on the BOD5/COD
ratio, by ozonation (Arslan-Alaton and Dogruel, 2004).
Arslan-Alaton et al. (2004) investigated the biodegrad-
ability improvement of a similar penicillin formulation
wastewater containing amoxicillin and clavulanic acid as
active ingredients ([COD]0 = 830 mg/L) by ozonation
and O3/H2O2 process. Under optimized conditions, the
wastewater biodegradability was improved from 0 to 0.37
and 0.45 by ozonation (2.5 g/L applied O3, pH 12) and
O3/H2O2 process [2.5 g/L applied O3 (1.34 g/L consumed)
and 2 mM H2O2, pH 10.5], respectively, in 1 h.
Combination of chemical pre-oxidation and biological
treatment [0.23 mg COD/(mg mixed liquor suspended
solids · day)] yielded an overall COD removal of 81%
and 72% with optimized ozonation and O3/H2O2 process,
respectively (Arslan-Alaton et al., 2004). A similar ozona-
tion-biological treatment study has been reported on a
different type of penicillin-type antibiotics, sultamicillin
(Cokgor et al., 2004).
A series of studies has been reported concerning the
treatment of another type of penicillin formulation, peni-
cillin G with procaine, a local anesthetic agent, by ozona-
tion and photo-Fenton-like process. Degradation of this
penicillin formulation in synthetic wastewater was quan-
tified by COD and TOC reductions in both cases. Arslan-
Alaton and Caglayan (2005) demonstrated the enhance-
ment of COD removal with increasing pH from 7 to 12
and hence the important contribution of hydroxyl radical
reactions in the degradation of penicillin G-procaine for-
mulation. Ozone absorption efficiency also increased at
elevated pH. About 50% of initial COD (= 600 mg/L)
and TOC (= 226 mg/L) and was removed by ozonation
December 2006
 NH2
NH2 H H
H H N S
N S
O N
O N O
HO O
OH O OH
O

amoxicillin (365.41) cefradine (349.40)

H H
O N S
N
H H
N S O N
N O
O N S N O OH
H2N S O O
N
O OH N OH penicillin G (334.39)

ceftriaxone (554.57)
O
O O
O N H
O
O N
H H O S O
N S H2N
O N S O
H H
O N
O
O sultamicillin (594.65)
O
penicillin VK (388.47) K+

N N
HS N S N
S S

5-methyl-1,3,4-thiadiazole-2-thiol 5-methyl-1,3,4-thiadiazole-2-methylthiol
(MMTD; 132.20) (MMTD-Me; 146.24)

FIGURE 3. b-Lactam antibiotics and intermediates.

at pH 12 with an applied ozone dose of 1.8 g/L in 1 h.
Overall second-order rate constants for the COD removal
from the penicillin formulation by ozonation was deter-
mined as 0.042 and 0.67 M1s1 at pH 3 and 7, respec-
tively (Arslan-Alaton and Caglayan, 2005).
Arslan-Alaton and Gurses (2004) investigated the
photo-Fenton-like process for the treatment of penicillin
G-procaine formulation using a 125-W black light emitting
UV-A in the range of 300 to 370 nm with an incident light
flux of 1.7 · 103 Einsteinmin1. Under optimum reaction
conditions ([Fe3+]0 = 1.5 mM, [H2O2]0 = 25 mM, pH 3),
56% and 42% of initial COD and TOC, respectively, were
removed after 30 min of photo-Fenton-like treatment. It
was also demonstrated that Fenton-like treatment without
UV-A irradiation was slightly less effective in COD
removal from the penicillin formulation and that
neither UV-A alone, ferric ion with UV-A, nor H2O2/
UV-A was effective (Arslan-Alaton and Gurses, 2004).
Biodegradability of the penicillin G-procaine formulation
was improved from 0.25 to 0.45, while acute toxicity
(assessed by Daphnia magna mortality) was reduced mark-
edly after the 30 min of photo-Fenton-like treatment men-
tioned previously (Arslan-Alaton and Gurses, 2004).
Andreozzi et al. (2005) investigated the kinetics and
pathway of amoxicillin degradation by ozonation. Rate
of reaction between amoxicillin and molecular ozone was
found to be strongly pH dependent: from 4 · 103 M1s1
at pH 2.5 to 6 · 106 M1s1 at pH 7. The second-order
rate constant for hydroxyl radical reaction with amoxi-
cillin was also calculated as 3.93 · 109 M1s1 at pH 5.5
using H2O2/UV AOP to generate hydroxyl radicals
(Andreozzi et al., 2005). Whereas hydroxylation of the
phenol ring was confirmed, no evidence was found for
S-oxidation of amoxicillin molecules by molecular ozone.
No further degradation was noticed, probably due to the
short reaction time (up to 4 min) and the absence of
hydroxyl radicals in the system as 2-methyl-2-propanol
was used as a scavenger.

Ozonation and Advanced Oxidation of Pharmaceuticals December 2006 361

 O O
N N N N
HO HO HO
OH O HO OH
HO HO OH
OH OH O
O O
O O O
O O O
O O O
O OH O OH O OH
O O O

O O O

azithromycin (748.88) clarithromycin (747.95) erythromycin (733.93)

O O
O N
N
HO
HO
O HO OH
N O S OH
O
N O
H O
HO OH O
OH O OH
O
lincomycin (406.54)
O
roxithromycin (837.05)

FIGURE 4. Macrolide antibiotics.

O O initial TOC (= 167 mg/L) was removed at pH 7. The

F N
OH
N N HO
N O
ofloxacin (levofloxacin, 361.37)
enrofloxacin (359.39)
FIGURE 5. Quinolone antibiotics.
Cefradine. Degradation of cefradine, a cephalos-
porin-type b-lactam antibiotic has been studied using an
immobilized titanium dioxide photo catalyst (Fan et al.,
2002). Near-complete conversion of 0.2 mM (70 mg/L)
cefradine was achieved by the TiO2/hn process using a 30-
W UV lamp (l = 253 nm) in 2 h (pH unknown) with
continuous aeration. Decomposition of aromatic ring,
amino and carboxyl groups was confirmed using UV
and infrared spectroscopy. Addition of hydrogen perox-
ide (1 to 5 g/L) in the system accelerated the cefradine
degradation, presumably due to enhanced production of
hydroxyl radicals through the photodecomposition of
hydrogen peroxide (Fan et al., 2002). Degradation by-
product was not determined in this study.
Ceftriaxone. Similar to the case of penicillin VK, a
buffered synthetic wastewater containing ceftriaxone was
treated by ozonation (Akmehmet Balcio glu and Ötker,
2003). After 1 h of ozonation at an applied ozone dose of
2.96 g/L, 74% of initial COD (= 450 mg/L) and 50% of
O N
N COD reduction was slightly improved to 82% by elevat-
ing pH from 7 to 11. Addition of hydrogen peroxide also
F improved the COD removal. The absorbance at 254 nm
O
in the synthetic wastewater was reduced by more than
90%, indicating effective destruction of aromatic rings in
the ceftriaxone molecules. Biodegradability (i.e., the ratio
of BOD5 and COD) of ceftriaxone solution was modestly
improved from zero to 0.1 after the ozonation treatment
(Akmehmet Balcioglu and Ötker, 2003). No degradation
by-product was identified for the ceftriaxone ozonation
or AOP.
MMTD and MMTD-Me. Photochemical degradation
of two intermediates used for the synthesis of cefazolin,
a cephalosporin-type b-lactam antibiotic, including 5-
methyl-1,3,4-thiadiazole-2-thiol (MMTD) and 2-
methyl-5-(methylthio)-1,3,4-thiadiazole (MMTD-Me),
was reported (Bozzi et al., 2002; Lopez et al., 2002,
2003). Lopez et al. (2002) demonstrated complete con-
version of MMTD in less than 20 min by H2O2/UV
treatment ([H2O2]0 = 26 mg/L, a 17-W low-pressure Hg
lamp emitting at 185 and 254 nm with light intensity of
2.8 · 106 Einsteins1, at 2 C), which was more effec-
tive than UV irradiation alone. The quantum yield for
MMTD photolysis was determined as 12
mmolEinstein1. About 60% of initial TOC was
removed during a prolonged H2O2/UV treatment of 1
mg/L MMTD for 4 h, and about 90% of sulfur and
14% of nitrogen was recovered as sulfate and nitrate
ions, respectively. Seven degradation intermediates and

362 K. Ikehata et al. December 2006

 O
O N N O O N
H H N H
H2N S N Cl H2N S N H2N S N N
O O N O
O
sulfachlorpyridazine (284.72) sulfadiazine (250.27) sulfadimethoxine (310.33)

O O
O N H N H
H H2N S N
H2N S N H2N S N
N O N O
O N O

sulfamerazine (264.30) sulfamethazine (277.34) sulfamethoxazole (253.28)

O O O N
O S H H
H H2N S N H2N S N
H2N S N
N
O N N O O

sulfamoxole (267.30) sulfapyridine (249.29)

sulfamethizole (270.32)

O S O
H H
H2N S N H2N S N
O N O O N

sulfathiazole (255.31) sulfisoxazole (267.30)

FIGURE 6. Sulfonamide antibiotics.

(hydroxyl radicals) was reported as 1.6 · 1010 M1s1 at

OH 25 C (pH unknown) (Lopez et al., 2003).
O H H
H N O O Degradation of MMTD-Me, which is a 2-S-methyl deri-
N N O
N vative of MMTD, has been studied in a similar manner to
O HO O
OH
the latter compound (Bozzi et al., 2002; Lopez et al., 2003). It
N
NH O was noted that MMTD-Me was more reactive toward direct
O
photolysis presumably due to the higher extinction coeffi-
spectinomycin (332.35)
carbadox (262.22) cient (4970 M1cm1) of MMTD-Me as compared with
that of MMTD (2100 M1cm1), while it is less reactive
NH2 toward H2O2/UV treatment because of the electron with-
HO N drawal property of methyl group (Bozzi et al., 2002).
O
OH N
Nevertheless, MMTD-Me could be completely converted
OH
NH2 H2N N O in 20 min by the equivalent H2O2/UV treatment mentioned
OH O OH O O
O above at 25  C (pH unknown). About 80% of initial TOC
was removed in 4 h, and a near-quantitative recovery of
trimethoprim (290.32)
tetracycline (444.44) sulfur as sulfate, as well as a 16% recovery of nitrogen as
nitrate, was observed as well. Degradation intermedi-
FIGURE 7. Miscellaneous antibiotics. ates and by-products of the MMTD-Me photochemical
treatment were also identified (Bozzi et al., 2002),
which are shown in Figure 9. Unlike MMTD degrada-
by-products were identified by LC-MS, and degradation tion, demethylation and S-oxidation of 2-methylthio
pathway was proposed as shown in Figure 8 (Lopez et al., group likely precede the ring opening and mineraliza-
2002). It is apparent that the 2-thiol group and the sulfur tion of MMTD-Me, but no dimerizaiton (disulfide for-
atom on the thiadiazole ring of MMTD are the prime mation) may occur because of the presence of methyl
targets of hydroxyl radical attack. The second-order rate group. The quantum yield and second-order rate con-
constant for MMTD degradation by H2O2/UV process stant for MMTD-Me photolysis and H2O2/UV

Ozonation and Advanced Oxidation of Pharmaceuticals December 2006 363

 Azithromycin. Huber et al. (2005) reported complete
S SH disappearance of azithromycin (initial concentration not
•OH N N specified) in biologically treated municipal wastewater by
MMTD ozonation at an applied ozone dose of 3.5 mg/L at pH 7.
S S They suggested that two tertiary-amine nitrogens in azithro-
SO3H N
hν -S
mycin molecule were the primary sites for molecular ozone
S S S N
N N
attack (see Figure 4 for the molecular structure of azithro-
S N N
•OH hν - S mycin). No degradation by-products were identified.
- SO4-
N N Clarithromycin and Erythromycin. Elimination
S O S (i.e., conversion) of trace clarithromycin and erythro-
SO3H S N
N N
•OH S N mycin in biologically treated municipal wastewater
N N has been studied using ozonation recently. Ternes et
or
O •OH al. (2003) reported an elimination of 0.21 mg/L clari-
O O thromycin and 0.62 mg/L erythromycin to levels
S
S SO3H O
O O S below the limit of quantification with as low as 5
N N S N mg/L of applied ozone at pH 7.2. A similar result
N N S N
•OH
was also reported by Huber et al. (2005). A biologi-
•OH N N
cally treated municipal wastewater was spiked with
•OH clarithromycin and dehydroerythromycin (both at 2
ring opening
and
mg/L; see Figure 10 for the structure of dehydroery-
mineralization thromycin, an environmental metabolite of erythro-
mycin), along with other pharmaceuticals and musk
FIGURE 8. Proposed pathway for MMTD degradation by H2O2/ fragrances, and was treated by ozonation at pH 7. It
UV process (Lopez et al., 2002). was found that an applied ozone dose of 3.5 mg/L
was sufficient to eliminate these two macrolide anti-
biotics. It was proposed a tertiary-amine nitrogen in
both macrolides and a carbon-carbon double bond in
S hν S SH hν S dehydroerythromycin molecule to be ozone attack
S
sites (Huber et al., 2005).
N N N N N N
•OH Roxithromycin. It has been reported that the reactiv-
MMTD-Me •OH ity of roxithromycin toward ozonation is similar to the
O •OH
S S other macrolide antibiotics discussed above (Ternes et al.,
•OH
mineralization 2003; Huber et al., 2005). In addition, one kinetic study of
N N
roxithromycin ozonation has been reported (Huber et al.,
FIGURE 9. Degradation of MMTD-Me by H2O2/UV process 2003). It was shown that this macrolide antibiotic reacted
(Bozzi et al., 2002). with ozone rapidly (kO3 > 105 at pH 7, 20  C) and that the
rate constant for the direct ozone reaction was pH-depen-
dent. The rate constant reaches to its maximum value of
4.5 · 106 M1s1 at pH 8.8, which corresponds to the pKa
treatment were reported as 12 mmolEinstein1 and 8.3 of roxithromycin, indicating the tertiary-amine nitrogen is
· 108 M1s1, respectively (Lopez et al., 2003). the primary site of ozone attack (Huber et al., 2003).

Macrolide Antibiotics
Among the antibiotics shown in Figure 4, azithro-
mycin, clarithromycin, erythromycin, and roxithromy-
N
cin are macrolide antibiotics, and lincomycin is a
HO
lincosamide antibiotic, which has an antibacterial spec- O OH
HO
trum similar to macrolides. Although not shown in OH
O
Figure 4, there is another lincosamide antibiotic called O
O
clindamycin, which is a derivative of lincomycin and O
more commonly prescribed nowadays because of its O
O
OH
improved absorption property after oral administration
(Merck & Co., 1999). These antibiotics are character- O
ized by a property to inhibit bacterial protein synthesis.
FIGURE 10. Chemical structure of dehydroerythromycin, an
These antibiotics are mostly excreted in the bile (Merck environmental metabolite of erythromycin (Huber et al., 2005).
& Co., 1999).

364 K. Ikehata et al. December 2006


O3 or •OH
HO O3 or •OH
O
N O S
N demonstrated that ozone treatment was effective in
H
HO OH
•OH OH
FIGURE 11. Possible sites of molecular ozone and hydroxyl
radical attacks in a lincomycin molecule (Qiang et al., 2004;
Addamo et al., 2005).
Lincomycin. Qiang et al. (2004) investigated a rapid
reaction of lincomycin toward ozonation (kO3 > 105
M1s1 at pH >7) using a stopped-flow technique.
Similar to the case of roxithromycin, lincomycin degrada-
tion by ozonation is pH dependent (pKa of pyrrolidine
nitrogen = 7.8), and the contribution of hydroxyl radical
reactions is considered to be negligible. Besides the pyr-
rolidine nitrogen, a sulfur atom of methylthio group is
suggested as a prime target of ozone attack (see Figure 11).
Based on their kinetic model, the absolute second-order
rate constants for lincomycin ozonation were calculated
as 3.26 · 105 and 2.43 · 106 M1s1 for protonated and
neutral forms, respectively (Qiang et al., 2004).
In addition to ozonation, Addamo et al. (2005)
reported photo-catalytic degradation of lincomycin
using two types of TiO2 catalysts. Addition of TiO2 pow-
der (0.4 g/L Degussa P25 or 1 g/L Merck TiO2) strongly
enhanced the degradation of lincomycin from UV irradia-
tion alone with a 125 W medium pressure Hg lamp with a
photo flux of 8.5 mWm2. Complete conversion of 50
mg/L lincomycin was achieved in 2 h by the TiO2/hn
treatment at pH 6 and 20  C, and about 60% of initial
TOC was removed from the solution. Although S-oxida-
tion of methylthio group and oxidation of pyrrolidine
ring followed by a cleavage of amide bond were suggested
as possible routes of lincomycin degradation by TiO2
process (Addamo et al., 2005), the actual degradation
intermediates and by-products were not determined,
with the exception of sulfate ion.
Quinolone Antibiotics
Two types of quinolone antibiotics, including enro-
floxacin and ofloxacin, have been studied for their
degradation by ozonation and AOPs. More specifi-
cally, both are fluoroquinolones. While enrofloxacin is
used as a veterinary antibiotic, ofloxacin is intended
for human consumption. These compounds have a
property to inhibit the activity of bacterial DNA gyr-
ase (Merck & Co., 1999). The chemical structure and
molecular weight of these quinolone antibiotics are
shown in Figure 5. Please note that ofloxacin is a
racemic mixture of chiral molecules, and the biologi-
cally active S-enantiomer, which is also called levoflox-
acin, is shown in the figure. It is known that the
Ozonation and Advanced Oxidation of Pharmaceuticals
quinolones are variably metabolized in the liver and
excreted in the urine (Merck & Co., 1999).
Enrofloxacin. Akmehmet Balcioglu and Ötker (2003)
degrading enrofloxacin in synthetic wastewater. About
90% of initial COD (= 450 mg/L) and 50% of initial
TOC (165 mg/L) was removed by ozonation in one
hour at an applied ozone dose of 2.96 g/L and pH 7.
The COD removal was less at pH 3 and pH 11, 65% and
79%, respectively. Addition of hydrogen peroxide (10 to
100 mM) did not show any impact on the COD removal.
Biodegradability, as expressed by the ratio of BOD5 and
COD, of the synthetic wastewater was improved consid-
erably from 0.07 to 0.38 after the ozone treatment at pH 7
(Akmehmet Balcioglu and Ötker, 2003). The same group
of authors also investigated the use of negatively charged
zeolite as natural adsorbent for the treatment of enroflox-
acin, which has three tertiary-amine nitrogens in its mole-
cular structure, and subsequent decontamination and
regeneration of zeolite by ozonation (Ötker and
Akmehmet-Balcioglu, 2005). They demonstrated the suc-
cessful decontamination of enrofloxacin-loaded zeolite
(equilibrated with 200 mg/L enrofloxacin for 24 h) by
30 min of ozonation (consumed ozone = 100 mg), sug-
gesting that the zeolite adsorption-ozonation system
might be a good method to control antibiotic pollution
due to animal manure land application.
Ofloxacin. Andreozzi et al. (2004) investigated the
ozonation, H2O2/UV, and TiO2 photo-catalysis for the
decontamination of an aqueous pharmaceutical mixture
containing ofloxacin, as well as five other drugs, namely
carbamazepine, propranolol, clofibric acid, diclofenac,
and sulfamethoxazole. It was shown that 2 min of ozona-
tion (13.9 mg/L absorbed O3) as well as H2O2/UV treat-
ment ([H2O2]0 = 5–10 mM, a low-pressure Hg lamp, at
254 nm, 2.51 · 106 Einsteins1) was sufficient for the
complete conversion of 560 mg/L ofloxacin at pH 7.4 and
25  C, whereas TiO2/hn process was less effective. Algal
(Synechococcus leopoliensis) and protozoan (Brachionus
calyciflorus) toxicities of the drug mixture were eliminated
completely by the ozone treatment in 2 min. The H2O2/
UV treatment was also effective for algal toxicity reduc-
tion; however, it was less effective for protozoan toxicity
reduction. Finally, the TiO2/hn treatment was ineffective
in either case (Andreozzi et al., 2004), probably because
of insufficient drug conversion. Degradation by-products
of ofloxacin were not determined.
Sulfonamide Antibiotics
Sulfonamides are synthetic antibiotics also called sulfa
drugs that inhibit multiplication of bacteria by acting as
competitive inhibitors of p-aminobenzoic acid in the folic
acid metabolism cycle (Merck & Co., 1999). A variety of
sulfonamides have been produced, consumed, and subse-
quently detected in the environment, and some of them
December 2006 365
have been studied for their degradation by ozonation and
AOPs. These compounds include sulfachlopyridazine, sul-
fadiazine, sulfadimethoxine, sulfamerazine, sulfametha-
zine, sulfamethizole, sulfamethoxazole, sulfamoxole,
sulfapyridine, sulfathiazole, and sulfisoxazole. They have
a common core chemical structure (p-aminobenzene sulfo-
namide), as can be seen in Figure 6. These sulfonamide
antibiotics are metabolized mainly by the liver to acetylated
forms (at p-amino group) and glucuronides, and subse-
quently excreted in the urine (Merck & Co., 1999).
Sulfachlorpyridazine. Adams et al. (2002) reported
the rapid conversion of sulfachlorpyridazine by ozona-
tion in a pre-filtered river water sample spiked with this
and three other antibiotics at an initial concentration of
50 mg/L each. More than 95% of initial sulfachlorpyrida-
zine was converted by ozonation in 1.3 min with a utilized
ozone dose of 0.3 mg/L at pH 7.5.
The second order rate constant for the reaction between
hydroxyl radicals and sulfachlorpyridazine, as well as those
for nine other sulfonamide antibiotics, has been reported
(Boreen et al., 2004; 2005) as shown in Table 2. Fenton
process was employed to generate hydroxyl radicals, and a
competition kinetics method was used to estimate the rate
constants using acetophenone as a reference compound.
Unlike direct photolysis, which is strongly affected by the
types of heteroaromatic ring attached to sulfonamide nitro-
gen, the rate constants for hydroxyl radical reactions are
nearly equal and close to diffusion-controlled limit of 1010
M1s1. It has been also shown that the reactivity of these
sulfonamides toward direct photolysis is dependent on the
protonation state of the concerned compound (Figure 12,
Table 2; Boreen et al., 2004; 2005), although the effect of
pH on hydroxyl radical reactions has not been studied. No
degradation by-product/intermediate was identified for sul-
fachlorpyridazine ozonation or AOP.
Sulfadiazine. Degradation of sulfadiazine has been
studied by ozonation (Huber et al., 2005) and TiO2 photo-
catalysis (Calza et al., 2004a). In addition, as shown in
Table 2, the second-order rate constant for the reaction
between hydroxyl radical and this sulfonamide antibiotic
has been reported (Boreen et al., 2005). Sulfadiazine was
completely converted by ozone (2 mg/L applied ozone
dose, pH 7) in a biologically treated wastewater sample
spike with this antibiotic at a concentration of 2 mg/L,
along with several other sulfonamide antibiotics, macrolide
antibiotics, estrogens, and iodinated X-ray contrast media
(Huber et al., 2005). Calza et al. (2004a) demonstrated
partial mineralization of 15 mg/L sulfadiazine by TiO2
photocatalysis. About 80% of sulfur atom was recovered
as sulfate after 30 min of treatment with 200 mg/L TiO2
and UV irradiation using a 1500-W xenon lamp (1.35 ·
105 Einsteinmin1) and a 340 nm cut off filter at 50  C
(pH unknown). On the other hand, the yield of inorganic
nitrogen (i.e., ammonium ion) was about 15%, indicating
the formation of stable organic by-products bearing nitro-
gen atom(s), although these by-products were not deter-
mined. During the TiO2/hn treatment, formation of
hydroxylated intermediate of sulfadiazine was suggested
(Figure 13), which quickly disappeared as the degradation
proceeded (Calza et al., 2004a). As aniline is not particu-
larly persistent toward advanced oxidation (Sauleda and
Brillas, 2001; Li et al., 2003), the N-bearing intermediates
suggested by Calza et al. are likely derived from 2-amino-
pyrimidine (R-NH2 in Figure 13) released by the cleavage
of S-N bond of sulfadiazine.
Sulfadimethoxine, Sulfamerazine and Sulfathiazole.
Similar to the cases of other sulfonamide antibiotics,
rapid conversion of sulfadimethoxine, sulfamerazine,
and sulfathiazole by ozonation in river water was
reported (Adams et al., 2002; Huber et al., 2005), and

TABLE 2. pKa, Second-Order Rate Constant for Hydroxyl Radical Reaction (kOH), and Quantum Yield (F) of Sulfonamide Antibiotics (Boreen
et al., 2004; Boreen et al., 2005)

FP (mMEins1)

pKa,1 pKa,2 k  OH (109 M1s1) SHþ

2 SH S
Sulfachlorpyridazine 2 5.9 4.4 nd 3.0 · 104 2.3 · 103
Sulfadiazine 2 6.4 3.7 nd 4.0 · 104 1.2 · 103
Sulfadimethoxine 2.9 6.1 6.1 nd 1.0 · 105 4.0 · 104
Sulfamerazine 2.5 7 3.8 nd 2.3 · 104 3.0 · 103
Sulfamethazine 2.6 8 5.0 nd 3.0 · 104 5.0 · 103
Sulfamethizole 2.1 5.3 4.9  0.01  5.0 · 103 0.05
Sulfamethoxazole 1.6 5.7 5.8 0 0.5 0.09
Sulfamoxole nd 7.4 nd nd nd nd
Sulfathiazole 2.2 7.2 7.1 0.02 0.07 0.40
Sulfisoxazole 1.5 5.0 6.6 0.7 0.17 0.07

Note: kOH was determined for neutral sulfonamide. SHþ 

2 ; SH, and S represent cationic, neutral, and anionic forms of
sulfonamides (see Figure 12). nd = not determined.

366 K. Ikehata et al. December 2006

 O Ka,1 O Ka,2 O
H H
H3N S N R H2N S N R H2N S N R
O O O

SH2+ SH S-

FIGURE 12. Protonation states of the sulfonamide antibiotics (Boreen et al., 2004). SHþ 
2 ; SH, and S represent cationic, neutral, and anionic
forms, respectively.

O O O
H •OH H
H2N S N R H2N S N R O N O N
H H
O O H2N S N N H2N S N
OH
hydroxylated sulfonamide
O O N
parent sulfonamide OH O OH
•OH •OH hydroxylated sulfamerazine
hydroxylated sulfadimethoxine
O O (aniline side)
H2N S OH + R-NH2 R-NH2 + H2N S OH
O O O
OH
O N
•OH •OH H N
•OH
•OH H2N S N N H2N
O N
SO42- SO42- HO O
Further degradation, release of NH 4+ 4-methyl-2-aminopyrimidine
hydroxylated sulfadimethoxine
FIGURE 13. Degradation of sulfonamides by advanced oxidation (pyrimidine side)
process (Calza et al., 2004a).
O S
H
O H2N S N
N O N
comparable second-order rate constants for the hydroxyl H2N N OH
radical reactions of these sulfonamide antibiotics were hydroxylated sulfathiazole
determined (see Table 2; Boreen et al., 2005). Calza O

et al. (2004a) demonstrated near-complete conversion of 2,6-dimethoxy-4-aminopyrimidine

these three sulfonamides by TiO2/hn treatment (see
Sulfadiazine for the reaction conditions). Like the case
of sulfadiazine, high levels (70% to 100%) of inorganic
sulfur were recovered as sulfate after the TiO2/hn treat-
ment of sulfadimethoxine, sulfamerazine, and sulfathia-
zole, while the yields of inorganic nitrogen (as ammonium
and nitrate) were substantially different: 70%, 18%, and
90%, respectively (Calza et al., 2004a). The behavior of
sulfamerazine resembles that of sulfadiazine, indicating
possible formation of persistent nitrogenous by-products.
On the other hand, the amount of ammonium ion
released by sulfadimethoxine and sulfathiazole degrada-
tion implies effective destruction of the heterocyclic ring,
i.e., 2,6-dimethoxypyrimidine and thiazole, respectively.
Several degradation intermediates were detected during
the TiO2/hn treatment of these sulfonamide antibiotics
(Calza et al., 2004a), which are shown in Figure 14. It
was noted that 2-aminothiazole, a possible degradation
intermediate of sulfathiazole, was not detected probably
due to its high reactivity toward hydroxyl radicals (Calza
et al., 2004a).
Sulfamethazine. Rapid conversion of sulfametha-
zine by ozonation was reported (Adams et al., 2002).
Ozonation at an absorbed ozone dose of 0.3 mg/L was
sufficient to transform 50 mg/L sulfamethazine in a pre-
filtered river water sample at pH 7.5 in 1.5 min. The
FIGURE 14. Possible degradation intermediates of sulfadi-
methoxine (two hydroxylated compounds, 2,6-dimethoxy-4-amino-
pyrimidine) and sulfamerazine (one hydroxylated compound, 4-
methyl-2-aminopyrimidine) and sulfathiazole (one hydroxylated
compound) detected during TiO2/hn treatment (Calza et al.,
2004a). See Figure 13 for the proposed general degradation
pathway.
second-order rate constant for the reactions between sul-
famethazine and hydroxyl radicals was also reported
(Boreen et al., 2005) as shown in Table 2. It has been
noted a slower reaction of N4-acetylated metabolite of
this sulfonamide antibiotic with ozone in a biologically
treated wastewater sample (Huber et al., 2005). No degra-
dation by-product/intermediate was identified.
Sulfamethoxazole. Like many other sulfonamide
antibiotics, sulfamethoxazole is readily degradable by
ozonation. Ternes et al. (2003) demonstrated that as low
as 5 mg/L of applied ozone could completely eliminate
(i.e., convert) 0.62 mg/L sulfamethoxazole present in a
biologically treated municipal wastewater below its detec-
tion limit. Similar results were also reported elsewhere
(Huber et al., 2003, 2005). A negative effect of dissolved
organic matter on the degradation of sulfamethoxazole
was noted during the ozonation of this sulfonamide

Ozonation and Advanced Oxidation of Pharmaceuticals December 2006 367

antibiotic in natural river water samples (Huber et al.,
2003). Huber et al. (2003) also determined the second-
order rate constants for both ozonation (2.5 · 106
M1s1) and advanced oxidation (H2O2/UV; 5.5 ·
109 M1s1) of sulfamethoxazole at pH 7 and 25  C
by a competition kinetics method with phenol and p-
chlorobenzoic acid as reference compounds, respec-
tively. The rate constant for the hydroxyl radical reac-
tions is in close agreement with the one reported for
neutral sulfamethoxazole by Boreen et al. (2004) using
Fenton process to generate hydroxyl radicals (Table 2).
Since majority of this sulfonamide antibiotic is present
in the anionic form at pH 7 (pKa2 = 5.7), it is apparent
that the dissociation of sulfonamide-N proton (see
Figure 12) have no effect on the advanced oxidation
of this antibiotic. It was suggested that aniline nitrogen
was the primary target of molecular ozone attack in
the sulfamethoxazole molecule (see Figure 6) and that
protonation of this nitrogen would diminish its reactiv-
ity toward ozonation (Huber et al., 2003). The first
point is evident from the fact that N4-acetylated sulfa-
methoxazole (Figure 15), which is a metabolite of this
sulfonamide antibiotic (Merck & Co., 1999), is shown
to be relatively persistent during ozonation treatment
as compared with the non-acetylated parent compound
(Huber et al., 2005).
Andreozzi et al. (2004) reported the effective detoxifi-
cation of a mixture of pharmaceuticals containing 2.24
mg/L sulfamethoxazole and five other drugs by ozona-
tion and H2O2/UV treatment (see Ofloxacin, quinolone
antibiotic for details). No degradation intermediate/by-
product was determined for sulfamethoxazole ozonation
and advanced oxidation.
Sulfamethizole, Sulfamoxole, and Sulfisoxazole.
Boreen et al. (2004) determined the second-order rate
constants (kOH) for sulfamethizole and sulfisoxazole
(see Table 2 and Sulfachlorpyridazine) using the Fenton
process to generate hydroxyl radicals. They also noted
that another sulfonamide antibiotic, sulfamoxole, was not
stable in weakly acidic (pH 4) solution. As a result, no
kinetic study was conducted on this compound (Boreen
et al., 2004). No further study was found on the degrada-
tion of these sulfonamide antibiotics by ozonation or
AOP.
Sulfapyridine. Huber et al. (2005) reported near-
complete conversion of 2 mg/L sulfapyridine by ozonation
O cline was achieved in two hour by the TiO2/hn treatment
O with 0.4 g/L of catalyst and a 125 W medium pressure
H
HN S N
O N O
FIGURE 15. N4-acetylsulfamethoxazole, an environmentally rele-
vant metabolite of sulfamethoxazole (Huber et al., 2005).
368 K. Ikehata et al.
(as low as 2 mg/L applied O3 at pH 7) in a biologically
treated wastewater sample. No further study has been
reported on the ozonation or advanced oxidation of this
sulfonamide antibiotic.
Other Antibiotics
In addition to the groups of antibiotics discussed here,
several other types of antibiotics have been studied for
their degradation by ozonation and/or AOPs (Figure 7).
Carbadox is a veterinary antibiotic, which can be added
to swine as a growth promoter although its use has been
banned in Europe because of its suspected carcinogenicity
and mutagenicity (Hutchinson et al., 2005).
Spectinomycin and tetracycline are bacteriostatic antibio-
tics that inhibit bacterial protein synthesis by binding the
30S subunit of the ribosome (Merck & Co., 1999).
Trimethoprim is a chemotherapeutic antibiotic, which is
commonly used in combination with sulfamethoxazole, a
sulfonamide antibiotic to maximize its effect on inhibiting
folate synthesis of bacteria (Merck & Co., 1999).
Carbadox and Trimethoprim. Adams et al. (2002)
demonstrated rapid conversion of carbadox and tri-
methoprim by ozonation in a pre-filtered river water
sample spiked with these antibiotics at an initial con-
centration of 50 mg/L each. More than 95% of these
antibiotics were converted by ozonation for 1.5 min
with a utilized ozone dose of 0.3 mg/L at pH 7.5.
Ternes et al. (2003) also reported a similar reactivity
of trimethoprim originally present in biologically trea-
ted wastewater toward ozonation. No further study has
been reported on ozonation or advanced oxidation of
these antibiotics.
Spectinomycin. Quang et al. (2004) investigated the
kinetics of spectinomycin ozonation using a stopped-flow
technique. As can be seen in Figure 7, this antibiotic has
two secondary amine groups (pKa = 7.10 and 8.90) that
can be primary targets of molecular ozone attacks. It was
shown that the protonation of these two amine groups in
acidic solution (pH < 5) diminished the reactivity of
spectinomycin toward ozonation. Absolute rate constant
was determined as 1.27 · 106 M1s1 and 3.30 · 105
M1s1 for neutral and mono-protonated forms of spec-
tinomycin, respectively (Qiang et al., 2004). No degrada-
tion by-product/intermediate was determined in this
study.
Tetracycline. Effective degradation and partial
mineralization of tetracycline by TiO2 photocatalysis
was reported (Di Paola et al., 2004; Addamo et al.,
2005). Almost complete conversion of 50 mg/L tetracy-
Hg lamp with a photon flux of 8.5 mWcm2 at 40  C,
and about 90% of TOC was removed in 6 h (Di Paola
et al., 2004). On the other hand, direct photolysis was
much less effective in tetracycline conversion and miner-
alization (Addamo et al., 2005). While the formation
December 2006
of 4a,12a-anhydro-4-oxo-4-dedimethylaminotetracycline
was suggested as a photolytic by-product (Addamo
et al., 2005), no degradation by-product/intermediate
was determined for the tetracycline decomposition cata-
lyzed by TiO2.
Summary of Antibiotics
All antibiotics discussed here are fairly reactive toward
ozonation and advanced oxidation in aqueous media.
Their high reactivity is accounted for the presence of
one or more reactive functional groups/moieties in the
antibiotic molecules, such as amine nitrogen, sulfur, acti-
vated aromatic ring, and carbon-carbon double bond. It
should be noted that acetylated sulfonamide metabolites,
such as N4-acetylsulfamethoxazole (Figure 15), are more
resistant to ozonation than the parent compounds (Huber
et al., 2005) because the acetylation blocks the aniline
amino group that is one of the targets of molecular
ozone reactions. It has been demonstrated in the studies
reviewed here that the complete conversion of antibiotics
is readily achievable by either ozonation or AOP; how-
ever, their mineralization is not always confirmed.
Similarly, the identity and quantity of degradation by-
products arising from ozonation and advanced oxidation
treatment are largely unknown for most antibiotics.
Sulfonamides are the only class of antibiotics whose
degradation pathway has been proposed (Figure 13),
although it applies only to AOPs and their degradation
mechanisms by molecular ozone alone is still elusive. On
the other hand, kinetic information for ozonation and
advanced oxidation is available for many antibiotics.
The kinetic data consistently indicate the high reactivity
of antibiotics toward molecular ozone (kO3 >105
M1s1) and hydroxyl radical (kOH >109 M1s1).
The effect of ozonation and AOPs on the toxicity and
biodegradability has been studied only for some b-lactam
antibiotics, two quinolones, and one sulfonamide. More
studies will be needed to ensure not only the complete
transformation of antibiotics but also the diminution of
toxicity toward environmental microbes and other aqua-
tic organisms, because once released these compounds
can directly interact with natural bacterial population.
Although the concentrations of antibiotics in the environ-
ment are generally low (less than one microgram per
liter), the bacterial population and aquatic life may be
disturbed and resistance against particular types of anti-
biotics may be developed by pathogenic bacteria in the
environment (Kümmerer, 2004). For the same reason,
major degradation intermediates/byproducts of antibio-
tics should be identified and characterized. Finally, there
are several other antibiotics that have been detected in
wastewater effluent and the environment but not studied
for their degradation by ozonation or AOP. These anti-
biotics include ciprofloxacin (Miao et al., 2004), clinda-
mycin (Christian et al., 2003; Batt and Aga, 2005),
norfloxacin (Kolpin et al., 2002; Miao et al., 2004),
Ozonation and Advanced Oxidation of Pharmaceuticals
doxycycline (Miao et al., 2004), and oxytetracycline
(Kolpin et al., 2002).
Anticonvulsants and Anti-anxiety Agents
Anticonvulsants, sometimes called antiepileptics, are the
group of pharmaceuticals used in drug therapy to control
seizures. The anticonvulsants covered in this review include
carbamazepine, diazepam, and primidone. Some anticon-
vulsants are also useful to treat some types of psychiatric
disorders such as anxiety, depression, and mood disorder.
Therefore, an anti-anxiety agent, buspirone, is also included
in this section. Chemical structure and molecular weight of
these pharmaceuticals are shown in Figure 16.
Buspirone. Calza et al. (2004b) investigated photo-
catalytic transformation of buspirone, an anti-anxiety
agent, using TiO2 as a catalyst to simulate the metabolic
system of living organisms. Complete transformation of
15 mg/L buspirone was achieved by TiO2/hn treatment
with 200 mg/L TiO2 and a 1500-W xenon lamp with a 340
nm cut-off filter (1.35 · 105 Einsteinmin1) at 50  C,
and a number of degradation intermediates were identi-
fied by LC-MS-MS as shown in Figure 17. It was sug-
gested that hydroxylation of pyrimidine ring and
azaspirone decane dione substructure occurred simulta-
neously followed by cleavage and eventual loss of pyri-
midine ring. The formation of another intermediate, 1-
pyrimidinyl-piperazine, was also confirmed (Figure 17).
These intermediates subsequently disappeared within 30
min of the TiO2/hn treatment (Calza et al., 2004b).
Carbamazepine. Carbamazepine is a carboxamide-
type anticonvulsant widely used to control generalized
tonic-chronic seizures (Merck & Co., 1999). This pharma-
ceutical has been found ubiquitously in the aquatic envir-
onment often at 1 to 2 mg/L levels (Ternes, 1998; Sacher
et al., 2001; Stackelberg et al., 2004) and is probably one of
the most persistent pharmaceuticals in the environment.
Carbamazepine is highly resistant to biodegradation
(Clara et al., 2004). It has been also suggested that
N
N N O
N N
N
O NH2
O
buspirone (385.51) carbamazepine (236.27)
H
O O N
N N NH
O
Cl primidone (218.25)
diazepam (284.74)
FIGURE 16. Anticonvulsants and anti-anxiety agents.
December 2006 369
 N
N N O N
•OH
N N NH
N N

buspirone O •OH 1-pyrimidinyl piperazine

•OH

N N
N N O N N O
N HO N
N N
hydroxy-bispirone hydroxy-bispirone
OH
O O
•OH •OH
•OH HN
•OH N N O
H2N
N N
N N O
HO N
O
N •OH
dihydroxy-buspirone despyrimidinyl
OH buspirone-amidine
N O
N N O
HN N O
N •OH
N
N
oxo-buspirone O despyrimidinyl
O
buspirone O
HN
N N O
H2N
N
despyrimidinyl-hydroxy-buspirone-amidine OH
O

FIGURE 17. Oxidative transformation of buspirone by TiO2/hn treatment (Calza et al., 2004b).

carbamazepine-glucuronide conjugate can be cleaved in
sewage treatment plant, which may contribute to the
increase of environmental concentration of this drug
(Ternes, 1998).
High reactivity of carbamazepine toward ozonation
was reported by several groups of researchers
(Andreozzi et al., 2002; Ternes et al., 2002; Huber et al.,
2003). For example, an applied ozone dose of 0.5 mg/L
was sufficient to convert 1 mg/L carbamazepine spiked in
surface water after flocculation ([DOC] = 1.3 mg/L) at
pH 7.8 (Ternes et al., 2002). Andreozzi et al. (2002) also
reported a complete conversion of 118 mg/L carbamaze-
pine and 30% mineralization monitored as CO2 evolution
in one hour of ozonation treatment at a utilized ozone
dose of 1.0 mg/L at pH 5.5. Algal toxicity of carbamaze-
pine was diminished after the ozone treatment (Andreozzi
et al., 2002).
Two considerably large second-order rate constants
for the molecular ozone reaction of carbamazepine at 25

C were reported: 7.81 · 104 M1s1 (Andreozzi et al.,
2002) and 3 · 105 M1s1 (Huber et al., 2003). The rate
constant was pH-independent (Huber et al., 2003), which
is apparent from the molecular structure of carbamaze-
pine. A number of degradation intermediates were iden-
tified in two separate studies (Andreozzi et al., 2002;
McDowell et al., 2005) as shown in Figure 18. It was
suggested that an ozone molecule first attacked the
non-aromatic carbon-carbon double bond of carbamaze-
pine, leading to ring opening through the Criegee
mechanism, followed by ring closure to form the quinazo-
line moiety of 1-(2-benzaldehyde)-4-hydro-(1H,3H)-quina-
zoline-2-one (BQM) shown in the figure [see McDowell et
al. (2005) for the detail of proposed reaction mechanism].
Quinazoline derivatives were also detected in the surface
water treated by ozone in a full scale water treatment
plant (McDowell et al., 2005). McDowell et al. (2005)
also presented a kinetic model that accounted for the
formation and subsequent degradation of these
intermediates.
Vogna et al. (2004b) reported a different pathway of
carbamazepine degradation by H2O2/UV AOP (Figure 19),
which involves epoxidation of the carbon-carbon double
bond followed by the formation of a heteroaromatic inter-
mediate, acridine. Carbamazepine could be converted

370 K. Ikehata et al. December 2006


N
O3
O N
N
O
O NH2
carbamazepine BQM
FIGURE 18. Degradation of carbamazepine by ozonation [BQM: 1-(2-benzaldehyde)-4-hydro-(1H,3H)-quinazoline-2-one, BQD: 1-(2-benzalde-
hyde)-(1H,3H)-quinazoline-2,4-dione, BaQD: 1-(2-benzoic acid)-(1H,3H)-quinazoline-2,4-dione] (Andreozzi et al., 2002; McDowell et al., 2005).
rapidly by H2O2/UV treatment; about 4.7 mg/L carbama-
zepine was completely converted within 4 min of treatment
with 170 mg/L H2O2 and UV irradiation at 254 nm using a
17 W low-pressure Hg lamp (2.7 · 106 Einsteins1) at pH
5.0 (Vogna et al., 2004b). About 35% of initial TOC was
also removed during the 4-min H2O2/UV treatment, which
is apparently more efficient than ozonation (Andreozzi
et al., 2002). A negative effect of humic substances on the
aqueous carbamazepine degradation was observed (Vogna
et al., 2004b). Two different second-order rate constants
for the hydroxyl radical reaction of carbamazepine were
reported: 2.05 · 109 M1s1 (Vogna et al., 2004b) and 8.8 ·
109 M1s1 (Huber et al., 2003). The difference might be
originated from the difference in the methods of rate con-
stant determination: the former group used a direct model
fitting with the experimental data, whereas the latter group
employed a competition kinetics method using p-chloro-
benzoic acid as a reference compound.
Recently, the carbamazepine degradation by TiO2
photocatalysis was investigated in a series of study (Doll
and Frimmel, 2004, 2005a, 2005b, 2005c). Doll and
Frimmel (2004) showed that as compared with other
persistent pharmaceuticals including clofibric acid, iome-
prol, iopromide, carbamazepine could be rapidly
degraded by TiO2/hn process. More than 90% of initial
carbamazepine (4.2 mg/L) was converted in nine minutes
by treatment using 100 mg/L TiO2 (P25) and a 1000-W
xenon short-arc lamp as a source of simulated solar UV
rays (1.35 · 104 Einsteinm2s1, l <400 nm) at pH 6.5
(Doll and Frimmel, 2005a). A successful pilot-scale inves-
tigation of the continuous treatment of carbamazepine by
the TiO2/hn process was reported using a cross-flow
microfiltration to retain catalyst (Doll and Frimmel,
2005b). The degradation of carbamazepine was strongly
inhibited in the presence of NOM in a lake water sample
by competing for hydroxyl radicals, as well as by deacti-
vating TiO2 catalyst surface by adsorption (Doll and
Ozonation and Advanced Oxidation of Pharmaceuticals
O O
HN HN
O3 O3
O N O N O
O OH
BQD BaQD
(further degradation)
oxamic acid, oxalic acid,
glyoxylic acid, glyoxal, CO 2
Frimmel, 2005a). Doll and Frimmel (2005c) identified a
number of carbamazepine degradation products during
the TiO2/hn treatment, and a degradation pathway simi-
lar to the one proposed for H2O2/UV AOP (see Figure 19)
was indicated. They also suggested the possible environ-
mental impact of acridine and its derivatives generated
during the carbamazepine degradation as these com-
pounds are polycyclic heteroaromatics known to be
toxic to aquatic organisms, especially via photosensitiza-
tion (Wiegman et al., 2002).
Diazepam. Diazepam is a benzodiazepine-type anti-
anxiety agent that is also used to treat many other
neurological and psychiatric disorders such as sleep dis-
order, movement disorders, and motion sickness (Merck
& Co., 1999). After administration, diazepam is meta-
bolized and excreted mainly in the urine. Huber et al.
(2003) reported very slow degradation of diazepam by
molecular ozone with a second-order rate constant of
0.75 M1s1 at 20 C. Ozonation of 142 mg/L diazepam
in natural water samples resulted in 24% to 65% con-
version of this pharmaceutical (applied ozone dose = 2
mg/L, 10 min, pH 8, 10 C). Their kinetic analysis
revealed that the diazepam was mostly degraded
through hydroxyl radical reactions (kOH = 7.2 · 109
M1s1) (Huber et al., 2003). Deactivation of aromatic
rings by the imine group (C=N-) and chlorine atom
(Beltrán, 2003) may be the reason for the low reactivity
of diazepam toward ozonation. No degradation inter-
mediate/by-product was determined.
Primidone. Primidone is an anticonvulsant of the pyr-
imidinedione class, which used to treat disorders of move-
ment such as tremor (Merck & Co., 1999). This drug is
metabolized in the liver to phenobarbital, which is also an
anticonvulsant (Bergey, 2004), and excreted in the urine.
Ternes et al. (2002) reported moderate reactivity of primi-
done toward ozonation. About 87% of 1 mg/L primidone
spiked in a flocculated surface water sample was converted
December 2006 371

•OH/HO2•
N
O NH2
carbamazepine
organic acids
O O
OH
NH2
2-aminobenzoic acid salicylic acid catechol
FIGURE 19. Degradation of carbamazepine by H2O2/UV treatment (Vogna et al., 2004b). Compounds in square brackets were not
identified.
by ozonation at an applied ozone dose of 3 mg/L, pH 7.8
and 23  C. No further study has been reported on the
degradation of this anticonvulsant by ozonation or AOP.
Summary of Anticonvulsants and Anti-Anxiety
Agents
Anticonvulsants and anti-anxiety agents reviewed here
showed different reactivity toward ozonation and AOPs.
This is primarily due to their structural diversity and the
absence of common reactive functional groups (see Figure 16).
Of the four pharmaceuticals, carbamazepine is readily degrad-
able by either molecular ozone or hydroxyl radicals.
Diazepam and primidone are relatively resistant to ozonation,
and the ozone treatment of buspirone has not been documen-
ted. Carbamazepine degradation by ozonation and AOPs
(H2O2/UV and TiO2/hn) has been extensively investigated,
probably due to its relevance and persistence in the aqueous
environment. Degradation pathways for this drug during
these oxidative treatment processes have been proposed by
several groups of investigators (Figures 18 and 19). While one
report has demonstrated the diminution of algal toxicity of
carbamazepine by ozonation, the formation of acridine deri-
vatives through advanced oxidation of the same drug (see
Figure 19) may warrant closer attention and possible caution
because of the potential ecotoxicity of these heteropolyaro-
matic by-products. Further study may be required on the
372 K. Ikehata et al.
HO OO O
N N
O NH2 O NH2
R R
N N
O NH2 •OH
R = -COOH
•OH N
•OH
acridine
OH
OH
OH OH
N OH
hydroxyacridine
other three drugs, as well as on those anticonvulsants/antide-
pressants currently marketed and prescribed frequently, such
as paroxetine (Kwon and Armbrust, 2004).
ANTIPYRETICS AND NON-STEROIDAL ANTI-
INFLAMMATORY DRUGS (NSAIDS)
Antipyretics and non-steroidal anti-inflammatory
drugs (NSAIDs) comprise one of the major classes of
pharmaceuticals commonly consumed in both prescrip-
tion and non-prescription drugs. The NSAIDs covered in
this review include diclofenac, ibuprofen, indomethacin,
naproxen, and salicylic acid. These are the drugs with
analgesic (reduce pain), antipyretic (reduce fever), and
anti-inflammatory effects by inhibiting prostaglandin
synthesis by inhibition of cyclooxygenase (COX) (Merck
& Co., 1999). Another popular antipyretic agent, para-
cetamol, which is also known as acetaminophen and
covered in this section, has negligible anti-inflammatory
effect and is not classified as NSAID. Molecular structure
and molecular weight of these pharmaceuticals can be
found in Figure 20. It should be noted that they are all
acidic drugs.
Diclofenac. Diclofenac is a NSAID commonly used
for musculoskeletal complaints such as arthritis. This
acidic drug has been frequently detected in surface water
December 2006

O conversion) in 1.5 h using a 17-W low-pressure Hg lamp
Cl
O
NH
O O
Na+
Cl OH
diclofenac (318.13)
ibuprofen (206.28)
indomethacin (357.79)
OH
O
O O
O HO
OH
naproxen (230.26)
OH
paracetamol (151.17)
salicylic acid (138.12)
FIGURE 20. Antipyretics and non-steroidal anti-inflammatory
drugs (NSAIDs).
(Ternes, 1998), groundwater (Sacher et al., 2001), and
wastewater effluent (Ternes, 1998; Soulet et al., 2002;
Ternes et al., 2003), with concentration levels up to 1.3
mg/L (Ternes et al., 2003). A number of studies indicated
a high reactivity of diclofenac toward ozonation (Zwiener
and Frimmel, 2000; Ternes et al., 2002, 2003; Huber et al.,
2005). For example, as low as 1 mg/L applied ozone was
enough to convert 1 mg/L diclofenac spiked in a floccu-
lated surface water sample at pH 7.8 and 23  C (Ternes
et al., 2002). Huber et al. (2003) reported a large second
order rate constant (1 · 106 M1s1) for the reaction of
ozone with this pharmaceutical in the dissociated form at
pH 5–10 and 20  C. Another kinetic study indicated
smaller rate constants ranging from 1.76 · 104 to 1.84 ·
104 M1s1 at pH 5–6 and 25  C (Vogna et al., 2004a).
The inconsistency may be due to the difference in meth-
ods used by these two groups of investigators: the com-
petition kinetics method employed by the former
researchers and the direct measurement of residual drug
using HPLC by the latter. Various degradation intermedi-
ates have been identified during the ozonation treatment
of 1 mM (296 mg/L) diclofenac at pH 7.0 (Vogna et al.,
2004a). Hydroxylation of the aromatic rings and cleavage
at the diphenyl amine nitrogen likely occur simulta-
neously during the treatment (Figure 21), followed by
the ring opening and further mineralization. About 95%
of chlorine from diclofenac molecules was released as
chloride and more than 30% of initial TOC was removed
after 1.5 h of ozonation treatment (Vogna et al., 2004a).
Several AOPs have been also evaluated for the degra-
dation of diclofenac. Zwiener and Frimmel (2000) noted a
positive effect of hydrogen peroxide addition on the
diclofenac conversion by ozone. A second-order rate con-
stant for the reaction of hydroxyl radical and diclofenac
was determined as 7.2 · 109 M1s1 (Huber et al., 2003).
Vogna et al. (2004a) investigated H2O2/UV treatment of
this pharmaceutical and compared the results with
Ozonation and Advanced Oxidation of Pharmaceuticals
ozonation and direct photolysis. Diclofenac (296 mg/L)
O
OH was degraded by direct photolysis to some extent (>45%
emitting UV light at 254 nm with an intensity of 2.7 ·
N 10–6 Einsteins1. The diclofenac degradation was
O strongly enhanced by the addition of hydrogen peroxide
Cl
(170 mg/L; H2O2/UV AOP) to more than 90% conver-
sion. About 50% of chlorine was recovered as chloride
ion and about 40% of TOC was removed during the
treatment (Vogna et al., 2004a). Although the extent of
diclofenac dechlorination was apparently less than that
NH achieved by ozonation, this is likely due to the incomplete
degradation of parent compound and intermediates in the
H2O2/UV treatment, and may be improved by optimizing
hydrogen peroxide dose. A number of degradation inter-
mediates were identified during the H2O2/UV treatment
of diclofenac as shown in Figure 21. Substitution of one
of two chlorine atoms with hydroxyl group was one of the
unique degradation pathways of this UV assisted AOP
(Vogna et al., 2004a). Andreozzi et al. (2004) reported the
effective detoxification of a mixture of pharmaceuticals
containing 2.8 mg/L diclofenac and five other drugs by
ozonation and H2O2/UV treatment (see Ofloxacin, qui-
nolone antibiotic for the details).
The Fenton-type process has an apparent disadvan-
tage on the degradation of acidic drugs such as diclofenac
(pKa = 4.15) because the drug precipitates in an acidic
medium, which is required maintaining iron in solution.
Packer et al. (2003) observed no conversion of diclofenac
by Fenton treatment at pH 3.5 and 22  C. While increas-
ing pH can help the dissolution of the drug, precipitation
of iron hydroxides occurs at high pH. To overcome this
difficulty, it was suggested that the addition or generation
of organic ligands or photo-reduction of colloidal iron to
soluble ferrous ion by UV irradiation might improve the
performance of Fenton-type oxidation of diclofenac
(Pérez-Estrada et al., 2005b). Ravina et al. (2002) investi-
gated photo-Fenton oxidation of diclofenac using a con-
centric photo-reactor with a 400 W low-pressure Hg lamp
(l = 254 nm). Majority of initial TOC (> 90%) could be
removed from 10 to 80 mg/L diclofenac solution within 1
h by photo-Fenton treatment with 14 mg/L Fe2+ and 340
mg/L H2O2 at pH 2.8 and 50  C. No remark was given on
the solubility of diclofenac in this study, although it may
be possible that the drug solubility increased at the ele-
vated temperature. It was noted that dark Fenton and
H2O2 alone with UV irradiation (H2O2/UV) were much
less effective than the photo-Fenton treatment (Ravina
et al., 2002).
Perez-Estrada et al. (2005b) reported that neutral and
acidic photo-Fenton treatment in buffered media was not
very effective for diclofenac degradation because of the
precipitation of either drug or iron hydroxides. The
photo-Fenton treatment was performed in a pilot scale
solar photo reactor at 35  C ([diclofenac]0 = 50 mg/L,
concentration of H2O2 was maintained around 200 to
December 2006 373
 Cl
Cl
O NH2 ring
(only by NH opening
H2O2/UV) OH Cl +
Cl
diclofenac O
OH HO
O OH
NH
OH
Cl
OH Cl
HO O
Cl
Cl O HO NH
O NH OH
NH OH Cl
OH Cl
Cl (only by
H2O2/UV)

OH Cl
Cl
HO HO OH
NH2 O
O O
H2N
HO HO Cl
Cl OH
OH OH

ring opening

FIGURE 21. Degradation of diclofenac by ozonation and H2O2/UV AOP (Vogna et al., 2004a).

400 mg/L by continuous addition). A non-buffered sys-
tem with an initial pH of 7.0 was superior to the buffered
systems; however, some precipitation and subsequent
re-dissolution of diclofenac was observed during the treat-
ment. This was likely due to the pH drop (around pH 4.0)
as a result of the generation of organic acids intermediates.
Consequently, Perez-Estrada et al. (2005b) recommended a
pH control around 4.5 to 5 for the photo-Fenton treat-
ment of diclofenac. A number of degradation intermedi-
ates were detected during the photo-Fenton treatment
(Ravina et al., 2002; Pérez-Estrada et al., 2005a).
Hydroxylation and subsequent quinoneimine formation
depicted in Figure 22 was considered as the major degra-
dation pathway of diclofenac in the photo-Fenton process
(Pérez-Estrada et al., 2005a). These quinoneimine inter-
mediates are likely decomposed into hydroquinone deriva-
tives and aniline derivatives that have been detected in
ozonation and H2O2/UV treatment (Figure 21). Near-
quantitative recovery of chlorine and nitrogen as chloride
and ammonium, respectively, was also confirmed during
the treatment (Pérez-Estrada et al., 2005a).
Titanium dioxide photocatalysis was also evaluated for
the degradation of diclofenac in the same solar photo
reactor employed in the photo-Fenton process discussed
above (Pérez-Estrada et al., 2005b). Complete conversion
of 43 mg/L diclofenac was achieve with 0.2 g/L TiO2 in 200
min, which was twice longer than the case of photo-Fenton
treatment. Chloride and ammonium ions were detected
during the TiO2/hn treatment (Pérez-Estrada et al., 2005b).
Ibuprofen. Ibuprofen is a NSAID widely used for the
relief of headache, rheumatoid arthritis, fever, and
general pain, and is an active ingredient of a number of
over-the-counter pain-relief drugs. Ibuprofen has been
frequently detected in the aquatic environment (Halling-
Sørensen et al., 1998; Ternes, 1998; Heberer, 2002; Kolpin
et al., 2002; Boyd et al., 2003). Moderate reactivity of this
NSAID toward ozonation was reported (Zwiener and
Frimmel, 2000; Ternes et al., 2003; Huber et al., 2005).
A second-order rate constant for the molecular ozone
reaction of ibuprofen was reported as 9.6 M1s1
(Huber et al., 2003), which is much lower than that of
diclofenac. This is primarily due to the absence of reactive
functional group or moiety such as amine and non-aro-
matic carbon-carbon double bonds in the ibuprofen
molecule, besides the aromatic ring that is weakly acti-
vated by the isobutyl group (see Figure 20).
Zwiener and Frimmel (2000) reported that ozonation
(1 mg/L applied ozone) alone was not sufficient to

374 K. Ikehata et al. December 2006


Cl Cl
O O
NH
OH
Cl Cl
diclofenac
O O
O O
Cl
Cl
N OH
N HO
Cl
Cl
FIGURE 22. The major degradation pathways of diclofenac (via quinoneimine formation) by photo-Fenton process (Pérez-Estrada et al., 2005).
convert 2 mg/L ibuprofen in distilled water, resulting in
only 12% conversion in 10 min. However, increasing the
ozone dose and adding hydrogen peroxide (O3/H2O2
AOP) greatly improved the ibuprofen conversion. They
also investigated the effect of water matrix on the degra-
dation of ibuprofen using a river water sample. The pre-
sence of hydroxyl radical scavenger, bicarbonate ion and
natural DOC, in the river water significantly reduced the
extent of ibuprofen conversion by O3/H2O2 AOP, imply-
ing the importance of hydroxyl radical reactions. In the
river water, they noted that the treatment with 5.0 mg/L
applied ozone and 1.8 mg/L hydrogen peroxide was suffi-
cient to convert 2 mg/L ibuprofen in 10 min at pH 7.5 and
10  C (Zwiener and Frimmel, 2000). Two comparable
second-order rate constants for the hydroxyl radical reac-
tion of this pharmaceutical were reported: 6.5 · 109
M1s1 at pH 3.5 and 22  C by Fenton (Packer et al.,
2003) and 7.4 · 109 M1s1 at pH 7 and 25  C by H2O2/
UV (Huber et al., 2003). No further study was found on
the mineralization of ibuprofen by ozonation or AOP, or
the degradation pathway of this NSAID.
Indomethacin and Naproxen. Indomethacin and
naproxen are NSAIDs having methylated indole and
naphthalene rings, respectively. Like other acidic
NSAIDs, the occurrence of these compounds in the
aquatic environment have been reported (Halling-
Sørensen et al., 1998; Ternes, 1998), although their
environmental concentrations are generally less than
those of diclofenac and ibuprofen. Ternes et al. (2003)
reported the effective abatement of 0.1 mg/L indometha-
cin and 0.1 mg/L naproxen present in a biologically
treated wastewater sample by ozonation at pH 7.2 with
an applied ozone dose of 5 mg/L. Similar result was
reported by Huber et al. (2005) as well, although the
concentrations of these drugs were not specified. A
second-order rate constant for the hydroxyl radical
Ozonation and Advanced Oxidation of Pharmaceuticals
OH O
Cl
O
NH N
OH OH
Cl
Cl-
OH
Cl
O
O
N
N
OH
OH
Cl
Cl
reaction of naproxen has been reported as 9.6 · 109
M1s1 at pH 3.5 and 22  C using Fenton reaction to
generate hydroxyl radicals (Packer et al., 2003). No
further study has been found on the ozonation or
advanced oxidation treatment of these NSAIDs.
Salicylic Acid. Salicylic acid is a decomposition pro-
duct of acetylsalicylic acid (aspirin), which is a common
over-the-counter NSAID. Salicylic acid itself, which is
derived naturally from willow tree bark, has been also
used as an antipyretic since ancient times, and still been
used as an additive of some skin-care products (Merck &
Co., 1999). Only one study on salicylic acid removal by
ozonation has been reported. Khan et al. (2004) demon-
strated partial degradation of salicylic acid by ozonation
in the advanced water recycling demonstration plant in
Australia. The demonstration plant consists of lime clar-
ification, dissolved air flotation, dual media filtration,
ozonation, biological activated carbon filtration, micro-
filtration, combined reverse osmosis/nanofiltration, and
UV disinfection. About 60% of 0.65 mg/L salicylic acid
found in the influent of ozonation unit was degraded by
ozonation at an ozone dose of 17.5 mg/L for 15 min
(Khan et al., 2004). No further study has been reported
on the degradation of salicylic acid or acetylsalicylic acid
by ozonation or AOP.
Paracetamol. Paracetamol, also known as acetami-
nophen, is a non-NSAID antipyretic agent used for the
relief of fever, headaches, and other minor aches and
pains. This drug is metabolized in the liver to mostly
sulfate- and glucuronide-conjugates and excreted in the
urine (Johnson and Plumb, 2005). Andreozzi et al.
(2003a) showed that ozonation at pH 2 and 7 could
effectively degrade 0.8 g/L paracetamol in 30 min with
an ozone flow rate of about 72 g/h (reactor
volume = 1.09 L). After two hours of ozonation, about
20% and 30% of initial TOC was removed from the
December 2006 375
paracetamol solution at pH 2 and 7, respectively. A num- 1,4-hydroquinone and 1,4-benzoquinone as a result of
ber of degradation intermediates were formed during the either para-hydroxylation (with respect to hydroxyl
ozone treatment. The evolution of intermediates follows group) or hydrogen abstruction from a phenoxyl OH
typical phenol ozonation pathways, such as hydroxyla- can occur during the H2O2/UV treatment of paracetamol
tion of phenol ring, anomalous ozonation to cleave aro- (Figure 24) (Vogna et al., 2002).
matic ring of hydroquinone, and decarboxylation by In addition to ozonation and H2O2/UV AOP, anodic
hydroxyl radicals [see Andreozzi et al. (2003a) for the oxidation using a boron-doped diamond electrode has
details]. A simplified version of the proposed degradation been investigated for paracetamol degradation (Brillas
scheme of paracetamol is shown in Figure 23. In addition, et al., 2005). This electrochemical treatment employs
Andreozzi et al. (2003a) suggested the acid-catalyzed adsorbed hydroxyl radicals generated at anode surface
hydrolysis of amidic intermediates to occur. Second- by electrolysis of water:
order rate constants were determined for the reaction
between molecular ozone and two forms of paracetamol H2 O ! OHads þ Hþ þ e
as 1.41 · 103 M1s1 (neutral) and 9.91 · 108 M1s1
(dissociated, pKa = 9.36) (Andreozzi et al., 2003a). OH ! OHads þ e
Andreozzi et al. (2003a) also investigated the parace-
The boron-doped diamond thin-film anode is much more
tamol degradation by H2O2/UV AOP. They noted that
efficient in generating hydroxyl radicals than other con-
strong enhancement of photo-degradation of this phar-
ventional anodes such as platinum, PbO2, doped PbO2,
maceutical by the addition of hydrogen peroxide. More
doped SnO2 and IrO2, and enabled 70% to 98% miner-
than 90% of 1.51 mg/L paracetamol was converted in one
alization (monitored as TOC) of up to 948 mg/L para-
minute by the H2O2/UV treatment at pH 5.5
cetamol after 4 h of treatment (Brillas et al., 2005). The
([H2O2]0 = 170 mg/L, a low-pressure Hg lamp, l = 254 nm).
TOC removal by this electrochemical treatment was pH-
Mineralization monitored as TOC removal was also
independent in the pH range of 2.0 to 12.0. Oxalic acid
confirmed during the treatment (Andreozzi et al.,
and oxamic acid were detected as degradation intermedi-
2003a). A variety of degradation products were identified
ates, which further degraded into carbon dioxide, ammo-
as shown in Figure 23 (Vogna et al., 2002; Andreozzi
nium, and nitrated (Brillas et al., 2005).
et al., 2003a), and kinetic rate constants for paracetamol
degradation by hydroxyl radicals was determined as 2.2 ·
109 M1s1 at pH 5.5 (Andreozzi et al., 2003a). Besides Summary of Antipyretics and NSAIDs
the hydroxylation of the aromatic ring, the formation of
Antipyretics and NSAIDs reviewed here have shown
relatively low (e.g., ibuprofen) to high reactivity (e.g.,
HO
diclofenac) toward ozonation. Except for the cases of
O O3 or •OH O diclofenac and paracetamol, the information on the
HO NH HO NH
degradation of these pharmaceuticals by ozonation and
paracetamol O AOPs is generally limited. Degradation pathways have
O3
O NH2 been proposed for diclofenac and paracetamol using var-
•OH •OH ious treatment processes (Figures 21–24). Some kinetic
NH2 OH OH
HO O O data are available for diclofenac, ibuprofen, naproxen,
O3 O and paracetamol. No potential ecological impact of
HO OH HO OH HO NH
•OH these pharmaceuticals and their treatment by ozone and
O3 or advanced oxidation has been yet clearly addressed.
•OH •OH CO2
HO •OH Information is lacking on the treatment of other envir-
O O
O
onmentally relevant NSAIDs including ketoprofen
OH HO OH HO
HO O O (Ternes, 1998; Soulet et al., 2002) and mefenamic acid
HO
HO
O
HO
O
HO NH (Soulet et al., 2002), although their occurrences are less
HO OH frequent than the ones covered in this review, such as
O O diclofenac and ibuprofen.
OH OH
O3 or •OH
O3 or •OH
b-Blockers
Beta (b)-blockers are a class of drugs used to treat a
organic acids
(e.g., oxalic acid, formic acid, glyoxalic acid, ketomalonic acid), variety of cardiovascular diseases, such as hypertension,
mineralization of organic acids coronary artery disease, and arrhythmias, by blocking the
action of epinephrine and norepinephrine on the b-adre-
FIGURE 23. Degradation of paracetamol by ozonation and H2O2/
nargic receptors in the body, primarily in the heart
UV AOP (Vogna et al., 2002; Andreozzi et al., 2003).
(Merck & Co., 1999). The b-blockers covered in this

376 K. Ikehata et al. December 2006

 O

NH
O HO OH
•OH HO NH
OH
O 1,4-hydroquinone
HO NH - H•
O
paracetamol HO NH
- H• •OH OH O
O
O NH NH2

O O
- H•
O
O N 1,4-benzoquinone
O

NH2

FIGURE 24. Formation of 1,4-hydroquinone and 1,4-benzoquinone from paracetamol by H2O2/UV AOP (Vogna et al., 2002).

section include atenolol, celiprolol, metoprolol, propra- required to completely convert 0.36 mg/L atenolol and
nolol, and sotalol. While propranolol and sotalol are non- 1.7 mg/L metoprolol (Ternes et al., 2003). No further
selective b-blockers, the others are b1 antagonists (selec- study has been published on the degradation of these
tive b-blockers). Chemical structure and molecular weight b-blockers, except for propranolol (see below), by ozona-
of these pharmaceuticals are shown in Figure 25. tion or AOP.
Atenolol, Celiprolol, Metoprolol, and Sotalol. Ternes Propranolol. In addition to the study conducted by
et al. (2003) demonstrated that ozonation at pH 7.2 was Ternes et al. (2003) above, the high reactivity of propra-
effective for the degradation of five b-blockers, namely nolol toward ozonation was also reported elsewhere
atenolol, celiprolol, metoprolol, propranolol, and sotalol, (Andreozzi et al., 2004). Complete conversion of 325.5
present in an effluent from municipal sewage treatment mg/L propranolol was achieved by ozonation in 2 min at
plant. Celiprolol, propranolol, and sotalol were appar- an absorbed ozone dose of as low as 4.75 mg/L, pH 7.4
ently more reactive than atenolol and metoprolol: 5 mg/L and 25  C in a mixture of six pharmaceuticals, including
of applied ozone was sufficient to convert 0.28 mg/L ofloxacin, sulfamethoxazole, carbamazepine, clofibric
celiprolol, 0.18 mg/L propranolol, and 1.32 mg/L sotalol, acid, diclofenac, and propranolol. Besides ozonation,
whereas higher ozone dose (i.e., 10 to 15 mg/L) was H2O2/UV treatment ([H2O2]0 = 5–10 mM, a low-pressure
Hg lamp, l = 254 nm, 2.51 · 106 Einsteins1) was also
effective for the complete conversion of propranolol at
NH2 O
H pH 7.4 and 25  C, whereas TiO2 photocatalysis was less
O N N
N O effective (Andreozzi et al., 2004). Algal (Synechococcus
H
OH N O
O leopoliensis) and protozoan (Brachionus calyciflorus) toxi-
H
atenolol (266.34) OH cities of the drug mixture were eliminated completely by
celiprolol (379.50) the ozone treatment. It was also shown that the H2O2/UV
O treatment was also effective in algal toxicity reduction;
O N
however, it was less effective in protozoan toxicity reduc-
N O H
H
OH OH tion. Finally, no toxicity reduction was achieved by the
TiO2/hn treatment (Andreozzi et al., 2004). Degradation
metoprolol (267.37)
intermediates or by-products of propranolol were not
propranolol (259.35)
OH
determined.

O O
S HN
N
H
Summary of b-Blockers
Despite their prevalence in the aquatic environment
sotalol (272.36) (Ternes, 1998; Sacher et al., 2001; Bendz et al., 2005),
there have been very few reports on the degradation of
FIGURE 25. Beta-blockers.
aqueous b-blockers by ozonation and AOPs. Neither

Ozonation and Advanced Oxidation of Pharmaceuticals December 2006 377

kinetics nor degradation by-product information is avail-
able. Based on the limited information in the literature, it
seems that all b-blockers reviewed here are fairly reactive
toward ozonation. These pharmaceuticals contain a sec-
ondary amine group and a weakly/moderately activated
aromatic ring that are probable targets of molecular
ozone and hydroxyl radical attacks (see Figure 25). It
has been reported that the toxicity of a drug mixture
containing one of the b-blockers (propranolol) can been
removed by ozonation and H2O2/UV AOP. However, the
toxicity of degradation by-products/intermediates of indi-
vidual compounds is still unknown. Although the pre-
sence and extent of ecological impact of environmental
b-blockers is uncertain, more study may be needed to
confirm no generation of potentially toxic intermediates
and by-products from the oxidative treatment of these
pharmaceuticals.
Cytostatic Drugs
Cytostatic drugs, also known as antineoplastic agents,
are the pharmaceuticals used to treat various forms of
cancers. Some cytostatic drugs are also used to treat
autoimmune diseases and to suppress transplant rejec-
tions. There are a number of classes of cytostatic drugs,
such alkylating agents, anti-metabolites, alkaloids, and
anti-tumor antibiotics. The majority of these drugs inter-
fere with mitosis (cell division) to selectively kill fast-
growing tumor cells through a number of mechanisms
such as inhibition of DNA synthesis. Cytostatic drugs
are cytotoxic by nature, as well as potentially carcino-
genic and genotoxic (Merck & Co., 1999). The cytostatic
drugs reviewed here include six anthracyclines anti-tumor
antibiotics (aclarubicin, daunorubicin, doxorubicin, epir-
ubicin, idarubicin, and pirarubicin; Figure 26a), four anti-
metabolites (5-fluorouracil, azathioprine, cytarabine, and
methotrexate; Figure 26b), and three nitrogen mustard
alkylating agents (cyclophosphamide, ifosfamide, and
melphalan; Figure 26b, inset).
Anthracyclines (Aclarubicin, Daunorubicin, Doxo-
rubicin, Epirubicin, Idarubicin, and Pirarubicin).
Anthracyclines are chemotherapeutic antibiotics that
inhibit DNA and RNA synthesis by intercalating between
base-pairs of the DNA or RNA strands. They have a
common structure: 7,8,9,10-tetrahydro-5,12-naphthace-
nedione moiety with a sugar chain (see Figure 26a).
Castegnaro et al. (1997) evaluated Fenton reagent as
well as sodium hypochlorite and hydrogen peroxide to
effectively decompose six anthracyclines, including aclar-
ubicin, daunorubicin, doxorubicin, epirubicin, idarubicin,
and pirarubicin, that may be found in hospital wastes at
high concentrations. All anthracyclines (0.4 to 5 g/L; see
Appendix for the concentrations of individual drugs)
were completely degraded after 1 h of treatment with
either 2.6% sodium hypochlorite or Fenton reagent
(10.3 g/L Fe2+, 150 g/L H2O2, pH unknown), and there
was no residual mutagenicity, assayed by the Ames test
378 K. Ikehata et al.
with or without metabolic activation. It was also noted
that hydrogen peroxide alone (150 g/L) was not very
effective. No degradation products were detected by
HPLC with a spectrofluorimeter, indicating effective
destruction of the naphthacenedine moiety (Castegnaro
et al., 1997). No further study has been reported on the
degradation of anthracyclines by ozonation or AOP.
Anti-Metabolites (Azathioprine, Cytarabine, 5-Fluor-
ouracil, and Methotrexate). Anti-metabolites are cyto-
static drugs that mimic purine or pyrimidine and keep
them from being incorporated into DNA or RNA.
Azathioprine is an immunosuppressive agent widely
used in transplantations to control rejection reactions
(Merck & Co., 1999). Rey et al. (1999) reported effective
degradation of four anti-metabolite cytostatic drugs (269
to 499 mg/L), including azathioprine, cytarabine, 5-fluor-
ouracil, and methotrexate, by ozonation at pH 3 and 7
(not azathioprine because of its poor solubility at neutral
pH) within 1 h. They noted that there was no apparent
difference in the reaction rates at two pHs, indicating the
major contribution of molecular ozone reactions over
hydroxyl radicals, and that the presence of multiple
reactive sites, which is apparent from their molecular
structures (see Figure 26b). Mutagenicity of these anti-
metabolites, with or without metabolic activation, were
diminished after the ozone treatment (Rey et al., 1999).
Degradation by-products were not identified in this
study.
Alkylating Agents (Cyclophosphamide, Ifosfamid,
and Melphalan). As the name suggests, alkylating
agents are cytostatic drugs capable to covalently modify
electronegative groups of DNA (i.e., DNA alkylation),
and thus interfere DNA replication in tumor cells. Similar
to the cases of anthracyclines above, Fenton oxidation, as
well as chlorination, of three alkylating agents, including
cyclophosphamide, ifosfamid, and melphalan, were inves-
tigated as an effective treatment of hospital wastes con-
taminated with these cytotoxic pharmaceuticals (Hansel
et al., 1997). It was demonstrated that complete conver-
sion of these alkylating agents could be achieved by the
treatment with Fenton reagent (10.3 g/L Fe2+, 150 g/L
H2O2, pH unknown) within one hour. However, the for-
mation of unidentified direct mutagens was noticed by
the Ames test in the treated cyclophosphamide formula-
tion that had also contained 5% dextrose (Hansel et al.,
1997). As no residual mutagenicity was found in the same
formulation without dextrose, this additive was complet-
ing for the oxidant (hydroxyl radicals) with cyclopho-
sphamide, resulting in incomplete destruction of
mutagenic degradation by-products.
Summary of Cytostatic Drugs
A large number of cytostatic drugs have been exam-
ined for their degradation by ozonation or Fenton pro-
cess in a very limited number of studies. The
concentrations of the drugs treated therein were very
December 2006
 feces of patients as suggested by Castegnaro et al.
O
O O
O
(1997). In addition to the cytostatic drugs reviewed
O OH
here, further study is needed on the ozone and advanced
OH OH oxidation treatment of many other drugs used for che-
motherapy. One of the cytostatic drugs whose occur-
OH O OH O O O OH O rence has been described in the literature but not
O O covered here is bleomycin, a chemotherapeutic antibiotic
N NH2
O OH (Halling-Sørensen et al., 1998).
O
daunorubicin (527.53)
O OH
Histamine H2-Receptor Antagonists
O Histamine H2-receptor antagonists (H2 antagonist for
O OH O short) are the drugs used to block the action of histamine
O aclarubicin (811.88) OH
on the production of acid in the stomach. Two H2
OH
antagonists have been detected in surface water samples
O OH O
OH O O OH O in the U.S., including cimetidine and ranitidine (Figure 27),
OH HO O at concentrations up to 0.58 mg/L and 0.01 mg/L, respec-
NH2 tively (Kolpin et al., 2002).
O O OH O epirubicin (543.52) Cimetidine. Latch et al. (2003) investigated the reac-
O tion of cimetidine (and ranitidine) with hydroxyl radicals
NH2
OH
as one of the environmental degradation process. A sec-
O OH O ond-order rate constant for protonated form of cimeti-
doxorubicin (543.52) OH
dine (pKa = 7.1; Figure 28) was determined as 6.5 · 109
OH
M1s1 using a competitive kinetics method with aceto-
O
O OH O O OH O phenone as a reference compound (Latch et al., 2003).
OH O Several degradation products of cimetidine by Fenton
NH2 oxidation were reported elsewhere as shown in Figure 29
O
O OH O (Zbaida et al., 1986).
O
O Ranitidine. A very high second-order rate constant
NH2
OH pirarubicin (627.64) for the hydroxyl radical reactions was reported for the
protonated form of ranitidine (pKa = 8.2; Figure 28) as
idarubicin (497.50)
1.5 · 1010 M1s1 (Latch et al., 2003). Addamo et al.
FIGURE 26a. Cytostatic drugs, anthracyclines. (2005) reported the degradation of this H2-antagonist by
TiO2 photocatalysis. Almost complete conversion of
50 mg/L ranitidine was achieved by the TiO2/hn treat-
high (269 mg/L to 27 g/L) as compared with their envir- ment in 1 h with 0.4 g/L of catalyst and a 125 W medium
onmentally relevant concentrations (<0.1 mg/L) (Halling- pressure Hg lamp with a photon flux of 8.5 mWcm2 at
Sørensen et al., 1998; Ternes, 1998). This is due to the fact 40  C (Addamo et al., 2005). In addition, about 60% of
that these studies have been conducted to explore effec- TOC was removed by prolonged treatment for 5 h. On
tive treatment methods for highly polluted wastewaters. the other hand, direct photolysis was much less effective
The evaluated treatment methods were generally effec- in ranitidine conversion and mineralization (Addamo
tive to degrade the cytostatic drugs and to remove muta- et al., 2005). Hydroxylation of furan ring and S-oxidation
genicity, except for one case in which a were suggested as possible degradation pathways,
cyclophosphamide formulation was treated by the although they were not experimentally demonstrated.
Fenton process in the presence of 5% dextrose. This
emphasizes the importance of monitoring the evolution
of degradation intermediates and ensuring the complete Summary of Histamine H2-Receptor Antagonists
destruction of by-products during the treatment, espe- Very few studies have been published on the degrada-
cially when other wastewater constituents that may com- tion of histamine H2-receptor antagonists by AOPs, and
pete for oxidants are present. none has been reported on their ozone treatment. Since
No kinetics data are available for the degradation of two H2 antagonists appear to be fairly reactive toward
cytostatic drugs by ozonation or AOP. Although their ozonation because of the presence of a few reactive func-
environmental occurrence is rather rare because of their tional groups/moieties such as furan ring, amine, and
limited usage in the hospitals, effective treatment meth- thioether sulfur (see Figure 27), ozonation may be a
ods should be investigated for the hospital wastes con- good treatment process for surface water contaminated
taining parent cytostatic drugs as well as their active with these pharmaceuticals. Further study is required to
(i.e., cytotoxic) metabolites excreted in the urine and address the potential ecotoxicity of environmental H2

Ozonation and Advanced Oxidation of Pharmaceuticals December 2006 379

 NH2
N NO2
N
N S
H HO O N
N N HO
O
N N
OH
azathioprine (277.26) cytarabine (243.21)

H2N N N
O
F N N
HN N OH
H
NH2 N
O N O
H
O
5-fluorouracil (130.08) methotrexate (454.44)
O OH

O
Cl Cl
Cl
Cl OH
N Cl NH2
NH N
O P NH
O P N
O
O
Cl

cyclophosphamide (261.09) ifosfamid (261.09) melphalan (305.20)

FIGURE 26b. Cytostatic agents, anti-metabolites and nitrogen mustard alkylating agents (inset).

antagonists as well as their degradation by-products aris-

H
H
ing from the oxidative treatment such as ozonation and N NH2 HN S
N NH
HN S
advanced oxidation. N N
N N NH2
N O
N-desmethylcimetidine
cimetidine guanylurea derivative
HORMONES AND ORAL CONTRACEPTIVES
OH
A number of natural and synthetic steroid hormones H H
N NH N NH
are used in treatment of various types of medical condi- HN S HN S
N O N N O N
tions such as menopausal symptoms, growth hormone N N
deficiency, hypothyroidism, and some forms of cancers cimetidine sulfoxide 5-hydroxylmethylimidazole cimetidine sulfoxide

H H H FIGURE 29. Degradation products of cimetidine by Fenton pro-

N NH O N N
HN S N S cess (Zbaida et al., 1986).
N N
NO2
N
cimetidine (252.34) ranitidine (314.40) (Arcand-Hoy et al., 1998). Some natural and synthetic
estrogen hormones are also used as oral contraceptives.
FIGURE 27. Histamine H2-receptor antagonists.
Four types of estrogen hormones are covered in this
review, including 17b-estradiol, estrone, 17a-ethinylestra-
diol, and diethylstilbestrol (Figure 30). While the former
H H H
N NH O N N two are natural (endogenous) estrogens, the latter two are
HN S NH S
NH N
synthetic estrogens.
NO2
N 17b-Estradiol. 17b-Estradiol is an endogenous estro-
gen responsible for the development of female secondary
FIGURE 28. Protonated forms of cimetidine (left) and ranitidine
sex characteristics and reproduction. In addition to its
(right).
endogenous occurrence, this natural estrogen is

380 K. Ikehata et al. December 2006


OH
HO
HO
17β-estradiol (272.38) estrone (270.37)
HO
diethylstilbestrol (268.35)
FIGURE 30. Hormones and oral contraceptives.
manufactured and used in oral contraceptives and hor-
mone replacement therapy in large quantities. 17b-
Estradiol is metabolized in the body to a number of
metabolites, including estrone, hydroxylated estrones, 2-
methoxyestrone, estriol, and their conjugates, and subse-
quently excreted in the urine (Arcand-Hoy et al., 1998).
Deconjugation of sulfate and glucuronide derivatives of
estradiol in sewage treatment plant is also suggested
(Arcand-Hoy et al., 1998; Belfroid et al., 1999). 17b-
Estradiol has been frequently detected in the aquatic
environment (Ternes, 1998; Kolpin et al., 2002; Snyder
et al., 2003), and is considered as a major contributor of
estrogenic activity found in municipal sewage treatment
plant effluent (Onda et al., 2002).
Several groups of investigators reported the effective
decomposition of 17b-estradiol by ozonation (Onda
et al., 2002; Alum et al., 2004; Kim et al., 2004; Huber
et al., 2005). For example, ozonation at 2 mg/L applied
ozone dose was sufficient to convert 0.5 mg/L 17b-estradiol
spiked in biologically treated municipal wastewater at pH
7 and 16  C (Huber et al., 2005). Some studies also
addressed the effects of ozone treatment on estrogenic
activity, which is assayed by a number of methods such
as recombinant yeast assay (Onda et al., 2002), estrogen
competition binding assay (Kim et al., 2004), E-screen
assay (Alum et al., 2004), MCF-7 cell proliferation assay
(Liu et al., 2005), and ER-binding assay combined with
ultrafiltration (Liu et al., 2005). Generally, all of these
studies indicated that estrogenic activity of 17b-estradiol
solution decreased upon the ozone treatment. A slight
increase of estrogenicity assayed by E-screen was noted
in the first five minutes of ozone treatment (Alum et al.,
2004), indicating the formation of more potent estrogenic
intermediates, although the estrogenicity decreased during
the subsequent 5 min of treatment. Huber et al. (2004)
identified four degradation intermediates of 17b-estradiol
by ozonation in the presence of a hydroxyl radical
Ozonation and Advanced Oxidation of Pharmaceuticals
O OH
HO
17α-ethinylestradiol (296.41)
OH
scavenger (Figure 31). It is apparent that ozone molecules
attack and cleave hydroxylated aromatic ring of this estro-
gen to produce these intermediates. Huber et al. (2004)
suggested that the destruction of aromatic ring virtually
diminished estrogenicity of estrogens including 17b-
estradiol.
It was also documented the effectiveness of several
AOPs including O3/H2O2 (Shishida et al., 2000; Onda
et al., 2002) H2O2/UV (Rosenfeldt and Linden, 2004)
and TiO2/hn processes (Ohko et al., 2002) on the degra-
dation of 17b-estradiol and the removal of associated
estrogenicity. Shishida et al. (2000) showed that in addi-
tion to estrogenicity, cytotoxicity, mutagenicity, and gen-
otoxicity initially present in a secondary effluent from
domestic wastewater treatment plant containing 17b-
estradiol (concentration not shown) was reduced by the
O3/H2O2 treatment with 30 mg/L ozone and 2 mg/L
H2O2. A second-order rate constant for the reaction of
17b-estradiol and hydroxyl radical was determined as
1.41 · 1010 M1s1 using a competitive kinetics method
with isopropyl alcohol as a reference compound
(Rosenfeldt and Linden, 2004). Ohko et al. (2002) demon-
strated complete mineralization of 0.272 mg/L 17b-
estradiol by TiO2 photocatalysis with 1.0 g/L TiO2 and
a 200-W Hg-Xe lamp (with a 365 nm band-pass filter) in 3
h. They also identified several degradation intermediates
detected during the TiO2 photocatalytic treatment of 17b-
estradiol, including 10-17b-dihydroxy-1,4-estradien-3-
one, androsta-4,16-dien-3-one, and testosterone (Figure 32),
although it is unlikely to occur the introduction of methyl
group on the C10 position by the TiO2/hn treatment. Ohko et
al. (2002) suggested that hydroxyl radical attacked the hydro-
xylated aromatic ring of 17b-estradiol to initiate its degrada-
tion. In addition to the three AOPs discussed here, the
degradability of 17b-estradiol by photo-Fenton-like process
was briefly compared with that of three estrogens, including
diethylstilbestrol, 17a-ethinylestradiol, and estrone (Feng
December 2006 381
 O
OH O

HO

O
HO HO
HO O
17β-estradiol estrone

OH OH
OH
O

O O HO
HO
HO O

FIGURE 31. Proposed degradation pathways for 17b-estradiol and estrone by ozonation (Huber et al., 2004).

(Ternes et al., 2003). Huber et al. (2004) proposed a

18
12 13 OH
11 17
1 10 9 16
2 8 14 15
7
HO 3
4
5
6 among three estrogens tested, including 17b-estradiol,
17β-estradiol
OH
HO
O O
O
1 2
FIGURE 32. Proposed degradation intermediates of 17b-estra-
diol by TiO2 photocatalysis (Ohko et al., 2002): 1) 10-17b-dihy-
droxy-1,4-estradien-3-one, 2) androsta-4,16-dien-3-one, and 3)
testosterone.
et al., 2005). The order of degradability was diethylstilbestrol
> 17b-estradiol > 17a-ethinylestradiol > estrone
([estrogen]0 = 5 mg/L, 0.5 mg/L Fe3+, 28.3 mg/L H2O2, a
250-W metal halide lamp, pH 3.0).
Estrone. Estrone is one of the natural metabolites of
17b-estradiol having weaker estrogenic activity than the
parent compound (Arcand-Hoy et al., 1998). Sulfate ester
of this natural estrogen is one of the active ingredients of
conjugated equine estrogens used for the treatment of
hormone replacement therapy. Estrone sulfate undergoes
hydrolysis to allow its absorption by the gastrointestinal
tract. Estrone has been detected in treated domestic was-
tewater and surface water nearly as frequently as 17b-
estradiol (Belfroid et al., 1999; Kolpin et al., 2002).
Degradation of aqueous estrone by ozonation and
photo-Fenton-like treatment was investigated. Complete
conversion of 0.015 mg/L estrone present in a municipal
sewage treatment plant effluent was achieved by ozona-
tion at an applied ozone dose of 5 mg/L and pH 7.2
degradation pathway identical to that of 17b-estradiol
by ozonation (Figure 31). Huber et al. (2005) also showed
that estrone was the least reactive toward ozonation
17a-ethinylestradiol, and estrone. Consistent, lower reac-
tivity of estrone was observed in photo-Fenton-like treat-
OH
ment as well (Feng et al., 2005), although the reason for
this relative recalcitrance was not given in either case.
Complete conversion and about 15% mineralization
(monitored as CO2 evolution) of 5 mg/L estrone was
3 achieved in 160 min by the photo-Fenton-like treatment
with 1.1 mg/L Fe3+, 56.6 mg/L H2O2, and a 250-W metal
halide lamp at pH 3.0. Six unidentified degradation inter-
mediates, which are more polar than the parent com-
pound, were detected by HPLC with a UV detector
during the treatment (Feng et al., 2005).
17a-Ethinylestradiol. 17a-Ethinylestradiol is a syn-
thetic estrogen commonly used in oral contraceptives.
Introduction of ethinyl group to estradiol inhibit its meta-
bolism in the liver, resulting in enhanced bioavailability
and effectiveness (Arcand-Hoy et al., 1998). At the same
time, this synthetic estrogen is known to be more resistant
than 17b-estradiol against biodegradation (Ternes et al.,
1999; Jürgens et al., 2002). Their frequent occurrences in
sewage treatment plant effluents and surface water have
been also reported, however, at concentrations generally
lower than those of natural estrogens, such as estrone and
17b-estradiol (Belfroid et al., 1999; Ternes et al., 1999).
Huber et al. (2003) demonstrated very rapid reaction
of 17a-ethinylestradiol and molecular ozone with a max-
imum second-order rate constant of 7 · 109 M1s1 at
20 C at pH 10. The reaction rate is pH dependent; the
dissociated (phenolate) form of this compound
(pKa = 10.4) is more reactive than the neutral molecule
toward molecular ozone. Actually, this synthetic estrogen
has two reactive moieties with different reactivity: a

382 K. Ikehata et al. December 2006

hydroxyl aromatic ring (kO3 = 3 · 106 M1s1 at pH 7)
and an ethinyl group (kO3 = 200 M1s1) (Huber et al.,
2004). These moieties are attacked by molecular ozone
simultaneously, resulting in a complex mixture of degra-
dation products shown in Figure 33. A negative effect of
dissolved organic matter in natural water samples on 17a-
ethinylestradiol conversion was reported (Huber et al.,
2003). Similar to the case of 17b-estradiol, decrease of
estrogenic activity upon ozonation of this synthetic estro-
gen was also demonstrated (Alum et al., 2004; Huber
et al., 2004; Liu et al., 2005).
Rosenfeldt and Linden (2004) observed the improve-
ment of UV photodegradation of 17a-ethinylestradiol
(concentration not specified) by the addition of hydrogen
peroxide (i.e., H2O2/UV AOP). Two consistent second-
order rate constants were reported for the hydroxyl radi-
cal reaction of 17a-ethinylestradiol: 9.8 · 109 M1s1
(Huber et al., 2003) and 1.08 · 1010 M1s1
(Rosenfeldt and Linden, 2004), both using a competition
kinetics method. A kinetic model was developed to pre-
dict the degradation of this synthetic estrogen by H2O2/
UV AOP under various reaction conditions, such as
water quality, concentration of hydrogen peroxide, and
type of UV sources (Rosenfeldt and Linden, 2004). Other
than H2O2/UV, photo-Fenton-like process has been eval-
uated for the degradation of 17a-ethinylestradiol (Feng
et al., 2005) as described here (see 17b-Estradiol).
Diethylstilbestrol. Relatively high degradability of
diethylstilbestrol, a synthetic estrogen, by photo-Fenton-like
O
HO
O
HO
O
HO O
HO
O
HO HO
O O
HO O HO
O OH
O O
HO HO
HO
HO
FIGURE 33. Some ozonation by-products of 17a-ethinylestradiol. The compounds in brackets were not detected, but likely formed during
ozonation, based on the results of model compound degradation [see Huber et al. (2004) for the details of the degradation mechanisms].
Ozonation and Advanced Oxidation of Pharmaceuticals
process was briefly described (see 17b-Estradiol) (Feng et al.,
2005). No further study was found on the degradation of this
synthetic estrogen by AOP or ozonation. It should be noted
that although diethylstilbestrol once had been often pre-
scribed to prevent miscarriages, the use of this highly potent
estrogen is now limited to the treatment of prostate cancer
because of its carcinogenicity (Arcand-Hoy et al., 1998).
Summary of Hormones and Contraceptives
Two estrogenic steroid hormones and two synthetic
estrogens have been studied for their degradation by ozo-
nation and several AOPs. It can be concluded that these
natural hormones and synthetic drugs are generally reactive
toward the oxidative degradation, although some studies
have suggested that estrone is relatively resistant.
Estrogenicity associated with these compounds can be
reduced by ozonation and O3/H2O2 (most likely by other
AOPs as well) to virtually undetectable levels. The degrada-
tion of these estrogens is initiated by the hydroxylation of
highly reactive aromatic ring followed by the ring opening
and further degradation (Figures 31 and 33). Since the
phenolic A ring (i.e., the hydroxylated aromatic ring) of
these compounds is the structural component responsible
for the high-affinity binding to the estrogen receptor
(Arcand-Hoy et al., 1998), its modification and cleavage
likely lead the diminution of estrogenicity of degradation
products produced by ozonation or AOPs. In addition to
the four estrogenic compounds, there are other steroid
hormones for therapeutic use such as equilin, a horse
O
HO
O
O
O
O
OH O OH
O O
HO
O
O HO O
O
HO OH
O
O
O O
HO
HO
December 2006 383
estrogen often used in combination with estrone for hor-
mone replacement therapy, and testosterone have been
detected in surface water (Kolpin et al., 2002), although
their degradation by ozonation or AOP has yet been
studied.
Lipid Regulators
Fibrate lipid regulators are the pharmaceuticals used
for a range of metabolic disorders, mainly hypercho-
lesterolemia (Merck & Co., 1999). They are phenox-
yalkanoic acid derivatives, either free acid or esters,
and accelerate the clearance of very-low-density lipo-
proteins (VLDL). Bezafibrate, clofibrate, fenofibrate,
and gemfibrozil, and their hydrolyzed metabolites,
including clofibric acid and fenofibric acid (Figure 34)
have been frequently found in the aquatic environment
in a number of countries (Buser et al., 1998; Ternes,
1998; Kolpin et al., 2002; Soulet et al., 2002; Bendz
et al., 2005). It should be noted that bezafibrate and
gemfibrozil are acidic drugs on their own, while clofi-
brate and fenofibrate become acidic metabolites after
the hydrolytic biotransformation.
Bezafibrate. It was shown that bezafibrate was rela-
tively resistant to the degradation by ozone as compared
with other pharmaceuticals such as carbamazepine, diclo-
fenac, and 17a-ethinylestradiol (Ternes et al., 2002;
Huber et al., 2003). A second-order rate constant for the
reaction of bezafibrate and molecular ozone was deter-
mined as 590 M1s1 at pH 5 to 10 and 20  C (Huber
et al., 2003). The negative impact of DOC in natural
water on bezafibrate conversion by ozonation was
observed. Huber et al. (2005) also suggested the impor-
tance of hydroxyl radical reactions (kOH = 7.4 · 109
M1s1 at pH 7 and 25  C) during the ozonation of
this pharmaceutical. No degradation by-product was
identified in any of these studies.
O OH
HN
Cl
O
bezafibrate (361.82)
O O
O HO
O Cl
O O
fenofibrate (360.84)
FIGURE 34. Fibrate lipid regulators and metabolites.
384 K. Ikehata et al.
Clofibric Acid. Clofibric acid, a metabolite of fibrate
lipid regulators clofibrate and etofibrate, was detected in
domestic wastewater effluent nearly 30 years ago (Hignite
and Azarnoff, 1977). More recently, the persistence and
mobility of this acidic drug metabolite in the aquatic
environment has been recognized (Buser et al., 1998).
This compound is relatively resistant to ozone treatment.
For example, only 8% of 2 mg/L clofibric acid was con-
verted by ozonation in 10 min at an applied ozone dose of
1 mg/L and pH 7, by which more than 96% of 2 mg/L
diclofenac, a NSAID, was converted (Zwiener and
Frimmel, 2000). Similar results were also reported else-
where (Ternes et al., 2002, 2003; Andreozzi et al., 2004;
Huber et al., 2005). Huber et al. (2005) reported a rela-
tively small second-order rate constant of <20 M1s1
for the molecular ozone reaction of this acidic drug meta-
bolite. It can be suggested that weak deactivation by
p-chloro group (Beltrán, 2003) (see Figure 34) is respon-
sible to this low reactivity of aromatic ring toward
ozonation.
Degradation of clofibric acid by ozone can be
enhanced by increasing ozone dose (Ternes et al., 2003),
adding hydrogen peroxide (i.e., O3/H2O2 AOP) (Zwiener
and Frimmel, 2000), or elevating pH (Andreozzi et al.,
2003b). Latter two approaches indicate the importance of
hydroxyl radical reactions for the degradation of this
acidic drug metabolite. The apparent second-order rate
constants for the clofibric acid decomposition were pH
dependent; 29.8 M1s1 at pH 2.0 and 2550 M1s1 at
pH 6.5, both in the absence of hydroxyl radical scavenger
(Andreozzi et al., 2003b). Andreozzi et al. (2003b) also
demonstrated that complete conversion and 49% miner-
alization, monitored as TOC removal, of 322 mg/L clo-
fibric acid could be achieved by continuous ozonation
(0.48 mg O3/L in bulk liquid) in one hour at pH 5.0 and
25  C. Almost complete dechlorination (>90%) was also
observed under the same conditions.
O O
O
O O
OH
O
Cl Cl
clofibrate (242.70) clofibric acid (214.65)
O OH
O Cl
O
gemfibrozil (250.34)
fenofibric acid (318.75)
December 2006
 In addition to ozonation and O3/H2O2 process, H2O2/
UV and TiO2 photocatalysis have been evaluated for the
degradation of clofibric acid. Andreozzi et al. (2003b)
demonstrated the more than 90% conversion of 322 mg/
L clofibric acid by H2O2/UV treatment in 1 h with 34 g/L
H2O2 and a 17 W low-pressure lamp (l = 254 nm, 2.7 ·
106 Einsteins1) at pH 5.0 and 25  C. More than 80%
of chlorine was recovered as chloride during the treat-
ment, whereas TOC removal was modest. A second-order
rate constant for the hydroxyl radical reaction of clofibric
acid was determined as 2.38 · 109 M1s1, which is
independent of pH in the range of 4 to 7 (Andreozzi
et al., 2003b). This rate constant is smaller than the one
estimated in a separate study (4.7 · 109 M1s1) using
Fenton reaction to generate hydroxyl radicals at pH 3.5
and 22  C (Packer et al., 2003). A kinetic model was
successfully developed to predict the clofibric acid degra-
dation at more dilute acid solution (10.7 mg/L) that repre-
sents a sewage treatment plant effluent. Andreozzi et al.
(2004) also investigated the detoxification of a drug mix-
ture that contained clofibric acid by ozonation, H2O2/
UV, TiO2 photocatalysis (see Propranolol, b-blocker for
the results).
A series of studies was published on the clofibric acid
degradation by TiO2 photocatalysis (Doll and Frimmel,
2004, 2005a, 2005b, 2005c). More than 90% of 0.53 mg/L
clofibric acid was converted in five minutes with 80 mg/L
TiO2 (P25) and a 1000-W xenon short-arc lamp as a
source of simulated solar UV rays (1.35 · 104
Einsteinm2s1, l <400 nm) at pH 6.5 (Doll and
Frimmel, 2004). The degradation of clofibric acid was
dependent on the initial concentration of substrate;
degradation efficiency was higher as the initial clofibric
acid concentration decreased, indicating that the capacity
of catalyst is a limiting factor (Doll and Frimmel, 2004).
HO
O OH
O
OH
Cl
clofibric acid
O
O
OH
HO
HO
hydroquinone
2-(4-hydroxyphenoxy)-isobutyric acid
FIGURE 35. Degradation of clofibric acid by TiO2 photocatalysis (Doll and Frimmel, 2004).
Ozonation and Advanced Oxidation of Pharmaceuticals
Degradation efficiency was also decreased in the presence
of NOM, which completes with clofibric acid for the
active site of the catalyst (Doll and Frimmel, 2005a). It
was also shown that clofibric acid was more readily
degradable by TiO2/hn than two X-ray contrast media,
namely iomeprol and iopromide, but less degradable than
an anticonvulsant carbamazepine. A successful pilot-scale
investigation of the continuous treatment of this drug
metabolite by the TiO2/hn process was reported using a
cross-flow microfiltration to retain catalyst (Doll and
Frimmel, 2005b). A number of degradation products
were identified and degradation pathway was proposed
as shown in Figure 35 (Doll and Frimmel, 2004). Among
the degradation by-products, 4-chlorophenol was more
resistant to further degradation and accumulated in the
solution during the TiO2/hn treatment (Doll and
Frimmel, 2004), which may raise concerns over the resi-
dual toxicity, although it was not addressed therein.
Fenofibric Acid. Complete elimination of 0.13 mg/L
fenofibric acid, a metabolite of lipid regulator fenofibrate,
in a sewage treatment plant effluent was achieved by
ozonation with an applied ozone dose of 10 or 15 mg/L
at pH 7.2 (Ternes et al., 2003). No further study was
found on the degradation of fenofibric acid or its parent
compound fenofibrate by ozonation or AOP.
Gemfibrozil. Huber et al. (2005) mentioned the pre-
sence of another fibrate lipid regulator, gemfibrozil, in a
municipal wastewater effluent that was subsequently trea-
ted by ozonation; however, no description was given on
the removal efficiency of this pharmaceutical. It can be
anticipated that gemfibrozil is probably more reactive
toward ozonation than clofibric acid because of the
absence of chlorine on the aromatic ring, although aro-
matic hydroxylation is somehow hindered by the two
methyl groups (see Figure 34).
O O
OH
OH
O +
Cl
OH
4-chlorophenol
HO
OH
OH
Cl OH
4-chlorocatachol
ring opening
and
mineralization
December 2006 385
Summary of Lipid Regulators and Metabolites
It can be concluded that lipid regulators and metabo-
lites, especially clofibric acid, are not very reactive toward
ozonation. On the other hand, advanced oxidation is
apparently more suitable for the degradation of these
pharmaceuticals. Degradation of clofibric acid has been
extensively studied and various treatment processes have
been evaluated. Whereas some kinetic data on the degra-
dation of this drug are available (see Appendix), degrada-
tion pathway is only proposed for TiO2 photocatalysis
(Figure 35). Such information is largely missing for the
other lipid regulators. Generation and accumulation of
toxic chlorinated intermediates such as 4-chlorophenol
was observed in one study on clofibric acid degradation
by TiO2/hn process (Doll and Frimmel, 2004).
X-RAY CONTRAST MEDIA
X-ray contrast media are the non-therapeutic medical
agents used to enhance the visibility of internal body struc-
tures by X-ray imaging technologies. Triiodinated benzene
derivatives are widely used for this purpose because of their
high water solubility and biologically inert (i.e., stable)
nature. However, these biologically stable compounds are
also proven highly resistant to biodegradation and thus
persistent in the aquatic environment (Ternes and Hirsch,
2000; Drewes et al., 2001). In addition, the removal of
triiodinated X-ray contrast media by sorption is poor due
to their high hydrophilicity. These contrast agents are
excreted with no marked metabolic transformation and
contribute to the increase of absorbable organic halogens
(AOX) in hospital wastewater (Gartiser et al., 1996), as well
as high concentration of absorbable organic iodine (AOI)
in sewage treatment plant effluent (5 to 40 mg I/L) (Drewes
et al., 2001), surface water and raw drinking water (11 to 13
mg I/L) (Putschew et al., 2000). Although it has been sug-
gested that no environmental risk is evident based on a
battery of acute and chronic toxicity test data of triiodi-
nated X-ray contrast media (Steger-Hartmann et al., 1999),
their relatively high environmental concentrations, persis-
tence, mobility, as well as the lack of information regarding
potential sub-lethal effects have generated interests in the
application of advanced water and wastewater treatment
processes including ozonation and AOPs. The X-ray media
investigated include diatrizoate, iomeprol, iopamidol,
iopentol, and iopromide (Figure 36). Diatrizoate is the
only ionic contract media, while the others are non-ionic.
Diatrizoate. Diatrizoate is an anionic triiodinated
X-ray contrast medium. Ternes et al. (2003) reported
the high recalcitrance of this compound against ozona-
tion. No conversion of 5.7 mg/L diatrizoate in a sewage
treatment plant effluent was observed by ozonation at an
applied ozone dose of 5 mg/L at pH 7.2. Increasing ozone
dose to 15 mg/L, addition of hydrogen peroxide (10 mg/L
H2O2 and 10 mg/L O3; O3/H2O2), or UV irradiation (15
mg/L O3 and a 110-W low-pressure UV unit, 254 + 185
386 K. Ikehata et al.
nm; O3/UV) slightly enhanced the degradation of dia-
trizoate to 14%, 25%, and 36%, respectively. Huber et
al. (2005) also noted the negligible and very little reactiv-
ity of diatrizoate toward molecular ozone and hydroxyl
radicals, respectively. No further study was found on the
degradation of diatrizoate by ozonation or AOP. It
should be noted that ionic contrast media like diatrizoate
are less commonly used nowadays than non-ionic coun-
terparts as relatively high nephrotoxicity of the former
compounds has been recognized (Soejima et al., 2003).
Iomeprol. Ternes et al. (2003) demonstrated partial
degradation of iomeprol (from 34% to 90%) by ozonation
and two types of ozone-based AOPs (see Diatrizoate for
reaction conditions). This non-ionic triiodinated X-ray con-
trast medium was more degradable than diatrizoate. A
comparable result was also reported by Huber et al.
(2005). Unlike the case of diatrizoate, UV irradiation did
not improve the conversion of iomeprol by ozonation
(Ternes et al., 2003). Doll and Frimmel (2004) investigated
the degradation of iomeprol by TiO2 photocatalysis. About
68% of 4.1 mg/L iomeprol was converted and about 40% of
quantitative iodine was released as iodide after 3 min of
TiO2/hn treatment with 500 mg/L TiO2 (Hombikat UV
100) and simulated solar radiation using a 1000-W Xe
short-arc lamp at pH 6.5 and 20  C. As compared with the
iomeprol conversion and deiodination, DOC removal was
very slow, indicating the generation of organic by-products
and intermediates (Doll and Frimmel, 2004), although their
identities were unknown. Similar to the cases of carbamaze-
pine and clofibric acid, negative impacts of NOM and other
organic constituents in water was observed during the TiO2/
hn treatment of iomeprol (Doll and Frimmel, 2005a).
Iopamidol. Degradability of iopamidol by ozone-
based processes was equivalent to that of iomeprol
(Ternes et al., 2003; Huber et al., 2005). No further
study was found on the degradation of this non-ionic
X-ray contrast medium by ozonation or AOP.
Iopentol. Sprehe et al. (2001) demonstrated complete
AOX removal and partial mineralization (up to 80% as
TOC removal) of 785 mg/L iopentol by H2O2/UV AOP
in 3 and 5.5 h, respectively, with a 1 kW high-pressure Hg
lamp (output adjusted to 500 W) at pH 6.6. Hydrogen
peroxide was supplied based on the COD of the solution.
It was suggested that deiodination mostly occurred by
UV photolysis of the parent compound:
Iopentol þ hnðat 242 nmÞ ! deiodinated intermediates þ 3I
I þ H2 OðorsubstrateÞ ! I þ OH þ Hþ
Subsequently, two iodides react in the presence of a
molecule of hydrogen peroxide and two protons,
forming elemental iodine, which can be stripped out
by air:
2I þ H2 O2 þ 2Hþ Ð I2 " þ2H2 O
December 2006
 HO
O OH OH
HN I O
O HO HN I
OH O
HO I
I N
I NH
I NH
O I
O O I O OH
NH
NH I O HO NH
OH

HO OH
diatrizoate (613.91)
iomeprol (777.09) iopamidol (777.09)

O O
HO HN I HO HN I
O
HO I N OH HO I NH

O I O O I O O
NH N

HO OH HO OH

iopentol (835.17)
iopromide (791.12)

FIGURE 36. X-ray contrast media.

Because of the high UV absorbance of iodine in the
aqueous solution, iopentol mineralization was inhibited,
although it was found that air stripping could solve this
problem (Sprehe et al., 2001). They also suggested that
the iodine recovery from the exhaust air by the use of
solvent or sublimation might be feasible as about 85% of
elemental iodine could be recovered this way.
Iopromide. Iopromide is another non-ionic triiodi-
nated X-ray contrast medium resistant to oxidative degra-
dation. However, as compared with other triiodinated
contrast media, this compound was apparently more reac-
tive, but very slightly, toward ozonation (Ternes et al.,
2003; Huber et al., 2005). As the second-order rate con-
stant for the reaction between iopromide and molecular
ozone is very small: less than 0.8 M1s1 at pH 5 to 10
and 20  C, the degradation of this compound mostly occur
by hydroxyl radicals, although the rate constant for the
hydroxyl radical reaction is also fairly small: 3.3 · 109
M1s1 at pH 7 and 25  C (Huber et al., 2003).
Like the case of iopentol, effective AOX removal and
mineralization of iopromide by H2O2/UV AOP was
demonstrated (Sprehe et al., 2001). Major contribution
of direct UV photolysis to the deiodination was con-
firmed in a separate photolysis experiment without
hydrogen peroxide addition. In addition to ozone-based
and H2O2/UV AOPs, TiO2/hn process was evaluated for
the iopromide degradation. It was shown that the degra-
dation rate of this contrast medium was comparable to
that of iomeprol (Doll and Frimmel, 2004). Degradation
by-products or intermediates were not identified in any of
these studies.
Summary of X-ray Contrast Media
It is evident that triiodinated X-ray contrast media are
the most refractory class of pharmaceutical/medical
agents reviewed in this review. Anionic diatrizoate is
particularly resistant to ozone-based treatment, whereas
non-ionic contrast media (iomeprol, iopamidol, iopentol,
and iopromide) are somewhat degradable, especially by
AOPs such as H2O2/UV and TiO2/hn. It has been shown
that deiodination of these contrast media occurs chiefly
by direct UV photolysis in the H2O2/UV treatment. Other
than that, degradation mechanisms of these contrast
media by ozonation and AOPs are still largely unknown;
kinetic data are very scarce and no degradation by-
product was identified. It is probably desirable to discern
the identity and property of degradation by-products of
triiodinated X-ray contrast media because even though
the parent compounds are non-toxic (Steger-Hartmann
et al., 1999), their degradation products may have some
potential ecological and public health impacts. Finally,
there are two ionic triiodinated X-ray contrast media,
iothalamic acid and ioxithalamic acid, that have not
been studied for their degradation by ozonation or AOP
but been detected in the aquatic environment (Ternes and
Hirsch, 2000).

Ozonation and Advanced Oxidation of Pharmaceuticals December 2006 387

CONCLUDING REMARKS
Pharmaceutical contamination of surface water and
groundwater is an emerging issue in environmental
science and engineering. After the administration to
humans and animals, these medical drugs and non-ther-
apeutic agents are partially metabolized and excreted in
the urine and/or the feces, and subsequently enter the
aquatic environment through a number of routes (see
Figure 1). Some of the pharmaceuticals are fairly biode-
gradable, while others are more persistent and mobile in
the aquatic environment. A large number of pharmaceu-
ticals have been detected in domestic sewage treatment
plant effluents, hospital wastewaters, surface water, and
groundwater at ng/L to mg/L levels. Although there is no
clear evidence of immediate public health impacts of these
trace pharmaceuticals in water, there are several groups
of substances with unambiguous toxic and estrogenic
properties such as antibiotics, cytostatic agents, and nat-
ural and synthetic hormones, which can indeed affect
populations of aquatic organisms. Besides, the chronic
health effects of a mixture of biologically active sub-
stances are still largely unknown. Therefore, the removal
of these substances before entering the aquatic environ-
ment and drinking water is probably desirable based on
the precautionary principle. Chemical oxidation by ozone
and AOPs has been thought to be one of the promising
treatment methods to deal with this problem.
The studies reviewed here have indeed showed satisfac-
tory efficiencies of ozonation and AOPs for the degradation
of a wide range of pharmaceutical compounds in aqueous
solution. Some pharmaceuticals are extremely reactive
toward molecular ozone, including some antibiotics, an
anticonvulsant carbamazepine, a NSAID diclofenac, and
an estrogen 17b-estradiol. These pharmaceuticals can be
characterized by one or more functional groups and moi-
eties in the molecules such as non-aromatic carbon-carbon
double bonds, amines, thioether sulfurs, and activated aro-
matic rings. There are also some pharmaceuticals relatively
resistant to ozonation, including a lipid regulator metabo-
lite clofibric acid, an anti-anxiety agent diazepam, and a
NSAID ibuprofen. Triiodinated X-ray contrast media,
which are biologically stable, non-therapeutic medical
agents, are particularly refractory to ozonation. Ozone-
based AOPs, Fenton-type processes and photochemical
AOPs are generally more effective than ozonation alone
primarily due to enhanced generation of hydroxyl radicals
and photon-initiated cleavage of carbon-halogen bonds,
thus are recommended for the treatment of these recalci-
trant substances. There are a number of pharmaceuticals
that have not been studied for their degradation by ozona-
tion or AOP but been found in the aquatic environment
(Table 3). These pharmaceuticals may warrant further
study.
The degree of degradation of water and wastewater
pollutants, including pharmaceutical compounds, achieved
388 K. Ikehata et al.
by ozonation and AOPs depends on a number of factors.
Oxidant dose, concentration of pharmaceuticals, various
water quality parameters, and mode of operation are a few
examples. It has been demonstrated that the presence of
inorganic and organic water and wastewater constituents
often inhibit the degradation of target pollutants through
oxidant competition and/or radical scavenging mechan-
isms, which has resulted in higher oxidant requirements.
In addition to the oxidative transformation of parent phar-
maceuticals, certain levels of mineralization have been
demonstrated by ozonation and AOPs. It should be
noted that complete mineralization may not be an absolute
requirement in both water and wastewater treatment. In
wastewater treatment, improvement of biodegradability is
perhaps the more important goal to be achieved, especially
for the pharmaceuticals that are resistant to biodegrada-
tion, such as antibiotics, cytostatic agents, hormones,
X-ray contrast agents, carbamazepine, and some acidic
drugs like clofibric acid. However, the achievement of
this goal has been confirmed only for some antibiotics
through limited types of treatment process (see
Appendix). Likewise, toxicity reduction by ozonation or
AOPs has been evaluated in just a handful of cases, exclud-
ing the estrogenicity of natural and synthetic hormones. In
water treatment, considering the very small amounts of
pharmaceuticals in finished drinking water, the destruction
of key molecular structures for biological activity may be
sufficient to protect public health, if the degradation by-
products do not exert similar or other unprecedented and
undesirable effects. Thus, identification and characteriza-
tion of degradation by-products and intermediates is
highly important task, although this has not been done
yet for all the substances discussed here. In addition,
kinetic data are still scarce for many pharmaceuticals
reviewed here. Further validation may be as well required
for those substances already studied for their degradation
kinetics by ozone or hydroxyl radicals, because of some
discrepancies, high experimental errors, or limited pH and
temperature coverage.
In order to minimize the load of pharmaceuticals in the
aquatic environment, a number of actions should be
taken simultaneously, besides the end-of-pipe treatment
approach discussed in this review. It has been recognized
that source separation is one of the key for a successful
waste management practice in general (Jonsson et al.,
1997; Tanskanen et al., 1998), and this approach should
be applicable to wastewater pollutants such as pharma-
ceuticals. As many pharmaceuticals are excreted mostly
in the urine, its separation from the solids portion (feces)
of wastewater and the provision for separate treatment
system may be of an ultimate solution particularly for
highly contaminated hospital wastewater (Larsen et al.,
2004). Ozonation and advanced oxidation are likely sui-
table for the treatment of the pharmaceutical-laden urine,
as suggested by Larsen et al. (2004); thus this strategy
should be investigated in the future.
December 2006
TABLE 3. Pharmaceuticals Not Studied for Ozonation or AOP but Detected in the Aquatic Environment

Pharmaceutical Class Occurrences

Ciprofloxacin Antibiotics, fluoroquinolone Up to 0.4 mg/L in final effluents from WWTP
(Miao et al., 2004)
Norfloxacin Antibiotics, fluoroquinolone Up to 0.112 mg/L in final effluents from WWTP
(Miao et al., 2004), up to 0.12 mg/L in surface water
(Kolpin et al., 2002)
Clindamycin Antibiotics, lincosamide Up to 1.1 mg/L in surface water (Batt and Aga, 2005),
up to 32 ng/L in surface water (Christian et al., 2003)
Doxycycline Antibiotics, tetracycline Up to 0.046 mg/L in WWTP (Miao et al., 2004)
Oxytetracycline Antibiotics, tetracycline Up to 0.34 mg/L in surface water (Kolpin et al., 2002)
Paroxetine Antidepressant Its environmental fate was studied (Kwon and Armbrust,
2004), a low risk to environment (Cunningham et al., 2004)
Ketoprofen Non-steroidal anti-inflammatory Up to 0.38 and 0.12 mg/L in effluents from WWTP and
drug surface water, respectively (Ternes, 1998), up to 0.2
mg/L in effluents from WWTP (Soulet et al., 2002)
Mefenamic acid Non-steroidal anti-inflammatory Up to 0.6 mg/L in effluents from WWTP (Soulet et al., 2002)
drug
Belomycin Cytostatic drug Up to 19, 17, and 13 ng/L in effluents from WWTP,
surface water, and potable water, respectively
(Halling-Sørensen et al., 1998)
Equilin Steroid hormone, estrogen Up to 0.147 mg/L in surface water (Kolpin et al., 2002)
Testosterone Steroid hormone, androgen Up to 0.214 mg/L in surface water (Kolpin et al., 2002)
Iothalamic acid Triiodinated X-ray contrast media Up to 0.049 mg/L in groundwater (Ternes and Hirsch, 2000)
Ioxithalamic acid Triiodinated X-ray contrast media Up to 0.010 mg/L in groundwater (Ternes and Hirsch, 2000)

Note: WWTP = wastewater treatment plant.

ACKNOWLEDGMENT Ozonation Treatment and Preliminary Assessment on Algal

The authors greatly appreciate the financial support
provided by Alberta Ingenuity Fund (AIF) and Alberta
Ingenuity Centre for Water Research (AICWR).
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 APPENDIX. Summary of the Degradation of Pharmaceuticals by Ozonation and AOPs

Pharmaceutical Applied Intermediates/ Biodegradability and

(CAS #) Class process Degree of degradation Kinetic parameters by-products toxicity
Amoxicillin Antibiotic, Ozonation Complete conversion of kO3 = 4 · 103 M1s1 Elemental sulfur BOD5 increased from
(61336-70-7) b-lactam 400 mg/L amoxicillin at pH 2.5, 6 · 106 (Arslan-Alaton zero to 60 mg/L at pH
(Arslan-Alaton and M1s1 at pH 7 and Dogruel, 11.5 (non-buffered)
Dogruel, 2004), 86% (Andreozzi 2004), (Arslan-Alaton and
of initial COD et al., 2005) hydroxylation of Dogruel, 2004),
(=1,395 mg/L) phenol ring BOD5/COD increased
removed at pH 11.5 (Andreozzi et al., from zero to 0.08
(buffered) from 2005) (Arslan-Alaton and
filtered formulation Dogruel, 2004), to 0.37
wastewater. 49% of (Arslan-Alaton et al.,
initial COD and 52% 2004)
of initial TOC (=920
mg/L) removed in
non-buffered system
(Arslan-Alaton and
Dogruel, 2004), 81%
COD removal by
simulated chemical-
biological treatment
(Arslan-Alaton et al.,
2004)
O3/H2O2 83% of initial COD N/D N/D BOD5/COD increased

Ozonation and Advanced Oxidation of Pharmaceuticals

(=830 mg/L) removed from zero to 0.45
at pH 10.5, 72% COD (Arslan-Alaton et al.,
removal by simulated 2004)
chemical-biological
treatment (Arslan-
Alaton et al., 2004)
H2O2/UV 22% of initial COD kOH = 3.93 · 109 N/D BOD5 increased from

December 2006
(=1,395 mg/L) and M1s1 at pH 5.5 zero to 10 mg/L
6% of initial TOC (Andreozzi (Arslan-Alaton and
(=920 mg/L) removed et al., 2005) Dogruel, 2004)
at pH 7
([H2O2]0 = 1.02 g/L)
(Arslan-Alaton and
Dogruel, 2004)
(Continued)

393
 APPENDIX. (Continued)

394
Pharmaceutical Applied Intermediates/ Biodegradability and
(CAS #) Class process Degree of degradation Kinetic parameters by-products toxicity

Fenton/ Complete conversion of N/D N/D BOD5 increased from

Fenton-like 400 mg/L amoxicillin zero to 6 mg/L
(Arslan-Alaton and (Arslan-Alaton and
Dogruel, 2004), 61% Dogruel, 2004)
of initial COD
(=1,395 mg/L) and
33% of initial TOC
(=920 mg/L) removed
by Fenton, 46% COD
and 18% TOC by
Fenton-like, both at
pH = 3, 1 mM Fe2+
or Fe3+, 20 mM H2O2
(Arslan-Alaton and
Dogruel, 2004)
Photo-Fenton/ 56% of initial COD N/D N/D BOD5 increased from
Photo- (=1,395 mg/L) and zero to 4 mg/L (photo-

K. Ikehata et al.
Fenton-like 46% of initial TOC Fenton) and 21 mg/L
(=920 mg/L) removed (photo-Fenton-like)
by photo-Fenton, 66% (Arslan-Alaton and
COD and 42% TOC Dogruel, 2004)
removed by photo-
Fenton-like, both at
pH 3, 1 mM Fe2+ or

December 2006
Fe3+, 20 mM H2O2
(Arslan-Alaton and
Dogruel, 2004)
Photolysis No COD/TOC FP = 0.571 N/D No BOD5 increase
reduction (Arslan- molEinstein1 at pH (Arslan-Alaton and
Alaton and Dogruel, 5.5 (Andreozzi et al., Dogruel, 2004)
2004) 2005)
Penicillin VK Antibiotic, Ozonation 70% of initial COD N/D N/D BOD5/COD increased
(132-98-9) b-lactam (=450 mg/L) and from 0 to 0.25
40% of initial TOC (Akmehmet Balcio glu
(=162 mg/L) removed and Ötker, 2003)
at pH 7-11
(Akmehmet Balcioglu
and Ötker, 2003)
 O3/H2O2 95% of initial COD N/D N/D N/D
(=450 mg/L) removed
at pH 7 (O3:H2O2
molar ratio = 3.08:1)
(Akmehmet Balcioglu
and Ötker, 2003)
Penicillin G Antibiotic, Ozonation 50% of initial COD kCOD,O3 = 0.67 M1s1 N/D N/D
(61-33-6) b-lactam (=600 mg/L) and at pH 7, 0.042 M1s1
50% of TOC (=226 at pH 3 (Arslan-
mg/L) removed at pH Alaton and Caglayan,
12 (Arslan-Alaton and 2005)
Caglayan, 2005).
Photo-Fenton- 56% of initial COD N/D N/D Daphnia magna acute
like (=600 mg/L) and toxicity reduced,
42% of initial TOC BOD5/COD increased
(=226 mg/L) removed from 0.25 to 0.45
at pH 3 (Arslan- (Arslan-Alaton and
Alaton and Gurses, Gurses, 2004)
2004)
Sultamicillin Antibiotic, Ozonation- biodegradation 33% of initial COD N/D N/D
(76497-13-7) b-lactam (=710 mg/L) and
24% of initial TOC
(=200 mg/L) removed

Ozonation and Advanced Oxidation of Pharmaceuticals

at pH 11 (Cokgor
et al., 2004).
BOD5/COD
increased from
0.02 to 0.27
(Cokgor et al.,
2004)

December 2006
Cefradine Antibiotic, TiO2/hv Complete conversion of N/D N/D N/D
(38821-53-3) b-lactam 70 mg/L cefradine,
(cephalosporin) addition of H2O2
accelerate
decomposition (Fan
et al., 2002)

(Continued)

395
 APPENDIX. (Continued)

396
Pharmaceutical Applied Intermediates/ Biodegradability and
(CAS #) Class process Degree of degradation Kinetic parameters by-products toxicity
Ceftriaxone Antibiotic, Ozonation 53%, 74% and 82% of N/D N/D BOD5/COD increased
(73384-59-5) b-lactam initial COD (=450 from zero to 0.10
(cephalosporin) mg/L) removed at pH (Akmehmet Balcio glu
3, 7, and 11 and Ötker, 2003)
(Akmehmet Balcioglu
and Ötker, 2003)
O3/H2O2 About 90% of initial N/D N/D N/D
COD (=450 mg/L)
removed at pH 7
(Akmehmet Balcioglu
and Ötker, 2003)
MMTD Intermediate of H2O2/UV Complete conversion of kOH = 1.6 · 1010 Degradation N/D
(29490-19-5) cefazolin 1 mg/L MMTD in 20 M1s1 at 25  C pathway
(cephalosporin min, 60% TOC (Lopez proposed (Lopez
antibiotic) removed in 4 h (Lopez et al., 2003) et al., 2002)
et al., 2002)
Photolysis About 90% conversion FP = 12 One by-product N/D

K. Ikehata et al.
of 1 mg/L MMTD in mmolEinstein1 identified (Lopez
60 min, no (Lopez et al., 2002) et al., 2002)
mineralization (Lopez
et al., 2002)
MMTD-Me Intermediate of H2O2/UV Complete conversion kOH = 8.3 · 108 S-Oxidation N/D
(1925-78-6) cefazolin of 1 mg/L MMTD-Me M1s1 precedes
(cephalosporin in 20 min, 80% TOC at 25  C (Lopez mineralization

December 2006
antibiotic) removed in 4 h (Bozzi et al., 2003) (Bozzi et al.,
et al., 2002) 2002)
photolysis Complete conversion FP = 14.1 Two by-products N/D
of 1 mg/L MMTD-Me mmolEinstein1 identified (Bozzi
in 60 min, no (Lopez et al., 2003) et al., 2002)
mineralization (Bozzi
et al., 2002)
Azithromycin Antibiotic, Ozonation Complete conversion of N/D N/D N/D
(83905-01-5) macrolide azithromycin
(concentration
unknown) at pH 7
(Huber et al., 2005)
 Clarithromycin Antibiotic, Ozonation Complete conversion of N/D N/D N/D
(81103-11-9) macrolide 0.21-2 mg/L
clarithromycin at pH
7-7.2 (Ternes et al.,
2003; Huber et al.,
2005)
Erythromycin Antibiotic, Ozonation Complete conversion of N/D N/D N/D
(114-07-8) macrolide 0.62-2 mg/L
(dehydro)erythromycin
at pH 7-7.2 (Ternes
et al., 2003; Huber
et al., 2005)
Lincomycin Antibiotic, Ozonation N/D kO3 = 3.26 · 105 N/D N/D
(154-21-2) lincosamide M1s1 (protonated),
2.43 · 106 M1s1
(neutral) (Qiang et al.,
2004)
TiO2/hn Complete conversion of Langmuir–Hinshelwood Sulfate ion N/D
50 mg/L lincomycin in kinetic model (Addamo et al.,
2 h at pH 6, 60% TOC developed (Addamo 2005)
removal in 5 h et al., 2005)
(Addamo et al., 2005)
Roxithromycin Antibiotic, Ozonation Complete conversion of kO3 = 4.5 · 106 M1s1 N/D N/D
(80214-83-1) macrolide 0.54-2 mg/L at pH >8.8 (Huber
roxithromycin at pH et al., 2003)
7-7.2 (Ternes et al.,

Ozonation and Advanced Oxidation of Pharmaceuticals

2003; Huber et al.,
2005)
Enrofloxacin Antibiotic, Ozonation 88% of initial COD N/D N/D BOD5/COD increased
(93106-60-6) quinolone (=450 mg/L) and from 0.07 to 0.38
(veterinary) 50% of initial TOC (Akmehmet Balcio glu
(=165 mg/L) removed and Ötker, 2003)
at pH

December 2006
7 (Akmehmet
Balcioglu and Ötker,
2003), successfully
decontaminated
enrofloxacin-loaded
zeolite (Ötker and
Akmehmet-Balcioglu,
2005)
(Continued)

397
 APPENDIX. (Continued)

398
Pharmaceutical Applied Intermediates/ Biodegradability and
(CAS #) Class process Degree of degradation Kinetic parameters by-products toxicity
Ofloxacin Antibiotic, Ozonation Complete conversion of N/D N/D Algal and protozoan
(levofloxacin; quinolone 560 mg/L ofloxacin in toxicity eliminated (as
637328-10-0) a mixture of six a mixture) (Andreozzi
pharmaceuticals at pH et al., 2004)
7.4 (Andreozzi et al.,
2004)
H2O2/UV Complete conversion of N/D N/D Algal toxicity
560 mg/L ofloxacin in eliminated, protozoan
a mixture of six toxicity reduced (as a
pharmaceuticals at pH mixture) (Andreozzi
7.4 (Andreozzi et al., et al., 2004)
2004)
TiO2/hn Incomplete conversion N/D N/D No toxicity reduction
of 560 mg/L ofloxacin (as a mixture)
in a mixture of six (Andreozzi et al.,
pharmaceuticals 2004)
(Andreozzi et al.,

K. Ikehata et al.
2004)
Sulfachlorpyridazine Antibiotic, Ozonation Complete conversion of N/D N/D N/D
(80-32-0) sulfonamide 50 mg/L
sulfachlorpyridazine at
pH 7.5 in 1.5 min
(Adams et al., 2002)
Fenton N/D (See Table 2) N/D N/D

December 2006
Sulfadiazine Antibiotic, Ozonation Complete conversion of N/D N/D N/D
(68-35-9) sulfonamide 2 mg/L sulfadiazine at
pH 7 (Huber et al.,
2005)
Fenton N/D (See Table 2) N/D N/D
þ
TiO2/hn 80% conversion of 15 N/D SO2
4 ; NH 4; N/D

mg/L sulfadiazine in NO3 ; hydroxy-
30 min, 80% and 15% lated sulfadiazine
recovery of sulfur and (Calza et al.,
nitrogen, respectively 2004b)
(Calza et al., 2004b)
 Sulfadimethoxine Antibiotic, Ozonation Complete conversion of N/D N/D N/D
(122-11-2) sulfonamide 50 mg/L
sulfadimethoxine at
pH 7.5 in 1.5 min
(Adams et al., 2002)
Fenton N/D (See Table 2) N/D N/D
þ
TiO2/hn Complete conversion of N/D SO2
4 ; NH 4; N/D

15 mg/L NO3 ; two types
sulfadimethoxine in 30 of hydroxylated
min, 90% and 70% sulfadimethoxine,
recovery of sulfur and 2,6-dimethoxy-4-
nitrogen, respectively, aminopyrimidine
in 1 h (Calza et al., (Calza et al.,
2004b) 2004b)
Sulfamerazine Antibiotic, Ozonation Complete conversion of N/D N/D N/D
(127-79-7) sulfonamide 50 mg/L sulfamerazine
at pH 7.5 in 1.5 min
(Adams et al., 2002)
Fenton N/D (See Table 2) N/D N/D
þ
TiO2/hn 85% conversion of 15 N/D SO2
4 ; NH 4; N/D

mg/L sulfamerazine in NO3 ; hydroxy-
30 min, 70% and 18% lated sulfamera-
recovery of sulfur and zine, 4-methyl-2-
nitrogen, respectively aminopyrimidine

Ozonation and Advanced Oxidation of Pharmaceuticals

in 30 min (Calza et al., (Calza et al.,
2004b) 2004b)
Sulfamethazine Antibiotic, Ozonation Complete conversion of N/D N/D N/D
(57-68-1) sulfonamide 50 mg/L
sulfamethazonie at pH
7.5 in 1.5 min (Adams
et al., 2002),

December 2006
N4-acetylation lower
the reactivity toward
ozonation (Huber
et al., 2005)
Fenton N/D (See Table 2) N/D N/D
(Continued)

399
 APPENDIX. (Continued)

400
Pharmaceutical Applied Intermediates/ Biodegradability and
(CAS #) Class process Degree of degradation Kinetic parameters by-products toxicity
Sulfamethoxazole Antibiotic, Ozonation Complete conversion of kO3 = 2.5 · 106 M1s1 N/D Algal and protozoan
(723-46-6) sulfonamide 0.62-2 mg/L at 20  C (Huber et al., toxicity eliminated (as
sulfamethoxazole at 2003) a mixture) (Andreozzi
pH 7-7.2 (Ternes et al., et al., 2004)
2003; Huber et al.,
2005), Complete
conversion of 2.24 mg/
L sulfamethoxazole in
a mixture of six
pharmaceuticals at pH
7.4 (Andreozzi et al.,
2004), N4-acetylation
reduces reactivity
(Huber et al., 2005)
H2O2/UV Complete conversion of kOH = 5.5 · 109 N/D Algal toxicity
2.24 mg/L M1s1 at pH 7 and eliminated, protozoan
sulfamethoxazole in a 25  C (Huber et al., toxicity reduced (as a

K. Ikehata et al.
mixture of six 2003), see also Table 2 mixture) (Andreozzi
pharmaceuticals at pH et al., 2004)
7.4 (Andreozzi et al.,
2004)
TiO2/hn Incomplete conversion N/D N/D No toxicity reduction
of 2.24 mg/L (as a mixture)
sulfamethoxazole in a (Andreozzi et al.,

December 2006
mixture of six 2004)
pharmaceuticals
(Andreozzi et al.,
2004)
Sulfamethizole Antibiotic, Fenton N/D (See Table 2) N/D N/D
(144-82-1) sulfonamide
Sulfamoxole Antibiotic, Fenton Unstable in weakly (See Table 2) N/D N/D
(729-99-7) sulfonamide acidic solution (Boreen
et al., 2004)
Sulfapyridine Antibiotic, Ozonation Complete conversion of N/D N/D N/D
(144-83-2) sulfonamide 2 mg/L sulfapyridine at
pH 7 (Huber et al.,
2005)
 Sulfathiazole Antibiotic, Ozonation Complete conversion of N/D N/D N/D
(72-14-0) sulfonamide 50 mg/L
sulfadimethoxine at
pH 7.5 in 1.5 min
(Adams et al., 2002),
Complete conversion
of 2 mg/L sulfathiazole
at pH 7 (Huber et al.,
2005)
Fenton N/D (See Table 2) N/D N/D
þ
TiO2/hn Complete conversion of N/D SO2
4 ; NH 4; N/D

15 mg/L sulfathiazole NO3 , hydroxy-
in 30 min, quantitative lated sulfathia-
recovery of sulfur, zole (Calza et al.,
90% recovery of 2004b)
nitrogen (Calza et al.,
2004b)
Sulfisoxazole Antibiotic, Fenton N/D (See Table 2) N/D N/D
(127-69-5) sulfonamide
Carbadox Antibiotic, Ozonation Complete conversion of N/D N/D N/D
(6804-07-5) veterinary 50 mg/L carbadox at
pH 7.5 in 1.5 min
(Adams et al., 2002)
Spectinomycin Antibiotic, Ozonation N/D kO3 = 1.27 · 106 N/D N/D
(1695-77-8) miscellaneous M1s1 (neutral), 3.30
· 105 M1s1 (mono-

Ozonation and Advanced Oxidation of Pharmaceuticals

protonated) (Adams
et al., 2002)
Tetracycline Antibiotic, TiO2/hn (+ Complete conversion of Kinetic model presented N/D N/D
(60-54-8) tetracycline direct 50 mg/L tetracycline in (Addamo et al., 2005)
photolysis) 2 h, 90% TOC
removal in 6 h (Di
Paola et al., 2004;

December 2006
Addamo et al., 2005)
Trimethoprim Antibiotic, chemotherapeutic Complete N/D
(738-70-5) conversion of
0.34-50 mg/L
trimethoprim at
pH 7-7.5 (Adams
et al., 2002;
Ternes et al.,
2003)

401
(Continued)
 APPENDIX. (Continued)

402
Pharmaceutical Applied Intermediates/ Biodegradability and
(CAS #) Class process Degree of degradation Kinetic parameters by-products toxicity
N/D N/D
Buspirone Anti-anxiety TiO2/hn Complete conversion of N/D Degradation N/D
(36505-84-7) agent 15 mg/L buspirone in pathway
30 min (Calza et al., proposed (Calza
2004a) et al., 2004a)
Carbamazepine Anticonvulsant Ozonation Complete conversion of kO3 = 7.81 · 104 Degradation Algal toxicity
(298-46-4) 0.5-118 mg/L M1s1 (Andreozzi pathway diminished (Andreozzi
carbamazepine et al., 2002), 3 · 105 proposed et al., 2002)
(Andreozzi et al., M1s1 (Huber et al., (Andreozzi et al.,
2002; Ternes et al., 2003) 2002; McDowell
2002; Huber et al., et al., 2005)
2003), 30%
mineralization as CO2
(Andreozzi et al.,
2002)
H2O2/UV Complete conversion of kOH = 2.05 · 109 Degradation N/D
4.7 mg/L M1s1 (Vogna et al., pathway

K. Ikehata et al.
carbamazepine and 2004a), 8.8 · 109 proposed (Vogna
35% TOC removal in M1s1 (Huber et al., et al., 2004a)
4 min at pH 5.0 2003)
(Vogna et al., 2004a)
TiO2/hn >90% conversion of 4.2 Pseudo-1st-order Degradation N/D
mg/L carbamazepine kinetics (Doll and pathway
in 9 min (Doll and Frimmel, 2004) proposed (Doll

December 2006
Frimmel, 2005c), pilot and Frimmel,
scale treatment (Doll 2005b)
and Frimmel, 2005a)
Diazepam Anti-anxiety Ozonation 24%-65% conversion of kO3 = 0.75 M1s1 at N/D N/D
(439-14-5) agent/ 142 mg/L diazepam at 20  C (Huber et al.,
anticonvulsant pH 9 and 10  C 2003)
(Huber et al., 2003)
H2O2/UV, g- N/D kOH = 7.2 · 109 N/D N/D
radiolysis M1s1 at pH 7 and
25  C (Huber et al.,
2003)
Primidone Anticonvulsant Ozonation Up to 87% conversion N/D N/D N/D
(125-33-7) of 1 mg/L primidone at
pH 7.8 and 23  C
(Ternes et al., 2002)
 Diclofenac Non-steroidal Ozonation Complete conversion of kO3 = 1 · 106 M1s1 Degradation Algal and protozoan
(15307-86-5) anti- 1 mg/L – 296 mg/L at 20  C (Huber et al., pathway toxicity eliminated (as
inflammatory diclofenac (Zwiener 2003), 1.84 · 104 proposed (Vogna a mixture) (Andreozzi
drug (NSAID) and Frimmel, 2000; M1s1 at 25  C et al., 2004b) et al., 2004)
Ternes et al., 2002; (Vogna et al., 2004b)
Ternes et al., 2003;
Vogna et al., 2004b;
Huber et al., 2005),
>30% TOC removal,
95% dechlorination
(Vogna et al., 2004b)
O3/H2O2 Complete conversion of N/D N/D N/D
2 mg/L diclofenac in 10
min (Zwiener and
Frimmel, 2000)
H2O2/UV Complete conversion of N/D Degradation Algal toxicity
296 mg/L diclofenac, pathway eliminated, protozoan
40% TOC removal, proposed (Vogna toxicity reduced (as a
50% dechlorination et al., 2004b) mixture) (Andreozzi
(Vogna et al., 2004b) et al., 2004)
g-radiolysis N/D kOH = 7.2 · 109 N/D N/D
M1s1 at pH 7 and
25  C (Huber et al.,
2003)
Fenton No conversion at pH 3.5 N/D N/D N/D
and 22  C (Packer

Ozonation and Advanced Oxidation of Pharmaceuticals

et al., 2003)
Photo-Fenton Complete conversion of N/D Degradation N/D
10-80 mg/L diclofenac, pathway
>90% TOC removal proposed (Pérez-
at pH 2.8 and 50  C Estrada et al.,
(Ravina et al., 2002), 2005b)
poor performance in

December 2006
buffered acidic and
neutral media (Pérez-
Estrada et al., 2005a)
TiO2/hn Complete conversion of N/D N/D No toxicity reduction
50 mg/L diclofenac, (as a mixture)
55% DOC removal (Andreozzi et al.,
(Pérez-Estrada et al., 2004)
2005a)
(Continued)

403
 APPENDIX. (Continued)

404
Pharmaceutical Applied Intermediates/ Biodegradability and
(CAS #) Class process Degree of degradation Kinetic parameters by-products toxicity
Ibuprofen Non-steroidal Ozonation Less reactive than other kO3 = 9.6 M1s1 at 20 N/D N/D

(15687-27-1) anti- NSAIDs (Zwiener and C (Huber et al., 2003)
inflammatory Frimmel, 2000; Ternes
drug (NSAID) et al., 2003; Huber
et al., 2005)
O3/H2O2 Complete conversion of N/D N/D N/D
2 mg/L diclofenac at
pH 7.5 and 10  C
(Zwiener and
Frimmel, 2000)
H2O2/UV N/D kOH = 7.4 · 109 N/D N/D
M1s1 at pH 7 and
25  C (Huber et al.,
2003)
Fenton N/D kOH = 6.5 · 109 N/D N/D
M1s1 at pH 3.5 and
22  C (Packer et al.,

K. Ikehata et al.
2003)
Indomethacin Non-steroidal Ozonation Complete conversion of N/D N/D N/D
(53-86-1) anti- 0.1 mg/L indomethacin
inflammatory at pH 7.2 (Ternes
drug (NSAID) et al., 2003)
Naproxen Non-steroidal Ozonation Complete conversion of N/D N/D N/D
(22204-53-1) anti- 0.1 mg/L naproxen at

December 2006
inflammatory pH 7.2 (Ternes et al.,
drug (NSAID) 2003)
Fenton N/D kOH = 9.6 · 109 N/D N/D
M1s1 at pH 3.5 and
22  C (Packer et al.,
2003)
 Salicylic acid A decomposition Ozonation 60% conversion of 0.65 N/D N/D N/D
(69-72-7) product of mg/L salicylic acid
acetylsalicylic (Khan et al., 2004)
acid
Paracetamol Antipyretic/ Ozonation Complete conversion of kO3 = 1.41 · 103 Degradation N/D
(103-90-2) analgesic 0.8 g/L paracetamol at M1s1 (neutral), 9.91 pathway
pH 2 and 7 in 20 min, · 108 M1s1 proposed
20% and 30% TOC (dissociated) (Andreozzi et al.,
removal at pH 2 and (Andreozzi et al., 2003a)
7, respectively, in 2 h 2003a)
(Andreozzi et al.,
2003a)
H2O2/UV >90% conversion of kOH = 2.2 · 109 Degradation N/D
1.51 mg/L M1s1 (Andreozzi pathway
paracetamol at pH 5.5 et al., 2003a) proposed (Vogna
in 1 min, 40% TOC et al., 2002;
removal in 4 min Andreozzi et al.,
(Andreozzi et al., 2003a)
2003a)
Anodic Complete conversion N/D Oxalic acid, oxamic N/D
oxidation and 70%-98% TOC acid (Brillas
using a removal of 78-948 mg/ et al., 2005)
boron-doped L paracetamol (Brillas
diamond et al., 2005)
anode
Atenolol b-blocker Ozonation Complete conversion of N/D N/D N/D

Ozonation and Advanced Oxidation of Pharmaceuticals

(29122-68-7) 0.36 mg/L atenolol at
pH 7.2 (Ternes et al.,
2003)
Celiprolol b-blocker Ozonation Complete conversion of N/D N/D N/D
(56980-93-9) 0.28 mg/L celiprolol at
pH 7.2 (Ternes et al.,
2003)

December 2006
Metoprolol b-blocker Ozonation Complete conversion of N/D N/D N/D
(37350-58-6) 1.7 mg/L metoprolol at
pH 7.2 (Ternes et al.,
2003)
Propranolol b-blocker Ozonation Complete conversion of N/D N/D Algal and protozoan
(525-66-6) 0.18-325.5 mg/L toxicity eliminated (as
propranolol at pH 7.2- a mixture) (Andreozzi
7.4 (Ternes et al., 2003; et al., 2004)
Andreozzi et al., 2004)
(Continued)

405
 APPENDIX. (Continued)

406
Pharmaceutical Applied Intermediates/ Biodegradability and
(CAS #) Class process Degree of degradation Kinetic parameters by-products toxicity
H2O2/UV Complete conversion of N/D N/D Algal toxicity
325.5 mg/L eliminated, protozoan
propranolol at pH 7.4 toxicity reduced (as a
(Andreozzi et al., mixture) (Andreozzi
2004) et al., 2004)
TiO2/hn Incomplete conversion N/D N/D No toxicity reduction
of 325.5 mg/L (as a mixture)
propranolol (Andreozzi et al.,
(Andreozzi et al., 2004)
2004)
Sotalol (3930-20-9) b-blocker Ozonation Complete conversion of N/D N/D N/D
1.32 mg/L sotalol at
pH 7.2 (Ternes et al.,
2003)
Aclarubicin Cytostatic drug, Fenton Complete conversion of N/D Absence of No residual
(57576-44-0) anthracycline 0.5 g/L aclarubicin fluorescent by- mutagenicity
(Castegnaro et al., products (Castegnaro et al.,

K. Ikehata et al.
1997), H2O2 alone was (Castegnaro 1997)
less effective et al., 1997)
(Castegnaro et al.,
1997)
Daunorubicin Cytostatic drug, Fenton Complete conversion of N/D Absence of No residual
(20830-81-3) anthracycline 5 g/L daunorubicin fluorescent by- mutagenicity
(Castegnaro et al., products (Castegnaro et al.,

December 2006
1997), H2O2 alone was (Castegnaro 1997)
less effective et al., 1997)
(Castegnaro et al.,
1997)
Doxorubicin Cytostatic drug, Fenton Complete conversion of N/D Absence of No residual
(23214-92-8) anthracycline 0.4 g/L doxorubicin fluorescent by- mutagenicity
(Castegnaro et al., products (Castegnaro et al.,
1997), H2O2 alone was (Castegnaro 1997)
less effective et al., 1997)
(Castegnaro et al.,
1997)
 Epirubicin Cytostatic drug, Fenton Complete conversion of N/D Absence of No residual
(56420-45-2) anthracycline 2 g/L epirubicin fluorescent by- mutagenicity
(Castegnaro et al., products (Castegnaro et al.,
1997), H2O2 alone was (Castegnaro 1997)
less effective et al., 1997)
(Castegnaro et al.,
1997)
Idarubicin Cytostatic drug, Fenton Complete conversion of N/D Absence of No residual
(58957-92-9) anthracycline 0.5 g/L idarubicin fluorescent by- mutagenicity
(Castegnaro et al., products (Castegnaro et al.,
1997), H2O2 alone was (Castegnaro 1997)
less effective et al., 1997)
(Castegnaro et al.,
1997)
Pirarubicin Cytostatic drug, Fenton Complete conversion of N/D Absence of No residual
(72496-41-4) anthracycline 1 g/L pirarubicin fluorescent by- mutagenicity
(Castegnaro et al., products (Castegnaro et al.,
1997), H2O2 alone was (Castegnaro 1997)
less effective et al., 1997)
(Castegnaro et al.,
1997)
Azathioprine Cytostatic drug, Ozonation Complete conversion of N/D N/D No residual
(446-86-6) anti-metabolite 499 mg/L azathioprine mutagenicity (Rey
at pH 3 in 45 min (Rey et al., 1999)
et al., 1999)
Cytarabine Cytostatic drug, Ozonation Complete conversion of N/D N/D No residual

Ozonation and Advanced Oxidation of Pharmaceuticals

(147-94-4) anti-metabolite 401 mg/L cytarabine mutagenicity (Rey
at pH 3 and 7 in 60-75 et al., 1999)
min (Rey et al., 1999)
5-Fluorouracil Cytostatic drug, Ozonation Complete conversion of N/D N/D No residual
(51-21-8) anti-metabolite 269 mg/L 5- mutagenicity (Rey
fluorouracil at pH 3 et al., 1999)
and 7 in 45 min (Rey

December 2006
et al., 1999)
Methotrexate Cytostatic drug, Ozonation Complete conversion of N/D N/D No residual
(59-05-2) anti-metabolite 491 mg/L mutagenicity (Rey
methotrexate at pH 3 et al., 1999)
and 7 in 60-75 min
(Rey et al., 1999)
(Continued)

407
 APPENDIX. (Continued)

408
Pharmaceutical Applied Intermediates/ Biodegradability and
(CAS #) Class process Degree of degradation Kinetic parameters by-products toxicity
Cyclophosphamide Cytostatic drug, Fenton Complete conversion of N/D N/D Mutagenic by-products
(50-18-0) alkylating 4 g/L formed in the presence
agent cyclophosphamide of 5% dextrose
(Hansel et al., 1997) (Hansel et al., 1997)
Ifosfamid Cytostatic drug, Fenton Complete conversion of N/D N/D No residual
(3778-73-2) alkylating 27 g/L ifosfamid mutagenicity (Hansel
agent (Hansel et al., 1997) et al., 1997)
Melphalan Cytostatic drug, Fenton Complete conversion of N/D N/D No residual
(148-82-3) alkylating 2 g/L melphalan mutagenicity (Hansel
agent (Hansel et al., 1997) et al., 1997)
Cimetidine Histamine H2- Fenton N/D kOH = 6.5 · 109 Four degradation N/D
(51481-61-9) receptor M1s1 (Latch et al., products
antagonist 2003) identified
(Zbaida et al.,
1986)
Ranitidine Histamine H2- Fenton N/D kOH = 1.5 · 1010 N/D N/D
(66357-35-5) receptor M1s1 (Latch et al.,

K. Ikehata et al.
antagonist 2003)
TiO2/hn Complete conversion of Kinetic model presented N/D N/D
50 mg/L ranitidine in (Addamo et al., 2005)
1 h, 60% TOC
removal in 5 h
(Addamo et al., 2005)
17b-Estradiol Hormone, Ozonation Complete conversion of N/D Degradation Estrogenicity removed

December 2006
(50-28-2) natural 0.02 mg/L–1.4 mg/L of pathway (Onda et al., 2002;
estrogen 17b-estradiol (Onda proposed (Huber Alum et al., 2004; Kim
et al., 2002; Alum et al., 2004) et al., 2004; Liu et al.,
et al., 2004; Kim et al., 2005)
2004; Huber et al.,
2005)
O3/H2O2 Complete conversion of N/D N/D Estrogenicity removed
7-36 ng/L (Shishida et al., 2000;
17b-estradiol (Onda Onda et al., 2002)
et al., 2002)
H2O2/UV Complete conversion of kOH = 1.41 · 1010 N/D N/D
17b-estradiol M1s1, a kinetic
(unknown model presented
concentration) (Rosenfeldt and
(Rosenfeldt and Linden, 2004)
Linden, 2004)
 Photo-Fenton- >85% conversion of N/D N/D N/D
like 5 mg/L 17b-estradiol
at pH 3.0,
intermediate reactivity
among four estrogens
(Feng et al., 2005)
TiO2/hn Complete conversion N/D Three Estrogenicity removed
and mineralization of intermediates (Ohko et al., 2002)
0.272 mg/L (Ohko et al.,
17b-estradiol in 2002)
4 h (Ohko et al., 2002)
Estrone (53-16-7) Hormone, Ozonation Complete conversion of N/D Degradation N/D
natural 0.015 mg/L estrone pathway
estrogen (Ternes et al., 2003), proposed (Huber
incomplete (> 90%) et al., 2004)
conversion of 0.5 mg/L
estrone (Huber et al.,
2005)
Photo-Fenton- Complete conversion An apparent kinetic Six unidentified N/D
like and 15% equation reported intermediates
mineralization of (Feng et al., 2005) (Feng et al.,
5 mg/L estrone in 160 2005)
min at pH 3, least
degradable among
four estrogens (Feng

Ozonation and Advanced Oxidation of Pharmaceuticals

et al., 2005)
17a-Ethinylestradiol Synthetic Ozonation Complete conversion of kO3 = 7 · 109 M1s1 Five intermediates Estrogenicity removed
(57-63-6) estrogen, 0.15 mg/L 17a- at pH 10 (Huber et al., (Huber et al., (Alum et al., 2004;
contraceptive ethinylestradiol at pH 2003) 2004) Huber et al., 2004; Liu
8 and 10  C (Huber et al., 2005)
et al., 2003)
H2O2/UV Complete conversion of kOH = 1.08 · 1010 N/D N/D

December 2006
17a-ethinylestradiol M1s1 (Rosenfeldt
(unknown and Linden, 2004), 9.8
concentration) · 109 M1s1 (Huber
(Rosenfeldt and et al., 2003), a kinetic
Linden, 2004) model presented
(Rosenfeldt and
Linden, 2004)
(Continued)

409
 APPENDIX. (Continued)

410
Pharmaceutical Applied Intermediates/ Biodegradability and
(CAS #) Class process Degree of degradation Kinetic parameters by-products toxicity
Photo-Fenton- >85% conversion of N/D N/D N/D
like 5 mg/L 17a-
ethinylestradiol at pH
3.0, intermediate
reactivity among four
estrogens (Feng et al.,
2005)
Diethylstilbestrol Synthetic Photo-Fenton- Complete conversion of N/D N/D N/D
(56-53-1) estrogen, like 5 mg/L
contraceptive diethylstilbestrol at pH
3.0, highest reactivity
among four estrogens
(Feng et al., 2005)
Bezafibrate Lipid regulator Ozonation Complete conversion of kO3 = 590 M1s1 at N/D N/D
(41859-67-0) up to 181 mg/L pH 5-10, 20  C (Huber
bezafibrate at pH 8 et al., 2003)
and 10  C (Huber

K. Ikehata et al.
et al., 2003),
incomplete conversion
at lower ozone doses
(Ternes et al., 2002)
H2O2/UV N/D kOH = 7.4 · 109 N/D N/D
M1s1 at pH 7, 25  C
(Huber et al., 2003)

December 2006
 Clofibric acid Lipid regulator Ozonation Complete conversion of kO3 > 20 M1s1 N/D Algal and protozoan
(882-09-7) metabolite 0.12 mg/L – 322 mg/L (Huber et al., 2005), toxicity eliminated (as
clofibric acid apparent rate a mixture) (Andreozzi
(Andreozzi et al., constants = 29.8 et al., 2004)
2003b; Ternes et al., M1s1 at pH 2 –
2003), 49% TOC 2550 M1s1 at pH
removal in 1 h at pH 6.5 (Andreozzi et al.,
5.0 (Andreozzi et al., 2003b), a kinetic
2003b), incomplete model presented
conversion at lower (Andreozzi et al.,
ozone doses (Zwiener 2003b)
and Frimmel, 2000;
Ternes et al., 2002;
Ternes et al., 2003),
quantitative
dechlorination
(Andreozzi et al.,
2003b)
O3/H2O2 98% conversion of 2 mg/ N/D N/D N/D
L clofibric acid at pH
7 and 10  C in 10 min
(Zwiener and
Frimmel, 2000)
H2O2/UV >90% conversion of FP = 1.08 · 10–2 N/D Algal toxicity
322 mg/L clofibric molEinstein1 at pH eliminated, protozoan
acid at pH 5.0 and 25 5.5 and 254 nm, toxicity reduced (as a

Ozonation and Advanced Oxidation of Pharmaceuticals


C, 12% TOC kOH = 2.38 · 109 mixture) (Andreozzi
removal, >80% M1s1, a kinetic et al., 2004)
dechlorination model presented
(Andreozzi et al., (Andreozzi et al.,
2003b) 2003b)
Fenton N/D 4.7 · 109 M1s1 at pH N/D N/D
3.5 and 22  C (Packer

December 2006
et al., 2003)
TiO2/hn Complete conversion of Pseudo-1st-order Degradation No toxicity reduction
0.5 mg/L clofibric acid kinetics (Doll and pathway (as a mixture)
at pH 6.5 in 4 min Frimmel, 2004) proposed (Doll (Andreozzi et al.,
(Doll and Frimmel, and Frimmel, 2004)
2004), pilot scale 2004)
experiments
performed (Doll and
Frimmel, 2005a)

411
(Continued)
 APPENDIX. (Continued)

412
Pharmaceutical Applied Intermediates/ Biodegradability and
(CAS #) Class process Degree of degradation Kinetic parameters by-products toxicity
Fenofibric acid Lipid regulator Ozonation Complete conversion of N/D N/D N/D
(42017-89-0) metabolite 0.13 mg/L fenofibric
acid at pH 7.2 (Ternes
et al., 2003)
Gemfibrozil Lipid regulator Ozonation Presence of unknown N/D N/D N/D
(25812-30-0) amount of gemfibrozil
was reported in a
sewage treatment
plant effluent that was
treated by ozonation
(Huber et al., 2005)
Diatrizoate Triiodinated Ozonation 0% to 14% conversion N/D N/D N/D
(737-31-5; X-ray contrast of 5.7 mg/L diatrizoate
sodium salt) medium at pH 7.2 (Ternes
et al., 2003), no
conversion of 5.0 mg/L
diatrizoate at pH 7

K. Ikehata et al.
(Huber et al., 2005)
O3/H2O2 25% conversion of 5.7 N/D N/D N/D
mg/L diatrizoate at pH
7.2 (Ternes et al.,
2003)
O3/UV 36% conversion of 5.7 N/D N/D N/D
mg/L diatrizoate at pH

December 2006
7.2 (Ternes et al.,
2003)
Iomeprol Triiodinated Ozonation 34% to 90% conversion N/D N/D N/D
(78649-41-9) X-ray contrast of 2.3-5 mg/L iomeprol
medium at neutral pH (Ternes
et al., 2003; Huber
et al., 2005)
O3/H2O2 85% conversion of 2.3 N/D N/D N/D
mg/L iomeprol at pH
7.2 (Ternes et al.,
2003)
O3/UV 88% conversion of 2.3 N/D N/D N/D
mg/L iomeprol at pH
7.2 (Ternes et al.,
2003)
 TiO2/hn 68% of 4.1 mg/L Pseudo-1st-order Unidentified N/D
iomeprol in 3 min at kinetics (Doll and organic by-
pH 6.5, 40% Frimmel, 2004) products (Doll
deiodination (Doll and and Frimmel,
Frimmel, 2004), pilot 2004)
scale experiments
performed (Doll and
Frimmel, 2005a)
Iopamidol Triiodinated Ozonation 33% to 84% conversion N/D N/D N/D
(62883-00-5) X-ray contrast of 1.1-5 mg/L
medium iopamidol at neutral
pH (Ternes et al.,
2003; Huber et al.,
2005)
O3/H2O2 80% conversion of 1.1 N/D N/D N/D
mg/L iopamidol at pH
7.2 (Ternes et al.,
2003)
O3/UV 90% conversion of 1.1 N/D N/D N/D
mg/L iopamidol at pH
7.2 (Ternes et al.,
2003)
Iopentol Triiodinated H2O2/UV Complete AOX removal N/D N/D N/D
(89797-00-2) X-ray contrast and 80% TOC
medium removal of 785 mg/L
iopentol at pH 6.6,

Ozonation and Advanced Oxidation of Pharmaceuticals

85% of iodine
recovered as elemental
iodine (Sprehe et al.,
2001)
Iopromide Triiodinated Ozonation 42% to 91% conversion kO3 < 0.8 M1s1 at N/D N/D
(73334-07-3) X-ray contrast of 5 – 5.2 mg/L pH 5 to 10 and 20  C

December 2006
medium iopromide at neutral (Huber et al., 2003)
pH (Ternes et al.,
2003; Huber et al.,
2005)
O3/H2O2 89% conversion of 5.2 kOH = 3.3 · 109 N/D N/D
mg/L iopromide at pH M1s1 at pH 7 and
7.2 (Ternes et al., 25  C (Huber et al.,
2003) 2003)
(Continued)

413
414
APPENDIX. (Continued)

Pharmaceutical Applied Intermediates/ Biodegradability and

(CAS #) Class process Degree of degradation Kinetic parameters by-products toxicity
O3/UV 90% conversion of 5.2 N/D N/D N/D
mg/L iopromide at pH
7.2 (Ternes et al.,
2003)
H2O2/UV Complete AOX N/D N/D N/D
removal, >90% TOC

K. Ikehata et al.
removal of 769 mg/L
iopromide at pH 6.6
(Sprehe et al., 2001)
TiO2/hn Similar degradability to N/D N/D N/D
iomeprol (Doll and
Frimmel, 2004)

December 2006
Note: N/D = not determined, TOC = total organic carbon, BOD5 = 5-day biochemical oxygen demand, COD = chemical oxygen demand,
DOC = dissolved organic matter, AOX = absorbable organic halogens, kO3 = second-order rate constant for molecular ozone reaction, kOH = second-order
rate constant for hydroxyl radical reaction, FP = quantum yield of direct photolysis.