Benzophenones

Benzophenones are the synthesized chemicals that block UV and are widely used in
inks, imaging, and clear coatings in the printing industry.

From: Vitamins & Hormones, 2014

Related terms:

Gas Chromatography, Benzodiazepines, Enzymes, Apoptosis, Benzophenone-

, Beta-Glucuronidase, Oximes, In Vitro, Flavonoid

View all Topics

Endocrine Disrupters
Leping Ye, ... Ren-Shan Ge, in Vitamins & Hormones, 2014

4.2.5.7 Benzophenone
Of nine benzophenones (1–8 and 12) tested, benzophenone 1 is the most potent
inhibitor of human 17 -HSD3 activities with IC50 of 1 μM, while others have IC50s
around 47–111 μM (Nashev et al., 2010). Apparently, the inhibition of benzophe-
none 1 on human 17 -HSD3 activity is selective, since it inhibits 17 -HSD1 and
17 -HSD2 activities with IC50 values over 20 μM and has no inhibition on 17 --
HSD5 activity (Nashev et al., 2010). Rodent models also show that benzophenone 1
significantly inhibited testosterone production in mouse and rat testes (Nashev et
al., 2010).

> Read full chapter

Eight-membered and larger Hetero-

cyclic Rings and their Fused Deriva-
tives, Other Seven-membered Rings
I. Shcherbakova, in Comprehensive Heterocyclic Chemistry III, 2008
14.06.3.4.2 Intermolecular condensation reactions
Since 1995, a few examples of the 1,4-diazocine synthesis by condensation reactions
with the formation of two C–N bonds have been described.

The coupling reactions of 2-carboxyl benzophenones with ethylenediamine resulted

in 2,5-benzodiazocin-1-ones 26 (Equation 11) (see Section 14.06.3) <2003JOC92>.

(11)

Cycloalkylation of the N,N -disubstituted 1,2-diamines 80 with dihalides 81 pro-

duced the diazocines 82 in an optically active form (Equation 12) <2004TA2437,
2005TL3473>.

(12)

Reaction of the bis-tetrazole 83 with dibromoethane led to the formation of

the cyclophane 23 in moderate yield (Equation 13) (see Section 14.06.3.1-
) <1999J(P1)3507>.

(13)
> Read full chapter

Sun Protection in Man

Ann Cantrell, ... T. George Truscott, in Comprehensive Series in Photosciences, 2001

26.2.3 Benzophenones
This category of sunscreen comprises a variety of ortho substituted benzophenones
with electron-donating groups that lead to increased electron delocalisation. The
spectrum of benzophenone (given in Fig. 6A) consists of a π–π* transition at 250 nm
and a much weaker ( 102 M−1 cm−1) n–π* transition at 350 nm, which is not shown.
The spectra of benzophenone derivatives used as sunscreens (Fig. 6B), however, are
shifted (to 325 nm) [7]. The principal benzophenone sunscreen in current use is
2-hydroxy-4-methoxybenzophenone (HM-BZP, its tradenames include Benzophe-
none-3 and Oxybenzone). A drawback with these filters is their comparatively low
absorption coefficients (only 9400 M−1 cm−1 at 325 nm for HM-BZP) and thus they
do not afford high sun protection factors (SPF) at low to moderate concentrations.
Also they offer only limited protection at longer UVA wavelengths.

Figure 6. Absorption spectra of benzophenone (A) in ethanol ( max = 251 nm, the
weak n–π* transition at 350 nm is not shown) and HM-BZP in ethanol (B).

There have been few reports on the photochemistry of benzophenone-based sun-

screens although there are reports that they exhibit good photostability [27,28].
Indeed, Deflandre and Lang showed that HM-BZP exhibited only a 1% loss of
absorbance (at 320 nm) following one hour of irradiation with a 250 W xenon arc
lamp (using a 320 nm cut-off filter) in a model emulsion sample [27]. Further-
more, Tarras-Wahlberg et al. showed that the UV spectrum of HM-BZP and 2-Hy-
droxy-4-methoxy-4 -methylbenzophenone in petroleum jelly was stable to both
UVA and UVB radiation [28]. The benzophenone sunscreens form strong intramole-
cular hydrogen bonds between the carbonyl oxygen atom and the hydrogen atom of
the ortho hydroxyl group, which stabilise the molecule and extend the conjugation
of the chromophore. Of course, there have been many photochemical studies of
carbonyl compounds and early work by Porter and Suppan led to an understanding
of the photoreactivity of benzophenone and its derivatives [29,30]. Benzophenone
undergoes efficient ISC to form the lowest excited triplet state, from which many
photochemical reactions proceed, including H-abstraction to form the ketyl radical:

3BZP* + RH → BZPH˙ + R˙

The photoreactivity of benzophenone derivatives is dependent on the nature and

position of substituents (which affect the electronic distribution within the lowest
triplet state, these may be n–π* or π–π* states). Porter and Suppan first studied a
variety of benzophenone derivatives including halogenated, amino and hydroxylated
substituents and showed that n–π* states are more reactive than π–π* states [29].

The principal photochemical reactions of carbonyl compounds are well documented

and include -cleavage, intra- and intermolecular hydrogen abstraction.

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Garcinia cambogia
Rajinder Raina, ... Ramesh C. Gupta, in Nutraceuticals, 2016

Phytochemical Ingredients
G. cambogia is endowed with diverse phytochemical ingredients such as organic
acids, xanthones, polyisoprenylated benzophenones, and isoxanthohumols, some
of which are depicted in Figure 48.1. Various organic acids like HCA, citric tartaric,
and malic and succinic acid are isolated from this plant. HCA is the principal acid
present not only in fruit rinds of G. cambogia, but also in G. Indica and G. atrovidis.
Chemically, HCA is 1,2 di-hydroxy propane 1,2,3 tricarboxylic acid and is very similar
to citric acid found in oranges and other citrus fruits (Lewis and Neelakantan, 1965;
Jena et al., 2002).
Figure 48.1. Chemical structures of active phytochemical ingredients isolated from
Garcinia cambogia.

HCA molecule exists in four different isomers, which are (–)-HCA, (+)-HCA,
(–)-allo-HCA, and (+)-allo-HCA. The most potent inhibitor of ATP citrate lyase
(ACLY) is the (–)-HCA isomer, also known as 2S,3S–HCA (Stallings et al., 1979).
Commercially available G. cambogia extracts are prepared from the fruit rinds and
contain 20–60% (–)-HCA (Jena et al., 2002). HCA of high purity can be chemically
synthesized from citric acid. HCA can exist as a free acid or lactone form. (–)-HCA as
free acid is biologically active but chemically unstable, and gets converted into the
less biologically active but highly stable lactone form. The lactone form, because of
low bioavailability, is not therapeutically preferred. (–)-HCA is combined with various
counter ions to form single, double, or triple stable salts to prevent cyclization of
HCA into the lactone form and thus increase its solubility and bioavailability (Downs
et al., 2005). Sodium salt of HCA is physiologically more effective than the lactone
form, but it is highly hygroscopic and unfavorable for use in dietary supplements
in the dry form. Currently, double or triple salts of calcium, magnesium, and
potassium, instead of the single salt of HCA, are being used because of their
higher solubility and stability. HCA-SX or super CitriMax, which is a Ca+2/K+ salt
of (–)-HCA, is completely soluble in water, which confers higher bioavailability to it
(Downs et al., 2005). The fruit rind of G. cambogia is also rich in polyisoprenylated
benzophenones (Garcinol/comboginol), tetra cyclic xanthones (oxyguttiferones), and
isoxanthohumol (guttiferones I, J, K, M, and N) (Masullo et al., 2008). Garcinol is also
found in the latex and bark of the plant (Iinuma et al., 1998, Masullo et al., 2008). The
presence of phenolic hydroxyl groups and -diketone moiety in garcinol molecule
imparts strong antioxidant activity to it (Padhye et al., 2009). Garbogiol, a xanthone,
is found in the roots, whereas another xanthone, Rheediaxanthone A, is present in
the bark of the plant (Iinuma et al., 1998).

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Red Propolis: Phenolics, Polypheno-

lics, and Applications to Microbiologi-
cal Health and Disease
Irlan A. Freires, ... Bruno Bueno-Silva, in Polyphenols: Prevention and Treatment of
Human Disease (Second Edition), 2018

2 Propolis Chemical Composition

Propolis consists of approximately 50% resin and vegetable balsam, 30% wax, 10%
essential and aromatic oils, 5% pollen, and 5% of other substances. Normally, < 3%
are the active compounds [7].

Several different substances can be found in propolis, including hydrocarbons,

alcohols, aliphatic acids, aromatic acids, fatty acids, aldehydes, ketones, flavones and
flavonols, flavanones, chalcones and dihydrochalcones, terpenoids, steroids, amino
acids, sugars, lignans, vitamins, and minerals. Phenolic acids and flavonoids are
considered the bioactive compounds of propolis, which means the compounds with
pharmacological activity [7].
Phenolic acids are aromatic compounds found in several plant species and widely
distributed in the plant kingdom. Phenolic compounds are acidic, polar, and water
soluble. In addition, they may contribute to plants’ odor, taste, and pigmentation.
Among the biological activities already reported on phenolic compounds, we high-
light antioxidant, antimicrobial, and antiinflammatory activity [8,9].

Flavonoid compounds are a group of phenolic acids composed of low molecular

weight molecules containing 15 carbon atoms in their fundamental nucleus. In
red propolis, different flavonoid compounds have already been found, including
compounds classified as flavanones, isoflavones, dihydro flavones, chalcones and
dihydrochalcones [10].

The propolis chemical composition variation is mainly due to the plant species
around the hive. Moreover, seasonal variations may occur in the number of com-
pounds present in propolis. These compounds are found in cuts, exudates, shoots,
resins, and others. Therefore, the biological properties of propolis are directly linked
to its botanical origin. In Europe, North America, West Asia and temperate countries,
the main source for propolis production is the poplar exudate (Populus sp.). These
countries possess only one type of propolis. However, in South America, the plant
of the genus Populus is not commonly found.

Since Brazil is a country with prodigious geographical extension and a diverse

vegetation along its length, several types of propolis can be found there [3]. As
a result, an extensive analysis of Brazilian propolis was carried out encompassing
propolis from Southeast, South, Center, West, and some Northeastern states. Due
to its geographical, vegetal, and chemical biodiversity, unlike the other countries of
America, Asia and Europe, in Brazil more than 500 samples of propolis were collected
in distinct geographical locations and, consequently, having different vegetal origins
and exhibiting chemical biodiversity. After processing and analyzing these samples,
the Brazilian propolis types were classified into 12 groups based on their complex
chemical profile, which was determined by extract appearance and color, UV-visible
absorption spectrum, high efficiency thin-layer chromatography, and high-perfor-
mance liquid chromatography [11]. Groups 3 (southern region), 6 (coastal region of
Bahia), and 12 (southeast region) were demonstrated to have a better antimicrobial
activity and they have received more attention from the scientists.

In 2008, the propolis popularly known as red propolis, found on the coast of Maceió,
Alagoas, was considered the 13th group, according to the previous proposed classif-
ication. Fig. 24.1 shows the crude Brazilian red propolis as produced on the beehive.
The red propolis of Alagoas has as its botanical origin the Dalbergia ecastophyllum, a
plant belonging to the Leguminosae family, the same family as soybeans and beans.
Several isolated compounds from this propolis are commonly found in plants of the
leguminosae family, which belongs to the botanical origin of red propolis [3].
Fig. 24.1. Propolis being produced in the beehive.

Among these groups, group 12, also known as green propolis, collected from the
Minas Gerais state, was the first to be distinguished due to its antimicrobial and
antiinflammatory properties. In addition, some patents regarding the obtaining
and usage of isolated bioactive compounds such as Artepelim C were granted
[12]. However, the red propolis is recently taking prominence due to its biological
properties and isolated compounds.

Red propolis can also be found in other countries such as Cuba, Mexico, and
Venezuela; however, Brazilian red propolis is more prominent in both consumption
and number of published works [13–16]. Within Brazil, the red propolis can be found
over Sergipe, Alagoas, Pernambuco, and Paraíba states. However, propolis from
different states shows slight differences in chemical composition and, consequently,
distinct biological activity [17–20].

2.1 Compounds Identified in Brazilian Red Propolis

The main compounds found in red propolis are isoflavonoids, pterocarpans, chal-
cones, flavonoids, prenylated benzophenones, terpenes, and tannins. Among the
main chemical markers, formononetin, biochanin A, pinocembrin, medicarpin,
neovestitol, and vestitol were highlighted [3,13,20–22].

Since Brazilian red propolis can be found in different Brazilian states, and due to
the prodigious Brazilian biodiversity, different chemical compounds can be found
in red propolis produced in various Brazilian states, even in neighboring states
such as Sergipe, Alagoas, Pernambuco, and Paraíba [3,20]. Fig. 24.2 illustrates the
geographical location of Brazilian red propolis.
Fig. 24.2. Geographical location (approximately) of Brazilian states that produce
Brazilian red propolis.

Apparently, formononetin is the major compound of propolis collected in all states

of the Brazilian northeast. In addition, biochin A is present in a greater quantity in
Sergipe state propolis than that of other states, while guttiferone E/xanthochymol
are found mainly in red propolis produced in Paraíba and Pernambuco, and also, to
a lesser extent, in Alagoas state propolis [13,18,20]. Finally, neovestitol and vestitol
were only isolated from the red propolis of Alagoas [23–25], and it is the only one
to obtain the Geographical Indication (GI) by the Brazilian National Institute of
Industrial Property (INPI) and is the only red propolis of certified origin in Brazil
[26]. Other compounds identified and/or isolated from red propolis include methyl
eugenol, elemicin, cycloartenol, lupeol, isosativan, isoliquiritigenin, liquiritigenin,
7-O-methylvestitol, vesticarpan, oblongifolin A, naringenin, mucronulatol, retusa-
purpurin A and B, hesperetin 7-rhamnoglucoside, and others [13,22,27,28].

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Personal Care Products and Cosmetics

Changqing Zhou, ... Jodi A. Flaws, in Reproductive and Developmental Toxicology
(Second Edition), 2017

Effects of UV Filters on Reproductive Health

UV filters were developed to absorb UVA or UVB radiation to protect the skin
from sunburn. UV filters, including benzophenones (BPs), octyl methoxycinnamate
(OMC), and 3-(4-methylbenzylidene)-camphor (4-MBC), are widely used in many
PCPs such as lotions, creams, lipsticks, hairspray, and sunscreens (reviewed in
Witorsch and Thomas, 2010). Although studies have shown that UV filters protect
against sunburn, solar keratosis, and nonmelanoma skin cancer, some UV filters
might have adverse effects on reproduction (Krause et al., 2012).

UV filters have been associated with adverse human reproductive health, pregnancy,
and birth outcomes. In a study conducted in the United States, creatinine concentra-
tions of two UV filters (2, 4-dihydroxybenzophenone and 2, 2 -dihydroxybenzophe-
none) were higher in women with fibroids than women without fibroids; however,
the odds were not significant after adjusting for relevant covariates (Pollack et al.,
2015). One study also showed that urinary concentrations of BP derivatives were
significantly associated with the odds of endometriosis diagnosis (Kunisue et al.,
2012). In the Longitudinal Investigation of Fertility and the Environment Study in
the United States, urinary levels of BP2 and 4-hydroxybenzophenone (a metabolite
of BP) in male partners were associated with reduced fecundity (longer time to
pregnancy) (Buck Louis et al., 2014a). Another report from this study showed that
BP2 and BP8 were significantly associated with some semen end points, including
diminished sperm concentration, movement, number of immature sperm, and
sperm tail abnormalities (Louis et al., 2015). In that study, maternal urinary level of
4-hydroxybenzophenone was also significantly associated with an excess of male
births, and both maternal and paternal urinary levels of BP2 were associated with an
excess of female births (Bae et al., 2016). In a study conducted in France, maternal
urinary levels of BP3 were positively associated with weight and head circumference
at birth in the male infants (Philippat et al., 2012). In a study conducted in New York
City, third-trimester maternal urinary levels of BP3 were inversely associated with
birth weight among girls, but positively associated with birth weight in boys (Wolff e
t al., 2008). In a study conducted in China, maternal urinary concentration of BP3
was associated with decreased gestational age in infants, especially in male infants
(Tang et al., 2013).

UV filter exposure induces reproductive toxicity in some, but not all animal studies.
BP3 (1525 mg/kg/day), OMC (935 mg/kg/day), and 4-MBC (309 mg/kg/day) have
been shown to increase uterine weight when rats were exposed through the diet
for 4 days (Schlumpf et al., 2001). In female rats, exposure to a metabolite of BP,
4-hydroxybenzophenone (3 days, 100–400 mg/kg/day) increased uterine weights,
luminal epithelial height, and thickness of vaginal epithelial cell layers (Nakagawa
and Tayama, 2001). Exposure to BP at 400 mg/kg/day, however, did not affect uterine
weight or the histology of the uterus and vagina. Furthermore, in a two-generation
rat study, dietary exposure to BP (100, 450, and 2000 ppm) did not affect estrous
cyclicity, reproductive capability, delivery and lactation, sperm parameters, serum
hormone levels, AGD, or number of pups delivered in F0 and F1 generations
(Hoshino et al., 2005).

OMC treatment (500, 750, and 1000 mg/kg/day) during gestation and lactation
reduced relative prostate and testis weights and testosterone levels, affected testis
and prostate histology on PND 16, and reduced sperm counts and prostate weight
at age of 8 months in male offspring (Axelstad et al., 2011). It also (1000 mg/kg/day)
reduced progesterone and estradiol levels on PND 28 in female offspring (Axelstad
et al., 2011).

In rats, exposure to 4-MBC during gestation every other day (100 mg/kg) signif-
icantly decreased GnRH, LH, and FSH levels in male offspring, but increased serum
LH and FSH levels and advanced vaginal opening in female offspring (Carou et al.,
2009a). When rats were exposed to 4-MBC daily during gestation, 4-MBC increased
LH (20, 100, and 500 mg/kg/day) and FSH (100 and 500 mg/kg/day) serum levels in
male offspring on PND 30, but decreased testicular weight, LH, and GnRH levels
(100 and 500 mg/kg/day) on PND 15 in males (Carou et al., 2009b). In another
study in which rats were exposed to 4-MBC during gestation, 4-MBC (7 mg/kg/day)
significantly increased tissue volume in prostate and accessory sex glands, the
number of ducts in the caudal dorsal prostate, distal branching morphogenesis,
and ductal volume on PND 1 (Hofkamp et al., 2008). Furthermore, continuous
exposure to 4-MBC from gestation to adulthood increased uterine weight, delayed
pubertal onset in males, reduced testis and prostate weights, disrupted several key
gene expression in uterus and prostate (Pr, Esr1, and Ar), affected sexual behaviors
(proceptive and receptive behaviors), and disrupted estrous cyclicity in rat offspring
(reviewed in Schlumpf et al., 2008).

2-Hydroxy-4-methoxybenzophenone (HMB) is another UV-absorbing compound.

Exposure to HMB (50,000 ppm) from GD 6 to PND 23 reduced AGD and impaired
spermatocyte development in male rats and delayed follicular development in fe-
male rats (Nakamura et al., 2015).

> Read full chapter

Recent Advances in the Discovery and

Development of CRTh2 Antagonists
Laurence E. Burgess, in Annual Reports in Medicinal Chemistry, 2011

2.3 Phenyl acetic acids

A plethora of CRTh2 antagonists based on the phenyl acetic acid template have
recently been disclosed, and they fall, generally, into three structural categories:
biphenyl ethers, benzophenones, and biphenyls. Of the biphenyl ether class, com-
pound 24 (IC50 = 3 nM in buffer; IC50 = 28 nM in human plasma) was one of the
first to enter clinical trials. Ultimately, compound 24 was abandoned in favor of
AMG-853 (25) because of a reduced plasma shift. AMG-853 has been extensively
profiled and also advanced to clinical studies [41]. AMG-853 is potent in both buffer
(IC50 = 3 nM) and human plasma (IC50 = 8 nM) and also possesses affinity for the
DP receptor (IC50 = 35 nM) [42]. In preclinical pharmacokinetic studies, this dual
CRTh2/DP antagonist showed low to moderate clearance across species, excellent
oral absorption, and low potential for drug–drug interactions as indicated by CYP
inhibition and induction studies. In single oral dose, first-in-human clinical studies,
AMG-853 pharmacokinetics were approximately dose proportional (i.e., 100 mg:
Cmax   500 ng/mL; 400 mg: Cmax   3000 ng/mL) and the drug was well tolerated
[43]. The major metabolite was the corresponding acyl glucuronide, and this was
observed at levels (based on AUC) approximating 70% of parent. As a pharma-
codynamic endpoint, CRTh2 receptor internalization in response to ex vivo PGD2
stimulation demonstrated that oral doses of 200 or 400 mg of AMG-853 could only
suppress this phenomenon for approximately 8–10 h, suggesting that this drug may
benefit from a BID dosing regimen.

Another series of structurally related biphenyl ether-based phenyl acetic acid CRTh2
antagonists includes 26, 27, and 28 (all IC50s < 300 nM) [44]. It is interesting to note
that the reverse amide, 27, and its analogous diphenyl methane, 28, both retain
CRTh2 affinity. These results suggest that the nature of the linker (benzamide vs.
anilide or ether vs. alkyl) is not crucial and, comparing to AMG-853, there seems
to be flexibility in the position of the linker relative to the acetic acid substituent
(i.e., meta versus para). The preferential use of the tert-butyl amide in both series of
compounds also suggests a similar binding mode to AMG-853.
A very potent series of biphenyl ether-containing phenyl acetic acid CRTh2 antago-
nists was recently disclosed [45]. Compounds 29–32 incorporate a 6-fluoro-3-methyl
naphthalene core and utilize either an ether (29; IC50 = 2.3 nM) or a keto-linker
without loss of affinity (31; IC50 = 2.1 nM) [46]. The terminal aryl sulfone can also
be replaced as a piperidinesulfonamide (32; IC50 = 2.4 nM), a common functional
group in many CRTh2 antagonists. In particular, compound 30, which incorporates
a bromo-substituted pyridine, demonstrates very high affinity for CRTh2 (IC50 = 0.02
nM).

A series of chroman-based compounds that incorporate a biphenyl ether have also

been reported to be potent CRTh2 antagonists [47]. Single enantiomers of these
chiral phenyl acetic acids were prepared, and a significant difference in affinity for
CRTh2 was demonstrated (33, eutomer; IC50 = 84 nM; distomer IC50 = 4000 nM).
One of the more potent, single enantiomer antagonists in this series incorporates a
pyridyl-containing biphenyl motif (34; IC50 = 22 nM).
Additional phenyl acetic acid CRTh2 antagonists that incorporate a biaryl arrange-
ment are represented by several active compounds related to previously disclosed
AM156 (35; IC50 = 24 nM) [48]. CRTh2 activity is maintained when a pyridine is used
in place of phenyl as evident in this series (36, 37; IC50 < 300 nM). Carbamate 38 was
quite potent (IC50 = 8 nM; ESC IC50 = 5 nM), demonstrated good selectivity over other
prostanoid receptors and good pharmacokinetics in rat (t1/2 = 8.7 h, F = 77%) and dog
(t1/2 = 7.4 h, F = 89%). This compound also provided similar efficacy (at a dose of 10
mg/kg) to dexamethasone (also at a dose of 10 mg/kg) in a murine model of allergic
rhinitis. The carbamate was later identified as a metabolic and potential toxicological
liability. In an effort to eliminate this functionality, the biphenyl was elaborated to a
pyridyl-containing triarene, and the cyclopropyl amide was reintroduced to provide
AM432 (39; IC50 = 31 nM) [49]. AM432 was considered as a clinical development
compound and profiled extensively in animal models. At an orally administered dose
of 10 mg/kg, AM432 provided protection from upper airway distress in a murine
model of allergic rhinitis and also reduced neutrophil influx in the lower airway in a
murine model of COPD involving cigarette smoke exposure. In addition to potent
CRTh2 activity and selectivity over related prostanoid receptors, AM432 was also
found to be devoid of agonist and antagonist activity at three isoforms of the PPAR
receptor up to concentrations of 250 μM. Reports of CRTh2 antagonist selectivity
screening versus nuclear hormone receptors have been rare; however, several clinical
CYP induction and drug–drug interaction studies have been disclosed that may be
linked to this activity [25].

> Read full chapter

Toxicology/Drugs of Abuse
M.-C. Huang, ... R.H. Liu, in Encyclopedia of Forensic Sciences (Second Edition),
2013

Acid and enzyme hydrolysis of conjugated drugs

Both acid hydrolysis and enzyme digestion have their merits. For example:

• -glucuronidase is known to release intact benzodiazepines from their glu-

curonide conjugates without converting to their corresponding benzophe-
nones, which is a typical product of acid hydrolysis.
• compared to -glucuronidase, acid hydrolysis of morphine glucuronide is less
time-consuming and can achieve a higher recovery rate. However, this process
tends to cause the decomposition of acidlabile compounds in the matrix,
leaving a dirty reaction mixture.

Enzyme hydrolysis may be preferred when the analyte is acid-labile and high re-
covery is not an important factor, i.e. when sensitive detection and quantification
methodologies are incorporated in the overall protocols.

> Read full chapter

Substance Misuse: Urine Analysis

A.K. Chaturvedi, R.H. Liu, in Encyclopedia of Forensic and Legal Medicine (Second
Edition), 2015

Specimen Pretreatment
Many drugs and their metabolites have strong affinity to proteins, whereas most of
their conjugates are highly hydrophilic and not amenable to organic solvent extrac-
tion. Thus, pretreatment procedures generally include the removal of the binding
proteins, the hydrolysis of drug conjugates, and the extraction of the analytes from
the resulting reaction mixture. Since urine has limited protein content, protein
removal is not necessary.

Drug conjugate hydrolysis: Acidic and enzymatic hydrolyses have their merits. For
example,

(1) -glucuronidase releases intact benzodiazepines from their glucuronides

without converting to their corresponding benzophenones, which is a typical
product of acid hydrolysis.
(2) Compared to -glucuronidase, acid hydrolysis of morphine glucuronide is less
time-consuming and can achieve a higher recovery rate. However, this process
tends to cause the decomposition of acid-labile compounds in the matrix,
leaving a dirty reaction mixture.

Enzymatic hydrolysis may be preferred when the analyte is acid-labile and high
recovery is not an important factor.

Extraction
This step typically removes interfering materials and concentrates the analyte.

Liquid–liquid extraction systems are designed to have the analyte partition, prefer-
ably into the organic phase in its unionized form or as an ion pair. The addition
of a proper counter ion or pH adjustment of the sample may be used to facilitate a
favorable partitioning of the drug. The analyte may also be ‘salted out’ of the aqueous
phase with high ionic strength of the medium. High concentrations of electrolytes
are used to generate the ionic strength of the medium in salting-out approaches.

In a solid-phase extraction process, separation is performed with a solid additive or

column material using hydrophilic, hydrophobic, or ionic groups attached to silica
gels. Over conventional liquid–liquid procedures, solid-phase extraction approaches
offer the advantages of less organic solvent usage, no foaming problems, shorter
sample preparation time, and ease of incorporation into an automatic operation
process.

Solid-phase extraction procedures widely adopted for the drug urinalyses include
four steps: (1) conditioning, (2) loading, (3) rinsing, and (4) eluting. The first con-
ditioning solvent should be as strong as, or stronger than the elution solvent. The
second conditioning solvent should be the same as or as close to the strength of
the loading solvent as possible. The loading solvent should be as weak as possible
to result in the tightest or narrowest band of adsorbed sample on the sorbent. A
solvent that is slightly stronger or the same strength as the loading solvent is used
as the rinse solvent. The rinse will elute unwanted sample components that are not
as strongly retained as the analytes and also wash down small droplets of loading
solvent adhering to the walls of the tube to ensure that the entire sample comes in
contact with the sorbent. An ideal eluting solvent should elute the analytes within
5–10 bed volumes. The optimal amount of solvent to elute the analytes from a
500-mg cartridge is about 0.6–1.2 ml. Using a too-strong solvent will cause the
elution of unnecessary sample components that are more strongly retained than the
analytes, whereas a too-weak solvent will cause excessive elution solvent volumes.
Sometimes, a desired solvent strength may be obtained by blending appropriate
amounts of miscible solvents.
 If a water-immiscible eluant is selected and the analysis is to be performed with
the GC, a ‘drying’ procedure should be applied between the rinsing and the eluting
steps. The combination of vacuum and a small amount of methanol can produce a
‘dry’ eluate without causing a substantial loss of drugs.

> Read full chapter

Silica-based nanostructured materials

for biomedical applications
A. Gallardo, ... S. Nonell, in Applications of Nanoscience in Photomedicine, 2015

20.4.1 Benefits of sunscreen encapsulation

Several currently used UV filters lose some of their photoprotective capacity after
exposure to UV radiation. Organic or “chemical” filters such as butyl methoxy
dibenzoylmethane and octyl methoxycinnamate suffer light-induced decomposi-
tion, whereas benzophenones are known to produce ROS [49]. Other problems
include their absorption through the skin [50], and their accumulation in aqueous
ecosystems, recently linked to the bleaching of corals [51]. Similar problems affect
the inorganic or “physical” filters such as titanium dioxide or zinc oxide, which may
act as photocatalysts and also generate ROS.

Encapsulation in suitable hosts would alleviate these problems, particularly as the

filters do not need to be released to exert their function. Nanosystems such as sol-
id-lipid nanoparticles, liposomes, polymeric nanoparticles and silica-based materials
have been considered as hosts for the organic filters. Titanium dioxide is normally
coated with silica or organic salts [52]. SNPs are attractive candidates due to both
their low dermal uptake and toxicity as well as their stability and optical properties.

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