Forensic Science International 220 (2012) e23e28

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Forensic Science International

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Rapid communication

Quantitative monitoring of corticosteroids in cosmetic products

manufactured in Korea using LCMS/MS
Yun Sik Nam a,b, Il Keun Kwon b, Yeonhee Lee a, Kang-Bong Lee a,*
a
b

Advanced Analysis Center, Korea Institute of Science and Technology, P.O. Box 131, Cheongryangri, Seoul 136-791, Republic of Korea
Department of Oral Biology and Institute of Oral Biology, School of Dentistry, Kyung Hee University, Seoul 130-701, Republic of Korea

A R T I C L E I N F O

A B S T R A C T

Article history:
Received 12 October 2011
Received in revised form 28 November 2011
Accepted 22 December 2011
Available online 28 January 2012

Some cosmetic products manufactured in Korea for the treatment of eczema, seborrhea and psoriasis
have been suspected to contain anti-inammatory corticosteroids such as prednisolone, hydrocortisone,
betamethasone, dexamethasone and triamcinolone acetonide without these ingredients being indicated
on the label. Due to their severe side effects such as permenent skin atopy, these corticosteroids have to
be monitored in cosmetic products from a forensic point of view. Many cosmetic product samples
(N = 65) have been collected from both local and online markets in Korea. The corticosteroid content of
these samples was analyzed by LCMS/MS with diagnostic ions (m/z).
Linearity was studied with 0.110 mg/mL range in all corticosteroids. Good correlation coefcients
(r2  0.997) were found and the limits of quantication were 4.687.97 ng/mL for each of the
corticosteroids. At three different concentrations spanning the linear dynamic ranges, mean recoveries
were 97.2113.5%and precisions (RSD) for intra-day and inter-day analysis were less than 8.9%. Also,
accuracy (Bias %) was less than 11.8%.
The results showed that between 0.760.94 mg/g levels of prednisolone were detected in four
cosmetic products and triamcinolone acetonidewas detected with a concentration in the range of 11.5
272 mg/g in nine samples. This fact reveals that some manufacturers have arbitrarily added these
corticosteroids in their cosmetic products without indicating them on the label. Thus, these cosmetic
products have to be monitored and if proven illegal preparations removed from the market.
2011 Elsevier Ireland Ltd. All rights reserved.

Keywords:
Prednisolone
Hydrocortisone
Betamethasone
Dexamethasone and triamcinolone
acetonide
LCMS/MS
Cosmetic products

1. Introduction
Corticosteroids are known to be highly effective drugs widely
used in dermatology for the treatment of inammatory diseases.
Typically these come in the form of creams, gels, solutions, and
ointments [14]. Clinical studies have shown that the use of
corticosteroids such as prednisolone, hydrocortisone, dexamethasone, betamethasone and triamcinolone acetonide has signicantly enhanced the treatment of patientswith skin problems, such as
psoriasisand eczema [57].
These corticosteroids (Fig. 1) reduce inammation and can
temporarily relieve the symptoms of inammatory skin problems
of severe plaque psoriasis. These corticosteroids have severe
potential side effects, such as permanent skin atopy, pustular
psoriasis, blood vessel expansion, and formation of red spots. There
are also some systematic side effects of corticosterids such as
hypertension, diabetes mellitus, osteoporosis, allergic contact

* Corresponding author. Tel.: +82 2 958 5957; fax: +82 2 958 5969.
E-mail address: leekb@kist.re.kr (K.-B. Lee).
0379-0738/$ see front matter 2011 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.forsciint.2011.12.011

dermatisis, cushings syndrome, and other side effects. The risk

of these side effects increases with long-term use and high dosage,
especially if used without medical supervision. These steroids
should be kept away from the face, eyes, nose and mouth. Also,
chronic use of potent topical corticosteroids can be highly risk,
especially for babies and children.
For these reasons, these corticosteroids should not be contained
in over-the-counter cosmetic products. However, some manufacturers who advertize their cosmetic products as being effective for
the improvement of red, itchy, aky skin caused by eczema,
seborrhea and psoriasis may have already added corticosteroids
without indicating as such on the label. The consumers were not
aware of the presence of these corticosteroids in cosmetic
products, which can lead to improper exposure and possible
toxicity particularly over long term treatment [2,3].
Earlier papers have reported various analytical methods such as
radioimmunoassay [8], HPLCUV [911] and GCMS [12], LC/MS
and LCMS/MS for monitoring of these corticosteroids in
pharmaceutical formulations, biological and urine matrices [13
17]. However, to date, detection of these corticosteroids in
cosmetic products has not been reported [1,4,9,11,1820].

Y.S. Nam et al. / Forensic Science International 220 (2012) e23e28

e24

21

O
12

1
2
3
X

18
CH3

Y
19
11
13
C
CH3
10
5

9
B

20

16

15

[A]

OH
H
H

[B ]

[ C]

OH
OH

OH

HO

OH

HO

H
F

OH

HO

HO

OH

HO

17
D

14

O
HO

OH

H
F

[D]

[ E]

[F]

OH

O
H

Fig. 1. Chemical structure of corticosteroids monitored in this study: [A] general structure of corticosteroid, [B] prednisolone, [C] hydrocortisone, [D] betamethasone [E]
dexamethasone, and [F] triamcinolone acetonide.

This paper is aimed at detecting and monitoring corticosteroids

added illegally to cosmetic products (cream, skin, emulsion and
essence lotions) using an LCMS/MS instrument.
2. Materials and methods
2.1. Chemicals, solvents and samples
Distilled water was provided by Milli-Q water purication system from Millipore
(Bedford, MA, USA) and was used throughout the study. HPLC grade acetonitrile was
obtained from J.T. Baker (Philipsburg, NJ, USA). Prednisolone, hydrocortisone,
dexamethasone and betamethasone were purchased from Sigma (St. Louis, MO,
USA). Triamcinolone acetonide was obtained from Fluka (St. Louis, MO, USA). [2H4]Hydrocortisone-9,11,12,12 as an internal standard (IS) was obtained from Aldrich
(St. Louis, MO, USA). 65different kinds of cosmetic product which indicated that
they contained traditional herbal active ingredients were purchased from local or
online markets in Korea. These cosmetic samples were made from 34 different
manufacturers. Each stock solution (100 mg/mL) was freshly prepared in
acetonitrile and working standard solutions of 0.110 mg/mL were prepared from
stock solutions by dilution with acetonitrile.

source temperature of 400 8C, a desolvation temperature of 200 8C, a nebulizing gas
pressure of 60 psi, and a drying gas pressure of 20 psi. MS experiments were
performed at the optimized detection parameters during multiple reactions
monitoring (MRM). Each corticosteroid was dissolved at a concentration of 1 mg/mL
in solvent, and the solution was directly infused into ESI source at a ow rate of
10 mg/min via a syringe pump (Harvard apparatus, Holliston, MA, USA).
Capillary collision-induced dissociation (CID) values ranged from 5 to 80 eV
depending on corticosteroids and collision energies were selected from 13.5 to
26.0 V for SIM ions. The scan time was 2.0 s and detector multiplier voltage was set
to 1300 V. Scan width in SIM and MRM mode was 0.70 amu. The optimized
parameters for ESI source and MRM acquisition are listed in Table 1.
To maintain the formation of the desirable [M+H]+, standards and samples were
prepared in acetonitrile, since solvent adduct ion in acetonitrile was formed more
easily and increased in MS intensity than that in methanol [13]. Selection of
abundant product ions and optimization for the yield from collision energy were
automatically performed by the instrument control software. ESI with positive ion
mode was selected for the mass spectral analysis and scan mode was centroid.
The total ion spectrum for the precursor ion [M+H]+ was obtained from the range
50500 m/z. To identify a unique precursor and product ion for each analyte, the
detection parameters were optimized for the ion-transitions using the Varian
Analyst software, MSMS breakdown00 .

2.2. Instrumentation
2.5. Validation procedure
A Varian LCMS/MS system (Palo Alto, CA, USA) consisting of a Prostar 430
autosampler, two ProStar 210 pumps, and a 1200L triple quadrupole mass
spectrometer equipped with an Electrospray Ionization (ESI) Source was used for
this study. Varian MS/MS workstation with version 6.5 software was used for data
acquisition and processing.
2.3. HPLC conditions
Chromatographic separation was done using a ZORBAX1 Eclipse XDB-C18
column (4.6 mm  50 mm, 1.8 mm, Agilent Technologies, USA). The ow rate was
0.3 mL/min for 25 min. The mobile phases were distilled water containing 0.1%
formic acid (solution A) and acetonitrile (solution B). Standards and samples were
separated by an initial mixture of solution A with 20% of solution B and a
subsequent gradient up to 50% of solution B in 10 min and continued until there was
100% of solution B by 20 min. After this solution B was changed backed to 20% in
25 min. Afterwards the column was washed and prepped for the next sample by
using 20% solvent B for 7 min.
2.4. Mass spectrometric conditions
The API housing and drying gas temperatures were kept at 40 8C and 300 8C,
respectively. The argon pressure in the collision cell was kept at 1.5 mTorr for MS/
MS measurements. LCMS/MS was operated with a needle potential of 5 kV, a

Calibration standards of quality control (QC) samples containing different

amount of corticosteroids (0.1, 1 and 10 mg/mL) were prepared to be used for
calculation of validation parameters. The prepared solutions were then stored at
4 8C. Calibration curves were prepared for each analytical substance by adding
suitable amount of working standard solution to blank samples and those were
obtained by plotting the analyte and internal standard peak area ratios against the
analyte concentrations in triplicate, and analyzed by linear regression. Recovery,
matrix effect, specicity, linearity, limit of detection (LOD), limit of quantitation
(LOQ), precision and accuracy were measured. Recoveries were assessed by
comparing the peak area ratios for seven replicates of an extracted sample to the
calibration counterparts representing 100% recovery for each QC sample (0.1, 1,
10 mg/mL).
For an evaluation of matrix effect, the peak areas of analytes extracted from
blank creams spiked with QC samples were compared to those of pure analytes.
The method specicity was determined by checking the chromatograms
obtained from blank cosmetic samples, and no endogenous interferences were
encountered under the chromatography conditions (Fig. 2). Linearity was studied
by using a 5-points calibration curve for corticosteroids. Standard deviation (SD) of
the mean noise level over the retention time window of each analyte was used to
determine detection limit (LOD = 3SD) and quantitation limit (LOQ = 10SD).
Precision was expressed as the relative standard deviation (RSD) of concentrations
calculated for QC samples and accuracy was measured as the relative error of the

Y.S. Nam et al. / Forensic Science International 220 (2012) e23e28

e25

Table 1
Parameters for ESI source and MRM acquisition of the corticosteroids in cosmetics.
Retention time (min)

Q1 source CID (eV)

[M+H]+

Collision energy (V)

Product ions (m/z)a

Prednisolone

9.66

57

361.2

18.5
16.5
19.5

121.1
147.1
171.1

Hydrocortisone

9.87

55

363.1

15.0
21.5
23.0

121.1
147.1
267.1

Betamethasone

11.69

50

393.2

15.0
26.0
21.5

147.1
237.1
355.0

Dexamethasone

11.76

71

393.2

19.0
19.0
14.0

147.2
172.2
237.2

Triamcinolone acetonide

12.71

80

435.1

21.0
22.5
17.0

171.1
213.1
225.1

[2H4]-Hydrocortisone

9.78

5.5

367.1

20.0
13.5

121.0
331.0

Name of drugs

Product ion (m/z) with an underline is a fragment ion used for quantitation of each corticosteroid.

calculated concentrations. Both parameters were measured in intra- and inter-day

intervals.
2.6. Sample preparation
Cosmetic sample of ca. 2 g was blended to attain a homogeneous mixture, and 1 g
of the mixture was accurately weighed into a 10 mL volumetric ask, and then was
diluted with 10 mL acetonitrile, and shaken vigorously and precipitated by
centrifuge, and then it was ltered through a 0.45 mm lter paper and transferred
into a 1 mL vial.
To analyze samples containing corticosteroids at concentrations over the limit of
calibration range, some samples were diluted to 1020 times and calculated from
regression equations.

Average recoveries of each compound at three spiking levels

ranged from 97.2% to 113.5%. As an evaluation of the method
precision (RSD) for quantitation, the intra-day and inter-day
coefcients of variation (CV) for all the analytes were less than 5.7%
and 8.9%, respectively. Also, the intra-day and inter-day quantitation accuracy for all the analytes were within the range of 11.8
2.9% and 10.24.9% (Bias %), respectively. The results obtained for
precision and accuracy of intra-day and inter-day analysis were
satised with acceptance criteria [21,22]. This validation data is
summarized in Table 2.
3.2. Conrmation of analytes by LCMS/MS

3. Results and discussion

3.1. Chromatography and validation results
The calibration curves for detection of the target compounds
were obtained in the range of 0.110 mg/mL by performing a linear
regression analysis on a standard solution using peak area ratios of
IS vs. concentration of corticosteroid. Good linearity was obtained
for all analytes with correlation coefcients of r2 > 0.997. Their
limits of detection were 1.402.39 ng/mL and limits of quantitation were 4.687.97 ng/mL.

LCMS/MS experiments were performed to optimize the

detection parameters during multiple reactions monitoring
(MRM) for each corticosteroid. The most appropriate diagnostic
fragment ions were selected and all mass spectrometer parameters
were optimized to improve their intensities [13].
Fragment ions at m/z 121, 147 and 171 have been reported for
1,4-diene-3-keto or4-ene-3-keto forms of corticosteroids monitored in this study [1,23]. These ions were originated from the
fragmentation of B and C ring in the general structure of
corticosteroid (Fig. 1[A]). Monitoring m/z 237 has also been
reported as an efcient way to detect corticosteroids. This ion is

Fig. 2. Typical MRM chromatograms of [A] prednisolone (m/z 361.2 ! 147.1), [B] hydrocortisone (m/z 363.1 ! 121.1), [C] betamethasone (m/z 393.2 ! 147.1), [D]
dexamethasone (m/z 393.2 ! 147.2) and [E] triamcinolone acetonide (m/z 435.1 ! 213.1) spiked in blank cosmetic sample with 1 mg/mL level.

0.9
0.7
2.8
1.2
3.1
9.4
0.2
10.2
2.3
8.7
1.7
5.5
4.9
2.1
1.5
3.7
3.6
4.0
5.3
4.7
4.2
5.2
4.0
6.1
5.1
6.1
6.9
8.9
7.8
5.1
104.0  4.8
107.1  6.2
104.1  5.5
105.3  5.2
100.0  7.7

4.2
4.6
5.7
3.5
4.1

3.4
5.1
5.4
4.8
4.5

3.3
2.9
2.7
1.7
3.3

8.7
4.2
3.1
4.0
2.5

11.8
4.3
8.9
6.8
2.9
113.5  4.4
104.3  7.1
110.6  5.6
92.8  3.7
94.7  5.8
106.9  8.0
101.2  9.0
107.3  8.8
107.5  6.7
97.2  11.9
b

RSD (%) = (SD/mean Cobs)  100.

Accuracy (Bias %) = [(Cobs  Cnom)/Cnom]  100.

3.3. Analysis of cosmetic products

1.40
1.81
2.33
1.55
2.39
0.9977
0.9992
0.9998
0.9979
0.9970
Prednisolone
Hydrocortisone
Dexamethasone
Betamethasone
Triamcinolone acetonide

y = 1.5773x  0.224
y = 1.0613x  0.1771
y = 0.7211x  0.0583
y = 0.7405x  0.1009
y = 0.7043x  0.1405

4.68
6.02
7.78
5.17
7.97

10
1.0

produced by the fragmentation of C13C17 and C15C16 bonds of

Fig. 1[A], and it is observed for all corticosteroids investigated in
this paper [1,23]. Also, all corticosteroids tested with a uorine
atom in C9 showed rst the loss of HF and then consecutive loss of
water. Hence, the use of the neutral loss of 38 Da ([M+HHF
H2O]+) seemed to be the best indicator for the presence of a uorine
atom in corticosteroids such as betamethasone, dexamethasone
and triamcinolone acetonide. It can also be used for the detection
of corticosteroid metabolites containing uorine atom.
The product ions (m/z 237, 171, 147, 121, 105 and other ions) of
prednisolone were generated from the precursor ion (m/z 361). The
major fragment ions from this precursor ion were observed in the
spectra shown in Fig. 3[A]. MS spectra for prednisolone show the
highest intensity at product ion, m/z 147.1 with 57 eV of Q1 source
CID and 16.5 V of collision energy, and the relative abundance of
diagnostic ions m/z, 121.1 and 171.1 were used as an additional
evidence of prednisolone [13,24]. Typical MRM transitions (m/z
361.2 ! 147.1, 121.1 and 171.1) with the same retention time of
9.66 min in Fig. 4[A] show that those were obtained from QC
sample spiked with 1 mg/mL of prednisolone [13,23].
Hydrocortisone gave three product ions with m/z 121.1, 147.1,
and 267.1. Fragments of m/z 267.1may be attributed to the
consecutive loss of glycolaldehyde, [M+H2H2OHOCH2CHO]+
from the fragment at m/z 327 [M+H2H2O]+, the loss of two
water molecules [25].
All fragments of [M+H]+ ion (m/z 393) of betamethasone and
dexamethasone are shown in Fig. 3[C] and [D], respectively. A
fragment ion observed in MS spectra of betamethasone and
dexamethasone is m/z 355 (C22H26O4) which resulted from the
neutral loss of 38 Da ([M+HHFH2O]+) [1,23,26]. The representative ions (m/z 237, 171, 147, 121) of these two steroids should be
effectively distinguished on the basis of the mass spectra. The
problem is that these two steroids differ only in the stereochemistry of their C16 methyl group (Fig. 1), and they were not separated
in the reversed-phase chromatographic system as shown in of
MRM chromatograms of Fig. 2. Thus, no efcient discriminatory
parameters have clearly demonstrated to differentiate the two
stereoisomers in both standard mixtures and samples by LCMS/
MS on the basis of diagnostic ions [27]. Although new methodologies of LCMS/MS to distinguish between betamethasone and
dexamethasone were published [2628], analytical study to
differentiate two steroids has not been performed since none of
these were detected in our cosmetic samples.
The product ions (m/z 237, 225, 213, 171, 147, 121 and 105) of
triamcinolone acetonide were produced from precursor ion (m/z
435 [M+H]+ or 397 [M+H-38]+) as shown in Fig. 3[E] [1,13]. The
MRM transitions were m/z 435.1 (or 397) ! m/z 171.1, 213.1 and
225.1. The quantitation ion was m/z 213.1.

1.6
4.3
1.4
2.2
1.2

10
1.0
0.1
10
1.0
0.1
0.1
0.1

1.0

Accuracy (Bias %)
Precision (RSD)
1.0
0.1

LOQ
(ng/mL)
LOD
(ng/mL)
Regression
equation
Correlation
coefcient
(r2) (n = 3)
Analytes

Table 2
Validation data for samples containing spiked standard solutions (0.1, 1.0 and 10 unit mg/mL) in blank cosmetic cream.

10

Intra-day analysis (n = 5)
Mean recovery (%) (n = 7)

10

Precision (RSD)a

Accuracy (Bias %)b

Y.S. Nam et al. / Forensic Science International 220 (2012) e23e28

Inter-day (1st, 3rd,

5th day) analysis (n = 15)

e26

Although a number of different LC, GC/MS or LCMS/MS

methods for analysis of these corticosteroids in pharmaceutical
formulations or biological matrices have been published, these
steroids added illegally in cosmetic samples have barely been
analyzed [11], and we have presented LCMS/MS method for the
quantitative determinations of ve corticosteroids in four different
cosmetic products (cream, skin, emulsion and essence lotions) sold
locally and online in Korea.
LCMS/MS peaks from prednisolone, hydrocortisone, betamethasone, dexamethasone, triamcinolone acetonide and [2H4]Hydrocortisone (IS) were observed at 9.6, 9.8, 11.6, 11.7, 12.7 and
9.7 min retention times respectively in the analysis of standards
and cosmetic cream samples spiked with corticosteroids (Figs. 2
and 4). Mass fragmentation patterns for cosmetic samples
containing some corticosteroids did match well with standard

Y.S. Nam et al. / Forensic Science International 220 (2012) e23e28

e27

Fig. 3. Collision-induced dissociation (CID) mass spectra for [A] prednisolone, [B] hydrocortisone, [C] betamethasone, [D] dexamentasone and [E] triamcinolone acetonide and
[F] [2H4]-Hydrocortisone (IS).

mass spectra of steroids (Fig. 4). Traces of prednisolone and

triamcinolone acetonide were found in real samples, and their MS
spectra were accurately matched with those of each standard as
shown in MRM chromatograms (Fig. 4[A] and [E]).
Out of the 65 cosmetic samples tested, it was found that
prednisolone was present in four cosmetic cream samples and
triamcinolone acetonide was included in nine cream samples with
relatively high concentration. Also, three cosmetic samples
contained both of prednisolone and triamcinolone acetonide
[29]. Thus, it was revealed that ca. 15% of the tested cosmetic
samples included prednisolone and/or triamcinolone acetonide.
Although the levels of the two corticosteroids found in cosmetic
creams are not as high as those contained in medical formulations,
these over-the-countercreams and lotions are usually used for
long-term period and are not supervised by physicians. Therefore

these non-medical cosmetic products should not be allowed to

contain these corticosteroids.
4. Conclusion
A series of cosmetic products were assayed for the illegal
ingredients (prednisolone, hydrocortisone, betamethasone, dexamethasone and triamcinolone) by a validated LCMS/MS method.
The presence of these steroids was conrmed by product ions and
MRM transitions in LCMS/MS. The present methods allowed for
analysis of a large number of samples in a short period of time and
conrmed the presence of illegal steroids in four different types of
cosmetic products.
Although these steroids were generally found at therapeutic
levels of 0.020.06% in ointments, emollient creams and shampoos

Fig. 4. MRM chromatograms of real cosmetic samples at transitions [A] m/z 361 ! 121, 147, 171 (representatives of prednisolone), [B] m/z 363 ! 121, 147, 267
(representatives of hydrocortisone), [C] m/z 393 ! 147, 237, 355 (representatives of betamethasone), [D] m/z 393 ! 147, 171, 237 (representatives of dexamethasone) and
[E] m/z 435 ! 171, 213, 225 (representatives of triamcinolone acetonide). Chromatograms [A] and [E] were matched with product ions of standards, prednisolone and
triamcinolone acetonide, respectively.

e28

Y.S. Nam et al. / Forensic Science International 220 (2012) e23e28

with indication on the label of these products. These steroids

should not be contained in cosmetic creams for the treatment of
skin problems. As a result of our laboratory ndings, cosmetic
creams containing these steroids sold in local markets of Korea
have been withdrawn. However, regular and consistent monitoring of the use of steroids in cosmetic products is still needed.

[13]

[14]

[15]

Acknowledgements
[16]

The authors would kindly like to thank the Korean Ministry of

Education, Science and Technology for the nancial support
through the research projects (2N33010 and 2N34570).

[17]

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272.0 mg/g. Other corticosteroids were not monitored.