Hindawi Publishing Corporation

Advances in Pharmacological Sciences

Volume 2014, Article ID 981624, 7 pages
http://dx.doi.org/10.1155/2014/981624

Clinical Study
Simple and Robust Analysis of Cefuroxime in Human Plasma by
LC-MS/MS: Application to a Bioequivalence Study

Xingjiang Hu, Mingzhu Huang, Jian Liu, Junchun Chen, and Jianzhong Shentu
Research Center for Clinical Pharmacy, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases,
First Affiliated Hospital, Zhejiang University, Qingchun Road 79, Hangzhou 310003, China

Correspondence should be addressed to Jianzhong Shentu; hhfhxj@163.com

Received 11 January 2014; Revised 26 March 2014; Accepted 1 April 2014; Published 24 April 2014

Academic Editor: Brian R. Overholser

Copyright © 2014 Xingjiang Hu et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

A simple, robust LC-MS/MS assay for quantifying cefuroxime in human plasma was developed. Cefuroxime and tazobactam,
as internal standard (IS), were extracted from human plasma by methanol to precipitate protein. Separation was achieved on a
Zorbax SB-Aq (4.6 × 250 mm, 5 𝜇m) column under isocratic conditions. The calibration curve was linear in the concentration
range of 0.0525–21.0 𝜇g/mL (𝑟 = 0.9998). The accuracy was higher than 90.92%, while the intra- and interday precision were
less than 6.26%. The extraction procedure provides recovery ranged from 89.44% to 92.32%, for both analyte and IS. Finally, the
method was successfully applied to a bioequivalence study of a single 500 mg dose of cefuroxime axetil in 22 healthy Chinese male
subjects under fasting condition. Bioequivalence was determined by calculating 90% Cls for the ratios of 𝐶max , AUC0−𝑡 , and AUC0−∞
values for the test and reference products, using logarithmic transformed data. The 90% Cls for the ratios of 𝐶max (91.4%∼104.2%),
AUC0−𝑡 (97.4%∼110.9%), and AUC0−∞ (97.6%∼111.1%) values were within the predetermined range. It was concluded that the two
formulations (test for capsule, reference for tablet) analyzed were bioequivalent in terms of rate and extent of absorption and the
method met the principle of quick and easy clinical analysis.

1. Introduction enrichment of plasma samples, so as to get a lower limit of

quantification. To the best of our knowledge, there was only
Cefuroxime is a second-generation cephalosporin used one method with LLOQ of 25 ng/mL using simple protein
against a variety of infections. Due to its low oral bioavail- precipitation extraction [10]. Generally speaking, using LC-
ability, cefuroxime is administered orally as a prodrug in MS technique for quantification in biofluids, IS should have
the form of cefuroxime axetil [1]. Upon administration, similar physical, chemical, and chromatographic properties
the acid-stable lipophilic prodrug undergoes hydrolysis to as the analyte (ideally eluted at similar retention time) [11].
yield cefuroxime [2]. However, the oral bioavailability of this Nevertheless, in this literature, the retention time of cefurox-
ester prodrug would be changed violently for suffering from ime and IS was far apart, as 8 min and 4.4 min, respectively.
many factors, such as food [3]. To be able to optimize the Thus, it could not compensate for the sample losses that might
dosing, it is necessary to characterize the pharmacokinetics of occur during the sample preparation and chromatographic
cefuroxime which requires a selective and sensitive analytical steps as well as for matrix effects under certain conditions.
method for cefuroxime in plasma. In this study, we designed a sensitive and robust
Several methods, including HPLC-DAD, LC-MS/MS, LC-MS/MS method following simple protein precipitation
and UPLC-MS/MS, had been reported for the determination extraction with tazobactam as IS for determination of
of cefuroxime in human plasma. However, they all need cefuroxime in human plasma. This method was accurate,
a complicated and expensive sample pretreatment method, sensitive, robust, and simple and was successfully applied to
or solid-phase extraction [4–6], or protein precipitation a bioequivalence study of a single 500 mg dose of cefuroxime
combined with back-extraction [7, 8], or protein precipitation axetil formulations (test and reference) in 22 healthy Chinese
followed by supernatant evaporated [9], for cleanup and male subjects under fasting condition.
2 Advances in Pharmacological Sciences

Max. 1.8e6 cps.

m/z 207 317.9 Max. 2.1e6 cps. 137.9
2.1e6 O 1.8 e 6
m/z 336 m/z 255
N
2.0e6 O O
1.6e6
O H S S N N
1.8e6 N
O
N O NH2 1.4e6 N
O O
1.6e6 m/z 318
HO O O 1.2e6
HO O

Intensity (cps)
1.4e6 m/z 362
Intensity (cps)

362.0
207.0 1.0e6
1.2e6
423.0
8.0e5
1.0e6
336.1
8.0e5 6.0e5
206.9
6.0e5 4.0e5 67.9
255.0
380.2
284.2
4.0e5 167.5 2.0e5 299.0
59.1 149.5 214.9 273.7 289.8 72.8 185.6
328.0 90.6 119.1 142.2 163.3 252.8
2.0e5 191.5
50 100 150 200 250 300 350 400 450 500 550 600
60 80 100 120 140 160 180 200 220 240 260 280 300 320 340
m/z (amu)
m/z (amu)

-MS2 (423.00) CE (−52): 0.998 min from sample 22 (MS-2) of m. . . -MS2 (298.90) CE (−18): 0.101 min from Sample 9 (tazobactam . . .
(a) (b)

Figure 1: The structures and MS spectrums of cefuroxime (a) and IS (b).

2. Experimental 200 ms; ion spray voltage −4500 V; ion source temperature
400∘ C; declustering potential (DP) −40 V for cefuroxime and
2.1. Chemicals and Reagents. Cefuroxime (Batch No. 130493- −34 V for IS; collision energy −10 V for cefuroxime and −22 V
200704, purity 91.4%) and tazobactam (IS) (Batch No. 130511- for IS; collision exit potential (CXP) −10 V for cefuroxime and
200402, purity 99.1%) were supplied by the National Pharma- −9 V IS; and entrance potential (EP) −10 V for cefuroxime
ceutical Institute of China. The chemical structures are shown and IS. Unit resolution was used for both Q1 and Q3 mass
in Figure 1. HPLC grade methanol, acetonitrile were pur- detection.
chased from Merck KGaA Company (Darmstadt, Germany).
Water was purified using a Milli-Q system (Milford, MA,
USA). HPLC grade ammonium formate and formic acid were 2.4. Preparation of Standard Solution and Quality Control
purchased from Sigma (St. Louis, MO, USA). Human plasma (QC) Samples. Stock solution (1.05 mg/mL) of cefuroxime
was obtained from the Blood Center of Zhejiang Province was prepared in 50% methanol and was further diluted
(Hangzhou, China). with 50% methanol to achieve standard working solutions
at concentrations of 210, 105, 52.5, 21.0, 10.5, 5.25, 2.10, 1.05,
2.2. Instruments. The HPLC was performed on an Agilent and 0.525 𝜇g/mL. The QC stock solutions (low: 0.840 𝜇g/mL,
1200 system equipped with a G1367C autosampler, a G1379B medium: 16.8 𝜇g/mL, and high: 168 𝜇g/mL) were also pre-
degasser, a G1316B thermostatted column, and a G1312B pared in the same way. Tazobactam (IS), stock solution
binary pump (Agilent, Waldbronn, Germany). The HPLC 1.86 mg/mL prepared in 50% methanol, was diluted with 50%
system was coupled with an API 4000 triple-quadrupole mass methanol to give a final concentration of 18.6 𝜇g/mL. Both
spectrometer (Applied Biosystems, Concord, ON, Canada) of these stock solutions were stored at 4∘ C avoiding light for
via electrospray ionization interface for mass analysis and using.
detection. Data acquisition was performed with Analyst 1.4.2 The standard working solutions (20 𝜇L) were used to
software (Applied Biosystems). spike blank plasma samples (200 𝜇L). The final concen-
trations of cefuroxime standard calibration plasma sam-
ples were 21.0, 10.5, 5.25, 2.10, 1.05, 0.525, 0.210, 0.105,
2.3. LC-MS/MS Conditions. Separation was performed on an and 0.0525 𝜇g/mL, respectively. The QC samples were also
Agilent Zorbax SB-Aq (4.6 × 250 mm, 5 𝜇m) at a column prepared in the same way by adding 20 𝜇L diluted QC
temperature of 30∘ C. An isocratic mobile phase consisting of stock solutions to 200 𝜇L blank human plasma. The final
methanol/0.05% formic acid in water (42 : 58, v/v) was used at concentrations of cefuroxime in the low-, medium-, and
a flow rate of 1 mL/min, with the injection volume of 2 𝜇L. The high-QC plasma samples were 0.0842 𝜇g/mL, 1.68 𝜇g/mL,
autosampler was set at 4∘ C. A primary flow rate of 1 mL/min and 16.8 𝜇g/mL, respectively.
was split to 500 𝜇L/min using a T-piece. All measurements
were carried out with mass spectrometer operated under
the negative ESI mode. The multiple reaction monitoring 2.5. Sample Extraction Procedures. After frozen human
transitions were m/z 423.0 → 317.9 for cefuroxime and m/z plasma samples were thawed at ambient temperature and
298.9 → 138.0 for IS. Other parameters were as follows: adequately vortexed, a total of 200 𝜇L aliquot plasma sample
collision gas, curtain gas, ion source gas 1 and ion source was added with 20 𝜇L of 50% methanol (supplementary
gas 2 (nitrogen) 6, 15, 55, and 50 psi, respectively; dwell time volume) and 20 𝜇L IS (18.6 𝜇g/mL) solution. After a thorough
Advances in Pharmacological Sciences 3

vortex mixing for 30 s, mixtures were precipitated with (ANOVA) using DAS 2.1.1 was performed on 𝐶max , AUC0–𝑡 ,
600 𝜇L methanol, vortex-mixed for 30 s, and centrifuged at and AUC0–∞ values evaluating treatment, period, sequence,
13000 rpm for 5 min. Finally, 2 𝜇L of supernatant was injected and subject within sequence effects. Their ratios (test versus
into the LC-MS/MS system. reference) of log-transformed data were analyzed for relative
bioavailability. The 90% Cls served as interval estimates and
were determined by two 1-sided 𝑡-tests. If the differences
2.6. Method Validation. The current method was validated
in PK parameters between the two formulations were not
prior to the analysis of human plasma samples according
statistically significant (𝑃 > 0.05) and the 90% Cls for the
to the guidance of bioanalytical method validation [12]. The
ratios of 𝐶max , AUC0–𝑡 , and AUC0–∞ are located within the
selectivity, linearity, precision, accuracy, sensitivity, recovery,
bioequivalence criteria range (80∼125% for AUC and 70∼
matrix effect, and stability of cefuroxime in plasma sample
143% for 𝐶max ), then the two formulations were considered
were assessed and investigated.
to have met the regulatory requirement for bioequivalence.
To evaluate selectivity, drug-free plasma samples from 6
individuals were analyzed to check for the presence of any
interfering peaks at the elution times of both cefuroxime and 3. Results and Discussion
IS. The calibration curves were constructed using 9 standards
ranging in concentration from 0.0525 to 21.0 𝜇g/mL. The 3.1. Method Development. To optimize chromatography, sta-
validity of the linear regression equation was indicated by the tionary phase, the composition of mobile phase, and column
correlation coefficient (𝑟). temperature were investigated in the LC domain, so as to
The intraday and interday precision and accuracy were achieve optimal peak shape and good separation from the
evaluated by assessing QC samples at the following concen- void volume. Because of their amphotericity of chemical
trations (𝑛 = 6): LLOQ (0.0525 𝜇g/mL), low (0.0842 𝜇g/mL), properties, various available columns of different lengths
medium (1.68 𝜇g/mL), and high (16.8 𝜇g/mL). and bonded phases (Zorbax SB-C18 , Zorbax SB-Aq, Hypersil
The extraction recovery and matrix effect of cefuroxime GOLD Aq, and Atlantis T3) were carefully evaluated. Finally,
for three concentrations of QC samples was determined Agilent SB-Aq column was chosen in the present study
by comparing the response of analyte spiked plasma after for its high efficiency and peak symmetry. Different mobile
extraction to that of analyte spiked into the solution extracted phases (methanol-water and acetonitrile-water with different
from blank plasma and the response of analyte spiked after additives, such as formic acid and ammonium formate)
extraction to that of analyte dissolved in mobile phase, were examined to obtain efficient chromatography and rel-
respectively. atively short run time for cefuroxime and IS. It was found
Stability experiments involved leaving the untreated that the addition of formic acid could remarkably improve
plasma sample at ambient temperature for 6 h without light, the peak symmetry and ionization of cefuroxime and IS.
placing the treated plasma sample in an autosampler for 20 h, When methanol was used as the organic phase, the peak
three freeze-thaw cycles from −20∘ C to 25∘ C, and storing for of cefuroxime was further improved. Therefore, the mobile
145 days at −20∘ C, using three aliquots of each QC sample at phase was selected as methanol-mixture of 0.05% formic acid
three different concentrations. in water to achieve better separation and less interference
from other components in the plasma. The retention time for
cefuroxime and IS was 6.8 and 5.9 min, respectively. The total
2.7. Application of the Assay. The method described in this chromatographic run time was 8.0 min (Figure 2).
paper was applied to a bioequivalence study of two oral
formulations of cefuroxime axetil (test formulation, a 250 mg
cefuroxime axetil capsule from a Chinese company; reference 3.2. Selectivity. The typical MRM chromatograms of mixed
formulation, a 250 mg cefuroxime axetil tablet produced by blank plasma from six drug-free individuals, a spiked plasma
GlaxoSmithKline, UK). The study followed a single dose, sample with cefuroxime at LLOQ and IS, and a plasma sample
two-way randomized crossover design with a 1-week washout from a healthy volunteer 0.67 h after an oral administration
period between doses. After an overnight fast of at least 10 h, were shown in Figure 2. The results indicated that there was
subjects received a single oral 500 mg dose of either the test no apparent endogenous interference for the determination
or reference formulation with 240 mL of water. During both of cefuroxime.
treatment periods, heparinized blood samples were collected
at the following times: before (0.0 h) and at 0.33, 0.67, 1.0, 1.5, 3.3. Linearity of Calibration Curves and LLOQ. The stan-
2.0, 2.5, 3.0, 4.0, 5.0, 6.0, 8.0, and 10.0 h after dosing. The blood dard calibration curve for spiked human plasma containing
samples were centrifuged at 4000 rpm for 10 min, and plasma cefuroxime was linear over the range 0.0525–21.0 𝜇g/mL.
samples were separated and stored at −20∘ C until analyzed. Good linearity was observed for the analyte using a weighted
In addition to 𝐶max and 𝑇max obtained directly from the (1/𝑥) least squares linear regression analysis with a coefficient
measured data, other PK parameters (AUC0–𝑡 , AUC0–∞ , and of determination 𝑟 = 0.9998. Typical equations for the
𝑡1/2 ) were calculated by noncompartmental analysis using calibration curve were as follows: 𝑌 = (0.186 ± 0.002)𝑋 +
Drug Statistics (DAS) software 2.1.1 (University of Science and (0.00024 ± 0.00049) (𝑛 = 3), where 𝑋 represents the plasma
Technology, Hefei, China). The relative bioavailability (F%) concentration of cefuroxime (𝜇g/mL) and 𝑌 represents the
of the tested formulation was calculated as follows: 𝐹% = ratios of cefuroxime peak area to that of IS. LLOQ under
AUC0–𝑡 (test)/AUC0–𝑡 (reference)×100%. Analysis of variance the optimized conditions was 0.0525 𝜇g/mL for cefuroxime,
4 Advances in Pharmacological Sciences

4.84 4.35
20 3.86 40
18 35
4.83

Intensity (cps)
16 30 6.60
Intensity (cps)

14 25 6.20
12 5.45 5.73 7.40
10 20 1.12 1.83 7.11 7.54
8 15 4.20
6 10 0.39 2.102.58 3.75
4 2.97
2 5
0 0
1 2 3 4 5 6 7 1 2 3 4 5 6 7
Time (min) Time (min)
N-J1-1-1-tazobactem (IS) (unknown) 298.9/138.0 amu-sample28
N-J1-1-1-cefuroxime (unknown) 423.0/317.9 amu-sample 28
of 140 from data20111022.w. . . (peak not found)
of 140 from data20111022.wif. . . (peak not found)
(I) (II)
(a)
6.69
2.2e4 5.82
300 2.0e4
1.8e4
Intensity (cps)

250 1.6e4
1.4e4
Intensity (cps)

200
1.2e4
150 1.0e4
8000.0
100 6000.0
50 4.83 4000.0
2000.0
0 0.0
1 2 3 4 5 6 7 1 2 3 4 5 6 7
Time (min) Time (min)
CAL1-cefuroxime (standard) 423.0/317.9 amu-sample 24 CAL1-tazobactem (IS) (standard)298.9/138.0
of 140 from data20111022.wiff amu-sample 24 of 140 from data20111022.wiff
Area: 4014.9 counts height: 339 . cps RT: 6.69 min Area: 312710. counts height: 23100. cps RT: 5.82 min
(I) (II)

(b)
6.67 5.79
2.0e4
1.8e4
2.5e4 1.6e4
Intensity (cps)
Intensity (cps)

2.0e4 1.4e4
1.2e4
1.5e4 1.0e4
8000.0
1.0e4 6000.0
5000.0 4000.0
2000.0
0.0 0.0
1 2 3 4 5 6 7 1 2 3 4 5 6 7
Time (min) Time (min)
N-J1-1-3-cefuroxime (unknown) 423.0/317.9 amu -sample 30 N-J1−1−3-tazobactem (IS) (unknown)298.9/138.0amu-sample30
of 140 from data20111022.wif. . . of 140 from data20111022.w. . .
Area: 398080. counts height: 29400. cps RT: 6.67 min Area: 342080. counts height: 20900. cps RT: 5.79 min
(I) (II)

(c)

Figure 2: MRM chromatograms of cefuroxime (I) and IS (II) obtained from human plasma samples: (a) blank plasma, (b) blank plasma
spiked with standard solution (LLOQ), and (c) plasma sample from a healthy subject 0.67 h after oral administration.
Advances in Pharmacological Sciences 5

Table 1: Intraday and interday precision and accuracy of cefuroxime in human plasma.

Concentration Mean concentration found Precision Accuracy

QC levels
(𝜇g/mL) (𝜇g/mL) (RSD%) (%)
LLOQ 0.0525 0.0503 2.72 95.58
Intraday L 0.0842 0.0766 2.84 90.92
(𝑛 = 6) M 1.68 1.68 1.47 99.64
H 16.8 16.7 1.40 99.43
L 0.0842 0.0851 6.26 101.1
Interday
(3 days, 𝑛 = 6) M 1.68 1.71 2.19 101.8
H 16.8 16.8 2.09 100.1

which was judged from the fact that the precision and 8.0
accuracy were less than 20% (Table 1) and the 𝑆/𝑁 ratios
7.0
were much higher than 10. The LLOQ was sufficient for
the bioequivalence study of cefuroxime following an oral 6.0

Concentration (𝜇g/mL)
administration.
5.0

3.4. Precision and Accuracy. QC samples at three concentra- 4.0

tion levels were calculated over three validation runs (once a 3.0
day). Six replicates of each QC level were determined in each
run. Table 1 summarized the intraday and interday precision 2.0
and accuracy for cefuroxime. In this assay, the intraday 1.0
precision that was expressed by relative standard deviation
(RSD) was no more than 2.84% for all tested concentrations 0.0
0.0 2.0 4.0 6.0 8.0 10.0 12.0
(0.0842, 1.68, and 16.8 𝜇g/mL), and the interday precision
Time (h)
was less than 6.26%. The accuracy ranged from 90.92% to
101.8%. The above values were within the acceptable range, Reference
which demonstrated the good stability and repeatability of Test
this described method. Figure 3: Mean plasma concentration-time profile of cefuroxime
after oral administration of test and reference formulations to 22
3.5. Recovery and Matrix Effect. The recoveries of the protein healthy male subjects.
precipitation for cefuroxime were 89.44 ± 4.66%, 91.94 ±
0.94%, and 91.39 ± 1.67% at concentrations of 0.0842, 1.68,
and 16.8 𝜇g/mL, respectively. Mean recovery for the IS was 3.7. Bioequivalence Evaluation. The mean plasma concentra-
92.32 ± 0.90%. The RSDs for all recoveries were less than tion-time curves of cefuroxime after oral administration of
5.21% throughout the entire concentration ranges, indicating a single 500 mg dose of test and reference formulations in
assay consistency. 22 healthy Chinese male volunteers were shown in Figure 3.
The matrix effect was evaluated to determine the influ- The PK parameters of cefuroxime after oral administration
ence of matrix components on analyte quantification. Aver- of 500 mg test and reference formulations to 22 healthy
age matrix effect values obtained were 110.6 ± 5.10%, 109.8 ± volunteers were presented in Table 3. The results of the
1.58%, 111.4 ± 2.12%, and 108.8 ± 1.52% for QC samples at analysis of ANOVA for assessment of product, group, and
concentrations of 0.0842, 1.68, and 16.8 𝜇g/mL, and IS. The period effects and 90% Cls for the ratio of 𝐶max , AUC0–𝑡 ,
results obtained were well within the acceptable limit [12] and and AUC0–∞ values of test and reference products, using
indicated that the analysis of cefuroxime was not interfered logarithmic transformed data, were shown in Table 3. Power
with by endogenous substances in plasma. of statistical test was 97.6% for 𝐶max , 103.9% for AUC0–𝑡 , and
104.1% for AUC0–∞ .
3.6. Stability. The stability experiment was performed by No significant differences in AUC0–𝑡 or 𝐶max were
using QC samples at concentrations of 0.0842, 1.68 and found between the test and reference formulations. The
16.8 𝜇g/mL, except for long-term stability for 0.105, 1.68 and multivariate analysis accomplished through analysis of vari-
16.8 𝜇g/mL. The results indicated that cefuroxime was stable ance revealed the absence of period, group, and product
in untreated plasma when placed in the short-term (6 h) effects for AUC0–𝑡 , AUC0–∞ , or 𝐶max . The 90% Cls for
at room temperature, repeated three freeze/thaw cycles and the ratio of 𝐶max (91.4%∼104.2%), AUC0–𝑡 (97.4%∼110.9%),
stored at −20∘ C for 145 days. In addition, it was found also and AUC0–∞ (97.6%∼111.1%) values for the test and reference
stable in treated-plasma samples when placed in autosampler products were all located within the bioequivalence criteria
at 4∘ C for 20 h (Table 2). range (80∼125% for AUC and 70∼143% for 𝐶max ), proposed
6 Advances in Pharmacological Sciences

Table 2: Summary of the stability of cefuroxime in human plasma on different conditions (𝑛 = 3).

Calculated concentration
Stability conditions Concentration (𝜇g/mL)
Mean ± SD
Accuracy% RSD%
(𝜇g/mL)
0.0842 0.0799 ± 0.0022 94.97 2.75
Short-term
(6 h, 25∘ C) 1.68 1.70 ± 0.025 100.8 1.47
16.8 16.4 ± 0.06 97.63 0.40
0.105 0.103 ± 0.004 98.26 4.22
Long-term
(145 days, −20∘ C) 1.68 1.73 ± 0.038 103.0 2.25
16.8 16.77 ± 0.40 99.94 2.36
0.0842 0.0823 ± 0.0030 97.76 3.89
Autosampler
(20 h, 4∘ C) 1.68 1.71 ± 0.025 101.8 1.47
16.8 16.6 ± 0.27 98.79 1.63
0.0842 0.0837 ± 0.0048 99.46 5.76
Three freeze-thaw cycles
(from 25∘ C to −20∘ C) 1.68 1.72 ± 0.032 102.1 1.84
16.8 16.6 ± 0.36 98.65 2.15

Table 3: Mean pharmacokinetic parameters for cefuroxime after oral administration of 500 mg of test and reference formulations to healthy
human volunteers under fasting condition (𝑛 = 22).

Reference formulation Test formulation Point estimate

Parameters (units)
Mean ± SD Mean ± SD (90% Cls)
𝑇max (h) 2.14 ± 0.85 2.25 ± 0.95 —
𝐶max (𝜇g/mL) 6.42 ± 1.19 6.31 ± 1.45 97.6 (91.42–104.2)
𝑇1/2 (h) 1.33 ± 0.10 1.38 ± 0.16 —
AUC0–𝑡 (𝜇g⋅h/mL) 22.01 ± 3.95 23.02 ± 4.78 103.9 (97.4–110.9)
AUC0–∞ (𝜇g⋅h/mL) 22.30 ± 4.00 23.36 ± 4.87 104.1 (97.6–111.1)

by China Food and Drug Administration [13]. It was con- References

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