Synthesis and evaluation of fenofibric acid ester derivatives: Studies of different formulation with their bioavailability and absorption conditions

Article abstract of DOI:10.21577/0103-5053.20190170

A series of fenofibric acid ester pro-drugs (JF-1-7) were synthesized. The pharmacokinetic properties of these pro-drugs were examined after oral administration to rats at a dose of 20 mg kg^-1 to evaluate the relative bioavailability in rats. The bioavailability of the ester compounds, JF-1, 2, 3, 4, 5, 6, and 7, was significantly higher than that of fenofibrate. In particular, JF-2 proved to be most promising. The oral administration (20 mg kg^-1) of JF-2 showed a relative bioavailability of approximately 272.8percent compared to fenofibrate.

Full text of DOI:10.21577/0103-5053.20190170

http://dx.doi.org/10.21577/0103-5053.20190170
J. Braz. Chem. Soc., Vol. 31, No. 2, 280-287, 2020
Printed in Brazil - ©2020 Sociedade Brasileira de Química
Article
Synthesis and Evaluation of Fenofibric Acid Ester Derivatives: Studies of Different
Formulation with Their Bioavailability and Absorption Conditions
Zhixiang Lv,a Zhou Wang,b Fuyan Xiaoc and Guofan Jin *,c
aDepartment of Pharmacy, Danyang People’s Hospital, 212300 Danyang, P. R. China
bCollege of Vanadium and Titanium, Panzhihua University, 617000 Panzhihua, P. R. China
cSchool of Pharmacy, Jiangsu University, 212013 Zhenjiang, P. R. China
A series of fenofibric acid ester pro-drugs (JF-1-7) were synthesized. The pharmacokinetic
properties of these pro-drugs were examined after oral administration to rats at a dose of 20 mg kg-1
to evaluate the relative bioavailability in rats. The bioavailability of the ester compounds, JF-1,
2, 3, 4, 5, 6, and 7, was significantly higher than that of fenofibrate. In particular, JF-2 proved to
be most promising. The oral administration (20 mg kg-1) of JF-2 showed a relative bioavailability
of approximately 272.8% compared to fenofibrate.
Keywords: pharmacokinetic properties, fenofibrate, fenofibric acid, bioavailability
Introduction
hypertriglyceridemia. On the other hand, fenofibrate is a
neutral, lipophilic compound that is practically insoluble
in water, making it challenging to achieve consistent
therapeutic levels.2,3 One of the main disadvantages of this
drug is the low consistently achieved therapeutic levels,
because of its special chemical characteristics, such as its
high lipophilicity, and low water-solubility.4,5
This study examined the bioavailability and absorption
of various fenofibrate formulations.6-8 Furthermore, a series
of fenofibrates were prepared with different formulations
to increase its overall solubility. Four known (JF-1 to 4)
and three (JF-5 to 7) novel pro-drugs (Figure 2) were
Fenofibrate (Figure 1) is a pro-drug that is
pharmacologically inactive and undergoes rapid hydrolysis
at the ester bond to form the active metabolite fenofibric
acid.1 As a third-generation fenofibric acid derivative,
fenofibrate is used mainly as a monotherapy to reduce
elevated low-density lipoprotein cholesterol, total
cholesterol, triglycerides, and apolipoprotein B levels;
increase high-density lipoprotein cholesterol levels in
patients with primary hyperlipidemia or mixed dyslipidemia;
and reduce the triglyceride levels in patients with severe
Figure 1. Fenofibric acid derivatives.
*e-mail: 1000004770@ujs.edu.cn

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281
synthesized using side chain halide intermediates. The main
development of these derivatives is to change fenofibric acid
to a fenofibric acid prodrug ester.9,10 A series of fenofibrate
derivatives were synthesized based on the screened
pharmacokinetic properties of highly water-soluble lead
compounds.11-14
DGaA, Germany). All solvents were freshly distilled from
proper dehydrating agents under argon gas. All necessary
chemicals were purchased from Sigma-Aldrich Corp.
(USA) unless specified otherwise. JF-2, fenofibrate, and
fenofibric acid were supplied by J2H Biotech (Ansan,
South Korea). Sildenafil, an internal standard for high-
performance liquid chromatography (HPLC) analysis,
was purchased from Sigma-Aldrich Corp. (St. Louis,
MO, USA).Acetonitrile and methanol were products from
Burdick & Jackson (Muskegon, MI, USA). Polyethylene
glycol 400 (PEG-400) was a product from Showa Chemical
Corp. (Tokyo, Japan). All other chemical were of reagent
or HPLC grade.
Experimental
General
1
The H nuclear magnetic resonance (NMR) spectra
were taken at JEOL ECLITSE-300 Spectrometer (Japan).
The chemical shifts are reported in parts per million
(ppm) downfield relative to TMS (tetramethylsilane) as
the internal standard (IS). The mass spectra (MS) were
recorded on a Thermo Fisher (LCQ Fleet, Japan). The
matrix-assisted laser desorption/ionization-time of flight
(MALDI-TOF) mass spectra were recorded on a Voyager-
DE STR (Japan). Silica gel (200-230 mesh) was used for
open column chromatography. Thin layer chromatography
(TLC) was performed on silica gel 60 F254 (Merck
Syntheses
Synthesis of (4-chlorophenyl)(4-hydroxyphenyl)methanone
AlCl3 (4.0 g, 30 mmol) was added slowly to a stirred
solution of anisole (2.16 g, 20 mmol) in dry toluene at 0 °C
in an inert atmosphere. 4-Chlorobenzoyl chloride (3.5 g,
20 mmol) was added dropwise via a cannula. The reaction
mixture was heated slowly under reflux for 1.5 h, and the
Figure 2. Series of fenofibric acid derivatives JF-1-7.

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Synthesis and Evaluation of Fenofibric Acid Ester Derivatives
J. Braz. Chem. Soc.
reaction was monitored by TLC. When the reaction was
complete, it was cooled to room temperature, and then
quenched slowly with 40 mL of distilled water. The crude
product was washed with sufficient water and recrystallized
with ethanol to give (4-chlorophenyl)(4-hydroxyphenly)
methane as a white solid (3.86 g, 83%). 1H NMR (300 MHz,
CDCl3) d 7.75-6.89 (m, 8H), 5.66 (s, 1H).
MS (MALDI-TOF) m/z, calcd. for C22H19ClO7 [M − H]−:
430.1105, found: 430.1013.
Synthesis of 2-acetoxyethyl-2-(4-(4-chlorobenzoyl)
phenoxy)-2-methylpropanonate (JF-2)
This was obtained 3.4 g as a colorless oil liquid.Yield:
85%; 1H NMR (300 MHz, DMSO-d6) d 7.70-7.68 (m, 4H),
7.60-7.58 (d, 2H, J 6.3 Hz), 6.90-6.88 (d, 2H, J 6.3 Hz),
4.43-4.32 (t, 2H, J 3.3 Hz), 4.18-4.15 (t, 2H, J 3.3 Hz), 1.88
(s, 3H), 1.60 (s, 6H); MS (MALDI-TOF) m/z, calcd. for
C21H21ClO6 [M − H]−: 404.0942, found: 404.0921.
Synthesis of fenofibric acid
NaOH (0.6 g, 15 mmol) was added to a stirred solution
of (4-chlorophenyl) (4-hydroxyphenyl) methanone (3.49 g,
15 mmol) in dry 2-butanone (60 mL). The reaction mixture
was heated under reflux for 1 h and isopropyl-(2-bromo-
2-methyl)-propanonate (3.76 g) in dry 2-butanone (15 mL)
was then added. The reaction mixture was heated under
reflux for 8 h until the reaction was complete. Subsequently,
1 M NaOH 50 mL was added to the reaction, and the
resulting mixture was heated under reflux for 4 h. The
residue was partitioned between water with brine (20 mL)
and CH2Cl2 (80 mL). The separated organic layer was
washed with brine (20 mL), dried over anhydrous sodium
sulfate, filtered, concentrated, and recrystallized with
acetone to give fenofibric acid as a white powder (4.3 g,
90%). 1H NMR (300 MHz, CDCl3) d 11.2 (s, 1H), 7.75-6.93
(m, 8H), 1.70 (m, 6H).
Synthesis of 2-morpholinoethyl-2-(4-(4-chlorobenzoyl)
phenoxy)-2-methylpropanonate (JF-3)
This was obtained 3.5 g as a white solid. Yield: 81%;
1H NMR (300 MHz, DMSO-d6) d 7.69-7.67 (m, 4H),
7.60-7.58 (d, 2H, J 6.3 Hz), 6.90-6.88 (d, 2H, J 6.3 Hz),
5.80 (s, 2H), 1.59 (s, 6H), 1.07 (s, 9H); MS (MALDI-TOF)
m/z, calcd. for C23H26ClNO5 [M − H]−: 431.139, found:
431.1136.
Synthesis of (2-(4-(4-chlorobenzoyl)phenoxy)-2-methyl-
propanoyloxy)methylpivalate (JF-4)
This was obtained 4.0 g as a white solid. Yield: 93%;
1H NMR (300 MHz, DMSO-d6) d 7.69-7.67 (m, 4H),
7.60-7.58 (d, 2H, J 6.3 Hz), 6.90-6.88 (d, 2H, J 6.3 Hz), 5.80
(s, 2H), 1.59 (s, 6H), 1.07 (s, 9H); MS (MALDI-TOF) m/z,
calcd. for C23H25ClO6 [M − H]−: 432.0911, found: 432.0845.
Synthesis of fenofibric acid derivative analogous
General procedure
A solution of 4-chloromethyl-5-1,3-dioxolen-2-one
(2.94 g, 20 mmol) was added to fenofibric acid
(3.18 g, 10 mmol) and K2CO3 (2.76 g, 20 mmol) in
N,N-dimethylacetamide (64 mL) at room temperature
at such a rate that the reaction maintained an internal
temperature of 60-65 °C overnight. The reaction mixture
was cooled to 0 °C and water (100 mL) was added slowly.
The resulting mixture was stirred at room temperature for
1.5 h, extracted with ethyl acetate (100 mL), and washed
with brine (150 mL × 3). The solvent was distilled off
under reduced pressure to obtain a residue. The residue was
purified further by column chromatography to give the title
compounds. The following compounds were synthesized
according to this procedure.
Synthesis of (2-(4-(4-chlorobenzoyl)phenoxy)-2-methyl-
propanoyloxy)ethylmorpholine-4-carboxylate (JF-5)
This was obtained 4.1 g as a white solid. Yield: 86%;
1H NMR (300 MHz, DMSO-d6) d 7.70-7.67 (m, 4H),
7.60-7.58 (d, J 6.3 Hz, 2H), 6.90-6.88 (d, 2H, J 6.6 Hz),
4.35-4.33 (t, 3H, J 3.3 Hz), 4.18-4.16 (t, 3H, J 3.3 Hz),
3.43 (br, 4H), 3.18 (br, 4H), 1.60 (s, 6H); 13C NMR
(75 MHz, DMSO-d6) d 206.1, 184.5, 183.6, 131.4, 131.2,
130.8, 130.7, 130.4, 128.5, 126.8, 123.0, 85.5, 85.0, 30.4,
29.9, 23.1, 22.0, 21.5; MS (MALDI-TOF) m/z, calcd. for
C24H26ClNO7 [M − H]−: 475.1279, found: 475.1283.
Synthesis of (2-(4-(4-chlorobenzoyl)phenoxy)-2-methyl-
propanoyloxy)ethyl-2-amino-3-methylbutanonate mono-
benzenesulfonate (JF-6)
Synthesis of (5-methyl-2-oxo-1,3-dioxol-4-yl)-methyl-
2-(4-(4-chlorobenzoyl)phenxoy)-2-methylpropanonate
(JF-1)
This was obtained 4.0 g as a white solid. Yield: 93%;
1H NMR (300 MHz, dimethyl sulfoxide (DMSO-d6))
d 7.69-7.65 (m, 4H), 7.60-7.58 (d, 2H, J 6.3 Hz), 6.87-6.85
(d, 2H, J 6.6 Hz), 5.08 (s, 2H), 2.11 (s, 3H), 1.61 (s, 6H);
This was obtained 5.1 g as a white solid. Yield: 82%;
1H NMR (300 MHz, DMSO-d6) d 8.27 (s, 2H), 7.71-7.57
(m, 6H), 7.31-7.27 (m, 3H), 6.91-6.89 (d, 2H, J 6.3 Hz),
4.44-4.34 (m, 4H), 3.88-3.87 (d, 1H, J 3.0 Hz), 2.11 (m,
1H), 1.60 (s, 6H), 0.91-0.86 (m, 6H); 13C NMR (75 MHz,
DMSO-d6) d 206.9, 184.5, 163.3, 147.1, 138.8, 130.7,
130.6, 130.3, 129.7, 128.7, 128.6, 124.1, 123.8, 85.8, 28.6,

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23.0, 21.8, 21.7, 16.4, 16.2; MS (MALDI-TOF) m/z, calcd.
for C30H34ClNO9S [M − H]−: 619.2147, found: 619.2136.
IS).After vortex-mixing and centrifugation at 3000 rpm for
10 min, the supernatant was transferred to a vial and a 20 μL
aliquot was injected directly into the HPLC column.15-25
Synthesis of (2-(4-(4-chlorobenzoyl)phenoxy)-2-methyl-
propanoyloxy)ethyl-2-amino-3-methylbutanonate mono-
tosylate (JF-7)
HPLC analysis
This was obtained 4.9 g as a white solid. Yield: 77%;
1H NMR (300 MHz, DMSO-d6) d 8.26 (s, 2H), 7.71-7.61
(m, 4H), 7.60-7.59 (d, 2H, J 6.3 Hz), 7.47-7.45 (d, 2H,
J 6.3 Hz), 7.10-7.08 (d, 2H, J 5.7 Hz), 6.91-6.89 (d, 2H,
J 6.3 Hz), 4.44-4.30 (m, 4H), 3.87-3.86 (d, 1H, J 3.3 Hz),
2.26 (s, 3H), 2.11 (m, 1H), 1.60 (s, 6H), 0.91-0.86 (m,
6H); 13C NMR (75 MHz, DMSO-d6) d 206.5, 184.2,
165.7, 145.3, 138.4, 138.3, 132.6, 130.5, 130.3, 130.1,
129.9, 128.4, 124.9, 123.3, 122.2, 100.3, 87.5, 85.7,
30.6, 23.1, 22.0, 21.4; MS (MALDI-TOF) m/z, calcd. for
C31H36ClNO9S [M − H]−: 633.1581, found: 633.1572.
The HPLC system consisted of a Gilson-234 auto
sampler (Gilson, Middleton, WI, USA), a Gilson 307 pump
(Gilson), a capcell PACK (C18) column (250 × 4.6 mm,
i.d.: particle size, 5 mm, Shiseido, Tokyo, Japan), a model
UV-118 UV/VIS detector (Gilson), and a model Gilson
unipoint system software (Gilson). The mobile phase,
0.02 M ammonium acetate buffer:acetonitrile (35:36, v/v),
was run at a flow rate of 1.0 mL min-1, and the column eluent
was monitored using an ultraviolet detector at 280 nm at
room temperature. The retention times of sildenafil (an
internal standard) and fenofibric acid were approximately
5.9 and 7.7 min, respectively (Figure 3).26-32
Biology
Analytical method validation
Preparation of the calibration standards and quality control
samples
The analytical method was validated with regard to
its specificity, linearity, intra- and interday precision and
accuracy, matrix effect, and stability according to the US
Food and Drug Administration.33
A stock solution of fenofibric acid (1 mg mL-1) was
prepared in methanol. The appropriate dilutions of the
stock solution of fenofibric acid were then prepared with
methanol (0.003, 0.005, 0.01, 0.02, 0.05, 0.1, 0.2, 0.5, or
1 mg mL-1). Standard solutions of fenofibric acid in rat
plasma were prepared by spiking with the appropriate
volume (10 mg mL-1 of plasma) of the diluted stock
solutions, giving final concentrations of 0.03, 0.05, 0.1,
0.2, 0.5, 1, 2, 5, or 10 mg mL-1 for plasma. The IS working
solution was prepared by dissolving sildenafil in acetonitrile
to give a final concentration of 10 mg mL-1.
Pharmacokinetic and statistical analyses
The total area under the plasma concentration-time
curve to the last time (AUClast), maximum plasma
concentration (Cmax), time to reach Cmax (Tmax), and half-life
(T1/2) were estimated using noncompartmental calculations
carried out with WinNonlinTM 5.2.34 All data are expressed
as the mean standard deviation (SD). The statistical
significance of the differences between the 2 groups was
analyzed using a Student’s t-test carried out with SPSS.35
A p-value < 0.05 was considered significant.36-42
Preparation of plasma samples
A 50 μL aliquot of the sample was deproteinized with
75 μL of acetonitrile containing 1 μg mL-1 sildenafil (an
Figure 3. Representative HPLC chromatograms after deproteinization of drug-free rat plasma peaks: fenofibric acid (1) (5.9 min) and (2) (7.7 min).

284
Synthesis and Evaluation of Fenofibric Acid Ester Derivatives
J. Braz. Chem. Soc.
Animal experiments
the Friedel-craft reagent to afford (4-chlorophenyl)
(4-hydroxyphenyl)methanone. The addition of isopropyl-
2-bromo-2-methylpropanoate gave the fenofibrate, which
was then treated with a 1 M NaOH solution to hydrolyze
the ester to the acid form in the presence of the desired
fenofibric acid compound (Scheme 1). Finally, fenofibric
acid ester compounds were generated from fenofibric
acid and side alkyl halide chain reagents was treated with
potassium carbonate to produce the target compounds
JF-1-7 (Scheme 2).
The care and the use of experimental animals is in
accordance to the Laboratory Animal Ethics Committee
SamYang Company, South Korea (KR20170325142674).
Male Sprague-Daley rats, 6-8 week old and weighing
220-300 g, were purchased from Bio-Korea (Osan, South
Korea). The rats were maintained in a clean room at
between 23 2 °C with 12 h light (7:00 am-7:00 pm) and
dark (7:00 pm-7:00 am) cycles, and a relative humidity
of 55 5%. The rats were housed in metabolic cages
(Tecniplast, Varese, Italy) under filtered pathogen-free air
and with food (Sam Yang Company, PyeongTaek, South
Korea) and water supplied ad libitum. The rats were fasted
overnight before drug administration and for 4 h after
dosing. JF-2 was dissolved in PEG-400:distilled water
1:1 (v/v) to make a concentration of 5 mg mL-1. The rats
were placed in a restrainer and administered a dose of
20 mg kg-1 orally. Blood was collected in a heparinized tube
at the pre-dose stage, and at 0.25, 0.5, 1, 2, 4, 6, 8, 10, and
12 h after p.o. administration. Plasma was harvested after
centrifugation at 3000 rpm and 4 °C for 10 min and stored
frozen at −70 °C until it was analyzed.43-49
Plasma samples were collected after the oral
administrationofJF-2andfenofibrateandtheconcentrations
of fenofibric acid were determined using a validated HPLC
method (Figure 4). The mean plasma concentration-
time curves for fenofibric acid were measured after the
oral administration of JF-2 and fenofibrate to rats; the
pharmacokinetic parameters are presented. After the
oral administration of JF-2, the absorption of fenofibric
acid from the rat portal vein was slow and the plasma
concentrations of fenofibric acid decreased in a delay-
released manners with a Tmax and half-life of 6.0 and
7.9 h, respectively. The estimated total body clearance was
33.0 mL min-1 kg-1, which was considerably smaller than the
reported cardiac output of 295 mL min-1 kg-1 based on the
blood data in rats.50 This suggests that the first-pass effect of
JF-2 in the lung and heart could be almost negligible in rats.
The maximum plasma concentrations of fenofibric acid
were achieved 6.0 and 4.0 h after the oral administration
of JF-1-7 and fenofibrate, respectively (Table 1). The
Cmax values of JF-2 and fenofibrate were 39.19 6.65
and 22.78 3.68 mg mL-1, and the AUClast values were
343.13 61.79 and 125.80 22.42 mg mL-1 for JF-2
and fenofibrate, respectively (Table 2). The Cmax value
of JF-2 was 1.7 times higher than that of fenofibrate and
the AUClast value of JF-2 was 2.7 times higher than that
of fenofibrate. JF-2 appeared to have been well absorbed
Results and Discussion
Chemistry
A general procedure for the preparation of the fenofibric
acid pro-drug began from a serial reaction, such as
Friedel-crafts arylation, demethylation, deprotection, ester-
hydrolysis under basic conditions.
A series of fenofibric acid esters, JF-1-7, were
prepared using the optimized procedure from the starting
material, 4-chlorobenzoylchloride and anisole, dissolved
in dry dichloromethane using aluminum chloride as
Scheme 1. Reagents and conditions: (i)AlCl3, toluene, 0 °C; (ii) isopropyl 2-bromo-2-methylpropanotate, K2CO3, DMA; (iii) 1 M NaOH, 2-butaonone, reflux.

Vol. 31, No. 2, 2020
Lv et al.
285
Scheme 2. Reagents and conditions: (i) K2CO3, DMF, 65 °C; (ii) ethyl L-valinate, aryl sulfonic acid, THF.
Table 2. Pharmacokinetic parameters of fenofibric acid after a single oral
administration of JF-2 and fenofibrate at dose of 20 mg kg-1 to male rats
Parameter
JF-2 (n = 5)
343.13 61.79
39.19 6.65
6.00 0.00
Fenofibrate (n = 5)
125.80 22.42
22.78 3.68
4.00 0.00
AUC0-12 / (g h mL-1)
Cmax / (g mL-1)
Tmax / h
T1/2 / h
7.89 1.49
3.46 0.78
Data represent mean standard deviation (SD; n = 5). AUC: area under
the curve to the collected time point; Cmax: peak plasma concentration;
Tmax: time to reach the peak plasma concentration; T1/2: elimination
half-life.
via peptide transporter 1. The considerable effect of
JF-2 on peptide transporter 1 is being tested based on
homogenate studies.
Figure 4. Comparative pharmacokinetics of JF-2 and fenofibrate after
oral administration to rats.
Table 1. Comparison of JF series compounds and fenofibrate values
Conclusions
AUC0-12
/
Cmax /
(μg mL-1)
Compound
BA / %
(μg h mL-1)
A series of fenofibric acid-substituted polar-function
derivatives, such as dioxolone, alkyl acetate, alkyl none,
morpholinyl carboxylate, ethyl L-valinate, and sulfonic
acid salt, were synthesized. The coupling of the fenofebric
acid with chain functional groups to produce the target
compounds proceeded successfully, which can be further
one-top substituted to produce the final compound in
moderate yield. The effects of synthesized compounds on
the biology assay in pharmacokinetics showed outstanding
bioavailability. In particular, fenofebric acid and acetate-
containing compound code JF-2, showed strong absorption
and a high concentration. Overall, JF-2 is a type of pro-
drug with potential activity. JF-2 is a special product that
is closely related to human health. Further studies to find
the optimal conditions for fenofibric acid are currently
underway.
JF-1
61.28 21.64
343.13 61.79
157.03 31.33
167.14 28.39
157.58 26.83
112.20 21.13
156.09 11.77
125.80 22.42
8.65 3.24
39.19 6.65
29.61 5.78
19.05 3.23
22.41 4.44
15.57 2.54
25.50 1.80
22.78 3.68
48.7
272.8
124.8
132.9
125.3
89.2
JF-2
JF-3
JF-4
JF-5
JF-6
JF-7
124.1
−
Fenofibrate
AUC: area under the curve to the collected time point; Cmax: peak plasma
concentration; BA: bioaggregate.
from the gastrointestinal tract compared to fenofibrate.
The p-value of Cmax and AUClast between the 2 groups
were 0.020 and 0.005, respectively. This suggests that
JF-2 was well absorbed from the gastrointestinal tract

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Synthesis and Evaluation of Fenofibric Acid Ester Derivatives
J. Braz. Chem. Soc.
Supplementary Information
16. Li, F.; Wu, X. Y.; Zou, Y. M.; Zhao, T.; Zhang, M.; Feng, W.
W.; Yang, L. Q.; Food Chem. Toxicol. 2012, 50, 1623.
17. Ling, A.; Luoma, J. T.; Hilleman, D.; Cardiol. Res. 2013,
4, 47.
Supplementary information (NMR spectrum) is
available free of charge at http://jbcs.sbq.org.br as PDF file.
18. Li, Q. Q.; Sun, S. L.; Zhang, E.; Tan, K. R.; Wei, X. B.; Fan, H.
W.; Li,Y. J.; Jia, X. B.; J. Pharm. Biomed. Anal. 2012, 66, 392.
19. Liu, S.; Jiang, P.; Song, G. L.; Liu, R.; Zhu, H. J.; Dyes Pigm.
2009, 81, 218.
Acknowledgments
This study was supported financially by the talent
introduction of scientific research foundation of Jiangsu
University (grant No. 5501290005). All biological
experiment supported by Bio-Korea Research and Sam
Yang Company, Republic of Korea.
20. Michio, K.; Prabagaran, N.; Kallolmay, B.; Rakesh, D.; Dean,
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