DSpace at VNU: Development of a Sustained Release Solid Dispersion Using Swellable Polymer by Melting Method

Methods Polyethylene glycol 6000 PEG 6000 and hydroxy-propyl methylcellulose 4000 HPMC 4000 were used in solid dispersion for not only enhancing drug dissolution rate but also sustaining

RESEARCH PAPER

Development of a Sustained Release Solid Dispersion Using Swellable Polymer by Melting Method

Tuong Ngoc-Gia Nguyen1&Phuong Ha-Lien Tran1,2&Toi Van Vo1&Wei Duan2&Thao Truong-Dinh Tran1,3

Received: 19 February 2015 / Accepted: 4 August 2015

# Springer Science+Business Media New York 2015

ABSTRACT

Purpose This study is to design a sustained release solid

dis-persion using swellable polymer by melting method

Methods Polyethylene glycol 6000 (PEG 6000) and

hydroxy-propyl methylcellulose 4000 (HPMC 4000) were used in solid

dispersion for not only enhancing drug dissolution rate but

also sustaining drug release HPMC 4000 is a common

swellable polymer in matrix sustained release dosage form,

but could not be used in preparation of solid dispersion by

melting method However, the current study utilized the

swelling capability of HPMC 4000 accompanied by the

com-mon carrier PEG 6000 in solid dispersion to accomplish the

goal

Results While PEG 6000 acted as a releasing stimulant

car-rier and provided an environment to facilitate the swelling of

HPMC 4000, this swellable polymer could act as a

rate-controlling agent This greatly assisted the dissolution

en-hancement by changing the crystalline structure of drug to

more amorphous form and creating a molecular interaction

Conclusions These results suggested that this useful technique

can be applied in designing a sustained release solid dispersion

with many advantages

KEY WORDS poorly water-soluble drug solid dispersion sustained release swellable polymer

ABBREVIATIONS FTIR Fourier transform infrared spectroscopy HPMC 4000 Hydroxypropyl methylcellulose 4000 PEG 6000 Polyethylene glycol 6000

PXRD Powder X-ray diffraction

INTRODUCTION Oral route is preferable in drug administration because of its convenience, patient compliance and production costs Poor bioavailability and low dissolution rate of drug due to poor absorption, rapid metabolism, and rapid systemic elimination are challenging issues for scientists Improving the water solu-bility of drugs is one of the current strategies in the pharma-ceutical industry to overcome those issues (1

Sustained-release (SR) dosage forms were investigated to improve patient compliance through reduced multiple dosing regimens Moreover, these dosage forms could provide pa-tients with reduced high total dose, a uniform and prolonged therapeutic effect in systemic circulation, and minimized side effects (2) In general, the most important issue of SR dosage forms is the work dealing with poorly water-soluble drugs because the limited property usually leads to its low bioavail-ability The incorporation of poorly water-soluble drugs into

SR carriers using solid dispersion (SD) technique can solve the above issues by enhancement of dissolution rate, solubility, oral absorption of water insoluble drugs as well as sustaining drug release with appropriate polymers (3

Tuong Ngoc-Gia Nguyen and Phuong Ha-Lien Tran contributed equally to

this work.

* Phuong Ha-Lien Tran

phuong.tran1@deakin.edu.au

* Thao Truong-Dinh Tran

ttdthao@hcmiu.edu.vn

1

Pharmaceutical Engineering Laboratory, Biomedical Engineering

Department, International University, Vietnam National University, Ho

Chi Minh City, Vietnam

2

School of Medicine, Deakin University, Waurn Ponds, VIC, Australia

3 Institute for Frontier Materials, Deakin University, Waurn Ponds, VIC,

Australia

DOI 10.1007/s11095-015-1767-2

Advantages of polymers such as hydroxypropyl

methycellulose and polyethylene oxide are hydrophilic and

swellable properties which can be utilized in increasing

disso-lution rate (4–11) and modulating drug release profiles

(12–16) The application of these two polymer properties in

one system could facilitate the design of a dual function drug

delivery system by preparation of SD for dissolution

enhance-ment and compression of matrix tablets for sustained release

(3,17) Regarding conventional SDs, there are still some

dis-advantages to deal with the preparation methods With

re-spect to the solvent method, negative effects on the

environ-ment, residual of toxic solvent and high cost of production due

to the extra facility for removal of solvents are shortcomings

(9) On the other hand, for melting method, swellable

poly-mers are usually not used as carriers of SD preparation mostly

due to its high viscosity and undetermined melting point To

overcome those drawbacks, in the current study we would

explore the use of these polymers in SD with melting method

by swelling hydroxypropyl methycellulose in polyethylene

gly-col 6000 to take a full advantage of for both increasing the

drug solubility and sustained release of the system: (1) as a

carrier in SD for enhanced dissolution of poorly

water-soluble drugs and (2) as a polymer for a SR dosage form by

compression of SD powder to form a matrix tablet

MATERIALS AND METHODS

Materials

Sodium hydroxide (NaOH) was purchased from Guanghua

Sci-Tech Company (China) Hydroxypropyl methyl cellulose

(HPMC 4000) was provided by from Dow Chemical Company

(USA) Polyethylene glycol (PEG 6000) was purchased from

Sino-Japan chemical (Taiwan) Isradipine was purchased from

Shanghai Richem International Company (China) Methanol

(MeOH) and Acetonitrile was purchased from Fisher Scientific

International, Inc (US) Hydrochloric acid (HCl) and Sodium

chloride (NaCl) were purchased from Xilong Chemical

Indus-try Incorporated Company (China) Monopotassium

phos-phate (KH2PO4) was purchased from Wako Pure Chemical

Industries (Japan) Aerosil®200 was obtained from Jebsen &

Jessen Chemicals Holding Pte Ltd (Singapore) Mannitol

(Pearlitol®) was purchased from Roquette Pharma Company,

France Magnesium stearate was purchased from Nitika

Phar-maceutical Specialities Pvt Ltd (India)

Methods

Preparation of Sustained Release Solid Dispersion

PEG 6000 was melted at 160°C until a molten liquid

ap-peared This temperature was maintained until addition of

Aerosil® 200 HPMC 4000 was added into the beaker of melted PEG and stirred by a glass agitator for 5 min for the completed swelling Then, isradipine was dispersed in the molten mixture and stirred by a glass agitator for 5 min to obtain a transparent solution Next, Aerosil® 200 as a mois-ture absorbance co-efficient was applied to absorb the molten mixture The amount of Aerosil®200 was selected based on the wetting state of SD as percentage of carriers changed The mixture was then sieved with a 0.5 mm sieve The obtained SDs were kept in a dry place, and protected from light until further use The detailed formulations were illustrated in TableI

Preparation of Sustained Release Solid Dispersion Tablet

The procedure was repeated as the one in section

BPreparation of Sustained Release Solid Dispersion^ with the ratio 1:4:4 for isradipine, PEG 6000, and HPMC 4000, respectively However, a residual amount of HPMC 4000 was divided into 2 parts Part 1 was added after isradipine was dispersed in the molten mixture thoroughly Part 2 was added into the blend with Aerosil®200 to absorb water The mixture was sieved with a 0.5 mm sieve Mannitol was added into the mixture with an appropriate ratio to perform tablets ade-quately at a total weight of 150 mg (TableI) Magnesium stearate as a lubricant was added at the end (1% total mass

of tablet) Single punch-press machine (TDP 1.5, China) with

8 mm-diameter flat punch was used to prepare tablets with a hardness of around 35–40 N

Dissolution Studies Dissolution test machine (DT70 Pharmatest, Germany) was used for the dissolution studies These SDs were conducted at 37±0.5°C on an USP specification dissolution test type II apparatus (Paddle apparatus) The apparatus was set up at

50 rpm of rotation speed For in vitro dissolution test, buffer

pH 1.2 (900 ml) and buffer pH 6.8 (900 ml) were used as dissolution media 1 ml of sample was collected at 10, 20,

30, 60, 90, and 120 min and dissolution media were compen-sated by adding 1 ml of the corresponding fresh buffer 100μl sample solutions were diluted with 900μl MeOH for HPLC test

To evaluate sustained drug release capability, based on the previous research submitted by Ching, A.L.et al (18), each of

750 ml of pH 1.2 was added into dissolution vessel for 2 h and then 250 ml of 0.2 M sodium phosphate solution (reheated to 37°C) was added to the medium for adjusting to pH 6.8 2 M HCl solution (or 2 M NaOH solution) was used for minor adjustment of the pH of dissolution media 1 ml of sample was collected at 1, 2, 6, 10, 14, 18, and 24 h

HPLC Analysis

The quantification of isradipine was performed using an

Ul-timate 3000 HPLC Thermoscientific Inc., USA The mobile

phase consisted of methanol: water: acetonitrile mixture ratio

was 7:3:5 with a flow rate of 1 ml/min and the running time

was around 5 min The UV/VIS detector was set to a

wave-length of 325 nm 20μL of sample was injected to the HPLC

system

Characterization by Powder X-ray Diffraction (PXRD)

In this study, pure isradipine, PEG 6000, HPMC 4000,

physical mixture (PM), and SD samples were analyzed by

PXRD Diffraction patterns were recorded using a Powder

X-ray diffractometer (BRUKER’ D8 Advance Series

PXRD, Germany) using Ni-filtered, CuKα (λ=1.54060 Å)

radiation at 40 kV and 40 mA Samples were held on quartz

frame Drug sample was scanned in a 2θ range from 5 to 50°

with a receiving slit 0.1 mm

Characterization by Fourier Transform Infrared Spectroscopy

(FTIR)

The physicochemical properties of pure isradipine, PEG

6000, HPMC 4000, PM, and SD samples were characterized

by using Spectrotometer (Bruker’s Vertex 79 series FT-IR,

Germany) KBr were prepared by mixing 1 mg of samples

with 200 mg KBr The wavelength was from 500 to

4000 cm−1and the resolution was 2 cm−1

RESULTS AND DISCUSSION

Dissolution Studies of SDs

The aim of this study was to investigate a new method not only

to increase dissolution rate but also to sustain drug release by

coordinating a poorly water-soluble drug with a swellable

polymer in PEG 6000-based SD When pure isradipine was

sprinkled in water, the powder floated on the surface of the medium and prevented surface powder from contacting with the medium, resulting in poor solubility and low dissolution rate As expected, the presence of PEG 6000 increased drug dissolution directly proportional to PEG 6000 concentration

in the formulation The interfacial tension between hydropho-bic drug and dissolution medium was reduced by PEG 6000 due to hydrophilic property of the polymer, leading to more area surface and greater wetting (19) Thus, the higher PEG

6000 proportion, the higher drug dissolution rate Figure 1

illustrates dissolution profiles of isradipine from SDs at differ-ent ratios without HPMC 4000 as a function of time in gastric fluid (pH 1.2) and intestinal fluid (pH 6.8) SDs of the formu-lations at 1:2 and 1:4 ratio got the moderate percentage drug release after 2 h in both medium Specifically, at pH 1.2 drug released from F1 and F2 was reached at 42.7 and 53.8%, respectively; whereas, at pH 6.8 it increased to 44.8 and 60.5% for F1 and F2, respectively Generally, there is an in-significant difference between the drug releases in both disso-lution media regardless of isradipine pKadue to the formation

of SDs whose dissolution rates mainly depend on drug crystal changes or drug-polymer interactions

figure2shows the effect of HPMC 4000 at different ratios

on dissolution profiles of isradipine to determine a suitable HPMC proportion for a sustained release system The pres-ence of adequate HPMC 4000 in the formulation could in-crease dissolution rate of SD up to two folds compared to the formulation without HPMC 4000 Sufficient HPMC 4000 proportion introduced to the formulation could be observed through a yellow colored transparent blend The release rate

of SD at 1:2:1 ratio (F3) was increased to 80.8 and 81.7% at

pH 1.2 and pH 6.8, respectively This result was impressive as compared to the corresponding SD without HPMC 4000 Similarly, while SD at 1:4 ratio without HPMC 4000 (F2) reached the highest percentage drug release at 53.8 and 60.5% at pH 1.2 and pH 6.8, respectively, dissolution rate

of the formulation at 1:4:2 ratio (F4) in the presence of HPMC

4000, increased strongly to 87.5 and 85.1% at pH 1.2 and

pH 6.8, respectively Significantly, drug released from the for-mulation at 1:4:4 ratio (F5) was achieved at approximately

Table I Formulation Compositions of SD Powder (from F1 to F5) and Sustained Release Solid Dispersion Tablet (F6, F7, F8)

100% in the first 10 min Drug dissolution rate was increased

with the increase of HPMC 4000 concentration This

tenden-cy may occur due to the change in drug crystals or molecular

interactions, which will be discussed in the sections below For

these reasons, F5 with the ratio 1:4:4 was chosen to be the best

fit model in SD formulations

Dissolution Studies of Sustained Drug Delivery System

For a sustained release HPMC matrix tablet, the polymer has

to go through hydration process to form an outer gel layer on

the tablet surface This process occurs gradually when tablets

contact with the medium, leading to HPMC chain relaxation,

followed by the occurrence of erosion of the matrix Matrix

swelling, erosion and diffusion of drug are attributed to factors

which controlled the drug release rate and mechanism (20)

The preliminary studies obviously identified the relationship

between HPMC 4000 ratio and the release behavior of SDs

from the hydrophilic matrix system The percentage of

HPMC 4000 substantially affected the dissolution rate,

resulting in the reduction of dissolution rate with the

increasing HPMC content as polymer chain uncoil slowed (21) Chain entanglement increased the tortuousness of matrix tablet with the increasing concentration of higher levels of HPMC (22,23) Additionally, low porosity produced by high hardness also controlled dissolution rate because it inhibited liquid across the surface of matrix tablet system (24)

The sustained release profile was achieved at the 1:4:8 ratio while a little rapid release was observed at the ratios of 1:4:4 and 1:4:6 in tablet dosage forms Specifically, there was a strong burst release after 2 h from F6 tablets, increasing from 59.4 to 86.2% in the range of 2–6 h (Fig 3) However, a significant sustained release was observed as compared to the SD powder (F5) due to the presence of matrix tablets during the dissolution test The drug release was then in-creased slowly following a constant rate during the next

18 h Meanwhile, dissolution rate of SD from F7 tablets (1:4:6 ratio for IS: PEG: HPMC) exploded from 6 to 10 h, resulting in a twofold growth of drug release from 44.3 to 88.3% which then became stable Therefore, the increase in HPMC 4000 concentration could improve drug dissolution as well as control the percentage of drug release However, the

Time (min)

0

1:2 1:4

Time (min)

0 20 40 60 80 100 120

0 20 40 60 80 100 120

20

40

60

80

100

0

20

40

60

80

100

1:2 1:4 (a)

(b)

Fig 1 Dissolution profiles of isradipine from SDs of F1 and F2, at different

ratio without HPMC 4000, as a function of time in gastric fluid (pH 1.2) (a) and

intestinal fluid (pH 6.8) (b).

Time (min)

0 20 40 60 80 100 120

0 20 40 60 80 100 120

0 20 40 60 80 100 120

1:2:1 1:4:2 1:4:4

Time (min)

20 40 60 80 100 120

1:2:1 1:4:2 1:4:4

(b) (a)

Fig 2 Dissolution profiles of isradipine from SDs of F3, F4 and F5, based on different ratios with HPMC 4000, as a function of time in in gastric fluid (pH 1.2) (a) and intestinal fluid (pH 6.8) (b).

premature burst release may lead to a fast decrease of

drug concentration in effective life time Therefore, the

concentration of HPMC 4000 would be increased to

avoid the risk of burst release F8 tablets (1:4:8 ratio)

showed their ability in sustaining drug delivery system

through the capability of retaining the shape of matrix

tablets up to 10 h while this period of the same

perfor-mance in other SDs was 6 h Furthermore, drug was

gradually released from F8 during 24 h Gel layer

for-mation around the matrix tablet can control drug

re-lease rate regardless of the effect of drug solubility

Higher HPMC 4000 concentration in formulation

formed gel layer quicker and stronger, leading to

in-creased resistance of drug to diffusion and erosion

(23) Furthermore, the barrier of HPMC 4000 is less

efficient in diminishing drug release rate On the other

hand, the translocation of water insoluble drug particles

through the gel layer can disrupt the gel layer structure

(25), resulting in a burst release in dissolution The

for-mulation at 1:4:8 ratio (F8) provided sufficient amount

of HPMC 4000 to develop a rapid formed and strong

gel layer around the matrix tablet to sustain drug

re-lease and prevent burst rere-lease during dissolution or

hydration

The empirical observations and experimental results

indi-cated that HPMC was a useful swellable polymer with high

applicability for both increased dissolution rate and sustained

drug delivery system Melting method has some advantages

including short time process, solvent-free, lower cost, and

pre-vention of toxicity in the environment Therefore, the

prepa-ration in the current study is very convenient for further

re-search and manufacturing Besides, time– controlled release

can be regulated by applying appropriate polymer carriers

concentration to optimize therapeutically efficiency with

bet-ter patient compliance

Physicochemical Characterization figure4a displays X-ray diffractograms of pure isradipine, PEG 6000, PM, SDs at ratio of 1:2 (F1) and 1:4 (F2) to inves-tigate the effect of different ratio between drug and PEG 6000 without HPMC 4000 on the physical state of SDs The diffractogram of isradipine showed numerous peaks, indicat-ing its high crystallinity in nature The change from crystalline state to amorphous state was identified by the disappearance

of instinctive peaks or great diminution in number of charac-teristic peaks In case of F1, although most of peaks disap-peared, peaks at 9.4, 9.8, 11.4, 11.8, 12.2, 13.9, 16.9, 17.6, 19.1, 20.5, 23.3, 25.5, 26.7, and 28.4 2θ still remained There-fore, SD was partially transformed into its amorphous form

In SD at 1:4 ratio (F2), the absence of peak at 9.4, 9.8, 11.4, 11.8, 12.2 2θ compared to F1 demonstrated that the amor-phous state of SD was improved with the increase of hydro-philic carrier PEG 6000 concentration A new peak was noted

at the position of 10.6 2θ The result suggested an interaction between isradipine and PEG 6000

The effect of HPMC 4000 concentration on the physical state of SDs was indicated in Fig.4b HPMC 4000 altered structure of SD formulations into more amorphous form SD with 1:2:1 ratio (F3) still kept some main peaks from pure isradipine such as 11.8, 13.9, 16.9, 17.6, 19.1, 20.5, 22.2, and 23.3 2θ However, some peaks at 9.4, 9.8, 11.4, 11.8, and 12.2 2θ were disappeared, leading to more amorphous form in SD formulation Some peaks at 9.4, 9.8, 25.5, 26.7, and 28.4 were reduced in intensity compared to F1 (1:2 ratio), suggesting that HPMC 4000 helped transformation easier from crystalline to amorphous form In case of F4 (1:4:2 ratio), there was the disappearance of some peaks at 11.8, 13.9, 17.6, 20.5 2θ compared to F3 (1:2:1 ratio) Meanwhile, F5 (1:4:4 ratio) just showed three main peaks of pure isradipine: 6.9, 19.1, 23.3 2θ While PEG 6000 provided one characteristic peak at 21.3 2θ in both F3 (1:2:1 ratio) and F4 (1:4:2 ratio), this peak didn’t appear in F5, F7, F8 (1:4:4, 1:4:6, 1:4:8 ratio) It was suggested that the amount of HPMC 4000 in F5 was sufficient to change SD to its amorphous form The appear-ance of the new peak at 10.6 2θ in both three SDs with a gradually decrease in intensity confirmed a reaction between isradipine and PEG 6000 The descending in intensity of this peak might be caused by the increased HPMC 4000 concen-tration in the formulation, which facilitated the dispersion of drug in carrier The excessive amount of HPMC 4000 changed the structural behavior of the drug into amorphous state, resulting in the increasing of dissolution rate

Research submitted by Ramasahayam at el showed the isradipine spectra with well-defined functional groups (26) A sharp peak at 3345 cm−1was aliphatic amine stretching (N-H group) Three characteristic bands of carboxylic acid groups was presented at 1700 cm1(C=O carboxylic acid stretching),

1366, 1309 cm−1 (C – O carboxylic acid stretching), and

Time (hours)

0 5 10 15 20 25

0

20

40

60

80

100

120

1:4:4 1:4:6 1:4:8

Fig 3 Dissolution profiles of isradipine from SR-SDs of F6, F7, and F8 in

24 h.

1001 cm−1(O– H carboxylic acid out of plane bending) The

alkane group assigned peaks at 2943 cm−1as C– H alkane

stretching and 1488 cm−1as CH3alkane in the plane bending

Moreover, peak at 1488 cm−1might identify C=C aromatic

Position (2-Theta)

PEG 6000

Pure Isradipine

1:2 1:4 PM

1:2:1

1:4:4

1:2 1:4

1:4:2

1:4:6 1:4:8

10 20 30 40 50

10 20 30 40 50

(a)

(b)

Fig 4 (a) PXRD patterns of isradipine, PEG 6000, PM and SDs of F1 and F2

in different ratios (b) PXRD patterns of isradipine, PEG 6000, HPMC 4000,

PM and SDs of F3, F4 and F5 in different ratios.

1000 2000

3000 4000

PEG 6000

Pure Isradipine

Wavelenth (cm -1 )

Wavelenth (cm -1 )

1:4 1:2 PM

1000 2000

3000 4000

1:2

1:4

1:2:1

1:4:2 1:4:4

1:4:6 1:4:8

(a)

(b)

ring stretching (26,27) C-N amine stretching was located at

1219, 1120, 1108, 1018 cm−1; whereas, C-H aromatic out of

plane bending was appeared at 868, 757, 742, 620 cm−1

Figure5ashows the FTIR spectrum of pure isradipine, PEG

6000, and SDs of 1:2 ratio (F1) and 1:4 ratio (F2) without the

presence of HPMC 4000 The spectrum of F1 showed that the

entirely main function groups of pure isradipine were

remained In F2 (1:4 ratio), there was two small peaks at

3345 and 2885 cm−1, indicating the existence of isradipine

and PEG 6000 in formulation Different from F1, the peak

at 1704 cm−1of F2 was divided into two small peaks, resulting

the formation of hydrogen bonding between carbonyl C=O

group of isradipine and O-H group of PEG 6000 There was

only one carbonyl peak shifted downwards, inferring that only

one of C= O groups of isradipine was hydrogen bonded;

whereas, the other was non-hydrogen bond or very weakly

hydrogen bond (28,29) It could explain why F2 was dissolved

better than F1 FTIR spectra in Fig.5billustrated the effect of

presence of HPMC 4000 at different ratios on dissolution

profile of isradipine In case of F3 (1:2:1 ratio), some

charac-teristic peaks of pure isradipine were still maintained Similar

to F2, the two carbonyl groups of isradipine in F3 were

ob-served, indicating the intramolecular hydrogen bonding in the

structure Thus, F3 with the presence of HPMC 4000 in

for-mulation gave better drug dissolution SDs at ratio 1:4:2 (F4)

and 1:4:4, 1:4:6, 1:4:8 (F5, F7, F8) showed that the only one

carbonyl group was observed at these SDs at around

1696 cm−1 This peak was overlapped by two carbonyl

groups, indicating that no hydrogen bonding occurred

How-ever, there was no amine group (N-H) at 3345 cm−1,

attrib-uting to the intramolecular hydrogen bonding with anion

be-tween aliphatic secondary amine NH of isradipine and OH

group of PEG 6000 (28,29) This might be explained that

N-H stretching frequency was quite high (3345 cm−1) as

com-pared to other compounds, leading to the fact that the

hydro-gen bonding was stronger than other counterparts (29) The

result also explained why the more HPMC 4000 the more

increased drug dissolution Furthermore, the IR spectra of

F4 and F5 were similar, suggesting that the increase of

HPMC 4000 concentration did not change the chemical

behaviors of relative formulations Nevertheless, F5 had

sig-nificantly higher drug dissolution might be due to the more

amorphous state

CONCLUSION

This study investigated a SR system based on the combination

of a hydrophilic carrier and a swellable polymer in SD melting

method The presence of the swellable polymer not only in-creased dissolution rate but also sustained drug release from the matrix tablet The interesting point herein is that although melting method is a promising method in solid dispersion preparation with some advantages such as short time process, solvent-free, lower-cost, and prevention of toxicity, etc., a swellable polymer was usually not applied as hydrophilic car-rier even This study indicated that the sustained release func-tion could be designed in a SD formulafunc-tion in addifunc-tion to the role of enhancing drug dissolution of poorly water-soluble drugs by a selection of an appropriate polymer type and con-centration Hence, the dual function SD could bring patients optimized therapeutic efficiency and compliance and phar-maceutical industry a potential product with convenient man-ufacture FTIR and PXRD results elucidated the ability of SD system in enhanced dissolution rate and sustained drug release

by structural behaviors changes from crystalline to amorphous form and intermolecular hydrogen bond

ACKNOWLEDGMENTS AND DISCLOSURES This research is supported by Vietnam National University–

Ho Chi Minh City We also thank to International University for their continued, generous and invaluable support to our studies as well as greatly boost the efficiency of our research activities

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