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Preparation and characterization of cross-linked excipient of coprocessed xanthan gum-acacia gum as matrix for sustained release tablets

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Abstract and Figures

Sustained release tablet is solid dosage form which is designed to release drugs slowly in the body. This research was intended to prepare and characterize the cross-linked excipients of co-processed xanthan gum-acacia gum (CL-Co-XGGA) as matrices for sustained release tablets with gliclazide as a model drug. CL-Co-XGGA excipients were cross-linked materials of co-processed excipients of xanthan gum-acacia gum (Co-XGGA) using sodium trimetaphosphate. Co-processed excipients of xanthan gum-acacia gum were prepared in the ratio of each excipient 1:2, 1:1 and 2:1. Co-XGGA and CL-Co-XGGA excipients were characterized physically, chemically and functionally. Then, the sustained release (SR) tablets were formulated by wet granulation method using CL-Co-XGGA excipients as matrices. Also, the dissolution study of the gliclazide SR tablets was carried out in phosphate buffer medium pH 7,4 containing sodium lauryl sulphate 0.2% for 12 hours. The results showed that the degree of substitution (DS) of CL-Co-XGGA 1:2, 1:1, 2:1 excipients were respectively 0.067, 0.082 and 0.08. Besides that, the excipients gel strengths were 14.03, 17.27 and 20,70 gF, respectively. The cross-linked excipients had improved flow properties and swelling capability compared to the Co-XGGA excipients. The results of the gliclazide SR tablets evaluations showed that all tablets were passed all tablet requirements. Moreover, the gliclazide release from SR tablets F1 - F6 revealed the sustained release profile, which was following zero order kinetics (F1, F2, F3, F6) and Higuchi kinetics (F4 and F5). It could be concluded that the obtained CL-Co-XGGA excipients might be used as matrices for sustained release tablets and could retard drug release up to 8 until 32 hours.
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Preparation and characterization of cross-linked excipient of coprocessed xanthan
gum-acacia gum as matrix for sustained release tablets
Silvia Surini, Dina Risma Wati, and Rezi Riadhi Syahdi
Citation: AIP Conference Proceedings 1933, 030009 (2018); doi: 10.1063/1.5023956
View online: https://doi.org/10.1063/1.5023956
View Table of Contents: http://aip.scitation.org/toc/apc/1933/1
Published by the American Institute of Physics
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Preparation and Characterization of Cross-linked Excipient
of Coprocessed Xanthan Gum-Acacia Gum as Matrix for
Sustained Release Tablets
Silvia Surini1,a), Dina Risma Wati1, and Rezi Riadhi Syahdi1
1Faculty of Pharmacy, Universitas Indonesia, Depok, Indonesia 16424.
a)Corresponding author: silvia@farmasi.ui.ac.id
Abstract. Sustained release tablet is solid dosage form which is designed to release drugs slowly in the body. Th is
research was intended to prepare and characterize the cross-linked excipients of co-processed xanthan gum-acacia gum
(CL-Co-XGGA) as matrices for sustained release tablets with gliclazide as a model drug. CL-Co-XGGA excipients were
cross-linked materials of co-processed excipients of xanthan gum-acacia gum (Co-XGGA) using sodium
trimetaphosphate. Co-processed excipients of xanthan gum-acacia gum were prepared in the ratio of each excipient 1:2,
1:1 and 2:1. Co-XGGA and CL-Co-XGGA excipients were characterized physically, chemically and functionally. Then,
the sustained release (SR) tablets were formulated by wet granulation method using CL-Co-XGGA excipients as
matrices. Also, the dissolution study of the gliclazide SR tablets was carried out in phosphate buffer medium pH 7,4
containing sodium lauryl sulphate 0.2% for 12 hours. The results showed that the degree of substitution (DS) of CL-Co-
XGGA 1:2, 1:1, 2:1 excipients were respectively 0.067, 0.082 and 0.08. Besides that, the excipients gel strengths were
14.03, 17.27 and 20,70 gF, respectively. The cross-linked excipients had improved flow properties and swelling
capability compared to the Co-XGGA excipients. The results of the gliclazide SR tablets evaluations showed that all
tablets were passed all tablet requirements. Moreover, the gliclazide release from SR tablets F1 - F6 revealed the
sustained release profile, which was following zero order kinetics (F1, F2, F3, F6) and Higuchi kinetics (F4 and F5). It
could be concluded that the obtained CL-Co-XGGA excipients might be used as matrices for sustained release tablets
and could retard drug release up to 8 until 32 hours.
INTRODUCTION
Sustained release dosage form is a modified release preparation where the rate of drug release slower than
conventional dosage form that administered on the same route [1]. Sustained release is designed to achieve extended
therapeutic effects and minimize unwanted side effects due to fluctuations in plasma drug levels. Sustained release
dosage form requires excipients which are capable of releasing drugs slowly. The excipients should be able to retard
the release of the drug when it contacts with body fluids and resistant to degradation by acid and enzyme, such as
acacia gum and xanthan gum.
Acacia gum is a stable natural polymer and can be used as binder for modified release [2]. Acacia gum can swell,
yet has low viscosity, while xanthan gum can swell with high viscosity. This is due to the water absorption and
slightly eroded [2], which may reduce the rate of drug release [3]. Xanthan gum is capable to form gel, both physical
and chemical in solution. However, the physical form of the xanthan gum gel is not used as a drug carrier, since it
easily dissolve in the solvent [4]. To cover the shortcomings of acacia gum and xanthan gum as well as to obtain
excipients, which are capable of retard drug release, those excipients were modified by co-processing and cross-
linking.
In a previous study [5], the co-processed excipients of xanthan gum-acacia gum (Co-XGGA) were used as tablet
matrices and revealed extended drug release profile. Co-XGGA excipients showed swelling capability and good gel
property, thus able to retard drug release [5]. Besides, in another study, the cross-linked modification has also been
studied to improve the functional properties of the parent excipients [6]. They were cross-linked excipients of co-
2nd Biomedical Engineering’s Recent Progress in Biomaterials, Drugs Development, and Medical Devices
AIP Conf. Proc. 1933, 030009-1–030009-10; https://doi.org/10.1063/1.5023956
Published by AIP Publishing. 978-0-7354-1625-3/$30.00
030009-1
processed amylose-xanthan gum, which were showed the extended drug release profile [6]. Therefore, the
modifications of xanthan gum and acacia gum with co-processing and crosslinking were expected to form excipients
which are suitable for sustained release tablet formulation and have the ability to retard drug release. Thus, it can
reduce a number of excipients used as matrices in sustained release formulations.
MATERIALS AND METHODS
Materials
Xanthan gum (Danisco, France), acacia gum (Jumbo Trading Co.,Ltd., Thailand), gliclazide (Dexa Medica,
Indonesia), sodium trimetaphosphate (Xinxiang Huaxing Chemical Co.,Ltd., China), PVP K-30 (Nanhang Industrial
Co., Ltd, China), magnesium stearate (Faci Asia Pacific Pte Ltd., Singapore), talc (Brataco, Indonesia), lactose
monohydrate (Brataco, Indonesia), sodium hydroxide (Brataco, Indonesia), chloride acid (Brataco, Indonesia), nitric
acid (Merck, Germany), potassium dihydrogen phosphate (Merck, Germany), ethanol 96% (Brataco, Indonesia),
methanol (Merck, Germany), potassium bromide (Merck, Germany), ammonium molybdate tetrahydrate (Merck,
Germany), ascorbic acid (Shandong Luwei Pharmaceutical Co.,Ltd., China), sulfuric acid (Merck, Germany),
sodium lauryl sulphate (Brataco, Indonesia), and aqua distilata (Brataco, Indonesia).
Methods
Preparation of Cross-linked Excipients of Coprocessed Xanthan Gum-acacia Gum
Co-processed excipients were prepared by dispersed both xanthan gum and acacia gum in aquadest with a
concentration of 3% b/v. Xanthan gum and acacia gum were mixed with ratio of 1:1, 1:2 and 2:1, then homogenized
with rotation of 3000 rpm for 30 minutes to obtain a homogeneous mass. The homogeneous mass was dried by
double drum drier at of 80±5ͼC. The obtained layer or flakes were mashed (milling) and sieved with 35 mesh [5].
Cross-linked excipients of co-processed xanthan gum-acacia gum was prepared by dispersing the co-processed
xanthan gum-acacia gum in aquadest with a concentration of 3% b/v. The 10N NaOH solution was added gradually
to maintain pH 11-12 during the reaction. Sodium trimetaphosphate solution with concentration 112.5 mg/mL was
added to the excipient mass with continuous stirring using a homogenizer 3000 rpm [7]. The reaction was continued
for 1 - 4 hours, then the suspension was neutralized with 7N HCl solution. Excipient mass was washed with 96%
ethanol and dried at room temperature, then mashed and sieved with 35 mesh.
Particle Shape and Size Distribution
Particle shape of the excipients was observed using Scanning Electron Microscope (SEM) (Zeiss EVO MA10,
Jerman) at various magnifications. Furthermore, particle size distribution was determined by sieving using 35, 45,
60, 80, 120 and 230 mesh sieving at 30 rpm for 20 minutes.
Moisture Content and Flow Properties
Water content was measured using moisture balance analyzer at 105°C. Flow properties were determined by
flow rate, repose angle, Hausner ratio and compressibility index. Flow rate and repose angle were determined using
flowmeter, while compressibility index was determined using bulk-tapped densitometer by comparing bulk density
and tapped density.
Thermal Properties
Thermal properties were observed with the Differential Scanning Colorimetry (DSC). Measurements were
examined at temperature 30ι-350ιC with heating rate of 10 ιC/min. The endothermic and exothermic processes,
which were occurring in the sample, were recorded [7].
030009-2
Chemical Structure
Functional group analysis was performed to determine the presence of functional groups in new excipients. The
examination was conducted using 8400 S Fourier-Transform Infrared (FTIR) Spectrometer (Shimadzu, Japan) at
wave number of 400 to 4000 cm-1 using the KBr-disk method.
Degree of Substitution
The degree of phosphate substitution was determined by the colorimetric method using a mixture of 1.0 mL
reagent A and 6.0 mL reagent B [8]. Reagent A was 10% ascorbic acid solution in aquadest and reagent B was
0.42% ammonium molybdate tetrahydrate solution in 1N H2SO4. Dissolved 43.95 mg KH2PO4 prepared standard
KH2PO4 (100 μg P in 1 mL) in 40.0 mL aquadest, then added 2.5 mL of 7N H2SO4 and aquadest up to 100 mL. The
calibration curve was prepared by diluting the standard solution to a concentration of 1.0 4.0 ppm. Three milliliters
(3mL) of standard solution at various concentrations were pipetted, then added 7.0 mL of the mixed reagent. The
mixed solution was shaken and incubated in a 45ͼC water bath for 20 minutes, then cooled. Phosphate concentration
was calculated by weighing 100 mg of sample and dried in kiln 600ͼC. The sample ash was cooled, and 8.0 mL of
0.1N H2SO4 was added, then heated to boiling water bath for 10 minutes. The filtrate was filtered and transferred
from 0.1 ml into 10.0 mL measuring flask, then added a mixture of aquadest 0.1N H2SO4 (1:1) up to 10.0 mL.
Three milliliters (3 mL) of samples were pipetted, then added 7.0 mL of the mixed reagent. The mixed solution was
shaken and incubated in a 45ͼC water bath for 20 minutes, then cooled. UV-Vis spectrophotometry measured the
standard and sample solutions at wavelength of 826 nm. The degree of substitution (DS) was determined using the
following formula, where P represents % phosphorus (%P) of phosphorylated gum xanthan.
P
P
DS 1023100
162
Gel Strength and Swelling Index
Gel strength was measured using texture analyzer by dispersing 10% w/v of the cross-linked excipients in
aquadest. The gel was stored in a container, and the penetration device was lowered to the surface of the gel.
Swelling index was measured using 200 mg of excipient powder molded into a tablet (W1), then put into beaker
glass containing 20 mL of HCl pH 1.2 at 37ιC. Tablets were weighed in several times interval (W2). Same
procedure was repeated using different medium, which were aquadest and phosphate buffer pH of 7.4.
%100%
1
12
x
W
WW
swelling
Preparation of Sustained Release Tablets
Gliclazide sustained release tablets were prepared by wet granulation method and using PVP K-30 in 96%
ethanol as the binder solution. The formulas of gliclazide SR tablets were listed in Table 1.
TABLE 1. Sustained release tablets formula (mg)
Materials
Formula
1
2
3
4
5
6
Gliclazide
30
30
30
30
30
30
CL-Ko-XGGA (1:2)
120
-
-
60
-
-
CL-Ko-XGGA (1:1)
-
120
-
-
60
-
CL-Ko-XGGA (2:1)
-
-
120
-
-
60
Lactose monohydrate
38
38
38
98
98
98
PVP K-30
6
6
6
6
6
6
Talc
4
4
4
4
4
4
Magnesium Stearate
2
2
2
2
2
2
Total
200
200
200
200
200
200
030009-3
Tablet Evaluations and Assay
Tablet evaluations were including physical appearance, size uniformity, weight variation, hardness, and
friability. Physical appearance was observed visually about shape, the texture of the surface, and the color of tablets.
Tablet size uniformity was observed by diameter and thickness using calipers. Tablet weight variation was tested by
weighing ten (10) tablets, one by one using analytical balance. Tablets are eligible if the relative standard deviation
(RSD) was less than or equal to 6% (9). Tablet hardness was determined using hardness tester with sample 10
tablets randomly. Friability of the tablets was determined using friability tester at 25 rpm for 4 minutes (100 lap
times). Friability of tablet calculated using the following equation:
%100(%)
1
21
x
W
WW
Friability
Drug content of the gliclazide SR tablets was measured by spectrophotometry. The 20 tablets were finely
ground, then it was weighed equivalent to 5 mg of gliclazide. The powder was dissolved with 10 mL of methanol in
a 50 mL volumetric flask and adjusted its volume to the limit using aquadest then filtered the solution. One milliliter
(1 mL) of filtrate was pipette and put into 10 mL volumetric flask, adjusted its volume to the limit using aquadest.
Spectrophotometer measured drug content at the maximum wavelength. The tablets were qualified if they are
contain gliclazide between 95.0 to 105.0% of those listed on the label (10).
In Vitro Drug Release Study
In vitro drug release study was performed using dissolution test apparatus 2 (paddle type). The medium used in
this study was 400 mL of phosphate buffer solution pH 7.4 containing 0.2% sodium lauryl sulphate at 37±0.5ºC with
75 rpm stirring speed (11). A sample of 10 mL was withdrawn at a predetermined time interval (15, 30, 45, 60, 90,
120, 180, 240, 300, 360, 420, 480, 600 and 720 minutes) and replaced with 10 mL fresh medium. The samples were
analyzed by 1800 UV-Vis spectrophotometer (Shimadzu, Japan) at the maximum wavelength.
RESULTS AND DISCUSSION
Cross-linked Excipient of Co-processed Xanthan Gum-acacia Gum
The results showed that the obtained co-processed excipients of xanthan gum-gum acacia gave a yield of 45.13
53.38%, since there were losing of weight occurred during drying process with double drum drier, milling, and
sifting. Crosslinked excipient of co-processed xanthan gum-gum acacia was prepared using sodium
trimetaphosphate as a cross-linker. During the reaction pH was kept at 11-12 by adding NaOH 10 N. NaOH would
degrade the sodium trimetaphosphate ring to form sodium tripolyphosphate. At pH of 10 - 13.5, so that sodium
trimetaphosphate can react with xanthan gum [12]. At alkaline pH, the hydroxyl group of xanthan gum and acacia
gum will also be ionized, so it can react with sodium tripolyphosphate form mono and phosphate diester. This
mixture can react with hydroxyl groups of xanthan gum and acacia gum resulting cross-linking [4].
Particle Shape and Size Distribution
Co-XGGA and CL-Co-XGGA excipients were coarse powder, yellowish, and odorless. Particle shape was
observed using the Scanning Electron Microscope (SEM). Figure 1(a) at magnification 100 times shows that CL-
Co-XGGA excipients have a form like solid chunks because the drying was done by spreading on the glass plate. In
contrast to previous research, Co-XGGA excipients have a form like flakes, because the drying was done by double
drum drier (5). Figure 1 (b) at magnification 1000 times shows that CL-Co-XGGA excipient have uneven and
slightly hollow surface. Similarly, the excipient Co-XGGA that was observed at magnification 2000 times [5]. The
cavity or pore allows water to enter the excipient so that the excipient can expand.
030009-4
FIGURE 1. SEM micrograph of CL-Ko-XGGA excipients at (a) magnification 100 times, (b) magnification 1000 times
Figure 2 shows that the Co-XGGA excipient with different composition ratios are distributed at various particle
sizes. This is due to the Co-XGGA excipients form like fiber layer that causes the milling process became more
difficult [5]. Meanwhile, the CL-Co-XGGA 1: 2, 1: 1, 2: 1 excipients were distributed on the particle size of 251 -
355 μm. The particle size affects powder flow properties. The smaller particle size of powder, the poor powder flow
properties due to high interparticle cohesiveness [13].
B
E
A
D
C
F
030009-5
FIGURE 2. Particle size distribution of Co-XGGA and CL-Co-XGGA excipients
Moisture Content and Flow Properties
The results show that Co-XGGA excipients with different composition ratio have different water content (Table
2). Co-XGGA 1:2 excipient had the smallest moisture content, whereas Co-XGGA 2:1 excipient had the highest
moisture content. CL-Co-XGGA 1:2, 1:1, 2:1 excipients had a water content almost the same for each composition
ratios.
Powder flow rate is the parameter which easily to correlated with powder flow properties. Flow rate is influenced
by shape, particle size, and water content of powder. Flow properties of powder can also be determined by repose
angles, compressibility index, and Hausner ratios. As shown at Table 2, CL-Co-XGGA excipients had good flow
properties compared to Co-XGGA excipients regarding flow rate and compressibility index. This was due to Co-
XGGA excipients had a form like fine fibers, while CL-Co-XGGA excipients have a physical form of granules so
that the flow rate of powder increases.
TABLE 2 Characterization of Co-XGGA and CL-Co-XGGA excipients
Excipient
Moisture content
(%)
Exothermic
peak (ͼ
ͼC)
Flow rate (g/sec)
Compressibility
index (%)
Gel strength (gF)
Co-XGGA 1:2
7,45
±
1,03
296,67
6,00
±
0,85
29,05
±
1,20
14,47
±
1,12
Co-XGGA 1:1
9,22
±
0,49
290,25
5,55
±
0,35
27,12
±
0,00
23,40
±
0,79
Co-XGGA 2:1
11,55
±
2,13
287,90
5,69
±
0,29
34,43
±
0,00
39,27
±
2,14
CL-Co-XGGA 1:2
9,69
±
0,68
511,91
7,17
±
0,41
16,73
±
0,59
14,03
±
0,30
CL-Co-XGGA 1:1
8,95
±
0,52
497,42
10,84
±
0,60
13,64
±
0,00
17,27
±
0,15
CL-Co-XGGA 2:1
8,56
±
0,27
520,91
15,59
±
2,56
17,71
±
0,00
20,70
±
0,83
Thermal properties
Figure 3 shows that CL-Co-XGGA excipients have melted at a temperature of less than 100ͼC. In accordance
with the other research conducted by Carbinatto, De Castro, Cury, Magalhães, & Evangelista, 2012, the
polysaccharide will be degraded at 40 - 110ͼC, which is associated with heat loss. Thermal stability decreases due to
physical interactions involving high temperature heating [7]. The physical interaction of the polymer generates the
formation of two peaks. The first peak was an endothermic peak characterized by heat absorption. The second peak
was an exothermic peak that occurs at a temperature of 200 - 400ͼC which indicated the occurrence of polymer
degradation process. The results show that the exothermic peak of CL-Co-XGGA excipient was at 287,90 -
296,67ͼC (Table 2). The exothermic peak of CL-Co-XGGA excipients decreased compared to the exothermic peaks
of xanthan gum and acacia gum. Meanwhile, the exothermic peak of Co-XGGA excipients approaches the
exothermic peak of xanthan gum (563,27C) and acacia gum (473,04C) [5]. It shows that there was no chemical
interaction between xanthan gum and gum acacia consisting in Co-XGGA excipients.
030009-6
FIGURE 3. Endothermic and exothermic curves of CL-Co-XGGA excipients
Chemical Structure
The functional group analysis aimed to ensure the presence of cross-linking reaction occurring in the presence of
substituted phosphate group in xanthan gum and/or acacia gum. Figure 4 shows that the FTIR spectrum of Co-
XGGA excipients looked like physically mixed excipient spectrum. The FTIR spectrum of Co-XGGA proved that
the interaction of xanthan gum and acacia gum in the Co-XGGA excipients did not involve chemical changes. The
FTIR spectrum of Co-XGGA excipients exhibited absorption bands at wave number 2400 - 3500 cm-1 which were -
OH carboxylic groups. But the intensity was decreased in spectrum of CL-Co-XGGA excipients. In addition, there
was new specific absorption band formed at wave numbers 1298,14 cm-1; 1300,07 cm-1; and 1296,21 cm-1, as well
as at wave numbers 1165,04 cm-1; 1170,83 cm-1; and 1163,11 cm-1 indicating the P = O group. Specific absorption
bands also formed at wave numbers 1101,39 cm-1; 1091,75 cm-1; and 1097,53 cm-1, as well as at wave numbers
997,23 cm-1; 983,73 cm-1; and 999,16 cm-1 representing the P - O - C group [14,15]. It shows that there was
chemical interaction between the phosphate group of sodium trimetaphosphate with xanthan gum and/or acacia gum.
FIGURE 4. Infrared spectrum of excipient: (a) Physical mixture, (b) Co-XGGA 1: 1, (c) CL-Co-XGGA 1:2, (d) CL- Co-XGGA
(1:1), (e) CL- Co-XGGA (2:1)
Degree of Substitution
The number of hydroxyl groups of xanthan gum and acacia gum substituted by the phosphate group of sodium
trimetaphosphate could be determined by calculating the degree of substitution. CL-Co-XGGA excipients 1:2, 1:1,
2:1 had degree of substitution of 0.067; 0.082; and 0.088. It means that there were 6 and 8 phosphate groups which
substituted in every 100 units of anhydro-glucose. The degree of substitution affected the functional characteristics
of the excipient, such as swelling index and gel strength, which could affect the excipient's ability on drug release.
Gel strength and swelling index
According to Table 2, the different compositions of xanthan gum and acacia gum provided different gel strength.
The larger composition of xanthan gum would provide greater gel strength. Co-XGGA excipients had greater gel
030009-7
strength than CL-Co-XGGA excipients. It was because the viscosity of excipients influenced the gel strength. Cross-
linked reaction decreased the viscosity of excipients so that Co-XGGA excipients had a greater viscosity than CL-
Co-XGGA excipients.
Figure 5 shows that Co-XGGA and CL-Co-XGGA excipients were capable of swelling in various pH mediums.
Differences pH of medium affects the swelling index of excipients. Co-XGGA and CL-Co XGGA excipients swell
better in water and phosphate buffer pH 7,4 medium than HCl pH 1,2 medium. The different composition of xanthan
gum and acacia gum also affected the swelling index of excipients. The greater composition of xanthan gum makes
the greater swelling index of excipient due to the cross-linking reaction that formed excipients with a strong
structure and resistant to erosion so that excipients could swell without erosion.
FIGURE 5. Swelling index of Co-XGGA and CL-Co-XGGA excipients: (a) HCl pH 1,2, (b) aquadest, (c) phosphate buffer pH
7,4
Tablet Evaluation
Tablets F1 - F6 were round and odorless with creamy yellowish color (F1 - F3) and white with yellowish spots
(F4 - F6). Table 3 shows that all formulas passed tablet evaluation tests. All formulas also passed the requirements
specified by drug content because of the drug content of the tablet range from 96.20 99.59%.
TABLE 3. Evaluations of gliclazide sustained release tablets
Formulae
Thickness
Diameter
RSD of Weight
variability (%)
Hardness (Kp)
Friability (%)
1
0.71
±
0.00
0.49
±
0.00
0.67
5.97
±
0.72
0.04
±
0.05
2
0.71
±
0.00
0.51
±
0.00
1.91
5.48
±
0.68
0.12
±
0.04
3
0.71
±
0.00
0.51
±
0.00
1.48
4.59
±
0.41
0.20
±
0.05
4
0.71
±
0.00
0.51
±
0.00
0.75
6.99
±
0.36
0.06
±
0.03
5
0.71
±
0.00
0.52
±
0.00
1.69
5.80
±
0.58
0.19
±
0.02
6
0.71
±
0.00
0.51
±
0.00
1.12
5.89
±
1.19
0.19
±
0.05
In Vitro Drug Release Study
The dissolution study of the sustained release tablets from F1 - F6 showed prolonged and slow release drug
profile. The amount of released drug was calculated and analyzed against several drug release kinetics, such as zero-
order, first order, Higuchi, and Korsmeyer-Peppas. Meanwhile, the Korsmeyer-Peppas equation was used to
determine the mechanism of drug release [16]. From the kinetic equation was obtained the value of drug release
constant (k), correlation coefficient (r), and the value of Peppas diffusion exponent (n). Based on correlation
coefficient (r), F1, F2, F3, and F6 follow zero-order kinetics, where drug release is constant over time regardless of
drug concentration in a tablet. While F4 and F5 follow Higuchi's kinetics, where drug release would be slower as the
distance of drug diffusion from the matrix to the outermost surface is longer. Drug release mechanism could be
analyzed from the value of n or Peppas diffusion exponent. For cylindrical geometric preparations such as tablets, if
030009-8
the value of n <0,45 then the drug release follows the Fickian diffusion mechanism. If it is in the range of 0,45 <n
<0,89 then the drug release follows non-Fickian diffusion mechanism. If n = 0,89 then the drug release follows case
II transport, whereas if the value of n> 0,89 then the drug release follows super case II transport mechanism. Tablets
F1, F2, F3, F5 and F6 follows the non-Fickian diffusion release mechanism, where the drug release was caused by
diffusion and controlled erosion. The drug release occured due to the diffusion of the drug from the matrix and
accompanied by the erosion of the matrix. Meanwhile, F4 followed the Fickian diffusion release mechanism, where
the drug release was caused by diffusion.
Banakar’s rules could be used to explained amount of drug dissolved associated with the frequency of drug
administration. If for 8 hours the dissolved drug percentage ranged 20-45%, the sustained release tablet could be
used for 32 hours, if the dissolved drug percentage ranged 45 - 75%, it canbe used for 16 hours, and if the dissolved
drug percentage ranged more than 75%, it can used only for 8 hours. The drug release profile of F1 and F2 for 8
hours showed the dissolved drug percentage about 59.72% and 46.70%. According to Banakar's rules, tablet F1 and
F2 can be used for 16 hours. Tablet F3 showed the dissolved drug percentage 35.96%, then it can be used for 32
hours. Tablets F4 - F6 showed the dissolved drug percentage about 100.72%, 96.16% and 80.35%. According to
Banakar's rules, it can be used for 8 hours.
FIGURE 6. In vitro release profile of gliclazide.
In conclusion, the gliclazide released from tablets F1 - F6 containing CL-Co-XGGA excipients revealed the
sustained release profile, which was following zero order kinetics (F1, F2, F3, F6) and Higuchi kinetics (F4 and F5).
In addition, CL-Co-XGGA excipients might be used as matrices for sustained release tablets and could retard drug
release up to 8 until 32 hours.
ACKNOWLEDGMENTS
The authors gratefully acknowledge to Dexa Medica Pharmaceuticals in providing active material (gliclazide)
and Directorate of Research and Community Engagements of Universitas Indonesia for financial support.
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