“A study of Gliclazide Solubility in Different pH media and factor
affecting parameters”
Harish Kumar Arjariya*
Research scholar Singhania University, Rajasthan
Email: Harish_chem_c@yahoo.com
ABSTRACT
Gliclazide is an oral hypoglycemic (anti-diabetic drug) and is classified as a
sulfonylurea. It is marketed as Glizid, Glyloc and Reclide in India and Diamicron
in Canada and Australia. In the Philippines, Servier markets it as Diamicron MR,
like in most countries across the world. Many generic equivalents are also
available e.g. Glubitor-OD, Clizid. It is not marketed in the United States. A
modified-release formulation is also marketed. Its classification has been
ambiguous, as literature uses it as both a first-generation
[1]
and second-
generation[2] sulfonylurea. Gliclazide was proven to protect human pancreatic betacells from hyperglycemia-induced apoptosis. It was also shown to have an
antiatherogenic effect in type 2 diabetes.
The aim of this study was established a study for impact of Gliclazide ingredient
solubility in different dissolution media and with and without surfactants also with
and without deaeration.
Keywords
Dissolution testing, Gliclazide MR Tablets, Method Validation, Reverse
phase – High performance liquid chromatography, Sodium lauryl
sulphate,Tween 20
Abbreviations
MR
: Modified Release
ER
: Extended Release
MG
: Milligram
HR.
: Hour
Fig.
: Figure
%
: Percen
NIDDM
: Non insulin dependent diabetes mellitus
SDS:
Sodium dodecyl sulphate
SLS:
Sodium lauryl sulphate
Introduction
Gliclazide is chemically known as 1-(hexahydrocyclopenta[c] pyrrol-2-(1H)-yl)-3[(4-methylphenyl) sulfonyl] urea. used for patients with Type 2 diabetes mellitus.
The Type 2 diabetes mellitus is a progressive disorder, and although oral
monotherapy is often initially successful, it is associated with a secondary failure
rate, which contributes to the development of long-term diabetes
complications resulting from persistent hypoglycemia.
Figure 1:chemical structure of Gliclazide
Mode of action:
Gliclazide selectively binds to sulfonylurea receptors (SUR-1) on the surface of the
pancreatic beta-cells. It was shown to provide cardiovascular protection as it does
not bind to sulfonylurea receptors (SUR-2A) in the heart.[5] This binding
effectively closes the K+ ion channels. This decreases the efflux of potassium from
the cell which leads to the depolarization of the cell. This causes voltage dependent
Ca++ ion channels to open increasing the Ca++ influx. The calcium can then bind
to and activate calmodulin which in turn leads to exocystosis of insulin vesicles
leading to insulin release.
Available Dosage form
The dosage for the 80 mg formulation is 40 to 320 mg daily in two divided
doses, while the 30 mg and 60 mg modified release formulation may be given
at a dose of 30 to 120 mg once daily at breakfast.
Biopharmaceutics Classification System
The Biopharmaceutics
Classification
System is
a
guide
for
predicting
the intestinal drug absorption provided by the U.S. Food and Drug Administration [1].
The fundamental basis for the BCS was established by Dr. Gordon Amidon who was
presented with a Distinguished Science Award at the August 2006 International
Pharmaceutical Federation (FIP) congress in Salvador, Brazil.
This
system
restricts
the
prediction
using
the
parameters solubility and intestinalpermeability. The solubility classification is based on
a United
States
Pharmacopoeia (USP)
aperture.
The intestinal
permeability classification is based on a comparison to the intravenous injection. All
those factors are highly important, since 85% of the most sold drugs in
the USA and Europe are orally administered.
According to the Biopharmaceutics Classification System, drug substances are
classified as follows:

Class I - High permeability, high solubility

Example: metoprolol

Those compounds are well absorbed and their absorption rate is usually higher than
excretion.

Class II - High permeability, low solubility

Example: glibenclamideThe bioavailability of those products is limited by their solvation
rate. A correlation between the in vivo bioavailability and the in vitro solvation can be
found.

Class III – Low permeability, high solubility

Example: cimetidine

The absorption is limited by the permeation rate but the drug is solvated very fast. If the
formulation does not change the permeability or gastro-intestinal duration time, then
class I criteria can be applied.

Class IV - Low permeability, low solubility

Example: hydrochlorothiazide
Those compounds have a poor bioavailability. Usually they are not well absorbed over
the intestinal mucosa and a high variability is expected
Solubility study of Gliclazide:
Solubility of Gliclazide has been performed in the following media and media prepared
as given below.
A. 0.1 N Hydrochloric acid: 8.5 ml of concentrate HCl into 1000ml of water.
B. 4.5 sodium Acetate buffer: weighed and transferred 29.9 gm of sodium
acetate trihydrate into 10000 ml of water added 16 ml of Acetic acid pH adjusted 4.50
with diluted acetic acid .
C.pH 6.8 phosphate buffer: weighed and transferred 68 gm of potassium
dihydrogen orthophosphate and 8g of sodium hydroxide into 10000 ml of water and pH
adjusted 6.80 with either sodium hydroxide solution or orthophosphoric acid solution.
D. pH 7.4 phosphate buffer: weighed and transferred 6.8 gm of potassium
dihydrogen orthophosphate and 0.9g of sodium hydroxide into 1000 ml of water and pH
adjusted 7.4 with either sodium hydroxide solution or orthophosphoric acid solution.
The pH solubility was investigated by measuring solubility of gliclazide using buffers of
various pH (1.2, 4.5, 6.8, 7.4). Weighted test sample of about 80 mg of gliclazide was
added to 250 mL of buffer solution and stirred magnetically in a water bath at 37˚C. five
hour later 10 mL were withdrawn and assayed by HPLC.
Figure: Solubility of Gliclazide in Different media
Table: 1
Solubility study data in Different pH media
Solubility study data in different pH media
Buffer /Media
Solubility(mg/ml)
0.1 N HCl
0.1529
0.1 N HCl
0.1516
0.1 N HCl
0.1425
pH 4.5 Acetate buffer
0.0419
pH 4.5 Acetate buffer
0.0417
pH 4.5 Acetate buffer
0.0416
pH 6.8 phosphate buffer
0.5585
pH 6.8 phosphate buffer
0.5577
pH 6.8 phosphate buffer
0.5594
pH 7.4 phosphate buffer
1.4191
pH 7.4 phosphate buffer
1.4570
pH 7.4 phosphate buffer
1.4762
Dissolution study of Gliclazide shown a lower side drug release in a model
formulation and it is also indicated that low solubility in lower pH buffer media.
Gliclazide - 8.985
AU
0.04
0.02
0.00
5.00
10. 00
15. 00
Minutes
Separation of Gliclazide Modified released tablets using a phosphate buffer .separation
conditions :RP C8(250*4.0) mm ,wavelength 230nm at 30ºC,1.9mL/min.,100RPM.
Table:2
Dissolution profiles of Gliclazide in multimedia at 100 rpm
pH 4.5 Acetate buffer
Unit
2 Hr
6 Hr
16 Hr
1
10
40
76
2
9
42
75
3
11
41
74
4
9
38
72
5
10
40
72
6
9
41
76
Mean
10
40
74
SD
0.7
1.2
1.7
0.1 N HCl
2 Hr
6 Hr
16 Hr
10
25
70
10
31
75
7
27
74
5
30
73
5
32
65
6
35
71
7
30
71
2.1
3.3
3.3
2 Hr
10
12
11
12
12
11
11
0.7
pH 6.8 Buffer
6 Hr
16 Hr
50
80
47
81
43
80
45
82
43
83
41
79
45
81
3.0
1.3
Table: 3
Degassing study of dissolution in pH 7.4 phosphate buffer by various techniques
Non-Degassed Media
Degassed Media
Degassed Media
Conventional method
By Mechanical degasser
#
2Hr
6Hr
16Hr
#
2Hr
6Hr
16Hr
#
2Hr
6Hr
16Hr
1
16
40
79
1
17
41
86
1
17
46
95
2
16
43
83
2
15
39
83
2
18
47
98
3
15
40
81
3
14
37
81
3
19
48
95
4
16
41
83
4
15
38
86
4
17
44
94
5
18
47
82
5
15
38
81
5
15
40
95
6
15
40
83
6
17
40
86
6
17
43
96
Mean
16
42
82
Mean
16
39
84
Mean
17
45
96
SD
1.1
2.8
1.6
SD
1.2
1.5
2.5
SD
1.3
2.9
4.4
Min
15
40
79
Min
14
37
81
Min
15
40
85
Max
18
47
83
Max
17
41
86
Max
19
48
98
Discussion
Above dissolution study shows that pH 7.4 phosphate buffer is suitable media for
drug dissolution of Gliclazide active in Modified release formulation of Gliclazide.
But a dissolution study shows that enhancement of Gliclazide drug dissolved is
significantly impacted by dissolved gases or bubbles if USP apparatus basket
used.also alternative sinkers a good option but it is a better recommendation to
treat media by a effective mechanical deaeration technique before choose a specific
concentration contained surfactant dissolution media. For poorly soluble drugs, a
percentage of surfactant can be used to enhance drug solubility and it is also
recommended by USFDA.
Then different concentrations of SLS (0.5% and 1 %) and also Tween 20 (0.5%,
1.0%) were prepared in purified water and used for dissolution study.
Table – 4
Dissolution profiles of Gliclazide in different concentrations of surfactant solution .
pH 7.4 buffer+0.5%SDS
pH 7.4 buffer+1%SDS
pH 7.4 Buffer+0.5% Tween 20
pH 7.4 Buffer+1% Tween 20
#
2Hr
6Hr
16Hr
#
2Hr
6Hr
16Hr
#
2Hr
6Hr
16Hr
#
21
6Hr
16Hr
1
29
81
99
1
41
97
101
1
22
59
100
1
21
55
97
2
28
80
99
2
39
95
98
2
23
59
100
2
21
53
98
3
26
80
96
3
38
95
98
3
21
58
104
3
21
49
95
4
28
80
99
4
38
97
101
4
22
59
100
4
21
49
97
5
26
81
99
5
41
95
98
5
23
59
100
5
21
44
98
6
29
80
99
6
41
95
98
6
21
58
104
6
21
47
95
Mean
28
80
99
Mean
40
96
99
Mean
22
59
101
Mean
21
50
97
SD
1.4
0.5
1.2
SD
1.4
0.9
1.4
SD
0.8
0.5
1.9
SD
0.0
3.6
1,2
Min
26
80
96
Min
38
95
98
Min
15
40
85
Min
44
95
Max
29
81
99
Max
41
97
101
Max
19
48
98
Max
55
98
21
21
Conclusions:
Solubility study is helpful to determine a dissolution or discriminating Media for
estimation of drug release in a particular dosage form this study focused on poorly
soluble drugs dissolution e.g. Gliclazide in Giclazide MR tablets and shows a
comparative model to design dissolution study or choose experimental condition
for such type of products.
Acknowledgement: Authour is thankful to Ranbaxy laboratories to provide
facility to conduct experimental work.
References
[1]KPR Chowdary, HPLC estimation of Gliclazide in formulation and in
pharmacokinetic studies, Asian J.chem 2009;21:5221-5227
[2] WA.Hanson, “Handbook of Dissolution Testing.”Pharmaceutical Technology
Publications, Springfield, Oregon, (1982).
[3] M.F.Griffth, Curley, T.E., Martin, GP,“Considerations in Choosing a
Deaeration Technique for Dissolution Media.” Dissolution Technologies, 4 (1,
February), 16-17,(1997).
[4] S.A.Qureshi, I.J.McGilveray,.,“Impact of Different Deaeration Methods on the
USP Dissolution Apparatus Suitability Test Criteria”; pg4-138; Pharmacopeial
Forum 20 (6), 8565-8566, (1994).
[5] BR.Rohrs, DJ Steiner, “Deaeration Techniques for Dissolution Media.”
Dissolution Technologies, 2 (2, winter), 7-8, (1995).
[6] T.W.Moore,.,“Dissolution Testing: A fast, efficient Procedure for Degassing
Dissolution Medium.”Dissolution Technologies, 3 (2, May), 3-5,
1996. Degenhardt, O.S., Waters, B., Toltl, N.P., etal,“Comparison of the
Effectiveness of VariousDeaeration Techniques.” Dissolution Technologies,
11(1, February) 6-11, (2004).
[7] USP Pharmacopeia
[8] Wikipedia