Professional Documents
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*1
Bioequivalence Study Centre, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India-700 03
2
Nandha College of Pharmacy and Research Institute, Koorapalayam “Pirivu”, Erode, Tamilnadu, India- 638052.
E-mail:radhi_kannan2005@yahoo.co.in
ABSTRACT
The aim of the present study was to design an oral sustained release matrix tablet of Glipizide and to optimize the drug
release profile using response surface methodology. Tablets were prepared by wet granulation method using HPMC K
100 and Eudragit L 100 as matrix forming polymers. A Central composite design for 2 factors at 3 levels each was
employed to systematically optimize drug release profile. HPMC K 100 and Eudragit L 100 were taken as the in-
dependent variables. The dependent variables selected were % of drug released in 2 hrs (rel 2 hrs), % of drug released in
8 hrs (rel 8 hrs), and % of drug released in 12 hrs (rel 12hrs). Contour plots were drawn and optimum formulations were
selected by feasibility and grid searches. The formulated tablets exhibited Non–fickian drug release kinetics approaching
Zero–order as the value of release rate exponent (n) varied between 0.6024 and0.7354, resulting in regulated and com-
plete release until 24 hrs. The polymer HPMC K 100 and Eudragit L 100 had significant effect on the drug release from
the tablets (P<0.05). Polynomial mathematical models, generated for various response variables using multiple linear
regression analysis, were found to be statistically significant (P<0.05).Validation of optimization study performed using 8
confirmatory runs indicated very high degree of prognostic ability to response surface methodology, with percentage error
varied between -0.0132 and 0.7566. Besides unveiling the effect of the 2 factors on the various response variables, the
study helped in finding the optimum formulation with sustained drug release.
Key words: Sustained Release: Matrix Tablet, Hydroxy propyl methyl cellulose (HPMC K 100), Eudragit L 100, and
Central Composite Design.
INTRODUCTION
Sustained or controlled release delivery systems can age form (1-4).
achieve predictable and reproducible release rates, extended Hydrophilic polymer matrix system are widely used for
duration of activity for short half – life drugs, decreased tox- designing oral sustained release delivery systems because of
icity, and reduction of required dose, optimized therapy and their flexibility to provide a desirable drug release profile, cost
better patient compliance. Matrix type sustained delivery sys- effectiveness, and broad regulatory acceptance. The hydro-
tems are popular because of their ease of manufactures. It philic polymer selected for the present study was HPMC K-
excludes complex production procedure such as coating and 100. HPMC K – 100 forms transparent tough and flexible
pellitization during manufacturing and drug release from the films from aqueous solution. The films dissolve completely in
dosage form is controlled mainly by the type and proportion the gastrointestinal tract at any biological pH and provide good
of the polymers used in the preparation. Hydrophilic polymer bioavailability of the active ingredient.Eudragit L 100 was also
matrix is widely used for formulating a sustained release dos- used along with the HPMC K-100 to get the required sus-
Journal of Pharmacy Research Vol.2.Issue 1. January 2009 94
tained release of the drug. Lactose, Povidone, Iso Propyl Alcohol (IPA), Aerosil, Mag-
Glipizide is widely used sulphonyl urea antidiabetic nesium Stearate, was of AR Grade.
agent, adjunct to diet to the management of type –2 (Non METHODS:
insulin dependent) diabetes mellitus in patients whose hyper-
glycemia cannot be controlled by diet and exercise alone. Preparation of Sustained Release Matrix Tablets
Glipizide stimulates insulin secretion from the β cells of pan- Table1enlists the composition of different sustain re-
creatic –islets tissue, increases the concentration of insulin in
lease formulations prepared using varying amounts of the
the pancreatic vein and may increase the number of insulin polymers (HPMC K 100 and Eudragit l 100) and granulated
receptors (5). It is a weak acid (pKa = 5.9) practically using Povidone in Iso- propyl alcohol along with the fixed
insoluble in water and acidic environment but highly perme- quantity of magnesium stearate as the lubricant. Drug and the
able (class 2) according to the Biopharmaceutical Classifica- excipient were homogeneously blended and subsequently
tion System (BCS) (6). The oral absorption is uniform, rapid compressed using double punch tabletting machine, equipped
and complete with a bioavailability of nearly 100% and an with beveled flat punch 8/32 mm, diameter (Cad mach Ma-
elimination half-life of 2–4 h (6). Glipizide is reported to have
chinery Co: Ahemedabad, India)
a short biological half-life (3.4 ± 0.7 h) requiring it to be ad-
Experimental Design:
ministered in 2 to 3 doses of 2.5 to 10 mg per day (7). Sus- A central composite design (CCD) with a= 1 was
tained release formulations that would maintain plasma levels employed as per the standard protocol(10, 11).The amounts
of drug for 8 to 12 hrs might be sufficient for once a day of HPMC K 100 (X1 ) and Eudragit L 100 (X 2 ) were se-
dosing for Glipizide. SR products are needed for Glipizide to lected as the factors, studied at 3 levels each. The central
prolong its duration of action and to improve patient compli- point (0, 0) was studied in quintuplicate. All ot6her formula-
ance. tion and processing variables were kept invariant throughout
In development of a sustain release tablet dosage the study. Table –2 summarizes an account of the 13 experi-
form, an important issue is to design an optimized formulation mental runs studied, their factor combination and the transla-
with an appropriate dissolution rate in a short time period tion of the coded levels to the experiment units employed
and minimum number of trials. For this purpose, a computer during the study. % of drug released in 2hrs ( rel 2 hrs ) ( Y1 ),
based optimization technique with a response surface meth- % of drug released in 8 hrs ( rel 8hrs) ( Y 2 ), % of drug re-
odology (RSM) is widely practiced in the development and leased in 12 hrs ( rel 12 hrs ) ( Y 3 ) were taken as the response
optimization of drug delivery devices. Based on the principal variables.
of design of experiments, the methodology encompasses the Tablet assay and Physical Examination
use of various types of experimental designs, generation of 10 tablets were taken and the drug was extracted
polynomial equations, and mapping of the response over the using methanol and the samples were analyzed spectropho-
experimental domain to determine the optimum formulations. tometrically (Shimadzu Model 1601) at 276 nm. Tablets were
The technique requires minimum experimentation and time, also evaluated for hardness (n=10), Friability (n=10), Weight
thus proving to be far more effective and cost effective than Variation (n=10) and thickness (n=10).
the conventional methods of formulating dosage forms. Invitro Drug Release Studies
The current study aims at developing and optimizing Dissolution studies were performed for all the for-
a sustained release matrix tablet of Glipizide using HPMC mulation combinations, in triplicate, determined using USP
K-100 and Eudragit L 100 by wet granulation method and 22 type I dissolution apparatus ( Electro lab , TDT- 08 L )
optimizes the formulation using RSM. Use of the response where 900 ml of 0.1 N HCl and phosphate buffer of pH 6.8
surface methodology has been proved to be a useful tool in were used as dissolution media maintained at 37o C ( ± 0.5 o c
the development and optimization (8). Different steps involved ) at 50 rpm . The release rates from the tablets were con-
in response surface methodology include experimental de- ducted in the dissolution medium of 0.1 N HCL for 2 hours
sign, regression analysis, constraint optimization and valida- and thereafter in phosphate buffer of pH 6.8. 5 ml of aliquot
tion. were withdrawn at 2, 4, 8, and 12 hours with replacement of
MATERIALS AND METHODS fresh media. Solution samples were analyzed by using UV-
MATERIALS: Spectrophotometer (Shimadzu Model 16010) at 276 nm.
Glipizide, HPMC K-100, Eudragit L-100, were re- Drug release profiles were drawn using MS-Excel Software
ceived as Gift sample from Aravind Remedies (AR), Chennai. and the values were obtained by interpolation from Excel
Graph.
Journal of Pharmacy Research Vol.2.Issue 1. January 2009 95
Table 1 Composition of 10 mg Glipizide Sus- Table 2 Factor combination as per the chosen experi-
tained Release Matrix Tablets mental design
Trial No: Coded factor levels.
Ingredients Amount (mg)
I 0.00 0.00
Glipizide 10 II -1.00 1.00
HPMC K-100 50-70 III -1.00 -1.00
Eudragit L 100 50-70 IV 1.00 1.00
Povidone 10 V 1.00 -1.00
Aerosil 1 VI 0.00 0.00
Iso Propyl Alcohol 100 VII 0.00 -1.00
Magnesium Stearate 2 VIII 1.00 0.00
Lactose q.s to 173 mg IX 0.00 0.00
X 0.00 0.00
XI 0.00 1.00
XII -1.00 0.00
XIII 0.00 0.00
Translation of coded levels
in actual units
Coded level -1 0 1
X1 HPMC K 100 (mg) 50 60 70
X2 Eudragit L 100 (mg) 50 60 70
Table 3: Drug Release Parameters of Various Trial Formulations Prepared as per the Experimental Design
X1 X2
X1 =HPMC K100, X2 = Eudragit L 100, rel 2 hrs = Release in 2 hours, rel 8 hrs=Release in 8
hrs, rel 12 hrs = Release in 12 hrs, n= Release component obtained from Koresmeyer Equation,
r2 = regression coefficient.
Significant effect (p value < 0.5) of factors on individual responses is shown in bold,
rel 2hrs: Release in 2 hrs, rel 8hrs: Release in 8 hrs, rel 12 hrs: Release in 12 hrs,
A- HPMC K 100, B- Eudragit L 100.
Table 5:Composition of the Checkpoint Formulations, the Predicted and Experimental Values of Response Vari-
ables, and Percentage Prediction Error
S. No. Composition HPMCK100 : Eudragit L100 Response Variable Experimental value Predicted value Residual
1. 60:50 Rel 2hrs 14.74 14.71 0.2039
Rel 8hrs 56.23 55.34 -0.1952
Rel 12hrs 85.56 84.22 0.1866
2. 60:70 Rel 2hrs 14.54 14.52 0.1377
Rel 8hrs 68.95 69.12 -0.2459
Rel 2hrs 85.37 85.54 -0.1987
3. 50:50 Rel 2hrs 14.28 14.25 0.2105
Rel 8hrs 78.46 78.95 -0.6206
Rel 12hrs 88.45 87.93 0.5913
4. 50 : 60 Rel 14.76 14.74 0.1356
2 hrs
Rel 56.38 56.45 -0.124
8 hrs
Rel 84.35 84.60 -0.2955
12 hrs
5. 70:50 Rel 2hrs 14.54 14.49 0.3450
Rel 8hrs 71.24 71.76 -0.6360
Rel 12hrs 88.56 88.54 0.0225
6. 50:70 Rel 2hrs 14.75 14.89 -0.9402
Rel 8hrs 55.54 55.75 -0.3766
Rel 12hrs 82.25 83.03 0.2682
7. 60:60 Rel 2hrs 14.76 14.84 0.4219
Rel 8hrs 54.52 54.86 -0.6197
Rel 12hrs 84.34 84.71 -0.4368
8. 70:70 Rel 2hrs 14.75 14.83 -0.5394
Rel 8hrs 55.54 55.49 0.0901
Rel 12hrs 85.56 85.47 0.1053
90
80
70
60
50
40
30
20
10
0
0 2 4 6 8 10 12
Time in Hours
Fig 1 Cumulative Glipizide Release (%) verses Time profiles for glipizide matrix formulation prepared as
per the experimental design. Each value represents the mean ±S.D, n= 13
Design-Expert® Software
1.00
Rel 2 hrs
Design-Expert® Software
Rel 2 hrs
Design Points Rel 2 hrs
21.45 Design points above predicted value
Design points below predicted value
21.45
14.74
0.50 21.5
14.74
X1=A:A X1 = A: A
X2 = B: B 19.725
X2 = B: B
16.7719 19.1069
Rel 2 hrs
15.6045
B: B
16.175
14.4
-0.50
1.00 1.00
0.50 0.50
0.00 0.00
-0.50 -0.50
-1.00 B: B A: A
-1.00 -1.00
-1.00 -0.50 0.00 0.50 1.00
A: A
Fig- 2 Response surface plot and corresponding contour plot showing the relationship between various
levels of polymer AA (HPMC K 15) and BB (Eudragit L 100) on drug release in 2 Hrs
Rel 8 hrs
0.00
58.2044 5
72.4437 58.2044
67.5
60.25
-0.50
53
62.9508
67.6973
1.00 1.00
72.4437
0.50 0.50
-1.00
0.00 0.00
-1.00 -0.50 0.00 0.50 1.00
-0.50 -0.50
B: B A: A
-1.00 -1.00
A: A
Figure 3. Response surface plot and corresponding contour plot showing the relationship between various
levels of polymer AA (HPMC K 15) and BB (Eudragit L 100) on drug release in 8 Hrs
Design-Expert® Software
1.00
Rel12hrs
Rel 12 hrs Design-Expert® Software
Design Points
Rel 12 hrs
100.2 Design points above predicted value
Design points below predicted value
82.25 100.2
0.50
82.25 101
X1=A:A
X2 = B: B X1 = A: A
X2 = B: B 96.25
94.5194
91.8179 86.4147
Rel 12 hrs
B: B
86.75
-0.50 94.5194 82
1.00 1.00
0.50 0.50
-1.00 0.00 0.00
-0.50 -0.50
-1.00 -0.50 0.00 0.50 1.00 B: B -1.00 -1.00
A: A
A: A
Fig 4: Response surface plot and corresponding contour plot showing the relationship between various levels of
polymer AA (HPMC K 15) and BB (Eudragit L 100) on drug release in 12 Hrs.
25 1.00
predicted value
20
Residual value
0.50
15
0.00
10 0 10 20 30
-0.50
5
0 -1.00
0 5 10 15 20 25 -1.50
experimental value Experimental value
(C) (D)
8 hr 8 hr
Predicted released in
80
Residual value 1.00
8 hrs (%)
60
0.50
40
0.00
20
-0.50 0 50 100
0
-1.00
0 20 40 60 80
Experimental release in 8 hrs (%) Experimental value
(E) (F)
12 hr 12 hr
120
0.60
100
0.40
Residual value
80
0.20
60
0.00
40
-0.20 0 50 100 150
20
-0.40
0
0 10 20 30 40 50 60 70 80 90 100 110
-0.60
experimental value Experimental value
Fig 5. Linear Correlation Plots (A, C, E) between Experimental and Predicted Values and the Corresponding
Residual Plots (B, D, F) for various variables.
Drug Release Kinetics diffusion exponent indications of the drug release mechanism.
In order to investigate the model of release from Optimum Release Profile
tablets, the drug release data of the formulation was ana- Optimum release profile for once daily
lyzed withthefollowing models,Q = K o
t ( Zero Order ki- SR formulation was calculated by the follow-
netics ), ln (100 –q ) = ln Qo K t ( first order kinetics ) , Q= ing equation (13) using available pharmacoki-
K t ( Higuchi Model ) and Koresmeyer etal’s equation(12) netic data (14)
Log ( Mt/ M& ) = log K + nlog t. where Mt is the amount of Dt= Dose (1+ 0.693 ×t/t1/2
the drug release at time t, M& is the amount of drug release where Dt = Total dose of drug
after infinite time, K is a release rate constant and n is the Dose= Dose of the immediate release