Research Article

Optimization of Glipizide sustained release matrix tablet formulation

by central composite design- response surface methodology
Parasuram Rajam Radhika*1 , Tapan kumar Pal1 , Thangavel Sivakumar2 .

*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.

For correspondence:Parasuram Rajam Radhika,Bioequivalence Study Centre, Department of Pharmaceutical Technology,

Jadavpur University, Kolkata, India-700 03

E-mail:radhi_kannan2005@yahoo.co.in

Received on:14-09-2008; Accepted on :08-12-2008

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
achieve predictable and reproducible release rates, extended
duration of activity for short half – life drugs, decreased tox-
icity, and reduction of required dose, optimized therapy and
better patient compliance. Matrix type sustained delivery sys-
tems are popular because of their ease of manufactures. It
excludes complex production procedure such as coating and
pellitization during manufacturing and drug release from the
dosage form is controlled mainly by the type and proportion
of the polymers used in the preparation. Hydrophilic polymer
matrix is widely used for formulating a sustained release dos-
Journal of Pharmacy Research Vol.2.Issue 1. January 2009
age form (1-4).
Hydrophilic polymer matrix system are widely used for
designing oral sustained release delivery systems because of
their flexibility to provide a desirable drug release profile, cost
effectiveness, and broad regulatory acceptance. The hydro-
philic polymer selected for the present study was HPMC K-
100. HPMC K – 100 forms transparent tough and flexible
films from aqueous solution. The films dissolve completely in
the gastrointestinal tract at any biological pH and provide good
bioavailability of the active ingredient.Eudragit L 100 was also
used along with the HPMC K-100 to get the required sus-
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

Trial No Factor amount

(mg) rel 2hrs(%) rel 8hrs(%) rel 12hrs (%) n r2

X1 X2

1 60 60 14.74 56.23 85.56 0.6889 0.9962

2 50 70 16.54 68.95 95.37 0.6024 0.9735
3 50 50 17.18 78.46 98.45 0.7037 0.9943
4 70 70 21.45 68.85 99.65 0.6947 0.9946
5 70 50 20.54 81.24 98.56 0.6282 0.9769
6 60 60 14.75 55.54 82.25 0.7354 0.9822
7 60 50 14.76 54.52 84.34 0.6273 0.9527
8 70 60 20.54 58.59 100.20 0.6414 0.9639
9. 60 60 14.75 56.38 82.54 0.6984 0.9918
10 60 60 14.75 55.54 85.56 0.6980 0.9918
11 60 70 14.78 55.29 84.34 0.6806 0.9786
12 50. 60 17.18 78.98 98.40 0.6935 0.9934
13 60 60 14.76 56.38 84.35 0.7000 0.9927

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.

Journal of Pharmacy Research Vol.2.Issue 1. January 2009 96

 Table 4: Analysis of variance (ANOVA) for all three Responses
rel 2hrs (Y1 ) rel 8 hrs (Y2 ) rel 12 hrs (Y3 )
Source F p-Value F p-value F p- value
Model 11.28 32130.00 179.69 28.33 96.20 40.45
A 16072.58 <0.0001 32.77 0.0023 0.68 0.4468
B 0.57 0.4845 0.047 0.8374 0.000 1.000
AB 710.17 <0.0001 0.33 0.5922 1.83 0.2343
A2 1.343 <0.0001 111.54 0.0001 243.63 <0.0001
B2 14.49 0.0125 1.94 0.2198 0.26 0.630
A2 B 12.55 0.0165 7.22 0.0435 0.14 0.7248
AB2 570.06 <0.0001 24.82 0.0042 0.022 0.8882

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

Journal of Pharmacy Research Vol.2.Issue 1. January 2009 97

 100
Cumulative Percentage Release

90
80
70
60
50
40
30
20
10
0
0 2 4 6 8 10 12
Time in Hours

60:60 55:55 65:55 65:65

55:65 12.1:37.4 1.95:9.90 1.10:33.15
37.95:32.4 32.4:49.20

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

0.00 5 15.6045 17.9394 17.95

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

Journal of Pharmacy Research Vol.2.Issue 1. January 2009 98

 Design-Expert® Software
1.00
Rel 8 hrs Design-Expert® Software
Rel 8 hrs 62.9508
Design Points Rel 8 hrs
81.24 Design points above predicted value
Design points below predicted value
54.52 81.24
0.50
54.52 82
X1 = A: A
X2 = B: B
67.6973 X1 = A: A
X2 = B: B 74.75
62.9508
B: B

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

0.00 5 86.4147 91.8179

89.1163 91.5
89.1163

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.

Journal of Pharmacy Research Vol.2.Issue 1. January 2009 99

 (A) (B)
2 hr 2 hr

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

Journal of Pharmacy Research Vol.2.Issue 1. January 2009 100

part were drawn using MS-Excel, forcing the line through origin.
t= Time during which the sustained re- RESULTS AND DISCUSSION
lease is desired (24 hrs)
t1/2 = Half –life of the drug ( 3hrs) Drug content and Physical Evaluation
The optimum formulation was selected on the The assayed content of drug in various formulations
above equation so that it could attain complete varied between 98.3 ± 0.43 to 99.5 ± 0.3 (mean 98.9 %).
and controlled drug release upon “trading off” Tablet weight varied between 0.250 ± 0.031 to 0.251± 0.032
various response variables; the following maxi- mg, Thickness between 2.45 to 2.59 mm, Hardness between
mizing criteria were adopted. 6.0-6.3 Kg/ cm2, and friability ranged between 0.079-0.081
rel 2hrs =14.74 percent. Thus all the physical parameters of the matrices
rel 8hrs =52.24 were practically within control.
rel 12 hrs =82.24 In-Vitro drug release studies
Optimization of Data Analysis and validation of optimi- The In-Vitro dissolution studies ere performed using
zation Model USP-22 type I dissolution apparatus at 50 rpm and analyzed
Various RSM computations for the current optimi- by UV- visible spectrophotometer. In the current study, the
zation study were performed employing Design Expert Soft- values of release rate exponent (n), calculated as per the
ware (Design Expert Version 7.1.3, Stat- Ease Inc, and Min- Koresmeyer model ranged between 0.6184 and 0.7280 and
neapolis, MN). Polynomial models including interaction and Zero order release were found to be 0.9867 and 0.9959
quadratic terms were generated for all the response variables (Table - 3) For matrix tablets n value of near 0.5 indicates
using multiple linear regression analysis (MLRA) approach. diffusion control and n value of near 1.0 indicates erosion or
The general form of the MLRA model is represented as the relaxation control. Intermediate values suggest that diffusion
following equation: and erosion contribute to the overall release mechanism. In
Y= Bo + B1 X1 + B2 X2 +B3 X1 X2 + B4 X1 2 + B5 X2 2 + B6 X1 our experiment the results of ‘n’ clearly indicated that the dif-
X2 2 + B7 X1 2 X2 fusion and erosion are the dominant mechanism of drug re-
Where B0 is the intercept representing the arithmetic average lease from these formulations. Diffusion is related to transport
of all quantitative outcomes of 13 runs. B1 to B7 are the coef-of drug from the dosage matrix into the Invitro study fluid
ficients computed from the observed experimental response depending on the concentration of the hydrophilic polymer.
values of Y: and X1 & X2 are the coded levels of the indepen- As gradient varies, the drug is released, and the distance for
dent variables. The terms X1 X2 and X12 (i = 1to 2) represent diffusion increases. This could explain why the drug diffuses
the interaction and quadratic terms respectively. Statistical at a comparatively slower rate as the distance for diffusion
validity of the polynomials was established on the basis of increases.
ANOVA provision in the Design Expert Software. Subse- Total amount of Glipizide released from all the for-
quently, the feasibility and grid searches were performed to mulations up to 8 hrs ranged between 55.24% and 78.46 %
locate the composition of optimum formulations (15). Two – indicating in complete drug release at higher concentration of
dimensional (2D) contour plots were constructed based on Eudragit L 100 as well as HPMC K 100. Rate of drug re-
the model polynomial functions using Design Expert Software. lease tended to decrease with increase in the content of either
These plots are very useful to see interactions effects on the Eudragit L 1000 or HPMC K 100. Thereby the viscosity of
factors on the responses. the gel layer around the tablet increases with increase in the
Eight optimum checkpoints were selected based on hydro gel concentration, thus limiting the release of active in-
the criteria from optimum formulation described earlier by gredient (16, 17). The gel formed during the penetration of
intensive grid search, performed over the entire experimental dissolution media into the matrix structure; consist of closely
domain, to validate the chosen experimental design and poly- packed swollen particles. With further increase in polymer
nomial equations. The formulations corresponding to these amount, thicker gel forms inhibiting dissolution media pen-
checkpoints were prepared and evaluated for various response etration more strongly, resulting in significant reduction in the
properties. Subsequently, the resultant experimental data of values of rel 8 hr indicates slower drug release. The values of
response properties were quantitatively compared with that rel 8hrs enhanced markedly from 55.24-78.46 % and rel 12 hrs
from 82.24-98.43, observed at high levels of both the vari-
of their predicted values. Also, linear regression plots between
observed and predicted values of the response properties ables. This indicated considerable release retarding potential
of the Eudragit L 100 and HPMC K 100.
Journal of Pharmacy Research Vol.2.Issue 1. January 2009 101
rel 12 hrs.Figure 2 exhibits that rel 2 hrs vary in a non linear to
circular fashion, but in a descending pattern with an increase
in the amount of HPMC K 15 and Eudragit L 100. In con-
trast to the results of drug release in 2 hr contour plot for drug
release in 8 hrs (Fig 3) reveal that rel 8 hrs varies in somewhat
linear with increase in polymers. Fig 4 exhibits an inverted
curve, but in an ascending pattern with an increase in the
amount of HPMC K 15 and Eudragit L 100. Fig 5 shows the
Linear Correlation Plots (A, C, E) between Experimental and
Predicted Values and the Corresponding Residual Plots (B,
D, F) for various variables.
Validation of RSM Results
For all of the 8 check point formulations, the results
of the physical evaluation and tablet assay were found to be
within limits. Table 5 lists the composition of the check points,
their predicted and experimental values of all the response
variables, and the percentage error in prognosis. Upon com-
parison of the observed responses with that of the anticipated
responses, the prediction error varied between -0.2222 and
+0.3287
CONCLUSION
Controlled drug release following Koresmeyer Model
attained in the current study indicates that the hydrophobic
matrix tablet of Glipizide, prepared using HPMC K 15 and
Eudragit L 100, can successfully be employed as once a day
oral controlled release drug delivery system. Both the poly-
mers play an important role for the sustained release of
Glipizide. However, appropriate balancing between various
levels of the polymers HPMC K 15 and Eudragit L 100may
contribute better results. High degree of prognosis obtained
using RSM signifies that a 2 – factor CCD is quite efficient in
Source of support: Nandha College of Pharmacy , Erode -52, Tamilnadu. , Conflict of interest: None Declared
Journal of Pharmacy Research Vol.2.Issue 1. January 2009
optimizing drug delivery systems.
REFERANCES
1. Vidyadhara S, Rao P.R, Prasad J.A, Indian J Pharm Sci; (2004):
66,188-192.
2. Reddy K.R, Mutalik. AAPS Pharm Sci Tech; (2003):4, 1-9.
3. Mohammed A.D, James L.F,Micheal H.R, John E.H, Raabi-
Siahboomi A.R, Pharm Dev Tech ; (1999): 4, 313-324 .
4. Lee B.J, Ryu S.G, Cui J.H, Drug Dev Ind Pharm, 25, 493-501 (1999)
5. R.K.Varma and S.Garg. Developmental and Evaluation of Osmotic
ally controlled oral drug delivery system of Glipizide, Eur J.Pharm
.Biopharm57 (2004) 513-525.
6. S. Jamzad and R. Fassihi, Development of Controlled Release Low
Dose Class II drug –Glipizide Int. J.Pharm ,312 (2006) 24-32.
7. Martindale, The complete drug Referance (ed S.C. Sweetman), 34th
ed, Pharmaceutical Press, London 2005, pp 324-348.
8. J.K. Patel, R.P Patel, A.F Amin and M.M Patel, Formulation and
Evaluation of Glipizide.
9. K.P.R. Chowdrary and Y.S Rao, Design and Invitro and In vivo
Evaluation of Mucoadhesive microcapsules of Glipizide for oral con-
trolled release, AAPS, Pharm sci, Tech 4 (2003).
10. Singh,B, Kumar R, Ahuja N, Crit Rev Ther Drug Carrier Syst 22,
27-105 (2005).
11. Singh B, Mehta G, Kumar R, Bhatia A, Ahuja N, Katare O.P, Curr,
Drug Deliv,2, 143-153 (2005).
12. Koresmeyer R W, Gurny R, Doelker E.M Buri P, Peppas N A, Int J
Pharm, 15,25 (1983).
13. Rawlins EA” Bentleys TextBook of Pharmaceutics’, Cassell and
Collier Macmillian London, 1977
14. Defang O, Shufang N, Wei L, Drug Dev Ind Pharm, 2005, 31,(677-
685).
15. Singh B, Ahuja N, Drug Dev Ind Pharm ., 28, 431-442, 2002.
16. Ford JL, Rubinstein MH, Hogan JE, Formulation of Sustained
Release Promethazine Hydrocholide Tablets using HPMC matrices
Int. J.Pharm 1985,24,327-33/8.
17. Vazques MJ, Perez- Marcos B, Gomez – Amoza JL, Martmez-
Pachero R, Souto C, Concheiro A. Influence of technological vari-
ables on release of drugs from hydrophilic matrices Drug. Dev.Ind.
Pharm, 1992:18, 1355-1375.
102