6.

1 Introduction
Glyceryl Monostearate has been used in preparation of hollow microspheres by
emulsification solvent diffusion technique. It works as wall membrane reinforcing
agent
1
.
Acryflow is hydrogenated castor oil which has been used in the novel pharmaceutical
composition containing an active ingredient which is retained in the stomach or upper
part of gastrointestinal tract for controlled delivery of medicament
2
.
It has been shown that the nature of the drug formulation can influence the dissolution
process. Solubility of glipizide increases by addition of HPMC which act as release
modifying ingredient of the formulation
3
. It has also been shown that by incorporating
polymers such as HPMC, Eudragit L100 and Ethyl cellulose within the shell of
microballoons, the release rate of riboflavin from the microballoons could be
controlled while maintaining high buoyancy
1
.
Present work involves attempts to improve floating by incorporating Glyceryl
Monostearate and acryflow. Further studies were done for the improvement of
dissolution of the Glipizide by addition of HPMC and other polymers like Eudragit
L100 and Ethyl cellulose.
6.2 Experimental
6.2.1 Preparation of standard curve of Glipizide
Glipizide (100 mg) was dissolved in Simulated Gastric Fluid containing 0.02%
Tween 20 and volume is made up to 100 ml in volumetric flask. The UV maxima of
Glipizide solution was found to be 276 nm. The standard curve was generated for
entire range from 10 to 35 mcg/ml. Five ml of stock solution (1 mg/ml) was further
diluted to 50 ml. This solution (100 mcg/ml) was further diluted to obtain solution of
10 mcg/ml to 35 mcg/ml. Absorbance of each solution was measured at 276 nm using
Shimadzu 1700 UV/Vis double beam spectrophotometer Simulated Gastric Fluid
containing 0.02% Tween 20 as a reference standard. The standard curve was
generated for entire range from 10 to 35 mcg/ml. The experiment was preformed in
triplicate and based on average absorbance; the equation for the best line was
generated. Standard curve was also generated similarly in Phosphate buffer pH 6.8.
Results of Standard Curve preparation are shown in Table 6.4, 6.5 & Figure 6.1, 6.2
6.2.2 Theoretical release profile of Glipizide
Calculation of the Immediate Release Dose
4

Vd
F
Css
IRP
-----6.1

Calculation of Dose
4

( )
1
]
1

1/2 t
t 0.693 1
IRP Dose
-----6.2
Where, IR = Immediate release,
C
SS
= Concentration at steady state,
V
d
= Volume of distribution,
F = Fraction bioavailable,
t = time up to which sustain release is required and
t
1/2
= half life.
The pharmacokinetic parameters of Glipizide were utilized for the calculation of
theoretical drug release profile for 12 hours dosage form. The immediate release part
for sustained release Glipizide was calculated using equation 6.1 and was found to be
3.5mg and dose was calculated using equation 6.2. Here, the formulation should
release 35% of drug in 1 hour like conventional tablet and 5.9 % per hour up to 12 h
thereafter.
Table 6.1 Important pharmacokinetic parameters of glipizide
5,6,7
Fraction of drug absorbed
Elimination half-life(t
1/2
)
Terminal disposition rate constant (k
el
or )
Apparent volume of distribution (V
d
)
Minimum effective concentration (C
ss min
)
Maximum effective concentration (C
ss max
)
Clearance
1
3.3 h
0.21 h
-1
0.17 l/kg
20 ng/ml
300 ng/ml
0.52 0.18 ml min
-1
kg
-1
6.2.3 Similarity between Phosphate Buffer pH 7.4 and Simulated Gastric Fluid
containing 0.02% Tween 20
The similarity factor, f2, given by SUPAC guidelines for modified release dosage
form was used as a basis to compare dissolution profiles
8
. The dissolution profiles are
considered to be similar when f2 is between 50 and 100. The method was first
reported by Moore and Flanner
9
.
To check the similarity between Phosphate Buffer pH 7.4 and Simulated Gastric Fluid
containing 0.02% Tween 20, dissolution of Glipizide sustained release tablet
GLYTOP SR (10mg) were taken in two dissolution media i.e. 900 ml Phosphate
Buffer pH 7.4 and 500 ml Simulated Gastric Fluid containing 0.02% Tween 20.
Similarity factor for these dissolution profiles was calculated using equation 6.3.

'

1
1
]
1

,
_

+ 100
0.5
n
1 i
2
Ti Ri
n
1
1 log 50
2
F
-----6.3
Where n is the number of dissolution time and R
i
and T
i
are the reference and test
dissolution values at time t. Two dissolution profiles are considered similar when the
F
2
value is 50 to 100.
6.2.4 Preparation and Optimization of Acrycoat S100 microspheres of Glipizide
Glipizide , Acrycoat S100, Acrycoat L100, Ethyl Cellulose, Hydroxy propyl methyl
cellulose ,Glyceryl Monostearate and acryflow in quantities shown in Table 6.2 and
6.3 were dissolved in a mixture of Ethanol, IPA and Dichloromethane (4:6:5). This
mixture was poured in a 500 ml water containing 1% PVA maintained at a
temperature of 30
0
C with stirring at 250 rpm. Stirring was continued for 1 hr. to allow
the volatile solvent to evaporate. The microspheres formed were filtered, washed with
D.M.water and dried overnight at 40
0
C

in oven.





6.2.5 In vitro drug release study
Drug release study from the hollow microspheres is complicated because the hollow
microspheres float and hence adhere to the inside surfaces of the dissolution basket
while the dissolution experiments are in progress, which leads to the nonparticipation
of the hollow microspheres or their surface in the release study. Hollow microspheres
have the propensity to exhibit a buoyancy effect in vivo, but the development of a
dissolution method as a quality control tool with the simulated buoyant condition is
difficult.
The drug release rate from floating microspheres was determined using USP XXIII
basket type dissolution apparatus. A weighed amount of floating microspheres
equivalent to 10 mg glipizide was taken for dissolution study. The microspheres were
placed in a non reacting mesh nylon bolting cloth that had a smaller mesh size(200 #)
than the microspheres. The mesh was tied with a nylon thread to avoid the escape of
any microspheres, and glass marble was used in the mesh to help induce any possible
sinking of the microspheres in the dissolution medium
10
. Simulated gastric fluid (SGF,
pH 2.0) (500 ml) containing Tween 20 (0.02 w/v %) was used as the dissolution
medium
11
and maintained at 37
0
C at a rotation speed of 100 rpm. 10 ml sample was
withdrawn at 1 hr interval and analyzed spectrophotometrically at 276 nm to
determine the concentration of drug present in the dissolution medium. The initial
volume of the dissolution fluid was maintained by adding 10 ml of fresh dissolution
fluid after each withdrawal. The dissolution studies were repeated using pH 6.8 All
experiments were conducted in triplicate. Results of Drug release study are shown in
Table 6.9 to 6.11 and Figure 6.7 to 6.9
6.2.6 Kinetics modeling of drug dissolution profiles
12
The dissolution profile of all the batches was fitted to Zero order, First order

and
Higuchi

to ascertain the kinetic modeling of the drug release. The method of Bamba
et al. was adopted for deciding the most appropriate model.
Zero order
In many of the modified release dosage forms, particularly sustained or controlled
release dosage forms (those dosage forms that release the drug in planned, predictable
and slower than the normal manner), is zero-order kinetic.
t k m
----- 6.4
Where, k is zero-order constant, m is the % drug unreleased and t is the time. The plot
of % drug unreleased (released) versus time is the linear.
First order
Most conventional dosage forms exhibits this dissolution mechanism. Some modified
release preparation, particularly prolonged release formulations, adheres to this type
of dissolution pattern.
ln (100-Q) = ln100-k1t ----- 6.5
Where Q is the percent of drug release at time t, and k1 is the release rate constant. It
assumes that the drug molecules, diffuses out through a gel like layer formed around
the drug during the dissolution process. A plot of log % drug release versus time is the
linear.
Higuchi Model:
A large number of modified release dosage form contain some sort of matrix system.
In such instances, the drug dissolves from the matrix. The dissolution pattern of the
drug is dictated by water penetration rate (diffusion controlled) and thus the following
relationship applies:
Q = k
2
t
1/2
----- 6.6
Where Q is the percent of drug release at time t, and k
2
is the diffusion rate constant
In higuchi model, a plot of % drug unreleased (released) versus square root of time is
linear.
The correlation coefficient values of the zero-order, first order and higuchi kinetics
are shown in Table 6.12.
6.3 Results and Discussion
6.3.1 Preparation of standard curve of Glipizide
Standard curve was prepared according to procedure given in 6.2.1.The method obeys
Beer's Law in the concentration range of 10 to 35 mcg/mL Standard drug solution was
analyzed repeatedly (n =3). The results of standard curve preparation are shown in
Table 6.4, 6.5 and Figure 6.1, 6.2.
Table 6.4 Standard curve of Glipizide in Simulated Gastric Fluid
containing 0.02% Tween 20
Sr.
No.
Concentratio
n
(mcg/ml)
Absorbance
I II III Mean
1
2
3
4
5
6
10
15
20
25
30
35
0.225
0.335
0.413
0.521
0.630
0.729
0.229
0.343
0.420
0.529
0.628
0.720
0.240
0.351
0.427
0.520
0.625
0.714
0.231t 0.00
7
0.343t 0.00
8
0.420t 0.00
7
0.523t 0.00
5
0.628t 0.00
3
0.721t 0.00
7
Absorption = 0.0203X + 0.017
Correlation Coefficient = 0.9975

Table 6.5 Standard curve of Glipizide in Phosphate Buffer pH 7.4
Sr.
No.
Concentratio
n
(mcg/ml)
Absorbance
I II III Mean
1
2
3
4
0
10
15
20
0
0.215
0.338
0.457
0
0.221
0.348
0.470
0
0.229
0.354
0.479
0
0.222t 0.00
7
0.347t 0.00
5
6
7
25
30
35
0.529
0.662
0.732
0.538
0.669
0.747
0.547
0.680
0.756
8
0.469t 0.01
1
0.538t 0.00
9
0.670t 0.00
9
0.745t 0.01
2
Absorption = 0.0215 X + 0.0124
Correlation Coefficient = 0.9957
Figure 6.1 Calibration Curve of Glipizide in Simulated
Gastric Fluid Containing 0.02% Tween 20
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0 10 20 30 40
Conc. (mcg/ml)
A
b
s
.
Figure 6.2 Calibration Curve of Glipizide in Phosphate
Buffer pH 7.4
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
0 10 20 30 40
Conc. (mcg/ml)
A
b
s
.
6.3.2 Theoretical release profile of Glipizide
Theoretical release profile of Glipizide was calculated by using pharmacokinetic
parameters shown in Table 6.1. Theoretical release profile of Glipizide is shown in
Table 6.6.
6.3.3
Similarity
between
Table 6.6 Theoretical Dissolution Profile of
Glipizide
Time in min Cumulative % drug release
0
60
120
180
240
300
360
420
480
540
600
660
720
0.00
35
40.9
46.8
52.7
58.6
64.5
70.4
76.3
82.2
88.1
94.00
99.99
Phosphate Buffer pH 7.4 and Simulated Gastric Fluid containing 0.02% Tween
20
F2 value of Dissolution Profile of Glipizide Tablet in Phosphate Buffer pH 7.4 and
Simulated Gastric Fluid containing 0.02% Tween 20 was found to be 76.654.
Cumulative % Drug Release of Glipizide Tablet (GLYTOP SR 10 mg) in Phosphate
Buffer pH 7.4 and Simulated Gastric Fluid containing 0.02% Tween 20 is shown in
Table 6.7
Table 6.7 Cumulative % Drug Release of
Glipizide Tablet (GLYTOP SR 10 mg)
Time
hr
Phosphate
Buffer 7.4
SGF containing
0.02% Tween 20
0
1
2
3
4
5
6
7
8
9
10
11
12
0
36.258
41.398
46.590
52.266
58.565
63.789
69.637
76.280
81.075
87.090
93.163
98.432
0
33.000
38.444
43.944
49.500
54.264
60.305
66.949
74.831
79.979
86.818
90.954
95.126
6.3.4 Preparation and optimization of Acrycoat S100 microspheres of Glipizide
Formulation 1 is the formulation of optimized composition prepared with optimized
condition selected in Chapter 5. It was good with Morphology, Yield and Drug
Entrapment and thus it is satisfying the objective and criteria of Chapter 5. But
%floating of the Formulation 4 was between 50 60% which is not satisfactory so
attempts have made to improve the floating of the microspheres.
Table 6.8 Evaluation of Acrycoat S100 microspheres of Glipizide batches
F1 to F7
Batches Mean particle size
(m)
%Yield % Floating Incorporation
Efficiency
F1
F2
F3
F4
F5
F6
F7
30025
41025
39531
30080
37020
34050
41035
92%
91%
90%
96%
94%
89%
97%
50%
87%
85%
85%
81%
60%
58%
80%
91%
92%
90%
85%
92%
89%
Figure 6.3 Mean Particle Size of Acrycoat S100
Microspheres Batches F1 to F7
0
50
100
150
200
250
300
350
400
450
500
F1 F2 F3 F4 F5 F6 F7
Batch
M
e
a
n

P
a
r
t
i
c
l
e

S
i
z
e

Figure 6.4 %Yield of Acrycoat S100 Microspheres
Batches F1 to F7
84%
86%
88%
90%
92%
94%
96%
98%
F1 F2 F3 F4 F5 F6 F7
Batch
%
Y
i
e
l
d
Figure 6.5 % Floating of Acrycoat S100 Microspheres
Batches F1 to F7
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
F1 F2 F3 F4 F5 F6 F7
Batch
%
F
l
o
a
t
i
n
g

Figure 6.6 Incorporation Efficiency of Acrycoat S100
Microspheres Batch F1 to F7
74%
76%
78%
80%
82%
84%
86%
88%
90%
92%
94%
F1 F2 F3 F4 F5 F6 F7
Batch
I
n
c
o
r
p
o
r
a
t
i
o
n

E
f
f
i
c
i
e
n
c
y
In Formulation 2, in addition to glipizide and Acrycoat S100, Glyceryl Monostearate
was also added which acts as a wall membrane Reinforcing Agent. In Formulation 3,
Glyceryl Monostearate was replaced with Acryflow. Acryflow is Hydrogenated
Castor Oil, which is having low density and it helps the microspheres to float.
Formulation 2 and 3 were evaluated for Mean particle size (m), %Yield%, Floating
and Incorporation Efficiency as shown in Table 6.8. It is comparable to Formulation 1
with respect to all parameters except %floating. Floating is reasonably good in
Formulation 2 and 3 as compared to Formulation 1.
In dissolution study, due to their floating nature, the microspheres were forcibly
immersed into the dissolution media to avoid adherence to the surface of the
dissolution jar, thus leading to nonparticipation in the dissolution process. The drug
release was extended to more than 12 hr.
From Table 6.9 it can be seen that drug release rate of the formulation 2 and 3 is much
less as compared to formulation 1. So in formulation 4 and 5, we decreased the
concentration of Glyceryl Monostearate and acryflow, respectively. As a result there
is some improvement in drug release and floating was also satisfactory. So we further
decreased the amount of Glyceryl Monostearate and acryflow in formulation 6 and 7
but there is no significant increase in dissolution profile while % floating was
decreased. So in further experiment, we have to use at least 0.25 mg of Glyceryl
Monostearate or acryflow.
Table 6.9 Drug Release Profile of Acrycoat S100 Microspheres of
Glipizide of Batches F1 to F7
Time (hr) F1 F2 F3 F4 F5 F6 F7
0
1
2
3
4
5
6
7
8
9
10
11
12
0
27.78
5
30.57
5
33.57
1
35.93
6
38.79
9
40.68
2
43.40
9
47.44
0
50.87
7
53.27
9
57.73
6
61.55
7
0
12.69
2
16.52
6
19.47
7
22.45
9
25.71
5
27.59
2
30.19
5
32.68
2
35.93
3
38.15
6
40.40
0
42.66
4
0
9.923
11.87
9
15.24
1
17.71
5
20.40
8
22.74
1
25.29
2
28.60
0
30.93
8
34.03
3
36.23
6
38.45
9
0
14.07
7
17.92
6
20.89
2
24.35
1
27.18
7
30.44
4
33.53
8
37.02
1
39.82
1
42.08
5
45.29
2
47.60
8
0
11.76
9
14.20
8
19.44
1
22.42
3
24.75
6
26.62
3
29.67
7
33.53
8
37.26
7
39.04
4
42.22
1
44.50
5
0
16.84
6
19.34
1
22.32
3
26.25
9
30.05
9
33.32
6
36.45
1
40.91
8
43.72
8
46.49
5
49.28
7
52.10
5
0
13.615
16.074
18.097
21.064
23.828
26.623
29.215
32.605
36.328
40.403
44.056
46.362
In formulation 4 and 5, little Glipizide was released from microspheres in 0.1N HCl
containing 0.02% Tween 20. Thus, in order to enhance the drug release rate from the
microspheres, they were prepared by mixing hydrophilic or hydrophobic polymer in
Acrycoat S100. (Batches F8 to F16)
The microspheres prepared upon mixing Acrycoat L100 in Acrycoat S100 (batches
F8 & F9) was having rough surface. The amount of Glipizide released from
microspheres prepared by mixing Acrycoat L100 was high, probably due to facilitated
penetration of dissolution media in the microspheres. Increased amount of Acrycoat
L100 (0.2 gm) was used in formulations F10 & F11 for further improvement of
dissolution rate but it didnt improve dissolution rate significantly.
Figure 6.7 Drug Release Profile of Glipizide from
Microspheres of Batches F1 to F7
0
20
40
60
80
100
120
0 2 4 6 8 10 12 14
Time (hr)
%

C
D
R
F1 F2 F3
F4 F5 F6
F7 Theoritical profile
Table 6.10 Evaluation of Acrycoat S100 microspheres of Glipizide
batches F8 to F16
Batches Mean particle
size (m)
%Yield % Floating Incorporation
Efficiency
F8
F9
F10
F11
F12
F13
F14
F15
F16
38645
42967
25656
51624
27636
41742
33515
35035
40080
72%
91%
69%
91%
96%
92%
95%
92%
93%
72%
74%
85%
85%
90%
91%
78%
77%
76%
83%
90%
91%
82%
87%
89%
93%
87%
90%
In the case of ethyl cellulose (EC), (batches F12 &F13) release profiles of the
microspheres exhibited a burst (6.8%) of glipizide during the initial stage (for 20
min), followed by a plateau pattern for 12 h. In addition, buoyancy appeared to be
high as a consequence of hydrophobic properties of the EC polymer.
In the case of hydroxypropyl methyl cellulose (HPMC) batches F14 to F16 ,
buoyancy was high. HPMC was considerably soluble and gelled in dissolution media.
Additionally, microspheres are having smooth surfaces. Thus, buoyancy appeared to
be high due to the difficulty in penetration of dissolution media through the rigid
smooth surfaces.
It has been shown that presence of HPMC improves the solubility of Glipizide in the
formulation. This was based on the assumption that polymer dissolution during the
time course of study changes the surface tension of the medium and increases drug
solubility. This can be attributed to the surface activity of the polymer. The surface
tension of water (at 20C) is ~72 mN/m and that of HPMC polymer at the same
temperature ranges from 42 to 64 mN/m.20 This reduction in surface tension can
increase the wetting of the drug particles and as a result, increase the solubility
3
.
It was found that the drug release rate and buoyancy of
microspheres prepared by co formulating HPMC was relatively
improved due to gelation in dissolution media. Therefore, the effect
of HPMC mixing ratio on physicochemical properties and drug
releasing behaviors of the microspheres were investigated as shown
in Table 6.11 and Fig 6.9. Although the recovery of microspheres
appeared unchanged by HPMC ratio, the buoyancy decreased with
increasing HPMC ratio. These results were attribuTable to the
conversion of spherical microspheres to needle-like particles
possessing no hollow structure. In addition, the dissolution media
can readily penetrate into microspheres the increased dissolution of
HPMC in the solution. The amount of Glipizide released from
microspheres in 0.1N HCl containing 0.02% Tween 20 (pH 1.2)
increased with increasing HPMC ratio. This behavior was explained
by the increased contact area of particles with the medium due to
the poor buoyancy associated with increased HPMC ratio. The
amount of Glipizide released from microspheres in dissolution media
significantly increased in association with increased HPMC ratio. In
conclusion, a recommendable preparation formulation of

microspheres to increase the bioavailability of Glipizide is
formulation F14 due to their desired drug release and floatable
properties. Formulation F15 containing 0.25 gm acryflow still need
improvement in drug release. So quantity of HPMC was increased to
0.2 gm. Similarity values between drug release profile of formulation
F14 and F16 to that of theoretical profile are 86.509 and 85.335,
respectively.
6.3.5 Kinetics modeling of drug dissolution profiles
The in vitro release data obtained were fitted in to various kinetic equations.
Correlation coefficients of individual batch with applied equation are given in Table
6.12. All batches showed higher correlation with Higuchi plot than zero order and
first order so predominant drug release mechanism is Diffusion controlled release.
Table 6.12 Correlation Coefficients of Drug Release Curves For
Acrycoat S100 Microspheres Batches F14 to F16 Based on Three
Models
Model
r
2
F14 F15 F16
Zero order
0.9368 0.9409 0.939
First order
0.8607 0.9691 0.8681
Higuchi
0.9875 0.9852 0.9768
Release
mechanism
Diffusion
controlled
Diffusion
controlled
Diffusion
controlled
Figure 6.8 Drug Release Profile of Glipizide From
Microspheres of Batches F8 to F13
0
20
40
60
80
100
120
0 2 4 6 8 10 12 14
Time (hr)
%
C
D
R
F8 F9 F10 F11 F12 F13 Theoritical profile
Figure 6.9 Drug Release Profile of Glipizide from
microspheres of Batches F14 to F16
0
20
40
60
80
100
120
0 5 10 15
Time (hr)
%

C
D
R
F14 F15 F16 Theoritical profile
6.4 Conclusions
The microspheres prepared by emulsification solvent diffusion technique, have lower
densities, exhibits buoyancy and retain in the gastric environment for more than 12 h.
Even though the CR systems released the drugs for a longer time, once these passed
through the upper portion of the small intestine, the released drug cannot be utilized
because of a gastric retention time less than 812 h. Therefore, it is not possible to
deliver the drug from the oral route for more than 12 h. The present study
demonstrated that the hollow microspheres developed floated for more than 12 h, so
we can deliver drugs like Glipizide for a longer time (>12 h) in body. Thus, major
advantages of the system include: (i) Ease of preparation, (ii) Good buoyancy, (iii)
High encapsulation efficiency, and (iv) Sustained drug release over several hours.
6.5 References

1. Sato, Y., Kawashima, Y., Takeuchi H.,Yamamoto, H., 2004. In vitro
evaluation of floating and drug releasing behaviors of hollow microspheres
(microballoons) prepared by the emulsion solvent diffusion method. Eur. J.
Pharm. Biopharm. 57,235-243.
2. Bhushan, B., 2006. Novel floating dosage form. US Patent Application,
20060013876, 19 January.
3. Jamzad, S., Fassihi, R., 2006. Role of Surfactant and pH on Dissolution
Properties of Fenofibrate and Glipizide: A Technical Note, AAPS Pharm Sci.
Tech. 7 Article.2.
4. Patel, S., Patel, J., 2005. Studies in Design and development of chitosan
microspheres using different techniques. M. Pharm. Thesis. North Gujarat
University.
5. US pharmacopeia 27, 2004.First Supplement. US Pharmacopeial Convention,
Rockville, MD, pp.867
6. Benet, L.Z., Oie, S., Schwartz, J.B., 1996. Design and optimization of dosage
regimens, pharmacokinetic data, In: Hardman, J.G., Limbird, L.E., Goodman
and Gilmans The Pharmacological Basis of Therapeutics, Ninth ed., McGraw
Hill, New York.
7. Verma, R.K., Garg, S., 2004. Development and evaluation of osmotically
controlled oral drug delivery system of glipizide. Eur. J. Pharm. Biopharm. 57,
513525
8. Guidance for Industry SUPAC-MR. Modified Release Solid Oral Dosage
Forms Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and
Controls. In vitroDissolution Testing and In Vivo Bioequivalence
Documentation.
9. Moore, J., Flanner, H., 1996. Mathematical comparison of dissolution profiles.
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