Post on 19-Aug-2021
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International Journal of Universal Pharmacy and Bio Sciences 10(2): March-April 2021
INTERNATIONAL JOURNAL OF UNIVERSAL
PHARMACY AND BIO SCIENCES IMPACT FACTOR 4.018***
ICV 6.16*** Pharmaceutical Sciences Research Article……!!!
DESIGN AND CHARACTERIZATION OF FLOATING IN SITU GEL
CONTANING ANTIHYPERTENSIVE DRUG
Srilatha K. S*1, Dr.Shyam Nandan Yadav
2 C.Geethapriya
3 Vinitha.R
1
1*Department of Pharmaceutics, R R College of Pharmacy, Bangalore, India.
2Department of Pharmacy Practice, R R College of Pharmacy, Bangalore, India.
3Department of Pharmaceutical chemistry, R R College of Pharmacy, Bangalore, India.
KEYWORDS:
Diltiazem HCL, Anti-
hypertensive agent, In
situ gelling systems.
For Correspondence:
Srilatha K. S*
ADDRESS:
Department of
Pharmaceutics, R R
College of Pharmacy,
Bangalore, India.
ABSTRACT
The purpose of present research work was to prepare and evaluate oral
floatable in situ gel of Diltiazem HCL, it is a calcium channel blocker,
which interfere with the movement of calcium into heart muscle cell
and smooth cells of arteries, this action relaxes blood vessels (causing
them to widen) which lowers the blood pressure, increase the blood
Supply to the heart and decreases the hearts overall work load.
Formulation was prepared by sodium alginate and gelrite. The
prepared formulations were in liquid state and becomes gel when it
enters in to the acidic environment (pH 1.2). Formulation was
evaluated for physicochemical parameters like pH, gelling capacity,
gel strength, viscosity, in vitro floating ability, drug content
uniformity, and in vitro drug release study. The best formulation was
selected and stability studies were performed as per ICH guidelines.
Thus, study concludes that the floating in situ gelling system of
Diltiazem HCL could be used for controlled drug delivery system.
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INTRODUCTION:
In-situ gel forming systems have been widely investigated as vehicles for sustained drug delivery. This
interest has been sparked by the advantages shown by in-situ forming polymeric delivery systems such
as ease of administration and reduced frequency of administration, improved patient compliance and
comfort. In-situ gel formation occurs due to one or combination of different stimuli like pH change,
temperature modulation and solvent exchange. So, In-situ gelling system via different route such as
oral, nasal and ophthalmic etc, can be formulated. Various natural and synthetic polymers such as
Gellan gum, alginic acid, xyloglucan, pectin, chitosan, poly (DL lactic acid), poly (DL-lactide-co-
glycolide) and poly- caprolactone are used for formulation development of in-situ forming drug
delivery systems. Gastro retentive in situ gelling system helps to increase bioavailability of drug
compared to conventional liquid dosage form. The gels formed from in-situ gelling system, being
lighter than gastric fluids, floats over the stomach contents or adhere to gastric mucosa due to presence
of bio adhesive nature of polymer and produce gastric retention of dosage form and increase gastric
residence time resulting in prolonged drug delivery in gastrointestinal tract.
FIGURE 1: PHYSIOLOGY OF STOMACH
Materials and methodology
Diltiazem HCl was obtained from Sun pharmaceuticals, Sodium alginate, Calcium carbonate Gelrite
and rest of the chemicals were obtained from laboratory grade.
1)Determination of absorption maximum (λmax) of Diltiazem HCL using Spectrophotometer.
Absorption maxima may be defined as the wave length at which the substance produces the maximum
absorption. Absorbance maximum for a drug was determined in 0.1N HCL buffer. A solution of
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Diltiazem HCL containing 10 mcg/ml was prepared in 0.1 N HCL and scanned in the range 200nm-
400nm against 0.1N HCL respectively as blank using UV spectrophotometer.
2) CONSTRUCTION OF STANDARD CALIBRATION CURVE FOR DILTIAZEM HCL
a) Preparation of 0.1 N HCL 8.5 ml of concentrated hydrochloric acid was diluted to 1000 ml with
distilled water.
b) Preparation of standard solution of Diltiazem HCL using 0.1N HCL (pH1.2) solution.
Stock I:
Accurately weighed 100 mg of Diltiazem HCL was transferred to a 100 ml volumetric flask. The
volume was made up to the mark by using 0.1 N HCL at room temperature (1000mcg/ml).
Stock II:
From the above stock solution1 10 ml was diluted to 100ml using 0.1 N HCL in volumetric flask
(100mcg/ml). From the above stock solution II, serial dilutions were made to obtain 10, 20, 30, 40 and
50 mcg/ml solution using 0.1 N HCL as diluents. Then the absorbance of these solutions was read at
237 nm using UV- visible spectrometer against using against 0.1 N HCL as blank and standard graph
was plotted using these values.
3) Preparation of In-situ gel of Diltiazem HCL (DHCL)
Active material (DHCL) was passed through sieve no. 60 while other inactive ingredients were passed
through sieve no. 40, and then aqueous solution of Gelrite was prepared in deionised water , solution
were heated up to 600C,after cooling to below 40
0C DHCL was added slowly to the above solution
while stirring on a magnetic stirrer so that there was proper and homogeneous dispersion of the drug. In
other beaker sodium alginate solution were prepared by heating up to 600C,after cooling to below 40
0C,
both solutions were mixed while stirring on magnetic stirrer. Then appropriate amount calcium
carbonate was added while stirring. Finally, the mixture was mixed well to get the final preparation.
Table no 1: Composition of floating in situ gel of Diltiazem HCL
F 1 F 2 F 3 F 4 F 5 F 6 F 7 F 8 F 9
Diltiazem HCL (mg) 300
300
300
300
300
300
300
300
300
Sodium Alginate
(mg)
750
750
750
1000
1000
1000
1500
1500
1500
Gelrite 400 400 400 400 400 400 400 400 400
Calcium carbonate
(mg) 500 750 1000 500 750 1000 500 750 1000
Sodium citrate (mg) 500 500 500 500 500 500 500 500 500
De-ionized water Qs
(ml) 100 100 100 100 100 100 100 100 100
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EVALUATION OF FORMULATION
1) pH measurement
pH of the each prepared gelrite and sodium alginate based in-situ gel solution of Diltiazem HCL were
checked used a calibrated pH meter at 25 0
C.
2) Determination of drug content
Prepared 10 ml of in-situ gel were measured and transferred to 100ml of volumetric flask. To this 70 ml
0.1 N HCL was added and sonicated for 30 minutes. Volume was adjusted to 100ml. Complete
dispersion of contents were ensured visually and filtered using Whatman filter paper. From this solution
10 ml of a sample was withdrawn and diluted to 100 ml with 0.1N HCL. Contents of Diltiazem HCL
were determined spectrophotometrically at 237 nm using UV- spectrophotometer.
3) Viscosity
Viscosity of prepared in-situ gel was determined by using Brookfield viscometer DV-III using spindle
number 21 with cup and bob setting and velocity increased to 10 to 100 rpm. Temperature of each
aliquot of the sample was kept at 27 ± 10 °C during each measurement.
4) Floating behaviour.
Floating study of prepared in situ gel was carried out using 0.1 N HCL (pH 1.2). The temperature of
medium was kept at 37°C .10 ml of prepared in situ gel was introduced into the dissolution vessel
containing medium without much disturbance. The time taken for the formulation to emerge on the
medium surface (floating time) and the time the formulation constantly floated on surface of the
dissolution medium (duration of floating) were noted.
5) In-vitro gelling capacity.
The formulations for their in-vitro gelling capacity by visual method, solution of in situ gel forming
drug delivery system were prepared. The in-vitro gelling capacity of prepared formulations was
measured by placing 5ml of the gelation solution (0.1N HCL, pH 1.2) in a test tube and maintained
temperature at 37± 10 °C temperature. The formulations were transferred in such a way that if the
pipette is placed at surface of fluid in the test tube and the formulation in the pipette. As the solution
comes in to the contact with gelation solution, it was immediately converted stiff gel like structure. The
gelling capacity of solution was evaluated on the basis of stiffness of formed gel and time period for
which the formed gel remains as such. The in-vitro gelling capacity was graded in three categories on
the basis of gelation time and time period for which the formed gel remains.
(+) Gels after few minutes, dispersed rapidly.
(++) Gelation immediate remains for 12 hours.
(+++) Gelation immediate remains for more than 12 hours.
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6) Measurement of water uptake by gel
The water uptakes by gel of the selected formulation of gelrite and sodium alginate were determined by
a simple method. In this study the in-situ gel formed in 40ml of 0.1 N HCL (pH 1.2) was used. From
each formulation the gel portion from the 0.1 N HCL was separated and the excess Hcl solution was
blotted out with a tissue paper. The initial weight of the gel taken was weighed and to this gel 10 ml of
distilled water was added and after every 30 minutes of the interval water was decanted and the weight
of the gel was recorded and the difference in weight was calculated and reported.
7) In-vitro drug release study
The study of Diltiazem release from the in-situ gelling preparation was carried out by using dissolution
test apparatus USP type II (paddle method) at a rate of 50 rpm. This speed was slow enough to avoid
the breaking of gelled formulation and the mild agitation conditions believed to exist in vivo. The
dissolution medium used was 900 ml of 0.1 N HCL (pH 1.2) and temperature was maintained at 37°C.
10 ml sample was withdrawn from dissolution apparatus at every 1-hour intervals for analysis and
replaced the same amount of the pre-warmed (37°C) fresh medium. Contents of Diltiazem HCL were
determined spectrophotometrically at 237 nm using a spectrophotometer.
8) Drug release kinetic studies
The release kinetics studies were done by various mathematical models (zero order, first order,
Higuchi’s square root, and Pappas equation). The model that best fits the release data is selected based
on the correlation co-efficient (r) value in various models. The model that gives high “r” value is
considered as the best fit of the release data. The release constant was calculated from the slope of the
appropriate plots, and the regression coefficient (r2) was determined.
9)Stability studies
The purpose of stability study is to provide evidence that the quality of a drug substance or drug
product will not vary with time under the influence of a variety of environmental factors such as
temperature, humidity and light during the storage period before consumption of the product. Stability
studies were performed for the formulation which was selected as best as per ICH guidelines. The
formulation was sealed in an aluminium foil and stored at specified condition 25±2ºC and 60± 5% RH
for 3 months. Samples were periodically taken and evaluated for physicochemical parameter, drug
content and in vitro release using the same procedure mentioned previously.
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Table-2: Standard plot of Diltiazem HCL in 0.1 N HCL at 237 nm.
Concentration (mcg/ml) Absorbance(nm)
0 0
10 0.116
20 0.266
30 0.338
40 0.450
50 0.566
60 0.678
FIGURE2 Standard plot of Diltiazem HCL
FIGURE 3: FTIR of Diltiazem HCL
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FIGURE4: FTIR of Diltiazem HCL with excipient.
FIGURE 5: Floating In situ of Diltiazem HCL
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Table-3Drug content estimation in situ gelling formulations batch F 1 to F 9
Formulations Drug content (%)
F 1 96.91 ± 0.47
F 2 98.95 ± 0.57
F 3 96.91 ± 0.46
F 4 97.41 ± 0.87
F 5 98.92 ± 0.27
F 6 97.92 ± 0.43
F 7 97.41 ± 0.23
F 8 99.22 ± 0.47
F 9 99.23 ± 0.48
Table-4: Evaluation of pH, floating lag time and floating duration
Formulations pH Floating lag time
(s)
Floating duration
(h)
F 1 6. 78 ± 0.032 18 ± 3.2 9
F 2 6. 98 ± 0.012 17 ± 1.2 9
F 3 6. 56 ± 0.031 19 ± 3.4 9
F 4 6. 79 ± 0.121 14 ± 5.2 12
F 5 6. 98 ± 0.456 13 ± 3.6 12
F 6 6. 77 ± 0.761 12 ± 4.2 12
F 7 6. 68 ± 0.789 11 ± 6.2 >12
F 8 6. 32 ± 0.068 10 ± 3.1 >12
F 9 6. 12 ± 0.124 8 ± 3.3 >12
Table-5: Evaluation of In vitro gelling capacity, viscosity and density
Formulations In vitro gelling
capacity Viscosity (Cps) Density(gm/cm2)
F 1 + 145 ± 0.23 0.837 ± 0.5
F 2 + 155 ± 0.20 0.643 ± 0.61
F 3 ++ 160 ± 0.44 0.737 ± 0.72
F 4 ++ 172 ± 0.54 0.698 ± 0.53
F 5 +++ 179 ± 0.66 0.737 ± 0.32
F 6 +++ 185 ± 0.45 0.641 ± 0.53
F 7 +++ 189 ± 0.67 0.842 ± 0.61
F 8 +++ 191 ± 0.87 0.8673± 0.43
F 9 +++ 195 ± 0.17 0.8916± 0.43
*Average of three trials (Average + S.D)
(+) Gels after five min, dispersed within 8 hr, (++) Gels within 60 sec and retains gel structure for 12
hr, (+++) Gels immediately and retains gel structure for more than 12hrs
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Table-6: Evaluation of gel strength.
Formulations Gel strength (gm/cm2 )
F 1 20.17 ± 0.20
F 2 19.27 ± 0.42
F 3 32.62 ± 0.30
F 4 53.96 ± 0.31
F 5 33.54 ± 0.29
F 6 55.17 ± 0.58
F 7 61.37 ± 0.32
F 8 63.57 ± 0.24
F 9 68.17 ± 0.63
Table-7: In-vitro drug release studies from F 1 to F 9
Ti
me
(hr)
F 1 F 2 F 3 F 4 F 5 F 6 F 7 F 8 F 9
1 57.05±1
.96
47.66±1
.02
53.65±0
.02
49.69±0
.34
46.27±0
.27
49.47±0
.36
50.87±0
.16
48.81±2
.16
46.82±2
.15
2 63.34±1
.24
61.09±1
.33
62.09±1
.15
60.65±1
.95
54.98±1
.96
53.31±1
.52
52.71±1
.36
51.11±1
.22
50.13±1
.29
3 70.05±1
.32
70.13±1
.99
72.24±0
.99
66.24±0
.32
58.24±0
.04
56.49±0
.35
56.19±0
.68
53.15±0
.39
53.28±0
.38
4 73.05±1
.22
73.23±1
.24
78.63±1
.56
70.64±1
.47
63.67±0
.47
60.87±0
.85
60.07±0
.74
56.07±0
.78
57.22±0
.74
5 78.06±1
.06
79.57±1
.77
80.66±1
.23
78.98±1
.62
68.34±1
.10
62.35±2
.10
63.20±1
.10
58.27±3
.10
59.88±3
.18
6 85.12±1
.96
83.16±1
.96
83.98±1
.76
83.98±1
.76
72.55±1
.23
68.56±7
.23
67.57±0
.23
61.37±0
.20
63.32±0
.27
7 94.44±1
.46
92.24±1
.56
94.23±1
.02
88.54±1
.68
81.66±1
.24
72.69±1
.94
79.68±1
.96
64.12±1
.97
65.18±1
.94
8 98.27±1
.16
98.20±1
.40
98.57±1
.43
92.02±1
.05
84.66±1
.80
87.68±1
.75
82.61±1
.02
68.62±1
.02
67.11±1
.05
9 94.65±1
.28
88.57±1
.31
98.87±0
.31
95.82±0
.34
71.87±0
.63
71.96±0
.69
10 95.22±1
.65
74.25±0
.76
74.25±0
.75
11 85.56±0
.48
81.86±0
.49
*Average of three trials (Average ± S.D.)
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Table-8: Drug release kinetic studies from F 1 to F 9
Formulations Zero order
R2
First order
R2
Higuchi R2
F 1 0.9778 0.9502 0.9738
F 2 0.9818 0.9528 0.9672
F 3 0.9814 0.9703 0.9736
F 4 0.9254 0.8153 0.9918
F 5 0.9349 0.9044 0.9941
F 6 0.9489 0.9151 0.9877
F 7 0.9536 0.9092 0.9863
F 8 0.9613 0.9638 0.9873
F 9 0.9636 0.9832 0.9885
Table-9: Drug release kinetic studies from F 1 to F 9 Formulations Korsmeyer -Peppas R
2 Korsmeyer -Peppas n
F 1 0.9872 0.6825
F 2 0.9848 0.6787
F 3 0.9877 0.6778
F 4 0.9483 0.6876
F 5 0.9563 0.6883
F 6 0.9606 0.6827
F 7 0.9612 0.6855
F 8 0.9730 0.6900
F 9 0.9793 0.6840
Table-10: Accelerated stability study at 40± 2 °Cand 75± 5%RH of the Formulation F8
Physicochemical
parameters
Initial 30 th
day 60 th
day 90 th
day
PH
6.32±0.068 6.31±0.060 6.32±0.088 6.32±0.096
Viscosity 191±0.87 192±0.86 195±0.88 193±0.99
Drug content 99.22±0.49 99.01±0.56 99.36±0.88 98.22±0.33
Table-11: Accelerated stability study at 40± 2 °Cand 75± 5%RH of the Formulation F9
Physicochemical
parameters
Initial 30 th
day 60 th
day 90 th
day
PH
6.12±1.24 6.12±0.88 6.12±0.994 6.33±0.942
Viscosity 195±0.17 195±0.76 195±0.98 195±0.84
Drug content 99.23±0.48 99.23±0.56 98.39±0.88 99.98±0.67
Table-12: In vitro drug release of formulation F8 after stability.
Time in hrs Initial 30 th
day 60 th
day 90 th
day
1 48.81±2.16 47.81±2.07 47.33±1.07 48.38±1.22
2 51.11±1.22 52.11±1.33 52.45±1.34 52.85±1.86
3 53.15±0.39 53.15±0.44 53.15±0.44 53.15±0.56
4 56.07±0.78 55.07±0.77 55.88±0.12 56.89±0.22
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5 58.27±3.10 57.88±3.56 58.88±1.56 58.94±2.50
6 61.37±0.20 62.34±0.24 61.34±0.55 61.88±0.65
7 64.12±1.97 65.12±1.96 65.65±2.96 65.89±1.96
8 68.62±1.02 66.63±1.54 67.63±2.56 67.64±1.56
9 71.87±0.63 72.80±0.44 71.80±0.42 71.82±0.43
10 74.25±0.76 73.44±0.78 74.44±0.84 73.12±0.08
11 85.56±0.48 86.57±0.55 86.86±0.56 86.42±0.01
Table-13: In vitro drug release of formulation F9 after stability.
Time in hrs Initial 30 th
day 60 th
day 90 th
day
1 46.82±2.15 46.56±0.15 45.45±0.16 45.23±0.22
2 50.13±1.29 51.13±1.22 51.22±1.36 51.96±1.44
3 53.28±0.38 53.99±0.24 53.26±0.29 53.05±3.29
4 57.22±0.74 57.27±0.88 57.39±0.63 57.36±0.45
5 59.88±3.18 58.56±0.18 58.06±0.22 58.96±0.93
6 63.32±0.27 63.22±0.66 63.06±0.35 63.96±0.65
7 65.18±1.94 65.63±0.95 65.12±0.63 65.22±0.54
8 67.11±1.05 67.23±1.23 67.03±0.23 67.96±0.69
9 71.96±0.69 71.69±0.32 70.62±0.02 70.85±0.45
10 74.25±0.75 73.26±0.76 74.27±0.88 74.65±0.78
11 81.86±0.49 82.86±0.55 82.56±0.32 82.99±0.68
CONCLUSION:
In the present study, an attempt was made to formulate and evaluate oral floating in-situ gel of
Diltiazem HCL which is an antihypertensive drug. Diltiazem HCL is well absorbed from stomach and
first part of the small intestine, Pre-formulation studies and estimation of drug by UV visible
spectrophotometer was carried out. The possible interaction between drug and polymer were studied by
performing FTIR study no interactions were observed p H
measurement, determination of drug content,
viscosity, floating behaviour, In vitro gelling capacity, measurement of water up taken by the gel, In
vitro drug release kinetic studies and stability studies were performed. Results were in the limit, The
optimum formulation F8 and F9 were selected based on good gelling capacity, viscosity and drug
content. Cumulative drug release was 71.87±0.63 and 71.96± 0.69 after 8hrs, which may give the
complete release in 12hrs.So F8 and F9 were selected as best formulations. All the formulations
followed non Fickian transport as the R 2 values were in the range of 0.9483-0.9848 and n=0.6778-0.
6900.Stubility study showed that there were no significant changes were found for the parameters
considered after 3 months. Thus floating in situ gelling system of Diltiazem HCL can be formulated
as sustained drug delivery of drug and recommended for further studies.
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