FORMULATION AND EVALUATION OF GASTRO RETENTIVE IN

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FORMULATION AND EVALUATION OF GASTRO RETENTIVE
IN-SITU GEL OF ZIPRASIDONE HYDROCHLORIDE
Sampangi Sreelekha, Maravajala Vidyavathi *, Morusu Keerthana
Institute of Pharmaceutical Technology, Sri Padmavathi Mahila Visva vidyalayam, Tirupathi517502.
* Address for correspondence
Telephone number: +91 9949576350
E-mail:[email protected]
Abstract: The present study aimed at development of Ziprasidone HCl ( anti-psychotic
agent) into a prolonged release oral dosage form to reduce the frequency of administration
which is very difficult for psychic patients. Ziprasidone has poor bio-availability, low
solubility and absorption at intestinal pH . Hence a gastro retentive in-situ gel of Ziprasidone
was formulated for easy administration of controlled release dosage form through oral route
to overcome the above drawbacks of ziprasidone and to keep the dosage form for long time in
stomach pH . Seven different formulations were prepared by varying the compositions of
sodium alginate and guar gum. All the formulations were evaluated and the best of the
formulations was optimized by calculating desirability function. Among all formulations,
ZF5 (drug 10 mg, sodium alginate 500 mg, guar gum 1g, calcium carbonate 2g ) was found to
possess maximum gel strength, floating ability,% drug content and prolonged drug release up
to 12 hrs. compared to other prepared formulations. The in-vitro release pattern of best
formulation was compared with release pattern of marketed Ziprasidone SR capsule and the
stability studies were conducted for the best formulation. The selected polymers i.e., sodium
alginate and guargum were found to possess good compatibility with the Ziprasidone
hydrochloride without any mutual interaction as per DSC and FTIR spectra. From the release
kinetic studies, it was concluded that ZF5 formulation indicated first order release with
Higuchi as a best fit model. From the stability studies, it was found that there was no
noticeable changes in drug content and % drug release during stability studies. Thus, the
gastro retentive in-situ gel of Ziprasidone is a promising approach for its prolonged, sustained
delivery with good stability by easy administration for the treatment of depression.
Key Words: Ziprasidone, Guargum,Sodium Alginate, Gastro retentive in-situ gel,
INTRODUCTION
Gastro retentive in-situ gelling system helps to increase bioavailability of drug
compared to conventional liquid dosage form. The gel 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 increase gastric residence time
resulting in prolonged drug delivery in gastrointestinal tract. The suitable drugs for gastro
retentive delivery are those which act locally in the stomach, poorly soluble at an alkaline pH,
has narrow window of absorption, absorbed rapidly from the GI tract or degrade in the colon.
Drugs unsuitable for gastro retentive drug delivery systems are those which have very limited
acid solubility e.g. Phenytoin, which suffer instability in the gastric environment e.g.
Erythromycin, drugs intended for selective release in the colon e.g. 5-amino salicylic acid and
corticosteroids. (1)
Floating drug delivery systems is one of the important approaches to achieve gastric
retention to obtain sufficient drug bioavailability (2). These systems have a bulk density lower
than gastric fluids and thus remain buoyant in the stomach without affecting the gastric
emptying rate for a prolonged period of time. While the system is floating in the gastric
contents, the drug is released slowly at a desired rate from the system. After the release of the
drug, the residual system is emptied form the stomach. This results in an increase in the
gastric retention time and a better control of fluctuation in plasma drug concentration. Gastro
retentive in-situ gel is a new dosage form which has been used in stomach specific drug
delivery recently. Oral administration of in-situ gels as low viscous solution and upon
contact with the simulated gastric fluid, the polymer changes conformation and producing a
gel, which prolongs the residence time and contact time between the drug and the site of
absorption in the stomach, along with continuous and slow drug release.(3)
MATERIALS AND METHODS
Ziprasidone hydrochloride, a gift sample from Therdose pharma pvt. Ltd., guar gum and
sodium alginate, obtained from Sd fine chem india, calcium carbonate , methyl paraben , and
propyl paraben were obtained from Glaxo -smith-kline pharmaceuticals ltd..
Method of preparation of gastro retentive in-situ gelling system: Drug and polymers were
made free of lumps to form free flowing powder and distilled water was boiled for sufficient
period in order to protect solutions from microbial contamination and degradation.
Both polymer solutions were prepared separately over mechanical stirrer and mixed to form
final solution. Accurately weighed quantity of drug, methyl paraben and propyl paraben
were added to the polymer solution and stirred thoroughly for 10-15 min. Pre-weighed
quantity of calcium carbonate dispersion was added with continuous stirring. Then mixing
was continued for 10-15 min. The solution so formed was sonicated for 10 min. in order to
find the most suitable combination of guar gum and sodium alginate. Thus total gel
formulations (ZF1-ZF7) were prepared according to the combination of polymers as shown in
table no.1 (4).
Table no: 1: Composition of various in-situ gel formulations
S.NO
INGREDIENTS
ZF1
ZF2
ZF3
ZF4
ZF5
ZF6
ZF7
(mg)
1
Drug
10
10
10
10
10
10
10
2
Sodium alginate
500
1000
1500
2000
500
1500
2000
3
Guargum
500
500
500
500
1000
1500
2000
4
Calcium carbonate
2000
2000
2000
2000
2000
2000
2000
5
Methylparaben
180
180
180
180
180
180
180
6
Propyl paraben
7
Distilled water
(upto 100ml)
200
Q.S
200
Q.S
200
Q.S
200
Q.S
200
Q.S
200
Q.S
200
Q.S
Characterization of gastro retentive In-situ gels
a) Gel strength: Gel strength was calculated by using the gel strength apparatus. It contains
two tubes; upper tube is attached with pan through thread in which weights are added. Two
surfaces were tightly covered with egg membranes.1 gm of gel was kept between the two
surfaces then the weights are added into pan. The weight at which the two surfaces detached
was noted and the gel strength was calculated by using formula. Gel strength=M.g/a (M:
weight at which the two surfaces detached g: gravitational force a: area of surfaces)
b)Viscosity:Viscosity of the samples was determined using Brookfield Digital
Viscometer
(Model: LV DV-E). Spindle no.LV-4 64 was used in cup and bob model of Brookfield
Digital Viscometer for determination of viscosity of the fixed volume of formulation.
Viscosities were determined at 20 rpm and room temperature. (5)
c)Gelling time: The in-vitro gelling capacity of prepared formulations was measured by
placing 10ml of the formulation in 100ml of 0.1N HCl. As the medium comes in contact with
the formulation, immediately it was converted into stiff gel like structure. The gelling
capacity of formulation was evaluated and graded on the basis of stiffness of formed gel, The
gelling time was noted by observing the time gap between addition of formulation and
formation of gel. (7)
d) Floating ability: The in-vitro floating study was carried out using 0.1N HCl (pH 1.2) at
37± 0.5°C.10 ml of formulation was introduced into the dissolution vessel containing
medium without much disturbance. The time, the gel form of formulation took to emerge on
the surface of medium (floating lag time) and the duration of time the formulation constantly
floated on surface of the dissolution medium (floating ability) were noted based on the
fig.no.1. (6)
Figure no.: 1. Floating ability testing
e) In-vitro drug release study: The in -vitro release of Ziprasidone hydrochloride from insitu gels was carried out with 0.1N HCl as dissolution medium using USP dissolution
apparatus type II (paddle method) at a rotating speed of 50rpm for 12hrs. Samples were
collected at specific time intervals and were analyzed using single beam UV
spectrophotometer at 318 nm.
f) Drug content: 10 ml of in-situ gel was measured and transferred to 100 ml of volumetric
flask. 50-70 ml of 0.1N HCl was added to this and shaken on mechanical shaker for 30 min,
followed by sonication for 15 min to ensure complete dispersion of contents and filtered
using 0.45 μ membrane filter. 10 ml of sample was withdrawn from this solution and diluted
to 100 ml with 0.1NHCl. Then % of Ziprasidone HCl was determined spectrophotmeterically
at 318 nm using double beam UV-Visible spectrophotometer. (8)
g) Calculation of Overall Desirability (OD) or Desirability Function (DF)
The OD (DF) was calculated for optimization of the formulations, by combining all
above characters in order to get desired characteristics. Optimized gastro retentive in-situ gel
should have low gelling time, high drug content and floating time. The individual desirability
of each formulation was calculated using the following method
The gelling time value was minimized in the optimization procedure, as optimized
gastro retentive in-situ gel formulation should have low gelling time. The desirability
function of this response was calculated using the equation 1:
ID1 = Ymax-Yi /Ymax-Ytarget ……………… (1)
ID1 =1 for Yi Ytarget
Where ID1 is the individual desirability of gelling time
The floating time, drug content and % drug release for12hrs.values were maximized
in the optimization procedure, as optimized gastro retentive in-situ gel formulation should
have high floating time, high drug content and high% drug release for12hrs. The desirability
functions of these responses were calculated using the equation 2:
ID2 , ID3 & ID4 = Yi -Ymin / Ytarget-Ymin…………….. (2)
ID2, ID3& ID4 =1 for Yi Ytarget
Where ID2, ID3, ID4 are the individual desirability of floating time , drug content and
% drug release respectively. The overall desirability values were calculated from the
individual desirability values by using the equation 3:
OD = (ID1 ID2 ID3…IDn) 1/n…………………….. (3)
Where n = number of desirable responses of the experiment. Then the optimized formulation
was selected by comparing OD values of all formulations. The selected optimized
formulation has the highest OD value and was used for further characterizations.
h) Drug-Polymer compatibility studies
Drug polymer compatibility studies were conducted using optimised formulation by DSC
and FTIR analysis.
i). Differential scanning calorimetry(DSC): DSC studies were performed to understand
the behaviour of cross linked polymers with drug on application of thermal energy. DSC
analysis was performed on a DSC (METLER STAR̊ SW 8.10) at a heating rate of 10º C/min
in the temperature range of 0-25ºC.
ii). FT-IR spectroscopy: This study was carried to find the compatibility between
drug(Ziprasidone) and polymers (Guargum & sodium alginate) by taking spectra in the range
of 4000cm-1 to 400 cm-1 using FT-IR spectrophotometer. The possible interaction between
Ziprasidone , guargum & sodium alginate was accessed by comparing FTIR spectra of pure
drug (Ziprasidone), individual polymers (Guargum & sodium alginate) and optimised in-situ
gel formulation.
i) Comparison of gastro retentive in-situ gel with marketed ziprasidone hydrochloride
capsules
f1 and f2 are the two factors representing dissimilarity and similarity factors
respectively to compare the release profile by mathematical approach. The in-vitro % drug
release of optimized best formulation was compared with in-vitro % drug release of marketed
Ziprasidone hydrochloride capsules by calculation of f1 and f2 using the equation (8)

 



f1     t 1 n R t  T  /   t 1 nR t   100
t



 

f2= 50xlog {[1+ (1/n)∑t=1n(Rt-Tt)2]-0.5x100}
n: number of dissolution sample times
R, T
: Mean percent dissolved at each time point for the reference and test
dissolution profiles
The two dissolution profiles are considered similar or closeness between two
dissolution profiles, if the f2 value is between 50-100 or the value of f1 is between1-15.
j) Stability Studies: Optimized in situ gel was subjected to stability testing. Optimized
formulation was filled into amber coloured bottles and sealed with rubber caps and
aluminium crimping. The experimental protocol followed was based on the ICH guidelines of
“Stability testing of existing active substances and related finished products”. (9)
Statistical Analysis: The results are expressed as Mean ± S.D by estimating all the above invitro parameters in triplicate.
RESULTS AND DISCUSSION:
In the present study different floating gastro retentive in-situ gels were prepared and
characterized to find out the effect of polymers of formulations on gel strength, viscosity, invitro floating ability , gelling time, drug content and % drug release. The floating gastro
retentive in-situ gels were formulated to get maximum gel strength, viscosity, floating time ,
drug content and minimum in-vitro gelling time with controlled drug release by altering the
ratios of polymers in the formulation.(11)
The gel strength was lowest for ZF1 i.e.,13.088 N/m2 and the highest for ZF5
i.e.237.77N/m2. as shown in table no.2. The gel strength was found to be increased with
increase in concentration of sodium alginate but decreased with increased concentration of
guargum in gastro retentive in-situ gel. Higher the gel strength of formulations higher the
floating ability. So it indicated that ZF5 floats for long time as it has the highest gel
strength.(12)
The viscosity of different gastro retentive in-situ gels was varied from 2864Cp to 87220Cp
and the floating ability of different gastro retentive in-situ gels was varied from 1hr to 11 hrs
as shown in table no.2. The viscosity, floating ability and gelling time were increased with
increase in concentration of sodium alginate (ZF1 to ZF4) and guargum (ZF5 to ZF7)
respectively. Among all the gastro retentive in-situ gel formulated, ZF5 was found to exhibit
moderate viscosity (4774 Cp), highest gel strength and lowest gelling time(8 seconds).
Table no: 2 Results of different parameters of all formulations
Sl.
Formulation
Gel
Viscosity
Floating
Gelling
Floating lag
Drug
NO
code
strength
(cp)
ability
time(sec)
time(min)
content(%)
(N/m2)
Mean±SD
(hrs)
Mean±SD
Mean±SD
Mean±SD
Mean±S
OD
Mean±SD
D
1
ZF1
13.088±0.
2864±0.4
1±0.85
6±0.4
6±0.92
94.34±0.06
0
5990±0.67
3±0.3
65±0.7
7±0.47
95.99±0.2
0
10230±0.04
5.30 ±0.2
85±0.7
10±0.44
96.08±0.8
0
06
2
ZF2
35.342±0.
03
3
ZF3
180.124±
0.2
4
ZF4
79. ±096
12336±0.08
8±0.2
11±0.4
15±0.91
96.47±0.6
0.515
5
ZF5
237.7±0.1
4774±0.19
8.10±0.06
8±0.41
12±0.88
97.01±0.6
0.56
16319±0.3
8.30±0.67
16±0.36
13±0,67
92.34±0.1
0.49
87220±0.51
11±0.88
10.6±0.23
13±0.76
90.07±0.4
0
4
6
ZF6
122.528±
0.63
7
ZF7
118.675±
0.07
The %drug content of all formulations was varied from 90.07% to 97.01% as per table
no.2. The % drug content was increased with increase in the concentration of sodium alginate
but decreased with the increasing in the concentration of guar gum. The drug content was
found to be the highest for ZF5 formulation.
The in-vitro % drug release studies were
conducted with all the gastro retentive in-situ gels for 12 hrs, the in-vitro % drug release of
different gastro retentive in-situ gel was found to be between 65.25% to 92.05% as shown in
table no.3. Among all the formulations, ZF5 was found to possess highest in-vitro % drug
release with in 12 hrs. The % drug release was increased with increase in concentration of
sodium alginate but decreased with increase in concentration of guar gum. It indicated the
role of polymers on diffusion of drug in gastro retentive in-situ gels. (13)
Table .no.3: In-Vitro dissolution profile of prepared formulations
Percentage drug release
Time
(hrs)
1
2
3
4
5
6
7
8
12
ZF1
ZF2
Mean±
Mean±
S.D
ZF3
ZF4
ZF5
ZF6
ZF7
Mean±
Mean±
Mean±
Mean± Mean±
S.D
S.D
S.D
S.D
S.D
S.D
27.75
11
28.5
29.5
28.40
30.75
17.5
±0.03
±0.002
±0.54
±0.03
±0.003
±0.01
±0.03
41.25
20.25
38.25
32.14
35.52
37.8
23.25
±0.02
±0.003
±0.01
±0.02
±0.002
±0.02
±0.02
43.5
27.75
48.75
46.03
49.25
43.5
30.02
±0.002
±0.001
±0.07
±0.02
±0.02
±0.01
±0.05
45.75
32.25
57.25
52.15
59
45.01
37.5
±0.002
±0.003
±0.02
±0.03
±0.03
±0.01
±0.01
49.5
35.25
64.09
63.90
66.75
51
40.5
±0.001
±0.001
±0.02
±0.03
±0.01
±0.01
±0.01
54.75
41.25
71.06
75.14
79.26
59.16
52.5
±0.001
±0.007
±0.02
±0.01
±0.04
±0.01
±0.7
59.25
51.5
79.02
80.01
82.16
62.14
63
±0.01
±0.004
±0.003
±0.04
±0.03
±0.09
±0.02
62.25
60.2
83.68
84.16
87.29
70.13
74.99
±0.001
±0.004
±0.02
±0.09
±0.04
±0.2
±0.9
65.25
78.02
88.01
89.07
92.05
78.07
79
±0.004
±0.003
±0.03
±0.04
±0.04
±0.02
±0.2
Desirability function or overall desirability (OD) was calculated to select the best
formulation as shown in table no.2 The OD was increased with lowest concentrations of
polymer. Formulation ZF1-ZF3 has shown the lowest overall desirability (0) and ZF5 has the
highest overall desirability (0.56). Therefore, ZF5 formulation was considered as the best
formulation and parameters of ZF5 formulation were considered to be optimum values to
prepare gastro retentive in-situ gel. Then the optimized best formulation (ZF5 ) was used for
stability studies and for comparison with marketed tablet.
It was evident from the DSC profiles (figure no 2 &3) that, pure Ziprasidone
exhibited a sharp exothermic peak at 296.7 corresponds to the reported melting temperature
of the drug. The DSC profile of gastro retentive in-situ gel has shown a peak at the
temperature corresponding to Ziprasidone melting point with loss of its sharp appearance. It
may be due to reduced drug crystallinity. Thus DSC profiles confirmed the compatibility
between drug and polymers. FTIR spectrum of pure Ziprasidone demonstrated the
characteristic absorption peaks at 3076 cm-1 for C-H stretching, at 33622 cm-1 for N-H
stretching shown in figure no 4. The absorption peaks with gastro retentive in-situ gel are
almost similar to those obtained with the pure drug as shown in figure no 5.
Figure no: 2 DSC thermogram of pure Ziprasidone
Fig no: 3 DSC thermogram of gastro retentive in-situ gel of Ziprasidone hydrochloride
Figure.no:4 FT-IR spectrum of pure
Ziprasidone
Fig.no: 5 FT-IR spectrum of Ziprasidone hydrochloride in-situ gel
The in vitro % drug release of optimized formulation (ZF5) was compared with
invitro % drug release of marketed tablet as shown in figure no 6.
(14)
Both have shown
sustained release and slightly fast release was observed with prepared formulation (ZF5). The
f2 similarity factor was found to be 64.62, which indicated the similar sustained release with
ZF5 to that of marketed formulation. Further, dissolution profiles are subjected to release
kinetics studies to confirm the mechanism of drug release and the best fit with the highest
correlation coefficient was found by Higuchi and first order equations. It indicated that the
drug release was in first order controlled by diffusion mechanism.
Figure no: 6 Comparison of dissolution profiles of optimized formulation ZF5 with
marketed Ziprasidone Hcl
No significant changes in drug content and % drug release were observed during
stability studies as the values after storage are found almost same as before storage.
(Deviation not more than 3 percent). (10)
Table no: 5 % Drug content of optimized gastro retentive in-situ gel during stability
studies
Sampling
% Drug content
intervals
25⁰ C± 2⁰ C
30⁰ c± 2⁰ C
40⁰ C± 2⁰ C
(Days)
60%±5 RH
65%±5 RH
65%±5 RH
Mean±S.D
Mean±S.D
Mean±S.D
15
97.40±0.01
96.85±0.27
96.92±0.03
30
96.80±0.02
95.92±0.3
97.01±0.04
45
95.99±0.43
97.17±0.002
97.14±0.7
60
97.00±0.7
95.80±0.004
96.48±0.12
75
96.32±0.72
97.06±0.007
95.86±0.87
90
97.00±0.8
97.29±0.003
97.00±0.27
So the present research work confirmed that the formulation of ziprasidone into gastro
retentive in-situ gel using sodium alginate and guar gum as polymers is stable and successful
for sustained release for about 12 hrs to treat Schizophrenia.
CONCLUSION
In order to the point of view of patient acceptability, a liquid dosage form that can
sustain drug release and remains in contact for extended period of time in stomach for
improving the bioavailability is required for Ziprasidone, an atypical antipsychotic. Thus,
Ziprasidone hydrochloride in-situ gel formulations were successfully prepared using sodium
alginate and guar gum with maximum gel strength, floating ability,% drug content, prolonged
drug release and good stability. Hence, it can be concluded that the gastro retentive in-situ
gel of Ziprasidone is a promising approach for easy swallowing and prolonged release in the
treatment of schizophrenia.
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