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IJPRD, 2014; Vol 6(08);October-2014 (086 - 101)
International Standard Serial Number 0974 – 9446
-------------------------------------------------------------------------------------------------------------------------------------------------FORMULATION AND EVALUATION OF CHITOSAN BASED SUPERPOROUS HYDROGEL OF METFORMIN
HYDROCHLORIDE
P. S. Labade*1, S. Z. Chemate1
1
Department of Quality Assurance Techniques, Padmashree Dr. Vithalrao Vikhe Patil Foundation’s, College of
Pharmacy, Vilad Ghat, Ahmednagar- 414111
ABSTRACT
Aim: The main aim of present research was to formulate and
evaluate chitosan based Metformin HCl Superporous Hydrogels
and to provide controlled release dosage form of Metformin HCl
by formulating gastric retention device.
Methods: SPHs were prepared by using chitosan and PVA
(polymers), glyoxal (crosslinker), sodium bicarbonate (foaming
agent), Span 80 (foam stabilizer). GAA and water were used to
prepare chitosan and PVA solutions respectively. Two different
drug loading methods were used viz. direct addition method and
soaking method. Suitable drug loading method was determined
on the basis of drug content and in-vitro dissolution study.
Optimized SPHs were evaluated for physical and mechanical
properties like swelling ratio, geletion kinetics, density, viscosity,
porosity, degradation kinetics, in-vitro test for slipperiness, FT-IR
spectroscopy, DSC.
Results: Soaking method showed % drug release 99.303% with
complete swelling of SPH within 30 min. Results for optimized
batch evaluation were found to be: The swelling ratio 5.4; after
80 min. at pH 1, Gelation time; 30 sec., Density; 0.82 ± 0.025
g/cm3, Viscosity; 201.2 ± 5.1 cP, Porosity; 73.2 ± 4.2, Degradation
study; WRt of 0.0338 after 60 hr, Static friction coefficient; 0.2.
Stability studies were carried out for 3 month as per ICH
guidelines. There was no significant change in % drug release and
other evaluation parameters.
Conclusion: From above studies it can be concluded that the SPH
of Metformin HCl can be successfully formulated and evaluated.
Correspondence Author
P. S. Labade
Padmashree Dr. Vithalrao Vikhe Patil
Foundation’s, College of Pharmacy,
Vilad Ghat, Ahmednagar- 414111
MH, India
Keywords- Superporous hydrogels, Gas blowing technique,
Soaking method, Metformin HCl etc.
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INTRODUCTION
The hydrogels since their discovery by
Wichterle and Lim in 1960 of poly (2-hydroxyethyl
methacrylate), have been of great interest to
biomedical scientists. [1, 2] Superporous hydrogels
were recently developed for their potential
applications in controlled drug delivery, especially
for developing oral gastric retention devices. A
superporous hydrogel is a three-dimensional
network of a hydrophilic polymer that absorbs a
large amount of water in a very short period of
time due to the presence of interconnected
microscopic pores.
Gastric retention of superporous hydrogels
is based on the fast swelling of dried hydrogels to a
size larger than the pyloric sphincter. When applied
as drug carriers, these highly swollen hydrogels
remain in stomach for a long time, releasing almost
all drugs loaded, as their volumes are too big to
transport through the pylorus. Chitosan is a natural
polysaccharide, is a biocompatible, biodegradable,
and nontoxic material. Because of abundant amine
groups within chitosan polymer chain, it dissolves
in acidic solution and forms a gel with dialdehydes
such as glutaraldehyde and glyoxal. Thus, in the
low pH solution, chitosan hydrogels swell due to
the presence of the positive charges in the
network. Poly (vinyl alcohol) is a well known
hydrophilic, biocompatible, and commercially
available polymer. The objective of the study was
to prepare and evaluate chitosan/PVA superporous
hydrogel. In this study, the interpenetrating
polymer network of chitosan/PVA superporous
hydrogel was prepared using a gas blowing
technique. It was prepared using glyoxal as a
crosslinking agent. [3]
Metformin HCl (1, 1-dimethylbiguanide
hydrochloride) is recommended for use as an
adjunct to diet and exercise in adult patients (18
years and older) with NIDDM. It may also be used
for the management of metabolic and reproductive
abnormalities associated with polycystic ovary
syndrome (PCOS). It improves glucose tolerance in
patients with NIDDM, lowering both basal and
postprandial plasma glucose and does not affect
insulin secretion. [4, 5, 6]
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ISSN: 0974 – 9446
EXPERIMENTAL
Materials
Chitosan was procured from Ozone
International, Mumbai, Glyoxal (40 % aqueous
solution), Span 80 and ethanol were procured from
LOBA Chemie Pvt. Ltd., Mumbai. Sodium
bicarbonate and polyvinyl alcohol were procured
from sd Fine-CHEM Ltd., Mumbai. Metformin HCl
was purchased from Balaji drugs Pvt. Ltd.
Preformulation studies
Differential scanning calorimetry
Thermogram of Metformin hydrochloride
was recorded on a TA-60 WS Thermal Analyzer
(Shimadzu).
FT-IR spectroscopy
The Fourier Transform Infrared (FTIR)
spectral measurements were recorded at ambient
temperature using IR spectrophotometer. The
spectrum of pure drug (Metformin hydrochloride)
was analyzed for the purity of the drug.
Compatibility study
It is carried out by using DSC and IRspectroscopy. Mixture of drug and polymer
(Metformin HCl, Chitosan, and PVA) was prepared
in 1:1:1 ratio and analyzed by DSC and IRspectrophotometry.
Determination of analytical wavelength
Accurately weighed 10 mg of Metformin
HCl was dissolved in distilled water and stock
solution of concentration 100 μg/ml was prepared.
From this stock solution, solution of 10μg/ml
concentration was prepared and scanned over the
range of 400-200nm against distilled water as blank
using UV-Visible Spectrophotometer. The λmax for
the pure drug was then determined. Form standard
solution dilutions of concentration 2, 4, 6, 8, 10 and
12μg/ml were prepared and resulting solutions
were analyzed by UV-Visible Spectrophotometer
(JASCO V-630) at 233nm and results were
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International Journal of Pharmaceutical Research & Development
recorded. The calibration graph was plotted as
concentration an x-axis and absorbance on y-axis.
Synthesis of SPH [7, 8]
A 3 % w/w stock solution was prepared by
dissolving chitosan in 0.1 M acetic acid. A 10 % w/w
aqueous PVA solution was also prepared. 10 % v/v
aqueous solution of span 80 was prepared. The
chitosan and PVA solutions were mixed together to
have different compositions. Each chitosan/PVA
mixture was placed in a beaker and its pH value
was adjusted to 5.0 by adding acetic acid. A glyoxal
aqueous solution, 10 % w/w, was added to each
chitosan/PVA mixture. 30 μl Span 80 solution, 10%
v/v was added and immediately 80 mg of sodium
bicarbonate powder was added to the stock
solution, and the mixture was stirred vigorously to
induce the gelation and foaming reactions,
simultaneously.
The foamed hydrogels were left to stand
overnight at room temperature. After keeping SPH
overnight at room temperature 2 ml ethanol was
added to it. Ethanol replaces water present in the
SPH and dehydrates it. Then it is oven dried at 55ºC
temperature till SPH gets completely dried. Two
methods were used to load Metformin
hydrochloride in the synthesized SPH.
Direct addition of drug during synthesis of SPH [8]:
In this method metformin HCl was added in
polymer solution prior to add the sodium
bicarbonate. Rest the procedure is same as
described above.
Soaking method [3]: In this method suitable solvent
is selected to make drug solution (in this case
distilled water). Suitable amount of solvent (water)
required to swell the SPH completely was taken
and metformin HCl (250mg) was dissolved in it.
Accurately weighed 1 gm of SPH was immersed in
the drug solution. It is covered by aluminium foil
and kept at room temperature overnight. When
solution is completely sucked up by SPH they are
again kept in hot air oven till it gets completely
dried.
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Drug loaded, completely dried SPH was
filled in size 000 hard gelatin capsule to provide
proper administration. Formula of the SPH is as
shown in the Table 1.
Characterization of SPH
Determination of drug content [3]
Accurately weighed amount of superporous
hydrogel containing 10mg of drug was taken in 100
ml volumetric flask and treated with about 10 ml
hydrochloric acid solution of pH 1.2 mixed well and
made up to volume. The mixture was filtered and
further diluted to produce 10μg/ml concn. Drug
content
was
determined
using
UV-Vis
spectrophotometer at 233 nm.
In vitro drug release studies [9]
In vitro drug release of Metformin HCl from
the superporous hydrogels was evaluated in order
to determine the most suitable method of drug
loading. This study is carried out in triplicate at
37±0.5ºC using a United States Pharmacopoeia
(USP) Dissolution Test Apparatus Type 1(basket
apparatus) at a rotation speed of 50 rpm in 900 ml
of 0.1M HCl (pH 1.2 buffer) for 8 hr. At time
intervals of 5, 10, 15, 30, 45, 60 min., 2 hr up to 8
hr, 5 ml sample of the dissolution medium were
withdrawn, replaced with an equivalent volume of
fresh dissolution fluid and analyzed for the drug
using a UV-spectrophotometer (Jasco V-630) at 233
nm. The release data obtained were fitted into
various release models. To determine release
mechanism, the parameters n and k of the
Korsmeyer-Peppas equation were computed.
Measurement of gelation kinetics [7]
It was measured by a simple tilting method
after adjustment of pH to 5.0. It was determined by
the duration time until the reactant mixture was no
longer descending in the tilted tube position.
Swelling studies [7]
To study the pH sensitivity of the
superporous hydrogels, HCl solutions with defined
pH of 1.0, 2.0, 3.0, 4.9, 6.2 and 7.4 were used as
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the swelling media. Results were calculated
according to the following equation (i).
the weight of the hydrogel at various exposure
times.
Q = (Ms – Md) / Md ……………………………eqn (i)
Where, Q is the swelling ratio, Ms the mass in the
swollen state and Md the mass in the dried state.
In-Vitro Test of Slipperiness [10]
Simple device was used to test the
slipperiness as shown in Figure 1. Coefficient of
static friction was calculated by using equation (iv).
Density measurement [7]
It is done by the solvent replacement
method by using hexane as a solvent.
μ= sin θ/cos θ =
H/B……………………………………………eqn(iv)
Viscosity measurement [7]
The viscosity of the polymer solution
(chitosan/PVA mixture) was measured using a
Brookfield viscometer (DVE Viscometer) at
temperature 25±0.5ºC.
Porosity measurement [3]
It is done by the solvent replacement
method using ethanol as asolvent. Porosity was
calculated by using following equation (ii).
Porosity = M2M1/ρV…………………………………………..eqn(ii)
Where, M1 and M2 are mass of SPH before and
after immersion in ethanol. ρ is density of absolute
ethanol. V is volume of hydrogel.
Evaluation of degradation kinetics [3]
The degradation kinetics of the hydrogels
was examined by measuring the swelling ratio as a
function of water retention. The hydrogels were
placed in pH 1.2 (0.1 M HCl) medium at 37oC for 12
h, and the samples were periodically weighed at 6
h interval. Water retention capacity (WRt) as a
function of time was assessed as in following
equation (iii):
WRt = (Wp - Wd) / (Ws Wd)……………………………...………………eqn(iii)
Where,Wd is the weight of the dried hydrogel, Ws
the weight of the fully swollen hydrogel, and Wp
where H is the height of the slope and B is the base
length of the slope.
In this study, the slipperiness of a
superporous hydrogel was represented by the
static friction coefficient (μ) between the
superporous hydrogel and a glass surface.
FT-IR spectroscopy
FT-IR spectroscopy was used to investigate
the chemical structure of the synthesized
hydrogels.
Differential scanning calorimetry (DSC)
Differential scanning calorimetry was
performed on the formulation as described
previously.
Stability study
The prepared batch was kept in airtight
container and stored in a stability chamber at 40oC
/ 75%RH for three months. Results of the in vitro
drug release studies obtained at each month were
compared with the data obtained at the time of
preparation. The similarity factor (f2), drug content
and swelling ratio were applied to study the effect
of storage. The similarity factor can be calculated
using following equation (v)
2
50
1 1/ |Rj Tj| .
!"
100# … … … … … … … … … … … . . eqn v
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International Journal of Pharmaceutical Research & Development
Where, n is the number of dissolution time points
and Rj and Tj are the dissolved percent of the
reference product and test product at each time
point j, respectively.
RESULT AND DISCUSSION
Preformulation study
Differential scanning calorimetry
The endothermic peak of Metformin HCl
was seen at 226.76˚C corresponding to its melting
point with onset at 218.31˚C. The endothermic
peak of Metformin HCl: Chitosan: PVA complex was
seen at 228.120C with an onset at 225.08 0C. This
shows the compatibility of drug with polymer. DSC
thermogram of Metformin HCl and drug-polymer
complex is as shown in Figure 2 and 3 respectively.
FT-IR spectroscopy
The IR spectrum of the drug agrees with its
1-dimethylbiguanide
chemical
structure1,
hydrochloride as shown in Figure 4. This spectra is
not altered by presence of polymers in drug
polymer mixture hence assuring the compatibility
of drug with polymers chitosan & PVA as shown in
Figure 5.
Determination of analytical wavelength
The results of UV spectrophotometric
analysis are as shown in Figure 6 and 7. λmax
matches with the reported value in literature.
Synthesis of SPH
In the above procedure, chitosan and PVA
are the polymers used. Glyoxal was used as
crosslinking agent. Sodium bicarbonate was used
as a porogen or foam generator. Span 80 was used
as foam stabilizer. Chitosan is crosslinked by glyoxal
by condensation reaction (Schiff base reaction).
PVA is crosslinked by physical method.
Interpenetrating polymer network is formed when
both chitosan and PVA are crosslinked. Physical
crosslinking occurs due to direct hydrogen bonding,
direct crystallite formation and liquid-liquid phase
separation followed by a gelation mechanism.
ISSN: 0974 – 9446
Evaluation of SPH
Drug content
The drug content analysis showed that the
drug loading is uniform in drug loading method II
i.e. by soaking method. Results are tabulated in
Table 2.
In vitro release studies and kinetics of drug release
In-vitro drug release study is separately
carried out for two drug loading methods. In direct
addition method burst release was observed while
soaking method shows controlled release of drug.
Comparison of drug release by both methods is as
shown in Figure 8. Hence soaking method is
considered as best suitable method for loading of
drug in SPH. Drug release profile and release
kinetics are shown in Table 3 and 4. Parameters for
Korsmeyer-Peppas equation are also calculated.
Best fit model for drug release was found to be
Korsmeyer-Peppas as shown in Figure 9.
Further studies are carried out on the SPH in which
drug is loaded by soaking method.
Measurement of gelation kinetics
The gelation kinetics gives good information
determining the introduction time of blowing agent
(sodium bicarbonate). Foaming and gelation
reactions should take place simultaneously to
obtain well-established porous structures. The
optimal pH for the gelation was around 7–8. At this
pH, the polymerization proceeds rapidly and the
gelling usually started within 0.5-1.0 min. This
clearly indicated that the blowing agent must be
introduced immediately after the adjustment of pH
to 5.0. Results are as shown in Table 5.
Swelling studies
Figure 10 shows the dynamic uptake of
water of formulation in the solutions with pH 1.2,
2.0, 3.0, 4.9, 6.2, and 7.4 HCl. Swelling of the
superporous hydrogels reduced as the pH
increased. In acidic environment, chitosan
superporous hydrogels showed higher swelling
ratio than in basic environment. Swelling ratio is
calculated by using equation (i).
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International Journal of Pharmaceutical Research & Development
Density, Viscosity, Porosity measurement and InVitro Test of Slipperiness
The apparent density of the formulations
increased with an increase in amount of PVA due
to the presence of the cellulosic fibers within the
polymer structure. The density of superporous
hydrogels increased with the increase in amount of
glyoxal. This is due to the incorporation of the
higher crosslink density within the polymer
structure leading to the decrease in the occupied
volume. At high viscosity, the evolution of CO2 gas
bubbles are not as easily detectable as that at a low
viscosity, leading to smaller pore sizes and slower
swelling.The porosity of superporous hydrogels
increases by the increase in amount of glyoxal.
Porosity was calculated by using equation (ii).
The slipperiness of a superporous hydrogel was
represented by the static friction coefficient (μ)
between the superporous hydrogel and a glass
surface. The lower static friction coefficient
indicates the more slippery superporous hydrogel.
Density, Viscosity, Porosity measurement and
coefficient of static friction was found to be 0.82 ±
0.025 g/cm3, 201.2 ± 5.1 cP, 73.2 ± 4.2, 0.2
respectively.
Evaluation of degradation kinetics
WRt was calculated by using equation (iii) .Figure
11 shows the degradation kinetics of SPH Lower
the concentration of crosslinking agent in the
hydrogel the faster and greater the water loss
(p < 0.05).
Wd = wt. of dried SPH = 0.5gm
Ws = wt. of SPH at swollen state = 3.9 gm
Wp = wt. of SPH at various exposure time
FT-IR spectroscopy
ISSN: 0974 – 9446
The peaks present in IR spectra of SPH
formulation as shown in Figure 12 are clearly seen
in the IR spectra of Metformin HCl: Chitosan: PVA
mixture, with minor shifts. It indicates that there
was no interaction between the drug, Chitosan and
PVA in the SPH.
Differential scanning calorimetry (DSC)
The
thermal
behaviors
of
these
superporous hydrogels were investigated using
DSC because the increase in the mechanical
strength was presumably due to increased
crosslinking density. From Figure 13 it is clear that
there is a shift in the glass transition temperature
to a higher temperature with increase in the
amount of glyoxal. Hence a higher amount of heat
energy is required to break the crosslinked chains
when compared to a loose network.
Stability study
The optimized formulation, stored at
40±2ºC/75±5% RH was found to be stable for 3
months. Drug release profiles of optimized
formulation before and at the end of study were
similar. Similar factor (f2) was found to be under
50-100 thus indicating the stability of formulation.
Stability study indicated that after storage drug
release, drug content, density, coefficient of static
friction, swelling ratio, degradation kinetics were
found to nearly similar to at the time of
preparation. Results are tabulated in Table 6-8.
CONCLUSION
Suitable chitosan based superporous
hydrogels of Metformin HCl, which swelled and deswelled reversibly depending on the pH of media,
were successfully formulated. Swelling of the
hydrogels was affected by ionic strength. This study
also demonstrates that superporous hydrogels of
chitosan may be suitable for use as a
gastroretentive drug delivery system.
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TABLES AND FIGURES
Table 1: Formula for Metformin HCl SPH
Ingredients
Quantity
Chitosan
8 ml
PVA
4 ml
Glyoxal
4ml
Span 80
0.03 ml
Sodium bicarbonate
80 mg
Metformin HCl
250 mg
Table 2: Drug content
Method of drug loading
Drug content (%)
Direct addition method
95.13
Soaking method
98.98
Sr.
No.
Time
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
0
5
10
15
30
45
60
120
180
240
300
360
420
480
Direct addition method drug release profile
Table 3: Drug release kinetics for direct addition method
% DR
Zero
First
Matrix
Peppas
order
26396
13816
10742
100
0.00
0.000
0.000
0.000
52.998± 0.012 2242.037 2008.413 1301.362 21.215
61.744±0.032 3354.507 2809.264 1830.649 4.832
63.661±0.013 3468.457 2677.567 1691.349 1.746
69.159±0.0211 3380.281 2036.222 1257.121 1.505
73.580±0.0413 3729.801 1877.080 1266.322 4.505
80.018±0.0312 4175.003 1861.389 1400.229 49.656
81.668±0.0521 2455.351 448.001 435.309
2.226
83.799±0.0327 1248.796 81.724
88.110
0.306
86.798±0.0431 440.275
5.474
0.002
2.499
89.436±0.0749 43.216
0.942
66.091
3.996
92.527±0.0124 50.199
1.963
209.425
1.526
94.772±0.651 531.828
8.018
500.765
6.167
97.599±0.741 1276.171
0.018
695.579
0.036
Hix.
Crow.
17885
0.000
2129.382
3086.197
3070.746
2660.703
2685.796
2814.988
1044.954
311.367
53.804
0.631
3.466
19.269
3.411
Parameters for
Korsmeyer-Peppas Equation
n=
0.1331
k=
43.0632
Soaking method drug release profile
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Sr.No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Time
0
5
10
15
30
45
60
120
180
240
300
360
420
480
Table 4: Drug release kinetics for soaking method
Avg. %R
Zero
1st
Matrix Peppas
Order
10355
1356
1927
1217
0.000
0.000
0.000
0.000
7.96±0.0512
55.917
13.937
8.160
56.676
27.61±0.0512 624.857 315.665 124.765 32.251
33.469±0.0123 844.512 345.609 165.531 47.744
38.899±0.0377 669.054 49.421 28.374
1.714
47.793±0.0563 1664.781 237.101 319.239 120.359
60.754±0.0212 1890.094 170.087 366.906 148.241
73.443±0.431 1900.229 19.477 347.842 144.429
79.66±0.0561 1067.329 13.433 121.164 26.157
82.281±0.0115 337.183 79.889
3.988
9.153
87.782±0.0716 54.488
57.403
5.747
42.178
91.65±0.0175
17.235
24.997 41.312 91.711
93.6±0.0763
381.364 28.329 185.157 249.654
99.303±0.0118 848.315
0.408 209.024 246.327
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Hix.Crow.
4173
0.000
37.894
501.806
636.938
347.566
935.731
940.865
585.208
147.023
1.905
4.327
8.308
25.669
0.059
Parameters for
Korsmeyer-Peppas Equation
n=
0.4286
k=
8.2023
Table 5: Gelation time for SPH in triplicates
Observation
Time in sec
Obs. 1
35
Obs. 2
25
Obs. 3
30
Mean
30
Table 6: Stability with respect to similarity factor, drug content, slipperiness, density
Month
1
2
3
Drug release (%)
(f2)
Drug
Density
content
98.10
74.99
98.57
0.81 ± 0.013 g/cm3
97.78
74.99
97.86
0.81± 0.025 g/cm3
96.61
75
97.10
0.799± 0.025 g/cm3
Where, (f2) = similarity factor; μ= static friction coefficient
Μ
0.23
0.27
0.30
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Table 7: Stability study with respect to swelling ratio
pH
Month 1
Month 2
Month 3
1
5.33
5.29
5.07
2
4.58
4.33
4.12
3
3.99
3.54
3.38
4.9
3.74
3.12
2.87
6.2
3.01
2.98
2.35
7.4
2.99
2.45
2.11
Table 8: Stability study with respect to degradation kinetics (WRt)
Time
Water retention capacity (WRt)
Month 1
Month 2
Month 3
6
0.9697
0.9602
0.9589
12
0.7543
0.7342
0.7311
18
0.6154
0.5978
0.5734
24
0.4009
0.3945
0.3798
30
0.2340
0.2334
0.2269
36
0.1201
0.1198
0.1107
42
0.9907
0.9824
0.9765
48
0.0832
0.0810
0.0799
54
0.0597
0.0546
0.0512
60
0.033
0.0325
0.028
Figure 1: Schematic description of the device used to measure the surface slipperiness of superporous
hydrogels.
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Figure 2: DSC Thermogram of Metformin HCl
Figure 3: DSC Thermogram of Metformin HCl: Chitosan: PVA mixture (1:1:1)
Figure 4: IR spectra of Metformin HCl
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Figure 5: IR spectra of Metformin HCl: Chitosan: PVA (1:1:1)
Figure 6: UV spectrum of Metformin HCl
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1.2
y = 0.081x + 0.005
R² = 0.999
1
0.8
Abs. 0.6
Series1
Linear (Series1)
0.4
0.2
0
0
5
10
15
concn. in µg/ml
Figure 7: Calibration curve of Metformin HCl
120.000
Drug Release
100.000
80.000
60.000
Series1
Series2
40.000
20.000
0.000
0
100
200
300
400
500
600
Time in min
Figure 8: In-vitro drug release study
Where,
series 1 is drug release for direct addition and series 2 is drug release for soaking
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Release Profile
140
% Drug Released
120
100
80
Actual
60
Zero
1st
40
Matrix
Peppas
20
Hix.Crow.
0
0
100
200
300
400
500
600
Time
Figure 9: Model fitting graph for soaking method
6
5
4
pH 1
Swelling 3
Ratio
pH 2
pH 3
pH 4.9
2
pH 6.2
pH 7.4
1
0
0
20
40
60
80
100
Time
Figure 10: Swelling ratio at different pH medium
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1.2
1
0.8
WRt 0.6
WRt
0.4
0.2
0
0
10
20
30
40
50
60
70
Time in Hour
Figure 11: Water retention capacity of SPH
Figure 12: FT-IR spectra of Metformin HCl SPH
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Figure 13: DSC thermogram of Metformin HCl SPH
ACKNOWLEDEMENT
The authors are thankful to P.D.V.V.P.F’s College Of
Pharmacy, Vilad Ghat, Ahmednagar, MS, India for
providing facilities to carry out this work.
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