Design and Development
of Bilayer Floating Tablets of Diltiazem
Hydrochloride
Aruna R.* and Venkateswara Rao T.
Bapatla College of Pharmacy, Bapatla Educational Society, Bapatla,
Guntur District, Andhra Pradesh-522101
ABSTRACT:
Diltiazem hydrochloride is a calcium
channel blocker which undergoes extensive hepatic first pass metabolism by liver;
its absorption from upper part of GIT is very low and has poor oral
bioavailability of 40% - 60%. In the present investigation Diltiazem Hydrochloride was formulated as a bi-layer
floating tablets in order to achieve the Gastric residence time and to minimize
the flactuations in blood level i.e
the drug was released from the SR layer. Bilayer
floating tablets were prepared by wet granulation method. Immediate release
layer was formulated by using various suerdisintegrantents
such as sodium starch glycolate, croscarmellose
sodium and crospovidone and sustained release layer was formulated by different
grades hydrophilic polymers i.e. HPMCK4M, HPMCE5 and HPMCK100M.The drug- excipient compatibility studies were conducted by IR
spectroscopy. The tablets were evaluated for weight variation hardness,
friability, drug content, swelling index, in-vitro
buoyancy studies and in-vitro
dissolution studies. The drug was
released from an immediate release layer was 20mins followed by sustained release layer for 12hrs.The
dissolution data were fitted into zero order, first order, Higuchi and Peppas mechanism. The drug release from the formulation F20
followed first order kinetics and exhibited Peppas transport
mechanism.
KEYWORDS: Diltiazem
Hydrochloride, SSG, Croscarmellose sodium, Crosovidone, HPMCK4M, HMCE5, HPMCK100M.
INTRODUCTION:1-3
One of the novel
approaches in the area of sustained drug delivery was Gastro rententive drug delivery systems (GRDDS).Several techniques
have been proposed to increases the Gastri residence
time of dosage forms such as floating systems, swelling systems, hydrodynamically balanced systems and low density systems
etc.
In the present investigation Diltiazem Hydrochloride
was selected as model drug is a calcium channel blocker and it is widely used
in the treatment of hypertension. The drug has short biological half life 3-4
hrs, low bioavailability and narrow absorption window in upper part of GIT.
Multi layer concept has been utilized in this present investigation. The compatibility
studies were conducted by FTIR spectroscopy, no compatibility between drug and
polymers were found. Bilayer floating tablets having
immediate release layer and sustained release layer, the drug was released
within 20 mins from the IR layer leads to a sudden
raise in blood concentration, blood level was maintained at steady state as the
drug was released from the sustained release layer.
Materials:
Diltiazem Hydrochloride, gift sample from Medreich Ltd Bangalore, SSG, Croscarmellose
sodium, Crospovidone, grades of HPMC (K4M, K100M, E5) obtained from Medreich Ltd Banglore. PVPK-30 and Lactose obtained from SD Fine Chemicals,
Mumbai. Talc and Magnesium stearate was obtained from
Qualigens Fine chemicals, Mumbai.
Methods4:
Analytical
methods of Diltiazem Hydrochloride:
The following analytical methods are
reported for the estimation of Diltiazem
Hydrochloride.
UV Spectroscopy, High Pressure Liquid
Chromatography Gas Chromatography Capillary zone electrophoresis. In present
investigation UV double beam
spectrophotometer was used for further studies.
Determination
of λ max:
Diltiazem Hydrochloride was dissolved in 0.1N HCI. Then
the solution was scanned for maximum absorbance in UV double beam
spectrophotometer (Shimadzu 1700) in the range from 200 to 400 nm, using 0.1N
HCI as blank. The λmax of the drug
was found to be 237nm1.
Construction
of Calibration Curve for Diltiazem Hydrochloride:
The calibration curve was constructed with
0.1N HCI. Accurately weighed 100 mg of Diltiazem Hydrochloride was dissolve
in 0.1N HCI and volume was made up to
the mark with 0.1N HCI to give a stock solution 1 mg/ml.
Further dilutions were made with 0.1N HCI
to obtain 2 to 10 µg/ml concentrations of Diltiazem Hydrochloride and the
absorbance was measured at 237 nm (Table-1, fig. 1).
Table:1
Calibration data of Diltiazem Hydrochloride
|
S.NO
|
Concentration
(µg/ml)
|
Absorbance ( ±
s d)
|
|
1.
|
0
|
0.000
|
|
2.
|
2
|
0.186±0.02
|
|
3.
|
4
|
0.312±0.04
|
|
4.
|
6
|
0.509±0.03
|
|
5.
|
8
|
0.722±0.02
|
|
6.
|
10
|
0.
912±0.04
|
Fig 1
calibration curve of Diltiazem
Hydrochloride
Pre formulation
study5:
Drug- Excipient
Compatibility by IR Spectroscopy
The physico-chemical
compatibility between Diltiazem Hydrochloride and the excipients,
(Crospovidone, HPMCE5, HPMCK4M, HPMCK100M, HPC, HEC, Methylcellulose,
Lactose, Talc and Magnesium stearate) used in the
research was tested by IR spectroscopy using Perkin Fourier Transform Infrared
Spectrophotometer (Chalapathi Institute of Pharmaceutical
Sciences, Guntur).
Micromeretic properties of prepared granules:
The prepared
granules were evaluated for the following parameters:
Bulk density, tapped bulk density and the angle of
repose for the immediate release and sustained release layers were determined
by fixed funnel method and by density apparatus. Carr’s index and Haussner’s ratios were calculated by the following
formulas.
Compressibility index (I) was calculated as
follows:
I = V0Vt/ V0×
100
Where, V0
- bulk volume
Vt - tapped volume
Haussner’s ratio = Tapped density / Bulk density
Preparation
of Diltiazem Hydrochloride Bilayer Floating tablets6:
The preparation of Bilayer
floating tablets involved two steps prepared by wet granulation method., superdisintegrants SSG, Croscarmellose
sodium, Crospovidone, PVP in isopropyl alcohol as
binding solution HPMCK4M, HPMCE5 and HPMCK100M as polymer lactose as diluent, talc and magnesium stearate as glidant and lubricant
in the formulation.
Preparation
of the immediate release layer:
The immediate release layer was prepared by wet granulation method, as per the formula
shown in table2. The damp mass was passed through
sieve no 12 , obtained granules dried in an oven at 50OC
until constant weight was obtained. The dried granules were sieved through
sieve no 16.The granules were lubricated with talc and magnesium stearate.
Preparation
of the floating sustained release layer:
The SR layer was prepared by wet granulation method as
for the formula shown in table 3. The damp mass was
passed through sieve no 12 to obtain granules. The granules thus obtained were
dried at 50 OC until constant weight was obtained. The dried
granules were re sieved through sieve no 16 and lubricated with talc and
magnesium stearate. The granules were compressed by
employing 9 mm round shaped tablet tooling.
Table2 : Composition of
Immediate release layer for bi-layer floating tablets of Diltiazem
Hydrochloride formulated with SSG, Croscarmellose sodium, Crospovidone.
|
S. NO
|
INGREDIENTS
|
Quantity per single tablet(mg)
|
|
F1
|
F2
|
F3
|
F4
|
F5
|
F6
|
F7
|
F8
|
F9
|
F10
|
F11
|
F12
|
|
1.
|
Diltiazem
hydrochloride
|
35
|
35
|
35
|
35
|
35
|
35
|
35
|
35
|
35
|
35
|
35
|
35
|
|
2.
|
Sodiumstarch glycolate
|
1.5
|
2.25
|
3
|
3.75
|
-
|
-
|
-
|
-
|
-
|
-
|
-
|
-
|
|
3.
|
Croscarmellose sodium
|
-
|
-
|
-
|
-
|
1.5
|
2.25
|
3
|
3.75
|
-
|
-
|
-
|
-
|
|
4.
|
Crospovidone
|
-
|
-
|
-
|
-
|
-
|
-
|
-
|
-
|
1.5
|
2.25
|
3
|
3.75
|
|
5.
|
PVPk-30
|
1.5
|
1.5
|
1.5
|
1.5
|
1.5
|
1.5
|
1.5
|
1.5
|
1.5
|
1.5
|
1.5
|
1.5
|
|
6.
|
Lactose
|
35.5
|
34.75
|
34.75
|
33.25
|
35.5
|
34.75
|
34
|
33.25
|
35.5
|
34.75
|
34
|
33.25
|
|
7.
|
Talc
|
0.75
|
0.75
|
0.75
|
0.75
|
0.75
|
0.75
|
0.75
|
0.75
|
0.75
|
0.75
|
0.75
|
0.75
|
|
8.
|
Magnesium
stearate
|
0.75
|
0.75
|
0.75
|
0.75
|
0.75
|
0.75
|
0.75
|
0.75
|
0.75
|
0.75
|
0.75
|
0.75
|
|
Total
tablet weight
|
75
|
75
|
75
|
75
|
75
|
75
|
75
|
75
|
75
|
75
|
75
|
75
|
Table3
:Composition of bi-layer
floating tablets of Diltiazem Hydrochloride formulated with HPMCK4M,HPMCE5
and HPMCK100M
|
S NO
|
Ingredients
|
Quantity per tablet (mg)
|
|
F13
|
F14
|
F15
|
F16
|
F17
|
F18
|
F19
|
F20
|
F21
|
|
Immediate release layer
|
|
1
|
Diltiazem
hydrochloride
|
35
|
35
|
35
|
35
|
35
|
35
|
35
|
35
|
35
|
|
2
|
Crospovidone
|
3.75
|
3.75
|
3.75
|
3.75
|
3.75
|
3.75
|
3.75
|
3.75
|
3.75
|
|
3
|
PVP
|
1.5
|
1.5
|
1.5
|
1.5
|
1.5
|
1.5
|
1.5
|
1.5
|
1.5
|
|
4
|
Lactose
|
33.25
|
33.25
|
33.25
|
33.25
|
33.25
|
33.25
|
33.25
|
33.25
|
33.25
|
|
5
|
Talc
|
0.75
|
0.75
|
0.75
|
0.75
|
0.75
|
0.75
|
0.75
|
0.75
|
0.75
|
|
6
|
Magnesium
stearate
|
0.75
|
0.75
|
0.75
|
0.75
|
0.75
|
0.75
|
0.75
|
0.75
|
0.75
|
|
Sustained release layer
|
|
7
|
Diltiazem
hydrochloride
|
55
|
55
|
55
|
55
|
55
|
55
|
55
|
55
|
55
|
|
8
|
HPMCK4M
|
60
|
80
|
100
|
-
|
-
|
-
|
-
|
-
|
-
|
|
9
|
HPMCE5
|
-
|
-
|
-
|
60
|
80
|
100
|
-
|
-
|
-
|
|
10
|
HPMCK100M
|
-
|
-
|
-
|
-
|
-
|
-
|
60
|
80
|
100
|
|
11
|
Sodium
bi
carbonate
|
30
|
30
|
30
|
30
|
30
|
30
|
30
|
30
|
30
|
|
12
|
Lactose
|
49
|
31
|
11
|
49
|
31
|
11
|
49
|
31
|
11
|
|
13
|
Talc
|
2
|
2
|
2
|
2
|
2
|
2
|
2
|
2
|
2
|
|
14
|
Magnesium
stearate
|
2
|
2
|
2
|
2
|
2
|
2
|
2
|
2
|
2
|
|
15
|
Total
weight
|
275
|
275
|
275
|
275
|
275
|
275
|
275
|
275
|
275
|
Compression
of bilayer floating tablets:
The required quantity of granules
for the SR layer was compressed lightly by using a rotary punch tablet machine
with 9mm punches. Then the required quantity of granules for the IR layer were
placed over the above compact ,both the layers were compressed by 9 mm round shaped tablet tooling.
Evaluation
studies on tablets:7
All the prepared bilayer
floating tablets were evaluated for following parameters.
Weight
Variation:
Formulated tablets were tested for weight
uniformity, 20 tablets were weighed collectively and individually. From the
collective weight, average weight was calculated. The percent weight variation
was calculated by using the following formula.
Hardness:
The hardness of tablets was measured by Monsanto
hardness tester. The hardness was measured in terms of kg/cm2.
Friability:
The Roche friability test apparatus was
used to determine the friability of the tablets. Twenty pre-weighed tablets
were placed in the apparatus and operated for 100 revolutions and then the
tablets were reweighed. The percentage friability was calculated according to
the following formula.
Drug content:
Twenty tablets were weighed and powdered. The quantity of powder equivalent to 100 mg of Diltiazem hydrochloride
was dissolved in 0.1 N HC1 diluted to 100ml with 0.1N HC1 then the
solution was filtered and suitably diluted. The drug content was estimated spectrometrically at 237 nm.
Swelling index:
Tablet was weighed (W0) and
placed in dissolution medium containing 0.1N HCl
maintained at 37°C. At predetermined time intervals the tablet was and blotted
to remove excess water and weighed (Wt). The percentage of swelling index
calculated.
Swelling index = (Wt
- Wo) x 100
Wt
Where, Wt= final weight of the tablet
Wo = initial weight of the table.
Floating characteristics:
Floating characteristics were
determined using USP dissolution XI apparatus at 100 rpm using 900 ml of 0.1 N HCl and temperature was maintained at 37°c.
Floating lag time: The tablet was placed in dissolution apparatus and the time taken to
float on the dissolution medium was noted.
Floating time:
The total duration of the time that the tablet float on dissolution medium was
noted.
In-vitro dissolution studies:
Dissolution rate
was studied using USP II paddle dissolution apparatus, in 900ml of 0.1N
Hydrochloric acid at 37±0.5°at 50 rpm8. Aliquot of dissolution
medium was withdrawn at regular time
intervals and the same volume of pre-warmed (37±0.5°) fresh dissolution medium
was replaced. The samples were filtered and drug content of Diltiazem
hydrochloride in each sample was analyzed after suitable Dilution by Shimadzu UV-spectrophotometer at 237
nm.
RESULTS:
Table 4: Physico- chemical evaluation of the for bilayer floating tablets of Diltiazem Hydrochloride
|
S. No.
|
Formulation
|
Average
weight (mg)
|
Hardness
(kg/sq cm)
|
Friability
(%)
|
Drug
content
(%)
|
Swelling index(%)
|
Floating
lag time (sec)
|
Total
floating time (hrs)
|
|
1
|
F13
|
275±0.2
|
4.3±0.14
|
0.72
|
99.2±0.02
|
36.3±0.02
|
90
|
6
|
|
2
|
F14
|
275±0.17
|
5.6±0.17
|
0.60
|
98.6±0.03
|
40.2±0.03
|
61
|
8
|
|
3
|
F15
|
275±0.23
|
3.8±0.2
|
0.64
|
99.5±0.02
|
47.6±0.03
|
55
|
10
|
|
4
|
F16
|
275±0.32
|
4.2±0.15
|
0.71
|
98.3±0.04
|
50.9±0.04
|
85
|
6
|
|
5
|
F17
|
275±0.15
|
4.1±0.11
|
0.72
|
96.8±0.02
|
45.1±0.03
|
60
|
8
|
|
6
|
F18
|
275±0.19
|
4.8±0.12
|
0.63
|
97.5±0.03
|
34.6±0.02
|
59
|
10
|
|
7
|
F19
|
275±0.21
|
3.9±0.31
|
0.68
|
97.3±0.01
|
37.4±0.03
|
77
|
10
|
|
8
|
F20
|
275±0.23
|
4.5±0.22
|
0.66
|
97.8±0.04
|
52.5±0.03
|
60
|
12
|
|
9
|
F21
|
275±0.34
|
5.3±0.17
|
0.75
|
98.6±0.05
|
56.2±0.04
|
55
|
>12
|
Table 4 In vitro drug release kinetics of immediate release layer for bilayer floating tablets of Diltiazem Hydrochloride formulated with SSG,Croscarmellose
sodium and Crospovidone
|
Formulation
|
Correlation coefficient
|
(K)
(min-1)
|
T50
(min)
|
T90 (min)
|
Exponential coefficient
value(n)
|
|
Zero order
|
First order
|
Higuchi
|
Peppas
|
|
F1
|
0.965
|
0.984
|
0.977
|
0.985
|
0.407
|
11
|
29
|
0.514
|
|
F2
|
0.912
|
0.984
|
0.994
|
0996
|
0.449
|
9
|
27
|
0.531
|
|
F3
|
0.879
|
0.958
|
0.978
|
0.998
|
0.479
|
8.5
|
26
|
0.463
|
|
F4
|
0.909
|
0.947
|
0.988
|
0.995
|
0.578
|
6
|
20
|
0.471
|
|
F5
|
0.988
|
0.990
|
0.965
|
0.997
|
0.211
|
18.5
|
29.9
|
0.578
|
|
F6
|
0.960
|
0.995
|
0.987
|
0.995
|
0.225
|
17.9
|
28.3
|
0.431
|
|
F7
|
0.951
|
0.994
|
0.990
|
0.992
|
0.227
|
16.1
|
24.1
|
0.584
|
|
F8
|
0.965
|
0.980
|
0.984
|
0.986
|
0.249
|
16
|
23.9
|
0.544
|
|
F9
|
0.937
|
0.982
|
0.994
|
0.996
|
0.220
|
14.2
|
28.4
|
0.577
|
|
F10
|
0.896
|
0.989
|
0.979
|
0.998
|
0.245
|
13.4
|
27.3
|
0.487
|
|
F11
|
0.816
|
0.979
|
0.992
|
0.993
|
0.273
|
7.7
|
24.6
|
0.419
|
|
F12
|
0.797
|
0.981
|
0.990
|
0.996
|
0.299
|
9.2
|
18.1
|
0.402
|
Table 5 In vitro drug
release kinetics of bilayer floating tablets of
Diltiazem Hydrochloride formulated
with HPMCK4M,HPMCE5 and HPMCK100M
|
Formulation
|
Correlation coefficient
|
(K)
(hr-1)
|
T50 (hr)
|
T90 (hr)
|
Exponential coefficient
value(n)
|
|
Zeroorder
|
Firstorder
|
Huguchi
|
Peppas
|
|
F13
|
0.4841
|
0.9174
|
0.936
|
0.9882
|
0.327
|
1.1
|
5
|
0.3342
|
|
F14
|
0.401
|
0.908
|
0.919
|
0.988
|
0.243
|
1.8
|
7.5
|
0.304
|
|
F15
|
0.442
|
0.926
|
0.919
|
0.983
|
0.196
|
2.6
|
8.5
|
0.287
|
|
F16
|
0.566
|
0.904
|
0.953
|
0.988
|
0.430
|
1.2
|
3.7
|
0.361
|
|
F17
|
0.556
|
0.939
|
0.951
|
0.992
|
0.351
|
1.8
|
5.4
|
0.347
|
|
F18
|
0.605
|
0.951
|
0.945
|
0.984
|
0.276
|
2.1
|
7.2
|
0.316
|
|
F19
|
0.848
|
0.964
|
0.965
|
0.990
|
0.381
|
1.8
|
5.3
|
0.387
|
|
F20
|
0.614
|
0.899
|
0.929
|
0.967
|
0.198
|
3.5
|
10.8
|
0.282
|
|
F21
|
0.656
|
0.930
|
0.949
|
0.972
|
0.185
|
3.7
|
12.4
|
0.300
|
|
|
|
|
|
|
|
|
|
|
Fig: 2 In
-vitro release profile of immediate release layer
for bilayer
floating tablets of Diltiazem Hydrochloride
formulated with SSG
Fig:3 In -vitro release profile of immediate
release layer for bilayer floating tablets of Diltiazem Hydrochloride
formulated with Croscarmellose sodium
Fig:4 In -vitro release profile of immediate
release layer for bilayer floating tablets of Diltiazem Hydrochloride
formulated with Cropovidone
Fig:5 In- vitro release profile of bilayer floating tablets of Diltiazem Hydrochloride formulated with HPMCK4M
Figure 6 In
-vitro release profile of bilayer floating tablets of
Diltiazem Hydrochloride formulated with
HPMCE5
Figure 7 In- vitro
release profile of bilayer floating tablets of Diltiazem
Hydrochloride
formulated with HPMCK100M
RESULTS AND DISCUSSION:
The formulations of IR layer were shown in table2.The Micromeritic properties for IR Layer granules of F1-F12
were evaluated. From results all the formulations exhibited good flow properties;
it was also further supported by Carr’s Index and Hausner’s
ratios value. The in-vitro release
data were fitted into various kinetic models i.e. First order, zero order,
Higuchi and Peppas, results were reported in table 4
and percent drug release plot for all IR layer formulations were shown in fig
2, fig3 and fig4. The drug release followed
first order kinetics and exhibited Peppas transport
mechanism. The exponential coefficient from the Peppas plots was found <0.5 indicating Fickian diffusion. Based
on the release rate, the order of drug release from the all formulations was
F12> F8>F11> F4>F7>F10> F3>F6>F2>F9>F1>F5 i.e.
increasing the concentrations of SSG, Croscarmellose
sodium and Crospovidone in formulations the drug
release rate was found to be increased.
Bilayer floating tablets were prepared by using optimized i.e F12 immediate release and further followed by floating
sustained release formula was shown in table3.The Micromeritic
properties for formulations F13-F21were evaluated. From the results, IR layer
and SR layer granules
exhibited good flow properties; it was also further supported by
Carr’s Index values and Hausner’s ratios values. The
formulated tablets were subjected to various quality
control tests and the results were shown in table 4. The obtained results were
found to be within limits specified in pharmacopoeia. The % drug content
in all bilayer
formulations were in the range of 98.6±0.03% to 99.±0.02%.The floating lag
time and total floating time of SR layer
for F13-F21 were found to be satisfactory.
The In-vitro release data were fitted into
kinetic models i.e. First order, zero order, Higuchi and Peppas,
results were shown in table 5 and percent drug release plot for all bilayer formulations were shown in fig 5, fig6 and fig7.
The drug release followed first order kinetics and exhibited the Peppas transport mechanism. The
exponential coefficient from the Peppas plots was
found to be <0.5 indicating Fickian
diffusion Based on the release rate, the order of
release retardent polymers as HPMCK100M>HPMCE5>HPMCK4M.
CONCLUSION:
The drug and excipients were
found to be compatible. The characteristics of the granules such as angle of
repose, bulk density, tapped density, Carr’s index, Hausner’s ratio were studied, found to be good flow
properties. Evaluation parameters of the tablets such as weight variation,
hardness, friability, drug content, swelling index, floating characteristics,
was found to be satisfactory. The buoyancy lag time was found to be
satisfactory. The swelling index was found to be increased with increase in the
amount of the polymer employed. The formulations F20 was found to be, sustained
the drug release for 12hrs.The optimized tablet formulations showed a
satisfactory dissolution profile and floating characteristics. The drug release
from all formulations followed first order kinetics and Fickian
diffusion. In the present investigation, successfully was developed bilayer floating tablets of Diltiazem Hydrochloride by wet
granulation method using super disintegrants Crospovidone for IR layer and HPMCK 100M for SR layer .
ACKNOWLEDGEMENTS:
The authors express their gratitude to Medreich Ltd. Bangalore for providing gift sample of
Diltiazem Hydrochloride. The authors are thankful to Bapatla
Educational Society, Bapatla for providing facilities
to carry out research.
REFERENCES:
1.
N. Damodharan, M. Mothilal,
M. Madhavi, P. Thejomayananthan,
“Formulation and evaluation of bi-layered floating tablets of Theophylline: Scholoars Research
Library, 2009, 1(2)227-233.
2.
CIMS-87, Oct-2004(update-4), 140.
3.
A.A. Shirwaikar and A. Srinath,
“Sustained Release Bilayered tablets of Diltiazem
hydrochloride using insoluble matrix system: Indian Journal of Pharmaceutical
Science, 2004, 66(4):433-437.
4.
Shah S.H., Patel J.K., Patel N.V. “Stomach specific floating drug
delivery system: A review: International Journal of Pharma Tech
Research Vol.1no.3, July-Sept 2009, pp 623-633.
5.
Pradeep Kare et al. Journal of Pharmacy
Research 2010, 3(6), 1274-1279.
6.
http://journal.pda.org/content/62/5/344.abstract
7.
Indian Pharmacopeia, The controller of Publications, Ministry of Health and
Family Welfare, Govt. of India, Vol No1,1996,256.