ISSN 0975-6299

Vol.1/Issue-3/Jul-Sep.2010

International Journal of Pharma and Bio Sciences

FORMULATION AND EVALUATION OF DILTIAZEM SUTAINED RELEASE
TABLETS
V.C. MODI*1 AND DR. A.K.SETH1
1

Department of Pharmaceutics, College of Pharmacy, Sumandeep Vidyapeeth University, Vadodara 391760,

India

* Correspondence Author

[email protected]

ABSTRACT
Sustained releases tablets of Diltiazem hydrochloride were formulated by employing hydroxypropyl
methylcellulose (HPMC K100 M) and the sustained release behaviour of the fabricated tablets was
investigated. Sustained release matrix tablets containing 120 mg Diltiazem hydrochloride were
developed using different drug: polymer (HPMC K100 M) ratios. Tablets were prepared by wet
granulation technique. Formulation was optimized on the basis of acceptable tablet properties and in
vitro drug release. The resulting formulation produced robust tablets with optimum hardness,
consistent weight uniformity and low friability. All tablets but one exhibited gradual and near-complete
sustained release for Diltiazem hydrochloride (96-100%) at the end of 24 h. The results of dissolution
studies indicated that formulation B5 (drug to polymer 1:1.25) was found to be most successful as it
exhibits drug release pattern very close to theoretical release profile. A decrease in release kinetics of
the drug was observed on increasing polymer ratio.

KEYWORDS
Sustained releases Tablets , Diltiazem hydrochloride, hydroxypropyl methylcellulose (HPMC K100 M)
missed doses, made up doses and patient
incompliance with the therapeutic regimen.
When conventional immediate release dosage
forms are taken on schedule and more than
once daily, there are sequential therapeutically
blood peaks and valley associated with taking
each dose. It should be emphasized that the
plasma level of a drug should be maintained
with in the safe margin and effective range.
For this proper and calculated doses of the

INTRODUCTION
For decades an acute or chronic illness is being
clinically treated through delivery of drugs to the
patients in form of some pharmaceutical dosage
forms like tablets, capsules, liquids, creams,
pills, aerosols, injectables, and suppositories.
However, these conventional dosage forms
have some drawbacks. Multiple daily dosing is
inconvenient to the patient and can result in
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drug need to be given at different time interval

by conventional dosage form. To achieve and
maintain the concentration of administered drug
within therapeutically effective range, it is often
necessary to take drug dosage several times
and this results in a fluctuating drug level in
plasma.
A simple dosing scheme with a once- or twicedaily administration of the antihypertensive
agent is known to increase patient compliance
For this reason, the pharmaceutical industry is
intensively
searching
for
longer-acting
antihypertensive
drugs,
either
by
the
development of novel agents with a longer
elimination half-life, or by the improvement of
the dosage form of existing shorter-acting
compounds, so that plasma concentrations
compatible with a blood-pressure-lowering
activity are maintained during the whole day.
The present research endeavor was directed
towards the development of a sustained release
tablet
formulation
containing
diltiazem
hydrochloride tablet taken once rather than two
or three times a day. The aim of present project
work was to design, process optimization and
evaluation of sustained-release tablet of poorly
soluble drug diltiazem.
Greater attention has been focused on
development of sustained or controlled release
drug delivery systems with concomitant
recognition of the therapeutic advantages of
controlled drug delivery. Controlled drug delivery
systems have been introduced to overwhelm the
drawback of fluctuating drug levels associated
with conventional dosage forms.
A simple dosing scheme with a once- or twicedaily administration of the antihypertensive
agent is known to increase patient compliance
For this reason, the pharmaceutical industry is
intensively
searching
for
longer-acting
antihypertensive
drugs,
either
by
the
development of novel agents with a longer
elimination half-life, or by the improvement of

the dosage form of existing shorter-acting

compounds, so that plasma concentrations
compatible with a blood-pressure-lowering
activity are maintained during the whole day.
The present research endeavor was directed
towards the development of a sustained
release tablet formulation containing diltiazem
hydrochloride tablet taken once rather than two
or three times a day.

MATERIALS AND METHODS

Diltiazem HCl was gift sample from Lincoln
pharmaceutical, Khatraj, kalol. HPMC K100M,
Lactose monohydrate, Talcum powder were
gift samples from Colorcon Asia Pvt ltd. Ethyl
cellulose and magnesium stearate were gift
samples from Signet Chemical Corporation Pvt.
Ltd. All the other chemicals used were of
analytical reagent grade.
Method for preparation of sustained
release tablet of Diltiazem HCl
Acurately weigh all the ingredients and pass
the materials (Diltiazem HCl and HPMC K100
M) through 40 # sieve and transferred into
RMG ( Rapid mixer and granulator) and mix for
10 min. Now add previously prepared solution
of ethyl cellulose in IPA slowly with appropriate
speed of impellor and chopper to obtained
granules. Now transferred material into fluid
bed drier and operate at inlet temperature 60o
C and outlet at 40o C to achieve % L.O.D
between 1.5 - 2.0 % then pass the dried
granules through 20 # sieve. Weight accurately
talcum powder, magnesium stearate and pass
through 40 # sieve and mix it with above
granules in octagonal blander for 5 min. Now
compressed the tablet on 16 station tablet
compression machine by using 13/32 mm SC
plain punches.

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FORMULATION BATCHES FOR B1-B5

Sr. No.

Item Name

B1

B2

B3

B4

B5

Mg/tab

Mg/tab

Mg/tab

Mg/tab

Mg/tab

MIXING

2
3

Diltiazem
Hydrochloride
IP
HPMC K100M
Lactose
(monohydrate)

120.00

120.00

120.00

120.00

120.00

100.00

120.00

130.00

150.00

150.00

69.00

49.00

39.00

19.00

19.00

BINDING
6
7

Ethyl cellulose
Isopropyl
alcohol

25.00

25.00

25.00

25.00

25.00

150.00

150.00

150.00

150.00

150.00

LUBRICATION
10

Magnesium
Stearate

3.00

3.00

3.00

3.00

3.00

11

Talcum

3.00

3.00

3.00

3.00

3.00

12

Total

320.00

320.00

320.00

320.00

320.00

The test was performed by keeping API(s)

and adjuvant mixed with 5%w/w water in
sealed containers for 6 months at 40 C 2
C, 75% 5% RH. The concentration of all
was kept as per the final formulation.

DRUG-EXCIPIENTS
COMPATIBILITY STUDY4
Compatibility study of Active Pharmaceutical
Ingredient (API) with exicipients was carried out
by performing Accelerated Stability Studies.

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Experiment (I)

Experiment (II)

API:
Diltiazem
hydrochloride

API:
Diltiazem
hydrochloride
EXCIPIENTS:
Lactose(monohydrate)
Ethyl cellulose
HPMC K-100M
Talcum
Magnesium stearate

Experiment (III)

Experiment (IV)
API:
Diltiazem
hydrochloride
EXCIPIENTS:
HPMC K-100M

API:
Diltiazem
hydrochloride
EXCIPIENTS:
Lactose(monohydrate)
Ethyl cellulose

After 1, 2, 3 and 6 Months, Samples were withdrawn and Compatibility of Active ingredients with excipients was
examined.

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101.5
101

% ASSAY

100.5
EXPERIMENT 1

100

EXPERIMENT 2

99.5

EXPERIMENT 3

99

EXPERIMENT 4

98.5
98
97.5
0

TIME(MONTHS)

Figure 1.
Chart showing compatibility study of API with chosen inactive ingredients.

DESCRIPTION
1. Tablet weight variation: Every individual
tablet in a batch should be in uniform weight
and weight variation within permissible limits.
Weight control is based on a sample of 20
tablets. Twenty tablets were randomly
selected and accurately weighed using
an electronic balance (Metteler Toledo
electronic balance: Model P G 03-S). The
results are expressed as mean values of 20
determinations.4

It remained same in experiments till 6 months.

CONCLUSION
a . Diltiazem hydrochloride was found to be
compatible with fillers, i.e. Lactose
(monohydrate).
b.Diltiazem hydrochloride was found to be
compatible with selected hydrophobic binding
agent i.e., ethyl cellulose.
c.Diltiazem hydrochloride was found to be
compatible with blend of filler (Lactose
monohydrate), selected hydrophobic binder,
(ethyl cellulose), rate-controlling polymer (HPMC
K-100M), glidant (talcum) and lubricant
(magnesium stearate).

2. Hardness: The hardness of the tablets

was determined using a Hardness testing
apparatus (Batch top Tablet Tester, Model:
5y, tablet tester, Dr. Schleuniger P
harmatron).5
3. Thickness : Control of physical dimension
of the tablets such as thickness, width and
length is essential for consumer acceptance
and to maintain tablet to tablet uniformity. The
thickness of the tablet is mostly related to the
tablet hardness can be uses as initial control
parameter.Ten tablets were randomly selected
form each formulation and their thickness was

EVALUATION PARAMETERS OF
DILTIAZEM HCL SR TABLET3
Prepared tablets were evaluated for certain
physical properties like Tablet wt. variation,
Assay, hardness, friability, dissolution study etc.
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measured by using vernier caliper. Thickness

values were reported in millimeters.3

sample of 10 tablets are dedusted in a drum for

a fixed time (100 revolutions) and weighed (W)
again. Percentage friability was calculated from
the loss in weight as given in equation as
below. The weight loss should not be more
than 1 % w/w.

4. Friability: The friability of the tablets was

measured in a Roche friabilator (Model:ED-2,
Electrolab). Tablets of a known weight (W 0) or a

% Friability = (W 0 - W)/W 0 X 100

5. In vitro dissolution study: Dissolution
tests were performed in a USP Dissolution
Tester Apparatus II (paddle method) (TDT-08
L, Electrolab, Mumbai, India.) at 37 0.5C. The
paddle were rotated at a speed of 100 rpm. The
prepared tablets were placed in the cylinder with

900 ml distilled water. 10 ml samples were

withdrawn at time intervals of 1, 4, 8, 12,
16, 20, and 24 hrs and replace with fresh
dissolution media. Samples were analyzed on
UV-spectrophotometer
at
237
[3,5,7,8,9]
nm.

CALCULATION FOR RELEASE PROFILE

Standard weight = ---------------

Sample abs
Formula = ---------------- X
Std.abs

Standard absorbance = ---------------

Std.abs
10
------------ X --------- X
200ml
100

6. Stability study : Compressed tablets were

packed
in alu-alu blister by packaging
machine
(RCS Engineering
Works,
Ahmedabad), labeled them and stored in
stability
chamber (Thermolab stability
chamber, Mumbai, India) at 30 2C / 65
5% RH, 40 2C / 75 5% RH for the period
of 1 month. Change occurs at any time during

900
---------- X
120mg

100
--------- X Std.Potency.
10

6 months testing at the accelerated storage

condition should
be
conducted
and
evaluated
against
significant
change
criteria.
The
Initial application should
include a minimum of 6 months data from
a 12- months study at intermediate storage
condition.

S ignificant C hange for a drug product is defined as

1. A 5% change in assay from its initial value;
2. Any degradation products exceeding its acceptance criteria;
3. Failure to meet acceptance criteria for appearance, physical attributes and
functionality test (eg. Color, phase separation, hardness, dose delivery per actuation);
4. Failure to meet the acceptance criteria for pH;
5. Failure to meet the acceptance criteria for dissolution for 12 dosage units.
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To develop a sustained release tablets of Diltiazem which is stable and gives in vitro drug
release according to Theoretical Release Profile.

Time(hours)

%CPR of
Diltiazem

Range

17.24

15-25%

20.94

24.53

28.12

31.78

35.31

38.90

42.5

46.09

10

49.68

11

53.28

12

56.87

13

60.48

14

64.06

15

67.65

16

71.25

17

74.84

18

78.43

19

82.03

20

85.62

21

89.21

22

92.81

23

96.4

24

99.98

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20-35%

35-50%

45-65%

65-80%

NLT 80%

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Vol.1/Issue-3/Jul-Sep.2010

COMPARISON OF OPTIMIZED FORMULATION WITH MARKETED FORMULATION

The dissolution profile of optimized diltiazem

hydrochloride formulation (B4) was compared
with that of marketed diltiazem hydrochloride SR
tablet (DILTIME SR) for t50% (time for 50% drug
release), regression coefficient (r2 fitted to various
models) and f2 (similarity factor). The in vitro
drug release for 24 hr of marketed formulation
was shown in table. The t50% of marketed

formulation was found to be 9.65 hours which is

close to that of optimized formulation.
In vitro release form marketed formulation was
fitted into different kinetic equation (zero order,
first order and Higuchi equation).The in vitro
drug release showed the highest regression
coefficient values (r2 = 0.9790) for Higuchis
model, indicating diffusion to be the
predominant mechanism of drug release.

8.Cummulative % drug release of marketed Formulation DILTIME SR TABLET10

Sr.
No.
1.
2.
3.
4.
5.
6.

Time
(Hrs)
0
1
4
8
12

Cumulative %
Drug Release
0
16.25
30.28
43.2
58.65

16
20

73.28
86.43

24

99.12

7.
8.

RESULT AND DISCUSSION

1.Physical properties of diltiazem tablet, in Mean S.D.

Formulati
on

Thickness
(mm)

Friability (%)

Hardness (Kg)

B1
B2
B3
B4
B5

3.510.25
3.420.26
3.670.30
3.590.18
3.610.31

0.15
0.21
0.26
0.19
0.22

6.71 0.9
6.95 0.5
7.33 0.7
6.68 0.55
6.84 0.32

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2.Physical properties of directly compressible powder mixture

Bulk
Formulati Density
on code g/cm3
B1 0.4212
B2 0.4316
B3 0.4813
B4 0.4128
B5 0.4352

Tapped
Density
g/cm3
0.4897
0.5124
0.5681
0.5056
0.5110

Compressibili Hausners
ty Index
Ratio
(%)
13.98
1.162
15.76
1.187
15.27
1.180
18.35
1.224
14.83
1.174

Angle of
Repose,
30
32
33
29
30

3. In-vitro release study of sustained release diltiazem tablet (B1-B5)

Time
(hour)
1
4
8
12
16
20(NLT 80%)
24

B1

B2

29.44
47.59
79.02
91.30

22.04
39.83
73.73
86.91
93.86

Batch B1-B5
B3
19.89
29.13
47.14
62.36
87.18
92.07

B4

B5

19.36
30.10
41.84
53.98
75.52
84.48
96.96

18.40
32.40
41.1
56.00
78.7
85.37
98.04

DISCUSSION11
Comparison of optimized formulation with
marketed formulation
The dissolution profile of optimized diltiazem
hydrochloride formulation (B5) was compared
with that of marketed diltiazem hydrochloride
SR tablet (DILTIME SR) for t50% (time for 50%
drug release), regression coefficient (r2 fitted to
various models) and f2 (similarity factor). The
in vitro drug release for 24 hr of marketed
formulation was shown in above table. The
Invitro-release profile of formulation (B5) was
similar to that of marketed product DILTIME
SR TABLETS.

The
present
study
concludes
that
combination of hydrophilic polymer such as
Hydroxy propyl methyl cellulose k 100 M and
hydrophobic polymer such as Ethyl cellulose
can
be
utilized
for
designing
and
development of controlled release solid
dosage form. Using selected polymers the
developed controlled release table of
diltiazem HCL drug was found to be
equivalent with regard to dissolution profile
with marketed product.
The best formulation (B5) has shown a drug
release NLT 80% in 20hr was in accordance
with the USP dissolution criteria for extended
release diltiazem hydrochloride formulation.
There was an excellent agreement for the
dissolution profile of the formulation B5 and
marketed product (DILTIME SR) .
In conclusion, in the present research,
sustained release tablet formulations of
diltiazem hydrochloride were successfully
prepared for a once daily administration.

ACKNOWLEDGEMENT
The authors thank Lincoln pharmaceutical ltd
kalol, India, for providing a gift sample of
Diltiazem hydrochloride and colorcon asia Pvt.
Ltd., and Signet Chemical Corporation Pvt. Ltd
for providing gift sample of other excipients.

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6) Moffat AC., Osselton MD. and Widdap B.

Clarkes analysis of drug and poison. 3rd ed.
vol. 2. .London (UK): Pharmaceutical press;
2004: 925-926
7) Indian pharmacopoeia. Vol 1. Delhi:
Published by the controller of publication;
1996: 256-257.
8) The united states of pharmacopoeia 26/
National formulary 21, The united states
pharmacopoeial convention,Inc., Rockville,
MD; 1995: 625-628
9) Britain Harry G., Analytical profiles of drug
substances and excipients, vol-23,Elsevier:
53-98
10) www.cimsasia.com
11) Ozturk AG., Ozturk SS., Palsson BO. et. al.
Mechanism of release from pellets coated
with an ethyl cellulose-based film. J Control
Release. 1990; 14(3): 203213.

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