ISSN No: 2321 8630, V 1, I 1, 2014

Journal Club for Pharmaceutical Sciences (JCPS)

Manuscript No: JCPS/RES/2014/13, Received on: 02/08/2014, Revised on: 07/08/2014, Accepted on: 12/08/2014

RESEARCH ARTICLE
Formulation and Evaluation of Sustained Release Matrix Tablets of Diltiazem
Hydrochloride
1

Bhut VZ*1, Shah KK1, Patel KN1, Patel PA1

Department of Pharmaceutics, Shree Swaminarayan Sanskar Pharmacy College, Zundal,
Gandhinagar, Gujarat, India.

ABSTRACT
The purpose of present investigation was to develop sustained release matrix tablet of highly
water soluble drug diltiazem hydrochloride by wet granulation method by using different
hydrophilic (HPMC K4M, HPMC K1M, HPMC K100 M, Na CMC, Na alginate) and
different hydrophobic (Eudragit RSPO, Eudragit RLPO, Eudragit RS-100, Eudragit RL-100,
Ethyl cellulose) polymers. A 32 full factorial design was applied. The concentration of HPMC
K15M in mg (X1) and concentration of Eudragit RSPO in mg (X2) were selected as
independent variables. The %CDR at the end of 3 hrs (Q3) and %CDR at the end of 12 hrs
(Q12) were selected as dependent variables. The prepared tablets were evaluated for
hardness, friability, drug content, In vitro drug release. FT-IR, DSC and physical
compatibility study were conducted for drug, and drug excipient mixture for interactions if
any. The results indicated that concentration of HPMC K15M (X1) and concentration of
Eudragit RSPO (X2) significantly affected the %CDR at the end of 3 hrs (Q3) and %CDR at
the end of 12 hrs (Q12). Regression analysis and numerical optimization were performed to
identify the best formulation. Formulation F11 prepared with HPMC K15M (70 mg) &
Eudragit RSPO (10 mg) was found to be the best formulation with % CDR 20.32% and
96.59% at the end of 3 hrs and 12 hrs respectively. Optimized batch F11 showed similarity
factor f2 value 69.14.
KEYWORDS
Diltiazem Hydrochloride, Sustained Release Matrix Tablet, HPMC K15M, Eudragit RSPO,
Sodium Alginate, Ethyl Cellulose, Calcium Channel Blocker

INTRODUCTION

delivery because of more flexibility in the

Oral route has been the commonly adapted

formulation,

patient

compliance

and

and most convenient route for drug

convenient for a physician during dose

adjustment. When conventional dosage

*Address for Correspondence:

Vibha Z. Bhut,
Department of Pharmaceutics,
Shree Swaminarayan Sanskar Pharmacy
College, Zundal, Gandhinagar, Gujarat,
India.
E-Mail Id: bhut_vibha@yahoo.com

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forms are taken on schedule and more than

once daily, leads to fluctuations in plasma
drug concentration and doses may be
missed. Side effects and the need for
administration two or three times per day

58

in case of drug having short half-life and

effectiveness

when larger doses are required can

acceptance hydrophilic polymer matrix

decrease patient compliance. To overcome

systems are widely used in oral controlled

above

drug delivery to obtain a desirable drug

demerits

conventional

associated

dosage

forms,

with

sustained

release formulations have been designed

which maintain plasma level of drug for
prolong

period

and

broad

regulatory

release profile.1
Materials & Methods
Materials

hence reduce dosing

frequency and blood level fluctuations.

Diltiazem hydrochloride was obtained as a

patient

gift sample from Torrent Research Centre

convenience and compliance, reduction in

Bhat. HPMC K4M, K15M, K100M and

There

is

also

enhanced

adverse side effects and reduction in

overall health care costs due to reduction

Ethyl Cellulose were purchased from

in dosing frequency.

Rankem RFCL limited, New Delhi. Na

In present investigation the selected drug is

CMC, Na alginate, Talc, Magnesium

Diltiazem hydrochloride which is a potent

calcium channel blocker, is used in the

stearate, MCC and PVP

K-30 was

pectoris,

purchased from Sd fine chem limited,

arrhythmia and hypertension. It has short

Mumbai. Eudragit RS-100, RL-100, RSPO

management

half-life

(t1/2

of

angina

3-4.5

hrs).

Dosing

frequency is thrice a day. Normal dose is

and RLPO were obtained as a gift sample

60 mg thrice a day and increased upto 360

from Evonik Degussa India Pvt Limited,

mg or 480 mg daily, if necessary. As a

Mumbai.

result of its short half-life and the need for

administration more times per day, it is

Method (Wet Granulation Method)

highly desirable to develop an oral

Diltiazem HCl and all the intra-granular

sustained release formulation of this drug,

ingredients were weighed accurately and

so as to reduced dosing frequency,

improve therapeutic effects with minimum
side

effects

and

improved

patient

compliance.

individually passed through 40# sieve

respectively as per batch formula and
mixed geometrically. Then dough mass

The matrix system is most common

method of modulating the drug release
because

of

their

flexibility,

cost-

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was prepared by using PVP K30 in IPA

(5% W/V) as a granulating fluid. Granules

59

were prepared by passing dough mass

preparation of the tablets possessing

through 10# sieve and then dried at 400C

optimal characteristics. The concentration

for 30 minutes in hot air oven. Dried

of HPMC K15M in mg (X1) and

granules were passed through 22# sieve in

concentration of Eudragit RSPO in mg

order to obtain uniform sized granules.

(X2)

Granules were lubricated with Magnesium

variables. The %CDR at the end of 3 hrs

stearate & Talc (which were passed

(Q3) and %CDR at the end of 12 hrs (Q12)

through

were selected as dependent variables

60#

sieve).

Granules

were

were

selected

as

independent

compressed into tablet in rotary tablet

Evaluation of Granules

compression machine by using 10 mm

Angle of Repose 2

punch.

The angle of repose of prepared Diltiazem

Formulation of Preliminary Batches

granules was evaluated by simple funnel

Batch F1-F5 were prepared by using

method. The accurately weighed granules

hydrophilic polymers and batch F6-F10

were taken in a funnel. The height of the

were

of

funnel was adjusted by stand in such a way

hydrophilic and hydrophobic polymers.

that the tip of the funnel approximately 2

Formulation of all ten batches were shown

cm upper from surface of graph paper and

in table 1 & 2

just touched the apex of the heap of the

Formulation of Batches by 32 Factorial

granules after flow.

Design

The granules were allowed to flow through

To investigate the effect of formulation

the funnel freely onto the surface. The

variables on the response variables and to

diameter of the powder cone was measured

predict an optimized formulation, it was

and angle of repose was calculated using

decided to apply an experimental design.

the following equation

prepared

by

combination

A 32 factorial design was employed for the

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60

Table: 1 Formulation Batches Containing Hydrophilic polymer

F1
90
90
q.s.
4
4
212

Ingredients (mg/tablet)
Diltiazem HCl
HPMC K4M
HPMC K15M
HPMC K100M
Na alginate
Na CMC
PVP K30 in IPA (5% w/v)
Mg stearate (1%)
Talc (1%)
MCC
Total weight

F2
90
90
q.s.
4
4
212

F3
90
90
q.s.
4
4
212
400 mg

F4
90
90
q.s.
4
4
212

F5
90
90
q.s.
4
4
212

Table: 2 Formulation Batches Containing Hydrophobic Polymer

Ingredients (mg/tablet)
Diltiazem HCl
HPMC K15M
Ethyl cellulose
Eudragit RSPO
Eudragit RLPO
Eudragit RS-100
Eudragit RL-100
PVP K30 in IPA (5% w/v)
Mg stearate (1%)
Talc (1%)
MCC
Total weight

F6
90
90
20
q.s.
4
4
192

F7
90
90
20
q.s.
4
4
192

F8
90
90
20
q.s.
4
4
192
400 mg

F9
90
90
20
q.s.
4
4
192

F10
90
90
20
q.s.
4
4
192

Table: 3 Selection of Levels for Independent Variables and Coding of Variables

Low
Intermediate
High

-1
0
1

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Independent Variables
X1 (mg)
X2 (mg)
70
10
90
15
110
20

61

Table: 4 Formulation Batches as Per 32 Factorial Design

Ingredients (mg/tablet)

F11

F12

F13

F14

F15

F16

F17

F18

F19

Diltiazem HCl

90

90

90

90

90

90

90

90

90

HPMC K15M

70

70

70

90

90

90

110

110

110

Eudragit RSPO

10

15

20

10

15

20

10

15

20

MCC

222

217

212

202

197

192

182

177

172

PVP K30 in IPA (5% w/v)

q.s.

q.s.

q.s.

q.s.

q.s.

q.s.

q.s.

q.s.

q.s.

Mg stearate (1%)

Talc (1%)

Total weight

400 mg

tan = H/R

was continued until no further change in

where H and R are the height and radius

volume was noted. LBD and TBD were

of the powder cone respectively

calculated using the following formulas-

Bulk Density and Tapped Density 3,4

LBD = weight of the Powder/Volume of

the packing
TBD = weight of the Powder /tapped
volume of the packing
Compressibility Index 5
The compressibility index of the granules

Both loose bulk density (LBD) and tapped

bulk density (TBD) were determined. A
quantity of 2g of powder from each
formula, previously lightly shaken to break
any agglomerates formed, was introduced

was determined by Carrs compressibility

index formula for that is below-

into a 10mL measuring cylinder. After the

initial volume was observed, the cylinder

Carrs Index (%) = {(TBD-LBD) 100}

was allowed to fall under its own weight

onto a hard surface from the height of

/TBD
Hausners Ratio

2.5cm at 5second intervals. The tapping

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62

It is the ratio of bulk volume to tapped

operated for 100 revolutions (25 rpm

volume or tapped density to bulk density.

speed).

Hausners ratio is an important character to

determine the flow property of powder and

Tablets were dusted and reweighed. The

granules. This can be calculated by the

test complies if tablets not loose more than

following formula-

1% of their weight.

Hausners ratio = Tapped density / Bulk

Drug Content
Three tablets were selected randomly and

density

powdered. A quantity of this powder

equivalent to 90 mg diltiazem HCl was

Evaluation of Tablets

dissolved in 100 ml of distilled water taken

Thickness6
The

in volumetric flask and filtered, 1.5 ml of

thickness

of

the

tablets

was

filtrate was taken in 100 ml volumetric

determined using a thickness venires

flask and diluted up to mark with distilled

calipers. Five tablets from each batch were

water (13.5 mcg/ml).

used, and average values were calculated.

Absorbance of this solution was measured
Hardness7

at 237 nm using distilled water as a blank

It is the tensile strength of tablets

and content of diltiazem hydrochloride

expressed

was estimated.

in

kg/cm2

by

using

the

Monsanto hardness tester. It is the pressure

required to break the tablet into two halves

In-Vitro Dissolution Study11

by compression.

The in vitro dissolution studies were

carried out using USP apparatus type II (at
8,9

Weight Variation Test

Weight variation test was done with 20
tablets. It is the individual variation of
tablet weight from the average weight of

Friability10
This test was performed to know the effect
friction

rpm.

The

dissolution

medium

consisted of distilled water (900 mL),

maintained at temperature of 37C
0.5C.

20 tablets.

of

100

and

shocks

on

tablets.

Preweighed sample of tablets were placed

The drug release at different time intervals

was

measured

by

UV-visible

spectrophotometer at 237 nm. Dissolution

was carried out upto 12 hrs.

in the friabilator (Roche friabilator), and

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63

RESULT AND DISCUSSION

Table: 5 Result of Evaluation of Precompression Parameters of Batches F1-F10
Batch
code

Bulk
density
(gm/ml)

Tapped
density
(gm/ml)

Carrs
index(%)

Hausners
ratio

Angle of
repose ( 0 )

Flow
property

F1
F2

0.200.01
0.190.06

0.220.05
0.200.02

100.21
50.09

1.100.01
1.050.07

26.560.11
25.460.29

Excellent
Excellent

F3

0.200.01

0.210.07

4.760.04

1.050.03

27.750.45

Excellent

F4

0.200.03

0.230.01

13.040.57

1.150.04

33.690.82

Good

F5

0.190.08

0.210.03

9.520.09

1.100.08

29.050.71

Excellent

F6
F7

0.190.01
0.190.07

0.220.05
0.210.02

13.60.18
9.520.07

1.150.01
1.100.07

35.530.33
27.750.84

Good
Excellent

F8
F9

0.190.01
0.210.03

0.220.07
0.220.01

13.60.42
4.50.05

1.150.03
1.040.04

33.690.53
25.46 0.25

Good
Excellent

F10

0.190.08
0.210.03 9.520.05
1.100.08
27.750.19
(All values are expressed as mean standard deviation, n=3)

Excellent

Both bulk density and tapped density for

index. The percent compressibility for all

all the formulations varied from 0.19 to

the formulations lies within the range of

0.21 gm/ml and 0.20 to 0.23 gm/ml

4.50 to 13.6 %. All formulations are

respectively.

showing good compressibility. Hausners

ratio for all the formulation batches lies
within the range of 1.04 to 1.15.

The values obtained lies within the

acceptable range and not large differences
found between bulk density and tapped

The result obtained for angle of repose of

density. This result helps in calculating the

all batches was found to be in the range of

% compressibility of the powder.

25.46 to 35.530. All the formulation

batches showed angle of repose below 300
which indicate that they have excellent

This percent compressibility of granules

flow property except batches F4, F6 and

was determined by Carrs compressibility

F8 which have good flow property.

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64

Table: 6 Result of Evaluation of Post compression Parameters of Batches F1-F10

Batch
code

Thickness
(mm)
[n=3]

Diameter
(mm)
[n=3]

F1

5.60.01

10.250.02

Weight
Variation
Test (5%)
[n=20]
Pass

Friability Hardness
test
(kg/cm2)
(<1%)
[n=3]
[n=5]
0.50.02 6.50.23

Drug
Content
(%)
[n=3]
99.060.13

F2

60.02

10.260.01

Pass

0.650.11

50.16

94.800.55

F3

5.70.10

10.250.04

Pass

0.550.01

60.20

98.710.90

F4

60.08

10.270.05

Pass

0.650.13

50.16

97.930.83

F5

5.80.05

10.250.03

Pass

0.60.10

5.50.24

94.950.66

F6

5.60.03

10.260.06

Pass

0.50.01

6.50.23

93.470.35

F7

5.90.06

10.250.02

Pass

0.60.09

5.50.20

98.420.15

F8

60.01

10.280.07

Pass

0.650.07

50.16

98.880.93

F9

5.80.05

10.250.03

Pass

0.60.10

5.50.20

98.940.82

F10

5.90.03

10.260.02

Pass

0.60.03

5.50.23

96.660.75

(All values are expressed as mean standard deviation)

Table: 7 Result of Evaluation of Precompression Parameters of Factorial Batches

Batch

Bulk density

Tapped

Carrs

Hausners

Angle of

Flow

Code

(gm/ml)

Density

index

ratio

repose( )

Property

(gm/ml)

(%)

F11

0.200.01

0.220.03

100.21

1.100.03

27.270.36

Excellent

F12

0.180.04

0.200.01

100.46

1.110.01

25.460.84

Excellent

F13

0.190.02

0.210.02

9.520.19

1.100.05

28.120.22

Excellent

F14

0.190.01

0.210.01

9.520.33

1.100.02

26.350.19

Excellent

F15

0.200.03

0.220.02

100.54

1.100.06

25.890.67

Excellent

F16

0.200.01

0.220.01

100.71

1.100.04

27.640.53

Excellent

F17

0.200.03

0.210.04

4.760.87

1.050.01

29.110.72

Excellent

F18

0.190.02

0.210.02

9.520.55

1.100.05

26.490.43

Excellent

F19

0.200.03

0.210.03

4.760.92

1.050.03

28.310.92

Excellent

(All values are expressed as mean standard deviation, n=3)

All the formulation batches passed the

diameter for all the formulation batches

weight variation test. The thickness and

was found to be in the range of 5.6 mm to

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65

6 mm and 10.25 mm to 10.28 mm

ranged from 0.18 to 0.20 gm/ml, tapped

respectively. The value obtained for %

density which ranged from 0.20 to 0.22

friability lies within the range of 0.50 % to

gm/ml, Carrs index ranged from 4.76 to

0.65 % which was within the standard

10 %, Hausners ratio ranged from 1.05 to

limit of % friability that is less than 1%.

1.11 and angle of repose ranged from

The hardness value for all batches was

25.46 to 29.11.

found to be in the range of 5 kg/cm2 to 6.5

kg/cm2.

All these results indicate that, the granules

The granules for all nine factorial batches

possess

were evaluated for bulk density which

compressibility properties.

excellent

flow

ability

and

Table: 8 Result of Evaluation of Post compression Parameters of Factorial Batches

Batch
code

Thickness
(mm)
[n=3]

Diameter
(mm)
[n=3]

Friability
test (<1%)
[n=5]

Hardness Drug Content

(kg/cm2)
(%)
[n=3]
[n=3]

10.270.02

Weight
Variation
Test
(5%)
[n=20]
Pass

F11

5.60.01

0.500.02

6.50.23

99.920.13

F12

5.90.02

10.250.01

Pass

0.600.11

5.50.16

99.910.55

F13

6.00.10

10.250.04

Pass

0.650.01

50.20

98.250.90

F14

5.70.08

10.260.05

Pass

0.550.13

60.16

98.740.83

F15

5.60.05

10.270.03

Pass

0.500.10

6.50.24

98.320.66

F16

6.00.03

10.250.06

Pass

0.650.01

50.23

99.290.35

F17

5.60.06

10.250.02

Pass

0.500.09

6.50.20

98.890.15

F18

5.70.01

10.250.07

Pass

0.550.07

60.16

99.500.93

F19

5.80.05

10.260.03

Pass

0.600.10

5.50.20

98.850.82

(All values are expressed as mean standard deviation)

Tablets of all nine factorial batches (F11 to

5.0 to 6.5 kg/cm2. Friability was in range

F19) passed weight variation test as the %

between 0.50 to 0.65 %. Thus, all the

weight

the

physical parameters of the manually

pharmacopoeial limits of 5%. Thickness

compressed tablets were quite within

of all tablets was in the range between 5.6

control. Friability values were less than 1

mm to 6.0 mm. Diameter of all tablets was

% in all cases shows good mechanical

in the range between 10.25 to 10.27 mm.

strength at the time of handling and

Hardness of tablets was in range between

transports.

variation

was

within

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66

In-Vitro Drug Release Study

Fig. 1 : Drug Release Profile of Formulation F1 to F5

In formulation batches F1 to F5, five

98.79% at the end of 10 hrs, F4 was

different hydrophilic polymers (HPMC

99.93% at the end of 6 hrs and % CDR

K4M, HPMC K15M, HPMC K100M,

from formulation F5 was 98.40% at the

Sodium alginate, Sodium carboxymethyl

end of 8 hrs. So from result, it was

cellulose respectively) were used in the 1:1

concluded that among the different grades

ratio of Drug: Hydrophilic polymer. From

of HPMC which were used in present

the In-vitro dissolution data, it was

investigation,

observed that % cumulative drug release

maximum release upto desired period that

(% CDR) from formulations F2 and F3

was 12 hrs in present investigation. So

was 97.96% and 78.68% at the end of 12

HPMC

hrs while %CDR from formulation F1 was

hydrophilic polymer for further study.

K15M

HPMC

was

K15M

selected

gave

as

Fig. 2 : Drug Release Profile of

In formulation F2, bursting effect was

Formulation F6 to F10

observed at the stage of initial release

profile. Because of this bursting effect
there was need to introduce hydrophobic
polymer to reduce bursting effect by
imparting some hydrophobicity to drug
molecule. So in formulation F6 to F10,
five different hydrophobic polymers (EC,
Eudragit RSPO, Eudragit RLPO, Eudragit
RS-100, Eudragit RL-100 respectively)
were used at a concentration of 5% w/w.

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67

The %CDR from formulations F6 to F10

must be selected in such a manner that it

was 63.75%, 57.49%, 59.51%, 68.39%

had less %CDR at the end of 3 hrs (initial

and 72.47% respectively at the end of 12

release profile) and 12 hrs so as it will not

hrs. From the dissolution data of F6 to

show bursting effect and maximum release

F10, it was clearly observed that the

of drug prior to desired period 12 hrs when

%CDR was less at the end of 12 hrs so in

quantity of hydrophobic polymer will be

further formulation there was only one

decreased in further study. From result,

option

conclusion drawn was that formulation F7

to

decrease

the

quantity

of

hydrophobic polymer so as to achieve

(containing

Eudragit

RSPO)

was

maximum release of drug at the end of 12

optimized as it had %CDR less at the end

hrs with no bursting effect at the initial

of 3 hrs and 12 hrs that was 14.14% and

stage of release profile. So formulation

57.49% respectively.

Fig. 3 : Drug Release Profile of Factorial Batches

From the dissolution data obtained from

due to hydrophobic nature of Eudragit

factorial batches, it was observed that in

RSPO which will impart hydrophobicity to

formulations containing same quantity of

the drug molecule so reduced bursting

HPMC K15M as quantity of Eudragit

effect at the initial stage of release profile.

RSPO increased the % CDR at the end of

It was also observed that in formulations

3 hrs and so as 12 hrs decreased that was

containing same quantity of Eudragit

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68

RSPO as the quantity of HPMC K15M

Summary Output of Regression Analysis

increased the % CDR at the end of 12 hrs

for Effect of X1 and X2 on Q3 (% CDR at

decreased that was due to increase in

the End of 3 hrs)

thickness of gel layer formed due to higher

The

quantity of HPMC

drug

equations generated using MLRA for %

molecule took more time to diffused out

CDR at the end of 3 hrs of the tablets

through more thickened gel layer. % CDR

containing

from all nine factorial batches was shown

HPMC K15M and Eudragit RSPO studied

in table. It was concluded that batch F11

are listed in Table 9 along with the values

containing HPMC K15M 70 mg and

of r2.

Eudragit RSPO 10 mg released maximum

represent the effect of that particular factor

amount of drug at the end of 12 hrs that is

on responses while the coefficients with

96.59% with no bursting effect at the

more than one factor and those with

initial stage of release profile (at the end of

second

3 hrs, %CDR was 20.32). So batch F11

interaction between those factors and the

was optimized.

quadratic

Data Analysis

respectively. Positive sign in front of the

The polynomial equations relating the

terms indicates synergistic effect while

responses, % CDR at the end of 3 hrs and

negative sign indicates antagonistic effect

12 hrs to the transformed factor are shown

upon the responses. The Q3 for all batches

in the Table 6.15 and 6.16 respectively.

F11 to F19 showed good correlation co-

The polynomial equations can be used to

efficient of 0.9824. Variables which have

draw conclusions after considering the

P-value less than 0.05, significantly affect

magnitude

the

release profile. For response Q3 reduced

mathematical sign it carries (i.e., negative

mathematical model was evolved omitting

or

the

of

positive).

K15M

coefficient

Analysis

of

so

and

variance

coefficients

of

the

varying

Coefficients

order

nature

insignificant

polynomial

concentration

with

terms

of

one

factor

represent

the

terms

of

the

phenomena,

(p>0.05)

by

(ANOVA), which was performed to

adopting multiple regression analysis. The

identify insignificant factors. Since the

main effect X1 and X2 and interaction

values of r2 are quite high for all the two

terms X1X2 were found significant as P

responses, i.e., 0.9824 to 0.9902, the

value was less than 0.05.

polynomial equations form excellent fits to

the experimental data and are highly
statistically valid.

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69

Table: 9 Summary Output of Regression Analysis for Effect of X1 and X2 on Q3

(% CDR at the end of 3 hrs)
Regression statistics
Multiple R

0.9935

R Square

0.9824

Adjusted R square

0.9531

Standard error

0.5233

Observations

Coefficients
Coefficient

Coefficient value

P-value

b0

18.88

0.0111

b1

-0.057

0.0278

b2

-3.43

0.0016

b12

-1.25

0.0472

b11

0.067

0.9098

b22

-0.56

0.3785

Equation:
Full Model
Y= 18.88-0.057X1-3.43X2-1.25X1X2+0.067X11-0.56X22
Reduced Model
Y= 18.88-0.057X1-3.43X2-1.25X1X2

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70

Table: 10 Summary Output of Regression Analysis for Effect of X1 and X2 on Q12 (%

CDR at the end of 12 hrs)
Regression statistics
Multiple R

0.9951

R Square

0.9902

Adjusted R square

0.9741

Standard error

0.3581

Observations

Coefficients
Coefficient

Coefficient value

P-value

b0

72.55

0.0078

b1

-5.49

0.0233

b2

-2.68

0.0361

b12

-15.49

0.0012

b11

-0.12

0.9603

b22

0.83

0.7317

Equation:
Full Model
Y= 72.55-5.49X1-2.68X2-15.49X1X2-0.12X11+0.83X22
Reduced Model
Y= 72.55-5.49X1-2.68X2-15.49X1X2

Summary Output of Regression Analysis

for Effect of X1 and X2 on Q12 (% CDR
at the End of 12 hrs)
The coefficients of the polynomial

of r2. The Q12 for all batches F11 to F19

showed good correlation co-efficient of
0.9902. Variables which have P-value less

equations generated using MLRA for %

than 0.05, significantly affect release
CDR at the end of 12 hrs of the tablets
profile.
containing

varying

concentration

For

response

Q12

reduced

of
mathematical model was evolved omitting

HPMC K15M and Eudragit RSPO studied

the

insignificant

terms

(p>0.05)

by

are listed in Table 10 along with the values

adopting multiple regression analysis. The

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71

main effect X1 and X2 and interaction

The best fit model was selected on the

terms X1X2 were found significant as P

basis of R2 value. It is evident from the

value was less than 0.05.

data

the

First

Order

Kinetic

and

Korsmeyer-Peppas model were the best fit

Application of Pharmacokinetic Study

model for batch F11.

Table 11 enlists the regression parameters

obtained after fitting dissolution release

The value of n is indicative of release

profile to various kinetics models. The in

vitro release data were kinetically analyzed

mechanism. The value of diffusional

for establishing kinetics of drug release.

Zero-order,

first-order,

exponent (n) of batch F11 is 0.78 that was

Higuchi,
0.45 < n < 0.89.

Korsmeyer-Peppas and Hixon Crowell

models were tested.

So, optimized batch F11 showed diffusion

R2

= Correlation Coefficient

= Release Rate Constant

SSR

= Sum of Squared Residuals

AIC

= Akaike Information Criterion

and erosion controlled release mechanism

(Anamolous non-fickian).

Table: 11 Model Fitting for Optimized Batch (F11)

Model
Zero Order
Kinetic
First
Order
Kinetic
Higuchi
KorsmeyerPeppas
HixonCrowell

R2
0.9059
0.9943
0.8315
0.9970
0.9400

K
0.123
7.794
21.955
6.411
0.036

SSR
1087.98
65.83
1947.8092
34.83
694.1802

AIC
92.89
56.43
100.4680
50.15
87.0555

Comparison of Optimized Formulation

equivalent dose of 90 mg. The release

with Marketed Product

profile of optimized formulation and the

Optimized formulation was compared with

marketed formulation at the end of 3 hrs

the marketed SR tablet of diltiazem

and 12 hrs is given in Table 12.

hydrochloride (DILZEM SR) having an

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72

Table: 12 Comparison of Marketed Formulation with Optimized Formulation

Parameters

Marketed formulation

Optimized formulation

Q3 (% CDR at the end of 3 hrs)

22.591.14

20.321.28

Q12 (% CDR at the end of 12 hrs)

98.151.23

96.591.65

From the result, it was concluded that

at the end of 3 hrs and 12 hrs with

optimized formulation had similar % CDR

marketed product.
Comparison of Dissolution Profiles

Fig. 4 : Comparative Release Profile between Marketed Formulation and Optimized

Batch (F11)

The similarity factor (f2) is a logarithmic

profiles. It approximates the per cent

reciprocal square root transformation of

error between curves. The per cent error

the sum of squared error and is a

is zero when the test

and

reference

measurement of the similarity in the

profiles

and

increases

percent (%) dissolution between the two

proportionally

curves.

are

between the two profiles. The dissolution

considered to be similar when f2 is

profiles are considered to be similar when

between 50 and 100. The f2 value

f1 is between 0 and 15.The f1 value

calculated using equation of similarity was

calculated using equation of dissimilarity

found to be 69.1405. So, f2 value ensures

was found to be 12.4659. So, f1 value

sameness or equivalence of two curves.

ensures sameness or equivalence of two

Dissimilarity factor (f1) describes the

curves.

The

dissolution

profiles

are

identical
with

the dissimilarity

relative error between two dissolution

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73

Stability

Study

of

Optimized

studies of the optimized formulation (F11)

Batch

revealed that no significant changes in %

(F11)12

drug content and % CDR at the end of 3

Stability study of SR tablet of diltiazem

hrs and 12 hrs when stored at temperature

hydrochloride was carried out for 4 weeks

and humidity conditions of 40 2oC/ 75

at specified condition. All data are

mentioned

in

Table

13.The

5 % RH. So, we can say that formulation

stability

having good stability.

Table: 13 Stability Study of Optimized Formulation (F11)

No. of

%Drug Content

weeks

Q3

Q12

(% CDR at the end of 3

(%CDR at the end of

hrs)

12 hrs)

99.920.13

20.321.28

96.591.65

99.041.52

19.981.21

96.481.53

98. 951.32

19.831.18

96.161.34

98.651.21

19.671.15

96.141.29

98.441.29

19.421.26

96.021.16

release

CONCLUSION
It

was

concluded

combination

of

mechanism

(Anamolous

non-

by

using

fickian) as the value of diffusional

hydrophilic

and

exponent (n) of batch F11 is 0.78 that was

that

hydrophobic polymer, it is possible to

0.45 < n < 0.89.

prepare SR matrix tablets of diltiazem

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Lachman, L., Liberman, H. A., &

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430-456.

dissimilarity factor f1 value 12.46 which

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Cooper, J., & Gunn, C.(1986). Powder

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233.

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HOW TO CITE THIS ARTICLE

Bhut, V, Z., Shah, K, K., Patel, K, N., Patel, P, A. (2014). Formulation and Evaluation of Sustained
Release Matrix Tablets of Diltiazem Hydrochloride. Journal Club for Pharmaceutical Sciences
(JCPS). 1(I), 58-75.

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