Formulation and Evaluation of Sustained Release Matrix Tablets of Diltiazem Hydrochloride

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

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Formulation and Evaluation of Sustained Release Matrix Tablets of Diltiazem Hydrochloride

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

1Department 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

Oral route has been the commonly adapted

and most convenient route for drug

delivery because of more flexibility in the

formulation, patient compliance and

convenient for a physician during dose

adjustment. When conventional dosage

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

*Address for Correspondence: Vibha Z. Bhut, Department of Pharmaceutics, Shree Swaminarayan Sanskar Pharmacy College, Zundal, Gandhinagar, Gujarat, India. E-Mail Id: [email protected]

mailto:[email protected]

© All Rights Reserved by “Journals Club & Co.” 59

in case of drug having short half-life and

when larger doses are required can

decrease patient compliance. To overcome

above demerits associated with

conventional dosage forms, sustained

release formulations have been designed

which maintain plasma level of drug for

prolong period hence reduce dosing

frequency and blood level fluctuations.

There is also enhanced patient

convenience and compliance, reduction in

adverse side effects and reduction in

overall health care costs due to reduction

in dosing frequency.

In present investigation the selected drug is

Diltiazem hydrochloride which is a potent

calcium channel blocker, is used in the

management of angina pectoris,

arrhythmia and hypertension. It has short

half-life (t1/2 = 3-4.5 hrs). Dosing

frequency is thrice a day. Normal dose is

60 mg thrice a day and increased upto 360

mg or 480 mg daily, if necessary. As a

result of its short half-life and the need for

administration more times per day, it is

highly desirable to develop an oral

sustained release formulation of this drug,

so as to reduced dosing frequency,

improve therapeutic effects with minimum

side effects and improved patient

compliance.

The matrix system is most common

method of modulating the drug release

because of their flexibility, cost-

effectiveness and broad regulatory

acceptance hydrophilic polymer matrix

systems are widely used in oral controlled

drug delivery to obtain a desirable drug

release profile.1

Materials & Methods

Materials

Diltiazem hydrochloride was obtained as a

gift sample from Torrent Research Centre

Bhat. HPMC K4M, K15M, K100M and

Ethyl Cellulose were purchased from

Rankem RFCL limited, New Delhi. Na

CMC, Na alginate, Talc, Magnesium

stearate, MCC and PVP K-30 was

purchased from Sd fine chem limited,

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

and RLPO were obtained as a gift sample

from Evonik Degussa India Pvt Limited,

Mumbai.

Method (Wet Granulation Method)

Diltiazem HCl and all the intra-granular

ingredients were weighed accurately and

individually passed through 40# sieve

respectively as per batch formula and

mixed geometrically. Then dough mass

was prepared by using PVP K30 in IPA

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


were prepared by passing dough mass

through 10# sieve and then dried at 400C

for 30 minutes in hot air oven. Dried

granules were passed through 22# sieve in

order to obtain uniform sized granules.

Granules were lubricated with Magnesium

stearate & Talc (which were passed

through 60# sieve). Granules were

compressed into tablet in rotary tablet

compression machine by using 10 mm

punch.

Formulation of Preliminary Batches

Batch F1-F5 were prepared by using

hydrophilic polymers and batch F6-F10

were prepared by combination of

hydrophilic and hydrophobic polymers.

Formulation of all ten batches were shown

in table 1 & 2

Formulation of Batches by 32 Factorial

Design

To investigate the effect of formulation

variables on the response variables and to

predict an optimized formulation, it was

decided to apply an experimental design.

A 32 factorial design was employed for the

preparation of the tablets possessing

optimal characteristics. 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

Evaluation of Granules

Angle of Repose 2

The angle of repose of prepared Diltiazem

granules was evaluated by simple funnel

method. The accurately weighed granules

were taken in a funnel. The height of the

funnel was adjusted by stand in such a way

that the tip of the funnel approximately 2

cm upper from surface of graph paper and

just touched the apex of the heap of the

granules after flow.

The granules were allowed to flow through

the funnel freely onto the surface. The

diameter of the powder cone was measured

and angle of repose was calculated using

the following equation


Table: 1 Formulation Batches Containing Hydrophilic polymer

Table: 2 Formulation Batches Containing Hydrophobic Polymer

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

Ingredients (mg/tablet) F1 F2 F3 F4 F5 Diltiazem HCl 90 90 90 90 90 HPMC K4M 90 - - - -

HPMC K15M - 90 - - - HPMC K100M - - 90 - -

Na alginate - - - 90 - Na CMC - - - - 90

PVP K30 in IPA (5% w/v) q.s. q.s. q.s. q.s. q.s. Mg stearate (1%) 4 4 4 4 4

Talc (1%) 4 4 4 4 4 MCC 212 212 212 212 212

Total weight 400 mg

Ingredients (mg/tablet) F6 F7 F8 F9 F10 Diltiazem HCl 90 90 90 90 90 HPMC K15M 90 90 90 90 90 Ethyl cellulose 20 - - - - Eudragit RSPO - 20 - - - Eudragit RLPO - - 20 - -

Eudragit RS-100 - - - 20 - Eudragit RL-100 - - - - 20

PVP K30 in IPA (5% w/v) q.s. q.s. q.s. q.s. q.s. Mg stearate (1%) 4 4 4 4 4

Talc (1%) 4 4 4 4 4 MCC 192 192 192 192 192

Total weight 400 mg

Independent Variables X1 (mg) X2 (mg)

Low -1 70 10 Intermediate 0 90 15

High 1 110 20


Table: 4 Formulation Batches as Per 32 Factorial Design

tanα = H/R

where H and R are the height and radius

of the powder cone respectively

Bulk Density and Tapped Density 3,4

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

into a 10mL measuring cylinder. After the

initial volume was observed, the cylinder

was allowed to fall under its own weight

onto a hard surface from the height of

2.5cm at 5second intervals. The tapping

was continued until no further change in

volume was noted. LBD and TBD were

calculated using the following formulas-

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

was determined by Carr’s compressibility

index formula for that is below-

Carr’s Index (%) = {(TBD-LBD) × 100}

/TBD

Hausner’s Ratio

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%) 4 4 4 4 4 4 4 4 4

Talc (1%) 4 4 4 4 4 4 4 4 4

Total weight 400 mg


It is the ratio of bulk volume to tapped

volume or tapped density to bulk density.

Hausner’s ratio is an important character to

determine the flow property of powder and

granules. This can be calculated by the

following formula-

Hausner’s ratio = Tapped density / Bulk

density

Evaluation of Tablets

Thickness6

The thickness of the tablets was

determined using a thickness venires

calipers. Five tablets from each batch were

used, and average values were calculated.

Hardness7

It is the tensile strength of tablets

expressed in kg/cm2 by using the

Monsanto hardness tester. It is the pressure

required to break the tablet into two halves

by compression.

Weight Variation Test8,9

Weight variation test was done with 20

tablets. It is the individual variation of

tablet weight from the average weight of

20 tablets.

Friability10 This test was performed to know the effect

of friction and shocks on tablets.

Preweighed sample of tablets were placed

in the friabilator (Roche friabilator), and

operated for 100 revolutions (25 rpm

speed).

Tablets were dusted and reweighed. The

test complies if tablets not loose more than

1% of their weight.

Drug Content

Three tablets were selected randomly and

powdered. A quantity of this powder

equivalent to 90 mg diltiazem HCl was

dissolved in 100 ml of distilled water taken

in volumetric flask and filtered, 1.5 ml of

filtrate was taken in 100 ml volumetric

flask and diluted up to mark with distilled

water (13.5 mcg/ml).

Absorbance of this solution was measured

at 237 nm using distilled water as a blank

and content of diltiazem hydrochloride

was estimated.

In-Vitro Dissolution Study11

The in vitro dissolution studies were

carried out using USP apparatus type II (at

100 rpm. The dissolution medium

consisted of distilled water (900 mL),

maintained at temperature of 37°C ±

0.5°C.

The drug release at different time intervals

was measured by UV-visible

spectrophotometer at 237 nm. Dissolution

was carried out upto 12 hrs.


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)

Carr’s index(%)

Hausner’s ratio

Angle of repose ( 0

)

Flow property

F1 0.20±0.01 0.22±0.05 10±0.21 1.10±0.01 26.56±0.11 Excellent F2 0.19±0.06 0.20±0.02 5±0.09 1.05±0.07 25.46±0.29 Excellent F3 0.20±0.01 0.21±0.07 4.76±0.04 1.05±0.03 27.75±0.45 Excellent F4 0.20±0.03 0.23±0.01 13.04±0.57 1.15±0.04 33.69±0.82 Good F5 0.19±0.08 0.21±0.03 9.52±0.09 1.10±0.08 29.05±0.71 Excellent F6 0.19±0.01 0.22±0.05 13.6±0.18 1.15±0.01 35.53±0.33 Good F7 0.19±0.07 0.21±0.02 9.52±0.07 1.10±0.07 27.75±0.84 Excellent F8 0.19±0.01 0.22±0.07 13.6±0.42 1.15±0.03 33.69±0.53 Good F9 0.21±0.03 0.22±0.01 4.5±0.05 1.04±0.04 25.46 ±0.25 Excellent

F10 0.19±0.08 0.21±0.03 9.52±0.05 1.10±0.08 27.75±0.19 Excellent (All values are expressed as mean ± standard deviation, n=3)

Both bulk density and tapped density for

all the formulations varied from 0.19 to

0.21 gm/ml and 0.20 to 0.23 gm/ml

respectively.

The values obtained lies within the

acceptable range and not large differences

found between bulk density and tapped

density. This result helps in calculating the

% compressibility of the powder.

This percent compressibility of granules

was determined by Carr’s compressibility

index. The percent compressibility for all

the formulations lies within the range of

4.50 to 13.6 %. All formulations are

showing good compressibility. Hausner’s

ratio for all the formulation batches lies

within the range of 1.04 to 1.15.

The result obtained for angle of repose of

all batches was found to be in the range of

25.46 to 35.530. All the formulation

batches showed angle of repose below 300

which indicate that they have excellent

flow property except batches F4, F6 and

F8 which have good flow property.


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

(All values are expressed as mean ± standard deviation)

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

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

All the formulation batches passed the

weight variation test. The thickness and

diameter for all the formulation batches

was found to be in the range of 5.6 mm to

Batch code

Thickness (mm) [n=3]

Diameter (mm) [n=3]

Weight Variation

Test (±5%) [n=20]

Friability test

(<1%) [n=5]

Hardness (kg/cm2)

[n=3]

Drug Content

(%) [n=3]

F1 5.6±0.01 10.25±0.02 Pass 0.5±0.02 6.5±0.23 99.06±0.13

F2 6±0.02 10.26±0.01 Pass 0.65±0.11 5±0.16 94.80±0.55

F3 5.7±0.10 10.25±0.04 Pass 0.55±0.01 6±0.20 98.71±0.90

F4 6±0.08 10.27±0.05 Pass 0.65±0.13 5±0.16 97.93±0.83

F5 5.8±0.05 10.25±0.03 Pass 0.6±0.10 5.5±0.24 94.95±0.66

F6 5.6±0.03 10.26±0.06 Pass 0.5±0.01 6.5±0.23 93.47±0.35

F7 5.9±0.06 10.25±0.02 Pass 0.6±0.09 5.5±0.20 98.42±0.15

F8 6±0.01 10.28±0.07 Pass 0.65±0.07 5±0.16 98.88±0.93

F9 5.8±0.05 10.25±0.03 Pass 0.6±0.10 5.5±0.20 98.94±0.82

F10 5.9±0.03 10.26±0.02 Pass 0.6±0.03 5.5±0.23 96.66±0.75

Batch

Code

Bulk density

(gm/ml)

Tapped

Density

(gm/ml)

Carr’s

index

(%)

Hausner’s

ratio

Angle of

repose( ° )

Flow

Property

F11 0.20±0.01 0.22±0.03 10±0.21 1.10±0.03 27.27±0.36 Excellent

F12 0.18±0.04 0.20±0.01 10±0.46 1.11±0.01 25.46±0.84 Excellent

F13 0.19±0.02 0.21±0.02 9.52±0.19 1.10±0.05 28.12±0.22 Excellent

F14 0.19±0.01 0.21±0.01 9.52±0.33 1.10±0.02 26.35±0.19 Excellent

F15 0.20±0.03 0.22±0.02 10±0.54 1.10±0.06 25.89±0.67 Excellent

F16 0.20±0.01 0.22±0.01 10±0.71 1.10±0.04 27.64±0.53 Excellent

F17 0.20±0.03 0.21±0.04 4.76±0.87 1.05±0.01 29.11±0.72 Excellent

F18 0.19±0.02 0.21±0.02 9.52±0.55 1.10±0.05 26.49±0.43 Excellent

F19 0.20±0.03 0.21±0.03 4.76±0.92 1.05±0.03 28.31±0.92 Excellent


6 mm and 10.25 mm to 10.28 mm

respectively. The value obtained for %

friability lies within the range of 0.50 % to

0.65 % which was within the standard

limit of % friability that is less than 1%.

The hardness value for all batches was

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

kg/cm2.

The granules for all nine factorial batches

were evaluated for bulk density which

ranged from 0.18 to 0.20 gm/ml, tapped

density which ranged from 0.20 to 0.22

gm/ml, Carr’s index ranged from 4.76 to

10 %, Hausner’s ratio ranged from 1.05 to

1.11 and angle of repose ranged from

25.46 to 29.11°.

All these results indicate that, the granules

possess excellent flow ability and

compressibility properties.

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

(All values are expressed as mean ± standard deviation)

Tablets of all nine factorial batches (F11 to

F19) passed weight variation test as the %

weight variation was within the

pharmacopoeial limits of 5%. Thickness

of all tablets was in the range between 5.6

mm to 6.0 mm. Diameter of all tablets was

in the range between 10.25 to 10.27 mm.

Hardness of tablets was in range between

5.0 to 6.5 kg/cm2. Friability was in range

between 0.50 to 0.65 %. Thus, all the

physical parameters of the manually

compressed tablets were quite within

control. Friability values were less than 1

% in all cases shows good mechanical

strength at the time of handling and

transports.

Batch code

Thickness (mm) [n=3]

Diameter (mm) [n=3]

Weight Variation

Test (±5%) [n=20]

Friability test (<1%)

[n=5]

Hardness (kg/cm2)

[n=3]

Drug Content (%)

[n=3]

F11 5.6±0.01 10.27±0.02 Pass 0.50±0.02 6.5±0.23 99.92±0.13

F12 5.9±0.02 10.25±0.01 Pass 0.60±0.11 5.5±0.16 99.91±0.55

F13 6.0±0.10 10.25±0.04 Pass 0.65±0.01 5±0.20 98.25±0.90

F14 5.7±0.08 10.26±0.05 Pass 0.55±0.13 6±0.16 98.74±0.83

F15 5.6±0.05 10.27±0.03 Pass 0.50±0.10 6.5±0.24 98.32±0.66

F16 6.0±0.03 10.25±0.06 Pass 0.65±0.01 5±0.23 99.29±0.35

F17 5.6±0.06 10.25±0.02 Pass 0.50±0.09 6.5±0.20 98.89±0.15

F18 5.7±0.01 10.25±0.07 Pass 0.55±0.07 6±0.16 99.50±0.93

F19 5.8±0.05 10.26±0.03 Pass 0.60±0.10 5.5±0.20 98.85±0.82


In-Vitro Drug Release Study

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

In formulation batches F1 to F5, five

different hydrophilic polymers (HPMC

K4M, HPMC K15M, HPMC K100M,

Sodium alginate, Sodium carboxymethyl

cellulose respectively) were used in the 1:1

ratio of Drug: Hydrophilic polymer. From

the In-vitro dissolution data, it was

observed that % cumulative drug release

(% CDR) from formulations F2 and F3

was 97.96% and 78.68% at the end of 12

hrs while %CDR from formulation F1 was

98.79% at the end of 10 hrs, F4 was

99.93% at the end of 6 hrs and % CDR

from formulation F5 was 98.40% at the

end of 8 hrs. So from result, it was

concluded that among the different grades

of HPMC which were used in present

investigation, HPMC K15M gave

maximum release upto desired period that

was 12 hrs in present investigation. So

HPMC K15M was selected as a

hydrophilic polymer for further study.

Fig. 2 : Drug Release Profile of

Formulation F6 to F10

In formulation F2, bursting effect was

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.


The %CDR from formulations F6 to F10

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

and 72.47% respectively at the end of 12

hrs. From the dissolution data of F6 to

F10, it was clearly observed that the

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

further formulation there was only one

option to decrease the quantity of

hydrophobic polymer so as to achieve

maximum release of drug at the end of 12

hrs with no bursting effect at the initial

stage of release profile. So formulation

must be selected in such a manner that it

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

release profile) and 12 hrs so as it will not

show bursting effect and maximum release

of drug prior to desired period 12 hrs when

quantity of hydrophobic polymer will be

decreased in further study. From result,

conclusion drawn was that formulation F7

(containing Eudragit RSPO) was

optimized as it had %CDR less at the end

of 3 hrs and 12 hrs that was 14.14% and

57.49% respectively.

Fig. 3 : Drug Release Profile of Factorial Batches

From the dissolution data obtained from

factorial batches, it was observed that in

formulations containing same quantity of

HPMC K15M as quantity of Eudragit

RSPO increased the % CDR at the end of

3 hrs and so as 12 hrs decreased that was

due to hydrophobic nature of Eudragit

RSPO which will impart hydrophobicity to

the drug molecule so reduced bursting

effect at the initial stage of release profile.

It was also observed that in formulations

containing same quantity of Eudragit


RSPO as the quantity of HPMC K15M

increased the % CDR at the end of 12 hrs

decreased that was due to increase in

thickness of gel layer formed due to higher

quantity of HPMC K15M so drug

molecule took more time to diffused out

through more thickened gel layer. % CDR

from all nine factorial batches was shown

in table. It was concluded that batch F11

containing HPMC K15M 70 mg and

Eudragit RSPO 10 mg released maximum

amount of drug at the end of 12 hrs that is

96.59% with no bursting effect at the

initial stage of release profile (at the end of

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

was optimized.

Data Analysis

The polynomial equations relating the

responses, % CDR at the end of 3 hrs and

12 hrs to the transformed factor are shown

in the Table 6.15 and 6.16 respectively.

The polynomial equations can be used to

draw conclusions after considering the

magnitude of coefficient and the

mathematical sign it carries (i.e., negative

or positive). Analysis of variance

(ANOVA), which was performed to

identify insignificant factors. Since the

values of r2 are quite high for all the two

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

polynomial equations form excellent fits to

the experimental data and are highly

statistically valid.

Summary Output of Regression Analysis

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

the End of 3 hrs)

The coefficients of the polynomial

equations generated using MLRA for %

CDR at the end of 3 hrs of the tablets

containing varying concentration of

HPMC K15M and Eudragit RSPO studied

are listed in Table 9 along with the values

of r2. Coefficients with one factor

represent the effect of that particular factor

on responses while the coefficients with

more than one factor and those with

second order terms represent the

interaction between those factors and the

quadratic nature of the phenomena,

respectively. Positive sign in front of the

terms indicates synergistic effect while

negative sign indicates antagonistic effect

upon the responses. The Q3 for all batches

F11 to F19 showed good correlation co-

efficient of 0.9824. Variables which have

P-value less than 0.05, significantly affect

release profile. For response Q3 reduced

mathematical model was evolved omitting

the insignificant terms (p>0.05) by

adopting multiple regression analysis. The

main effect X1 and X2 and interaction

terms X1X2 were found significant as P

value was less than 0.05.


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 9

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


Table: 10 Summary Output of Regression Analysis for Effect of X1 and X2 on Q12 (% CDR at the end of 12 hrs)

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

equations generated using MLRA for %

CDR at the end of 12 hrs of the tablets

containing varying concentration of

HPMC K15M and Eudragit RSPO studied

are listed in Table 10 along with the values

of r2. The Q12 for all batches F11 to F19

showed good correlation co-efficient of

0.9902. Variables which have P-value less

than 0.05, significantly affect release

profile. For response Q12 reduced

mathematical model was evolved omitting

the insignificant terms (p>0.05) by

adopting multiple regression analysis. The

Regression statistics

Multiple R 0.9951

R Square 0.9902

Adjusted R square 0.9741

Standard error 0.3581

Observations 9

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


main effect X1 and X2 and interaction

terms X1X2 were found significant as P

value was less than 0.05.

Application of Pharmacokinetic Study

Table 11 enlists the regression parameters

obtained after fitting dissolution release

profile to various kinetics models. The in

vitro release data were kinetically analyzed

for establishing kinetics of drug release.

Zero-order, first-order, Higuchi,

Korsmeyer-Peppas and Hixon Crowell

models were tested.

R2 = Correlation Coefficient

K = Release Rate Constant

SSR = Sum of Squared Residuals

AIC = Akaike Information Criterion

The best fit model was selected on the

basis of R2 value. It is evident from the

data the First Order Kinetic and

Korsmeyer-Peppas model were the best fit

model for batch F11.

The value of n is indicative of release

mechanism. The value of diffusional

exponent (n) of batch F11 is 0.78 that was

0.45 < n < 0.89.

So, optimized batch F11 showed diffusion

and erosion controlled release mechanism

(Anamolous non-fickian).

Table: 11 Model Fitting for Optimized Batch (F11)

Model R2 K SSR AIC Zero Order

Kinetic 0.9059 0.123 1087.98 92.89

First Order Kinetic

0.9943 7.794 65.83 56.43 Higuchi 0.8315 21.955 1947.8092 100.4680

Korsmeyer-Peppas

0.9970 6.411 34.83 50.15 Hixon-Crowell

0.9400 0.036 694.1802 87.0555

Comparison of Optimized Formulation

with Marketed Product

Optimized formulation was compared with

the marketed SR tablet of diltiazem

hydrochloride (DILZEM SR) having an

equivalent dose of 90 mg. The release

profile of optimized formulation and the

marketed formulation at the end of 3 hrs

and 12 hrs is given in Table 12.


Table: 12 Comparison of Marketed Formulation with Optimized Formulation

Parameters Marketed formulation Optimized formulation

Q3 (% CDR at the end of 3 hrs) 22.59±1.14 20.32±1.28

Q12 (% CDR at the end of 12 hrs) 98.15±1.23 96.59±1.65

From the result, it was concluded that

optimized formulation had similar % CDR

at the end of 3 hrs and 12 hrs with

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

reciprocal square root transformation of

the sum of squared error and is a

measurement of the similarity in the

percent (%) dissolution between the two

curves. The dissolution profiles are

considered to be similar when f2 is

between 50 and 100. The f2 value

calculated using equation of similarity was

found to be 69.1405. So, f2 value ensures

sameness or equivalence of two curves.

Dissimilarity factor (f1) describes the

relative error between two dissolution

profiles. It approximates the per cent

error between curves. The per cent error

is zero when the test and reference

profiles are identical and increases

proportionally with the dissimilarity

between the two profiles. The dissolution

profiles are considered to be similar when

f1 is between 0 and 15.The f1 value

calculated using equation of dissimilarity

was found to be 12.4659. So, f1 value

ensures sameness or equivalence of two

curves.


Stability Study of Optimized Batch

(F11)12

Stability study of SR tablet of diltiazem

hydrochloride was carried out for 4 weeks

at specified condition. All data are

mentioned in Table 13.The stability

studies of the optimized formulation (F11)

revealed that no significant changes in %

drug content and % CDR at the end of 3

hrs and 12 hrs when stored at temperature

and humidity conditions of 40 ± 2oC/ 75 ±

5 % RH. So, we can say that formulation

having good stability.

Table: 13 Stability Study of Optimized Formulation (F11)

CONCLUSION It was concluded that by using

combination of hydrophilic and

hydrophobic polymer, it is possible to

prepare SR matrix tablets of diltiazem

HCl with acceptable mechanical strength

and desired drug release property. Batch

F11 containing 70 mg HPMC K15M and

10 mg Eudragit RSPO was optimized as it

has similarity factor f2 value 69.14 and

dissimilarity factor f1 value 12.46 which

ensures sameness or equivalence with

release profile of marketed product

(DILZEM SR). Optimized batch F11

showed diffusion and erosion controlled

release mechanism (Anamolous non-

fickian) as the value of diffusional

exponent (n) of batch F11 is 0.78 that was

0.45 < n < 0.89.

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No. of

weeks

%Drug Content Q3

(% CDR at the end of 3

hrs)

Q12

(%CDR at the end of

12 hrs)

0 99.92±0.13 20.32±1.28 96.59±1.65

1 99.04±1.52 19.98±1.21 96.48±1.53

2 98. 95±1.32 19.83±1.18 96.16±1.34

3 98.65±1.21 19.67±1.15 96.14±1.29

4 98.44±1.29 19.42±1.26 96.02±1.16


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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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Formulation and Evaluation of Sustained Release Matrix Tablets of Diltiazem Hydrochloride

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