Results and Discussion

7.1 PREFORMULATION STUDIES

RESULTS AND DISCUSSION:

1) Characterization of Diltiazem HCl

a) Organoleptic characterization and Melting point determination
Table No.7.1: Organoleptic characterization and Melting point determination of
drug

Test Observation

Colour White To Off-White

Odour Bitter

Taste Odorless

Melting point 210 0C

b) Solubility Analysis:
Table No.7.2: Solubility profile of Diltiazem HCl

Sr. No. Solvent Solubility

1 Distilled water Freely soluble

2 Chloroform Freely soluble

3 Methanol Freely soluble

4 Formic acid Freely soluble

5 Ethanol Sparingly soluble

6 Ether Insoluble

c) Micromeritic characterization of drug:

The Micromeritic characterization of Diltiazem HCl was carried out and
following observations were made as given in table no. 12 below

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 Results and Discussion

Table No.7.3 : Micromeritic characterization of Diltiazem HCl

Sr. No. Parameters Result

1 Loose bulk density 0.45g/cm3

2 Tapped density 0.52g/cm3

3 Carr's Index 21.31%

4 Hausner's ratio 1.39

5 Angle of Repose 380 74’

2) Spectroscopic studies:
a) UV spectroscopy (Determination of λ max.)

Fig. No.7.1 : UV Spectra of Diltiazem HCL

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 Results and Discussion

b) FTIR Spectra of Drug

Fig. No.7.2: IR Spectra of Diltiazem HCl

c) Compatibility Studies between Drug and Polymer:

Fig. No.7.3: IR Spectra of Diltiazem HCl with Xanthan gum

Fig. No7.4: IR Spectra of Diltiazem HCl with Chitosan

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 Results and Discussion

Fig. No.7. 5: IR Spectra of Diltiazem HCl with chitosan & xanthan gum

FTIR spectra of drug and polymer were scanned over the wavenumber range of
4000 to 500 cm -1 .The principal peaks for Diltiazem HCl were obtained at wave no.3700,
1700, 3000, 2500, and 1800-600 cm -1. No significant changes in peak pattern in the IR
spectra of pure Drug and physical mixtures of drug with polymer indicates that there is
no interaction between pure drug and polymer.

3) Standard Calibration Curve of Diltiazem HCl:

a) Calibration curve of Diltiazem HCl in pH 1.2 buffer (0.1N HCl)
Diltiazem HCl was found to obey Beer’s Lambert’s law in the concentration
range of 0-18 µg/ml at 236 nm against 1.2 pH buffer (0.1N HCl).

Table No.7.4 Calibration Curve of Diltiazem HCl

in pH 1.2 buffer (0.1N HCl).

Sr. Concentration Mean absorbance

No (µg/ml) at 236.0nm
1. 0 0
2. 2 0.139
3. 4 0.254
4. 6 0.370
5. 8 0.477
6. 10 0.591
7. 12 0.732

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 Results and Discussion

y = 0.0667x - 0.0042
0.8
R² = 0.9981
0.6

Absorbance
0.4
A…
0.2

0
0 5 10 15
Concentration

Fig. No. 7.6: Calibration Curve of Diltiazem HCl

in pH 1.2 buffer (0.1N HCl).

b) Calibration curve of Diltiazem HCl in pH 7.4 buffer

Diltiazem HCl was found to obey Beer’s Lambert’s law in the concentration
range of 0-18 µg/ml at 236 nm against pH 7.4 phosphate buffer.

Table No.7.5: Calibration curve for Diltiazem HCl

in Phosphate buffer pH 7.4

Sr. Concentration Mean absorbance

No (µg/ml) at 238.0 nm

1. 0 0

2. 2 0.128

3. 4 0.266

4. 6 0.398

5. 8 0.501

6. 10 0.629

7. 12 0.766

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 Results and Discussion

y = 0.0631x + 0.0052
1
R² = 0.999
0.8

Absorba
0.6
0.4 ABS
0.2 Linear (ABS)
0
0 5 10 15

Concentration

Fig. No. 7.7: Calibration Curve of Diltiazem HCl in pH 7.4 buffer

4) Evaluation of prepared Diltiazem HCl granules:

All the formulation granules were evaluated for pre-compression parameters
such as Angle of the repose, Loose Bulk Density, Tapped Bulk Density, Carr’s Index
and Hausner’s Ratio and results obtained are shown in the table below.

Table No. 7.6: Evaluation of physical properties of granules

Form Loose bulk Tapped bulk Carr’s Hausner Angle of repose

ulati density(g/c density index ratio (degrees)
on m2 (g/cm2) (%)

F1 0.443±0.013 0.508±0.008 12.6±0.04 1.145±0.01 31002’±0.014

F2 0.466±0.009 0.528±0.017 11.7±0.03 1.13±0.009 32082’±0.019

F3 0.488±0.007 0.522±0.019 7.89±0.01 1.069±0.01 29075’±0.011

F4 0.455±0.011 0.495±0.013 8.68±0.02 1.08±0.004 30046’±0.008

F5 0.469±0.014 0.506±0.007 8.41±0.01 1.07±0.001 29064’±0.002

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 Results and Discussion

F6 0.434±0.008 0.498±0.021 11.3±0.02 1.14±0.009 32026’±0.009

F7 0.414±0.009 0.462±0.012 10.3±0.02 1.11±0.003 32045’±0.014

F8 0.472±0.015 0.532±0.014 11.3±0.03 1.127±0.01 29038’±0.026

F9 0.486±0.007 0.539±0.011 9.67±0.02 1.10±0.007 33018’±0.012

S. D. – standard deviation

a) Angle of repose:
The results of angle of repose of all the formulations were found to be in range
of 29038’±0.026 to 33018’±0.012, indicating good flow property and this was further
supported by lower compressibility index values. Thus it can be concluded that the
granules for all the batches possessed good flow characteristics.

b) Bulk Density:
It has been stated that the bulk density values less than 1.2 g/cm2 indicate
good packing & values greater than 1.5 g/cm2 indicate poor packing. The loose bulk
density and tapped bulk density values for all the formulation varied in range of
0.414±0.009 g/cm3 to 0.486±0.007 g/cm3 and 0.462±0.012 g/cm3 to 0.539±0.011
g/cm3 respectively. The values obtained lies within the acceptable range. These
results may further influence property such as compressibility and tablet dissolution.

c) Compressibility Index:
The percent compressibility of granules was determined by Carr’s
compressibility index, the results shown in table no.15. The percent compressibility
for all formulation lies within the range of 7.89±0.019% to 12.69±0.042% indicates
acceptable flow property.

d) Hausner’s Ratio:
Hausner’s ratio was found to be in a range of 1.069±0.014 to 1.148±0.009,
which shows acceptable flow property and good packing ability.

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 Results and Discussion

1) Evaluation of Sustained Release Diltiazem HCl Matrix Tablets:

Table No. 7.7: Standard Physical Tests For Matrix Tablets:

Formulation Hardness Percent Thickness Content Weight

friability( uniformit variation
(kg/cm2) %) (mm) y (%)

F1 6.3±0.1 0.57±0.03 2.8±0.02 101.93% 200.66±0.57

F2 6.5±0.3 0.68±0.01 2.5±0.06 98.86% 199.34±1.1

F3 6.2±0.2 0.49±0.04 2.4±0.03 99.28% 201.25±0.68

F4 6.1±0.2 0.65±0.02 2.7±0.02 98.77% 201.91±1.13

F5 6.4±0.4 0.51±0.06 2.6±0.04 99.81% 202.11±1.15

F6 6.2±0.3 0.62±0.04 2.8±0.07 100.47% 199.37±0.88

F7 6.4±0.2 0.67±0.06 2.4±0.06 98.23% 201.53±0.35

F8 6.5±0.2 0.69±0.03 2.7±0.08 99.76% 200.54±0.68

F9 6.4±0.1 0.55±0.05 2.6±0.04 99.21% 200.45±0.84

SD:-standard deviation

Tablets of all formulations (F1 to F9) were evaluated for different parameters such as
thickness, hardness, weight variation, drug content and friability and results shown in
table no.7.7.

a) Hardness:

Tablet hardness was determined by using Monsanto hardness tester.

Hardness of three tablets of each tablet was determined. Hardness values of the
formulation ranged from 6 to 6.5 kg/cm2, which indicate good strength of tablet.

b) Friability:

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 Results and Discussion

Tablet friability was determined by Roche friabilator and weight loss was
calculated and represented in the terms of % friability. Friability values of all the
formulation were less than 1%, indicating good strength of tablet.

c) Weight Variation:

In weight variation test, the Pharmacopoeial limit for percent of deviation

for tablets weighing between 130-324 mg is not more than 7.5%. The average percent
deviation of all tablets was found to be within the limit and hence all formulation
passes the weight variation test.

d) Thickness:

Examination of tablets from each batch showed flat circular shape with no
cracks having white colour. The thickness of tablets was determined using Vernier
caliper. The thickness of tablets ranged from 2.4±0.03mm to 2.8±0.07mm. All
formulations showed uniform thickness.

e) Content Uniformity:

The drug content was found to be uniform among all formulation and
ranged from 98.23% to 101.93%.

F) In-vitro Drug Release Studies:

The in-vitro drug release characteristics were studied in pH 1.2 buffer (0.1
N HCl) for first two hours and in phosphate buffer pH 7.4 for next 10 hours under sink
condition using USP dissolution apparatus type II. The theoretical release profile
calculation is important to evaluate the formulation with respect to release rates and
to ascertain whether it releases the drug in predetermine manner.

Table No.7.8: In-vitro dissolution data of F1, F2, F3 & Marketed formulation

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 Results and Discussion

Time in % Cumulative drug release (mean ± S.D.)

Hours
F1 F2 F3 Marketed

0 00.00 00.00 00.00 00.00

1 23.6±0.421 20.6±0.474 19.45±0.652 17.78±0.563

2 33.2±0.547 28.0±0.659 27.14±0.455 25.58±0.452

3 42.0±0,345 35.1±0.239 34.65±0.316 33.76±0.544

4 50.48±0.473 41.74±0.596 40.61±0.276 41.08±0.511

5 58.9±0.431 47.35±0.461 46.5±0.233 49.47±0.288

6 68.5±0.499 55.91±0.321 53.21±0.549 57.32±0.324

7 77.4±0.376 63.33±0.769 60.22±0.671 64.11±0.672

8 85.05±0.612 70.21±0.377 66.28±0.429 71.30±0.459

9 91.34±0.433 76.75±0.563 72.76±0.434 79.36±0.395

10 97.3±0.376 83.28±0.663 78.41±0.546 87.34±0.432

11 - 89.31±0.245 83.89±0.265 93.29±0.451

12 - 96.90±0.543 90.7±0.653 98.24±0279

S. D. – Standard deviation
120
100
% Cumulative Release

80
60
40
20
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Time in Hrs

Fig. No.7.8: In-Vitro Dissolution Profile of Formulation F1, F2, F3

& Marketed Formulation

Table No.7.9: In-vitro dissolution data of F4, F5, F6 & Marketed formulation

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 Results and Discussion

Time in % Cumulative drug release (mean ± S.D.)

Hours
F4 F5 F6 Marketed

0 00.00 00.00 00.00 00.00

1 26.2±0.564 21.8±0.563 18.5±0.319 17.78±0.563

2 34.6±0.5734 28.4±0.465 25.7±0.379 25.58±0.452

3 44.6±0.276 35.6±0.674 33.6±0.356 33.76±0.544

4 53.8±0.765 43.5±0.286 39.6±0.235 41.08±0.511

5 62.3±0.436 50.8±0.659 46.8±0.212 49.47±0.288

6 71.5±0.786 57.4±0.672 55.4±0.745 57.32±0.324

7 79.2±0.342 65.9±0.468 59.95±0.611 64.11±0.672

8 86.64±0.342 72.55±0.875 66.81±0.423 71.30±0.459

9 92.93±0.511 78.38±0.328 76.12±0.588 79.36±0.395

10 97.29±0.299 85.09±0.761 84.65±0.743 87.34±0.432

11 - 93.22±0.761 89.7±0.569 93.29±0.451

12 - 98.20±0.495 95.1±0.453 98.24±0279

S. D. – Standard deviation

120
% cumulative release

100
80
60
40
20
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
time in Hrs

Fig. No.7.9: In-Vitro Dissolution Profile of Formulation F4, F5, F6

& Marketed Formulation

Table No.7.10: In-vitro dissolution data of F7, F8, F9 & Marketed formulation

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 Results and Discussion

Time in % Cumulative drug release (mean ± S.D.)

Hrs.
F7 F8 F9 Marketed

0 00.00 00.00 00.00 00.00

1 20.0±0.521 18.36±0.124 16.59±0.233 17.78±0.563

2 29.21±0.424 26.4±0.175 24.64±0.587 25.58±0.452

3 36.9±0.711 34.3±0.212 30.98±0.764 33.76±0.544

4 44.8±0.563 42.2±0.405 38.13±0.431 41.08±0.511

5 52.7±0.654 50.1±0.489 46.81±0.266 49.47±0.288

6 60.7±0.561 58.7±0.476 53.73±0.769 57.32±0.324

7 68.6±0.634 65.3±0.554 62.86±0.299 64.11±0.672

8 75.2±0.256 73.8±0.619 69.83±0.535 71.30±0.459

9 81.02±0.387 81.1±0.625 74.35±0.481 79.36±0.395

10 89.7±0.268 87.65±0.551 84.54±0.365 87.34±0.432

11 91.56±0.562 93.84±0.605 89.53±0.276 93.29±0.451

12 95.18±0.769 97.16±0.479 94.44±0.679 98.24±0279

S. D. – Standard deviation

120
100
% cumulative release

80
60
40
20
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
time in hrs

Fig. No.7.10: In-Vitro Dissolution Profile of Formulation F7, F8, F9&Marketed

Formulation

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 Results and Discussion

All the formulations were subjected to in-vitro dissolution studies and results are shown
in table no.17, 18, 19 and Fig. no.8, 9 & 10. The results reveal that release profiles of
matrix tablets of diltiazem containing varying proportion of xanthan gum (15, 20, and
25% of total weight of tablet) i.e. batch F1, F2 and F3 showed drug release as 97.3% for
10 hrs, 96.9% for 12 hrs and 90.7 % for 12 hrs respectively (Table No.17 & Fig. No.8). In
the first two hrs, i.e. in pH 1.2 buffer, drug release is rapid, which may be due to ionization
of xanthan gum at lower pH and intramolecular hydrogelation is prevented due to the
absence of ionic bonds and such difference in the ionization state of polymer affects
hydrogel formation and drug release is retarded in the next 10 hrs. The drug release
occurs when solvent penetrates through dry matrix, gelation of polymer and then
dissolution and diffusion of drug through the resultant layer causing hydration of outer
layer. This shows that as the concentration of xanthan gum increases, the rate of drug
release decreases.

Release profiles of formulations containing various concentrations of chitosan (20, 30 &

40% of total weight of tablet) i.e. batch F4, F5 and F6 showed drug release as 97.29%,
98.2%, and 95.1% respectively (Table No.18 & Fig. No. 9). Batch F4 shown total drug
release in 10 hrs while batch F5 & F6 released the drug for 12 hrs. From release profiles
of chitosan batches, it can be seen that it gives slow steady release in lower pH and drug
release is retarded at higher pH environment. This may be due to formation of hydrogel
in 0.1 N HCl, low solubility of polymer in acidic media and retardation of drug release in
alkaline media on account of intramolecular hydrogelation. The drug release may occur
through erosion on hydration and dissolution of hydrogel layer.

The release profiles of combination batches i.e. F7, F8, and F9 containing a fixed
proportion of ratios xanthan gum and chitosan (F7; 15:25%, F8; 17.5:25% & F9; 20:25%
of total weight of tablet) showed 95.18%, 97.16% and 94.44% of drug release
respectively (Table No.19 & Fig. No. 10). All batches shown drug release for 12 hrs. On
combination of both polymers, a sustained drug release is obtained which was not
obtained in such a manner in case of either single polymer. This may be because the drug
release is not affected by pH environment of either acidic or alkaline media. This shows
that a combination of both polymers leads to pH independent release profile.

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 Results and Discussion

In-vitro release studies of all the formulations (F1-F9) were also compared with the
marketed preparation. The results showed that the drug release profile of formulation F8
resembles with that of marketed formulation. Hence formulation F8 containing
combination of Xanthan gum and Chitosan in the concentration ratio of 17.5:25% (of the
total weight of tablet) was considered as optimized formulation.

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