Formulation and Evaluation of
Sustained release matrix tablets of Atomoxetine HCl by using Natural and
Synthetic Polymers
Dr. Y. Krishna Reddy1*,
Fathima Umera2
1Department of
Pharmaceutics, Nalanda College of Pharmacy, Jawaharlal Nehru Technological
University, Hyderabad, Telangana.
2Department of
Industrial Pharmacy, Nalanda College of Pharmacy, Jawaharlal Nehru
Technological University, Hyderabad, Telangana.
*Corresponding Author E-mail: rajinisuralabs1@gmail.com
ABSTRACT:
The primary benefit of a
sustained release dosage form compared to a conventional dosage form, is the
uniform drug plasma concentration and therefore uniform therapeutic effect.
Matrix system are favored because of their simplicity, patient compliance etc,
than traditional drug delivery which have many drawbacks like repeated
administration, fluctuation in blood concentration level etc. The objective of
the present study was to develop, evaluate and compare once-daily sustained
release matrix tablets of Atomoxetine HCL using Xanthan gum, Karaya gum, Ethyl
cellulose and HPMC K 100 polymers. The matrix tablet formulations were prepared
by using different drug: polymer ratios (1:1, 1:2, and 1:3). The prepared
matrix tablets were evaluated for various parameters like hardness, thickness,
weight variation, friability, percent drug content and in vitro drug
release studies as per IP guidelines. Out of 12 formulations, the formulation
F5 is selected as best formulation which shows 98.56 % drug release in 12 hrs.
INTRODUCTION:1-9
Sustained release
tablets are commonly taken only once or twice daily, compared with counterpart
conventional forms that may have to take three or four times daily to achieve
the same therapeutic effect.
Sustained release,
prolonged release, modified release, extended release or depot formulations are
terms used to identify drug delivery systems that are designed to achieve or
extend therapeutic effect by continuously releasing medication over an extended
period of time after administration of a single dose.
Atomoxetine HCL for the
treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) alone or in
combination with behavioral treatment, as an adjunct to psychological,
educational, social, and other remedial measures.
The objective of the study includes:
·
To
improve the bioavailability
· Reduce the number
of doses and to increase patient compliance it was formulated as controlled
release tablets using various polymers.
MATERIALS AND METHODS:
Atomoxetine HCL was
Provided by Sura Labs, Dilsukhnagar, Hyderabad. Xanthan gum was gifted from Hi media Lab Pvt Ltd, Mumbai, India.
Karayagum, MCC was gifted form Merck
Specialities Pvt Ltd, Mumbai, India. Ethyl cellulose was gifted from Aravind Remedies (AR), Chennai, India.
HPMC K 100, was gifted from, Research- Lab
Fine Chem Industries. Mumbai. PVP K 30, Magnesium sterate, Talc was
gifted from S.D. Fine Chemicals. India
METHADOLOGY:
Preformulation parameters
The various characteristics of blends tested as per Pharmacopoeia.
Formulation development of Tablets:
All the
formulations were prepared by direct compression. The compositions of different
formulations are given in Table-1.
Table
No:1 Formulation composition for tablets
|
Ingredients |
Formulation code |
|||||||||||
|
F1 |
F2 |
F3 |
F4 |
F5 |
F6 |
F7 |
F8 |
F9 |
F10 |
F11 |
F12 |
|
|
Atomoxetine HCl |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
|
Xanthan gum |
20 |
40 |
60 |
- |
- |
- |
- |
- |
- |
- |
- |
- |
|
Karayagum |
- |
- |
- |
20 |
40 |
60 |
- |
- |
- |
- |
- |
- |
|
Ethyl cellulose |
- |
- |
- |
- |
- |
- |
20 |
40 |
60 |
- |
- |
- |
|
HPMC K 100 |
- |
- |
- |
- |
- |
- |
- |
- |
- |
20 |
40 |
60 |
|
PVP K 30 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
|
MCC |
108 |
88 |
68 |
108 |
88 |
68 |
108 |
88 |
68 |
108 |
88 |
68 |
|
Magnesium sterate |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
4 |
|
Talc |
3 |
3 |
3 |
3 |
3 |
3 |
3 |
3 |
3 |
3 |
3 |
3 |
|
Total weight |
150 |
150 |
150 |
150 |
150 |
150 |
150 |
150 |
150 |
150 |
150 |
150 |
Evaluation of post compression parameters for prepared Tablets
The designed formulation tablets were studied for their physicochemical
properties like weight variation, hardness, thickness, friability and drug
content.
Weight variation test:
To study the weight variation, twenty tablets were taken and their
weight was determined individually and collectively on a digital weighing
balance. The average weight of one tablet was determined from the collective
weight.
% Deviation = (Individual weight – Average weight / Average weight) ×
100
Hardness:
Hardness of tablet is defined as the force applied across the diameter
of the tablet in order to break the tablet. The hardness of three tablets was
determined using Monsanto hardness tester.
Thickness:
Tablet thickness is an important characteristic in reproducing
appearance.
Friability:
It is measured of mechanical strength of tablets. Roche friabilator was
used to determine the friability.
% Friability = [ ( W1-W2) / W] × 100
Where, W1 = Initial weight of three tablets
W2 = Weight of the three tablets after testing
Determination of drug content:
Ten tablets were finely powdered quantities of the powder equivalent to
one tablet weight of drug were accurately weighed, transferred to a 100 ml
volumetric flask containing 50 ml water The solution was suitably diluted and
the absorption was determined by UV–Visible spectrophotometer.
In vitro drug release studies
900ml 0f 0.1 HCL was placed in
vessel and the USP apparatus –II (Paddle Method) was assembled. Samples
analyzed by spectrophotometrically at 270 and 274 nm using
UV-spectrophotometer.
Application of Release Rate Kinetics to Dissolution Data:
To analyze the mechanism of the drug release rate kinetics of the dosage
form, the obtained data were fitted into zero-order, first order, Higuchi, and
Korsmeyer-Peppas release model.
Drug – Excipient compatibility studies
Fourier Transform Infrared (FTIR) spectroscopy:
Bruker spectrophotometer and the IR spectrum was recorded from 4000 cm-1
to 500 cm-1. The resultant spectrum was compared for any
spectrum changes.
RESULTS AND DISCUSSION:
Evaluation Parameters for
sustained release tablets of Atomoxetine HCL:
Pre-compression parameters:
The values for angle of repose
were found in the range of 27.00±1.94 - 28.65±1.09. Bulk densities and tapped
densities of various formulations were found to be in the range of 0.34±0.01 to
0.38±0.01 (gm/cc) and 0.41±0.01 to 0.45±0.02 (gm/cc) respectively. Carr’s index
of the prepared blends fall in the range of 11.30±0.74 % to 21.53±0.86 %. The
Hausner ration fall in range of 1.14±0.02 to 1.58±0.13.
Table No:2 Pre-compression
parameters
|
Formulations |
Bulk Density (gm/cm2) |
Tap Density (gm/cm2) |
Carr’s Index (%) |
Hausner ratio |
Angle of Repose (Ɵ) |
|
F1 |
0.36±0.01 |
0.44±0.01 |
19.85±0.86 |
1.18±0.03 |
28.65±1.09 |
|
F2 |
0.35±0.01 |
0.41±0.02 |
18.96±0.84 |
1.17±0.02 |
27.63±0.90 |
|
F3 |
0.35±0.02 |
0.41±0.02 |
17.56±0.84 |
1.21±0.02 |
28.15±1.39 |
|
F4 |
0.35±0.02 |
0.43±0.02 |
15.28±0.36 |
1.16±0.03 |
27.20±1.39 |
|
F5 |
0.37±0.02 |
0.41±0.30 |
17.35±0.85 |
1.18±0.04 |
28.00±2.05 |
|
F6 |
0.34±0.02 |
0.45±0.02 |
18.36±1.99 |
1.14±0.02 |
28.63±1.12 |
|
F7 |
0.34±0.01 |
0.44±0.015 |
11.30±0.74 |
1.18±0.06 |
27.00±1.94 |
|
F8 |
0.36±0.01 |
0.41±0.02 |
14.55±3.16 |
1.17±0.03 |
27.54±1.55 |
|
F9 |
0.35±0.01 |
0.44±0.01 |
21.53±0.86 |
1.17±0.05 |
28.00±1.97 |
|
F10 |
0.38±0.01 |
0.43±0.01 |
17.23±1.09 |
1.24±0.04 |
28.43±0.90 |
|
F11 |
0.35±0.02 |
0.41±0.01 |
12.54±0.12 |
1.30±0.05 |
28.60±1.94 |
|
F12 |
0.34±0.02 |
0.42±0.015 |
13.52±0.11 |
1.58±0.13 |
28.52±2.37 |
Table No:3 post compression
parameter
|
Formulation Code (F) |
Average weight (mg) |
Hardness (kg/cm2) |
Thickness (mm) |
Friability (%) |
Assay (%) |
|
F1 |
147.2 |
5.2 |
3.12 |
0.64 |
98.3 |
|
F2 |
149.8 |
5.9 |
3.95 |
0.39 |
97.1 |
|
F3 |
145.9 |
5.4 |
3.15 |
0.48 |
99.2 |
|
F4 |
148.2 |
5.6 |
3.62 |
0.33 |
96.1 |
|
F5 |
149.2 |
5.7 |
3.48 |
0.49 |
99.8 |
|
F6 |
150.0 |
5.3 |
3.25 |
0.18 |
100.0 |
|
F7 |
149.7 |
5.1 |
3.67 |
0.27 |
97.8 |
|
F8 |
148.6 |
5.8 |
3.55 |
0.35 |
99.1 |
|
F9 |
147.8 |
5.4 |
3.15 |
0.29 |
98.4 |
|
F10 |
145.5 |
5.9 |
3.42 |
0.71 |
99.0 |
|
F11 |
149.7 |
5.1 |
3.67 |
0.39 |
98.4 |
|
F12 |
149.6 |
5.0 |
3.47 |
0.26 |
98.7 |
In Vitro Dissolution
studies:
Table No:4 In vitro dissolution
data
|
Time (Hrs) |
F1 |
F2 |
F3 |
F4 |
F5 |
F6 |
F7 |
F8 |
F9 |
F10 |
F11 |
F12 |
|
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
|
0.5 |
11.15 |
16.58 |
19.87 |
12.31 |
13.21 |
10.18 |
9.26 |
8.72 |
6.90 |
9.99 |
10.66 |
13.94 |
|
1 |
18.41 |
23.57 |
27.18 |
16.93 |
17.98 |
19.56 |
12.74 |
12.49 |
8.15 |
15.78 |
14.29 |
18.59 |
|
2 |
22.27 |
27.94 |
38.98 |
27.61 |
28.85 |
24.70 |
16.86 |
24.79 |
13.13 |
26.73 |
18.85 |
23.49 |
|
3 |
29.11 |
35.42 |
43.67 |
36.35 |
41.51 |
35.37 |
28.49 |
37.65 |
21.91 |
39.12 |
28.38 |
32.19 |
|
4 |
37.75 |
38.95 |
48.48 |
45.62 |
46.28 |
43.51 |
41.97 |
47.79 |
36.92 |
47.11 |
35.92 |
43.16 |
|
5 |
42.29 |
43.11 |
55.76 |
51.72 |
51.28 |
53.19 |
56.49 |
56.86 |
45.39 |
53.78 |
43.77 |
49.11 |
|
6 |
47.37 |
49.28 |
60.91 |
62.83 |
58.84 |
64.91 |
65.75 |
67.58 |
49.27 |
57.24 |
58.67 |
56.19 |
|
7 |
53.81 |
55.27 |
68.12 |
73.21 |
67.87 |
66.28 |
78.43 |
74.93 |
62.67 |
64.37 |
65.00 |
62.37 |
|
8 |
56.91 |
60.39 |
77.93 |
78.87 |
74.11 |
72.62 |
83.26 |
82.42 |
68.17 |
69.28 |
78.33 |
67.91 |
|
9 |
62.67 |
64.19 |
86.26 |
81.25 |
82.29 |
74.98 |
89.95 |
85.75 |
72.91 |
78.24 |
86.16 |
73.49 |
|
10 |
68.85 |
68.78 |
89.45 |
86.56 |
87.74 |
78.75 |
94.83 |
90.62 |
78.47 |
82.75 |
91.05 |
79.12 |
|
11 |
75.95 |
77.61 |
93.15 |
90.49 |
92.66 |
86.42 |
96.39 |
95.36 |
83.50 |
87.38 |
93.03 |
83.14 |
|
12 |
82.18 |
86.42 |
95.87 |
96.78 |
98.56 |
92.81 |
98.19 |
86.12 |
89.97 |
97.29 |
87.29 |
Application of Release Rate Kinetics to Dissolution Data:
Table No:5 Release
kinetics data for optimised formulation
|
Cumulative (%) Release Q |
Time (T) |
Root (T) |
Log (%) Release |
Log (T) |
Log (%) Remain |
Release Rate (Cumulative % Release / t) |
|
0 |
0 |
0 |
|
|
2.000 |
|
|
13.21 |
0.5 |
0.707 |
1.121 |
-0.301 |
1.938 |
26.420 |
|
17.98 |
1 |
1.000 |
1.255 |
0.000 |
1.914 |
17.980 |
|
28.85 |
2 |
1.414 |
1.460 |
0.301 |
1.852 |
14.425 |
|
41.51 |
3 |
1.732 |
1.618 |
0.477 |
1.767 |
13.837 |
|
46.28 |
4 |
2.000 |
1.665 |
0.602 |
1.730 |
11.570 |
|
51.28 |
5 |
2.236 |
1.710 |
0.699 |
1.688 |
10.256 |
|
58.84 |
6 |
2.449 |
1.770 |
0.778 |
1.614 |
9.807 |
|
67.87 |
7 |
2.646 |
1.832 |
0.845 |
1.507 |
9.696 |
|
74.11 |
8 |
2.828 |
1.870 |
0.903 |
1.413 |
9.264 |
|
82.29 |
9 |
3.000 |
1.915 |
0.954 |
1.248 |
9.143 |
|
87.74 |
10 |
3.162 |
1.943 |
1.000 |
1.088 |
8.774 |
|
92.66 |
11 |
3.317 |
1.967 |
1.041 |
0.866 |
8.424 |
|
98.56 |
12 |
3.464 |
1.994 |
1.079 |
0.158 |
8.213 |
Continue
Table
No:5
|
1/CUM% Release |
Peppas log Q/100 |
% drug Remaining |
Q01/3 |
Qt1/3 |
Q01/3-Qt1/3 |
|
|
|
100 |
4.642 |
4.642 |
0.000 |
|
0.0757 |
-0.879 |
86.79 |
4.642 |
4.427 |
0.214 |
|
0.0556 |
-0.745 |
82.02 |
4.642 |
4.345 |
0.297 |
|
0.0347 |
-0.540 |
71.15 |
4.642 |
4.144 |
0.498 |
|
0.0241 |
-0.382 |
58.49 |
4.642 |
3.882 |
0.760 |
|
0.0216 |
-0.335 |
53.72 |
4.642 |
3.773 |
0.868 |
|
0.0195 |
-0.290 |
48.72 |
4.642 |
3.652 |
0.989 |
|
0.0170 |
-0.230 |
41.16 |
4.642 |
3.453 |
1.189 |
|
0.0147 |
-0.168 |
32.13 |
4.642 |
3.179 |
1.462 |
|
0.0135 |
-0.130 |
25.89 |
4.642 |
2.958 |
1.683 |
|
0.0122 |
-0.085 |
17.71 |
4.642 |
2.607 |
2.035 |
|
0.0114 |
-0.057 |
12.26 |
4.642 |
2.306 |
2.336 |
|
0.0108 |
-0.033 |
7.34 |
4.642 |
1.943 |
2.698 |
|
0.0101 |
-0.006 |
1.44 |
4.642 |
1.129 |
3.512 |
Figno 1: Dissolution profile of
All formulations
From the above results it was
evident that the formulation F5 is best formulation with desired drug release
pattern extended up to 12 hours.
Fig
No:2 Zero order release kinetics graph
Fig No:3 Higuchi release kinetics graph
Fig
No:4 Kars mayer peppas graph
Fig No:5 First order
release kinetics graph
From the above graphs it was
evident that the formulation F5 was followed peppas release mechanism.
CONCLUSION:
Result of the present study
ascertains that natural gum and synthetic employed was found to be successful
in formulating the sustained-release matrix tablets of Atomoxetine HCL. The
prepared matrix tablets were evaluated for various parameters like hardness,
thickness, weight variation, friability, percent drug content and in vitro
drug release studies as per IP guidelines. Out of 12 Formulation, the
formulation F5 is selected as best formulation which shows 98.56 % drug release
in 12 hrs.
АCKNOWLEDGEMENT:
Thе authors arе
thankful to Sura Labs, Dilshukhnagar, Hydеrabad for providing thе
nеcеssary facilitiеs for thе rеsеarch work.
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Received on 27.02.2020
Modified on 28.02.2020
Accepted on 01.03.2020 ©Asian Pharma Press
All Right Reserved
Asian J. Pharm.
Tech. 2020; 10(1):43-47.
DOI: 10.5958/2231-5713.2020.00009.4