L. Rajesh Patro et.al / IJIPSR / 1(1), 2013, 132-144
RESEARCH ARTICLE Department of Pharmaceutics
ISSN (online) 2347-2154
International Journal of Innovative Pharmaceutical Sciences and Research www.ijipsr.com FORMULATION AND DEVELOPMENT OF ORAL DISINTEGRATING TABLETS OF TORSEMIDE 1 1 2
L.Rajesh Patro*, 2Srikanth, 3Lingeswararao Punati
Dept. of Pharmaceutics, Avanthi Institute of Pharmaceutical Sciences, AP, India- 501505
Dept. of Pharmaceutics, JPNES group of Institutions, Mahaboobnagar, Andhrapradesh, India- 509001 3
Dept. of Pharmaceutical Analysis, Avanthi Institute of Pharmaceutical Sciences, AP, India- 501505
Abstract The aim of the present investigation was to develop oral disintegrating tablets of Torsemide. Oral disintegrating tablets (ODTs) were prepared by direct compression method. Disintegration time, resistance to crushing of tablets, porosity, friability, and dissolution tests was performed and dissolution profiles of ODTs were investigated. Morphological and interaction studies were also performed. Friability values were found to be less than 1%. All tablet formulations disintegrated within 1 min and fulfilled the 3 min disintegration time required for ODTs given in the European Pharmacopoeia. More than 85% of the labeled amount of Torsemide was dissolved in 15 min from the ODTs. No interaction or changes were found between active substance and excipients. As a result of the studies, ODT formulations developed in this study can be suggested as promising formulations, which assist development and manufacturing a generic product of Torsemide. Key words: Oral disintegrating tablets, Torsemide, Direct compression
Corresponding Author: L.Rajesh Patro Associate Professor Avanthi Institute of Pharmaceutical Sciences Email:
[email protected] Phone: 7799591117
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Department of Pharmaceutics
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INTRODUCTION An ideal dosage regimen in the drug therapy of any disease is the one, which immediately attains the desire therapeutics concentration of drug in plasma (or at the site of action) and maintains it constant for the entire duration of treatment. This is possible through administration of conventional dosage form in a particular dose and at a particular frequency. Thus drug may be administered by variety of routes in a variety of dosage forms. [1] Drugs are more frequently taken by oral administration. Although a few drugs taken orally are intended to be dissolved within the mouth, the vast majority of drugs taken orally are swallowed. Compared with alternate routes, the oral route of drug administration is the most popular and has been successfully used for conventional delivery of drug. It is considered most natural, uncomplicated, convenient, safe means of administering drugs, greater flexibility in dosage form design, ease of production and low cost. [2] Tablets and hard gelatin capsules constitute a major portion of the drug delivery systems that are currently available. However, many patient groups such as elderly, children, and patients mentally retarded, uncooperative, nauseated, or on reduced liquid intake diets have difficulty in swallowing these dosage forms. Many elderly persons face difficulties in administering conventional oral dosage forms because of hand tremors and dysphasia. Swallowing problem is common in children because of their underdeveloped muscular and nervous systems. In some cases like motion sickness, sudden episodes of allergic attack or coughing, and during unavailability of water, swallowing conventional tablets is difficult. To fulfill these medical needs, formulators have devoted considerable efforts for developing a novel type of dosage form for oral administration known as mouth dissolving tablets (MDT).[1,2] This is an innovative tablet technology where the dosage form containing active pharmaceutical ingredients disintegrates rapidly, usually in a matter of seconds, without the need for water, providing optimal convenience to the patient. Innovators and inventor companies have given these tablets various names such as orally disintegrating tablets (ODT), mouth dissolving (MD), fast melting, fast dissolving or Orodisperse.[1,2] The European Pharmacopoeia defines Orodisperse as a tablet that can be placed in the mouth where it disperses rapidly before swallowing. Researchers have formulated ODT for various categories of drugs, which are used for therapy in which rapid peak plasma concentration Available online: www.ijipsr.com
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L. Rajesh Patro et.al / IJIPSR / 1(1), 2013, 132-144
Department of Pharmaceutics
ISSN (online) 2347-2154
is required to achieve desired pharmacological response. These include neuroleptics, cardiovascular agents, analgesics, anti-allergic and drugs for erectile dysfunction. [1, 2] Techniques used for the preparation of oral disintegrating tablets are Freeze drying or Lyophilization, Tablet molding, Spray drying, Sublimation, Direct compression, Cotton candy process, Mass-Extrusion [3,4,5]. Torsemide is used to reduce extra fluid in the body (edema) caused by conditions such as heart failure, liver disease, and kidney disease. This can lessen symptoms such as shortness of breath and swelling in your arms, legs, and abdomen. This drug is also used to treat high blood pressure. Lowering high blood pressure helps prevent strokes, heart attacks, and kidney problems. Torsemide is a "water pill" (diuretic) that causes you to make more urine. This helps your body get rid of extra water and salt. Conventional Torsemide tablets available in market are not suitable where quick onset of action is required. Besides, the conventional tablets also show poor patient compliance particularly by the geriatric and pediatric patients who experience difficulty in swallowing, and by those who are bed ridden or who are traveling and do not have an easy access of water. To provide the patients with the most conventional mode of administration, there was a need to develop rapidly disintegrating dosage form, particularly one that disintegrates and dissolves/disperses in saliva and can be administered without need of water. In the present work, Torsemide was chosen as a model drug. Torsemide is diuretic of pyridine sulfonylurea class having half life of 3-6 hours. Its acceptable taste makes that an ideal drug candidate for mouth dissolving tablet. An attempt was made in the present work to formulate and evaluate mouth dissolving tablets of Torsemide.
MATERIAL & METHOD: Torsemide obtained as gift sample from Comed Chemicals Pvt. Ltd., Sayajiganj, Baroda, Gujarat., Crospovidone, Sodium starch glycolate and Croscarmellose sodium obtained as gift sample from Wockhardt Research Centre, Aurangabad, Magnesium stearate purchased from Strides Arco Labs, Bangalore, Di calcium phosphate and Pregelatinised starch obtained from Alkem Labs Pvt. Ltd., Mumbai, Talc and Potassium dihydrogen orthophosphate purchased from Sd Fine Chem Limited, Mumbai, Aspartame obtained from Medrich Pharmaceuticals, Bangalore.
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L. Rajesh Patro et.al / IJIPSR / 1(1), 2013, 132-144
RESEARCH ARTICLE
ISSN (online) 2347-2154
Department of Pharmaceutics
METHOD: Oral Disintegrating tablets of Torsemide were prepared by direct compression according to the formulae given in table. •
All the ingredients were passed through 60 mesh sieve separately.
•
The drug and DCP was mixed by small portion of both each time and blending it to get a uniform mixture and kept aside.
•
Then the ingredients were weighed and mixed in geometrical order and tablets were compressed at 8 mm size to get a tablet of 240 mg weight using a Rotary Clit 10 station compression machine. Table 1: Composition of Oral Disintegrating tablets of Torsemide F1
F2
F3
F4
F5
F6
F7
F8
F9
Formulation
(mg)
(mg)
(mg)
(mg)
(mg)
(mg)
(mg)
(mg)
(mg)
Torsemide
10
10
10
10
10
10
10
10
10
DCP
180
177.5
175
180
177.5
175
180
177.5
175
Crosspoidone
5
7.5
10
-
-
-
-
-
-
-
-
-
5
7.5
10
-
-
-
glycolate
-
-
-
-
-
-
5
7.5
10
Pregelatinised starch
30
30
30
30
30
30
30
30
30
Aspartame
5
5
5
5
5
5
5
5
5
Magnesium stearate
5
5
5
5
5
5
5
5
5
Talc
5
5
5
5
5
5
5
5
5
Total
240
240
240
240
240
240
240
240
240
Crosscaramellose sodium Sodium starch
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L. Rajesh Patro et.al / IJIPSR / 1(1), 2013, 132-144
RESEARCH ARTICLE
ISSN (online) 2347-2154
Department of Pharmaceutics
RESULTS AND DISCUSSION: Oral disintegrating tablets of Torsemide were prepared and evaluated. In the present study 9 formulations with variable concentration of polymer were prepared and evaluated for physiochemical parameters, in vitro release studies and release Kinetics Preparation of Standard Curve of Torsemide Standard curve of Torsemide was determined by plotting absorbance V/s concentration at 263 nm and it follows the Beer’s law. The results were shown in Table NO.
.The R 2 is 0.999
respectively. Table 2: Standard Calibration Curve S.No
Concentration µg/ml
UV Absorbance at 263 nm
1
0 µg/ml
0.00
2
10µg/ml
0.21±0.02
3
15µg/ml
0.301±0.02
4
20µg/ml
0.393±0.02
5
25µg/ml
0.498±0.02
6
30µg/ml
0.568±0.02
Figure 1: Standard graph of Torsemide in 0.1N Hcl Available online: www.ijipsr.com
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Department of Pharmaceutics
Fourier transforms Infrared spectroscopy (FTIR) studies: FTIR analysis of Torsemide individually and in combination with other ingredients of core tablets and CCT was investigated to identify any chemical interaction between the added excipients and torsemide. The major peaks for the pure drug were observed at 1697.42.31cm -1 (C= N stretch), 1282.15 cm -1 (C-N stretch) and 3279.94 cm -1 (presence of hetero atoms). The presence of sodium starch glycolate, croscaramellose sodium and crosspovidone do not produce any major shift in peak characteristics of Torsemide as shown in Figure 2 and 3. This indicates that there was no chemical interaction between drug and the excipients used in the study.
Figure 2: FTIR spectra of (A) Pure drug (B) sodium starch glycolate (C) Croscaramellose sodium
Figure 3: FTIR spectra of (A) Pure drug (B) Crospovidone (C) Aspartame Available online: www.ijipsr.com
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L. Rajesh Patro et.al / IJIPSR / 1(1), 2013, 132-144
RESEARCH ARTICLE Department of Pharmaceutics
ISSN (online) 2347-2154
PREFORMULATION STUDIES: [6, 7]
a) Determination of melting point: Melting point of Torsemide was found in the range of 1640c, which complied with the standard, indicating purity of the drug sample. b) Solubility: Torsemide is freely soluble in water, methanol and DMSO (dimethyl sulfoxide) c) Compatibility Study: Compatibility studies were performed using FTIR spectrophotometer. The FTIR spectrum of pure drug and physical mixture of drug and polymer were studied. Precompression studies: The granules for matrix tablets were characterized with respect to angle of repose, bulk density, tapped density, Carr’s index, and Hausner’s ratio. Angle of repose was less than 30° and Carr’s index values were less than 26 for the formulations of all the batches indicating good to fair flow ability and compressibility. Hausner’s ratio was less than 1.256 for all the batches indicating good flow properties. Table 3: Pre compression studies Oral Disintegrating tablets of Torsemide Bulk
Tapped
Angle of
Compressibility
Hausner
density
density
repose
index
ratio
F1
0.46
0.55
22.62
16.36
1.19
F2
0.59
0.68
22.29
13.04
1.15
F3
0.53
0.63
20.29
15.8
1.18
F4
0.47
0.59
28.23
20.3
1.25
F5
0.42
0.53
23.24
26.19
1.26
F6
0.48
0.57
27.4
14.04
1.14
F7
0.46
0.57
22.26
23.91
1.23
F8
0.44
0.53
23.62
20.45
1.2
Formulations
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F9
0.48
0.56
25.24
16.66
1.16
F10
0.52
0.63
24.69
21.15
1.21
F11
0.51
0.62
23.26
21.56
1.21
F12
0.43
0.54
25.19
25.58
1.25
Post compression studies: The results of the uniformity of weight, hardness, thickness, friability, and drug content of the tablets are given in the above Table. All the tablets of different batches complied with the official requirements of uniformity of weight as their weights varied between 99.5 and 100.66mg. The hardness of the tablets ranged from 3.00 to 4.2 kg/cm2 and the friability values were less than 0.6% indicating that the tablets were compact and hard. Disintegration time ranged from 23-60 seconds and dispersion time was ranged from 23-42 seconds All the formulations satisfied the content of the drug as they contained 99.3 to 100.6 % of Torsemide and good uniformity in drug content was observed. Thus all the physical attributes of the prepared tablets were found be practically within control. Table 4: Post compression Oral Disintegrating tablets of Torsemide
Formulations
Hardness Friability 2
Weight
Content
Dispersion
Time(sec)
Time (sec)
Kg/cm
(%)
F1
3.433
0.568
99.5
99.3
46.3
32
F2
3.283
0.531
100
99.8
39.5
27.3
F3
3.016
0.488
100.5
100.3
30
23
F4
4.0833
0.633
100.33
99.6
60.83
42.6
F5
3.816
0.605
99.66
100
53.6
36.1
F6
2.866
0.445
100.16
100.16
23.8
17.3
F7
4.2
0.52
100.3
100.3
40.3
28.1
F8
4.1
0.47
101.1
100.6
30.8
23.5
F9
3.7
0.44
100.5
100
24.5
16.3
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variation uniformity
Disintegration
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RESEARCH ARTICLE Department of Pharmaceutics
ISSN (online) 2347-2154
In-Vitro Drug Release Studies:
[8-11]
In-Vitro drug release studies were carried out using Tablet dissolution test apparatus USPXXIII at 50 rpm. The dissolution medium consisted of 900 ml of Standard buffer 6.8 Phosphate buffer. Temperature maintained at 37±1.The sample of 5ml was withdrawn at predetermined time intervals and an equivalent amount of fresh dissolution fluid equilibrated at the same temperature was replaced. The samples withdrawn were filtered through Whitman filter paper (No.1) and drug content in each sample was analyzed by UV-visible spectrophotometer at 263 nm. Table 5: In-Vitro Release Data of Torsemide from Crosspovidone. Time in Minutes
F1
F2
F3
0
0
0
0
5
33.45
23.67
21.98
10
47.98
38.43
45.56
20
65.55
59.88
61.19
30
79.99
79.91
76.37
40
91.78
86.55
89.94
50
99.98
98.75
99.94
Figure 4: Release Profiles of Torsemide Formulations using Crosspovidone
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Table 6: In-Vitro Release Data of Torsemide from crosscaramellose sodium Time in Minutes
F4
F5
F6
0
0
0
0
5
26.83
27.98
21.11
810
39.89
37.13
33.77
20
57.87
59.11
48.89
30
84.81
76.98
72.98
40
92.32
88.17
88.98
50
99.08
98.87
99.11
Figure 5: Release Profiles of Torsemide Formulations using Crosscaramellose Sodium Table 7: In-Vitro Release Data of Torsemide from sodium starch glycolate sodium Time in Minutes
F7
F8
F9
0
0
0
0
2
54.47
41.72
51.28
3
67.23
54.47
67.87
5
76.51
69.90
75.49
10
88.88
79.12
83.09
15
92.43
89.99
91.54
30
98.06
99.89
99.97
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Figure 6: Release Profiles of Torsemide Formulations using Sodium starch Glycolate Release Kinetics: Zero Order
Figure 7: Cumulative percentage drug release vs Time Plot of F9 First Order
Figure 8: Log Cumulative percent drug remaining vs Time Plot of F9 Available online: www.ijipsr.com
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The in vitro drug release data from the control, CCF and promising formulations were fitted into two popular models of data treatment. When the data was plotted as log cumulative percent drug remaining versus time, the plots obtained were linear indicating first order release kinetics. Statistical analysis of the data by the method of least squares gives correlation coefficient values in the range of 0.9975 to 0.938 for most of the formulations. CONCLUSION: Oral disintegrating tablets of Torsemide were prepared and evaluated. In the present study 9 formulations with variable concentration of polymer were prepared and evaluated for physiochemical parameters, in vitro release studies and release Kinetics. Melting point of Torsemide was found in the range of 1640c, which complied with the standard, indicating purity of the drug sample. Standard curve of Torsemide was determined by plotting absorbance V/s concentration at 263 nm and it follows the Beer’s law. The release kinetics for the optimized formulation (F9) was determined. Formulation (F9) follows first order release kinetics with R2 value of 0.938.
REFERENCE 1) Brahmankar D. M., Jaiswal S.B., Bio pharmaceutics& Pharmaceutics, First Edition, 1995, 335. 2) Howard C. Ansel, Nicholas G. Popvich, Loyd V. Allen, Pharmaceutical Dosage Forms and Drug Delivery System, First Edition, 1995, 78. 3) S. S. Biradar, S. T. Bhagavati and I. J. Kuppasad, Fast Dissolving Drug Delivery Systems: A Brief Overview, Internet J. Pharmacology, 2006, 4(2). 4) Kuccherkar B.S., Badhan A.C., Mahajan H.S., Mouth dissolving tablets: A novel drug delivery system, Phrma Times, 2003, 35, 3-10. 5) Kaushik D, Dureja H., Saini T. R., Mouth Dissolving Tablets: A review, Indian Drugs, 2004, 41(4), 187-193. 6) Lachman Leon, Liberman H.A.and Kanig J.L., “The Theory and Practice of industrial pharmacy” (3rd Edn), Varghese publishing House Bombay, p.no.430 Available online: www.ijipsr.com
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7) The merk index, an Encyclopedia of chemical drug and biologicals, 25 th Edition p. No. 161 8) “British Pharmacopoeia” 2004 9) Bhalla, H.L. and Raj, P.C., “Indian Drugs”, 1991,(28), p.no. 519. 10) Singhvi, I. And Chaturvedi, S.C., “Indian Drugs”, 1998, (35), p.no. 421. 11) Solinis M.A, Cruz Y. De, Gascon A, Calvo B, Pedraz J. L “Release of Ketoprofen enantiomeres
from HPMC K100M matrices –Diffusion studies” Int. J. Pharm.,
2002,239, p.no. 61-68.
Available online: www.ijipsr.com
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