Académique Documents
Professionnel Documents
Culture Documents
ISSN: 0975-766X
Research Article
Received on 12-04-2011
Accepted on 15-05-2011
Abstract
Hydroxy propyl--Cyclodextrin (HP--CD) inclusion complexes of mefenamic acid (MA) exhibited higher
dissolution rates and dissolution efficiency values than the corresponding un-complexed drug. The feasibility of
formulating the HP--cyclodextrin complexes of mefenamic acid (1:3) into tablet dosage forms is evaluated.
Solid inclusion complexes of mefenamic acid prepared by kneading method were formulated into tablets by wet
granulation and direct compression methods. All the tablets formulated employing HP--cyclodextrin complexes of
mefenamic acid gave rapid and higher dissolution rates when compared to that of mefenamic acid plain tablets. All
the prepared tablets fulfilled the official (I.P.) disintegration time specification of uncoated tablets. Overall, tablets
prepared by direct compression method disintegrate rapidly when compared to those prepared by wet granulation
method. Analysis of dissolution data as per zero-order and first order kinetic models indicated that the dissolution
of mefenamic acid from all the tablets followed first-order kinetics. In both direct compression and wet granulation
methods, tablets formulated employing cyclodextrin complexes (MAT2, MAT4) gave higher rates of dissolution
and dissolution efficiency values when compared to the corresponding tablets formulated with mefenamic acid as
such (MAT1, MAT3). Among all the mefenamic acid tablets formulated, formulation MAT2, which is based on
Page 2669
improving the dissolution rate and bioavailability , cyclodextrin complexation was found to be very successful with
a number of poorly soluble drugs such as Rofecoxib1, Nimesulide2, Ciprofloxacin3, Tolbutamide4, Paracetamol5,
Diclofenac sodium6 etc. Cyclodextrins such HP- cyclodextrin7-15, -cyclodextrin16,14,17, , , hydroxyl propyl-cyclodextrin, -cyclodextrin18,16, Triacetyl-- cyclodextrin , Methylated- cyclodextrin19, Hydroxy ethyl-cyclodextrin20 etc., are used for preparing cyclodextrin complexes. Most of the non-steroidal anti inflammatory
drugs belong to class II category under biopharmaceutical classification system (BCS) i.e., they are inherently
highly permeable through biological membranes, but exhibit low aqueous solubility. They need enhancement in
solubility and dissolution rate for improving their oral bioavailability. In the present investigation studies were
carried out on cyclodextrin complexes of mefenamic acid for enhancing the dissolution rate. Mefenamic acid, an
anthranilic acid derivative, is a non-steroidal anti-inflammatory drug (NSAID) 21. It is used in mild to moderate
pain including headache, dental pain, postoperative and postpartum pain, dysmenorrhoea, osteoarthritis. The usual
dose by mouth is 500 mg three times daily. Mefenamic acid is absorbed from gastro intestinal tract. Peak plasma
concentration occurs at about 2 to 4 hours after ingestion. Rate of absorption and/or extent of bioavailability for
such insoluble hydrophobic drug are controlled by rate of dissolution in gastro-intestinal fluids22. Cyclodextrin
complexes of mefenamic acid were prepared employing kneading method for enhancing the dissolution rate and
bioavailability of mefenamic acid.
Page 2670
spectrophotometer (ELICO SL-159). The method obeyed Beers law in the concentration range of 0-20 g/ml. 100
mg of inclusion complex was taken in a 50 ml volumetric flask. Methanol about 40 ml was added and mixed
thoroughly. The contents were repeatedly warmed in a hot bath while mixing to dissolve the drug in the solvent.
The solution was made up to volume with methanol. The solution was then suitably diluted with phosphate buffer
of pH 7.4 and assayed at 279 nm for mefenamic acid by the spectrophotometric method. The results are given in
Table 1.
Page 2671
Page 2672
Tablets
prepared by direct compression method disintegrate rapidly when compared to those prepared by wet granulation
method. Tablet formulations developed in the present study are quite stable with regard to various physical
characters such as hardness, friability, disintegration and dissolution rate. Analysis of dissolution data as per zeroorder and first-order kinetic models indicated that the dissolution of mefenamic acid from all the tablets followed
Page 2673
MA-HP- CD (1:3)
0.05 (0.20)
Ingredient
No.
(mg/tablet)
Direct Compression
Wet Granulation
MAT1
MAT2
MAT3
MAT4
100
100
400
400
400
100
1.
Mefenamic Acid
2.
MA-HP--CD(1:3)
3.
MCC PH 200
4.
Lactose
300
5.
12
12
6.
Ac-Di-Sol
15
15
16
16
7.
Talc
10
10
Page 2674
Magnesium Stearate
10
10
9.
535
535
444
444
Table-3: Drug Content, Hardness, Friability and Disintegration Times of Tablets prepared Employing
Mefenamic acid and its cyclodextrin Complexes.
Tablet
Formulation
Drug Content
(mg/tablet)
Hardness
Friability
Disintegration
(kg/sq.cm)
(%)
Time (min)
MAT1
98.9
7.5
0.56
2.5
MAT2
99.8
8.6
0.20
4.0
MAT3
99.1
8.1
0.35
3.5
MAT4
98.4
7.5
0.20
12.0
Table 4: Dissolution Profiles of Mefenamic acid Tablets Formulated Employing Mefenamic acid and its
Cyclodextrin complexes Prepared by Direct Compression Method (MAT1, MAT2) and Wet Granulation
Method (MAT3, MAT4)
Time
(min)
MAT1
MAT2
MAT3
MAT4
11.87 0.55
30.04 0.38
10.62 0.54
8.65 0.72
10
28.30 0.74
57.28 0.34
25.70 0.38
17.2 0.84
20
34.40 0.17
62.10 0.87
35.30 0.75
24.40 0.98
30
39.60 0.29
69.20 0.28
42.85 0.80
36.50 0.45
45
45.80 0.74
74.60 0.67
49.56 0.21
48.85 0.94
60
51.60 0.84
79.45 0.84
56.85 0.84
59.20 0.82
90
58.70 0.57
86.40 0.59
62.65 0.76
65.40 0.53
120
62.55 0.86
89.56 0.24
69.50 0.57
72.60 0.69
Page 2675
Table 5: Correlation Coefficient (r) values in the analysis of Dissolution data of MA-CD Tablets as per Zeroorder and First-order Kinetics
Correlation Coefficient (r)
Formulation
Zero-order
First order
MAT1
0.8885
0.9454
MAT2
0.9846
0.9998
MAT3
0.9800
0.9958
MAT4
0.9776
0.9997
Table 6: Dissolution Parameters of Tablets Formulated Employing Mefenamic Acid and its Cyclodextrin
Complexes.
Formulation
Dissolution Parameter
T50 (min)
T90 (min)
DE30 (%)
K1 (min-1)
MAT1
55.86
>120
27.12
0.0076
MAT2
8.66
>120
51.56
0.0851
MAT3
45.91
>120
27.10
0.0297
MAT4
46.67
>120
19.96
0.0189
Fig.1: Dissolution profiles of Mefenamic Acid Tablets prepared by Direct Compression and Wet
Granulation Methods.
Page 2676
Fig.2: First order dissolution plots of Mefenamic Acid Tablets prepared by Direct Compression and Wet
Granulation Methods
Acknowledgements
The authors would like to express sincere thanks to the management of DCRM Pharmacy College, Inkollu,
Prakasam district, Andhra Pradesh for their cooperation and encouragement in carrying out the research work. The
author also expresses sincere thanks to M/s. Sigma Laboratories, M/s.S.A. Pharmaceuticals, Mumbai for their
generous gift samples of mefenamic acid and HP-beta cyclodextrins.
References
1. Rawat S Jain, SK Chawan. Pharmazie, 2003, Vol 58, pp 63 .
2. BN Nalluri, KPR Chowdary, KV Murthy, AR Heyman, G Becket, 2003 AAPS Pharm. Sci. Tech., Vol 4, pp
102.
3. C Jianbin, C Liang, X Hao, M Dongpin, 2002, Spectrochim Acta A mol Biomol Spectrosc, Vol 58, pp 2809,.
4. MD Veiga, F Ahsan, 2000, Eur. Journal of Pharm. Sciences, Vol 9 pp. 291.
5. LM Tasic, MD Jovanovic, ZR Djuric,1992, Journal of Pharm Pharmacol., Vol 44 pp 52.
Page 2677
23.
H Teresa,. J of Inclusion Phenomena and Macro cyclic Chemistry, 1999, Vol. 35 pp. 3.
Page 2678
24.
L Lachman Theory and practice of Industrial Pharmacy. Lea and Febiger, Philadelphia,1976, pp101.
Corresponding Author:
Dr.M.V.Nagabhushanam M.Pharm., Ph.D., MBA.,
Professor & Principal,
D.C.R.M.Pharmacy College,
Inkollu 523 167. Prakasam District, A.P.
Page 2679