Synthesis and Evaluation of Some New Imidazole Derivatives for their Anti-Microbial and Anti-Inflammatory
activities
Hemlata Bhawar1*,
Nachiket Dighe1, Pankaj
Shinde1, Ravi Lawre2
and Sanjay Bhawar3
1Department of Pharmaceutical Chemistry, Pravara Rural College of Pharmacy, Loni,
MS, India-413736.
2Department of Quality Assurance
Technique, Pravara Rural College of Pharmacy, Loni, MS, India-413736.
3Department of Pharmacology, Pravara Rural College of Pharmacy, Loni,
MS, India-413736.
*Corresponding Author E-mail: nachiketvirat@gmail.com
ABSTRACT:
The synthesis, structure and biological activity of Imidazole derivatives have long been the focus of research
interests in the field of Medicinal Chemistry. A number of Imidazole
derivatives have been reported to possess interesting biological activities
such as Antimicrobial, Anti-inflammatory and Antifungal activities etc. Around
22 new derivatives were synthesized, with the standard chemicals and well
established procedures. The synthesized compounds were tested for their
preliminary tests, physical constants, TLC etc. IR, 1H-NMR Spectra and CHN
analysis confirmed the structures of the final compounds. The proposed
compounds were screened for their antimicrobial and anti-inflammatory
activities with the standard drugs in the well-equipped microbiology and
pharmacology lab by using standard methods.
KEYWORDS: Anti-inflammatory,
Antimicrobial and Imidazole
INTRODUCTION:
The diverse
biological activities of imidazole derivatives made
an impact to direct the attention of medicinal chemist as a promising class of
a heterocyclic compounds with profound biological activities. Varied
bioactivities exhibited by imidazole, efforts have
been made from time to time to generate libraries of these compounds and
screened them for potential biological activities. Also it is well documented
that imidazole nucleus is associated with a variety
of pharmacological actions. It displays pronounced anticonvulsant activity,
anticancer, anthelmintic activity, and antiproliferative activity. Extensive
biochemical and pharmacological studies have confirmed that imidazole
molecules are effective against various strains of microorganisms. Looking at
the importance of imidazole nucleus, it was thought
that it would be worthwhile to design and synthesize some new imidazole derivatives and screen them for potential
biological activities.
MARERIALS AND METHODS:
EXPERIMENTAL:
Melting points
were determined in open capillary method and are uncorrected. Purity of the
compound was checked on Silica gel TLC plates. IR spectra were recorded on Jasco FT/IR-4100 spectrophotometer using KBr disc method. 1HNMR spectra were recorded on Bruker Advance –II 400, DMSO as internal standard.
Combustion analyses were found to be within the limits of permissible errors.
ANTIBACTERIAL ACTIVITY:
The newly
synthesized compounds were screened for their antibacterial activity against Escherichia
coli (MTCC 443), Bacilus subtilis (ATCC12228) and Staphylococcus aureus (ATCC25923) bacterial strains by disc diffusion
method. In all the determinations tests were performed in triplicate and the
results were taken as a mean of three determinations. Ciprofloxacin was used as
a standard drug1.
ANTI-INFLAMMATORY ACTIVITY:
In-vitro anti-inflammatory activity
Inhibition of protein denaturation
The standard drug and synthesized compounds were dissolved in
minimum quantity of dimethyl formamide
(DMF) and diluted with phosphate buffer (0.2 M, pH 7.4). Final concentration of
DMF in all solution was less than 2.5%. Test solution (1mL) containing
different concentrations of drug was mixed with 1 mL
of 1mM albumin solution in phosphate buffer and incubated at 27° + 1° C in BOD
incubator for 15 min. Denaturation was induced by
keeping the reaction mixture at 60° + 1° C in water bath for 10 min. After
cooling, the turbidity was measured at 660 nm (UV-Visible Spectrophotometer).
Percentage of inhibition of denaturation was
calculated from control where no drug was added. Each experiment was done in
triplicate and average is taken. The Ibuprofen was use as standard drug. The
percentage inhibition of denaturation was calculated
by using following formula.
% of Inhibition = 100 X [1- Vt
/ Vc]
Where,
Vt = Mean
absorbance of test sample.
Vc = Mean
absorbance of control2-4
PROCEDURE FOR SCHEME-I
Synthesis of 2, 4, 5- trisubstituted imidazoles (A1-A11)
0.01 mole of benzil was mixed with 0.01
mole of aromatic aldehyde along with ammonium acetate
and PPA, and refluxed for 3 hrs. Cool pour the reaction mixture on ice to offer
solid mass, filtered and recrystallized from hot
ethanol to offer titled compounds (A1-A11).
PROCEDURE FOR SCHEME-II
Synthesis of 2, 4, 5- trisubstitutedimidazoles (B1-B11)
0.01 mole of ethanedione was mixed with
0.01 mole of aromatic aldehyde along with ammonium acetate
and PPA, and refluxed for 3 hrs. Cool pour the reaction mixture on ice to offer
solid mass, filtered and recrystallized from hot
ethanol to offer titled compounds (B1-B11).
SCHME: I
SCHME: II
SPECTRAL DATA:
A1: IR (KBr) cm-1: 3517.67 (-OH str.), 3213.45 (-NH str.), 3063.06 (Ar-CH str.), 2885.60 (-NH
str.), 1525.32 (-C=N str), 1245.36 (-C-N str). 1H NMR: (δ ppm): 6.8-7.2 (14 H phenyl), 9.68 (OH, Aromatic C-OH), 13.4 (1H NH).
A2: IR (KBr) cm-1:1320 (-C–O str.), 3010.23
(Ar-CH str.), 1525.32 (-C=N str), 1245.36
(-C-N str). 1H NMR: (δ ppm):
6.8-7.2 (14 H phenyl), 3.83(3H-OCH3), 13.4 (1H NH).
A3: IR (KBr) cm-1: 3213.45 (-NH str.), 3010.23
(Ar-CH str.), 1525.32 (-C=N str) 1245.36 (-C-N str). 1H
NMR: (δ ppm): 6.8-7.2 (15 H
phenyl), 13.4 (1H NH).
A4: IR (KBr) cm-1:3213.45 (-NH str.), 3010.23 (Ar-CH str.), 740 (-C –Cl str), 1525.32 (-C=N str), 1245.36 (-C-N str). 1H NMR: (δ ppm): 6.8-7.2 (14 H phenyl), 13.4 (1H NH).
A5: IR (KBr) cm-1: 3010.23 (Ar-CH
str.), 1510 (- N –O str), 1525.32 (-C=N str), 1245.36
(-C-N str). 1H NMR: (δ ppm): 6.8-7.2
(14 H phenyl), 13.4 (1H NH).
A6: IR (KBr) cm-1: 3010.23 (Ar-CH str.),
1510 (- N –O str), 1525.32 (-C=N str), 1245.36 (-C-N
str). 1H NMR: (δ ppm): 6.8-7.2
(14 H phenyl), 13.4 (1H NH).
A7: IR (KBr) cm-1:3213.45 (-NH str.), 3010.23 (Ar-CH str.), 740 (-C –Cl str), 1525.32 (-C=N str), 1245.36 (-C-N str). 1H NMR: (δ ppm):
6.8-7.2 (14 H phenyl), 13.4
(1H NH).
A8: IR (KBr) cm-1: 3010.23 (Ar-CH
str.), 1510 (- N –O str), 1525.32 (-C=N str), 1245.36
(-C-N str). 1H NMR: (δ ppm): 6.8-7.2
(14 H phenyl), 13.4 (1H NH).
A9: IR (KBr) cm-1: 3213.45 (-NH str.), 3010.23 (Ar-CH str.), 740 (-C –Cl str), 1525.32 (-C=N str), 1245.36 (-C-N str). 1H NMR: (δ ppm): 6.8-7.2
(14 H phenyl), 13.4 (1H NH).
A10: IR (KBr) cm-1: 3517.67 (-OH str.), 3213.45 (-NH str.), 3063.06 (Ar-CH str.), 2885.60 (-NH
str.), 1525.32 (-C=N str), 1245.36 (-C-N str). 1H NMR: (δ ppm): 6.8-7.2 (14 H phenyl), 9.68 (OH, Aromatic C-OH), 13.4 (1H NH).
A11: IR (KBr) cm-1:
3213.45 (-NH str.), 3063.06
(Ar-CH str.), 2885.60 (-NH str.), 1525.32 (-C=N str),
1245.36 (-C-N str). 1H NMR: (δ ppm): 6.8-7.2
(14 H phenyl), 13.4 (1H NH).
B1: IR (KBr) cm-1: 3517.67 (-OH str.), 3213.45 (-NH str.), 3063.06 (Ar-CH str.), 2885.60 (-NH
str.), 1525.32 (-C=N str), 1245.36 (-C-N str). 1H NMR: (δ ppm): 6.8-7.2 (14 H phenyl), 9.68 (OH, Aromatic C-OH), 3.07
(2H CH2), 1.25 (3H CH3), 13.4 (1H NH).
B2: IR (KBr) cm-1:1320 (-C–O str.), 3010.23
(Ar-CH str.), 1525.32 (-C=N str), 1245.36
(-C-N str). 1H NMR: (δ ppm): 6.8-7.2 (14 H phenyl), 3.83(3H-OCH3),
3.07 (2H CH2), 1.25 (3H CH3), 13.4 (1H NH).
B3: IR (KBr) cm-1:3213.45 (-NH str.), 3010.23 (Ar-CH str.), 1525.32 (-C=N str)
1245.36 (-C-N str). 1H NMR: (δ ppm): 6.8-7.2 (15 H phenyl), 3.07 (2H CH2),
1.25 (3H CH3), 13.4
(1H NH).
B4: IR (KBr) cm-1:3213.45 (-NH str.), 3010.23 (Ar-CH str.), 740 (-C –Cl str), 1525.32 (-C=N str), 1245.36 (-C-N str). 1H NMR: (δ ppm): 6.8-7.2 (14 H phenyl), 3.07 (2H CH2),
1.25 (3H CH3), 13.4
(1H NH).
B5: IR (KBr) cm-1:3010.23 (Ar-CH
str.), 1510 (- N –O str), 1525.32 (-C=N str), 1245.36
(-C-N str). 1H NMR: (δ ppm): 6.8-7.2 (14 H phenyl), 3.07 (2H CH2),
1.25 (3H CH3), 13.4
(1H NH).
B6: IR (KBr) cm-1:3010.23 (Ar-CH
str.), 1510 (- N –O str), 1525.32 (-C=N str), 1245.36
(-C-N str). 1H NMR: (δ ppm): 6.8-7.2
(14 H phenyl), 3.07 (2H CH2), 1.25 (3H CH3), 13.4 (1H NH).
B7: IR (KBr) cm-1:3213.45 (-NH str.), 3010.23 (Ar-CH str.), 740 (-C –Cl str), 1525.32 (-C=N str), 1245.36 (-C-N str). 1H NMR: (δ ppm): 6.8-7.2
(14 H phenyl), 3.07 (2H CH2), 1.25 (3H CH3), 13.4 (1H NH).
B8: IR (KBr) cm-1:3010.23 (Ar-CH
str.), 1510 (- N –O str), 1525.32 (-C=N str), 1245.36
(-C-N str). 1H NMR: (δ ppm): 6.8-7.2
(14 H phenyl), 3.07 (2H CH2), 1.25 (3H CH3), 13.4 (1H NH).
B9: IR (KBr) cm-1:3213.45 (-NH str.), 3010.23 (Ar-CH str.), 740 (-C –Cl str), 1525.32 (-C=N str), 1245.36 (-C-N str). 1H NMR: (δ ppm): 6.8-7.2
(14 H phenyl), 3.07 (2H CH2), 1.25 (3H CH3), 13.4 (1H NH).
B10: IR (KBr) cm-1:3517.67 (-OH str.), 3213.45 (-NH str.), 3063.06 (Ar-CH str.), 2885.60 (-NH
str.), 1525.32 (-C=N str), 1245.36 (-C-N str). 1H NMR: (δ ppm): 6.8-7.2
(14 H phenyl), 9.68 (OH,
Aromatic C-OH), 3.07 (2H CH2), 1.25 (3H CH3), 13.4 (1H NH).
B11: IR (KBr) cm-1:3213.45 (-NH str.), 3063.06 (Ar-CH str.), 2885.60 (-NH str.),
1525.32 (-C=N str), 1245.36 (-C-N str). 1H NMR: (δ ppm): 6.8-7.2
(14 H phenyl), 3.07 (2H
CH2), 1.25 (3H CH3), 13.4 (1H NH).
Table no. 1: Analytical and Physicochemical
data of the synthesized compounds (A1-A11)
|
Comp. |
Mol. Formula |
Mol. Wt. |
M.P. ° C |
Yield % |
Elemental analyses Calcd.
(found) |
||
|
C |
H |
N |
|||||
|
A1 |
C21H16
N2O |
312 |
445-450 |
68 |
80.71 |
5.11 |
8.93 |
|
A2 |
C22H18N2O |
326 |
380-384 |
65 |
80.94 |
5.52 |
8.53 |
|
A3 |
C21H16N2 |
296 |
334-344 |
67 |
85.5 |
5.40 |
9.40 |
|
A4 |
C21H15ClN2 |
330 |
376-385 |
56 |
76.19 |
4.52 |
8.42 |
|
A5 |
C21H15N3O2 |
341 |
410-415 |
58 |
73.85 |
4.39 |
12.30 |
|
A6 |
C21H15N3O2 |
341 |
425-435 |
69 |
73.59 |
4.39 |
12.30 |
|
A7 |
C21H15ClN2 |
330 |
376-384 |
72 |
76.20 |
4.52 |
8.42 |
|
A8 |
C21H15N3O2 |
341 |
430-440 |
58 |
73.85 |
4.39 |
12.31 |
|
A9 |
C21H15ClN2 |
330 |
376-386 |
71 |
76.20 |
7.52 |
8.42 |
|
A10 |
C21H16N2O |
312 |
445-455 |
72 |
80.70 |
5.11 |
8.93 |
|
A11 |
C23H21N3 |
339 |
67 |
81.32 |
6.20 |
12.35 |
|
Table no. 2: Analytical and Physicochemical data of the
synthesized compounds (B1-B11)
|
Comp. |
Mol. Formula |
Mol. Wt. |
M.P. ° C |
Yield % |
Elemental analyses Calcd.
(found) |
||
|
C |
H |
N |
|||||
|
B1 |
C13H16
N2O |
216 |
302-310 |
68 |
72.16 |
7.43 |
12.91 |
|
B2 |
C14H18N2O |
230 |
273-283 |
65 |
73.01 |
7.84 |
12.13 |
|
B3 |
C13H16N2 |
200 |
191-200 |
67 |
77.93 |
8.01 |
13.96 |
|
B4 |
C13H15ClN2 |
234 |
320-330 |
56 |
66.48 |
6.40 |
11.90 |
|
B5 |
C13H15N3O2 |
245 |
325-330 |
58 |
63.62 |
6.13 |
17.09 |
|
B6 |
C13H15N3O2 |
245 |
340-350 |
69 |
63.62 |
6.13 |
17.09 |
|
B7 |
C13H15ClN2 |
234 |
233-240 |
72 |
66.48 |
6.40 |
11.90 |
|
B8 |
C13H15N3O2 |
245 |
325-330 |
58 |
63.62 |
6.13 |
17.09 |
|
B9 |
C13H15ClN2 |
234 |
320-330 |
71 |
66.48 |
6.40 |
11.90 |
|
B10 |
C13H16N2O |
216 |
302-310 |
72 |
72.16 |
7.43 |
12.91 |
|
B11 |
C15H21N3 |
243 |
310-320 |
67 |
74.03 |
8.65 |
17.23 |
Table no: 3 Antibacterial activity of
synthesized compounds (A1-A11)
(Scheme-I)
|
Compd. |
Zone of inhibition at 200µcg/mL (in mm.) |
||||
|
|
E. coli |
B. Subtilis |
S. aureus |
A. niger |
C. albicans |
|
A1 |
24 |
25 |
26 |
15 |
22 |
|
A2 |
20 |
23 |
25 |
16 |
21 |
|
A3 |
20 |
24 |
25 |
19 |
22 |
|
A4 |
25 |
26 |
23 |
20 |
21 |
|
A5 |
24 |
23 |
26 |
21 |
22 |
|
A6 |
20 |
22 |
24 |
18 |
23 |
|
A7 |
21 |
23 |
22 |
20 |
21 |
|
A8 |
22 |
24 |
25 |
20 |
22 |
|
A9 |
23 |
22 |
20 |
18 |
22 |
|
A10 |
24 |
26 |
23 |
19 |
21 |
|
A11 |
21 |
23 |
22 |
20 |
21 |
|
Ciprofloxacin |
26 |
25 |
26 |
- |
- |
|
Griseofulvin |
- |
- |
- |
22 |
23 |
Table no: 4 Antibacterial activities of
synthesized compounds (B1-B11)
(Scheme-II)
|
Compd. |
Zone of inhibition at 200µcg/mL (in mm.) |
||||
|
|
E. coli |
B. Subtilis |
S. aureus |
A. niger |
C. albicans |
|
B1 |
24 |
26 |
23 |
19 |
21 |
|
B2 |
25 |
23 |
24 |
21 |
23 |
|
B3 |
26 |
22 |
24 |
20 |
22 |
|
B4 |
24 |
25 |
26 |
21 |
23 |
|
B5 |
23 |
25 |
26 |
20 |
22 |
|
B6 |
26 |
23 |
26 |
20 |
21 |
|
B7 |
26 |
23 |
25 |
19 |
21 |
|
B8 |
25 |
24 |
26 |
20 |
21 |
|
B9 |
25 |
26 |
26 |
21 |
20 |
|
B10 |
21 |
22 |
23 |
19 |
21 |
|
B11 |
23 |
26 |
22 |
19 |
21 |
|
Ciprofloxacin |
26 |
25 |
26 |
- |
- |
|
Griseofulvin |
- |
- |
- |
22 |
23 |
Table no. 5: Anti-inflammatory activity of
synthesized compounds (A1-A11)
(Scheme-I)
|
Treatment |
Mean increase in paw volume (ml)±SEM |
|||||||||
|
Time in minute |
||||||||||
|
0 |
% inhi. |
30 |
% inhi. |
60 |
% inhi. |
90 |
% inhi. |
120 |
% inhi. |
|
|
Carrageenan (Control) |
0.24±0.01 |
|
0.48±0.03 |
|
0.78±0.09 |
|
0.85±0.12 |
|
0.89±0.14 |
|
|
Ibuprofen |
0.24±0.03 |
0 |
0.31±0.07 |
35.41 |
0.30±0.07 |
61.53 |
0.27±0.06 |
68.23 |
0.26±0.13 |
70.78 |
|
A1 |
0.24±0.01 |
0 |
0.34±0.03 |
29.16 |
0.35±0.01 |
55.12 |
0.33±0.01 |
61.17 |
0.30±0.01 |
66.29 |
|
A2 |
0.24±0.02 |
0 |
0.33±0.03 |
31.25 |
0.32±0.01 |
58.97 |
0.30±0.01 |
64.70 |
0.28±0.02 |
68.53 |
|
A3 |
0.23±0.01 |
4.16 |
0.34±0.01 |
29.16 |
0.38±0.01 |
51.28 |
0.38±0.02 |
55.29 |
0.32±0.02 |
64.04 |
|
A4 |
0.24±0.02 |
0 |
0.33±0.01 |
31.25 |
0.33±0.02 |
57.69 |
0.31±0.02 |
63.52 |
0.29±0.01 |
67.41 |
|
A5 |
0.23±0.01 |
4.16 |
0.32±0.01 |
33.33 |
0.34±0.01 |
56.41 |
0.32±0.01 |
62.35 |
0.30±0.02 |
66.29 |
|
A6 |
0.24±0.02 |
0 |
0.35±0.01 |
27.08 |
0.39±0.02 |
50 |
0.38±0.01 |
55.29 |
0.32±0.03 |
64.04 |
|
A7 |
0.23±0.02 |
4.16 |
0.33±0.01 |
31.25 |
0.35±0.02 |
55.12 |
0.34±0.02 |
60 |
0.30±0.01 |
66.29 |
|
A8 |
0.24±0.02 |
0 |
0.33±0.02 |
31.25 |
0.35±0.03 |
55.12 |
0.31±0.02 |
63.52 |
0.30±0.02 |
66.29 |
|
A9 |
0.23±0.03 |
4.16 |
0.33±0.02 |
31.25 |
0.34±0.01 |
56.41 |
0.32±0.02 |
62.35 |
0.30±0.02 |
66.29 |
|
A10 |
0.24±0.01 |
0 |
0.32±0.02 |
33.33 |
0.34±0.02 |
56.41 |
0.33±0.01 |
61.17 |
0.29±0.01 |
67.41 |
|
A11 |
0.24±0.02 |
0 |
0.34±0.03 |
29.16 |
0.34±0.03 |
56.41 |
0.35±0.01 |
58.82 |
0.31±0.02 |
65.16 |
%
inhi.= % inhibition
Table no. 6: Anti-inflammatory activity of
synthesized compounds (B1-B11)
(Scheme-II)
|
Treatment |
Mean increase in paw volume (ml)±SEM |
|||||||||
|
Time in minute |
||||||||||
|
0 |
% inhi. |
30 |
% inhi. |
60 |
% inhi. |
90 |
% inhi. |
120 |
% inhi. |
|
|
Carrageenan (Control) |
0.24±0.01 |
|
0.48±0.03 |
|
0.78±0.09 |
|
0.85±0.12 |
|
0.89±0.14 |
|
|
Ibuprofen |
0.24±0.03 |
0 |
0.31±0.07 |
35.41 |
0.30±0.07 |
61.53 |
0.27±0.06 |
68.23 |
0.26±0.13 |
70.78 |
|
B1 |
0.24±0.01 |
0 |
0.34±0.02 |
29.16 |
0.34±0.02 |
56.41 |
0.31±0.01 |
63.52 |
0.30±0.01 |
66.29 |
|
B2 |
0.24±0.02 |
0 |
0.34±0.03 |
29.16 |
0.35±0.03 |
55.12 |
0.31±0.01 |
63.52 |
0.30±0.02 |
66.29 |
|
B3 |
0.23±0.03 |
4.16 |
0.31±0.04 |
35.41 |
0.30±0.01 |
61.53 |
0.30±0.02 |
64.70 |
0.28±0.03 |
68.53 |
|
B4 |
0.24±0.01 |
0 |
0.33±0.01 |
31.25 |
0.34±0.02 |
56.41 |
0.32±0.02 |
62.35 |
0.30±0.02 |
66.29 |
|
B5 |
0.24±0.01 |
0 |
0.32±0.01 |
33.33 |
0.30±0.01 |
61.53 |
0.29±0.02 |
65.88 |
0.28±0.01 |
68.53 |
|
B6 |
0.23±0.01 |
4.16 |
0.33±0.02 |
31.25 |
0.34±0.02 |
56.41 |
0.33±0.01 |
61.17 |
0.32±0.02 |
64.04 |
|
B7 |
0.23±0.01 |
4.16 |
0.31±0.02 |
35.41 |
0.31±0.02 |
60.25 |
0.28±0.02 |
67.05 |
0.27±0.01 |
69.66 |
|
B8 |
0.24±0.02 |
0 |
0.33±0.03 |
31.25 |
0.34±0.03 |
56.41 |
0.33±0.03 |
61.17 |
0.32±0.03 |
64.04 |
|
B9 |
0.24±0.02 |
0 |
0.31±0.02 |
35.41 |
0.30±0.02 |
61.53 |
0.28±0.03 |
67.05 |
0.28±0.02 |
68.53 |
|
B10 |
0.24±0.02 |
0 |
0.33±0.03 |
31.25 |
0.34±0.03 |
56.41 |
0.33±0.03 |
61.17 |
0.32±0.03 |
64.04 |
|
B11 |
0.24±0.02 |
0 |
0.34±0.03 |
29.16 |
0.35±0.03 |
55.12 |
0.31±0.01 |
63.52 |
0.30±0.02 |
66.29 |
Result and discussion:
Antibacterial
activity:
The compounds A1,
A2, A3, A5,
A8, B4, B5 ,B6, B7, B8,
B9 has excellent
Antibacterial activity against S. aureus, the compounds A1, B4,
B5 have shown Antibacterial activity against B. subtilis, while A4, B2, B3,
B6, B7, B8, B9 shows
Antibacterial activity against E.coli. when compared with standard Ciprofloxacin.
Anti-Inflammatory Activity:
All the
compounds were evaluated for Anti-inflammatory activity by Carrageenan
Induced Rat hind Paw method. The synthesized compounds A2, A4, A5, A6, A8,
B1, B3, B7,and B8 showed better
anti-inflammatory activity found comparable with standard drug Ibuprofen
(70.78% inhibition) at the same dose
(100µg/kg).
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Jagtap V. A., Agasimundin Y. S., Jayachandran
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Received on 10.11.2014 Accepted on 12.12.2014
© Asian Pharma
Press All Right Reserved
Asian J. Pharm.
Tech. 2014; Vol. 4: Issue 4,
Oct.-Dec., Pg 189-194