K. Usmanghani
Department of Pharmacognosy, Faculty of Pharmacy,
University of Karachi, Karachi-75270, Pakistan.
1.
2.
2.1
2.2
2.3
3.
4.
4.1
4.2
4.3
4.4
4.5
4.6
4.7
4.8
4.9
4.10
4.11
4.12
5.
5.1
5.2
5.3
INTRODUCTION
DESCRIPTION
Name, Formula, Molecular Weight
Appearance, Color, Odor and Taste
Proprietary Names
SYNTHESIS
PHYSICAL PROPERTIES
Melting Point
Solubility
Completeness of Solution
Acidity
Water Content
Residue on Ignition
Chromatographic Purity
Ultraviolet Spectrum
Infrared Spectrum
Nuclear Magnetic Resonance Spectrum
Mass Spectrum
Complex Formation
QUALITATIVETESTS
Identification
Color Tests
Field Test
43
44
5.4
6.
6.1
6.2
6.3
6.4
7.
7.1
7.2
8.
TOXICITY
ACKNOWLEDGEMENT
REFERENCES
1.
INTRODUCTION
DESCRIPTION
AMODIAQUINE HYDROCHLORIDE
CaH2zCIN30,2HC1, 2H20
45
464.8
3.
SYNTHESIS
,q+
46
C1
H2N a c H 2 N ( q H d 2
OH
c1
II
10
dilute
0". 2 HCl
hours
,@2N(c2H5)2
111
OH
The free base was recrystallized from absolute ethanol and converted
into the dihydrochloride by treating with hot concentrated hydrochloric
acid.
4.
PHYSICAL PROPERTIES
AMODIAQUINE HYDROCHLORIDE
4.3
47
Completeness of Solution
A solution of 200 mg in 10 ml of water is clear (10).
4.4 Acidity
The pH of a 2.0% w/v solution is 3.6 to 4.6 (4).
4.5 Water Content
Not less than 7.0% and not more than 9.0% (10)
4.6 Residue on Ignition
Not more than 0.2% (10)
4.7 Chromatographic Purity
Chromatographic purity of amodiaquine hydrochloride can be
examined on thin-layer plate coated with a 0.25 mm layer of silica gel G
using solvent system chloroform (saturated with ammonium hydroxide):
dehydrated alcohol (9: 1). Under short-wavelength ultraviolet light, the
chromatogram shows principal spot at about the same Rf value, and no
secondary spot, as obtained with the USP Amodiaquine Hydrochloride RS
(10).
4.8 Ultraviolet (UV) Spectrum
The ultraviolet spectra of amodiaquine and amodiaquine
hydrochloride have been reported by Sunshine (12) and Clarke (7)
respectively. The ultraviolet absorption characteristics are used for the
identification of these drugs (4,10,13). The absorption spectrum of
amodiaquine hydrochloride as a function of pH in the range 1-11.8 shows a
hypsochromic effect at 343 nm, a hyperchromic effect at 305 nm and the
isosbestic point at 323 rim (14). The effect of solvents and substitution on
the ultraviolet spectra of amodiaquine has been studied and the changes of
absorption bands E,K, and B discussed in detail (15).
The ultraviolet spectrum of amodiaquine hydrochloride in 0.1 M
hydrochloric acid was recorded on a Shimadzu 240 UV-Visible
spectrophotometer and is shown in Figure 2. The uv spectral data
reported for amodiaquine and amodiaquine hydrochloride are listed in
Table 1.
48
1.50
!r
1
Figure 2.
WAVELENGTH Cnml
3 .0
AMODIAQUINE HYDKOCHLORIDE
49
Table 1
Solvent
Amodiaquine
0.1 M HCl
Amodiaquine
hydrochloride
Water
0.1 M HCI
0.1 M HCl
Aq. acid
Aq. alkali
0.1 M HCl
Amax, nm
283
237
247
224
342
343
223
237
343
237
343
273
287
223
237
342.5
A (l%,Icm)
Molar
Absorptivity
890
530
470
41370
24630
21850
394410
366
1831019060
17010
366
600
17010
27890
Ref.
12
4
11
7
7
836
489
369
38850
22710
17160
5.a
..
4.0
0
L
7.0
60
I
8.g
I
5.0
I
10 0
zoo
15.0
:oo.o
0
0
0
20.0
00"
500
0.0
'I
'1500
40 0
I 2000
60-0
3000
0
ID
000
80.0
51
AMODIAQUINE HYDROCHLORIDE
Table I1
IR Spectral Assignments for Amodiaquine Hydrochloride
Frequency, cm-1
3420
3 170
1615
1585,1540,1505
1448
1265,1207
1095
852,840
Assignment
- NH stretching
- OH stretching
C = C stretching (aromatic)
C =C, C = N stretching
in disubstituted quinoline
- CH2-N- deformation
C-OH stretching (aromatic)
C-Cl stretching (aromatic)
isolated CH deformation
in disubstituted quinoline
d,
.I'
11-1'
L
11
I0
..,. ,...9 0 ..
8 0
1 0
. . :.
,.
P O
.. ..
:
. . .. -*
. .
. ...
4
PTL
-,rPPM
e
w
L
I
. . ,. . .. - , ._..
I!
-3r .
Iv,
h ?,
BIO
..
, ,1, 1, , , , , , , (
7.0
1 ,
6,O
PAI
, , , , , , , , r*~ , , , , , , , , ( , , , , , ,
5 0
4.0
, , , ,
I 0
2 0
--
LPr2
1 0
CH: CHdCH2
l,,c.3tii
14
1
C.ll..ll
C.5
I ICI.
cd
C.Y
C.2
I I
-I--
C4
11
A L
Figure R.
t'
-==i
7'1
-2
L.
'4
I
58
Table I11
Proton
coupling
constant
(J in Hz)
C-NMR
Chemicalshift
(PPd
156.04
138.87
7.67 (1H,d)
25
7.35 (lH,dd)
4.22 (lH,d)
4.22 (lH,s)
3.09 (4H,q)
1.27 (6H,t)
5
6
7
910
1112
8.62.5
8.6
8.44 (lH,d)
6.82 (1Hd)
2
3
8.% (lH,d)
7.78 (lH,dd)
5
6
6.7
1.2
7.0
7.0
9.1
9.12.1
l30.00
115.60
128.30
116.85
49.11
46.19
8.41
142.91
100.41
117.54
126.19
127.04
138.15
8.17 (lH,d)
2.1
118.97
Carbon
1
2
3
4
5
6
7
910
1112
2
3
4
5
6
T
8
154.85
127.92
10
NH/OH
10.89
60
Table 4
Proposed Fragmentation Pattern of Amodiaquine Hydrochloride
d z
Relative intensity %
355, 357
55.77, 16.83
283
43.05
Ion
NH
@CH2
OH
282
99.00
c'w
@CH
OH
I-
253
43.56
179
8.18
177
5.81
AMODIAQUINE HYDROCHLORIDE
61
QUALITATIVE TESTS
5.1
Identification (4)
62
METHODS OF ANALYSIS
AMODIAQUINE HYDROCHLORIDE
63
64
AMODlAQUlNE HYDROCHLORIDE
65
recoveries from authentic samples are obtained and the method is suitable
for routine analysis.
6.2.2 Colorimetry
Amodiaquine hydrochloride is determined colorimetricallyby complex
formation, in aqueous solution, with bromophenol blue, bromocresol
green, bromocresol purple, and methyl orange, respectively. The complex
with bromophenol blue has the highest molar absorptivity. Recoveries are
more than 98.6% for all complexes, and the absorbance is linear with
concentration in the range 1-11 pglml. The absorption maxima for the
complexes occur at 420 nm except for the bromocresol purple complex
which exhibits maximum at 415 nm. The various complexes are extracted
with chloroform and absorbance is measured at the respective maxima for
quantitative determination (28).
A simple, sensitive, and selective method for the determination of
amodiaquine hydrochloride in tablets has been developed. It is based on a
color reaction with chloramine-T in the pH range 7.4- 8.0. The chromogen
is extracted with chloroform and the absorbance is measured at 442 nm.
Beers law is obeyed in the concentration range 1-200 p g / l . The
coefficient of variation has been found to be 0.64% and the recovery
ranges between 100.3 and 102.5%. Chloroquine phosphate or primaquine
phosphate do not interfere with the method (29).
66
AMODIAQUINE HYDROCHLORIDE
67
Chromatographic Analysis
Solvent system
Methanol: ammonia
(1rn1.5)
Cyclohexane :toluene :
diethylamine
(751510)
Cbloroform:methanol
( 91)
Acetone
Rr
0.62
0.08
0.40
0.37
68
7.
7.1 Metabolism
Churchill et al. (42) have isolated four metabolites of amodiaquine in
humans using a reversed-phase HPLC method. The two major metabolites
have been identified as desethylamodiaquine and 2- hydroxy-
AMODIAQUINE HYDROCHLORIDE
69
Pharmacokinetics
TOXICITY
70
1.
2.
3.
4.
5.
6.
7.
8.
AMODIAQUINE HYDROCHLORIDE
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
71
12
29. Rao, G.R., Rao, Y.P. and Raju, I.R.K. (1982). Analyst (London) 107,
776.
30. Hassan, S.M., Metwally, M.E.S. and Abou-Ouf, A.A. (1982). Analyst
(London) 107,1235.
3 1. Dalal, R.R., Bulbule, M.V., Wadodkar, S.G. and Kasture, A.V.
(1982). Indian Drugs 19,361.
32. Issa, A.S., Mahrous, M.S., Salam, M.A.and Hamid, M.A. (1985). J.
Pharm. Belg. 40,339.
33. Mahrous, M.S., Salam, M A , Issa, A.S. and Hamid, M.A. (1986).
Talanta 33, 185.
34. Sastry, B.S., Rao, E.V. and Sastry, C.S.P. (1984). Indian J. Pharm. Sci.
46,186.
35. Sastry, B.S., Rao, E.V. and Sastry, C.S.P. (1986). Indian J. Pharm. Sci.
48,71.
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Carson, P.E. and Rieckmann, K.H. (1974). Bull. Wld. Hlth. Org. 51,
431.
37. Stead, A.H., Gill, R., Wright, T., Gibbs, J.P. and Moffat, A.C. (1982).
Analyst (London) 107,1106.
38. Musumarra, G., Scarlata, G., Romano, G., Clemente, S. and Wold, S.
(1984). J. Chromatogr. Sci. 22,538.
39. Wheals, B.B. (1980). J. Chromatogr. 187,65.
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Chromatogr. 10,1203.
41. Pussard, E., Verdier, F. and Blayo, M.C. (1986). J. Chromatogr. 374,
111.
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P.N. and Dickinson, C.M. (1985). Life Sci. 36,53.
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(1986). J. Chromatogr. 377,307.
44. White, A.I. (1977). In 'Textbook of Organic Medicinal and
Pharmaceutical Chemistry", 7th Edition (C.O. Wilson, 0. Gisvold
and R.F. Doerge, eds.), p. 258, J.B. Lippincott Co., Philadelphia.
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(1957). 'The Chemistry of Organic Medicinal Products", p. 361, John
Wiley and Sons, Inc., New York.
46. Atherden, L.M. (1969). "Bentley and Driver's Textbook of
Pharmaceutical Chemistry", 8th Edition, p. 638, Oxford University
Press, London.
47. "New Drugs" (1966). p. 81, American Medical Association, Chicago.
AMODlAQUlNE HYDROCHLORIDE
73
48. Akindele, M.O. and Odejide, A.O. (1976). Br. Med. J. 2,214.
49. 'The Physicians' and Pharmacists' Guide to Your Medicines",p. 18,
United States Pharmacopeial Convention, Ballantine Books, New
York.
50. Smith, C.C. (1950). J. Pharmacol. Exptl. Therap. 100,408.