Diloxamde Furoate
ARTICLE JANUARY 1999
DOI: 10.1016/S0099-5428(08)60624-3
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Abdulrahman Al-Majed
King Saud University
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Fathalla Belal
Facu;ty of Pharmacy
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DILOXANIDE FUROATE
247
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A. A. AL-MAJED ETAL.
Contents
1.
Description
1.1
Nomenclature
1.1.1 Chemical Names
1.1.2 Nonproprietary Names
1.1.3 Proprietary Names
1.2
Formulae
1.2.1 Empirical
1.2.2 Structural
1.3
Molecular Weight
1.4
CAS Number
1.5
Appearance
1.6
Uses and Applications
2.
Method of Preparation
3.
Physical Properties
3.1
X-Ray Powder Diffraction Pattern
3.2
Thermal Methods of analysis
3.2.1 Melting Behavior
3.2.2 Differential Scanning Calorimetry
3.3
Solubility Characteristics
3.4
Partition Coefficients
3.5
Spectroscopy
3.5.1 UVIVIS Spectroscopy
3.5.2 Fluorescence Spectroscopy
3.5.3 Vibrational Spectroscopy
3.5.4 Nuclear Magnetic Resonance Spectrometry
I
3.5.4.1
H-NMR Spectrum
13
3.5.4.2
C-NMR Spectrum
3.5.5 Mass Spectrometry
DILOXANIDE FUROATE
249
4.
Methods of Analysis
4.1
Identification
4.2
Elemental Analysis
4.3
Titrimetric Analysis
4.4
Electrochemical Analysis
4.5
Spectrophotometric Methods of Analysis
4.5.1 Ultraviolet Absorption Spectrometry
4.5.2 Colorimetry
Miscellaneous Non-Chromatographic Methods of Analysis
4.6
4.7
Chromatographic Methods of Analysis
4.7.1 Thin Layer Chromatography
4.7.2 Gas Chromatography
4.7.3 Supercritical Fluid Chromatography
4.7.4 High Performance Liquid Chromatography
5.
Pharmacology
6.
Acknowledgement
7.
References
A. A. AL-MAJED ETAL.
250
1.
Description
1.1
Nomenclature
2,2-dichloro-4-hydroxy-N-methylacetanilide-2-furoate
2,2-dichloro-N-(4-hydroxyphenyl)-N-methylacet~ide-2-furoate
N-dichloroacet-4-hydroxy-N-methylanilide-2-furoate
4-hydroxy-N-methy ldichloroacetanilide-2-furoate
dichloro-acet-4-hydroxy-N-methylanilide-2-furoate
4-(N-methyl-2,2-dichloroacetamido)-phenyl-2-furoate
1.1.2 Nonproprietary Names
Diloxanide furoate
1.1.3 Proprietary Names [5]
Furamide,Histomibal,Miforon
1.2
Formulae
1.2.1 Empirical
C14HllC12N04
1.2.2 Structural
1.3
Molecular Weight [ 5 ]
328.15 Daltons
CHC12
DlLOXANlDE FUROATE
1.4
2.5 1
CAS Number
3736-8 1-0
1.5
Appearance
1.6
2.
Method of Preparation
Diloxanide
Iol
NaOCl
G
/ C\ - O H
h o y l chloride
0
H D ~ l ' i J - 6 - C H C 1 2 ______)
or
k i c acid
CH3
soc12
Qc-c,
t;
Furoyl chloride
Qg-oe
0
r;J-C-CHClZ
II
CH3
Diloxanide filroate
Scheme 1
DILOXANIDE FUROATE
253
3.
Physical Properties
3.1
3.2.1
Melting Behavior
10
15
20
25
30
35
40
DILOXANIDE FUROATE
255
Table I
Crystallographic Data from the X-Ray Powder Pattern
of Diloxanide Furoate
Scattering Angle
(degrees 28)
d-Spacing (A)
Relative Intensity
(I/Imax * 100)
6.613
10.114
11.194
13.072
13.520
13.860
14.989
16.093
17.520
17.839
18.804
19.393
20.01 1
21.525
22.189
23.03 1
23.720
24.053
24.707
25.088
25.454
25.812
27.195
13.3550
8.7382
7.8980
6.7673
6.5438
6.3844
5.9056
5.5029
5.0578
4.9682
4.7151
4.5734
4.4335
4.1249
4.0029
3.8585
3.7479
3.6968
3.6004
3.5467
3.4841
3.4487
3.2764
1.97
8.09
17.26
2.16
9.66
39.83
2.36
11.96
8.20
33.49
4.85
5.05
100.00
3.06
9.15
5.1 1
25.39
94.46
2.26
2.58
19.64
14.43
3.26
A. A. AL-MAJED ET AL.
256
Table 1 (continued)
Crystallographic Data fiom the X-Ray Powder Pattern
of Diloxanide Furoate
Scattering Angle
(degrees 20)
d-Spacing (A)
Relative Intensity
(I/Imax * 100)
27.750
28.506
28.916
29.436
30.223
30.799
32.230
32.628
33.664
34.158
34.772
35.357
35.812
36.265
36.893
37.679
38.649
39.169
40.612
4 1.460
43.690
44.866
3.2121
3.1287
3.0852
3.0319
2.9547
2.9007
2.7751
2.7422
2.6601
2.6227
2.5779
2.5365
2.5053
2.4751
2.4344
2.3854
2.3277
2.2980
2.2196
2.1762
2.0701
2.0186
34.83
7.55
28.67
4.02
5.44
9.62
9.78
9.58
13.20
12.68
1.37
5.50
5.76
3.26
6.71
3.00
1.31
3.89
4.16
3.53
2.89
1.38
DILOXANIDE FUROATE
251
113 .58k
105.6J19
105
115
125
135
Ternperature (OC)
A. A. AL-MAJED ET AL.
258
3.3
Solubility Characteristics
Partition Coefficient
No partition coefficient data have been reported for diloxanide furoate, but
a theoretical log P value of 1.42 k 0.55 has been obtaining using the
predictive program of Advanced Chemistry Development Laboratories
[501.
3.5
Spectroscopy
3.5.1
UVNIS Spectroscopy
Fluorescence Spectroscopy
DILOXANIDE FUROATE
,'-\
I
#
\
\
i
\
J
I
I
I
I
L
L
I
I
I
259
I
I
I
I
I
I
I
I
I
\
\
I
\
\
\
240
260
7 -
'---
280
Wavelength (nm)
Figure 3.
A. A. AL-MAJED ETAL
260
.
240
280
320
360
400
440
Wavelength (nm)
Figure 4.
3500
---
3000
2500
2000
1800
1600
1400
1200
Energy (cm-')
Figure 5.
1000
800
A. A. AL-MAJED ET AL
262
1678, 1 197, 1093, 1290, 1727, and 1 167 cm-'. The same absorption
bands were reported by Clarke [7].
3.5.4 Nuclear Magnetic Resonance Spectrometry
3.5.4.1
H-NMR Spectrum
"C-NMR Spectrum
263
12
10
Figure 6.
264
II
A. A. AL-MAJED ETAL
%B
7.6
7.4
II
7.2
7.0
6.8
6.6
Figure 7.
265
DILOXANIDE FUROATE
Table 2
Assignments for the 'H-NMR Resonance Bands
of Diloxanide Furoate
Proton ID
Multiplicity
HI
doublet
7.630 - 7.634
H2
multiplet
6.535 - 6.546
H3
doublet
7.321 - 7.328
H4 and H5
two doublets
7.275
H6 and H7
two doublets
7.278
H8
singlet
3.238
H9
singlet
5.838
EZO si
u
zv
u
-
c=+ rn
z-5
. . . : .
v)
50
0
0
0
100
v)
150
0
0
200
aI
DILOXANIDE FUROATE
261
Table 3
Assignments for the I3C-NMR Resonance Bands
of Diloxanide Furoate
Carbon ID
c1
148.15
c2
139.43
c3
143.63
c4
150.68
c5
164.17
C6
128.77
c7
120.61
C8
112.86
c9
123.97
c10
112.86
Cll
120.61
c12
39.03
C13
156.68
C14
64.04
2mfro
5
3
CH3
12
14
;di
100
121
24 3
263
I
200
300
399
t
400
m/z
Figure 9.
4 3 6 6 5 5 474
530 5 4 9
500
DlLOXANlDE FUROATE
Table 4
Fragmentation Pattern in the Mass Spectrum
of Diloxanide Furoate
m/Z
Relative intensity
Fragment
328
243
25%
124
12%
122
32%
96
55%
95
100%
67
82%
Ql+
269
A. A. AL-MAJED ETAL
270
4.
Methods of Analysis
4.1
Identification
Clarke has reported that diloxanide furoate gives a blue color with the
Folin-Ciocalteu Reagent, and also yields a yellow color when subjected to
Libermanns test [7].
The British Pharmacopoeia has described three identification tests [6].
a. The infrared absorption spectrum of the substance is in
agreement with the reference spectrum of diloxanide furoate.
b. The light absorption of the substance in the range 240 to 350
nm of a 0.0014% w/v ethanolic solution exhibits a maximum
only at 258 nm. The absorbance at this maximum is about 0.98.
c. 20 mg of the substance is burned by the method for oxygenflask combustion, using 10 mL of 1 M sodium hydroxide as the
absorbing liquid. Upon completion of the process, the liquid is
acidified with nitric acid and silver nitrate solution is added. A
white precipitate is produced.
4.2
4.3
Titrimetric Analysis
DILOXANIDE FUROATE
27 1
Electrochemical Analysis
272
A. A. AL-MAJED ET AL.
DILOXANIDE FUROATE
213
metronidazole in a tablet preparation [21]. This study described the pHinduced difference spectrophotometric method for the quantitation of the
drugs and their excipients in the presence of each other. The difference
absorption of the drug solution showed maximum values of AA at 297 and
243 nm, and a minimum value of AA at 268 nm.
Sanghavi and Kulkarni estimated the drug in the presence of its degraded
products by differential spectroscopy [22]. Sastry et al. determined
diloxanide furoate by a spectrophotometric method [23].
Two differential spectrophotometric methods were used by Chatterjee et
al. for the simultaneous analysis of diloxanide furoate and metronidazole
in pharmaceutical formulations [24]. The first method involved
measurement of the absorbance of a methanolic solution of the two drugs
at 259 and 3 1 1 nm. Since the absorbance of diloxanide furoate at 3 1 1 nm
is zero, the concentration of metronidazole is directly measured, and a
simple equation based on absorbance ratios is used to calculate the
concentration of diloxanide furoate. The second method was a differential
spectrophotometric determination based on pH-induced spectral changes,
on changing from an acidic to an alkaline solution. A marked
bathochromic shift was exhibited by metronidazole, while diloxanide
furoate showed a slight hypsochromic shift. The wavelength of maximum
absorption difference for diloxanide furoate was 267 nm, where
metronidazole did not absorb. Similarly, diloxanide furoate did not
interfere with metronidazole at when measured at 322 nm.
Podder et al. used a simple and convenient spectrophotometric method for
the determination of tinidazole and diloxanide furoate in combined
pharmaceutical formulations [25]. The absorbance of a methanolic
solution of a sample containing 20 to 40 pg/mL of each drug was
measured between 254 to 3 10 nm. Diloxanide furoate was reported to
exhibit an absorption maximum at 254 nm.
Sadana and Gaonkar described a simultaneous derivative spectroscopic
method for the determination of diloxanide furoate and tinidazole in
pharmaceutical dosage forms [26]. Drugs were powdered and dissolved in
methanol, and the solution set aside for 30 minutes with frequent shaking.
After filtration, the filtrate and washings were diluted with methanol. A
suspension equivalent to 150 mg of diloxanide furoate was extracted with
chloroform. The filtered extract was evaporated to dryness, and the
A. A. AL-MAJED ETAL.
274
Colorimetry
DILOXANIDE FUROATE
275
ChromatographicMethods of Analysis
4.7.1
Clarke described three thin layer chromatography (TLC) systems for the
separation of diloxanide furoate [7].
Method 1 [34]
Plate:
4. A . AL-MAJED E T A L
216
Mobile Phase:
Developing Agent:
Rf:
Reference Compounds:
Method 2 [34]
Plate:
Mobile Phase:
Developing Agent:
Rf:
Reference Compounds:
Method 3 [34]
Plate:
Mobile Phase:
Developing Agent:
Rr:
Reference Compounds:
4.7.2
74
meclozine (Rf = 79), caffeine (Rf = 5 8 ) ,
dipipanone ( R f = 33), desipramine (Rf= 1 1 )
Gas Chromatography
DILOXANIDE FUROATE
211
A. A. AL-MAJED E T AL
278
4.7.4
5.
Pharmacolow
DILOXANIDE FUROATE
219
rapidly cleared [42]. The drug is well absorbed, and is present in serum
largely as the glucuronide conjugate that is almost entirely excreted in the
urine [ 1,431. The drug has a direct amoebicidal action, affecting the
ameba before encystment [2]. Diloxanide is considered as a luminal
amoebicide acting in the bowel lumen [4,[44-461. The drug is directly
toxic to Entameba histolytica when tested in vitro, but its mechanism of
action is still not known.
6.
Acknowledgement
7.
References
1.
2.
H.P. Rang, M.M. Dale, and J.M. Ritter, Pharmacology, 3rd edn.,
Churchill Livingstone, Edinburgh, 1992, p. 863.
3.
4.
5.
The Merck Index, 12'h edn., Merck and Co., Inc., Whitehouse
Station, NJ, 1996, p. 541.
6.
7.
280
A. A. AL-MAJED E T A L
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
S.M. Galal, M.M. Bedair, and M.A. El-Sayed, J. Pharm. Belg., 46,
315 (1991).
18.
19.
20.
21.
22.
23.
C.S.P. Sastry, B.G. Rao, and B.S. Reddy, Indian Drugs, 20, 294
(1 983j.
DILOXANIDE FUROATE
281
24.
P.K. Chatterjee, C.L. Jain, and P.D. Sethi, Indian Drugs, 23, 1 12
(1985).
25.
26.
27.
P.P. Shah and R.C. Mehta, Indian J. Pharm. Sci., 43, 147 (1981).
28.
R.T. Sane, S.V. Desai, and R.S. Samant, Indian Drugs, 23,369
(1 986).
29.
30.
31.
32.
33.
34.
35.
36.
R.T. Sane. G.J. Bhounsule, and V.G. Nayak, Indian Drugs, 24 202
(1 987).
37.
38.
39.
40.
282
A. A. AL-MAJED ETAL
41.
G.R. Rao, S.S.N. Murty, and K.R. Mohan, Indian Drugs, 20,455
(1983).
42.
43.
44.
45.
J.B. McAuley and D.D. Juranek, Clin. Infect. Dis., 14, 1161
(1 992).
46.
47.
48.
49.
50.