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GUAIFENESIN
GUAIFENESIN
1075-6280198 625.00
25
121
121
CONTENTS
1.
Description
1.1
Nomenclature
1.1.1 Chemical Name
1.1.2 Other Chemical Names
1.1.3 Pharmacopoeia Names
1.1.4 Proprietary Names
1.9
Formulae
1.2.1 Empirical Formula
1.2.2 CAS Registry Number
1.2.3 Structure
I .3
Molecular Weight
I .4 Elemental Composition
I .S
Appearance
I .6
Uses and Applications
2.
Synthesis
3.
Physical Properties
3.1
3.2
3.3
3.4
3.5
3.6
3.7
Microscopy
3.1.1 Particle Morphology
3.1.2 Optical Crystallography
X-Ray Powder Diffraction Pattern
Optical Activity
Thermal Properties
3.4.1 Melting point
3.4.2 Differential Scanning Calorimetry
3.2.3 Loss on Drying
Hygroscopicity
Solubility Characteristics
Spectroscopy
3.7.1 UVNIS Spectroscopy
3.7.2 Vibrational Spectroscopy
3.7.3 Nuclear Magnetic Resonance Spectrometry
3.7.3.1 'H-NMR
3.7.3.2 I3C-NMR
3.7.4 Mass Spectrometry
GUAIFENESIN
3.8
Micromeritic Properties
3.8.1 Particle Size Distribution
3.8.2 Bulk and Tapped Densities
3.8.3 Powder Flowability
4.
Methods of Analysis
4.1
Cornpendial Tests
4.2
Identification
4.3
Titrimetric Analysis
4.4
Spectrophotometric Methods of Analysis
4.5
Chromatographic Methods of Analysis
4.5.1 Thin Layer Chromatography
4.5.2 Gas Chromatography
4.5.3 High Performance Liquid Chromatography
4.5.4 Capillary Electrophoresis
Determination in Body Fluids and Tissues
4.6
5.
Stability
5.1
Solid-state Stability
5.2
Solution-Phase Stability
6.
Acknowledgment
References
123
I74
I.
DescriDtion
1.1
Nomenclature
1.1.1
Chemical Name
(R,S)-3-(2-methoxyphenoxy)-propane1 J-diol
1.1.2
(3-methoxyphenoxy)- 1,2-propanediol
(0-methoxyphenoxy)- 1,2-propanediol
Guaiacyl glyceryl ether
Guaiacol glycerol ether
GIycery lguaiacol
Glyceryl guaiacolate
Guajocolurn glycerolatum
Glycery lguayacolum
Glycerol a-(2-methoxypheny1)ether
o-Methoxyphenyl glyceryl ether
I. 1.3
Pharmacopoeia Names
British Pharmacopoeia: Guaiphenesin
GUAIFENESIN
Formulae
c,OH,
404
1.2.3 Structure
OH
1.3
Molecular Weight
198.22
1.4
Elemental Composition
Carbon
Hydrogen
Oxygen
1.5
60.59%
7.12%
32.29%
Appearance
125
196
1.6
Svnthesis
GUAIFENESIN
PH
Alternative method
Scheme 1.
127
128
3.
Phvsical ProDerties
3.1
Microscopy
3.1.1
Particle Morphology
GUAIFENESIN
Figure 1.
129
1 30
3.2
Optical Activity
Thermal Properties
3.4.1
Melting point
The melting range of racemic guaifenesin can be between 78OC and 82"C,
and current USP specifies that the magnitude of the temperature interval
spanning the beginning and end of melting cannot exceed 3C. The latest
issue of the Merck Index quotes a melting point of 78.5-79C.
GUAIFENESIN
131
n_
10
=?===+-7
15
20
25
30
Figure 2.
Table I
d-spacing (A)
Scattering Angle
(degrees 2-0)
6.865
12.897
("/I
4.3
13.055
7.354
100.0
I 3.460
6.589
85.2
13.780
6.437
4.4
15.525
5.717
0.6
18.030
4.928
3.4
20.530
4.272
32.7
22.340
3.986
3.8
23.570
3.946
3.7
23.205
23.795
24.255
75.435
77.1 10
27.485
39.075
29.585
I
I
3.840
3.746
3.676
3.508
3.295
3.251
3.076
3.024
I
I
I
I
I
12.8
9.8
6.6
6.2
3.0
4.1
3.4
3.2
~
30.220
2.962
3.1
3 1.240
2.868
0.7
GUAIFENESIN
Guaifenesin loses not more than 0.5% of its weight after being dried at
105C for three hours [7]. When dried over P,O, at 60C at a pressure of
1.5 to 2.5 kPa for three hours, the compound will not lose more than 0.5%
of its weight.
3.5
Hygroscopicity
Solubility Characteristics
133
134
!I
50
60
70
80
Temperature ("C)
E igurt.
90
GUAIFENESIN
135
Spectroscopy
3.7.1
UVNIS Spectroscopy
Vibrational Spectroscopy
'H-NMR
0.56
)...... ...................
0.34
J/J
D
'
, . ' A
.....
. . .
~
...
. .
0.12
.....................
200
240
280
320
Wavelength (nm)
Figure 4.
chlorofomi.
137
GUAIFENESIN
3800
3400
3000
2600
2200
Energy (cm-)
Figure 5 .
1%
Figure 6.
GUAIFENESIN
Table 2
Assignments for the Vibrational Transitions of Guaifenesin
Energy (cm-')
3600 - 3200
3200 - 2500
- 3000
1920 - 1600
~~
Assignment
1600 - 1510
1260 - 1350
1300 - 1200
1 150 - 1000
748
650 - 400
139
rc
Figure 7.
f
r
I
3.8
I
4.2
3.4
3.0
142
Table 3
Assignments for the Observed 'H-NMR Resonance Bands of Guaifenesin
Chemical Shift
1~
Number of
Protons
Assignment
(PV)
6.96 - 6.83
4.33
4.13, - 3.98
3.75
3.48
1 3 c -spectrum
~ of guaifenesin.
144
0
W
c-
0
W
160
140
120
100
80
60
136
3.6
3.8
I
1.0
1.2
IDm
nom
v--P
,
I
d ?
A0
38
3.6
Figure 12.
GUAIFENESIN
147
60
70
80
90
00
10
?O
m
Figure 13.
148
Table 4
Assignments for the Observed "C-NMR Resonance Bands of Guaifenesin
GUAIFENESIN
3.7.3.2
149
I3C-NMR
The I3C-NMRspectrum of guaifenesin was also obtained in deuterochloroform at ambient temperature, using tetramethylsilane as the internal
standard. The one-dimensional spectrum is shown in Figure 9, while the
DEPT 135, DEPT 90, COSY 45 (HOMOCOSY), and INVBTP
(HETEROCOSY) are shown in Figures 10 through 13, respectively. All
of these spectra were used to develop the correlation between chemical
shifts and spectral assignment that are given in Table 4, and which have
been identified according to the following numbering system:
10
W
OH
3.8
Micromeritic Properties
3.8.1
150
OH
OC~dHCt+OHl
wo%
OCH$X=OH
cbo%
Kh! 198
?&?
WZ137
OH
nJz 167
OH
Kh!124
OH
+ Ct-@WC)-CZOH
I
nJz 75
rrrrz 109
Figure 13.
GUAIFENESIN
151
Table 5
Particle Size Distribution Obtained for a Commercial
Sample of Guaifenesin
~
Particle Size
(Clm)
Percent of Particles
Found in the Size Band
Cumulative Percent of
Particles
6.3
2.16
2.16
9.0
9.52
11.68
25
11.63
23.33
36
29.16
52.49
50
18.58
71.07
71
16.05
87.12
100
140
7.11
5.79
94.23
100.02
152
3.8.3
Powder Flowability
The Carr Compressibility Index and Hausner Ratio are two measures
which can be used to predict the propensity of a given powder sample to
be compressed, and which are understood to reflect the importance of
interparticulate interactions. These interactions are generally less
significant for a free-flowing powder, for which the bulk and tapped
densities will be relative close in magnitude. Poorer flowing materials are
characterized by the existence of larger interparticle interactions, so a
greater difference between bulk and tapped densities is observed. The two
indices are calculated using the following relations [ 121:
Carr Compressibility Index
Hausner Ratio
V,,
V,
=
=
v, I v,
where:
original bulk volume of powder
final tapped volume of powder
4.
Methods of Analvsis
4.1
Compendia1 Tests
GUAIFENESIN
4.2
153
Identification
TitrimetricAnalysis
154
2.5 C (AdAs)
where C is the concentration (in units of pg/mL) of the guaifenesin
standard in the standard solution, and Au and As are the absorbencies of
the sample solution and the standard solution, respectively.
The United States Pharmacopoeia describes a spectrophotometric test for
the presence ofguaiacol in samples of guaifenesin [l 11. 1.O g of sample is
transferred to a 100-mL volumetric flask, and 25.0 mL of water is added
(warming the solution may be required to effect dissolution). To this is
added 1.O mL of potassium ferricyanide TS, the contents swirled to mix,
VI hereupon 5 mL of 4-aminoantipyrine solution (1 in 200) is added. At
this point, one begins timing the reaction with a stop watch. The flask is
swirled for 5 seconds, and the contents are immediately diluted to volume
tvith sodium bicarbonate solution ( I in 1200)to volume. After an
accurately timed fifteen minute time period commencing after the addition
of the 4-aminoantipyrine solution, the absorbance of the solution is
determined at 500 nm. The instrument blank is sodium bicarbonate
solution ( 1 in 1200). The absorbance of the sample solution is not to be
greater than that of a standard solution similarly prepared using 3.0 mL of
a 1 in 10,000 solution of USP Guaiacol RS.
GUAIFENESIN
155
ChromatographicMethods of Analysis
4.5.1
IS6
4.5.2
Gas Chromatography
GUAIFENESIN
4.5.3
157
15X
4.5.4
Capillary Electrophoresis
GUAIFENESIN
159
160
5.67%), respectively, over the range of the method (33-326 ng/mL). The
concentration-response relationship for guaifenesin was found to be linear
over a concentration range of 18 1-8136 ng/mL, with a detection limit of
30 ng/mL. The accuracy for this analyte was within 9.78 and 8.04%, and
the inter-day and intra-day precision values were reported to be 2.556.0790(mean 3.9Oo/o) and 3.12-3.90% (mean 3.52%), respectively, over
the range of the method (435-6430 ngimL). The percent recoveries of
dextrorphan, guaifenesin, and laudanosine were found to be 96%, 94%,
and 880/0, respectively. The benchtop and storage stability of the plasma
samples was found to be adequate, and frozen plasma samples could be
subjected to three freezelthaw cycles without undergoing a significant
change in the stability of guaifenesin or dextrorphan.
5.
Stability
5.1
Solid-state Stability
Solution-Phase Stability
6.
6.1
GUAIFENESIN
161
Metabolism
The major metabolite of guaifenesin in plasma [ 181 and urine [ 191 has
been found to be P-(2-methoxy-phenoxy) lactic acid.
6.3
Toxicity
I62
Acknowledgment
Dr. Shervington wishes to thank Dr. Adnan Badwan and Deema Jafarie for
their support.
References
1.
2.
3.
4.
H.L. Yale, E.J. Pribyl, W. Braker, F.H. Bergeim, and W.A. Lott,
J. Am. Chtm. Soc., 72, 3710 (1950).
5.
0.
Service.
GUAIFENESIN
163
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
154
20.
A.R. Lee and T.M. Hu, J. Pharm. Biomed. Anal., 12, 747
( 1994).
21.
22.
23
24.
2s.
36.
27.
28.
D.L. Wagner and V.S. Patel, Inr. J. Pharm., 114, 171 (1995).
29.
30.
31.
32.