Solubility behavior of phenolic compounds in hexane-ethyl acetate, hexane-ethyl myristate, and hexane-ethyl pivalate cosolvent systems


Akaho, E.; Iga, K.; Kraal, J.; Hussain, A.

Journal of Pharmaceutical Sciences 70(11): 1225-1228

1981


Interactions of phenolic compounds 4-hexylresorcinol and 3,4-dimethylphenol with esters were studied using hexane-ester cosolvent systems by both phase solubility and partitioning methods. The data obtained by the phase solubility method were variable and could not be analyzed by any mathematical model. The data obtained by the partitioning method, however, strongly suggest that 4-hexylresorcinol forms 1:1 and 1:2 complexes with the esters in hexane, while 3,4-dimethylphenol forms only 1:1 complexes with the same esters.

Solubility
Behavior
of
Phenolic
Compounds
in
Hexane
-Ethyl
Acetate,
Hexane
-Ethyl
Myristate,
and
Hexane
-Ethyl
Pivalate
Cosolvent
Systems
EIICHI
AKAHO
*,
KATSUMI
IGA
t,
JAN
KRAAL
§,
and
ANWAR
HUSSAIN
x
Received
February
1,
1980,
from
the
School
of
Pharmacy,
Kobe-Gakuin
University,
Tarumi-ku,
Kobe,
Japan,ITakeda
Chemical
Industries,
Ltd.,
Tokyo,
Japan,
and
the
§College
of
Dentistry
and
the
¶College
of
Pharmacy,
University
of
Kentucky,
Lexington,
KY
40506.
Accepted
for
publication
March
19,
1981.
Abstract
D
Interactions
of
phenolic
compounds
4-hexylresorcinol
and
3,4-dimethylphenol
with
esters
were
studied
using
hexane
-ester
cosolvent
systems
by
both
phase
solubility
and
partitioning
methods.
The
data
obtained
by
the
phase
solubility
method
were
variable
and
could
not
be
analyzed
by
any
mathematical
model.
The
data
obtained
by
the
parti-
tioning
method,
however,
strongly
suggest
that
4-hexylresorcinol
forms
1:1
and
1:2
complexes
with
the
esters
in
hexane,
while
3,4-dimethylphenol
forms
only
1:1
complexes
with
the
same
esters.
Keyphrases
D
Phenolic
compounds
-interaction
with
esters
using
hexane
-ester
cosolvent
systems,
phase
solubility
and
partitioning
methods
0
Phase
solubility
-interaction
of
phenolic
compounds
with
esters
0
4-Hexylresorcinol-formation
of
1:1
and
1:2
complexes
with
esters
in
hexane
3,4-Dimethylphenol-formation
of
1:1
complexes
with
esters
In
a
previous
investigation
(1),
the
permeability
coeffi-
cient
of
4-hexylresorcinol
through
an
ethylene
-vinyl
ace-
tate
copolymer
membrane
varied
in
a
nonlinear
fashion
as
a
function
of
the
vinyl
acetate
content
of
the
copolymers.
In
the
same
study,
the
partition
coefficient
of
the
drug
in
the
membrane
varied
nonlinearly
as
a
function
of
the
vinyl
acetate
content.
The
results
were
rationalized
on
the
basis
that
the
dihydroxy
compound
forms
1:1
and
1:2
complexes
with
the
vinyl
acetate
portion
of
the
copolymers.
A
study
was
undertaken
to
determine
the
solubility
behavior
of
4-hexylresorcinol
in
hexane
-ethyl
acetate
co
-
solvent
systems;
hexane
and
ethyl
acetate
represent
the
polyethylene
and
the
vinyl
acetate
portions
of
the
co-
polymer,
respectively.
Additional
data
in
other
cosolvent
systems,
hexane
-ethyl
myristate
and
hexane
-ethyl
piva-
late,
also
were
studied.
To
obtain
further
insight
on
the
mechanism
of
interaction
of
4-hexylresorcinol
in
the
de-
scribed
cosolvent
systems,
the
solubility
of
a
monohydroxy
compound,
3,4-dimethylphenol,
also
was
studied.
EXPERIMENTAL
Materials-4-Hexylresorcinoll
and
3,4-dimethylphenol
2
were
crys-
tallized
from
hot
benzene.
Ethyl
myristate,
ethyl
acetate,
and
ethyl
pi
-
valate,
reagent
grades,
were
purified
by
distillation.
Phase
Solubility
Study
-To
each
1.0
g
of
the
phenols
placed
in
re-
spective
10
-ml
volumetric
fl
asks,
a
10
-ml
solution
containing
1.5-30
X
10
-2
M
of
the
esters
in
hexane
was
added.
The
fl
asks
were
shaken
for
48
hr
in
a
water
bath
shaker
at
25°.
The
solutions
were
centrifuged,
exactly
1
ml
of
supernate
was
pipetted
into
a
volumetric
fl
ask,
and
the
volume
was
completed
to
the
mark
with
hexane.
Further
dilutions
were
carried
out
when
necessary
to
obtain
an
absorbance
range
within
the
Beer's
law
region.
The
absorbance
of
the
solutions
was
determined
spectrophoto-
metrically
3
at
277.5
nm.
The
solubilities
of
the
phenols
were
calculated
using
a
standard
curve
constructed
for
them
in
hexane.
This
procedure
was
previously
reported
(2).
1
Curtin
-Matheson
Scientific,
Cincinnati,
Ohio.
2
Aldrich
Chemical
Co.,
Milwaukee,
Wis.
3
Cary
118,
Varian
Associates,
Palo
Alto,
Calif.
Partitioning
Study
-Two
hundred
milligrams
of
the
phenol
was
dissolved
in
1
liter
of
phosphate
buffer
(0.1
M,
pH
7.5),
and
exactly
5
ml
of
the
aqueous
solution
was
pipetted
into
a
15
-ml
test
tube
with
a
stopper.
Exact
volumes
(between
2
and
5
ml)
of
the
solutions
containing
1.5-30
X
10
-2
M
of
the
esters
in
hexane
were
added
to
the
test
tubes,
which
then
were
shaken
for
10
min.
After
the
test
tubes
were
centrifuged,
the
aqueous
layer
was
taken
and
the
absorbance
of
the
solution
was
determined
spectrophotometrically
without
dilution
at
277.5
nm.
The
partition
coefficients
(PC)
were
calculated
from
the
change
in
UV
absorbance
at
277.5
nm
in
the
aqueous
layer
before
and
after
the
partition:
(volume
of
aqueous
layer)(Ao
-
A)
PC
-
(Eq.
1)
(volume
of
organic
layer)(A
)
where
Ao
-
A
is
the
absorbance
change
in
the
aqueous
layer
and
A
is
the
absorbance
in
the
aqueous
layer.
RESULTS
AND
DISCUSSION
Tables
I,
II,
and
III
show
the
total
solubility
of
4-hexylresorcinol
as
a
function
of
the
ethyl
acetate,
ethyl
myristate,
and
ethyl
pivalate
con-
centrations
in
hexane,
respectively.
Figure
1
shows
the
solubility
diagrams
of
the
drug
in
the
three
cosolvent
systems
and
demonstrates
that
the
solubility
increased
in
a
nonlinear
fashion
as
a
function
of
the
added
esters
and
that
the
solubility
behavior
was
different
in
the
three
cosolvent
systems.
To
characterize
these
systems
mathematically,
it
was
first
assumed
that
4-hexylresorcinol
forms
1:1
and
1:2
complexes
with
esters
according
Table
I
-Solubility
of
4-Hexylresorcinol
in
Ethyl
Acetate
-
Hexane
Concentration
of
Total
Ethyl
Acetate
in
Hexane,
X
10
2
M
Total
Solubility
of
4-Hexylresorcinol,
X
10
3
M
0
4.5
2.27
4.5
4.54
6.80
5.7
9.08
4.9
11.4
5.2
22.7
410
34.1
779
45.4
820
Table
II
-Solubility
of
4-Hexylresorcinol
in
Ethyl
Myristate-
Hexane
Concentration
of
Total
Ethyl
Acetate
in
Hexane,
X
10
2
M
Total
Solubility
of
4-Hexylresorcinol,
X
10
3
M
0
4.5
0.61
5.7
1.22
6.5
1.84
7.7
2.45
6.9
3.01
12.3
6.14
40.2
9.21
48.7
12.28
82.8
30.7
362
0022-3549/
81/
1100-1225$01.00/
0
©
1981,
American
Pharmaceutical
Association
Vol.
70,
No.
11,
November
1981
Journal
of
Pharmaceutical
Sciences
/
1225
Table
HI
—Solubility
of
4-Hexylresoreinol
in
Ethyl
Pivalate-
Hexane
Concentration
of
Total
Ethyl
Pivalate
in
Hexane,
X
10
2
M
Total
Solubility
of
4-Hexylresorcinol,
X
10
3
M
1.53
4.7
3.06
4.7
4.59
5.2
6.12
5.2
7.7
6.3
15.3
153
23.0
30.6
291
to
Eqs.
2
and
3
(3,
4):
HR
0
+
E
0
HR
-
E
HR
0
+
2E
0
=
HR
-
E
2
[HR
-
E]
-
[HR0]
[Ed
[HR
-
K12
[HRo]
2
(Eq.
2)
(Eq.
3)
(Eq.
4)
(Eq.
5)
where
[HR
0
],
[EA
[HR
-
E],
and
[HR
-
E
2
]
represent
the
concentrations
of
free
4-hexylresorcinol,
free
ester,
the
1:1
complex,
and
the
1:2
complex,
respectively.
The
total
concentration
of
4-hexylresorcinol,
[MT],
and
the
total
concentration
of
the
ester,
[E
T
],
can
be
written
according
to:
[HRT]
=
[HR0](1
+
Ki:i[Eo]
+
Ki:2[E0]
2
)
[ET]
=
[Err]
+
Ki:i[E0][HRo]
+
2
Ki:dEoP[HRo]
Elimination
of
[E
0
1
2
from
Eq.
7
by
using
Eq.
6
gives:
[Eo]
-
1
-
Kia[HR0]
1[ET]
-
2
([HRT]
-
Mop]
The
combination
of
Eqs.
6
and
8
to
eliminate
[E
0
]
gives:
Ki.i[HRe]
[HRT]
=
+
1[ET]
-
2([HRT]
-
[HR
O
])I
1
-
1{
1
,
1
[HR
0
]
K1:2[HRo]
+
(1
-
K1:1IHROD
2
1[ETI
-
2
([HRT]
IHR01)1
2
80
x
70
cc
60
0
z
cc
(3
50
0
U)
w
CE
40
>-
X
30
O
2
>-
I
co
10
0
Cf3
<
0
to
20
30
40
CONCENTRATION
OF
TOTAL
ESTER,
[Er],
IN
HEXANE,
X
10
2
M
Figure
1
—Plot
of
the
total
solubility
of
4-hexylresorinol,
[HRT],
as
a
function
of
the
total
ester
concentration
[ET]
,
in
hexane
at
25°.
Key:
0,
ethyl
acetate;
0,
ethyl
myristate;
and
A,
ethyl
pivalate.
(Eq.
6)
(Eq.
7)
(Eq.
8)
(Eq.
9)
46
80
2
70
0
La
0
_
60
>-
I
I
50
2
0
40
U.
O
}
30
I—
:5
1373
20
0
_1
10
O
I-
10
20
30
40
CONCENTRATION
OF
TOTAL
ESTER,
[ET],
IN,HEXANE,
X
10
2
M
Figure
2
—Plot
of
the
total
solubility
of
3,4-dimethylphenol
as
a
func-
tion
of
the
total
ester
concentration,
[ET],
in
hexane
at
25°.
Key:
0,
ethyl
acetate;
•,
ethyl
myristate;
and
A,
ethyl
pivalate.
Bringing
[HR
0
]
to
the
left
side
of
Eq.
9
and
dividing
both
sides
of
Eq.
9
by
[ET]
-
2([HRT]
-
[HR
0
])
gives:
[HR
T
]
-
[HRo]
_
Kia[HRo]
[E
T
]
-
2([HRT]
-
[HRo])
1
-
Ki:i[HRe]
Ki
:
2[HRo]
+
(1
-
Ki:i[HR0])2
1[ET]
-
2
([HRT]
-
[HRo]))
(Eq.
10)
A
plot
of
the
left-hand
side
of
Eq.
10
versus
[ET]
-2([HRT]
-
[HRo])
should
give
a
straight
line
with
a
positive
intercept.
However,
the
phase
solubility
data
plotted
according
to
Eq.
10
gave
a
negative
intercept
value,
and
the
concentration
of
the
free
ester,
[E
0
],
calculated
from
Eq.
8
also
gave
a
negative
value.
This
result
was
evident
from
the
data
in
Tables
I
-III
where
at
30
X
10
-2
M
esters
in
hexane,
the
total
solubility
of
4-
hexylresorcinol
was
equivalent
or
slightly
greater
than
that
of
the
ester
added.
Other
assumptions
based
on
the
formation
of
dimer
or
higher
order
complexes
failed
to
explain
the
solubility
behavior
of
4-hexylresorcinol
in
these
systems.
Similarly,
the
phase
solubility
diagrams
of
3,4
-di
-
70
60
50
40
E
g
30
20
10
0
10
20
30
40
50
60
70
80
CONCENTRATION
OF
TOTAL
ESTER,
[Er],
IN
HEXANE,
X
10
2
M
Figure
3
—Plot
of
[Illicomp]
I
[H&J
as
a
function
of
the
total
ester
concentration,
[ET]
,
in
hexane
alilicompi
=
[HRT]
-
[HR
0
]).
Key:
ethyl
acetate;
0,
ethyl
myristate;
and
A,
ethyl
pivalate.
1226
/
Journal
of
Pharmaceutical
Sciences
Vol.
70,
No.
11,
November
1981
Table
IV
-Extent
of
Complex
Formation
between
4-
Hexylresorcinol
and
Ethyl
Acetate
in
Hexane
Determined
by
Partitioning
Study
Concentration
of
Total
Ethyl
Acetate,
X
10
2
M
Partition
Coefficient
[HEW
0
0.754
0
4.80
1.97
1.48
9.61
3.46 3.36
14.4
5.57
6.03
19.2
7.55
8.52
28.5
12.1
14.2
48.1
25.7
31.5
Table
V
-Extent
of
Complex
Formation
between
4-
Hexylresorcinol
and
Ethyl
Myristate
in
Hexane
Determined
by
Partitioning
Study
Concentration
of
Total
Ethyl
Myristate,
x
10
2
M
Partition
Coefficient
[HR
comp
]
[HRo]
0
0.754
0
1.53
1.33
0.674
3.07
1.90 1.40
6.14
3.45
3.35
9.21
5.48
5.91
15.0
10.7
12.4
30.1
29.5
36.2
Table
VI
-Extent
of
Complex
Formation
between
4-
Hexylresorcinol
and
Ethyl
Pivalate
in
Hexane
Determined
by
Partitioning
Study
Concentration
of
Total
Ethyl
Pivalate,
x
10
2
M
Partition
Coefficient
[11R
ec
,„,
p
1
[HRo]
0
0.754
0
3.84
1.56
0.962
7.68
2.66
2.361
15.4
5.26
5.63
23.0
9.23
10.6
38.4
18.6
22.5
76.4
54.3
66.6
methylphenol
were
different
in
the
three
cosolvent
systems
(Fig.
2).
It
is
known
that
the
monohydroxy
compound
forms
a
1:1
complex
with
esters.
If
that
is
the
case,
then
one
should
observe
a
linear
increase
in
the
total
solubility
of
the
phenol
as
a
function
of
added
esters
in
hexane.
In
Fig.
2,
the
increase
in
the
solubility
of
3,4-dimethylphenol
as
a
function
120
100
CC
80
w
E
0
CC
40-
2
60
20
O
10
20
30
40
50
60
70
80
CONCENTRATION
OF
TOTAL
ESTER,
[Er],
IN
HEXANE,
X
10
2
M
Figure
4
-Plot
of
[111?.p]1[HR0.]
[ET]
as
a
function
of
the
total
ester
concentration,
[ET],
in
hexane
according
to
Eq.
16
([HR
comp
]
=
[HRT]
-
[H&]).
Key:
II,
ethyl
acetate;
•,
ethyl
myristate;
and
A,
ethyl
pi-
valate.
of
added
esters
in
hexane
is
nonlinear
for
ethyl
pivalate
and
ethyl
acetate
and
appears
to
be
linear
for
ethyl
myristate.
Further
examination
of
the
equilibrated
systems
showed
that,
in
ad-
dition
to
the
supernatant
and
crystalline
phases,
an
oily
third
phase
ex-
isted.
It
was
assumed
that
the
abnormalities
in
the
phase
solubility
di-
agrams
of
4-hexylresorcinol
and
3,4-dimethylphenol
were
due
to
the
formation
of
a
eutectic
phase
between
the
low
-melting
-point
phenols
and
the
esters.
It
is
known
that
low
-melting
-point
phenols
form
a
eutectic
mixture
upon
their
interaction
with
a
low
-melting
-point
proton
ac-
ceptor.
The
irreproducibility
of
the
phase
solubility
data
of
4-hexylresorcinol
led
to
a
study
to
characterize
the
nature
of
the
complexes
formed
using
partitioning
methods.
The
data
obtained
for
4-hexylresorcinol
in
the
three
cosolvent
systems
are
shown
in
Tables
IV
-VI.
The
concentration
of
free
4-hexylresorcinol,
[11R
0
],
in
hexane
was
obtained
as
follows:
[HRo]
=
(PC
at
0%
ester)
[HRH
2
oi
(Eq.
11)
where
PC
at
0%
ester
is
the
partition
coefficient
of
4-hexylresorcinol
at
zero
ester
concentration,
[HRH
2
01
is
the
aqueous
phase
concentration,
and
the
concentration
of
4-hexylresorcinol
in
the
complex
is
equal
to
[HRT]
-
[HR0].
A
plot
of
([HRT]
-
IHR
0
1)/IHR
0
1
versus
added
ester
is
shown
in
Fig.
3
for
ethyl
acetate,
ethyl
myristate,
and
ethyl
pivalate.
As
seen
in
Fig.
3,
the
increase
in
the
total
drug
concentration
as
a
function
of
added
esters
showed
a
positive
curvature.
The
ratio
of
the
free
form,
[HR0],
and
the
complex
form
of
4-hexylresorcinol,
[HRcomp],
in
the
or-
ganic
layer
is:
IHRcompi
[HRT]
[HRO]
[HRd
[HR
0
]
(Eq.
12)
[HRT]
-
[HRo]
is
given
from
Eq.
6;
i.e.,
[HRT]
-
[Hilo]
=
K
1:1[Eo][HRo]
+
K
1:MR011E0P
(Eq.
13)
Substituting
the
[1111T]
-
[Hilo]
value
from
Eq.
12
in
Eq.
13
gives:
[HRo]
-
K1:1[Eo]
+
Ki:21E0P
Dividing
both
sides
of
Eq.
14
by
[E
0
]
gives:
[HRcomp]
_
K
1:1
[HRol
[Ed
-+
K
1:2[E
o]
Since
the
partitioning
study
used
very
dilute
solutions
of
4-hexylresor-
cinol,
the
concentrations
of
the
complexes
also
are
fairly
small.
Even
if
100%
of
4-hexylresorcinol
complexes
with
esters,
it
is
reasonable
to
replace
the
concentration
of
the
free
ester,
[E
0
],
by
the
concentration
of
the
total
ester
concentration,
[Er]:
IH
RI
R0
R
irEpT
i
l
=
K1:2[ET1
(Eq.
16)
A
plot
of
11
-
1Ecompi/EHRoi
[ET]
versus
[E
T
]
provides
a
straight
line
with
a
slope
of
K1:2
and
an
intercept
of
Km.
The
experiments
were
repeated
(Eq.
14)
(Eq.
15)
Table
VII
-Stability
Constants
of
4-Hexylresorcinol
and
3,4-
Dimethylphenol
in
Hexane
-Ester
Systems
Ester
4-Hexylresorcinol
K
ia
a
,
M-1
K
I:2
6
,
M-2
3,4-Dimethylphenol,
M
1
Ethyl
acetate
Ethyl
pivalate
Ethyl
myristate
28
21
40
80
100
266
9.24
9.18
15.5
°
Stability
constant
of
1:1
complex.
bStability
constant
of
1:2
complex.
Table
VIII
-Extent
of
Complex
Formation
between
3,4-
Dimethylphenol
and
Ethyl
Acetate
Determined
by
Partitioning
Study
Total
Concentration
of
3,4-Dimethylphenol,
x
10
2
M
Partition
Coefficient
[DMP
comp
]
[DMPo]
0
1.37
4.80
1.96
0.44
9.16
2.53
0.85
19.23
3.86
1.83
28.48
5.00
2.67
48.07
7.60
4.57
Journal
of
Pharmaceutical
Sciences
/
1227
Vol.
70,
No.
11,
November
1981
Table
IX
-Extent
of
Complex
Formation
between
3,4-
Dimethylphenol
and
Ethyl
Myristate
Determined
by
Partitioning
Study
1
a.
6
2
O
Total
Concentration
of
3,4-Dimethylphenol,
Partition
[DMP,
(
up
]
12
x
10
2
M
Coefficient
[DMP
0
]
0
1.53
1.37
1.73
0.27
a
E
3.07
6.14
1.96
2.61
0.43
0.91
U
0_
2
4
9.21
3.31
1.43
a
15.03
4.57
2.35
30.00
7.94
4.83
for
various
cosolvent
systems,
and
each
showed
a
straight-line
relation-
ship
between
the
two
parameters
(Fig.
4).
The
stability
constants,
Kia
and
K1:2,
for
each
ester
were
calculated
from
Fig.
4
and
are
shown
in
Table
VII.
It
is
evident
from
these
results
that
4-hexylresorcinol
forms
not
only
1:1
but
also
1:2
complexes
with
esters
in
hexane.
The
stability
constant
values
obtained
for
ethyl
myristate
were
somewhat
higher
than
those
for
the
other
esters.
This
result
is
probably
due
to
the
fact
that
ethyl
my-
ristate
has
a
larger
hydrocarbon
chain,
which
results
in
a
better
interac-
tion
with
the
hydrophobic
portion
of
phenols.
To
ascertain
whether
the
formation
of
1:2
complexes
is
due
to
the
in-
volvement
of
the
two
hydroxy
groups
of
4-hexylresorcinol,
the
parti-
tioning
study
was
repeated
with
3,4-dimethylphenol.
The
data
obtained
from
this
study
are
shown
in
Tables
VIII
-X.
A
plot
of
[DMPcomp]i
Table
X
-Extent
of
Complex
Formation
between
3,4-
Dimethylphenol
and
Ethyl
Pivalate
Determined
by
Partitioning
Study
Total
Concentration
of
3,4-Dimethylphenol,
x
10
2
M
Partition
Coefficient
[DMP
eomp
]
REFERENCES
(1)
E.
Akaho,
Ph.D.
dissertation,
University
of
Kentucky,
Lexington,
Ky.
1979.
[DMPo]
0
1.37
(2)
H.
B.
Kostenbauder
and
T.
Higuchi,
J.
Am.
Pharm.
Assoc.
Sci.
Ed.,
3.82
1.78
0.30
45,
518
(1956).
7.68
2.33
0.70
(3)
T.
Higuchi,
J.
H.
Richards,
S. S.
Dacis,
A.
Kamada,
J.
P.
How,
M.
15.36
3.33
1.44
Nakano,
N.
I.
Nakano,
and
I.
H.
Pitman,
J.
Pharm.
Sci.,
58,
661
23.04
38.40
4.32
6.63
2.17
3.86
(1969).
(4)
H.
Fung
and
T.
Higuchi,
ibid.,
60,
1782
(1971).
••
0
10
20
30
40
50
60
CONCENTRATION
OF
TOTAL
ESTER,
[ET],
IN
HEXANE,
X
10
2
M
Figure
5
-Plot
of
[DM1
3
,,,,,
p
]
I[DMPfred
[ET]
as
a
function
of
the
total
ester
concentration,
[ET],
in
hexane;
[DMPeornp]
and
fDMPf„,1
rep-
resent
the
concentrations
of
complexed
and
free
forms
of
3,4-dimeth-
ylphenol,
respectively.
(
IDMPconTp1
=
IDMPTJ
-
[3MP
0
]).
Key:
•,
ethyl
acetate;
•,
ethyl
myristate;
and
•,
ethyl
pivalate.
EDMP
o
ll
ET1
versus
the
total
ester
concentration
is
shown
in
Fig.
5;
[DMP,,„,„,]
is
the
concentration
of
3,4-dimethylphenol
in
the
complex
form,
and
[DMP
O
]
is
the
concentration
of
the
free
form.
As
seen
in
Fig.
5,
the
monohydroxy
compound
forms
only
a
1:1
complex
with
the
esters.
The
stability
constants
calculated
from
Fig.
5
are
given
in
Table
VII.
The
results
of
this
study
substantiate
the
conclusion
that
the
diffusion
of
4-hexylresorcinol
through
ethylene
-vinyl
acetate
co-
polymers
involved
the
formation
of
1:1
and
1:2
complexes
between
the
drug
and
the
vinyl
acetate
portion
of
the
copolymers.
High
-Performance
Liquid
Chromatographic
Analysis
of
Chemical
Stability
of
5-Aza-2'-deoxycytidine
KUN-TSAN
LIN*x,
RICHARD
L.
MOMPARLER*t,
and
GEORGES
E.
RIVARD*
Received
December
17,
1979,
from
the
*Centre
de
Recherche
Pediatrique,
Hopital
Sainte
-Justine,
and
the
fDepartement
de
Pharmacologie,
University
de
Montreal,
Montreal,
Quebec,
Canada
H3T
1CS.
Accepted
for
publication
March
31,
1981.
Abstract
The
chemical
stability
of
5-aza-2'-deoxycytidine
(I)
in
acidic,
neutral,
and
alkaline
solutions
was
analyzed
by
high-performance
liquid
chromatography.
In
alkaline
solution,
I
underwent
rapid
reversible
de-
composition
to
N-(formylamidino)-N'43-D-2-deoxyribofuranosylurea
(II),
which
decomposed
irreversibly
to
form
1-(3-D-2'-deoxyribofurano-
sy1-3-guanylurea
(III).
The
pseudo
-first
-order
rate
constants
for
this
reaction
were
determined.
The
decomposition
of
I
in
alkaline
solution
was
identical
to
that
reported
previously
for
the
related
analog,
5-aza-
cytidine.
However,
in
neutral
solution
(or
water),
there
was
a
marked
difference
in
the
decomposition
of
I
and
5-azacytidine.
The
same
de-
composition
products
were
formed
from
5-azacytidine
in
neutral
solution
as
in
alkaline
solution.
However,
in
neutral
solution,
I
decomposed
to
II
and
three
unknown
compounds
that
were
chromophoric
at
254
nm.
Compound
I
was
most
stable
when
stored
in
neutral
solution
at
low
temperature.
Keyphrases
D
5-Aza-2'-deoxycytidine-analysis
of
chemical
stability
using
high-performance
liquid
chromatography
0
Antileukemic
agents-5-aza-2'-deoxycytidine,
analysis
of
chemical
stability
using
high-performance
liquid
chromatography
0
High-performance
liquid
chromatography
-analysis
of
chemical
stability
of
5-aza-2'-deoxycyti-
dine
5-Aza-2'-deoxycytidine
(I),
a
nucleoside
antimetabolite,
is
a
very
active
antileukemic
agent
in
mice
(1,
2)
and
a
potent
cytotoxic
agent
against
neoplastic
cells
in
vitro
(2,
3).
This
antimetabolite
is
related
to
5-azacytidine,
an
agent
currently
used
in
the
clinical
treatment
of
acute
leukemia
(4).
1228
/
Journal
of
Pharmaceutical
Sciences
0022-3549/
81/
1100-1228$01.00/
0
Vol.
70,
No.
11,
November
1981
©
1981,
American
Pharmaceutical
Association