- Email: [email protected]
Quantitative MS methods for the determination of drug impurities
269
International Jaurnal of Mass Spectrometry and Ion Physics, 48 (1983) 269-272
Elsevier ScientificPublishing Company,Amsterdam-Printedin
QUANTITATIVE
MS
METHODS
FOR
THE
TheNetherlands
DETERMINATION
OF
DRUG
IMPURITIES
J.BALLA
and
Institute
J.BRLIK
for
University,
General
and
Budapest,
Analytical
H-1111
Chemistry
of
Gellert
Budapest,
Technical
t6.r 4
/Hungary/
ABSTRACT The two variants of the internal standard method were investigated for the MS quantative determination of drug impurities in the case of direct sample introduction. We have suggested PFK for use as a universal internal standard and defined a specific relative response factor. We have worked out a new quantitative evaluation method, based on the combination of the addition and the internal standard methods. The multiple ion monitor technique was applied for the MS measurements.
INTRODUCTION The
technical
methods GC-MS as
were
be
seen
combination sample tion
MS
or
cannot
be
it
is
avoided.
In our
applied
is
the
standard
the
used
last
to
of
use
of
the
biochemical
MS
or
an
the
be
this
used
report
different
an
the
preconcentra-
on
candirect
internal
- which
as
of
determination
universal PFK
the
analysis
When
heat-sensitivity
/ref.4/
as how
- can
Particularly
a separation
methylstearate
reliability
the
coauthors
investigated
determination
1,2,3,/.
introduction
and
material
in the
/ e.g.ref.
because
sample
MS
decades.
importance
difficult
using we
in
big
F.Heresch
work
quantitative
literature
direct
calibration
what
ternal
to
the
measurement
ard.
and
the
the
only
have
in
method, be
of
developed
combinations
can
not
solutions
stand-
is commonly
internal
versions
of
standard the
in-
methods.
METHODS Experimental The double The of
measurements focusing
accelerating 75
eV,
the
were
mass
on
spectrometer
voltage electron
taken
of
OOZO-7381/83/0000-0000/$03.00 0
using
10 kV,
current
a JEOL
of
the 200
made the
direct
ionising PA
JMS-OlSG-2
were
inlet
electron applied.
1983 ElsevierScientiEic PublishingCompany
type system. energy
270
The
pressure
torr
and
in
resolution mass
tage
was
data
analyzer
a
the
ion
frequenay
the
by
tisercinmaleinate
portions
sample
of
holder
acetone.
tion
of
Results
The
1~1
of
peaks
the
MDFA's
and
discussion
Internal bear
that
the
standard found
the
pressure
the
0231/0241
on-
accelerating
vol-
30 Hz.
of
was
matrix
in
introduced
is
selection
relative
response
in
and
area
PFK
peak
amount the
chosen of
the
substance
last
sguare
substance the
value
method:
this
199.
have
internal can
be
main
to
of
source
of
-trimethyl-
the
determina-
great He
well
lo-700
it
in-
/ref.61
very
during
experiment
solution
bring
reference
O,l-5
evaporatj.on
standard.
used
range
ion
the
disturbe
number
we
mass
the
the
peak
the
the
in
the
of
the
not
/"monitorisable"/
where
base
mass
Usually of
response
A=
of
/PFX/
constant
from
of
/2-methoxy-N,N,,
does
acetone
concentration
tisercin
method.
a suitable
in
free
peak
because
dissolved
after
relative
the
monitoring
JEOL
measured
specific
of
the
and
perfluorokerozine
ways
the
than by
/MDFA/
were
MS
base
standard
upon
the
ternal
area
less
of
lOH-phenothiazine-lo-propanaminel
of
-6 was less than 10 -7 10 torr. The low
source
evaluated
3-methoxydiphenylamine
)Isl)ll* The
to
ion
it was
were
For
with
impact
tube
/2000/
system.
changed
saturated
the
the
electron
mixture
Pure
to
the
spectra
line
Model -
in
have as
it
care found
an
can
in-
be
al-
PFX
peak.
the
determination
can
be
When
defined
a
factor:
of
the
/in to of
be the
substance
this
case
/MDFA/; the
peak
As= of
analized.
Changing
f'
calculated
can
be
the
193/;
the
peak m=
amount
easily
by
271 In
the
main
/mx/can the
be
experiment
the
calculated
substance
/A*/
by and
unknown
the
the
quantity
formula
chosen
/3/
PFK's
of
the
substance
measuring peak
peak
/A: J
areas
of
respectively.
(31 The In
Table
these
TABLE The
case
1 shows
the
f' was
2,59.
of
one
series
of
determinations.
1 quantitative
determination
cinmaleinate using -~ NO Area of peak mass number 199,A 1 2 3 4 .5
results
of
internal
3-methoxydiphenylamine
standard
tiser-
method
Area of PFK peak m.n.193,A
1044,8 1107 1066,8 1296,3 1148
in
183,3 172,5 168 165 175
A
Results
A,
m&W
5,70 6,42 6,35 7,25 6,56
2,20 2,48 2,45 2,80 2,53
Avaradqe value:i$=2,33$./True value:2,50 pg/ Relative error: - 6,8% ,standa$d deviation: 0,28 pg. The most probable result: 2,33-0,35 JXJ in the case of statistical reliability of 95 8 /when the Stydent distribution coefficient Areas are given in mm. t =2,776/. Combined This
method
can
the
relative
needs the
- internal
addition
join
the
mass
standard
features and
peak
determination
of
the
relative
two measurements.
In
the
first
the
substance sured. In our 193. /m/
In is
of
both
area
original
response
one
the
to
measurement
the
sample
torized
peaks.
If
culated
by
formula/4/:
the
these
and
were
Aa
areas
a well
known
measured
the
and
methods.
determination
A", than
and
factor. of
/A'/ and the chosen PFK peak /A's/ example they were the peaks of mass
-the second added
method
It
the
It avoids
it
consists
base
peak
of of
have to be meaand number 199
amount
of
peak
area
the
result
substance of
the
can
be
monical-
272
The
Table
2 shows
diphenylamine This
method
tography
10-0,Ol TABLE
result /The
- originally
/ref.5/
impurities
the
content.
of
- was
different
of
the
determinations
addicionated
it was
worked
succesfully other
m= out
of
3-methoxi-
1-2 pg/ in
the
gas
used
in
the
too
in
concentration
droqs
chroma-
determination
of
range
of
ppm. 2
The sercin
quantitative maleinate
NO
determination using
combined Area
1 2 3 4 5 Avaradge standard
of
3-methoxydiphenylamine
addition
-internal
ratios
standard
ti-
method
Results
A' /A's
z/A",
17,88 25,82 14,87 18,14 14,45
23.56 34,60 20,23 24,14 20,23
value:$=2,%2.../True value: 0,31/69.The most deviation:
in
3,OOflj probable
mx&3/ 3,12 2,94 2,78 3,30 2,50 Relative result:
erro$:-2,7%, 2,92-0,37 I-19.
REFERENCES 1. 2. 3. 4. 5.
6.
A.P. De Leenheer, R.R. Roncucci: Quantitative Mass Spectrometry in Life Sciences. Elsevier, Amsterdam, 1977. B-J-Millard: Quantitative Mass Spectrometry, Heyden, London, 1977. W.D.Lehmann, H-R.SchuPten: Angewandte Chemie, 90 /1978/233-250 Biomed.Mass Spectrometry, E.R.Schmid, A. Wefszbart: H.Heresch, 6 /1979/ 566-569. J.Gajhri /Dr.J.Balla/: The critical evaluation of internal standard methods in gas-liquid chromatography. Budapest,l973./Diplam work/ EPA/NIH Mass Spectral Data Base, Vol.3, NSRDS,1978. pp.2527.
International Jaurnal of Mass Spectrometry and Ion Physics, 48 (1983) 269-272
Elsevier ScientificPublishing Company,Amsterdam-Printedin
QUANTITATIVE
MS
METHODS
FOR
THE
TheNetherlands
DETERMINATION
OF
DRUG
IMPURITIES
J.BALLA
and
Institute
J.BRLIK
for
University,
General
and
Budapest,
Analytical
H-1111
Chemistry
of
Gellert
Budapest,
Technical
t6.r 4
/Hungary/
ABSTRACT The two variants of the internal standard method were investigated for the MS quantative determination of drug impurities in the case of direct sample introduction. We have suggested PFK for use as a universal internal standard and defined a specific relative response factor. We have worked out a new quantitative evaluation method, based on the combination of the addition and the internal standard methods. The multiple ion monitor technique was applied for the MS measurements.
INTRODUCTION The
technical
methods GC-MS as
were
be
seen
combination sample tion
MS
or
cannot
be
it
is
avoided.
In our
applied
is
the
standard
the
used
last
to
of
use
of
the
biochemical
MS
or
an
the
be
this
used
report
different
an
the
preconcentra-
on
candirect
internal
- which
as
of
determination
universal PFK
the
analysis
When
heat-sensitivity
/ref.4/
as how
- can
Particularly
a separation
methylstearate
reliability
the
coauthors
investigated
determination
1,2,3,/.
introduction
and
material
in the
/ e.g.ref.
because
sample
MS
decades.
importance
difficult
using we
in
big
F.Heresch
work
quantitative
literature
direct
calibration
what
ternal
to
the
measurement
ard.
and
the
the
only
have
in
method, be
of
developed
combinations
can
not
solutions
stand-
is commonly
internal
versions
of
standard the
in-
methods.
METHODS Experimental The double The of
measurements focusing
accelerating 75
eV,
the
were
mass
on
spectrometer
voltage electron
taken
of
OOZO-7381/83/0000-0000/$03.00 0
using
10 kV,
current
a JEOL
of
the 200
made the
direct
ionising PA
JMS-OlSG-2
were
inlet
electron applied.
1983 ElsevierScientiEic PublishingCompany
type system. energy
270
The
pressure
torr
and
in
resolution mass
tage
was
data
analyzer
a
the
ion
frequenay
the
by
tisercinmaleinate
portions
sample
of
holder
acetone.
tion
of
Results
The
1~1
of
peaks
the
MDFA's
and
discussion
Internal bear
that
the
standard found
the
pressure
the
0231/0241
on-
accelerating
vol-
30 Hz.
of
was
matrix
in
introduced
is
selection
relative
response
in
and
area
PFK
peak
amount the
chosen of
the
substance
last
sguare
substance the
value
method:
this
199.
have
internal can
be
main
to
of
source
of
-trimethyl-
the
determina-
great He
well
lo-700
it
in-
/ref.61
very
during
experiment
solution
bring
reference
O,l-5
evaporatj.on
standard.
used
range
ion
the
disturbe
number
we
mass
the
the
peak
the
the
in
the
of
the
not
/"monitorisable"/
where
base
mass
Usually of
response
A=
of
/PFX/
constant
from
of
/2-methoxy-N,N,,
does
acetone
concentration
tisercin
method.
a suitable
in
free
peak
because
dissolved
after
relative
the
monitoring
JEOL
measured
specific
of
the
and
perfluorokerozine
ways
the
than by
/MDFA/
were
MS
base
standard
upon
the
ternal
area
less
of
lOH-phenothiazine-lo-propanaminel
of
-6 was less than 10 -7 10 torr. The low
source
evaluated
3-methoxydiphenylamine
)Isl)ll* The
to
ion
it was
were
For
with
impact
tube
/2000/
system.
changed
saturated
the
the
electron
mixture
Pure
to
the
spectra
line
Model -
in
have as
it
care found
an
can
in-
be
al-
PFX
peak.
the
determination
can
be
When
defined
a
factor:
of
the
/in to of
be the
substance
this
case
/MDFA/; the
peak
As= of
analized.
Changing
f'
calculated
can
be
the
193/;
the
peak m=
amount
easily
by
271 In
the
main
/mx/can the
be
experiment
the
calculated
substance
/A*/
by and
unknown
the
the
quantity
formula
chosen
/3/
PFK's
of
the
substance
measuring peak
peak
/A: J
areas
of
respectively.
(31 The In
Table
these
TABLE The
case
1 shows
the
f' was
2,59.
of
one
series
of
determinations.
1 quantitative
determination
cinmaleinate using -~ NO Area of peak mass number 199,A 1 2 3 4 .5
results
of
internal
3-methoxydiphenylamine
standard
tiser-
method
Area of PFK peak m.n.193,A
1044,8 1107 1066,8 1296,3 1148
in
183,3 172,5 168 165 175
A
Results
A,
m&W
5,70 6,42 6,35 7,25 6,56
2,20 2,48 2,45 2,80 2,53
Avaradqe value:i$=2,33$./True value:2,50 pg/ Relative error: - 6,8% ,standa$d deviation: 0,28 pg. The most probable result: 2,33-0,35 JXJ in the case of statistical reliability of 95 8 /when the Stydent distribution coefficient Areas are given in mm. t =2,776/. Combined This
method
can
the
relative
needs the
- internal
addition
join
the
mass
standard
features and
peak
determination
of
the
relative
two measurements.
In
the
first
the
substance sured. In our 193. /m/
In is
of
both
area
original
response
one
the
to
measurement
the
sample
torized
peaks.
If
culated
by
formula/4/:
the
these
and
were
Aa
areas
a well
known
measured
the
and
methods.
determination
A", than
and
factor. of
/A'/ and the chosen PFK peak /A's/ example they were the peaks of mass
-the second added
method
It
the
It avoids
it
consists
base
peak
of of
have to be meaand number 199
amount
of
peak
area
the
result
substance of
the
can
be
monical-
272
The
Table
2 shows
diphenylamine This
method
tography
10-0,Ol TABLE
result /The
- originally
/ref.5/
impurities
the
content.
of
- was
different
of
the
determinations
addicionated
it was
worked
succesfully other
m= out
of
3-methoxi-
1-2 pg/ in
the
gas
used
in
the
too
in
concentration
droqs
chroma-
determination
of
range
of
ppm. 2
The sercin
quantitative maleinate
NO
determination using
combined Area
1 2 3 4 5 Avaradge standard
of
3-methoxydiphenylamine
addition
-internal
ratios
standard
ti-
method
Results
A' /A's
z/A",
17,88 25,82 14,87 18,14 14,45
23.56 34,60 20,23 24,14 20,23
value:$=2,%2.../True value: 0,31/69.The most deviation:
in
3,OOflj probable
mx&3/ 3,12 2,94 2,78 3,30 2,50 Relative result:
erro$:-2,7%, 2,92-0,37 I-19.
REFERENCES 1. 2. 3. 4. 5.
6.
A.P. De Leenheer, R.R. Roncucci: Quantitative Mass Spectrometry in Life Sciences. Elsevier, Amsterdam, 1977. B-J-Millard: Quantitative Mass Spectrometry, Heyden, London, 1977. W.D.Lehmann, H-R.SchuPten: Angewandte Chemie, 90 /1978/233-250 Biomed.Mass Spectrometry, E.R.Schmid, A. Wefszbart: H.Heresch, 6 /1979/ 566-569. J.Gajhri /Dr.J.Balla/: The critical evaluation of internal standard methods in gas-liquid chromatography. Budapest,l973./Diplam work/ EPA/NIH Mass Spectral Data Base, Vol.3, NSRDS,1978. pp.2527.