Biomedical Engineering Reference
In-Depth Information
and costs [
121
]. However, UPLC has been applied only for quantification of the
TKIs sunitinib [
113
] and axitinib [
120
] .
A publication describes a column switching procedure for an imatinib assay,
involving a C8 extraction column, followed after activation of the switching valve
by the back-flushing of imatinib onto a C18 analytical column [
107
] . The run time
was 10 min. The other published methods use HPLC with C18 columns with ana-
lytical times of 2 min [
106
] , 3 min [
103
] , 6 min [
110
] , 10 min [
107
] , 14 min [
108
] ,
and 20 min [
109
]. C8 columns were used by two groups with analytical times vary-
ing between 2.5 min [
104
] and as much as 40 min [
105
] .
Nilotinib was analyzed by HPLC onto a C18 column [
111,
112
] , with a reported
run time of 15 min [
111
] .
Interestingly, the two methods published for quantification of sunitinib used
either HPLC [
114
] or UPLC [
113
] but the analytical time periods were of similar
duration (run time of 3 min and 4 min, respectively). Of note, we observed during
the course of our own method development [
122
] the presence of two peaks with the
same molecular mass/signal transition for sunitinib, which, to the best of our knowl-
edge, has not been reported elsewhere [
113,
114,
123
] . The phenomenon was
known, however, and is due to a
Z
-
E
isomerization reaction of sunitinib [
124
] .
Previous studies by the sunitinib manufacturer have shown that
E
isomer can be
generated from the
Z
isomer in a reversible manner in solution [
124
] . The rate of
interconversion between the
Z
-
E
configurations in solution is dependent on a num-
ber of factors, most notably exposure to light. In our studies [
122
] , we found that
both isomers could be detected in the pharmaceutical preparation (tablet) at ratios
of about 1:2, as well as in patients' plasma samples (variable ratios).
The determination of sorafenib plasma concentrations was performed by HPLC
onto a C8 column (4 min run time) [
115
] and C18 column (6 min run time) [
116
] .
Similarly, HPLC C18 columns have been used for the quantification in plasma of
lapatinib [
117
] , vatalanib [
119
] (3 and 8 min run time, respectively), and also for
bosutinib [
88
], whereas UPLC was used for the TKI in development of axitinib
(1.2 min run time) [
120
] .
Detection of imatinib is performed by triple quadrupole mass spectrometer with
an electrospray ionization (ESI) interface operated in positive ion mode [
103,
104,
106,
107,
109,
110
]. Except the methods published by Parise et al. for imatinib and
its main metabolite [
108
] , and for nilotinib [
111
], where a single quadrupole mass
spectrometer was used, most TKIs are analyzed in plasma by atmospheric pressure
ionization (electrospray or turbo ion spray) coupled to triple stage mass spectrom-
eter. Expectedly, higher limit of quantifications for imatinib (30 ng/ml) [
108
] , and
nilotinib (5 ng/ml) [
111
], are obtained for the assays using single quadrupole MS
(see Table
2
).
In general, triple stage quadrupole mass spectrometer with ESI in positive ion
mode is perceived as the most appropriate MS technique available at present for
small—mostly basic—molecules and was used for the assay of nilotinib [
112
] ,
sorafenib [
115,
116
] , lapatinib [
117
] , sunitinib [
113,
114
] , bosutinib [
88
] , vatalanib
[
119
] axitinib [
120
] , vandetanib [
118
] neratinib [
87
] , and crizotinib [
125
] . The latter
assay for crizotinib was developed for preclinical experiments and does not contain
