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1. Introduction
Lucie Novakova*,
Dalibor Satnsky, Petr Solich
Department of Analytical
Chemistry, Faculty of
Pharmacy, Charles University,
Heyrovskeho 1203, 500 05,
Hradec Kralove, Czech
Republic
Corresponding author.
Tel.: +420 495067345;
Fax: +420 495067164;
E-mail: novakoval@faf.cuni.cz
352
0165-9936/$ - see front matter 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.trac.2008.01.013
Trends
Figure 1. Biosynthesis of cholesterol. Cholesterol is synthesized from acetyl coenzyme A. The synthesis of mevalonate, mediated by HMG-CoA
reductase is the rate-limiting step, which regulates the cholesterol synthesis. It is the step where the statin molecule competitively effects the
synthesis of cholesterol.
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353
Trends
H3C
H3C
CH3
H3C
HO
COOH
OH
CH3
F
N
CH3
H
N
O
acid forms [2,9]. All statins are absorbed rapidly following administration, reaching peak plasma concentration within 4 hours.
Statins exist in two forms, lactone and open-ring
hydroxy acid [10,11]. In vivo, the hydroxy acid forms
are the active drugs that lower plasma cholesterol while
the lactone forms are inactive (prodrug). The lactone
form of statin can be absorbed from the gastrointestinal
tract and transformed into the active drugs in liver and
non-hepatic tissues [11]. Depending upon chemical
structure, statins have different affinities for HMG-CoA
reductase, which determines their pharmacological
effects and different pharmacokinetic properties (e.g.,
tissue distribution, metabolic stability, enzymes and
transporters involved in their metabolism) [2]. We will
provide further information on simvastatin and atorvastatin, the most widely used statins in clinical treatment Fig. 2.
Simvastatin is a prodrug, which is administered as
an inactive lactone form. The lactone is absorbed from
gastrointestinal tract and hydrolyzed to the active
b-hydroxy acid form in the liver. Simvastatin and its
hydroxy acid are extensively (95%) bound to plasma
proteins. The substance undergoes extensive first-pass
metabolism in the liver and is mainly excreted in the bile.
About 85% of administered dose has been recovered
from the feces as metabolite and about 1015% from
urine, mainly as inactive forms [12,13].
Atorvastatin is administered in the open-ring hydroxy
acid form the active form. It is absorbed from the
354
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gastrointestinal tract and it undergoes extensive firstpass metabolism in the liver. Liver metabolism produces
two active hydroxy metabolites ortho-hydroxyatorvastatin and para-hydroxyatorvastatin and three
inactive metabolites corresponding to the lactone form.
More than 98% is bound to plasma proteins. It is
excreted mainly in feces via the bile, with a smaller
proportion excreted in the urine. About 70% of the total
plasma HMG-CoA activity is attributed to active metabolites of atorvastatin, even if their concentrations are
very low [1214].
As apparent from the information above, the levels
of statins in biological fluids are very low, probably
because only about 5% of dosed statin reaches the
systemic circulation. For atorvastatin and simvastatin,
the plasma concentrations are typically at ng/ml levels.
The active metabolites of atorvastatin are present at
plasma concentration corresponding to pg/ml levels
[13], the typical concentration range being 0.120 ng/
ml.
Trends
4. Analytical methods
The determination of drugs is a multi-disciplinary task.
During the manufacturing process of a drug substance
and drug formulation, there is a need for QC analytical
methods to include all known and unknown impurities.
Bio-analytical methods are necessary for clinical trials,
therapeutic drug monitoring and individual dosagescheme adjustment. Recently, there has also been great
interest in monitoring pharmaceutical residues in the
environment, so environmentally-focused analytical
methods are also necessary.
Determination of drugs in biological materials is an
important step in drug discovery and drug development, as it provides pharmacokinetic information, and
is necessary when the treatment-dose schedule and
safety margins need to be established. High-performance liquid chromatography (HPLC) together with
various types of detection UV (ultraviolet), FD (fluorescence detection) and MS has become the method of
choice for bio-analytical method development. Gas
chromatography (GC) is somewhat suppressed because
of the need for a derivatization step prior to analysis in
order to obtain volatile derivatives of the drug molecule,
which is often not volatile in the case of pharmaceuticals.
As expected from the different structures of simvastatin and atorvastatin, analytical methods for their quantitative determination were developed individually.
Because of the structural properties, there are not many
analytical methods that determine these two compounds
together in one analytical run or even in combination
with other statin molecules. This is also probably
because statins are not used with other statins simultaneously during treatment of hyperlipidemic patients.
There are only two works that describe the determination of a number of statin structures together in one
analytical run:
an environmental application where simvastatin,
atorvastatin, lovastatin and pravastatin (internal
standard (IS) = mevastatin) were determined in
aqueous samples [19]; and,
a pharmaceutical application where atorvastatin,
lovastatin, pravastatin, rosuvastatin and simvastatin
were determined together for QC of pharmaceutical
formulations [20]. Theophylline was employed as IS
for quantitation. The analytical run took about 40
min.
There have been two reviews on analytical methods
for the determination of HMG-CoA reductase inhibitors.
The first, published in 2003, referred to lovastatin,
simvastatin, pravastatin, fluvastatin and atorvastatin
[12]. HPLC and GC methods were discussed. Generally,
fluorescence and UV detection were applied together
with HPLC. Only two methods for the determination of
atorvastatin were available at that time. The second
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Stationary phase
analytical column
Mobile phase
Detection
Time [min]
Validation data
LOQ/LOD
Ref.
SV, SVA
LOV, LOVA
PRA
Luna C18
(4.6 250 mm, 5 lm)
ESI+
MS-MS
SRM
Not stated
15
[11]
SV, AT
LOV
PRA
IS = MEV
Aqueous samples
SPE
Genesis C18
(2.1 50 mm, 3 lm)
Gradient elution A:
ACN + 2 mM MeA + 0.1%
AcAc B: water + 2 mM
MeA + 0.1% AcAc
ESI+
MS-MS
SRM
[M + CH3NH3]+
[M + H]+
[M + CH3NH3]+
[M + CH3NH3]+
5.5
[19]
SV
AT, LOV
PRA, ROS
IS = theophylline
Pharmaceutical
formulation
metabolism study
in vitro
extraction MeOH
Interstil ODS 3V
(4.6 250 mm, 5 lm)
UV 237 nm
40
[20]
SV, SVA
IS = LOV, LOVA
Human plasma
SPE
ACN-water (80:20)
FD
360 nm
430 nm
Derivatization by
1-bromoacetylpyrene
35
[21]
SV, SVA
No IS
Human plasma
LLE
ODS Hypersil
(4.6 250 mm, 5 lm)
0.025 M sodium
dihydrogenphosphate pH4.5
ACN (35:65)
UV
238 nm
10
LOD = 15 ng/ml
[22]
SV
IS = LOV
Human plasma
LLE
ACN 20 mM potassium
phosphate
buffer pH 5.6 (65:35)
30
[23]
SV and impurities
(SVA, LOV
Me-SV, dimmer
acetate ester
anhydro-SV
IS = propyphenazon
Tablets extraction MP
X-Terra (4.6
50 mm, 3.5 lm)
Microemulsion: 0.9%
diisopropylether
1.7% SDS 7.0%
co-surfactant 90% 25
mM di-sodium
phosphate pH 7.0
25
LOD = 5 ng/ml
LOQ = 10 ng/ml
(SV and SVA)
[24]
UV
238 nm
UV
238 nm
Determined
substances
Table 1 (continued)
Matrix sample
preparation
Stationary phase
analytical column
Mobile phase
Detection
Precursor
ions notes
Time
[min]
Validation
data LOQ /LOD
Ref.
SV, LOV
Standard solutions
No LC
No LC
ESI+MSMS SRM
[M+H]+its
fragmentations
using MS
Not stated
fragmentation study
[25]
SV, SVA
Standard solutions
ESI+
MS-MS
SRM
[M + H]+
[M + NH4]+
2.5
Chromatographic and
mass resolution study
[26]
SV + impurities
No IS
SV substance tablets
Extraction ACN/FAc
Zorbax C8
(4.6 150 mm,
3.5 lm)
Gradient elution
A: 0.085 phosphoric acid
B:ACN
A: 0.001% FAc in water
B: 0.001% FAc in CAN
DAD
ESI+
MS-MS
45
Identification of
impurities
[27]
SV, SVA
IS = LOV, LOVA
Human plasma
SPE
Discovery C18
(4.6 50 mm, 5 lm)
ESI+/
MS-MS
SRM
[M + CH3CN + Na]+
[M H]
4.5
[28]
SV, SVA
IS = LOV, LOVA
Human
plasma on-line
SPE
ESI+
MS-MS
SRM
[M + H]+
2.5
[29]
SV
IS = LOV
Shim-pack ODS
(4.6 150 mm,
5 lm)
MeOHwater (9:1)
ESI+
MS
SV
[M + Na]+
[30]
SV, SVA
IS = deuterium labeled
Eects of
mobile phase
on ionization/
fragmentation
plasma
LLCE
Kromasil C18
(2.0 50 mm, 4 lm)
ACN-buffer 2 mM pH 4.5
(70:30) buffers: AmAc,
hydrazine acetate, alkylammonium acetates
ESI+
MS-MS
SRM
3.5
LOQ = 50 pg/ml
[31]
Human plasma
LLCE
Kromasil C18
(2.0 50 mm, 5 lm)
TIS
+
MS-MS
SRM
[M + H] SV
[M H] + SVA
3.5
LOQ = 50 pg/ml
[32]
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Determined
substances
Trends
357
358
[34]
LOQ = 0.05 ng/ml
Kromasil C18
(2.0 50 mm, 5 lm)
Human plasma LLE
SV, SVA
IS = stable isotope
labeled
TIS
+
MS-MS
SRM
[M + H] SV
[M H] + SVA
3.5
[33]
LOQ = 0.05 ng/ml
3.0
[M H] SVA
[M + CH3NH3]+ SV
TIS+
MS-MS SRM
Synergie Max RP
(2.0 50 mm, 4 lm)
Human plasma ulv-SPE
Precursor
ions notes
Table 1 (continued)
Stationary phase
analytical column
Matrix sample
preparation
Determined
substances
Mobile phase
Detection
Time
[min]
Ref.
Validation
data LOQ /LOD
Trends
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Determined substances
Mobile phase
Detection
Precursor
ions (notes)
Time
[min]
Validation data
LOQ /LOD
Ref.
AT, SV
LOV, PRA
IS = MEV
Gradient elution
A: ACN + 2 mM
MeA + 0.1% AcAc
B: water + 2 mM
MeA + 0.1% AcAc
ESI
+
MS-MS
SRM
[M + CH3NH3]+
[M + H]+
[M + CH3NH3]+
[M + CH3NH3]+
5.5
[19]
AT, LOV
PRA
ROS, SV
IS = theophylline
Pharmaceutical
formulation
metabolism study
in vitro extraction:
ACN:buffer
Interstil ODS 3V
(4.6 250 mm, 5 lm)
UV
237 nm
40
[20]
AT impurities = DSAT,
DFAT, no IS
C18 Luna
(4.6 250 mm, 5 lm)
Gradient elution
ACN-ammonium acetate
buffer pH 4.0 THF
UV
248 nm
32
[36]
AT, amolodipine
+ impurities
no IS
Tablets
MeOH extraction
UV
237 nm
18
[37]
AT amlodipine
No IS
Drug products
MeOH extraction
50 mM potassium dihydrogen
phosphate buffer pH 3.0
ACN (40:60)
UV
254 nm
[38]
AT
IS = DCF
Human serum
LLE
Shim-pack CLC-ODS
(4.6 150 mm, 5 lm)
UV
247 nm
LOQ 4 ng/ml
LOD = 1 ng/ml
[39]
AT
IS = ibuprofen
RP Supelcosil C18
(4.6 150 mm, 5 lm)
ACN:MeOH:water
(45:45:10)
UV
240 nm
[40]
Trends
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Trends
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Table 2 (continued)
Matrix sample preparation
Mobile phase
Detection
Precursor
ions (notes)
Time
[min]
Validation data
LOQ /LOD
Ref.
AT novobicin
roxytromycin
Aqueous samples
SPE
Gradient elution
A: ACN
B: 10 mM AmAc
ESI+
MS-MS
SRM
[M + H]+
5.0
ILOQ = 1 pg
[41]
AT, ATA
2-OH-AT/L
4-OH-AT/L
IS = deuterium labeled
Gradient elution
A: water, MeOH, FAc 88%
B: ACN, MeOH, FAc 88%
(950 ml:50 ml:43 ll)
ESI+
MS-MS
SRM
[M + H]+
3.5
[42]
AT o-OH-AT, p-OH-AT
IS = deuterium labeled
ESI+
MS-MS
SRM
[M + H]+
[43]
AT, ATA
p-OH AT/L
o-OH AT/L
IS = metachalon
Omnisphere C18
(2.0 30 mm, 3 lm)
Gradient elution
A: ACN, water, FAc 1mM
(30:70)
B: ACN, water, FAc 1mM
(60:40)
ESI+
MS-MS
SRM
[M + H]+
21
[18]
AT
p-OH AT
o-OH AT
IS = ROS
0.03%
FAc ACN (30:70)
TSI+
MS-MS
SRM
[M + H]+
2.5
[44]
AT
2-OH-AT
IS = clindamycin
ESI+
MS-MS
SRM
[M + H]+
4.0
[45]
AT, AT-L
p-OH AT/L
o-OH AT/L
IS = deuterium labeled
Gradient elution
A: 0.1% AcAc in water
B: ACN
ESI+
MS-MS
SRM
[M + H]+
1.65
[46]
Determined Substances
Trends
4
simvastatin
atorvastatin
0
1992
1997
1999
2000
2001
2002
2003
2004
2005
2006
2007
Figure 3. Analytical methods for the determination of simvastatin and atorvastatin first analytical methods for the determination of simvastatin
were published in the early 1990s, and the first for atorvastatin in 1999. The increasing trend for new methods to be developed for both statins
can be observed since 2003.
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Trends
OH
H3C
H3C
R=
Lovastatin
R
O
O
O
CH3
CH3
H3C
H3C
R=
H3C
Simvastatin
O
CH3
H3C
R=
D313C
[13CD3] Simvastatin
Figure 4. Similarity of simvastatin and lovastatin structures, and stable-isotope labeling of simvastatin.
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Trends
Table 3. Specific SRM transition for the determination of simvastatin, its various precursor ions, simvastatin hydroxy acid and their stable-isotope
labeled forms
Compound determined
Simvastatin
Molecular weight
Precursor ion
+
418.27
[M + H]
[M + Na]+
[M + CH3NH3]+
[M + CH3CN + Na]+
[13CD3]-simvastatin
[M + H]+
422.27
[M + CH3NH3]+
Simvastatin acid
436.27
[M H]
[13CD3]-simvastatin acid
440.27
[M + H]+
[M H]
Two HPLC-UV assays for the determination of atorvastatin in biological materials have been published.
Determination of atorvastatin in human serum using
diclofenac as the IS was published by Bahrami et al. [39]
with an LOQ of 4 ng/ml. Altuntas et al. developed a
method for the determination of atorvastatin in human
serum, bulk drug and tablets using ibuprofen as the IS
with an LOQ of 18 ng/ml [40].
HPLC-UV methods generally utilize the C18 stationary
phase. In most cases, a combination of acetonitrile and
buffer (ammonium acetate or phosphate) with the aim of
keeping pH between 4 and 5. Both isocratic and gradient
elution has been utilized. Detection has usually been
performed at 237 nm [20,37], 247 nm [36,39] or 254
nm [38]. Analytical run times have been very variable,
the shortest about 34 min [39,41], the longest about
30 min [36]. None of HPLC-UV methods also determined
the active metabolites of atorvastatin or its lactone form.
Ref.
419.1 285.1
419.1 199.1
441 (SIM)
450.3 285.1
481.2 440.9
[29,32]
[34]
[30]
[31,33]
[28]
423.2 285.1
423.2 199.1
454.3 285.1
[32]
[34]
[31,33]
435.3 114.0
435.3 319.1
437.3 303
439.2 319.1
[28]
[3134]
[29]
[3134]
Table 4. Specific SRM transition for the determination of atorvastatin, its metabolites and their stable-isotope-labeled forms
Compound determined
Molecular weight
Precursor ion
+
Ref.
559.2 440.2
564.2 440.2
564.2 445.2
541.2 448.2
546.2 448.2
546.2 453.2
[18,4246]
[42]
[43,46]
[18,42,46]
[42]
[46]
Atorvastatin
[d5]-atorvastatin
558.25
563.25
[M + H]
[M + H]+
Atorvastatin lactone
[d5]-atorvastatin lactone
540.25
545.25
[M + H]+
[M + H]+
p-hydroxy atorvastatin
[d5]-p-hydroxyatorvastatin
p-hydroxyatorvastatin lactone
[d5]-p-hydroxyatorvastatin lactone
574.25
579.25
556.25
561.25
[M + H]+
[M + H]+
[M + H]+
[M + H]+
575.2 440.2
580.2 445.2
557.2 448.2
562.2 453.2
[18,4246]
[42,43,46]
[18,42,46]
[42,46]
o-hydroxyatorvastatin
574.25
[M + H]+
[d5]-o-hydroxyatorvastatin
o-hydroxyatorvastatin lactone
[d5]-o-hydroxyatorvastatin lactone
579.25
556.25
561.25
[M + H]+
[M + H]+
[M + H]+
575.2 440.2
575.2 466.2
580.2 445.2
557.2 448.2
562.2 453.2
[4246]
[18,44]
[42,43,46]
[18,42,46]
[42,46]
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Table 5. Extraction procedures utilized for sample preparation during simvastatin analysis
Matrix
Extraction
procedure
Stationary phase
LLCE cartridge
SPE eluent/LLE
extraction agent
Stabilization/
pre-extraction
treatment
Interconversion
data
Validation data:
recovery
Ref.
SV, SVA
LOV, LOVA, PRA
Pu-Ehr tea
SPE
90% MeOH
None
Given at various
conditions
recSV = 95.098.9%
[11]
SV, AT
LOV, PRA
Aqueous samples
SPE
1. Filtration
2. Oasis HLB
MeOH
1%
recSV = 6984%
[19]
SV, SVA
Human plasma
SPE
C8
1. MeOH, water
6:4 2. ACN
None
Not significant
recSV = 40%
recSVA = 40%
[21]
SV, SVA
Human plasma
LLE
ACN:water
(60:40) ACN
None
Not given
recSV = 95.296.3%
recSVA = 92.895.1%
[22]
SV
Human plasma
LLE
diethylether
10 M HCl
Not given
recSV = 86.990.7%
[23]
SV, SVA
Human plasma
SPE
Oasis HLB
None
Not given
recSV = 88.8%
recSVA = 85.6%
[28]
SV, SVA
Human plasma
on-line SPE
Oasis HLB
ACN 3.0 mM
FAc (10:90)
<1%
recSV P 75%
recSVA P 38%
[29]
SV
Human plasma
LLE
Et-Ac
None
Not given
rec = 101.4%
[30]
SV, SVA
Plasma
LLCE
ChemElut cartridge
MTBE
<0.07%
recSV = 78%
recSVA = 87%
[31]
SV, SVA
Human plasma
LLCE
ChemElut cartridge
MTBE
<0.07%
recSV = 66%
recSVA = 73%
[32]
SV, SVA
Human plasma
ulv-SPE
ACN:water (95:5)
<0.08%
recSV = 66%
recSVA = 73%
[33]
SV, SVA
Human plasma
LLE
MTBE
<0.06%
lactonization
<0.07%
hydrolysis
recSV = 87.1%
recSVA = 72.7%
[34]
Substances
isolated
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Substances isolated
Matrix
Extraction
procedure
Stationary phase
Interconversion
data
Validation data:
recovery
Ref.
AT, SV
LOV, PRA
Aqueous samples
SPE
1. Filtration - Soxhlet
2. Oasis HLB
MeOH
10%
recAT = 6486%
[19]
AT
Human serum
LLE
Et-Ac
0.1 M phosphate
buffer pH 7.0
Not given
recAT = 95%
[39]
AT novobiocin
roxytromycin
Aqueous samples
SPE
1. Filtration - Soxhlet
2. HLB
MeOH
pH 4.0 by
3.5 M H2SO4
Not given
recAT = 70.572.2%
[41]
AT, ATA
2-OH-AT/L
4-OH-AT/L
Human serum
LLE
MTBE
0.1 M sodium
acetate buffer pH 5.0
Given at various
conditions
rec = 60100%
all analytes
[42]
AT o-OH-AT,
p-OH-AT
Human, dog
and rat plasma
LLE
Diethyl ether
0.1 M NaOH
Given at various
conditions
recAT = 100107%
[43]
AT, ATA
p-OH AT/L
o-OH AT/L
Human plasma
SPE
Varian C18
1 M sodium
formate pH 3
<4%
rec = 5378%
all analytes
[18]
AT
p-OH AT
o-OH AT
Human plasma
LLE
Diethyl ether
dichloromethane (7:3)
Not given
recAT = 54.2%
[44]
AT
2-OH-AT
Human plasma
LLE
Diethyl ether
dichloromethane (60:40)
0.01 M sodium
acetate pH 6.0
Not given
recAT = 89.692.5%
[45]
AT, AT-L
p-OH AT/L
o-OH AT/L
Human plasma
SPE
Isolute C-18
95% MeOH
100 mM AmAc
pH 4.6
Not given
Not given
[46]
Table 6. Extraction procedures utilized for sample preparation during atorvastatin analysis
Trends
365
Trends
negative-ion mode (ESI ), probably because this compound contained two nitrogen groups [42,43]. The
precursor ion chosen for quantitation was [M+H]+ in all
methods developed (see Table 2). The monitored SRM
transition for atorvastatin therefore utilized 559 440
(which was also the most intensive transition in all
methods).
Compared to HPLC-UV methods, all LC-MS/MS
methods determined atorvastatin together with its phydroxy and o-hydroxy metabolites, except [45] where
only the o-hydroxy metabolite was determined. All
metabolites including hydroxy acid and lactone forms
were determined by Jemal et al. [42], Hermann et al.
[18] and Van Pelt et al. [46]. Atorvastatin metabolites
were all also determined in ESI+ using [M + H]+ as a
precursor ion; the specific transition for each metabolite
and their stable isotope-labeled forms can be seen in
Table 4.
Atorvastatin and its metabolites have been separated
on the C18 analytical column using acetonitrile usually about 70% (to shorten retention times of analytes;
containing methanol only they would be eluted much
later) as part of the mobile phase, together with acetic
or formic acid as additives to enhance ionization. Both
isocratic and gradient elution have been utilized. Analytical run times were, in most cases, about 6 min or less,
except for one method [18].
The best ISs for precise and accurate quantitation in
MS are stable-isotope-labeled standards. In the case of
atorvastatin and its metabolites, [d5] labeling usually
occurs on the phenyl ring, which does not contain
fluorine [42,43]. Only three works employed deuteriumlabeled ISs [42,43,46] because they were very expensive
and sometimes they were not easily available. Other
works utilized ISs of various structures, including
metachalon [18], rosuvastatin [44] or clindamycin [46].
Method sensitivity expressed as LOQ was quite similar for
all methods, typically in the range 0.5 ng/ml [42] to 0.1
ng/ml [45]. [Please check this range?]
5. Sample preparation
A convenient sample-preparation procedure should isolate the analytes from the complex matrix while
removing endogenous interfering substances. This is
often the most time-consuming, critical step of analysis.
The analytes should be pre-concentrated in order to increase the sensitivity and the selectivity of the method.
The procedures for sample preparation of simvastatin
and atorvastatin have in most cases included LLE (liquidliquid extraction), and SPE (solid-phase extraction).
However, simple extraction into the organic solvent has
also been used in pharmaceutical applications
[20,24,27,3638,40] see Tables 1 and 2. There have
also been specific approaches to sample preparation (e.g.,
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LLCE (liquid-liquid cartridge extraction) [31,32] or online SPE utilizing a column-switching technique).
Tables 5 and 6 give overviews of LLE and SPE samplepreparation techniques utilized for the isolation of simvastatin and atorvastatin, focusing on data recovery,
interconversion during sample preparation (details given
in the work of Herman et al. [18], Zhao et al. [32] and
Zhang et al. [34]) and stabilization data.
Statins have mostly been isolated using SPE on the
Oasis HLB cartridge, employing methanol for elution, or
using LLE, where MTBE, ethyl acetate or diethyl ether
have generally been applied as extraction agents.
6. Conclusions
Analysis of statins is a current problem, because these
drugs are widely used for the treatment of hypercholesterolemia.
This review has presented HPLC methods for the
determination of simvastatin and atorvastatin in various
fields of application (pharmacology, clinical medicine
and environmental). We divided the methods according
to the type of detection. We discussed interconversion
between acid and lactone form of statins.
LC-MS/MS methods have undoubtedly become the
method of choice. In order to get high selectivity and
sensitivity, MS/MS techniques employ specific SRM
conditions, which are convenient, especially in bioanalytical applications. There is no problem in determining the metabolites, even if they are not also sufficiently separated chromatographically.
Chromatographic conditions must be carefully arranged, as must selection of a precursor ion for a specific
SRM transition in order not retain the sensitivity and the
selectivity of the method.
Acknowledgement
The authors gratefully acknowledge the financial support of IGA MZ CR No. 1A/8689-4.
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