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Corelatii structura – retentie in cromatografia de lichide de inalta performanta si aplicatii pentru compusi de importanta farmaceuticaContractul PN2_Idei 55/28.09.2007 (Cod ID_957/2007)
Director Proiect: Profesor Dr. Victor David
Institutia: Universitatea din Bucuresti, Facultatea de Chimie.
- Proiect interdisciplinar (analitica, organica, chimie-fizica; farmacie);- Directie fundamentala, dar si cu aplicatii concrete;- De mare interes in domeniul separarilor;- Foarte discutat in literatura de specialitate;- Cu mare potential pentru cercetari si publicatii;- Se bazeaza pe instrumentatie moderna;- S-au realizat colaborari, printre care si studenti sau tineri cercetatori.
Membrii echipei: Prof. Dr. Victor DavidLect. Dr. Emilia-Elena IorgulescuLect. Dr. Florentin TacheDrd. Medeea RadulescuMasterand Alina Cristian
Colaborari: Prof. Dr. Andrei MedvedoviciProf. Dr. Mihaela HillebrandConf. Dr. C. MihailciucLect. Dr. Sorana IonescuDr. Iulia SoraDrd. Toma GalaonDrd. Stefan UdrescuDrd. Jana PetreStudent Edvin Caiali
Rezumatul proiectului:
PROIECTUL PROPUNE O TEMA FUNDAMANTALA DE CERCETARE IN DOMENIUL CROMATOGRAFIEI DE LICHIDE: MODELAREA SI CORELAREA INTRE REZULTATELE EXPERIMENTALE ALE SEPARARILOR HPLC SI STRUCTURA COMPUSILOR INVESTIGATI, CU APLICATII PE COMPUSI DE IMPORTANTA FARMACEUTICA (QSRR). VOR FI STUDIATE CELE MAI IMPORTANTE MECANISME DE SEPARARE HPLC (FAZA INVERSA, FAZA NORMALA SI CHIRALA) SI SE VOR PROPUNE MODELE SI ABORDARI ORIGINALE PENTRU DESCRIEREA INTERACTIEI DINTRE ANALIT SI FAZA STATIONARA. VOR FI CERCETATE EXPERIMENTAL SI CLASE NOI DE COMPUSI FARMACEUTICI DIN PUNCT DE VEDERE AL COMPORTARII CROMATOGRAFICE SI SE VOR CORELA DESCRIPTORI MOLECULARI CU PARAMETRII EXPERIMENTALI. DINTRE DESCRIPTORII MOLECULARI, HIDROFOBICITATEA ANALITILOR STUDIATI VA FI CEA MAI UTILIZATA IN STUDIILE QSRR. SE VA PROPUNE O MODALITATE DE ATRIBUIRE A UNEI MARIMI DE HIDROFOBICITATE SI FAZEI STATIONARE. SE DORESTE CA REZULTATELE OBTINUTE SA FIE VALORIFICATE PRIN PUBLICARE A MINIMUM 6 ARTICOLE IN REVISTE ISI DIN STRAINATATE.
Proiectul nu este unul pur teoretic. Studiile de corelaţie proprietati-structura se bazează in primul rând pe o cantitate mare de informaţie experimentala. In cazul de fata, partea experimentala este decisiva; in plus, un sistem cromatografic trebuie calificat, verificat, iar rezultatele obţinute de cele mai multe ori sunt prelucrate statistic, pentru care sunt necesare seturi de determinări paralele. Aşadar, proiectul isi propune atât o abordare experimentala pentru obţinerea de rezultate experimentale in diverse condiţii de separare cromatografica si pentru o gama mare de compuşi organici, cat si una de interpretare, pe baza literaturii si a propriilor realizări, parte din ele recunoscute in literatura de specialitate prin citarea lor.
In principiu, tema aleasă va fi îndreptată pe următoarele direcţii:a) Alegerea claselor de compuşi de importanta farmaceutica vor fi investigate atât in cadrul a doua teme de doctorat, cat si in afara pregătirii doctorale;b) Dezvoltarea unui cadru teoretic original, bazat pe experienţa si realizările anterioare;c) Studii practice de retenţie, în diverse condiţii de separare: compoziţii de faza mobila (pH-ul fazei mobile, natura modificatorului organic), temperatura din coloană, tipul de fază staţionară, parametrii constructivi ai coloanei cromatografice, pe un număr mare de reprezentanţi ai claselor de compuşi organici;d) Studii experimentale privind volumele de injecţie si parametrii care influenţează aceasta etapa;e) Studii şi metodologii de corelaţie între rezultatele obţinute si structura compuşilor aleşi.
Rezultate:Articole publicate in reviste ISI cu F.I., avand acknowledgements:
1. A.Medvedovici, D.I.Sora, S.Ionescu, M.Hillebrand, V.David, Characterization of a new norfloxacin metabolite monitored during a bioequivalence study by means of mass-spectrometry and quantum computation. Biomedical Chromatography, 22 (10), 1100-1107 (2008). F.I. = 1.505
2. St.Udrescu, A.Medvedovici, V.David, Effect of large volume injection of hydrophobic solvents on the retention of less hydrophobic pharmaceutical solutes in RP-LC. Journal of Separation Science, 31 (16-17), 2939-2945 (2008). F.I. = 2.746
3. J.Petre, V.Iancu, V.David, Benzene/water partition constants and thermodynamic parameters estimated from liquid chromatography retention of some herbicides using phenyl-silica stationary phase. Revue Roumaine de Chimie, 54 (4), 261-266 (2009). F.I. = 0.284
4. T.Galaon, F.Tache, V.David, Retention behaviour of two biguanidines in liquid chromatography based on cyano stationary phase. Revue Roumaine de Chimie, 54 (5), 361-364 (2009). F.I. = 0.284
5. A.Medvedovici, F.Albu, I.D.Sora, S.Udrescu, T.Galaon, V.David, Assay of free captopril in human plasma as monobromobimane derivative, using RPLC/(+)ESI/MS/MS: validation aspects and bioequivalence evaluation. Biomedical Chromatography, 23 (10), 1092-1100 (2009). F.I. = 1.505
6. M.Albu, V.David, F.Tache, A.Medvedovici, HPLC/DAD assay of related impurity ethyl-4-oxopiperidine-1-carboxylate in loratadine through derivatization with 2,4-dinitrophenylhydrazine. Journal of Liquid Chromatography and Related Technologies, 32 (17), 2569-2583 (2009). F.I. = 1.026
7. V.David, T.Galaon, E.Caiali, A.Medvedovici, Competitional hydrophobicity driven separations under RP-LC mechanism: application to sulphonylurea congeners. Journal of Separation Science, 32 (18), 3099-3106 (2009). F.I. = 2.746
8. V.Voicu, A.Medvedovici, M.Radulescu, E.E.Iorgulescu, V.David, Unusual retention behavior of some cationic-type aldoximes used as AChE reactivators under ion-pairing liquid chromatographic mechanism. Analytical Letters, 43, in press, (2010). F.I. = 1.135
9. A.Cristian, E.E.Iorgulescu, C.Mihailciuc, Electrochemical study of meloxicam using activated glassy carbon. Revue Roumanie de Chimie, 55, in press (2010). F.I. = 0.284
10. A.Cristian, E.E.Iorgulescu, C.Mihailciuc, Electrochemical study of piroxicam using activated glassy carbon. Revue Roumanie de Chimie, 55, in press (2010). F.I. = 0.284
11. J.Petre, S.Ionescu, M.Hillebrand, V.David, Quantitative correlations between chromatographic data and molecular parameters for some weakly related pesticides. Journal of Liquid Chromatography and Related Technologies, 33, in press (2010). F.I. = 1.026
12. V.Voicu,, I.Sora, C.Sarbu, V.David, A.Medvedovici, Hydrophobicity/hydrophilicity descriptors obtained from extrapolated chromatographic retention data as modeling tools for biologicaldistribution: application to some oxime-type acetylcholinesterase reactivators.Journal of Pharmaceutical and Biomedical Analysis, 52 (4), 508-516 (2010). F.I. = 2.629
13. T.Galaon, C.Mihailciuc, A.Medvedovici, V.David, Estimation of thermodynamic parameters for some polar compounds using different mobile phase flow-rates in RP-LC. F.I. = 1.026
Journal of Liquid Chromatography & Related Technologies, trimis spre publicare, (2010).
14. A.Medvedovici, V.Voicu, I.D.Sora, M.Radulescu, V.David, Discontinuous double mechanismfor the retention of some cation-type oximes on hydrophilic stationary phases in liquid chromatography, Chromatographia, in curs de redactare. F.I. = 1.312
15. T.Galaon, A.Medvedovici, C.Mihailciuc, V.David, Deviation from van’t Hoff dependence in RP-LC induced by tautomeric inter-conversion observed for three compounds. Journal of Separation Science, in curs de redactare. F.I. = 2.746
1. A.Medvedovici, D.I.Sora, S.Ionescu, M.Hillebrand, V.David, Characterization of a new norfloxacin metabolite monitored during a bioequivalence study by means of mass-spectrometry and quantum computation. Biomedical Chromatography, 22 (10), 1100-1107 (2008).
Articol citat în:1. N.R.Srinivas, Biomedical Chromatography, 23 (6), 674-675 (2009).2. N.R.Srinivas, Arzneimittel-Forschung/Drug Researsch, 59 (4) 155-165 (2009).
N
F
N
N
OCOOH
CH2
CH3
NH
+
F
N
N
OCOOH
CH2
CH3
NH
+
F
NN
O
CH2
CH3
N
F
NHNH2
OHCOOH
N
F
NHNH3
+
OHCOOH
NC
F
NH3+
OHCOOH
NH2 C CH2
- CO2
(norfloxacina)
MS
fragmentare
m/z = (M + 1) m/z = (M + 1 - 44)
metabolizare
fragmentare MS
m/z = (M + 1)
MS2
MS2
m/z = (M + 1 - 42)
2. St.Udrescu, A.Medvedovici, V.David, Effect of large volume injection of hydrophobic solvents on the retention of less hydrophobic pharmaceutical solutes in RP-LC. Journal of Separation Science, 31 (16-17), 2939-2945 (2008).
Articol citat si discutat pe larg în:E.Loeser, S.Babiak, P.Drumm, J. Chromatogr. A, 1216 (15), 3409-3412 (2009).
O
O
H
H
HO
OHH
NO2
O
O
H
H
HOH
OH
O2N
N
N
O
CH3
O N
NCH3
CH3
O
C
OH
O
O
CH3
NOH
N
O
Isosorbide 2-nitrate (log P = -0.40)
Isosorbide 5-nitrate (log P = -0.15)
Pentoxifylline (log P = 0.56)
Methyl p-hydroxybenzoate(log P = 1.96)
Tropicamide (log p = 1.19)
0 100 200 300 400 500
1.01.5
2.0
2.5
3.0
3.5
4.04.5
5.0
5.5
6.0
6.57.0
7.5
8.0
MPHB
Tropicamide
Isosorbite 5-nitrate
Pentoxifylline
Cap
acity
fact
or
Injection volume (µL)
Isosorbite 2-nitrate
Sample solvent: Hexane
0 100 200 300 400 500
1.01.5
2.0
2.53.0
3.5
4.04.5
5.0
5.56.0
6.5
7.07.5
8.0
Sample solvent: HeptaneMPHB
Pentoxifylline
Isosorbite 2-nitrate
Cap
acity
fact
or
Injection volume (µL)
Tropicamide
Isosorbite 5-nitrate
0 100 200 300 400 500
1.0
1.5
2.0
2.5
3.0
3.5
4.04.5
5.0
5.5
6.0
6.5
7.0
7.5
8.0
Sample solvent: i-octane
Pentoxifylline
MPHB
Tropicamide
Isosorbite 2-nitrateCap
acity
fact
or
Injection volume (µL)
Isosorbite 5-nitrate
0 100 200 300 400 500
0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0
Tropicamide
MPHB
Pentoxifylline
Isosorbite 5-nitrate
Cap
acity
fact
or
Injection volume (µL)
Isosorbite 2-nitrate
Sample solvent: Hexane
0 100 200 300 400 500
0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0
TropicamideMPHB
Pentoxifylline
Isosorbite 5-nitrate
Cap
acity
fact
or
Injection volume (µL)
Isosorbite 2-nitrate
Sample solvent: Heptane
0 100 200 300 400 500
0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0
Tropicamide
MPHB
Pentoxifylline
Isosorbite 5-nitrate
Cap
acity
fact
or
Injection volume (µL)
Isosorbite 2-nitrate
Sample solvent: i-octane
C8 – stationary phase C18 – stationary phase
3. J.Petre, V.Iancu, V.David, Benzene/water partition constants and thermodynamic parameters estimated from liquid chromatography retention of some herbicides using phenyl-silica stationary phase. Revue Roumaine de Chimie, 54 (4), 261-266 (2009).
Compound IUPAC name (CAS number) Structure
Diuron3-(3,4-dichlorophenyl)-1,1-dimethylurea
(000330-54-1)
Isoproturon3-(4-isoprpylphenyl)-1,1-dimethylurea
(034123-59-6)
Linuron3-(3,4-dichlorophenyl)-1-methoxy-1-
methylurea (000330-55-2)
Monolinuron3-(4-chlorophenyl)-1-methoxy-1-methylurea
(1746-81-2)
Propanil3’4’-dichloropropionanilide
(000709-98-8)
Cl
ClNH
NOCH3
CH3
CH3
CH3NH
NOCH3
CH3
Cl
ClNH
NOCH3
OCH3
ClNH
NOCH3
OCH3
ClNH
CH2
OCH3 Cl
44 46 48 50 52 54 56 58 60 62 64 66 68 70
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
log
k'
% methanol
Isoproturon Monolinuron Diuron Linuron Propanil
25 30 35 40 45 500.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
Diuron Monolinuron Isoproturon Linuron Propanil
log
k'
% acetonitrile
T1
RH
RS
VV
lnkln00
mp
sp
0.00310 0.00315 0.00320 0.00325 0.00330 0.00335 0.00340 0.003451.8
2.0
2.2
2.4
2.6
2.8
3.0
ln k
'
1/T
Isoproturon Monolinuron Diuron Linuron Propanil
Si O SiCH3
CH3
4. T.Galaon, F.Tache, V.David, Retention behaviour of two biguanidines in liquid chromatographybased on cyano stationary phase. Revue Roumaine de Chimie, 54 (5), 361-364 (2009).
0 20 40 60 80 100
2
4
6
8
10
12
14
16
18
20
Model: ExpGro1Equation: y = A1*exp(x/t1) + y0Weighting: y No weighting Chi 2/DoF = 0.13473R 2 = 0.9964 y0 3.15112 ±0.15813A1 0.00021 ±0.00016t1 8.02013 ±0.52079R
eten
tion
time
(min
)
%ACN
N-methylbiguanidine
(a)
0 20 40 60 80 100
3
4
5
6
7
8
9Model: ExpGro1Equation: y = A1*exp(x/t1) + y0Weighting: y No weighting Chi 2/DoF = 0.0103R 2 = 0.99763 y0 3.13138±0.05012A1 0.00239±0.00089t1 11.6477±0.56224
Ret
entio
n tim
e (m
in)
%MeOH
N,N-dimethylbiguanidine
(b)
0 20 40 60 80 1002
3
4
5
6
7
8
9
Model: ExpGro1Equation: y = A1*exp(x/t1) + y0Weighting: y No weighting Chi 2/DoF = 0.01538R 2 = 0.99626 y0 2.96694 ±0.06319A1 0.00364 ±0.0016t1 12.36566 ±0.74763R
eten
tion
time
(min
)
%MeOH
N-methylbiguanidine
(b)
0 20 40 60 80 100
2
4
6
8
10
12
14
16
18
20
22
Model: ExpGro1Equation: y = A1*exp(x/t1) + y0Weighting: y No weighting Chi 2/DoF = 0.18592R 2 = 0.99542 y0 3.40127 ±0.18693A1 0.00029 ±0.00023t1 8.2126 ±0.59561R
eten
tion
time
(min
)
v%ACN
N,N-dimethylbiguanidine
(a)
OHNC OHNC 33
BgNC BgNC
Si O SiCH3
CH3
CH2CH2CH2C N
Mecanism mixt de retentie: NP + RP.
Metformin (log Kow = -2,64)
Metilbiguanidina(log Kow = -2,85)
Si OOSi
SiCH3
CH3
C N(CH2)3
NH CNH2
NHCNH
NCH3
CH3
Si OOSi
SiCH3
CH3
C N(CH2)3
NH CNH2
NHC
NNH
CH3CH3
-q+q
-p +p
(I) (II)
5. A.Medvedovici, F.Albu, I.D.Sora, S.Udrescu, T.Galaon, V.David,Assay of free captopril in human plasma as monobromobimane derivative, using RPLC/(+)ESI/MS/MS: validation aspects and bioequivalence evaluation. Biomedical Chromatography, 23 (10), 1092-1100 (2009).
NN
O O
CH3
CH3
CH3
CH2 S
CH3
N
OO O
H
NN
O O
CH3
CH3
CH3
CH2 S
CH3
N+
O
NN
O O
CH3
CH3
CH3
CH2 S
CH3
N
O O+O
H
H
NN
O O
CH3
CH3
CH3
CH2 SC
+
CH3
O
N
NN
O O
CH3
CH3
CH3
CH2 SH+
CH3
N
OO O
H
NN
O O
CH3
CH3
CH3
CH2 SH
CH2+
CH3
N
OO O
H
CH3 C+
CH3
N
OO O
H
m/z=184
- HOH- CO
m/z = 362
M = 407
+ H+
m/z = 408
m/z = 293
+ H+
m/z = 408
0 1 2 3 4 5 6 7 80
10
20
30
40
50
60
70
80
90
100
% R
esid
ual C
apto
pril
Time (hours)
Oxidation kinetics of captopril to disulphide compound, determined by means of derivatization of free sulphide group with monobromobimane and MS detection.
x104
00.10.20.30.40.50.60.70.80.9
1
100 125 150 175 200 225 250 275 300 325 350 375 400 425 450 475 500
362.2
184.2293.3
216.3
114.2 311.3265.1
6. M.Albu, V.David, F.Tache, A.Medvedovici, HPLC/DAD assay of related impurity ethyl-4-oxopiperidine-1-carboxylate in loratadine through derivatization with 2,4-dinitrophenyl hydrazine.Journal of Liquid Chromatography and Related Technologies, 32 (17), 2569-2583 (2009).
Typical chromatograms obtained on method application: A –loratadine and related compounds monitored at 220 nm, according to EP compendial method; B – derivatization reagent (2,4-DNPH), chromatogram monitored at 368 nm; C –chromatogram of a sample containing the derivatization productof impurity H with 2,4-DNPH, monitored at 368 nm; D – detail from a chromatogram corresponding to a sample having the concentration of impurity H at the LOQ level (0.1 mg=mL), monitored at 368 nm, used to evaluate the signal to noise ratio.
7. V.David, T.Galaon, E.Caiali, A.Medvedovici, Competitional hydrophobicity driven separations under RP-LC mechanism: application to sulphonylurea congeners. Journal of Separation Science, 32 (18), 3099-3106 (2009).
NSNH
NH
O O O
CH3
Cl
NH
OOCH3
SNH2
O O
Cl
NH
OOCH3
SNH
O
O O OCH3
OCH3 N
O
CH3CH3
OS
NH
O O
NH
O
N
N
NH
O
SNH
NH
O O OCH3
Cl
NH
OOCH3
SNH
NH
O O O
NSNH
NH
O O O
CH3
N
O
C
CH3
H5C2 NH
O
S NH
O
OCO
NH
CH3
(1)
(6)
(4)
(2)
(3)
(7)
(5)
(8)
-1.0 -0.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.51.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0
5.5
6.0
y = -0.0994x2 - 0.1114x + 3.4882
R2 = 0.9876
y = -0.1391x2 - 0.0248x + 3.5794
R2 = 0.9876
y = -0.1207x2 - 0.0870x + 3.1425
R2 = 0.9931lo
g k'
w
log Kow (solvent)
GLB GLB A GCZ GPZ
y = -0.0916x2 - 0.1268x + 4.7811
R2 = 0.9877
OH
Ana
lit (A
) Modificator
organic (S)
Liga
nd C
18 (L
)
Spacer
Suport Silica gel
OH
A B
OH
C
MetanolEtanol1-Propanol2-PropanolButanolPentanolOctanol
-1.0 -0.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0
-1.0
-0.5
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
log
Kow
(exp
erim
enta
l)
log Kow (teoretic)
y = -0.1214 + 1.12805*xR = 0.99751
1-Octanol
1-Pentanol
1-Butanol
1-Propanol
2-PropanolEtanol
Metanol
LA AL A
ow1sms
s
ms
sLA K
]L[1
]A[]L[]A[
]A[]L[]LA[K
LS SL S
ow2sms
s
ms
sLS K
]L[1
]S[]L[]S[
]S[]L[]LS[K
Modelul adsorbţiei (tratare matematică):
nLS nSL
nSow2
smn
s
sn
nms
snLS )K(
]L[1
]S[]L[]S[
]S[]L[]LS[K
n
mSALS ALS mnn
msn
mmsmn
ALS ]A[]LS[]S[]ALS[K
mn
Alte echilibre competiţionale:
Echilibre competiţionale de adsorbţie-desorbţie între analit, solvent şi ligand:
Sow
AowA KlogKlog'klog
2Sow
Sow
AowA )K(logKlogKlog'klog
8. V.Voicu, A.Medvedovici, M.Radulescu, E.E.Iorgulescu, V.David, Unusual retention behavior of some cationic-type aldoximes used as AChE reactivators under ion-pairing liquid chromatographic mechanism. Analytical Letters, acceptat spre publicare, (2010).
N+
ON
OO N
+N
NOH
I I
(C2)Dimethyl-carbamic acid 1-[2-(hydroxyimino-methyl) -3-methyl-3H-imidazol-1-ylmethoxymethyl]-1-aza- bicyclo[2.2.2]octane-3-yl ester
N+ N
NOH
I
(C4)2-(Hydroxyimino-methyl)-1,3-dimethyl-3H-imidazol-1-ium
N+
OO N
+N
NOH
I I
Quinuclidinium derivative (C3)1-Methyl-3-(3-oxo-1-aza-bicyclo[2.2.2]octane -1-ylmethoxymethyl)-1H-imidazole- 2-carbaldehyde oxime
N+ O
O
NBr Pyridostigmine (PRDS)
Dimethyl-carbamic acid 1-methyl- pyridin-3-yl ester
N+
N
OH N
N
O
Br
Pralidoxime (PAM)2-[(hydroxyimino)methyl]-1-methylpyridin-1-ium
N+
N+
O
NOH
N
OH
Cl Cl
Obidoxime (LuH-6)1,3-bis(4-hydroxyiminomethylpyridinium) -2-oxapropane
35 40 45 50 55 60 65 70 75 80 850.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
PRDS
LuH-6
PAM
C4
log
k
Co (% MeOH)
C2
C3
IPA = C6H13SO3
-Na+
A
50 55 60 65 70 75 80 850.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
log
k
Co (% MeOH)
C4 PAM
PRDS
LuH-6
C2
C3
IPA = C8H
17SO
3
-Na+
B
2
1i
i0iw Cklogklog
9. A.Cristian, E.E.Iorgulescu, C.Mihailciuc, Electrochemical studies using activatedglassy carbon. I Meloxicam, Revue Roumaine de Chimie, in press (2010).
-1.5 -1.0 -0.5 0.0 0.5 1.0
-1.2x10-5
-8.0x10-6
-4.0x10-6
0.0
4.0x10-6
E / V
I / A
B
1
2
0.0 0.2 0.4 0.6 0.8 1.0 1.2
-2.0x10-6
0.0
2.0x10-6
4.0x10-6
6.0x10-6
8.0x10-6
I / A
E / V
A
v
10. A.Cristian, E.E.Iorgulescu, C.Mihailciuc, Electrochemical studies using activated glassy carbon. II Piroxicam, Revue Roumaine de Chimie, in press (2010).
O O
N
S
OH
NCH3
NH
O
O O
N
S
OH
NCH3
N
OH
O O
N
S
O
NCH3
NH
OH
O O
N
S
O
NCH3
NH
O
Piroxicam (I) (II)
(III) (IV)
11. J.Petre, S.Ionescu, M.Hillebrand, V.David, Quantitative correlations between chromatographic data and molecular parameters for some weakly related pesticides. Journal of Liquid Chromatography and Related Technologies, spre publicare (2010).
M(in vacuo)
M(octanol) M(water)(Gsol)
(Gsol)w(Gsol)o
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.00.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
r2=0.8734
lg k
exp
wlg ktheor
w
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.00.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
r2=0.7953
lg k
exp
w
lg ktheorw
b
a
AnalyteShake-flask
values
ACN MeOH
lg Kow
from C8
lg Kow
from C18
lg Kow
from C8
lg Kow
from C18
Dichlorvos 0.706 1.270 1.370 2.114 2.086
Isoproturon 2.319 1.858 1.893 2.268 2.291
Diuron 2.784 1.869 1.917 2.648 2.666
Monolinuron 2.300 1.828 1.873 2.690 2.718
Propanil 3.179 2.263 2.358 3.057 3.075
Linuron 3.201 2.474 2.553 3.093 3.080
Fenitrothion 3.204 2.466 2.428 3.318 3.404
Coumaphos 3.857 2.707 2.900 4.236 4.291
Phoxim 4.390 3.120 2.962 4.348 4.549
n
0i
imiCklg
12. V.Voicu,, I.Sora, C.Sarbu, V.David, A.Medvedovici, Hydrophobicity/hydrophilicity descriptors obtained from extrapolated chromatographic retention data as modeling tools for biological distribution: application to some oxime-type acetylcholinesterase reactivators. Journal of Pharmaceutical and Biomedical Analysis, 52, 508-516 (2010).
-2.50
-2.00
-1.50
-1.00
-0.50
0.00
0.50
1.00
1.50
10 20 30 40 50 60 70 80 90
Organic modifier (%)
log
k'
PAMHi-6Hlo-7LuH-6
-0.6
-0.4
-0.2
0
0.2
0.4
0.6
0.8
1
1.2
0 10 20 30 40 50 60 70 80
Organic modifier (%)
log
k'
PAMHi-6Hlo-7LuH-6
A
B
Analyte PAM PRDS HI-6 HLo-7 LuH-6 (1) (2) (3)
Column HILIC (polyol) analyte’s H-bond donor interactions, dipole-dipoleA 0.00131 0.00165 0.00362 0.00448 0.00353 -0.00026 0.00223 0.00219B -0.1959 -0.26584 -0.54862 -0.69362 -0.5398 0.12786 -0.32721 -0.32479C 6.426 10.002 20.713 26.787 20.379 -9.574 11.614 11.645bin
-0.064 -0.082 2.051 2.225 1.699 0.622 1.193 1.066S 0.0329 0.02262 0.08484 0.08965 0.07863 0.08252 0.06379 0.05814I -3.55129 -2.57672 -6.91034 -7.36951 -6.58931 -7.59667 -5.43685 -5.05365lin
-0.261 -0.315 1.574 1.595 1.274 0.655 0.942 0.760Column ZIC-HILIC(*) Electrostatic interactions, ion dipoleA 0.07692 -0.03879 -0.06384 -0.07023 -0.06807 -0.06255 -0.06116 -0.06407B -0.00035 0.00040 0.00072 0.00075 0.00070 0.00069 0.00064 0.00066C -4.909 0.187 1.366 1.405 1.375 0.628 1.247 1.341bin -0.683 0.345 2.142 1.858 1.519 1.252 1.485 1.501S 0.02978 0.01613 0.03355 0.03147 0.02648 0.03102 0.02528 0.02527I -3.365 -1.612 -1.823 -1.925 -1.721 -2.435 -1.584 -1.585lin
-0.387 0.001 1.532 1.222 0.927 0.667 0.944 0.942Column AGP Protein binding abilityA 0.00061 0.00054 0.00151 0.0016 0.00166 0.00059 0.00134 0.00135B -0.08661 -0.06948 -0.20023 -0.21814 -0.23023 -0.08332 -0.18537 -0.1876C 2.491 1.435 6.927 7.813 8.261 2.288 6.513 6.604bin
-0.050 -0.081 2.004 1.999 1.838 -0.061 1.376 1.344S 0.01437 0.02016 0.04887 0.04664 0.04336 0.0154 0.03564 0.0357I -1.65897 -2.24906 -3.31044 -3.06927 -2.98315 -1.76863 -2.56979 -2.57299lin
-0.222 -0.233 1.577 1.595 1.353 -0.229 0.994 0.997
Extrapolated retention at 100% organic solvent () and parameters of the binomial and linear regressions, according to equations (1) and (2), relating retention data (log k’) to the content of the organic modifier in the mobile phase (), for analyte/stationary phase interactions accounting for hydrophilic mechanism.
COOCH3
OH
COOC3H7
OH
COOHOH
COOHCl
Cl
Cl NH
COOHSO
NH2O
O
S
OH
NH
O O
O
CH3
N
SCH3
N
S
OH
NH
O O
O
CH3
ONHSO2CH3
NO2
CO
Cl OH
Methyl p-hydroxybenzoate
Propylp-hydroxybenzoate
Salicylic acid
2,4-Dichlorobenzoic acid(impurity E of furosemide)
Furosemide
MeloxicamPiroxicam
Nimesulide(4-chlorophenyl)(4-hydroxyphenyl) methanone
(impurity A of fenofibrate)
13. THE INFLUENCE OF MOBILE-PHASE FLOW-RATE IN RP-LC ON THERMODYNAMIC PARAMETERS STUDIED FOR SOME POLAR COMPOUNDS
T.Galaon, C.Mihailciuc, A.Medvedovici, V.David,
Journal of Liquid Chromatography and Related Technologies, spre publicare, 2010.
0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2-20
-18
-16
-14
-12
-10
-8
-6
-4
Enth
alpy
(
0 )
Mobile phase flow-rate (mL/min)
MePa AcS Furo Piro ImpE PrPa Melo ImpA Nime
0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2
-45
-40
-35
-30
-25
-20
-15
-10
-5
0
Ent
ropy
S0 )
Mobile phase flow-rate (mL/min)
MePa AcS Furo Piro ImpE PrPa Melo ImpA Nime
0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2-9
-8
-7
-6
-5
-4
-3
-2
-1
Gib
bs fr
ee e
nerg
y (
G
Mobile phase flow-rate (mL/min)
MePa AcS Furo Piro ImpE PrPaMelo ImpA Nime
lnRS
RTH'kln
00
N
SN
OH
CH3
CNH
O
O O
N
SN
OH
CH3
CN
OH
O O
N
SN
O
CH3
CNH
OH
O O
N
SN
O
CH3
CNH
O
O O
(I)log Kow = 2.58
(II)log Kow = 0.01
(III)log Kow = 0.99
(IV)log Kow = 1.53
min2 4 6 8 10 12 14
mAU
0
20
40
60
80
100
120
140
160
Fur
Pir
PrPa
MePa
Sac FurE
Mel FenANim
14. A.Medvedovici, V.Voicu, I.D.Sora, M.Radulescu, V.David, Discontinuous double mechanism for the retention of some cation-type oximes on hydrophilic stationary phases in liquid chromatography, Chromatographia, in curs de redactare.
10 15 20 25 30 35 400
2
4
6
8
10
k
Cm (% ACN)
B0 10 20 30 40 50 60 70 80 90
0
2
4
6
8
10
12
14
16
PAM HI6 HLo7 LuH6k
Cm (% ACN)
A
40 45 50 55 60 65 70 75 80 850
2
4
6
8
10
12
14
16
k
Cm(% ACN)
C
2111 mm CCk
mCk 22
1
2/1
2112
21212,1 2
4)(
mC
N+
NOH N
N
O
N+
N+
O
NOH
NH2
O
N+
N+
O
NOH
NOH
N+
N+
O
NOH
NOH
NH2
O
Br
Cl Cl
Cl Cl
N+
SO3O -...
Pralidoxime (PAM)2-[(hydroxyimino)methyl]-1-methylpyridin-1-ium
(HI-6)2,1-(2-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium)-2-oxapropane
Obidoxime (LuH-6)1,3-bis(4-hydroxyiminomethylpyridinium) -2-oxapropane
(HLo-7)1-(4-aminocarbonylpyridinio)methoxymethyl- 2,4-bis(hydroxyiminomethyl)pyridinium
2 CH3SO3-
ZIC-HILIC stationary phase
15. T.Galaon, A.Medvedovici, C.Mihailciuc, V.David, Deviation from van’t Hoff dependence in RP-LC induced by tautomeric inter-conversion observed for three compounds. Journal of Separation Science, in curs de redactare.
0.0030 0.0031 0.0032 0.0033 0.0034 0.0035 0.00361.90
1.95
2.00
2.05
2.10
2.15
2.20
2.25
2.30
2.35
Y = A + B * XParameter Value Error------------------------------------------------------------A -0.10605 0.08123B 686.51455 24.64706------------------------------------------------------------R SD N P------------------------------------------------------------0.99616 0.01201 8 <0.0001
ln k
'
1/T (K-1)
Drotaverina - pH 9,0
0.0030 0.0031 0.0032 0.0033 0.0034 0.0035 0.0036
1.49
1.50
1.51
1.52
1.53
1.54
1.55
1.56
1.57
Y = A + B1*X + B2*X^2
Parameter Value Error------------------------------------------------------------A -4.76891 0.33387B1 3973.86118 204.98223B2 -623098.17156 31388.32625------------------------------------------------------------
R-Square(COD) SD N P------------------------------------------------------------0.99378 0.00231 8 <0.0001------------------------------------------------------------
Drotaverina - pH 4,5
ln k
'
1/T (K-1)
pH 4,5 – retenţia creşte moderat cu temperatura în intervalul 10 – 40°C; după 40°C retenţia scade; la acest pH molecula Drotaverinei este protonată în proporţie de 99,9%
pH 9,0 – retenţia scade liniar cu creşterea temperaturii pe întreg domeniul studiat (conform ecuaţiei van’t Hoff); la acest pH molecula Drotaverinei se află în stare neprotonată în proporţie de 97,6%
Tautomer (b)
Tautomer (a)
O
ONH2
+
O
O
O
ONH
O
O
O
ON
O
O
O
ONH
+
O
O
(a) log D = 1.46 (b) log D = 2.71
Drotaverina
(a) log D = 4.18 (b) log D = 4.44
pH 4.5
pH 9.0
Capitole in monografii (fara acknowledegements):
1.V.David, A.Medvedovici, Chapter: Sample Introduction Techniques for HPLC, in Encyclopedia of Chromatography (Editor. J. Cazes), Francis & Taylor Publications, New York, Vol. 1, p. 2067-2076 (2009).
2.A.Medvedovici, A.Farca, V.David, Chapter 8: Derivatization reactions in liquid chromatography for drug assaying in biological fluids.
Advances in Chromatography (Editori: E.Grushka, N.Grinberg), CRC Press –Francis and Taylor Publications, Boca Raton, USA, vol. 47, 283-322 (2009).
Monografie in Editura Nationala cu mentionarea in Prefata a Proiectului de fata:
1. V.David, A.Medvedovici, Metode de separare si analiza cromatografica, Ed. Universitatii din Bucuresti (2008), ISBN: 978-973-737-590-2.
Conferinte:
1.V.David, Aspecte extra-analitice in cromatografia de lichide, Conferinta la Societatea de Chimie Analitica din Romania (SCAR), 27 feb. 2008.
2.V.David, Modelare in cromatografia de lichide in faza inversa: partitie versusadsorbtie, Conferinta la Universitatea Babes-Bolyai din Cluj-Napoca, 15 aprilie 2008.
3.A.Medvedovici, V.David, V.Voicu, Prediction of the hydrophilic character (as molecular descriptor) for organic compounds from chromatographic retention data under HILIC partition mechanism, 10th International Congress of Clinical Pharmacology, Therapeutics and Toxicology, Sinaia, June 9-12 2009.
Teza de doctorat finalizata:
Mecanismul de retenţie în cromatografia de lichide în fază inversă cu eluţie izocratică.Modelare şi parametri extraanalitici. Drd. Toma Galaon (sustinuta in 26 martie 2010).
Acknowlegements:
The authors acknowledge and they highly appreciate the financial support of this study given by the Romanian Agency CNCSIS for the grant PN2-ID no. 55/2007.
(Journal of Separation Science)
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