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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)


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


Cap

acity

fact

or


Tropicamide


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



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


Cap

acity

fact

or



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


Cap

acity

fact

or



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


Cap

acity

fact

or



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


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


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-methylpyridin-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 )


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


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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