Anal. Chem. 1992, 64, 1345-1349
1345
Novel Computational Method for the Determination of Partition Coefficients by Planar Chromatography Aaron D. Kossoy*and Donald S. Risley Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285
Robert M. Kleyle Department of Mathematical Sciences] Indiana University-Purdue University at Indianapolis, Indianapolis] Indiana 46205
David Nurok' Department of Chemistry, Indiana University-Purdue University at Indianapolis, Indianapolis, Indiana 46205
An emplrlcal method for the determination of log Pvalues by elther overpremuredlayer chromatography or thln-layer chromatography Is dercrlbed, udng bonded Coplatesand aqueous methanol. Tho method Is based on the Socrewlnskl equatlon and elther uses standards to deflne a solvent composition at whlch RM Is q u a l to log P or uses a serles of standards at an arbltrary solvent compositlon to deflne a callbratlon curve for rdatlng RM to log P. The correlatlon coefflcknts ( I ) are In the range 0.866-0.980 for the comparlron of Rrr to log P obtalned by elther the shake flask method or as detennlned by hlgh-performance llquld chromatography.
INTRODUCTION Partition coefficients-usually expressed as log P values-have been used for almost a century as measures of lipophilicity.1 Traditionally, these physical constants have been obtained by partitioning analytes between an aqueous and an immiscible organic phase-usually n-octanol-in a shake flask. Sample throughput is generally slow and problems are often encountered that include association, adsorption, micelle and/or emulsion formation, and impurity effecta.2 An additional shortcoming of this method is ita limitationtolog Pvaluesof a b o u t 4 5 toabout +4.5,2although alternate procedures involving either slow stirring3 or generator columns4 have been used in a limited number of cases to extend this method to include more lipophilic analytes. These difficulties and limitations have stimulated the development of alternative approaches. Computational methods have been introduced that yield calculated log P values as the summation of group ( T ) or fragment (f) contributions.5~6These procedures are often quite s u c c e ~ s f u 1 in , ~ ~spite of difficulties that arise where complex intramolecular interactions are present. (1)Leo, A.; Hansch, C.; Elkins, D. Chem. Reu. 1971,71, 525-616. (2)Dearden, J. C.; Bresnen, G. M. Quant. Struct.-Act.Relat. 1988,7, 133-144. (3)Dick,S.T.H.M.; Wever,H.;deVries,P. J.;Opperhuizen,A. Chemosphere 1989,19,263-266. (4)Hawker, D.W.;Connell, D. W. Enuiron. Sci. Technol. 1988, 22, 382-387. ( 5 ) Fujita, T.; Iwasa, J.; Hansch, C. J. Am. Chem. SOC. 1964,86,51755180. (6)Rekker,R. F. TheHydrophobicFragment Constant;Elsevier: New York, 1977. (7)Lyman, W. J.;Rechl, W. F.; Rosenblatt, D. H.Handbook of Chemical Property Estimation Methods; McGraw-Hill: New York, 1982;Section 1, pp 1-38. (8) Kakoulidou, A.; Rekker, R. F. J. Chromatogr. 1984,295,341-353. (9)Koopmans, R. E.; Rekker, R. F. J. Chromatogr. 1984,285,267-279.
Thin-layer chromatography (TLC) and high-performance liquid chromatography (HPLC) are the most widely used chromatographic alternatives to the shake flask method, but other related methods such as droplet countercurrent chromatography'o and centrifugal partition chromatography11 have also been used. The use of TLC and HPLC is based on the assumed linear relationship between the logarithm of the chromatographic capacity factor (log k' for HPLC and RMfor TLC) and log P.lz RM is defined as R M = log ( l / R f -1)
(1)
where R, is the retardation factor. (A strong case can be made for using log k' instead of RM,as this emphasizes the essential similarity between TLC and HPLC. However, the RM nomenclature has been used for all previous TLC correlations with log P and in this paper the convention is followed that log k' refers only to HPLC.) Representative reports of the use of RMfor correlations in TLC for the determination of log P are by Hulshoff and Perrin,13Biagi and co-workers,l4 Tsantili-Kakoulidou and Antoniad~u-Vyza,~~ Renberg and co-workers,l6Birdand Marshall,17and de Voogt and co-workers.18 The use of the correlation for the determination of log P by HPLC has been summarized in a recent book19 and review.20 A similar linear correlation exista also between RM and log P calculated using either the group constant, T ,or the fragment constant, f; representative studies include those by Guerra and co-workers,21Hulshoff and Perrin,22and Biagi and c o - w o r k e r ~ . ~ ~ (10)Gago, F.; Alvarez-Builla, J.; Elguero, J. J. Chromatogr. 1986,360, 247-251. (11)Gluck, S.J.; Martin, E. J. J. Liq. Chromatogr. 1990,13, 25292551. (12)Boyce, C.B. C.; Milborrow, B. V. Nature 1965,208,537-539. (13)Hulshoff, A.; Perrin, J. H. J. Med. Chem. 1977,20, 430-439. (14)Biagi, J. L.;Guerra, M. C.; Barbaro, A. M.; Barbieri, S.; Recanatini, M.; Borea, P. A.; Pietrogrande, M. C. J. Chromatogr. 1990,498, 179-190. (15)Tsantili-Kakoulidou, A.: Antoniadou-Vvza, A. J. Chromatom. 1988,445,317-326. (16)Renbera, L. 0.: Sundstrom. S. G.: Rosen-Olofsson, A . 4 . Toxicol. Enuiron. Che& 1985,10,333-349. (17)Bird, A. E.;Marshall, A. C. J. Chromatogr. 1971,63,313-319. (18)de Vwgt, P.; van Zijl, G. A.; Govers, H.; Brinkman, U. A. Th. J. Planar Chromatogr. 1990,3,24-33. (19)Kaliszan, R.Quantitative Structure-ChromatographicRetention Relationships; Chemical Analysis, Volume 93;Wiley: New York, 1987; Chapter 11. (20)Hafkenscheid, T. L.;Tomlinson, E. In Aduances in Chromatography; Giddings, J. C., Grushka, E., Cazes, J., Brown, P. R., Eds.; Marcel Dekker: New York, 1986;Vol. 25,pp 1-35. 0 lQ92 American Chemical Sockty
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ANALYTICAL CHEMISTRY, VOL. 64, NO. 13, JULY 1, 1992
Chromatographic determinations of partition coefficients are usually performed in the reversed-phase mode, with bonded C8 or CIS being the widely used stationary phases, even though bonded Cz has been used24 in a comparative study of different phases. Acetonitrile or methanolare widely used organic modifiers for this purpose in both TLC and HPLC. The use of reversed-phase ion-pair systems for strongly ionized solutes has been described.26 The retention of analytes can be determined a t a fixed arbitrary solvent composition2'j-28but are generally considered to have a better correlation with log P when determinedover a range of solvent compositions and extrapolated to 0 % organic modifier; using either the assumed linear relationship between log k' (HPLC) or RM (TLC) and the volume percentage of the organic modifier. However there are systems which are linear only over a limited range of solvent composition or which fit a quadratic function better than a linear one. Representative examples of the respective cases are given in refs 29 and 30. An alternative linear relationship that exists in HPLC and TLC and that is usually valid for a mobile phase that consists of a binary mixture of a strong and weak solvent is
R , = a log X,+ b where a and b are empirical constants and X,is the mole fraction of the strong solvent. This equation was originally introduced by S o c z e w i n ~ k i ~ ~ but, as noted by that author, can also be considered as a special case of an equation derived by Snyder32for normalphase systems. More recently it has been applied to reversedphase s y ~ t e m s . ~ The ~ , ~ *equation obviously cannot be used to extrapolate to 0 % strong solvent because of its logarithmic nature. However, in principle, a value of X,could be selected such that the value of RMcorresponds to log P for a suitable standard. It seems reasonable to expect that, a t this value of Xs,the equation can be used to estimate log P values for other compounds of the same structural class. The use of this approach is discussed below with reference to both TLC and overpressured layer chromatography (OPLC) which is a forced-flow mode of planar chromatography.
EXPERIMENTAL SECTION OPLC was performed in a Chrompres 25 (Labor MIM, Budapest, Hungary) system using 20- X 20-cm reversed-phase plates containinga fluorescentindicator ( K C 8plates, CatalogNo. 4808820, Whatman Inc., Clifton, NJ). Silicone I1 (General Electric Co., Waterford,NY) wasusedastheplateedgesealant. Detection was in the fluorescenceshadowing mode using a hand-held 254nm UV source. TLC was performed in a flat-bottom chamber (CamagScientific Inc., Wilmington,NC), with 20- X 20-cm K C P plates and the same mobile phase as used for the corresponding measurements by OPLC. (21) Guerra, M. C.; Barbaro, A. M.; Biagi, G. L.; Pietrogrande, M. C.; Borea, P. A.; Andreani, A.; Cantelli-Forti,G. J. Chromatogr. 1985,320, 281-291. (22) Hulshoff, A.; Perrin, J. H. J. Chromatogr. 1976, 120, 65-80. (23) Biagi, G. L.; Guerra, C. M.; Barbaro, A. M. J . Med. Chem. 1970, 13, 944-948. (24) Cserhati, T.; Kiss-Tamas, A.; Mikite, Gy. Chromatographia 1988, 25,82-86. (25) Pietrogrande, C.; Borea, P. A.; Lodi, G.; Bighi, C.; Chromatographia 1987, 23, 713-716. (26) Thus, J. L. G.; Kraak, J. C. J. Chromatogr. 1985, 320, 271-279. (27) Eadsforth, C. V. Pestic. Sci. 1986,17, 311-325. (28) Klein, W.; Kordel, W.; Weiss, M.; Poremski, H. J. Chemosphere 1988,17,361-386. (29) Garst, J. E.; Wilson, W. C. J. Pharm. Sci. 1984, 73, 1616-1623. (30) Dorsey, J. G. Chromatography 1987,2, 37-41. (31) Soczewinski, E.Anal. Chen. 1969, 41, 179-182. (32) Snyder,L. R. Principles of Adsorption Chromatography;Marcel Dekker: New York, 1968. (33) Soczewinski, E. J. Chromatogr. 1987, 388.91-98. (34) Habibi-Goudani,S.;Ruterbories,K. J.; Steinbrunner,J.E.;Nurok, D. J. Planar Chromatogr. 1988,1, 161-167.
Table I. Phenols ~~
Reb
compd
OPLC
R&c TLC
1.80
OH
CI
slopee
intercepte
1.58
-1.817 -1.610
-0.7699 -0.7019
2.40
-2.127 -2.621
-0.7224 0.8424
2.35
-2.098
-0.6487
2.54
-2.199 -2.666
-0.7667 -0.8224
2.63
-2.172 -2.731
-0.7020 -0.8093
2.26
-2.501 -2.817
-0.6066 -0.8204
4.23
-2.826 -3.832
4,4870 -0,7479
1.32
2.27 D
logpd
O
OH
2.00
H
2.30
2.33 2.53 Br
&
2.36 2.62
Br
2.91 2.72
OH
3.49 4.06
Br*Br Br
*
RMvalues from eq 2. Midrange log X. = -1.4079. Methanol/ M aqueous trifluoroacetic acid as mobile phase. RM values from eq 2. Midrange log X,= -1.2555. logP by shakeflask. Values a
0.004
are from ref 38. e Slope and intercept in eq 2.
The HPLC system consisted of two pumps (Model 110,Beckman Instruments, Berkeley, CAI, a controller (Model 4, Beckman Instruments, Berkeley,CA),an injection valve (Mode17125, Rheodyne Inc., Cotati, CA), and a UV detector (Spectroflow Model 757, Kratos Analytical, Ramsey, NJ)operated at 280 nm. The columns (Aquaporeseries, Brownlee Labs Inc., Santa Clara, CA) were 46 X 150 mm and contained a 7-pm wide pore (3004) bonded CSpacking. Nicotinic acid hydrazide N-oxide was used as the void volume marker.29 Aqueousmethanol,with the aqueouscomponent0.5 M in NaC1, was used as the mobilephase for OPLC. Either aqueousmethanol or, for solutes with log P > 9.0, aqueous methanol/ethanol (50% v/v), was the mobilephase for HPLC. Trifluoroaceticacid (0.004 M) for the acidic solutes or triethylamine (0.035 M) for the basic and neutral compoundswas added to the aqueous component as suggested by Garst and Wilson for HPLC.29 For OPLC each solvent system was run at five mole fractions and the results for each solute were fitted to eq 2. All results reported are derived from data with a value ofR2of 0.99 or better. For HPLC the columns were calibrated with halophenols of known shake flaskvalues and fitted to eq 3 (see below) for which an R2 value of 0.96 was obtained. The leukotriene antagonists were synthesized at Eli Lilly and Co. and have been described previously.36@The phenols, quinolines, and miscellaneousneutral compoundsreported in Tables 1-111 as well as trifluoracetic acid, the various halophenols, and nicotinic acid hydrazide N-oxide were purchased from Aldrich Chemical (Milwaukee, WI). Methanol and 95% ethanol were purchased from Baxter Burdick and Jackson (Muskegon,MI); sodium chloride and triethylamine were purchased from EM Science (Cherry Hill, NJ). ~
(35) Bollinger, N. G.; Goodson, T.; Herron, D. K., Eur.Pat. 276065, 1988; Chem. Abstr. 1988,109,230544d. (36) Gapinski,D. M. Eur.Pat. 276064,1988; Chem. Abstr. 1989,110, 94687~.
ANALYTICAL CHEMISTRY, VOL. 64, NO. 13, JULY 1, 1992
Table 11. Quinolines compd R&’b OPLC
log F
sloped
interceptd
WNH2
1.63
-2.247
-1.0645
“’a3
2.57
-2.519
-0.7748
2.20
-2.464
-0.7051
1.56
2‘17
“30m
Figure 1. Leukotriene antagonists of structures I and I1 (left and right). See Tables IV and V for the respective structures of R.
Table IV. Leukotriene Antagonists of Structure I RMw
2.18 2.26
1.86
-2.639
R
-0.8243
HN-N
-~
m
CF3
3.01
2.73
-3.310
-0.8568
3.35
3.02
-3.626
-0.8923
2
CH3-
3.90
AN/!!
)
4.27
-4.387 -3.8218
-1.2381 -1.0265
4.41
-3.803 -4.040
-1.1658 -0.9375
5.37
-4.956 -4.737
-0.8153 -0.7017
5.00
-5.064 -4.673
-0.8309 -0,6992
5.62
-5.557 -5.6667
-1.0996 -1.0888
5.43
-5.636 -5.216 -6.547 -5.762
-0.9265 -0.7779 -0.8328 -0.6484
3.88
r
N-N
AN/!! -(CH34
4.46 4.25 4.99 5.38
N
5.10
Table 111. Neutral Compounds compd R e b OPLC log F
5.41
0 11
1.71
1.58
sloped interceptd -2.322
mBr B
4.10
Br
6.19 5.67 5.92 6.83
3.64
-4.200
-0.7157
3.87
3.79
-3.907
-0,6135
4.90
4.51
-4.732
-0.5333
r
nBr
5.31
-0.9578
mNHCCH3
Cg,O-
Br
RMb,c
OPLC TLC logWd slopee intercepte
a RMvalues from eq 2. Midrange log X , = -1.1690. Methanol/ 0.035 M aqueous triethylamine as mobile phase. log P by shake flask. Values are from ref 38. d Slope and intercept in eq 2.
W
1347
6.28 6.76
a RM values from eq 2. Midrange log X, = -1.1709. RM values from eq 2. Midrange log X , = -1.2853. Methano1/0.004 M aqueous trifluoroacetic acid as mobile phase. d log P values from eq 3, with V cobtained ~ from HPLC data. e Slope and intercept in eq 2.
3 h for TLC when the same development distance is used. Chromatographic efficiency is also substantially greater for Brf i B r OPLC than for TLC due to solvent flow being closer to 5.46 6.03 -5.186 -0.4926 optimum. For these reasons OPLC was selected as the experimental technique in an initial study. A comparison of results obtained by OPLC and TLC are included for two of the five series of compounds studied in response to a RMvalues from eq 2. Midrange log X,= -1.1472. * Methanol/ suggestion by the editor. 0.035 M aqueous triethylamine as mobile phase. log P by shake The initial study included groups of phenols, quinolines, flask. Values are from ref 38. Slope and intercept in eq 2. and neutral compounds (see Tables 1-111) for which the corresponding shake flask values are available.38 An additive RESULTS AND DISCUSSION (see Experimental Section) of either trifluoroacetic acid for the phenols or triethylamine for the quinolines or neutrals For any given compound the value of RM in eq 2 can be was used. The value of X, in eq 2 was arrived at by two made equal to the corresponding value of log P, by inserting different methods. In the first method a value of log X,was an appropriate value of X,,providing the empirical constants calculated for each compound, such that RM was equal to the a and b are known. It was assumed, as a hypothesis, that this corresponding log P value. For each series of compounds, value of X,in eq 2 would be very similar for all members of the highest and lowest of these log X,values was averaged a group of compounds. to yield a midrange value which was then used to calculate Both OPLC and TLC were used to test this hypothesis. The former technique, introduced by Tyihak and c o - ~ o r k e r s , ~ ~ the log Pvalue for each compound in the series. The rationale for this procedure is to utilize a region of the RM-X, plane is a forced-flow method where the TLC plate is covered by such that the RM values obtained are close to those of the a pressurized flexible membrane and the mobile phase is corresponding log P values. However, it is not necessarily pumped through the layer. Separation is substantially more assumed that a linear relationship between RM and log P will rapid in OPLC than in TLC. This is of consequence when have a slope of 1and an intercept of 0. These conjectures are working with aqueous methanol and bonded Cs plates where discussed later in the paper, and these results are listed in analysis time for OPLC is about 10min as compared to about (37) Tyihak,E.; Mincsovics, E.; Kalasz, H. J . Chromatogr. 1979,174,
75-81.
(38) Hansch, C.; Leo, A. Pomona College Medicinal Data Base, MED-
CHEM, ver. 3.53. Claremont, CA.
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ANALYTICAL CHEMISTRY, VOL. 64, NO. 13, JULY 1, 1992
Table V. Leukotriene Antagonists of Structure I1 R
-CHzCH,
- (CHzhCH,
OPLC 5.70
R M O S ~
log p b - c 5.40
log p b * d
RM OPLCc*e 0.17
slop$ -4.472
interceptf -2.0446
6.38
6.77
0.60
-4.669
-1.7062
7.74
7.82
1.06
-5.402
-1.6120
8.17
8.11
1.28
-5.571
-1.4720
8.75
8.57
1.37
-5.974
-1.5876
9.34
9.12
8.72
1.64
-6.229
-1.4475
9.28
1.84
-6.479
-1.3673
9.85 10.48
10.09
9.55
1.96
-6.895
-1.4532
10.52
9.29
9.17
1.89
-6.975
-1.5591
10.69
10.40
2.57
-6.558
4.6775
10.87
10.18
2.30
-6.935
-1.1342
0 RMvalues from eq 2. Midrange log X,= -1.7312. log Pvalues from eq 3, with V,, obtained from HPLC data. Methano1/0.004 M aqueous trifluoroacetic acid as mobile phase. Methanobethano1 (5050)/0.004 M aqueous trifluoroacetic acid as mobile phase. e RMvalues from eq 2, with X, = 0.32. f Slope and intercept in eq 2.
Tables 1-111. The alternative method differed in that a representative compound, selected in an arbitrary manner, was used to determine log X,for each series. Using either method of calculation, the difference between log P and the calculated RM value based on OPLC was less than 0.5 of a unit for all but three of the eighteen compounds tested. p-Ethylphenol was one of the three anomalous compounds by either method, with the remaining two anomalous compounds being different in each method. RM values for the phenols by TLC-the quinolines and neutrals were not determined in this mode-exhibit a difference between log P and calculated RM within 0.5 unit by either method. In order to further define the scope of the method, it was employed with the two series of leukotriene antagonists of structures I and I1 shown in Figure 1. The log P values for most of these compounds are sufficiently high to preclude determination by the shake flask method. Therefore the values were obtained by reversed-phase HPLC with a bonded Cs column with the same mobile phase used for the phenols (i.e., using aqueous methanol with trifluoroacetic acid as the additive) as originally suggested.29 Equation 3 wm established using five halophenols with known shake flask values as calibrants (2,4-dibromophenol,3.22; 3,4,5-trichlorophenol,4.15; pentachlorophenol, 5.18; pentabromophenol, 5.30; hexachlorophene, 7.45) and had a good experimental fit with an r of 0.98 log P = 1.13 log V,,+ 0.79 (3) where V , is the corrected retention volume.29 The log Pvalues of the leukotriene antagonists were calculated from the retention volumes on the same column. The results for OPLC are listed in Tables IV and V. The
agreement between RMand log P varies from 0.06 to 0.69 log unit for 17 of the 18 compounds. The remaining compound exhibits a difference of 1.23 or 1.35 log units (depending on which HPLC value was used) between the two parameters; the source of the discrepancy is unknown. The TLC results are included in Table IV and exhibit a comparable range of agreement between RM and log P (0.01-0.57) to that found for OPLC. The method described above assumes a linear relationship-with a slope of unity and an intercept of zero-between RM and log P a t an appropriate solvent composition. While most chromatographic methods yield a linear relationship between RM (or log k’ and log P, the slope and intercept are generally not unity and zero, respectively. The only exception is for chromatography under conditions which closely mimic those of shake flask determinations, i.e. using stationary phases impregnated with octan01 or silicone oil. However, even under these conditions, while the slopes are very close to unity, the intercepts are not zero; see, e.g., ref 39. In order to test the significance of the current results, the slope and intercept values were each used as the null hypotheses in a separate statistical test. The relevantp values are listed in Table VI, together with other relevant statistics. T h e p value is the smallest significancelevel at which the null hypothesis can be rejected and is in effect a measure of its validity. The higher the p value, the greater the confidence in the null hypothesis. It is interesting to note that for a given system, the p values are of the same magnitude for the slope and intercept tests. The analysis indicates that, for two of these systems, the slope is most probably unity and (39) Mirlees,M.S.;Moulton, S. J.;Murphy,C. T.;Taylor,P.J. J. Med. Chem. 1976,19, 615-619.
ANALYTICAL CHEMISTRY, VOL. 64, NO. 13, JULY 1, 1992
1349
Table VI. Statistics
phenols in Table I by OPLCn phenols in Table I by TLCa quinolines in Table I1 by OPLCO neutral compds in Table I11by OPLCn leukotriene ktagonista of structure I in Table IV bv OPLCb leukotriene anta-gonists of structure I in Table IV by TLCb leukotriene antagonists of structure I1 in Table V by OPLCb
std error of regression
p valuec
slope
p valuec intercept
0.299 0.331 0.338 0.398 0.315
0.041 0.911 0.793 0.351 0.206
0.058 0.977 0.904 0.309 0.208
judgement on hypotheses tested both probably false both probably correct both probably correct both inconclusive both inconclusive
0.980
0.223
0.020
0.027
both probably false
0.978
0.388
0.124
0.252
both inconclusive
slope
intercept
0.5852 0.9800 1.0798 0.8640 1.2663
0.9906 -0.0141 -0.0868 0.6285 -1.3871
r 0.866 0.946 0.885 0.971 0.951
1.4385
-2.0903
1.1356
-0.8575
Correlation between RM and log P by shake flask. Correlation between RM and log P by HPLC. Hypotheses tested are slope = 1.0, intercept = 0 in linear correlation between R M and log P. the intercept zero. For two other systems, the slope and intercept are significantly different from unity and zero, respectively. The results for the remaining three systems are inconclusive. It is not possibleto state whether the variability in significance of the slope and intercept value is due to the nature of the systems used or is simply a manifestation of the rather small number of compounds in each series. The utility of this approach is not dependent on the value of the above slope and intercept. If the relevant values are indeed unity and zero respectively, then the appropriate RM values can be used as estimates of log P. However, for those systems where the values are significantly different from unity and zero, respectively, the appropriate value of log P for a compound can be estimated from the relevant regression equation. The data in Tables I, IV, and VI indicate that both OPLC and TLC yield comparable results. The difference in development time between the two techniques is not significant, as TLC chambers are inexpensive and development with different solvent compositions can proceed in parallel.
A N ALTERNATIVE APPROACH The preceding approach-referred to hereafter as method I-uses standards to define a solvent composition that in turn defines R M values using eq 2. An alternative approach-referred to as method 11-is to determine the correlation between RM and log P a t an arbitrary solvent composition for all solutes of a given structural type. As an example, the 11leukotriene antagonists of structure I1 have RM values at a methanol mole fraction of 0.32 (Table V) that are substantially lower than, but which nevertheless correlate strongly with, the corresponding log P values (F = 0.983).
This correlation coefficient compares favorably to correlation coefficients between log P and RM,or between RM and log P, reported by other authors.18925940 Such a correlation indicates that regressiontechniques can be used to estimate log Pvaluea for other members of the same class of compounds. The procedure would be very rapid because, for OPLC, 36 compounds can be run in parallel on a single high-performance plate and only one solvent composition need be considered because Rf values can be accurately measured at this mole fraction. In practice several standards might be included on the plate and duplicate spotting of compounds of interest could be performed in order to improve accuracy. This would decrease the number of compounds determined in a run but would still result in a rapid analysis time per sample. The two methods are complementary. Method I is useful when log P needs to be determined for only a few compounds or when only one or two calibration standards are available. Method I1 should be useful where sufficient calibration standards are available and where log P values need to be determined for a large number of compounds.
ACKNOWLEDGMENT D.N. thanks Whatman Inc. for a gift of KC$ reversedphase thin-layer plates.
RECEIVED for review December 10, 1991. Accepted March 31, 1992. (40) Barbaro, A. M.; Guerra, M. C.; Biagi, G. L.; Pietrogrande,M. C.; Borea, P. A. J . Chromatog. 1986,347, 209-218.
