logD values for basic compounds @ pH 2 units below pKa

User 5508363905

19-02-2006 00:04:36

Does anyone know if there are guidelines concernng these use of log D for basic compounds when the pH is more than 2 units below the pKa of the compound. I am a chromatographer and use logD as an indicator of hydrophobicity at different pHs. However, the logD continues to decrease when the pH is more than 2 units below the pKa. The percent ionization is changing little to none beyond that point so why does the logD continue to decrease? I've seen the simple equations for calculating logD and know why this happens mathematically. Is the continued decrease meaningful or a known limitation in the use of logD?

User 851ac690a0

20-02-2006 09:44:46

Dear Carls,

As far as basic compound is considered I can say that when the pH is well below of the pKa then molecule is 100% ionized and logD is equal with the ionic logP(i). When the pH is well above of the pKa then molecule is neutral and logD is equal with the neutral logP(n).

logD as function of pH is changing between these two limits, namely logP(n) and logP(i).

When the pH is below of the basic pKa then logD is decreasing while asymptotically reaches the logP(i) value,

and logD is increasing when the pH is above of the basic pKa.

This characteristic of logD curve can be explained with the partition contribution of the ionized species to logD.

Some references for logD:

Pagliara et.al., Chem. Rev., 1997, 97, 3388

Clarke et al., J.Pharm.Sci., 1987, 76, 611

http://www.chemaxon.com/conf/Prediction_of_distribution_coefficient_using_microconstants.pdf

Jozsi

User 5508363905

21-02-2006 17:22:42

"As far as basic compound is considered I can say that when the pH is well below of the pKa then molecule is 100% ionized and logD is equal with the ionic logP(i). When the pH is well above of the pKa then molecule is neutral and logD is equal with the neutral logP(n). "

I agree, however, the predictions for logD seem to contradict this logic unless I'm missing something.

For example, use pseudoephedrine (CAS#90-82-4). The predicted basic pKa is 9.48. At pH 7.4 the molecule is ~99+% ionized but the logD is still decreasing at a high and ~constant rate all the way down to pH ~5. The % ionization has increased by <1% but the log D has decreased another 2.3 units (pH 7.4 logD = -0.47, pH 5 logD = -2.74). Additionally, at pH 6.6 the logD is -1.26 and the molecule is 99.9% ionized. At pH 5.6 the logD is -2.23 and the molecule is 99.99% ionized. So an additional 0.1% ionization has given a logD decrease of ~-1. This does not make intuitive sense.

Are these changes in line with the intended use of logD (biological systems?

It certainly is not supported by chromatographic behavior.

User 851ac690a0

21-02-2006 23:49:04

Dear Carl,

I have reproduced the equation of "D" for a basic molecule from ref. Clarke et al., J.Pharm.Sci., 1987, 76, 611.

If Pn>>Pi then contribution of the ionized species to the ‘D’ could be damped even if the molecule is significantly ionized at a given pH.

For 'pseudoephedrine' it holds that Pn>>Pi, therefore, you could find that the logD decreased under extreme ionization conditions. (I don’t know what was the ionic strength you used.)

I think that the logD was DEFINED to satisfy certain practical purposes as well.

Yes, predicted logD can be a useful parameter for biological systems, but of course it has limitations.

Please note that logP and logD are calculated between water and octanol binary systems. pKa is calculated in water. Probably these are not always appropiate for chromatographic purposes depending from the circumstances (colunm coating, composition of mobile phase, etc.).

Jozsi

ChemAxon 43e6884a7a

22-02-2006 07:27:18

When I examined this problem many years ago, ionic species needed special care in reversed phase HPLC, because for example cations interacted with the silanol groups in the column. Technology may have changed, but I guess this is still a complex issue.

User 5508363905

22-02-2006 17:20:03

Here is the problem is see with logD, esp in chromatography:

pseudoephedrine (CAS#90-82-4)

The predicted basic pKa = 9.48

logD (pH 9.5) = 1.32 (50% ionized)

logD (pH 7.4) = -0.47 (99+% ionized)

logD (pH 6.6) = -1.26 (99.9% ionized)

logD (pH 5.6) = -2.23 (99.99% ionized)

The large changes in logD with small changes in % ionization do not make sense.

In chromatography, retention typically follows:

r=10^pH-pK/1+10pH-pK

which is essentially the % ionizatin of the molecule.

As you can see from the example, logD does not follow the % ionization of the molecule.

Ion exchange with the support is a different topic. I'm investigating the utility of using logD in chromatography and trying to reconcile the difference between it and % ionization. This discrepancy applies to acidic as well as basic compounds.

User 851ac690a0

23-02-2006 18:45:11

Dear Carl,

"The large changes in logD with small changes in % ionization do not make sense."

If you try the equation I attached in my previous answer you will get almost the same results for logD.

I think logarithm of the retention factor/time can be correlated with logD at given pH.

References:

K. Valkó, J. Liq. Chromatogr., 7 (1984) 1405.

http://wwwsoc.nii.ac.jp/jsac/analsci/ICAS2001/pdfs/0200/0217_3e09n.pdf

Jozsi