ACD/LogD

Technical Information

Introduction

Lipophilicity is a very significant physicochemical property used in different areas of chemistry, medicine, and pharmacology. It is an important indicator of transport and permeation through membranes, interaction with biological receptors and enzymes, toxicity, and biological potency [1, 2]. In environmental sciences, lipophilicity is often used to predict solubility, the bioconcentration factor, and the adsorption coefficient [3].

The octanol-water partition coefficient, P (typically used in its logarithmic form, logP), is a measure of a compound's lipophilicity, which in many cases correlates well with the above chemical and biological properties. ACD/Labs has already become well-established for its unique additive-constitutive algorithm for the prediction of logP, based on the well-characterized logP contributions of separate atoms, structural fragments, and intramolecular interactions between different fragments.

However, logP can be accurately calculated only for uncharged substances. If the chemical compound contains one or more ionizable groups (i.e., functional groups which can easily form ions), it may exist as a mixture of different ionic forms. The composition of this mixture depends strongly on pH.

In such cases, the effective partition coefficient for dissociative systems (octanol-water partition coefficient, logD) gives a more appropriate description of complex partitioning equilibria. In fact, it is a common mistake to quote "logP" values at a fixed pH for a set of compounds. The following scheme presents an example of the complex equilibrium which exists for a solution of alanine in a water-octanol mixture:

K_i - the ionization constant of the i-th microspecies

K_i(org) - the ionization constant of the i-th microspecies in octanol

P_i - the partition coefficient of the i-th microspecies

If such complex equilibrium exists, then the partitioning of chemicals between water and the organic phase must be a function of:

• the extent of ionization and
• the partition constants

of the numerous different microspecies shown in the above diagram. For the alanine species shown, only one equilibration (P₂) actually involves neutral species (logP). All of the others involve partially dissociated species (logD).

These problems have already been addressed, and with a good degree of success, by two ACD/Labs algorithms.

• The acid-base ionization coefficient, pK_a, can be predicted for most functional groups by ACD/pK_a DB
• The octanol-water partition coefficients logP by ACD/LogP DB.

Thus, it only makes sense to combine the capabilities of both "prediction engines" in one simple-to-use prediction of logD: ACD/LogD Suite.

Calculation Theory

The octanol-water distribution coefficient for dissociative mixtures, logD, is defined as follows:

( I )

is the concentration of the i-th microspecies in water, and

is the concentration of the i-th microspecies in organic phase.

For the correct solution of a proposed scheme of equilibrium we use the master equation approach. We construct a system of equations in which the concentrations of all microspecies (both in organic and aqueous phase) are represented by a set of independent linear equations.

To calculate the concentrations of all microspecies at any pH we need to solve the following system of equations:

( II )

K_i - the ionization constant of the i-th microspecies, K_i = 10 ^{- pKa}

P_i - the partition coefficient of the i-th microspecies

a_i - the total concentration of the i-th microspecies in both H₂O and octanol

a_j - the total concentration of the j-th microspecies having one more H⁺
      than the i-th.

Once the concentrations are known, the ratio in equation (I) can be easily determined and thus the logD value.

Calculation of LogP for microspecies

To calculate the logP of the neutral form of a given chemical structure, ACD/LogD applies its unique additive-constitutive algorithm. It is based on the well characterized contributions to logP of separate atoms, structural fragments, and intramolecular interactions between different fragments.

Further details may be found in the ACD/LogP DB documentation.

To calculate logP of the charged microspecies certain empirical rules are applied. Different corrections to the logP values of neutral form are applied, depending on the charge of the microspecies. For example, for zwitterions an adjustment of -2.5 is made for logP of the neutral form.

Ionization constants of microspecies

To calculate the ionization constants of microspecies, the program creates a full scheme of the dissociation of the compound. All microconstants are then calculated by an algorithm based on

• Hammett equations and corresponding core fragments
• Additional core fragments for initial pK_a (pK_ao) estimation
• Electronic constants for substituents
• Some special methods for the calculation of electronic constants

These special methods are related to the prediction of poly- and heteroaromatics (Dewar-Grisdale method) and prediction transmission of nonaromatic rings (Exner-Fiedler method).

Further details for the prediction of ionization constants of microspecies may be found in the ACD/pK_a DB documentation.

1. "Handbook of Chemical Property Estimation", American Chemical Society, Washington, DC, 1990.

2. Hansch, C., J.E. Quinlan and G.L. Lawrence, "The Linear Free-Energy Relationships between Partition Coefficients and the Aqueous Solubility of Organic Liquids," J. Org. Chem., 33, 347-50 (1968).

3. Veith, G.D., K.J. Macek, S.R. Petrocelli and J. Carroll, "An Evaluation of Using Partition Coefficients and Water Solubility to Estimate Bioconcentration factors for Organic Chemicals in Fish," J. Fish. Res. Board Can. (1980) (Preprint).