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Partitioning (logP or logD)—are you using/measuring the right descriptor?

by Sanji Bhal, Director of Marketing & Communications (ACD/Labs)

Bubbles (logP)In my past life, before ACD/Labs, I was an organic/medicinal chemist. I share this because it’s relevant to the topic. My first responsibility at ACD/Labs was to create materials to support our PhysChem product line. Many of the descriptors that made up the products I was charged with talking about—such as pKa, solubility, etc.—were first introduced to me by Mr. Jackson, my chemistry teacher in secondary school (high school). The others I learned about during my BSc and PhD—logP (from Lipinski’s rule-of-5), for example. I will confess, however, that when I was asked in my interview how I applied/considered logD values in my research I was completely stumped. What’s logD? I’d never heard of it!

Once it was explained to me it made total sense. If logP describes the differential solubility of a compound in two immiscible solvents, and the majority of compounds investigated in pharmaceutical research contain ionizable sites, then it’s not logP we should be concerned about, but logD (which describes the distribution of the various ionized species at any given pH). In fact logP (applicable only for neutral, uncharged molecules) is hardly applicable in pharmaceutical R&D.

Unfortunately, over the years I learned that I wasn’t the only one who didn’t understand the importance of logD. Perhaps if Dr. Lipinski had referred to logD instead of logP and lauded its importance in his ‘rule-of-5’ I wouldn’t be writing this. It seems even today many chemists either use the terms interchangeably or simply refer to logD measurements, incorrectly, as logP. Let me use an example to illustrate the difference between these two partitioning descriptors.

Let’s take the changing pH environment for orally administered Omeprazole (5-Methoxy-2-(1-piperidin-4-ylpropyl)pyridine) in the gastrointestinal (GI) tract. This drug has two ionization centers (pyridine pKa 4.8; piperidine pKa 10.9). Figure 2 illustrates the pH profile of Omeprazole and Figure 3 shows changing ionic forms with pH.

Logd_1

Figure 1 Changing pH environment in the GI tract.

Logd_2

Figure 2 The logD curve of Omeprazole.

Logd_3

Figure 3 The changing ionic forms of Omeprazole with pH.

The plot of logD versus pH illustrates that ionization of Omeprazole greatly affects octanol-water partitioning and that lipophilicity cannot be simplified to a constant. The conclusion we draw from predicting the logD profile is contradictory to that derived from looking at logP alone. Negative values of logD (-1.44 to 0) in the physiologically relevant pH range (pH 1–8) show that Omeprazole would be more susceptible to higher aqueous solubility and lower lipophilicity in the body and, therefore, we would expect membrane permeability to be poor.

While this example is in drug discovery, the reasoning is equally relevant for other areas of research. In environmental chemistry, the presence of different ionic species of a compound is relevant when studying the behavior of chemicals affected by the pH of different soil or acid rain.

Finally, while it’s important to understand the implications of pH when predicting compound behavior, it is equally critical that the difference between logP and logD is understood for experimental measurements. Scientists must take great care in the measurement of logP at a pH where the compound exists in its neutral form (>pH 12 in the case of Omeprazole) and/or report logD at a specific pH to accurately measure and report lipophilicity.

Comments

novi1

do you think that molecule is the omeprazole? I'm a novice and I couldnt find such molecule from wikipedia.. with that structure

Sanji Bhal

Hi Navi, sorry for the belated response. There is a mistake in the graphic and the molecule shown is not omeprazole which has an S=O moeity in it. The graphs are of Omeprazole behaviour though. Thank you for pointing out our mistake

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