ACD/LogD
vs. Competition
See how misleading an official reference can be...
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Ask yourself: what is it that you
are really interested in. Is it actually the logP? Remember, the
partition coefficient, logP, is technically defined only for the
neutral form of the molecule.
But is it really the logP
that you need? Even though some pharmaceutical compendia list "logP" for a compound, they will often list it at a specified pH
(most often the blood pH). This is actually logD that they are
quoting.
At a pH of 7.4 or 7.0, many
molecules exist in a partially-dissociated or ionized form. This
is not a surprise, because most drugs are designed to be taken up
into the aqueous layer, and water (a polar solvent) readily
dissolves ionic forms.
Clearly, the pharmaceutical
compendia are listing a values of great physiological relevance
when they state "logP (pH = 7.4)." We just want to warn
you that appearances are deceiving, and this is a different
partition coefficient from the actual "neutral form" logP of physical chemistry.
ACD/LogD
clarifies matters enormously. It utilizes two popular ACD/Labs algorithms
- and their databases - with already-proven success:
pKa - to determine the
extent of acid-base ionization of a compound; and
logP - to determine the
relative hydrophilicity of the compound and its ionic forms.
What is called "LogP" is
often really "LogD"
As examples of where
you can go wrong by confusing LogP and LogD determinations:
| Drug Name and Structure |
Pharmacopoeia "LogP (at pH...)" |
ACD/LogP |
ACD/LogD at pH 7.4 |
| alprenolol
|
0.5 (at pH 7.0) |
2.88
±
0.26 |
0.76 (at pH 7.0) |
| amantadine
|
-0.4 (at pH 7.4) |
2.22
±
0.24 |
-0.69 |
| clomipramine
|
3.3 (at pH 7.4) |
5.53
±
0.51 |
3.50 |
| diazepam
|
2.7 (at pH 7.4) |
2.96
±
0.55 |
2.96 |
| diphenhydramine
|
3.3 (no pH listed) |
3.66
±
0.37 |
2.29 |
| ethopropazine
|
4.8
(no pH listed)
(note: listed as 3.48 at pH 7.8 in the
ACD/LogP database) |
5.84
±
0.32 |
3.45 |
| hydroquinone
|
0.6 (at pH 7.4) |
0.64
±
0.20 |
0.64 |
| isoniazid
|
-1.1 (at pH 7.4) |
-0.89
±
0.24 |
-0.89 |
These
are but a few of the compounds for which partition coefficients are
even listed.
Consider the following points
carefully when you are deciding whether to purchase ACD/LogD:
- Would it be helpful to
estimate the hydrophilicity of a compound even before it is
measured?
- Would it be helpful to
estimate the hydrophilicity of a mixture of ionized and
unionized forms of the chemical compound?
- Is it a time-saving device, to
have the acid-base dissociation constant being determined at
the same time that the partition coefficient can be done?
- Do you want to be able to see
the predominant ionic form of the molecule for any given pH?
- Would you also like to access
plots of the bioconcentration factor (BCF)
and adsorption coefficient (KOC) as a function of
pH?
Version 5.0 of the ACD/LogD algorithm was used for above calculations.
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