Subject: aqueous solubilities of organic compounds

From: [email-masked]
Date: Wed, 20 Feb 2002 14:59:13 +0100

Dear collegues,

as I promised, I provide you with a summary of replies, that I received upon
my request about methods for the prediction of aqueous solubilities. 

I would like to thank everyone, who responded !

Best regards,

Christian

________________________________________________________________

   Dr. Christian Pilger
   Dept. Chemical Research / Structural Research
   K91-00-10
   Boehringer Ingelheim Pharma KG
   D-88397 Biberach/Germany
   Phone: 07351-545749
   Fax:     07351-5497924
   mailto: [email-masked]

---------------------------

Carlos Faerman [[email-masked]]

Dear Dr. Pilger,
This is a very important issue in the pharma/biotech world !
I have two remarks to make:

1) The experimental values for solubilities are available, among other
sources, in the Beilstein database, currently available online.

2)Without endorsing any specific software company, Gastro Plus by
Simulations Plus, Lancaster California seems to have a reasonable
success in predicting solubility.

I would be very interested in finding out what your experience or
someone else's is in this field.

---------------------------

David Gallagher [[email-masked]]

There is a zipped file which includes a water solubility QSPR  along with 
the calibration set of 156 environmentally significant organic molecules 
and water solubility data available at: 
http://www.cachesoftware.com/downloads/LogW.zip The QSPR uses descriptors 
calculated by MOPAC-COSMO. The r^2 correlation is 0.95.

It is located on: http://www.cachesoftware.com/cache/applications.shtml If 
you do not already have the CAChe software to open the files, you can 
download a free evaluation copy from the same site.

David Gallagher, Fujitsu

---------------------------

David van der Spoel [[email-masked]]

Check out:
@Article{Wang2001b,
  author = 	 {J. M. Wang and W. Wang and S. H. Huo and M. Lee and P. A.
Kollman},
  title = 	 {Solvation model based on weighted solvent accessible
surface area},
  journal = 	 {J. Phys. Chem. B},
  year = 	 2001,
  volume =	 105,
  pages =	 {5055-5067}
}
A very simple area based method. However, I haven't been able to get 
meaningful numbers out of it..

---------------------------

Dearden John [[email-masked]]

We have recently tested the ability of a number of software packages to
predict aqueous solubility, and I attach a few PowerPoint slides with some
preliminary results. We took our 113 compounds from a data-set of over 600
solubilities published by Abraham and Le (J. Pharm. Sci. 88 (1999) 868-880,
by taking roughly every sixth compound. I've included a similar comparison
of log P predictions, from which you can see that the ability to predict log
S is nothing like so good as the ability to predict log P.

---------------------------

Erik Johansson [[email-masked]]

Arne Brändström (retired from AZ Mölndal) has worked a lot on his own method
for aqueous solubility.
I saw a early manuscript a couple of years ago but I am not sure if this is
published.

---------------------------

George Vacek [[email-masked]]

QikProp predicts a variety of pharmaceutical properties, including
solubility,
that are
important in determining ADME characteristics for drug candidates.  The
complete
set
of  properties predicted by QikProp, methods, data and literature references
are
available at
http://www.schrodinger.com
For the specific case of solubility, the data set and descriptors are
detailed in
the article
W. L. Jorgensen and E. M. Duffy, Bioorg. Med. Chem. Lett., 10 (2000) 1155-8.

---------------------------

Igor Tetko [[email-masked]]

You can use our ALOGPS software that predict both aqueous  solubility 
and lipophilicity of chemicals. The description of this software can 
be found at:

Tetko, I.V.; Tanchuk, V. Yu.; Kasheva, T. N.; Villa, A. E. P. 
Estimation of Aqueous Solubility of Chemical Compounds Using E-state 
Indices, J. Chem. Inf. Comput. Sci., 2001, 41, 1488-1493.

Tetko, I.V.; Tanchuk, V. Yu.; Villa, A. E. P. Prediction of 
n-Octanol/Water Partition Coefficients from PHYSPROP Database Using 
Artificial Neural Networks and E-state Indice, J. Chem. Inf. Comput. 
Sci., 2001, 41, 1407-1421.

Tetko, I.V.; Tanchuk, V.Yu.; Kasheva, T.N.; Villa, A.E.P. Internet 
Software for Calculation of Lipophilicity and Aqueous Solubility of 
Chemical Compounds, J. Chem. Inf. Comput. Sci., 2001, 41, 246-252.

We have new version 2.1 of this program that is available for testing 
as a standalone program. You can also use free on-line version ALOGPS 
2.0 available at WWW http://www.lnh.unil.ch/~itetko/logp. A nice 
feature of the standalone version is a possibility to create a user's 
LIBRARY  of compounds. This can improve prediction of this software 
for similar compounds in 2-3 times (article in preparation). The 
ALOGPS 2.1 will be available at the WWW soon. The description of the 
algorithm used in the LIBRARY mode, Associative Neural Network, will 
be published in JCICS soon (I am waiting for the galley-proof of the 
article).

You can download the set of compounds used in the aqueous  solubility 
study at  http://www.lnh.unil.ch/~itetko/logp/logs.html

---------------------------

John McKelvey [[email-masked]]

I think that one of the best beople to talk to about this might be Andreas
Klampt there in [email-masked]

---------------------------

Hugo Kubinyi  [[email-masked]]

Dear Dr. Pilger, 

there is a simple solution for liquids - just take the inverse lipophilicity
as a good estimate. The problem is much more difficult for solids. Most
probably you know about the correlation of solubility with log P and mp. -
however there is no method to predict the mp., the crystal lattice, the
intermolecular forces in the crystal and, therefore, no possibility to
predict the solvation enthalpy and entropy - which influences lipophilicity.

If somebody (especially vendors) tells you something else, you should be a
little suspicious. 
For a database that is not too expensive see: 
http://esc.syrres.com/interkow/PhysProp.htm 

---------------------------

Robert L. Lipnick [[email-masked]]

Check papers on water solubility estimation from chemical structure and log
P and MP by Samuel Yalkowsky, Univ. of Arizona. Also, he maintains a water
solubility database. 

---------------------------

Lowell Hall [[email-masked]]

Dear Christian:

I collaborate with Marc Parham of Interactive analysis, Bedford, MA.  We 
have a model that is available for evaluation on a web site.  The model is 
based on a very large database of experimental data.  You can contact Marc
at

Marc Parham <[email-masked]>

and view the site at

www.InteractiveAnalysis.com

The computation is very fast.

---------------------------

Phil Howard [[email-masked]]

We have a program that predicts water solubility from 
octanol/water partition coefficient (see 
http://esc.syrres.com/interkow/wskow.htm) and it is available for free from 
the U.S.EPA (http://www.epa.gov/oppt/exposure/docs/episuitedl.htm). We are 
working on a program that will calculate water solubility using fragment 
constants that will be available soon.  One of the nice features of this 
program is that it will allow one to calculate the water solubility from a 
close structural analog by using only the fragments that are different 
between the structural analog and the chemical of interest.
         We also have a database of water solubility data (see 
http://esc.syrres.com/interkow/PhysProp.htm) that has over 6000 water 
solubility values.  This is available in a variety of formats including 
ISISBase; the latter allows substructure searching.

---------------------------

J. W. McFarland [[email-masked]]

Dear Dr. Pilger:

Here is a recent publication that describes one method and refers to some
others
that have been published. Some of these contain extensive datasets. Others
have
been published since. If you send me your address I will send you a reprint.

McFarland, J. W.; Avdeef, A.; Berger, C. M.; Raevsky, O. A. Estimating the
Water
Solubilities of Crystalline Compounds from Their Chemical Structures Alone.
J.
Chem. Inf. Comput. Sci. 2001, 41(5), 1355-1359.

---------------------------

Stephen  Bowlus [[email-masked]]

The most extensive commercial effort I am aware of is ACD, which uses
variants of the general solubility equation, with terms as surrogates for
melting point where this is not known.

Most of the models of which I am aware are based on the Yalkowsky model, or
that is the one most frequently discussed in the literature.  The main
problem with it seems to be the melting point:  there is limited utility to
the model if you can't get an accurate estimate (i.e. measurement) of mp.
So within this framework, methods to estimate mp are of great interest.

A frequently overlooked program in this area is a group contribution method,
Chemicalc (Suzuki & Kudo, JCAMD, 1990, 4, 155; Suzuki, JCAMD, 1991, 5, 149).
I have used this mostly for logP estimation, so I can't comment on its
strength for solubility, which it also calculates.  The program is available
> from QCPE, or I can send you the code for the PC (runs in a DOS window).