1. Barbara Mason, UCB Darren Edwards, Organon UK
Solubility Database
Barbara Mason, UCB
Darren Edwards, Organon UK

2. Agenda Problems with finding solubility data
Go over some of the factors that can effect solubility data
Show what has been done so far on producing a solubility database
End with some discussion points

3. Introduction
At first Physchem Forum (Nov 2005) problems with obtaining solubility data were highlighted:
Difficult to find data
High variability in reported results
Often no indication of conditions used to test solubility
Lack of “quality” solubility data was causing problems in developing and validating new solubility methodology

4. Sources of Solubility Data
Few databases
e.g. AQUASOL
Drug like?
Not free!
Drug reference books?
Often just (unhelpful) comments
e.g. Progesterone,
Merck Index “Insoluble in water”
Martindale “Practically Insoluble in water”

5. Sources of Solubility Data
Internet?
“Solubility” and “progesterone” in Google
hits!
Quickly found values from 7 to 61 mg/l!
Non-ionisable compound!
Why is it so difficult to find consistent solubility data?

6. Factors that can influence solubility assays
Temperature
Value?
Controlled?
Purity
Value?
Method of measurement?
Effect of impurity?
Solid-state form
Amorphous/ crystalline?
Particle size?
Pre-dissolution?
Solvent?
Concentration?
Analytical method
Specific/non-specific?
Nephelometry/UV/LC?
Co-solvents
Type?
Amount?
Solubility
Agitation method
Vortex?
Shake?
Sonicate?
Agitation time
How long?
Consistent?
Separation of precipitate
Method?
Centrifuge/filter?
Filter type?
Test medium
Buffered?
Buffer type?
Strength?
Ionic strength?

7. Factors that can influence solubility assays
Temperature
Value?
Controlled?
Solid-state form
Amorphous/ crystalline?
Particle size?
Purity
Value?
How measured?
Effect of impurity?
Pre-dissolution?
Solvent?
Concentration?
Analytical method
Specific/non-specific?
Nephelometry/UV/LC?
Co-solvents
Type?
Amount?
Solubility
Agitation method
Vortex?
Shake?
Sonicate?
Agitation time
How long?
Consistent?
Separation of precipitate
Method?
Centrifuge/filter?
Filter type?
Test medium
Buffered?
Buffer type?
Strength?
Ionic strength?

8. Issues
Many…..
Can the PC Forum do anything useful to help the situation?
Decision made to set up a database of experimental solubility data

9. Solubility Database
Experimental conditions (as far as possible) would be described
Commercially available compounds would be used
Web-based
Easily accessible

10. Solubility Database
Initial database set-up with solubility measurements buffered at pH 7.4
141 compounds chosen
Most pharmaceuticals
Purity/identity checked by LC-UV and LC-MS

11. Solubility Database Data from UCB Organon Literature data
AKAS – Automated Kinetic Aqueous Solubility
QSol – Pseudothermodynamic Solubility
Organon
SolKin - solubility screen
Literature data
Not extensive
There to give idea of solubility already in press
Accord for Excel used to construct database

12. Experimental conditions…..
E.g. for the Organon SolKin method:
Starting from 10mM DMSO stocks, a 2% DMSO solution in 0.05 M phosphate buffered saline, pH7.4 buffer (ionic strength adjusted) was incubated at room temperature (22 ± 2°C) for 24 hours with vortex mixing (1500 rpm).  After mixing, samples were filtered through a filter (Millipore Multiscreen Solubility plate, 0.4 µm, modified PCTE). Sample analysis is achieved using gradient HPLC with a mobile phase of water/acetonitrile+0.1% formic acid (95/5 to 5/95).  Detection was at 230 and 254 nm. A calibration curve was produced by injecting three volumes (4, 8 and 12 µl) of a 50 µM DMSO solution of the compound under test, and this curve is used to quantify how much material is in the filtrate of the sample solutions. Each experiment was performed in duplicate.

13. Experimental conditions…..
E.g. for the Organon SolKin method:
Starting from 10mM DMSO stocks, a 2% DMSO solution in 0.05 M phosphate buffered saline, pH7.4 buffer (ionic strength adjusted) was incubated at room temperature (22 ± 2°C) for 24 hours with vortex mixing (1500 rpm).  After mixing, samples were filtered through a filter (Millipore Multiscreen Solubility plate, 0.4 µm, modified PCTE). Sample analysis is achieved using gradient HPLC with a mobile phase of water/acetonitrile+0.1% formic acid (95/5 to 5/95).  Detection was at 230 and 254 nm. A calibration curve was produced by injecting three volumes (4, 8 and 12 µl) of a 50 µM DMSO solution of the compound under test, and this curve is used to quantify how much material is in the filtrate of the sample solutions. Each experiment was performed in duplicate.

16. Benefits of Database Easily available for reference
Help groups to validate new methods
Would expect differences between methods (for reasons given above) but these could be (partly) rationalised because methodology known

17. Issues with data? Work in progress Need more low-solubility compounds!
Data from other groups?
Need more low-solubility compounds!
Difficult to find marketed drugs with low solubility
Agrochemicals/Veterinary
Use compounds that aren’t drug-like?
Additional pH values
Variability of data?
e.g. Standard deviation for n≥3

18. For Discussion…… How can we improve the database? Is it useable?
Is anything missing?
More low solubility compounds?
More data from other groups!

19. Thanks…….. UCB Organon Barbara Mason Christine Prosser Emily Freeman
Wullie Arbuckle
Yvonne Lamont