Transcript Slide 1

Solubility Database
Barbara Mason, UCB
Darren Edwards, Organon UK
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
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
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”
Sources of Solubility Data
• Internet?
 “Solubility” and “progesterone” in Google
 130000 hits!
 Quickly found values from 7 to 61 mg/l!
 Non-ionisable compound!
• Why is it so difficult to find consistent
solubility data?
Factors that can influence
solubility assays
• Solid-state form
• Temperature
 Amorphous/
crystalline?
 Particle size?
• Purity
 Value?
 Value?
 Controlled?
 Method of
• Pre-dissolution?
measurement?
 Effect of impurity?
• Analytical method
 Specific/non-specific?
 Nephelometry/UV/LC?
• Separation of
precipitate
 Method?
 Solvent?
 Concentration?
• Co-solvents
Solubility
• Agitation time
 Type?
 Amount?
• Agitation method
 Vortex?
 How long?
 Shake?
 Consistent?
 Sonicate?
• Test medium
 Centrifuge/filter?
 Buffered?
 Filter type?
 Buffer type?
 Strength?
 Ionic strength?
Factors that can influence
solubility assays
• Solid-state form
• Temperature
 Value?
 Amorphous/
 Controlled?
crystalline?
 Particle size?
• Purity
• Pre-dissolution?
 Value?
 How measured?
 Effect of impurity?
• Analytical method
 Specific/non-specific?
 Nephelometry/UV/LC?
• Separation of
precipitate
 Method?
 Solvent?
 Concentration?
• Co-solvents
Solubility
• Agitation time
 Type?
 Amount?
• Agitation method
 Vortex?
 How long?
 Shake?
 Consistent?
 Sonicate?
• Test medium
 Centrifuge/filter?
 Buffered?
 Filter type?
 Buffer type?
 Strength?
 Ionic strength?
Issues
• Many…..
• Can the PC Forum do anything useful to
•
help the situation?
Decision made to set up a database of
experimental solubility data
Solubility Database
• Experimental conditions (as far as
•
•
possible) would be described
Commercially available compounds would
be used
Web-based
 Easily accessible
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
Solubility Database
• Data from UCB
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
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.
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.
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
Issues with data?
• Work in progress

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
For Discussion……
•
•
•
•
How can we improve the database?
Is it useable?
Is anything missing?
More low solubility compounds?
• More data from other groups!
Thanks……..
• UCB
 Barbara Mason
 Christine Prosser
 Emily Freeman
• Organon
 Wullie Arbuckle
 Yvonne Lamont