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Solubility Database

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.

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Solubility Database

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  1. 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 • 130000 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 influencesolubility assays • Solid-state form • Amorphous/ crystalline? • Particle size? • Temperature • Value? • Controlled? • Purity • Value? • Method of measurement? • 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?

  7. Factors that can influencesolubility assays • Solid-state form • Amorphous/ crystalline? • Particle size? • Temperature • Value? • Controlled? • 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 • 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.

  14. 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

  15. 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

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

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

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