High throughput solubility measurement with automated polarized light microscopy analysis

Area of Science:

• Drug discovery
• Materials science
• Analytical chemistry

Background:

• The solution-precipitation method using dimethyl sulfoxide (DMSO) sample stock solution (DMSO-SP) is a common high-throughput solubility assay in drug discovery.
• The solid form of the precipitate in DMSO-SP assays has not been previously investigated.
• Understanding precipitate characteristics is crucial for accurate solubility determination.

Purpose of the Study:

• To investigate the influence of precipitant solid form on solubility data obtained via the DMSO-SP method.
• To determine optimal experimental conditions for DMSO-SP assays.
• To develop an automated system for diagnosing precipitate birefringence.

Main Methods:

• Investigated experimental conditions of the DMSO-SP method, focusing on precipitant solid form.
• Utilized polarized light microscopy to analyze the crystalline nature of precipitates.
• Compared solubility data from DMSO-SP assays with solubility from powder material (PWD) under varying incubation times and precipitate forms.
• Developed an automated birefringence diagnosis system.

Main Results:

• Over half of the model compounds formed crystalline precipitates.
• When incubation time was 20 hours and precipitates were crystalline, DMSO-SP solubility matched PWD solubility.
• Shorter incubation times (10 min) and/or non-crystalline precipitates led to higher DMSO-SP solubility compared to PWD solubility.
• An automated birefringence diagnosis system was successfully developed.

Conclusions:

• The solid form of the precipitant is a critical factor in interpreting DMSO-SP solubility data.
• Accurate solubility assessment requires consideration of precipitate crystallinity and incubation time.
• The developed automated system aids in drug discovery by providing rapid precipitate analysis.