Researchers led by Bernhard Spingler, professor at the Department of Chemistry of the University of Zurich, have modified a method – previously used exclusively for protein crystallization – and applied it to organic salts.
Spingler, who has more than 20 years of experience in small molecule crystallography and more than 15 years in macromolecular crystallography, was looking for a way to apply the methods of macromolecular crystallography for a certain class of small molecules, he told us.
"As organic salts make up about 40 percent of all active pharmaceutical ingredients, this new method can greatly speed up the development of drugs," said Spingler.
“Traditional salt screening is normally done by manually weighing the APIs in the form of a free base, dissolve them in different solvents, add certain amounts of acids, mix and dry. The powdery solids are then analyzed,” he explained.
However, with the new method, the researchers started with hydrochloride salt, generated an aqueous solution, and from then on used robots instead of manual labor, Spingler told us.
“As the robot can precisely handle extremely small amounts of volume (100 nl per tested condition), our method only requires 12 microliter of an almost saturated solution for the testing of 96 conditions with the help of a screen we have developed,” he explained.
Spingler said the method has three main advantages compared to the traditional salt screening: The method uses less material, requires less manual labor, and in many cases, produces single crystals.
As Spinger explained, single crystals can often be directly analyzed by single crystal X-ray analysis, which enables faster determination of false positives compared with traditional screening.
The researchers are currently working with an unnamed company to commercialize the screen.
As for next steps, Spingler said the researchers want to expand the method to a non-aqueous solvent in order to handle salt that is less soluble in water than 2 mg/ml.