Collections of compounds used within drug discovery screening projects have to be tested in a variety of different assay types and therefore are stored in a liquid form. The most widely used solvent for this purpose is DMSO (Dimethyl sulfoxide).
However some compounds do not remain in solution and fall out forming a precipitate. A team at GlaxoSmithKline investigated this issue, in this publication – (Ioana Popa-Burke and John Russell, “Compound Precipitation in High-Concentration DMSO Solutions.,” Journal of biomolecular screening, 19 (2014), 1302–8 .http://jbx.sagepub.com/content/19/9/1302
In the article the team noted that from one library of compounds – the “Tox Set” stored at 100mM they measured a 15.17% precipitation rate (by means of visual inspection). This was compared to a collection of fragment based compounds (at 100mM concentration) which had a 4.76% precipitation observed. It should be noted the there was a difference in the total number of theses set of compounds 422 versus 1995 respectively, which may explain some differences. The team also investigated other fragment and diversity compound collections with a higher number of members but at a lower concentration (a 40mM Fragment set with 7137 members and 10mM diversity set of 38,360 members). These both gave similar observed precipitates of 3.45% and 3.11% respectively.
The water content of all the DMSO samples was measured using Echo 555 acoustic dispenser, and this was similar across the samples ranging from 90.9% to 92.0% in all collections apart from the fragments at 100mM which had 85.8% DMSO. It was therefore assumed that % water content was not to a cause for precipitation. As all these compounds had been prepared and solubilised in the same manner, it was concluded that a chemical property must be the driver of precipitation of these compounds.
To determine if a physicochemical property could be identified as a correlating factor for increased precipitation rate in the Tox set compared to the fragment set , the MW, clogP, fsp3 (fraction of sp3 carbons) and TPSA (total polar surface area) were analysed with three different data mining techniques however no relationship was uncovered.
The identified precipitating compounds soluble concentration and purity was determined using LC-UV-MS-ELSD system. This revealed that concentration was, as to be expected lower in the free solution of precipitated samples, however the level of purity was similar for precipitating compounds as fully soluble compounds, suggesting that impurities are not the causative factor in the production of precipitates.
To determine if number of freeze thaw cycles would increase the number of precipitates observed, the team took the identified 110 precipitating compounds from the 100mM tox and 100mM Fragment set and made fresh solution in DMSO at different concentrations. These samples were then exposed to 1, 2, 5, and 10 freeze thaw cycles, and the number of precipitates was observed.
Number of Freeze thaw cycles did not have a significant increase in the number of compounds that precipitated however there was a correlation with compound concentration.
A key result was that from this set of precipitating compounds was 86% were unable to go into a solution at 100mM initially before any freeze thaw cycle.
So to answer the question – no, from this latest publication the authors cannot predict which compounds will precipitate from a DMSO solution. Compound concentration does have an effect on the number of precipitates observed, which is important to remember when thinking about compound library composition and stored concentration.