The precipitation of candidate drugs on mixing DMSO stock solutions with aqueous buffers

The precipitation of candidate drugs from dimethylsulfoxide (DMSO) stock solutions and buffer mixtures has practical importance within the pharmaceutical industry. At the drug discovery stage, mixing of drug DMSO stocks and aqueous buffer is a common procedure for many analyses, such as bioassay screening and some solubility screens. Precipitation from these mixtures, whilst a recognised issue, has little in the way of published work. This thesis explores in detail the precipitation of three poorly water soluble, commercially available drug molecules, namely amiodarone HCl, clotrimazole and tolnaftate. The work presented here assesses the process from a physical chemistry point of view. Upon mixing the DMSO drug stock and aqueous buffer, all three compounds form particulates in the nanometre size region, which grow over time. The growth of these particles can be monitored using nanoparticle tracking analysis (NTA) and the NanoSight. We show that the presence of these particles can interfere with the results of 'kinetic solubility' measurements, depending on the exact analysis used. It is already known that these types of particles can interfere with bioassay results, causing false positives. Variables such as the mixing employed, the exact percentage of DSMO present in the samples and the concentration of protein present in the samples all affect the formation and growth of these particles. The results were correlated to high performance liquid chromatography (HPLC) measurements. It can therefore be concluded that there are several, controllable variables which can affect the precipitation of the three test compounds investigated here, and thus potentially the results of some discovery stage pharmaceutical screening assays.

Name dc:type.qualificationname

phd

Level dc:type.qualificationlevel

doctoral-pg

Grantor dc:publisher.institution

University of Strathclyde

Year dc:date.issued

2013

Author dc:creator

• Gillespie, Cheska

DOI

10.48730/4vj6-z540

Identifier

T13609

OAI identifier oai:identifier

oai:strathclyde:nc580m649