I work in a pharmaceutical R+D lab, and currently aim to develop a validatable potentiometric method for determining the optimal amount of acid to add to a basified small organic molecule for conversion to an ionic species (i.e. sulfate salt, hydrochloride salt). Our API (active pharmaceutical ingredient) has two protonation sites, so I also need to determine the stoichiometric ratio of API to counterion, and therefore which specific salt is present at specific points of the titration curve. Ideally, this will be carried out in methanol or ethanol.
Is it possible to accomplish these goals by titrating with acid and monitoring with a conductivity meter/probe? A consultant has advised me to do so, and I have a meter with two conductivity probes. I've already tried using a pH meter, but neglected to factor in that pH is only relevant to aqueous systems. The pH method did produce decent looking titration curves with obvious inflection points. However, as major amounts of salt 'crash out' of solution, meter drift becomes an issue, the reference junction gets clogged, etc. It gets messy and I have to continually clean the probe. I've read that they make pH meters that can withstand as much as 80% organic in solution, but this is not representative of our 100% organic protocol. Furthermore, I'm having trouble finding non-aqueous calibration solutions for the pH (and conductivity) meter.
My idea: Make a set of organic conductivity calibration solutions using methanol (and/or ethanol) and neat sulfuric acid at concentrations of, say, 0.010 M, 0.10 M, and 1.0 M (arbitrarily chosen), and then carry out the titration. Ignoring solutes, this is the most representative solvent system I can think of since I would be adding acid to methanol during the titration.
Or, am I completely going about this the wrong way? My boss and I have been researching this for over a month and have found nothing specific to the application. I suspect that I'm over complicating the matter. This type of process is surely carried out daily in drug manufacturing facilities (tons of API's are in salt form, and GMP facilities require method validation/quality assurance/etc of all analytical methods), so I assume that there is a known and developed method for this out there somewhere.