Is there a potentiometric method for monitoring salt formation in organic solvent?

Question

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.

Answer 1

1. Add methanol with excess $\ce{H2SO4}$ to your solution. In acid solution to can use HPLC to determine the concentration of your mystery goo compound.

2. Add water to ppt whatever organic goo you're making.

3. Mechanically separate your organic goo (filter, centrifuge.). Instead of 2-3 maybe solvent extraction?

4. Back-titrate excess $\ce{H2SO4}$ in water/methanol solution with $\ce{NaOH}$ and phenolphthalein.

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There has to be a wealth of information on the titration of "dicarboxylic acids" in methanol.

Answer 2

If I understand your problem, you have a diamine of low molecular weight which is insoluble in water, and you wish to convert it to a water-soluble (ionic) solid by using the minimum amount of acid (presumably to get near neutral pH).

A very concentrated solution of the API in methanol or ethanol should be clear: no Tyndall effect, no turbidity. As a tiny amount of added water is added, a Tyndall effect will appear (use a narrow-beam flashlight, darkened room). If you then add a tiny amount of acid (in water or solvent), the solution will become clear again. By alternating water and acid, you will be able to decrease the solvent concentration to essentially zero, but the API will still be in solution as shown by no Tyndall effect. At this point, a pH measurement would be easy. Perhaps if the Tyndall effect is always maintained very small, the pH electrode might not clog during the whole process.

With the required maximum pH determined in this way, the alkaline API can be dissolved in acidic water. Then increase the pH with your favorite alkali until you see a Tyndall effect - this indicates that the pH is now too high, and the API is precipitating out, so you can have a pH range which might be small enough to be your answer. At least you should be pretty close to being able to decide what the optimum is. Knowing the amounts of acid and API, you can calculate what kind of protonation you have achieved.