Organic pH modifier

[JBush]

I am working with a compound that is sensitive to water, however we need to go to a pH of approximately 10 in order to fully dissolve some of the excipients for a recovery study. Does anyone know of an organic modifier that may be used in our solvent preparation to make the pH basic without the presence of water?

[tom jupille]

Without getting into thorny questions about the definition of pH in a totally non-aqueous system, I would think that any quaternary ammonium hydroxide would do the job.

[Kostas Petritis]

I was thinking of something milder than a quartenary amine such as aliphatic alkylamines, i.e. hexylamine...

[Bill Tindall]

You haven't provided enough information to answer the question. How do you know that you need pH 10? Is that pH 10 in water, or some solvent. What solvent, for this matters a lot. I would be curious as to what sort of compound is stable in base but not in water since bases are typically better nucleophiles than water.

If you need to make a nonaqueous solvent basic then just add any organic base- methoxide,acetate, quat. salt hydroxide, amine of whatever pKb works best, etc. Amines of various kinds will give orders of magnitude range of pH in your nonaqueous solvent, so this is a versatile approach. Ditto for salts of organic acids. Depending on the solvent you can vary the pH up to 30 orders of magnitue.

[JBush]

My apologies, the pH of 10 was a misrepresentation, I meant to say that one of the exipients along with the API are fully soluble at a pH of about 10. However I am trying to achieve full dissolution in a non-aqueous system. The API tautomerizes in even a slight amount of water. This changes the AUC due to the eq'm between the two epimers for our recovery study. I have worked fairly in depth with the HPLC method and am ONLY concerned with area recovery at this point. I'm stuck using a HILIC column due to the properties of the compound and the separation is horrible but like i said I am only concerned with recovery and we are missing approximatley 15% of the total area for recovery of a photodegraded sample.

I get near 95% (good enough) AUC recovery when using a 1:1 ACN:water at 0.01M NaOH as a diluent, however I want to eliminate any effects due to the epimer. The presence of the epimer was reduced greatly by increasing the flow rate and temperature but ideally i would like to run the original separation method without worrying about the formation of epimers. Also, the gradient method goes no higher than 15% water content and does not seem to cause epimerization, however any % higher than that does contribute to epimerization as represented by increases in area and broadening/formation of second peak.

This particular compound is very insoluble in water and to make things even more interesting it actually is less soluble at higher temperatures (without degrading)

[Bill Tindall]

I must admit that the additional information left me more confused about your need than before. If you need a nonaqueous solvent that is basic then add a base to it. Typical bases were listed previously. But, if your problem is to dissolve something in a basic nonaqueous solvent and then do chromatography, then the problem becomes vastly more complicated. Just because something is soluble in aqueous base does not mean that it will be soluble in nonaqueous base, or even that one needs a base to dissolve it in a nonaqueous solvent. Cellulose phthalate would be a good example of such a situation. It sounds like you have a very difficult problem. Without knowing the details of the problem it is difficult to offer suggestions beyond what have been provided.

[HW Mueller]

...thought that someone would end the confusion about this...... My trouble stems mainly from Bush´s statement that a slight amount of water causes tautomerization (also having trouble with how this is also epimerization) but 15% water in the mobile phase is ok. Also that the substance is "very insoluble" in H2O, but more insoluble in hot water (without degrading? tautomerization is not dergrading?). On the latter it would interest me how that was ascertained. It would also be interesting to know what sort of material is less soluble in hot than in cold water, at the moment I can think only of proteins, as even highly exothermic (on dissolution) substances are usually more soluble at higher temps.
Could it be that this problem also goes away if the compound is handled at a reasonable pH (near neutral) with rp (in lets say 15 min) with more sensitive detection (other wavelength or whatever)?

[oldtimer]

Aspirin is also very sensitive to water presence: it starts forming salicylic acid almost immediately in the presence of water. One solution we have applied is a sample solvent of ACN/formic acid/citric acid in a ratio of 99:1:0.1 v/v/w, approximately. Aspirin solution is then very stable at room temp. If your target compound is organic soluble, this may provide an option. Recovery studies of your target compound should still be achievable even though excipient(s) may not be soluble.

[JBush]

But one of our theories is that some of our API may be covalently bonding to the HPMC-AS (excipient)

[Bill Tindall]

I have no idea what any of the abbreviations you used mean.

[HW Mueller]

If your ?? binds covalently to ??-? and you dissolve that you will have ??-??-? in solution which is not ?? so the results will be ?????????? anyway. (Law of multiple blind studies)

[Chris Pohl]

Hans,

Although it's uncommon, there are certainly other examples of compounds which dissolve better at low temperatures than at elevated temperatures. A good example are aliphatic amines. Tripropylamine, for example, is considerably more soluble in water at 4°C than at elevated temperature. This makes it a bit difficult to use in producing colloidal ion exchange materials in aqueous solution since elevated temperature is needed for achieving a decent reaction rate with a suitable substrate but the maximum achievable concentration is quite low at reasonable reaction temperatures.

[HW Mueller]

Chris,
do you know whats behind this? Entropy?

[Chris Pohl]

Hans,

I believe so but aliphatic amines are a bit weird in that in a certain size range they don't dissolve well in much of anything. For example tributylamine has surprisingly low solubility in most common HPLC solvents or in mixtures with such solvents and water. Of course the salt form is reasonably soluble but it's difficult to make a 0.1 molar solution of the free base.