USP <467> RS Unknown Peaks

[Jana P]

Hi everyone

Wondering if anyone can point me in the right direction…

We are running the USP <467> Residual Solvents method on an API. We know that we have Methanol, Dichloromethane, Hexane and Isopropyl Alcohol are present in small quantities and have had no trouble detecting these residual solvents and they are all below the limit (i.e. less than the peak area of the corresponding peak in the standard).

We are encountering problems as we have a few (5) "unknown" peaks present in out chromatograms, at very low levels (peak areas) and they can not be attributed to blank peaks. We are unsure if/where the USP method advices on what to do with unknown peaks?

I can tell you that the unknown peaks don't correspond to any of the Class 1, Class 2A or Class 2B residual solvents.

Do they need to be identified?

As they are so small and as we know the manufacturing process and the solvents used and can show that it is not any of these.

Can we "ignore" the unknowns??

Thanks

[krickos]

Hi Jana

Could you please specify which method of those you are running? The updated USP 467 chapter came into operation the first of July so please state if your run the water or non water solouble option and which procedure.

the origin of the peaks could be several hence good to know the specific like sample solvent etcetera.

Just tossinng out a couple of possibilities:

-As just recently discussed in another thread, biproducts can be formed in sample solvents such as DMF, DMAA and DMSO. Variation of water content in sample/solvent and pH from API can catalyse this reaction.

-Even in water solutions degradation can occur depending on temperature pH and structure of API.

Seems like you have ruled out any process releated issues´which is good from a quality aspect..

Sometimes a "residual solvent" can be a process biproduct, usually alcohols or esters but even solvents such as toluene.
One of my weirder cases I had related to hexanes and heptans, I was assumed the supplier used purer solvents but it turned out that the extra peaks in the final API related to the supplier using "coarse" hexane/heptan meaning about 50% n-hexane and n-heptane the rest position isomers where a few of them ended up on trace levels in the API.

-Have you always had the peaks or did they show up after something specific? New method ?(due to USP update?), process change?

-AS for the need to investigate unknown peaks. Well do not recall USP 467 specificlly adressing it.
Seems like you are in Australia, but if I recall FDAs recently updated guide on out of soecification/out of tred guide, investigations include "abnormal" results. Regardless of regulatory that applies I would think you would have to look in to the matter, but not necessarly identfy each peak if for instance yo comes to the conclution that is degradation of the API or side reaction with the sample solvent.

Cheers Chris

[usv]

Hexanes will contian positional isomers and it is quite possible that this is what you are observing. Some grades of bulk hexanes used in manufacturing contains only about 60% n-hexane. The rest are isomers. You should chekc what type of hexane was used in the process.

[chromatographer1]

I would discuss this issue with your regulatory people.

Most reviewers do not like "unknowns".

Since you seem sure that the peaks do not match known solvents you should investigate their origin.

Are they 'caused' by heating the sample?

Do they grow with increased heating time?

I would not "ignore" these peaks.

I would sleep better if I knew their source and the reviewers of your results would too.

best wishes,

Rod

[kcvichare@yahoo.com]

Residual solvent unknown peaks should be identified. There are other number of methodologies available but best is GC-MS.