by
krickos » Wed Mar 30, 2011 3:27 pm
Hi
Sorry did miss that you edited your post. Your situation indicates many possible issues and choices of analytical strategy.
From an overall perspective: Acetic acid and ethylacetate is class 3 solvents and could be controlled via loss of drying (max 0,5%), which would leave you only with the class 2 solvent methylene chloride to worry about, so thats a possible control strategy unless you have a higher allowed loss of drying spec.
You still have no revealed if there are other potential solvents present. The unknow peaks can therefore have several sources. Nor have described if the same unknow peaks appears both in split and HS injection just that unknows appear, is it the same pattern?
Your substance in my experiance with regard to certain functional groups are often not particular stable, so unknowns ie degradation products can appear both in split injection and headspace (you did not state sample solvent used and headspace oven temp and time). I had a case where a drug substance was dissolved in water and unknowns appeared late in the chromatograms from HS injections, the developing chemist disreagarded those so when the final procedure came into use on a regular basis our headspace injectors became badly contaminated.
So you need to find out if the unknows are degradation products or actually volatile solvents or impurities. GC/MS is of course nice to have here. HS injection is generally more gentle so you could try setting HS oven to 35C°C for only 10mins for a spiked sample and then increasing HS oven temp in 10C°C steps to see how it changes.
Then we have some potential chemistry issues as well. Acetates like ethyl acetate are pH sensitive, your case indicates an acidic enviroment which could lead to acidic hydrolysis of both the drug and the acetate.(Ethyl acetate is synthesized industrially mainly via the classic Fischer esterification reaction of ethanol and acetic acid. This mixture converts to the ester in about 65% yield at room temperature).
So the case may be difficult hence I proposed using loss of drying for class 3 solvents.
Another option for headspace analysis is to dissolve lets say 0,2g of substance in DMF or suiteble sample solvent add 1-2ml pH 7 buffert and dilute to 10ml and analyse 1-4ml of this solution. However as acetic acid is/may be present it may not necesarly protect the ethyl acetate or the substance.
Finally acetic acid is difficult to analyse by GC, if you use the search funtion you will find some good threads on this topic. Sometimes one might get it to work othertime IC, titration (not this case it seems) or other approches such as loss of drying might be good enough/better.
