drug substance residual solvent analysis using headspace，

[dogcatlike]

for Metoprolol Tartrate，if a vial with mixed water solution of Metoprolol Tartrate and alcohols，incubation 45min，105 degree，is there ester reaction occur in the vial？

[chromatographer1]

Whenever you have water, alcohols, and an acid capable of forming esters with the alcohols involved, there will be an equilibration.

You certainly indicate conditions that COULD result in an esterification reaction as well as a cyclic intracondensation and elimination of water.

Not that either is likely, but I would not forbid the possibility.

TLC would show the resultant chemical products.

I would expect alcohol HS equilibration could be attained in 15 min MAX as long as sample size is not excessive,

best wishes,

Rod

[dogcatlike]

in usp467，the most mild incubation parameter of headspace is：45 min，80 degree。will it impact on the recovery of my analytical method？

it's hard to infer，and i have to practice to gain the data of recovery。

[chromatographer1]

In this procedure HUGE amounts of sample are used. It is meant to be a easy to use method, not a state of the art method. If you think the USP test is state of the art, you are greatly mistaken.

I have validated methods for dozens of residual solvents of over 100 different drugs, none of which uses more than 0.25mL dissolution solvent and 100mg of drug sample.

One large pharmaceutical company based in Chicago was doing residual ethanol at 1 ppm levels using 100mg of drug in 1995. This used to be state of the art. My competitor company developed a procedure that used two orders of magnitude less sample at the same LOD of ethanol, 1 ppm. The heating time was 10 minutes at 85C. Did my employer use the USP method? No. It took too much time and was not accurate enough.

My generic headspace method that used 25 microliters of dissolution matrix and 1 milligram of drug sample measuring levels of residual solvent at less than 1 ppm was published in Analytical Chemistry in June of 1997.

Few small companies want to spend the time to validate a HS method. It is 'cheaper' to avoid arguments with other companies by relying on the generic USP method. And good luck with that.

Rod

[dogcatlike]

i'm freshman exactly。

for us，usp is god。we must do as it say。 i have to do as my boss say。

although usp467 cost too much time，and very boring，it's unbelievable to test with another method for me。

maybe rod is a learner or professor in college，while i work in pharmaceutical company，which lead to different

analytical method，different mind。for us，comply with USP，it's absolutely spotless。

[dogcatlike]

rod‘s method is leading edge。but we have to use well-known and generally accepted method，in order to avoid

arguments。my present work focus on validation of GC method usp467 residual solvents in drug substance。

usually not smoothly going。it's a fussy work，or i'm not competent enough？

[chromatographer1]

Few chemists have an easy time with the USP 467 method. Companies seem to think USP procedures are perfect and easy to implement. Actually, in the case of USP 467 it is a method full of 'compromises' which try to give a generic procedure which settle disputes between companies and regulatory administrations between continents.

I don't know how it came to be approved. In trying to make things 'easy' they have made it very difficult to get good results for the average chemist with average equipment. But that is my opinion. But look at the archives and you will find many chemists who have troubles with it. A smart company will design and validate their own methods which are cheaper over the long run and will be superior to any generic method. But not many will hire competent people to do the work and end up contracting the work outside of the company.

I have always worked in industry: QA in a fine chemicals company, doing R+D research at the headquarters of two different large Pharmaceutical companies, a petroleum company, a natural gas pipeline company, and my last ten years was with a chromatography products company doing research in new products.

So I have been 'around the block' so to speak. I am competent in TLC, GC, GC-HS, HPLC, and SFC and experienced in flash chromatography as well.

I was blessed to spend two years investigating headspace analysis before providing my employer a generic method which allowed expansion of the application with minimal validation requirements for any new drug substance. This method was optimized for small 1mg samples (exceptional cases of very expensive drugs and experimental prototypes) and was published. I was a beta tester of fused silica coated hardware for HS analysis and my original research using small samples prompted one international company to add my hardware changes to their product line.

My generic general purpose method used 5 to 25 mg of sample and 100mL of solvent with three different dissolution solvents This was suitable for most drugs, present and future. It saved my former employer hundred of thousands of dollars in research costs. Unfortunately, this information is proprietary as it is quite valuable.

Good luck in your work. I hope you don't get blamed for the inherent problems with USP 467. I would NOT want to be forced to use it on a daily basis.

best wishes,

Rod

[dogcatlike]

dear rod maybe u're excellent expert with burning heart to guide me, or u want to advertise your residual solvents analytical method. is it a patent?

i wonder how u do in residual solvents assay of drug substance. could u send me relative materials? i'm studious.

[chromatographer1]

It is not MY method. It belongs to my former employer. I only developed it.

good research,

Rod

[dogcatlike]

show me bright and broad road，powerful rod。maybe i should search your paper to study。

[chromatographer1]

http://pubs.acs.org/doi/pdf/10.1021/ac970040u

[dogcatlike]

rod is canon，grant whatever is requested。if free，better。thank u all the same。

[chromatographer1]

Here is a good article for free if you can't get to a library to read ANALYTICAL CHEMISTRY.

http://www.chromatographyonline.com/lcg ... =&pageID=2#

best wishes,

Rod

[dogcatlike]

thanks rod。i will read seriously，and learn from it。

[dogcatlike]

i realize that esterization reaction , need catalyst and no water enviroment。So in headspace hardly exist this reaction。all that i'm concerned is not necessary。

esterization reaction is reversible，water is one of product。in vial too much water，it should inhibit the reaction enough。