Potency of impurity

[albatran]

Hello,
I have a problem with impurities. How can I calculate the potency of impurity without any official impurity reference standard?

Can I use NMR to find the potency?

In some cases I use HPLC, but the problem when I have some traces of other impurities in my impurity sample. Note that the serious problem if these impurities have a different max wavelength.

Ok, my friend faced the problem in the raw material production.
Please help….

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[maris]

NMR is most suitable for identification, the potency can be better estimated by eveluation of purity (HPLC) and residulal solvents /water levels (GC, KF, TGA).

[albatran]

Ok Sir,
I’m agreeing with you.

But, how can I find the potency (by GC, HPLC, TLC, ...etc) with out a reference standard? As I mentioned the main problem when you have some traces of other impurities. Can I use area ratio function? If I can at which wavelength I should run the injection?

Let us consider the impurity as active substance and all other traces are the related substances of our interested impurity. In such a case we need reference standard to calculate the potency of the impurity. If we dont have? Some thing should be done.

Actually, I saw some COA for impurities from different sources; some of COA used TLC to calculate the potency. In such a case potency mentioned as NLT XX %. I think this is not the sufficient to run your recovery test.
Some other sources used HPLC. I agree:

1- If the impurity is 100% pure. The potency should be 100%. Excluded water content.
2- If they have a reference standard. This will solve the problem.


Al.Batran [/img]

[maris]

"Can I use area ratio function?"

the answer is yes if the linear detector responce for main peak was demonstrated. Otherewise use "self dilution" of the tested sample.

If I can at which wavelength I should run the injection?

I recommend to analyse at number of wawelenghs ( including prescribed by your method ) and to compare peak responces, in the case responce factors change for impurities are similar at different wawelenghts you can substract sum of them from 100%. In case the responces changes aren't similar calculate the sum of maximum values of each impurity at corresponding wawelenghts (the "worse case") and , again, substract from 100%.

Then substracte from the rest LOD, ROI, and you will get the potency of your impurity.

In my practice I never met the 100% sunstance, but if you are lucky, and your test compound has a purity above 99.5% and sharp melting point you can use alternative approach - to check the "absolute" potency (purity) by DSC.


Of course all this can be done without reference standard.
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[Carlos Teixeira]

Dear Friend,

My personal opinion is that the use of Area Ration function as Impurity Content is not GOOD, buICH agree with the Area Ration when there are not Reference Standard of Impurity.
But the Maris' procedure is interesting!!

[jan]

I think there is a problem for lacking of ref. material. If you know the response factor from a certain method, one will be able to calculate the purity. But if you do not have response factor and also ref. material, how can we do it? Is it suitable to use area percentage of HPLC? Thanks.

[Kostas Petritis]

If your compounds contain nitrogen you could use LC with chemiluminescence nitrogen detector (CLND) to calculate the purity of your analyte. This detector has an equimolar response towards the nitrogen so you can use another compound (i.e. caffeine) and by external calibration calculate your compound of interest. Some people use LC-UV and the CLND in tandem in order to calculate the UV response factor of that particular compound and then use UV for the rest of the work.

[albatran]

but ICH agree with the Area Ration when there are not Reference Standard of Impurity.

Can you give me the guidelines?

[maris]

www.ich.org

[albatran]

Thanks sir,

But as you know many ICH guidelines are there. Can you give me the name of the guidelines?

[Jam]

Does anyone know a good book or any article or a reference to a guideline concerning reference standard, especially second reference (in-house!) standard? Speciafications and analysis of purity?

Thanks in advance!

JAM

[maris]

ICH Q3A(R), Q3B(R), Q7A,

Also see FDA's guidance for Drug substabnce(chemistry, manufacturing and controls information) at www.fda.gov

[msrinureddi]

Dear All,

The answers are quiet interesting. You can use Chemstation Software (Max Plot macro) or Chromeleon software for finding out the potency. This software will help you to extract all the peaks present in the UV-VIS region to their maximum wavelengths in the same chromatogram where chromatographic purity can be taken and then apply the same for potency purpose. If the impurity quantity available is high then take the chromatographic purity and apply the mass balance formula by performing LOD, Residual Solvents, Residue on Ignition etc and establish the potency. This is the best method for performing the the potency.

Srinivas Reddy

[JNF]

NMR (1HNMR) can be used to calculate concentrations. However it only works if in the mix you have a substance which concentration you know precisely (you could always add – internal standard). The conditions are that the signal to be used for quantification has to be known (as in assigned) and well resolved (separated form any other peak present). If this technique is accepted by the authorities is another matter.