USP Residual Solvent Standards

[Jana P]

Hello all

I am having a little trouble understanding how the USP has worked out the concentration of the Residual Solvent Standard Solutions.

My understanding is that for Procedures A and B, as documented in USP <467>, the standards would have been prepared at the limits. However when I calculate the concentrations for each residual solvent in the standard solutions (prepared using the USP Residual Solvents Mixtures) I get results which are approximately 1/5 of the limit; for example the limit for Acetonitrile is 410ppm, but the concentration of Acetonitrile in the standard is only 82ppm (i.e. 20%). The consequence of this is that if you analyse a sample, using procedure A, and obtain a peak which corresponds to a particular residual solvent; if that peak is larger than the standard peak it is not necessarily above the limit (it is only above 1/5 of the limit) but the USP still requires you to continue with the test procedure and quantify the peak. Is this correct?

Additionally this causes confusion when one wishes to utilise Procedure C. In the Standard Preparation for Procedure C it states that when preparing individual standards of interest that you should "...obtain solutions having a final concentration of 1/20 of the value stated in table 1 or 2 (under Concentration limit)..." Is the correct interpretation of this statement that you need to prepare standards at 5% of the concentration limit? For example if you wanted to quantify for Acetonitrile you would prepare a standard with a concentration of 21ppm?

This seems to make little sense as why would you wish to quantify with a standard that is so much smaller than the amount you suspect to be in the sample?

I really am struggling to see the logic in this and hoping that someone can shed some light on the matter.

If any clarification is needed for you to help me answer i will be more than happy to answer any questions about how i am calculating or preparing solutions etc.

Thanks

[mbicking]

I agree that this is a confusing document, but it's pretty typical for USP. (Science by committee rarely results in the best method ... but that's another discussion.)

You have to remember that for the Class 1 and 2A mixtures, you add 5 mL to the vial. You can then calculate the total mass in the vial (Conc.XVol.).

For the sample, you dissolved 250 mg in 25 mL, which produces a concentration of 10 mg sample/mL. If you use 5 mL of this sample, you are adding the equivalent of 50 mg to your vial.
So, dividing the mass of solvent by the mass of sample gets you your concentration in the sample (not the sample solution).

If you go through the math, remembering the volumes and masses involved, it should make some sense. I have this all done at the lab, and can respond in more detail tomorrow if you still have questions.

[mbicking]

OK, I'm back in the lab, and my brain is no longer in weekend mode. So, here's the way I look at the calculations.

For acetonitrile, the standard mixture I am using lists a concentration of 2.01 mg/mL. This is diluted 1/100 to prepare the working standard, producing a solution at 20.1 ug/mL. A 1 mL aliquot is analyzed, meaning that the standard contains 20.1 ug.

The sample is prepared at 250 mg/25 mL = 10 mg/mL. A 5 mL aliquot is used, representing 50 mg of sample.

The standard therefore represents a concentration of:
20.1 ug/50 mg = 0.402 ug/mg = 402 ug/g (ppm).

The concentration limit for acetonitrile listed in Table 2 of USP 467 is 410 ppm. So, the standard does represent the lower limit.

Write back if you have any other questions.

[Jana P]

That makes complete sense!! Everything suddenly seems much clearer.

Thank you for your help.

[mbicking]

You are very welcome.

As for your questions about Procedure C, I share your confusion. I have some contacts who may be able to explain, and will write back if they offer any insights.

[Jana P]

Yes the thinking behind procedure C is not clear.

It would be great if you could let me know if you hear anything.
In the mean time I will continue to try to nut it out

[mbicking]

I spent some time today carefully reading Procedure C, and I think if finally make some sense (scary thought, that I understand this!).

If you read the text, it says prepare solutions of individual solvents at 1/20 of the levels listed in Tables 1 and 2, under Concentration Limit. These are the limit levels for the solvent in product, not the concentration of the standard that you prepare.

Examples:
Acetonitrile: The Table 2 listing is 410 ppm. 1/20 of this value is 20.5.
The USP Ref Std Mix 2A has a conc. of 2.01 mg/mL. After dilution, the concentration would be 20.1 ug/mL.

Benzene: Table 1 says 2 ppm; 1/20 is 0.10.
The Class 1 Ref Std Mixture starts at 10.2 mg/mL and after dilution is at 0.102 ug/mL.

So, the proposed 1/20 spiking solutions are actually at the same level as the standards that you analyze; you are essentially spiking at the USP limit. I suppose you could look at this as a clever way to design the dilutions, but the explanations certainly are not very good.

And this approach, although mathematically correct, ignores all the units, which is probably why we were both confused initially. The concentration limits are in ppm, but this means ug/g in product. The dilutions of standards are really in ug/mL. In water the differences are insignificant, but this is one reason why I do not like the "ppx" way to describe concentrations.

Hope this helps. Good luck with your analyses.