Chromatography Forum

Question: for cGMP, is there a limit of maximum RSD for standardization of titrants for cGMP use? I couldn't find anything in USP or FDA. FDA ORA seems to indicate to do three parallel determinations, but doesn't state how precise such results should be.

So does anyone KNOW, and can link/provide official source for this RSD limit? Thanks a lot.

according to USP 37, in the volumetric solutions section there is this:

1.3 Correction Factor: It is frequently difficult to prepare standard solutions of a desired theoretical normality or molarity, and this is not essential. A solution of approximately the desired normality or molarity is prepared and standardized by titration against a standard. The correction factor so obtained is used in all calculations where such solutions are used. If necessary, the concentration of the solution may be adjusted to a given normality or molarity, by dilution or by addition of the appropriate reagent.
The concentration of the volumetric solution does not differ from the prescribed one by more than 10%. The correction factor is determined by an appropriate number of replicates. The repeatability does not exceed 0.2% (relative standard deviation). The correction factor should be redetermined frequently.

This is what we use as our limit.

according to USP 37, in the volumetric solutions section there is this:

1.3 Correction Factor: It is frequently difficult to prepare standard solutions of a desired theoretical normality or molarity, and this is not essential. A solution of approximately the desired normality or molarity is prepared and standardized by titration against a standard. The correction factor so obtained is used in all calculations where such solutions are used. If necessary, the concentration of the solution may be adjusted to a given normality or molarity, by dilution or by addition of the appropriate reagent.
The concentration of the volumetric solution does not differ from the prescribed one by more than 10%. The correction factor is determined by an appropriate number of replicates. The repeatability does not exceed 0.2% (relative standard deviation). The correction factor should be redetermined frequently.

This is what we use as our limit.

Great. I hadn't noticed the change in that Chapter from USP 36 to USP 37, but it is there. But it really isn't there, it's in the section for correction factor, not in standardization, so confusing. Very confusing.

But, question: does your lab have any difficulties meeting such tight 0.2% RSD limit? That does seem awfully tight. Also, USP states "appropriate number of replicates" - so what exactly is this? 3?

Hi

EP has a bit further and posted what they expect in general depending on type of titration:

http://www.google.se/url?sa=t&rct=j&q=& ... 0786,d.bGQ

Check page 72.

Generally I would expect a factor of 0,99-1,01 for volumetric solution prepared via a "Titrosol" ampule rather than 0,90-1,10, but there are of course exceptions and dependent on how you prepare the solution (from scratch or via ampule).

Of course it depends on the substance but if I generalize a bit, we have with some irritation noted that USP/EP etc sometimes shifts from for example 1M NaOH to 0.1M NaOH, while seemly saving sample, basic titrants are more sensitive to CO2 and that gets worse when you drop to 0.1M.
So regardless if you look at 0,2% or 0,33% in EP (n=6 or more) that will be difficult at times. Note that the EP requirement on page 72 concerns the development of the monograph not the daily use/standardization but it is a good pointer when you try out a new monograph.

/Chris

according to USP 37, in the volumetric solutions section there is this:

1.3 Correction Factor: It is frequently difficult to prepare standard solutions of a desired theoretical normality or molarity, and this is not essential. A solution of approximately the desired normality or molarity is prepared and standardized by titration against a standard. The correction factor so obtained is used in all calculations where such solutions are used. If necessary, the concentration of the solution may be adjusted to a given normality or molarity, by dilution or by addition of the appropriate reagent.
The concentration of the volumetric solution does not differ from the prescribed one by more than 10%. The correction factor is determined by an appropriate number of replicates. The repeatability does not exceed 0.2% (relative standard deviation). The correction factor should be redetermined frequently.

This is what we use as our limit.

Great. I hadn't noticed the change in that Chapter from USP 36 to USP 37, but it is there. But it really isn't there, it's in the section for correction factor, not in standardization, so confusing. Very confusing.

But, question: does your lab have any difficulties meeting such tight 0.2% RSD limit? That does seem awfully tight. Also, USP states "appropriate number of replicates" - so what exactly is this? 3?

As far as I know, we haven't had many issues meeting that requirement. Most of the time we buy higher concentrations of the titrants (1M, 2M, 5M) and dilute down to what we need a few days before titrating. this way we eliminate the CO2 absorption effect.

We've asked some suppliers of standardized titrants (I think they all buy from just a few sources worldwide), and I've received responses of meeting 0.2% RSD, some say three titrations, some say more can be used. One large supplier responded 0.5% RSD.

Our automatic titrators seem to be able to deliver results about 0.5% RSD. Our Karl Fischer titrator supplier has RSD limits higher than that, from the supplier's own data. So I'd say write your own SOP, and then follow it. I think if your SOP states to meet 0.2% RSD you'd have situations that fail to meet this, and then OOS investigations. Honestly, I believe that the suppliers can do a better job of standardization than most labs.

Sorry, people, can't help more than that.