Use of volumetric solutions

Off-topic conversations and chit-chat.

20 posts Page 1 of 2
I work in a GMP regulated laboratory and we purchase NIST traceable volumetric solutions for our titrations from VWR. We currently use the CofA value for the normality for the calculations instead of standardizing the solutions ourselves. This has not been an issue until recently but now my management is questioning this practice.

I am wondering if others out there periodically confirm the normality of solutions that have been purchased as traceable to NIST.
If the solutions are truly traceable they should have a certified value with uncertainties, which should be good enough for anyone's management.

Peter
Peter Apps
Thanks, that was my arguement in a futile attempt to avoid a complete waste of time and resources.
Presumably your managers want you to standardize the solutions against other certified standards ? If you do a rough uncerainty budget, including the uncertainty in the other certifed standards and some sensible estimates of volumetric uncertainties in your lab you will find that any result that you can generate has larger uncertainties than the CoAs on the solution that you are trying to standardize.

If you start with highly pure, certified solid compounds, and can assay with only a few steps you might get lower uncertainties than the labs whose business it is to make up solutions, but I wouldn't bet on it.

Peter
Peter Apps
Hi

Well, I can potentially see what management might be aiming at but hard to give a direct recommnedation. Below is the intro from USP regarding volumetric solutions in the reagent chapter, note the comment around NaOH that I will get back to.

The USP titrimetry chapter <541> do not add much as I see it in this question. We typically buy ampules and standaize, so never have had the question.

What I potentially see as an argument is that you never check if the prediluted volumetric solution is OK. NaOH may be packed under inert enviroment but tends to attract CO2 (think there is a carbonate test) overtime when opened. perchloric acid like 0,1M in glacial actic acid attracts moist overtime and is temperture sensitive (may be corrected for differencesbetween standardization temp and analytical temp), certain complex or redox solutions may also be sensitive over time.

So while not being able to give a direct recommendation, it might be good idea/start to make a scientific rationale regarding which solutions in use that are more sensitive than others. (note the word recently regarding NaOH)

Preparation and Methods of Standardization of Volumetric Solutions
The following directions give only one method for standardization, but other methods of standardization, capable of yielding at least the same degree of accuracy, may be used. The values obtained in the standardization of volumetric solutions are valid for all Pharmacopeial uses of these solutions, regardless of the instrumental or chemical indicators employed in the individual monographs. Where the apparent normality or molarity of a titrant depends upon the special conditions of its use, the individual monograph sets forth the directions for standardizing the reagent in the specified context. For those salts that usually are available as certified primary standards, or that are available as highly purified salts of primary standard quality, it is permissible to prepare solutions by accurately weighing a suitable quantity of the salt and dissolving it to produce a specific volume of solution of known concentration. Acetic, hydrochloric, and sulfuric acids may be standardized against a sodium hydroxide solution that recently has been standardized against a certified primary standard.All volumetric solutions, if practicable, are to be prepared, standardized, and used at the standard temperature of 25. If a titration is carried out with the volumetric solution at a markedly different temperature, standardize the volumetric solution used as the titrant at that different temperature, or make a suitable temperature correction.
Izaak Kolthoff: “Theory guides, experiment decides.”
I haven't commented on this topic until now. However, that's mainly because I wrote a reply yesterday, and submitting "didn't Take", and I didn't want to re-type.

For a while our QA desk jockeys felt we should assay every chemical that gets used in the lab, not just volumetric solutions. For example, assay 1.000 N NaOH (as used in the citric acid USP monograph). So, to do that, we need a primary standard, like potassium acid phthalate. So how do we assay the potassium acid phthalate? Titrate with 1.000 N NaOH? See where I'm going with this? Sooner or later one has to trust "something".

So now we can use volumetric solutions of acids, bases, silver nitrate, EDTA, thiosulfate, etc., as purchased, as long as containers are stored properly and such solutions are within their expiration times.

Right now I've got an opened 0.1000 N silver nitrate that expired April 30, 2011 that cannot be used and must be disposed of. It was fine to use April 30, but could not be used the next day, that's "science".
In our laboratory made the following rule.
If we prepare the titrant from the vial - the day we have no doubt that he is 0.1000 M.
Naturally if you can not clearly delusional end result (for example 49% of the pure substance, then we recalibrate the solution).
If we leave the solution for the future then before each series of titrations we set its caption curtain as described in the Pharmacopoeia of at least three definitions, so that the precision of his RSD was less than 1 / 6 of the interval of expected values ​​(if the concentration is expected to 98-101% that RSD should be less than 0,5). It's even tougher than those calculated EDQM the benchmark for precision results.

Analyses of titrant held only before a series of titrations. To be accomplished in one day.


As the substances to test titer (such as potassium biftalate ), we use commercially available reagents were the highest purity. We do not check them, focusing on the passport producer, but the trace.
Validator of the EDQM and regulator the WHO endorsed this approach.
DSP007 wrote:
In our laboratory made the following rule.
If we prepare the titrant from the vial - the day we have no doubt that he is 0.1000 M.


So is a "day" 24 hours after you prepare the solution, or does it magically "expire" at midnight?

We've posed such question to our QA "minds", and have not obtained a response. Apparently our QA "minds" think that if they ignore us that we'll "forget".
Actually, I am getting tired of commenting on regulatory measures, but, CPG, some might not understand your statement "It was fine to use April 30, but could not be used the next day, that's "science"."
I understand this to mean that you sarcastically point out that this is indeed NOT science.
I just saw another writeup on the detrimental effects of the regulatory apparatus, I don´t remember where, but I think it was by Grob (the junger). Anyway, many prominent Chemists have pointet out the problems. In this forum the connection between not using professionals and ever new regulatory requirements have been pointed out, among other things.
Yes, "hedgehog clearly mean" (everybody knows) , that there was nothing with a solution for the night will not. But regulators like :lol: , and staff discipline ... 8)
HW Mueller wrote:
Actually, I am getting tired of commenting on regulatory measures, but, CPG, some might not understand your statement "It was fine to use April 30, but could not be used the next day, that's "science".

I understand this to mean that you sarcastically point out that this is indeed NOT science.


That's right, I'm a sarcastic American !!!! Somebody better weigh out that chemical before midnight !!!
Totally agree with CPG...sometimes the regulations themselves can be pretty counterproductive to the scientific method. What's worse is when your QZ department will go above and beyond regulations to cover their behinds out of fear (of nothing).

Using a volumetric solution here as received would be unheard of, even with a certificate. I have tried the rhetorical question of how do we know the primary standard is pure, but they just ignore that.

It's ok though, since I've been in R&D developing and validating the methods QC will use, I've been pushing them to use their brains everyday and challenging things that do not make sense.

It's really unfortunate when people above you who have the final decision on what you're doing don't even understand what you're doing.
Normalized standards cannot, by definition, be primary standards, and thus you must verify the normality. Primary standards have to be able to be traced to a gravimetric determination, as weight, and volume by default through weight, are your primary measures. A normality can change, due to absorption, evaporation, chemical reaction, etc. While a CoA for a primary standard is sufficient to validate its purity (it is in solid form, after all), a CoA for a titrant or other normalized solution is not sufficient to validate the normality.

That said, most labs that I have been in do not have issues with titrant normality drifting, and present the same arguments that have been presented here. However, any well written titrimetric method should include verification of the titrant normality.

On the other hand, use of a 1N NaOH solution in, for example, a colorimetric method or extraction method certainly does not require standardization - it is not serving a role as a secondary standard in the method.
Mark Krause
Laboratory Director
Krause Analytical
Austin, TX USA
mckrause wrote:
Normalized standards cannot, by definition, be primary standards, and thus you must verify the normality. Primary standards have to be able to be traced to a gravimetric determination, as weight, and volume by default through weight, are your primary measures. A normality can change, due to absorption, evaporation, chemical reaction, etc.so can the amount of substance (or the mass fraction) in a primary standard - hence the choice of compounds that are resistant to most environmental influences While a CoA for a primary standard is sufficient to validate its purity (it is in solid form, after all), a CoA for a titrant or other normalized solution is not sufficient to validate the normality Because both primary and secondary standards can deteriorate in storage and in use, in both cases the CoA will have, in addition to a statement of amount of substance content, whether as mass, mass fraction or concentration, a stated requirement for storage conditions, and an expiry date.

That said, most labs that I have been in do not have issues with titrant normality drifting, and present the same arguments that have been presented here. However, any well written titrimetric method should include verification of the titrant normality.

On the other hand, use of a 1N NaOH solution in, for example, a colorimetric method or extraction method certainly does not require standardization - it is not serving a role as a secondary standard in the method but in normal use an NAOH solution will turn into sodium carbonate solution, and sooner or later will no longer be fit for purpose - just like an expired standard.


Checking everything against something else every time leads to an infinite regress - ultimately we have to "trust" something. CoAs and traceability chains are place precisely to allow working labs to use certified materials and calibrated instruments to get their day to day business done cost effectively while still providing strict comparability (in the proper sense) of results between labs. What level of "trust" a lab uses depends on where it is in the traceability chain - an in-plant QC lab would use ampouled titrant references where a metrology lab would use weighed primary standards.

Peter
Peter Apps
I see this topic has not had any new replies in a while, but I'll add on.

In a Feb. 17, 2012 FDA warning letter to BioChem, item 5 (copied below)deals with titrants. Going from this, I'd say that for the assay of the pharmaceutical actives, one needs to confirm strength of purchased titrants before first use, and/or initiate a written program for re-checking them if the next use is longer than a specified interval. Note that the warning letter addresses titration of APIs titanium oxide (an SPF active) and salicylic acid (an anti-acne active). My guess would be that assays for incoming non-API raw materials would not require this, and maybe many of those assays are not validated anyway; but that's just a guess.

Anyone know, and can anyone detail what might be the minumum program/process with volumetric solutions to comply with cGMP/FDA? Thanks.

"5. Your firm has failed to maintain complete records of all testing and standardization of laboratory reference standards and standard
solutions [21 CFR 211.194(c)].

For example:
a. Your firm used unqualified secondary standards for the assay analysis of over-the-counter (OTC) drug products, including but not
limited to (b)(4). Therefore, you have no assurance that the assay results determined with these reference standards are accurate
and reliable.
b. Your firm failed to standardize the titrant solutions prior to using them for the titration assay analysis of titanium dioxide and
salicylic acid. In addition, your firm failed to establish a schedule for required restandardization of commercially purchased standard
solutions
. Therefore, you lack assurance that the assay results determined with these titrants are accurate and reliable.
In your response, you state that "we are already using the USP standards" or that you have implemented the use of USP standards since the
inspection. In addition, you state that you are implementing a new SOP to restandardize titrants."
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