Tablets assay 120 % / Triturated: 100 %

[LCFan]

Hello,

I analyse tablets. I have to perform dosage uniformity determination, where I make 10 sample preparations in parallel with single tablets.

With the same tablets, I make a trituration and make the same sample preparation.

The trituration result: 100% (with RSD <= 1.0 %)
The mean assay of 10 tablets: 120 % (with RSD >= 10%*)

Does anybody know such a phenomenon?

* RSD is not only analytical variance, but also tablet-to-tablet variance (but the analyzed batch has (with an older method) shown to have an RSD of < 5% between the tablets)

Florian

[DR]

First guess: you spilled a bit of your standard material between the balance and the flask.

Second guess: there's a problem with the LC method (it has not been validated, a wrong setting or other variable has been introduced).

Are you using an EP method? Is the standard used a compendial standard prepared as directed?
Is there a fudge factor not being taken into account (for example - if you use the hydrochloride salt of a drug substance to assay tablets whose claim is expressed in terms of free base, there's a formula weight ratio that must be applied)?

Provide more information about both procedures if you want better answers.

PS - it's Titrated

[Consumer Products Guy]

I had NEVER heard of that word trituration either, I looked it up on Google. I guess it means reducing several tablets to a uniform powder for sampling.

[LCFan]

Hello,

it is indeed a trituration. That's what comes out when you take mortar and pestle and make a certin number of tablets to a powder.

And that's exactly my problem:

- taking 10 single tablets results in a mean of 100%
- taking the mean of three weights of a trituration (powder) of 10 tablets, I find 120 % (with a good RSD)

The method is an old fashioned method which has been used up to now for trituration only:

- ACE C18 column
- mobile phase: A: 2 g sodium octane sulfonate per 300 mL, adjusted to pH 3.5 (CH3COOH) / B: methanol
A:B = 26:74
- flow = 1.0 mL/min
- T = 30°C
- detection: UV 240 nm
- sample dissolved in mobile phase; injection volume: 5 uL

Analyte has tensidic character but elutes with good symmetry based on the ion-pairing agent. The injection precision is very good (usually below 0.3 % RSD).

Now, I intended to use the method for non-powdered tablets and I expected some extraction problems. But I found an assay of 120% of the declaration. Thus, I immediately prepared a trituration and found 100% within the same sequence as the non-powdered tablets (=> no cleaning problems with the mortar). The tablet contains glycerin dibehenate, sodium cyclamate, lactose, two aromes and povidone.

My problem might be a general powder/tablet problem not really related to HPLC. But it might also be that any chromatographer in the world had the same problem as I currently have and that he was able to solve it.

Regards

Florian

[DR]

Well, at least I've learned something.

As to your results... There's a reason that tituration is sometimes not used in favor of just taking a handfull of tablets and throwing them all into a large flask and dissolving them in there and your results are an example of it.

With many formulations, it is very easy for segregation, or "unmixing" of the powders to occur once tablets are ground. When you have excipients of a different particle size from that of the API, segregation is almost certain to happen. Talk to the formulator(s) about what you're testing - see if they had trouble coming up with a blending and tabletting procedure that would keep things uniform. I bet they did.

Segregation can be exacerbated if the analyst pours the sample from a container instead of scooping it.