Calculation of Impurity by using Formula

[Troubleshooter]

Hi,

I have a problem regarding Impurity only in sample i.e. ciprofloxacin ( Active pharmaceutical Ingredient ) while standadrs are free from any impurity. How can i calculate impurity which is only in sample ( By using formula ). I hope any one of you may experienced such type of problem as you are professionals while i am new on this forum and this field as well. So, please do reply.

Regards,
kashif Riaz

[chromatographer1]

You can only compare the purity of the sample to the purity of the standard.

You are not able to calculate the amount of an impurity for which you do not have a standard to evaluate from.

The first step is to identify the impurity. Manufacture a pure sample of the impurity and then compare it against the impurity in the sample.

best wishes,

Rod

[AdrianF]

In many cases it is impractical to identify and synthesise the impurity. It is then usual to estimate the amount of impurity by assuming it has the same response as the active.

A highly concentrated sample (1) is injected where the main peak is overloaded in order to give a reasonable response from the impurity. The impurity peak is compared with the active peak in (1) diluted 1 to 100. (2)

eg if the peak area of impurity in (1) was 50% of the peak area of the active in(2) the impurity level would be estimated as 0.5%.

This kind of method can be found in BP and USP

[moraespack]

There are also other ways to estimate the concentration of impurities.
- If you have a universal detector as refraction index or light scattering detector, you can inject a sample in a concentration where the impurities have reasonable response and the main active ingredient does not exceed the linear response of the detector. Once the run is made, you can integrate all peaks and quantify them by area percentage. If you have only a DAD detector, you can choose the best wavelength among all peaks and integrate them and quantify them as above.
- If you are using DAD as a detector, you can look the UV spectrum of the impurity and compare it to the spectrum of the main active ingredient. If the UV spectra are similar to each other, then you can quantify the impurity using the main active ingredient standard as a analogue one. I know that it is not the perfect way to do, but it is an ultimate solving.
I hope that it helps,
regards
Marcelo

[HW Mueller]

AdrianF, moraespack, you are assuming, you don´t KNOW, if you proceed as described. What do you do with these assumptions? Sell the drugs with a statement that contamination by other substances is PROBABLY below a certain %?
If this is allowed by authorities I would like to point out that there are people out here who disagree sharply.

[AdrianF]

I have just checked the BP and you can see the main features of the Rel subs method below.

http://www.pharmacopoeia.co.uk/ixbin/bp ... &a=display

In this case each of the impurities is given a response factor. It is essential you use a pharmacopoeial method.

[moraespack]

Dear colleagues,
I didn´t say that this can be done in order to sell a drug.
I´ve just described an simpler way to estimate the % of similar impurities to the main active ingredient in case of developing a method or a product Indeed, I was not sure if the reason of the quantification of the impurity. Sorry, there was a misunderstanding.

Marcelo

[HW Mueller]

Well, there appear to have been maybe 10 or more "misunderstandings" of this type in the last couple of years. For a pill swallower, like me, a bit scary.

[chromatographer1]

I agree with Dr. Mueller.

When I worked in the pharmaceutical industry we never 'estimated' an impurity.

We identified impurities, characterized them, synthesized them, and made 'standards' of them for evaluation of stability and purity of new drug formulations.

We even did stability evaluations of the impurities and determined their proper storage conditions. We checked their purity every three or six months.

It is no wonder that drugs cost so much. But I would not have it any other way.

best wishes,

Rod

[Troubleshooter]

Thanx a lot. I am surprised to see your replies. Thanx a lot again.

Regards,
Kashif Riaz

[HW Mueller]

Rod, just a guess: It could wll be that the costs of a drug are mostly due to all those biological/hospital tests. These are useless if a substance is not "pure".
(In our physical organic group at Boulder, CO we couldn´t get a doctorate if the "purity" of compounds we needed to synthesize was not within the required elemental analysis %).

[Troubleshooter]

Now sample is BISPROL FUMERATE and impurity is unknown means not mentioned in B.P. and USP. Can we quantify ?

[JA]

Going back to the case of Ciprofloxacin I'm wondering how appropriate are the Pharmacopoeial methods really? I mean, the monograph linked by AdrianF seems to indicate the identity of one of five related substances and provides response factors for only four.

Unless I am hugely mistaken (and in which case I will add a preemptive ) the related substances and possible impurities are wholly dependent on the synthetic route. I haven't seen the Pharmacopoeias define the manufacturing process and I guess this is a large part of the way generics are made. How are these methods considered valid?

[HW Mueller]

JA, I also read this ref and wondered from where the response factors came. But this sort of thing doesn´t surprise me anymore, for instance the quality control of radiolabelling is often even much more sloppy. (One must mention, though, that amounts involved are extremely low, and application maybe once in a lifetime). National required QC of clinical laboratory values come with a VERY large allowed range.
Now, if you synthesize very similar compounds a 100 times and the UV were all the same one might be inclined to think that statistics are in his favor regarding an assumption that the 101th compound will also have the same spectrum. Since millions of people might take a drug for years, I am still inclined to go with Rod on this.

[JA]

My employer is not in the business of manufacturing generics and we have no call for compendial methods but as a consumer I am mightily interested...

Why would a manufacturer chose to go through the costly process of all the work advocated by Rod if the regulatory authority (the UK's MHRA, for example) will accept QC release on a Pharmacopoeial method (BP method, linked earlier).

Unless Pharmacopoeial methods are intended for pre-commerical material, i.e. pre-clinical work and early stage clinical trials?