By Anonymous on Friday, December 5, 2003 - 03:52 am:

i m looking a stability indicating hplc method fort pseudoephedrine hydrochloride syrup with a clear resolution of more than 2.0 between pseudoephedrine hydrochloride and ephedrine and also a method for pantoprazole sodium and its related impurities.

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By Bharat kumar Agarwal on Thursday, May 6, 2004 - 05:31 am:

How we studied the aerial oxidation of drug ? is there any methdology ?

Thanks

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By lime on Monday, May 10, 2004 - 06:41 am:

Hi !

We use 0.1 N HCl, 0.1 N NaOH and 3% H2O2 for degradation. Why 10% ? Actually ICH requires. The reason is as other people said that secondary degradation products. I also check heat and sunlight effects on product. About the concentration, the last conc. which you give HPLC must be the same as working conc. and we adjust degradatin samples' pH to normal sample's pH if they need.

hope helps.

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By Dave Curran on Friday, May 21, 2004 - 10:58 am:

Hi all,

Wondering if anyone has any good (i.e., tested) ideas for quenching a peroxide-stressed drug preparation. Many forced degradations I've seen involve "quenching" the oxidized sample by dilution with water, however I've seen situations in which the reaction rate is still too high after quenching and if anything goes wrong during analysis, the samples have degraded beyond 30% before they get reinjected. I'm sure refrigeration would help but that's not always practical. What about the addition of a base metal to the preparation to react with the peroxide? Copper? Iron? What about platinum to catalyze the reduction of peroxide to O2 and water?

Comments welcome.

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By Chris Pohl on Sunday, May 23, 2004 - 10:38 am:

Hydrogen peroxide degradation via platium is a standard technique as you mention. It's quite fast and efficient and you can tell when it's done via the end of bubble formation. Pt wool works best. You might want to do a control expt. to see if the Pt has an effect on your target analyte, though.

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By zelechonok on Sunday, May 23, 2004 - 03:16 pm:

Catalase is another option. Tiny amount of catalase powder will destroy excess of H2O2 very quicly.

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By Anonymous on Wednesday, May 26, 2004 - 03:30 pm:

Can I jump in here. There is something I've always wondered about. Why is 0.1N HCl one of the common reagents used to accomplish forced degradation. I always understood (from the days when I used to do a lot of digestions: for atomic absorption work) that hydrochloric acid is mildly *reducing*, and not an oxidant at all. But with forced degradation I thought the idea was to oxidize the analyte.

Appreciate your thoughts.

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By A.Nonymous on Thursday, May 27, 2004 - 08:53 am:

Anonymous may 26:

You can perform multiple forced degradations:
0.1N HCl: acid condition
0.1N NaOH: basic condition
1% H2O2: oxidizing condition
You can also try temperature, stability in your solvent, light stability, electrochemical oxidation, .....

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By Anonymous on Thursday, May 27, 2004 - 10:07 am:

The 10-15% degradation guidline makes sence to me, not only to reduce the potential for secondary degradation, but it also falls within the typical range for a release/stability specifcation for a drug product (90-110%). If the method is selective at this level of degradation, (in my opinion) the method is valid and good to go. No need to kill yourself developing or doing extra validation past 10-15%.

For the peroxide try using potassium metabisulfite. I havn't used it during forced degradation studies, but it woked for another procedure to inhibit peroxide activity in a sample preparaion. Just a thought.

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By Anonymous on Thursday, May 27, 2004 - 01:09 pm:

Although I've never convinced management, I would prefer to only stress to the point of product failure. This failure point, however, is not a 10% loss of active, but usually only a small (0.5%-1%) icrease in an impurity. This way, the method is being validated with more realistic solutions.

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By Anonymous on Wednesday, June 9, 2004 - 10:55 am:

I'm with you on that one. 10-30% loss of active may be a good goal for method development, but not so good for validation. In other words, it would be great if your method was still specific for you analyte of interest even after it's fallen apart into all a whole zoo of compounds, and that's a worthy goal to go after, but in the world of real pharmaceutical analysis, for example, you'll never get there, so how meaningful is that? It seems to me the target degradation should be no more than the potency spec (e.g., 90% of label) for validating specificity.

Only degrading down to the impurities spec I think has its ups and downs and requires a much longer discussion, which I'll forego for now... Anyone else want to joump in?

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By Anonymous on Wednesday, June 9, 2004 - 09:22 pm:

hello,

I have seen that everybody is referring to 10% degradation guideline.Can somebody pl. let me know if there any official guidelines for fixing the allowed limits for degradation and also how the degradation calculation is to be carried out.

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By jjj on Thursday, June 10, 2004 - 02:37 am:

Can somebody specify what are the limits for RRT for identifying the impurities.
Thanks

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By khimik on Friday, June 11, 2004 - 10:47 am:

My experience with RRTs is thus: avoid them if at all possible. There are just too many variables that can change RRTs. I've seen too many methods in which RRTs are not adequate. Using marker solutions for the ID of known impurities is far superior.

I you have no choice but to use RRTs, the limits should be supported by any ruggedness and/or robustness data on the method.

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By Anonymous on Friday, June 27, 2003 - 07:46 am:

Can someone provide me with the conditions to use of acid/base/peroxide (type, conc, exposure time)stress sample (tablet) and the rationale for choosing such parameters? In addition, what conc to use?

THANKS!

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By Anonymous on Friday, June 27, 2003 - 08:29 am:

I came up with a good acid stress technique
Take ten percent of the material that you are going to use in the test and place in a 10ml beaker. Fill another 10ml beaker with hydrochloric acid place both beakers inside of a 1000 ml beaker and cover with parafilm for a couple of hours(maybe longer or shorter depending on stability). Now combine the 10% of stressed material with 90% fresh material in a volumetric flask and dissolve and dilute. What you will be left with is a 10% degraded product that doesn't need to be quenched.

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By Tom Mizukami on Friday, June 27, 2003 - 01:44 pm:

>By Anonymous on Friday, June 27, 2003 - 08:29 am:

I'm sorry but this makes no sense to me. The reason degradation is limited to 10-15% is to prevent the generation of secondary degradation products. You can not degrade a sample 100% then dilute it with sample to get a 10% degraded sample. I also don't understand why you think you shouldn't just add the acid directly to your sample solution.

What most people are looking for is about a 10% reduction in main peak area as the indication of a 10% degraded sample.

Common starting conditions are 0.1N HCl and NaOH, and 3% H2O2. Degradation is going to be a function of time, concentration, and temperature. I usually use the above conditions and take a look at the samples afer a few hours and see where I'm at. If there has been little degradation, the rate of chemical reactions very approximately doubles for every 10C you raise the temp. You can increase the acid/base concentration, exposure time, and temperature as necessary to produce 10-15% degradation.

If you continue to see no degradation at some point most people will stop and assume that a given pathway is not going to be available to your drug, others will continue to boiling concentrated acid to force degradation.

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By Anonymous on Wednesday, July 2, 2003 - 09:51 am:

Thanks Tom.
But what I am looking for is the rationale for why 10% degradation. I think we should choose the conditions and time of exposure based on what is physiologically relevant or mimic typical storage conditions (e.g.liquid dosage). For simplicity, lets use a tablet dosage. The drug (e.g. table) probable will not be subject to 0.1N HCL for more than 5 hrs (fast state). Therefore, you should not stress the drug for more than 1 day at 0.1 N HCl (conservative). If your drug degrades significantly, you have a potential formulation problem. Even if you get less than 1% degradation at 0.1N HCL after 1 day, you probable should not stress the drug further. This rational also apply for the 0.1N NaOH condition. Do you agree? If you agree with my rationale, what would be the ratioale for using 3% H2O2?

I think the purity method should be develop for monitoring the related substances found under typical stress conditions and force degradation conditions that is physiologically relevant or mimic typical storage conditions. If you need 1N HCl for 10 days to achieve 5-10% degradation, then this condition should not be use to develop your method. I look forward for some guidance on this topic.

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By A.Nonymous on Thursday, July 3, 2003 - 11:33 am:

When you degradate only 10%, you assume that you dont have secondary degradation.

But has someone tested secondary or primary degradations on a finished product? How is the correlation between stress tests and reality?

Plz give some references.

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By Tom Mizukami on Wednesday, July 9, 2003 - 01:55 am:

>By Anonymous on Wednesday, July 2, 2003 - 09:51 am:

I'm not clear on why you think we should limit forced degradation condition to those that are "physiologically relevent."

We normally try to explore the pathways that could be expected to be encountered in long term storage. We use harsher than normal conditions to speed up the degradation process. The 10-15% degradation range is a compromise between sufficient degradation to make identification of multiple degradants easier and not so much degradation that we start to generate lots of secondary degradation products.

The H2O2 is used to test for oxidative degradation because we live and store our products in an oxidative environment.

How hard you stress the drug/product is a point of continuous discussion. Personally, I don't think 1N solutions are excessive.