Degradation by extraction with an ultrasonic bath?

[AdrianF]

I have recently been told that some degradation of pharmaceutical actives can take place when extracting with an ultrasonic bath prior to HPLC. eg racemization of chiral compounds and break down of some actives.

I have always used ultrasonication as the most effective way of extracting actives from tablets. I have never noticed a problem.

Has anyone out had a problem with ultrasonication?

[Bryan Evans]

I remember an application where we added ice cubes to the ultra sonic bath to prevent overheating of the samples.

I imagine that once you're working with something that sensitive, you need to take extra precautions as well
(actinic glassware, aluminum foil covering the glassware and autosampler window, ect.).

I remember one lab that had to work with the lights off b/c the compound
was so sensitive to UV light.

In theory - this should all be flagged during the development / validation process.
But - often times these things come up after the method is transferred
to another laboratory.

[chromatographer1]

The answer to your question is YES. It can happen.

Bryan gave a more lengthy answer to his credit. And he is quite right.

Care must be exercised when using sonication. Use no more than necessary. You are essentially adding energy to a chemical system and the added energy can cause reactions to take place, just as though you were merely heating a solution, which sonication can do if done for more than a few seconds.

best wishes,

Rod

[Bruce Hamilton]

You have the answers above. I've certainly had sample degradation in ultrasonic baths, mainly on non-formulated APIs and metabolites, even without any heating, but often with just 5 - 10 minutes exposure.

Ultrasonication is most effective on crystalline samples, and works quite well wiith many formulated tablets, which may also present a stabilising matrix for the API during extraction.

However ( my experience - your's may differ.. ),
1. Modern ultrasonic baths are quite powerful - I use a cheap dentist's implement cleaning bath which has 100 watts of output power, and can shatter some glass vials if held stationary at a energy node.
2. Any heat will accelerate API decomposition, especially if extracted into solvents, so several brief exposures to ultrasonic energy followed by shaking are often preferred, and more effective.
3. Amorphous/polymeric materials don't dissolve easily, and using heat and longer ultrasonication, instead of shaking, can lead to analyte decomposition.
4. Ultrasonication can also degrade some excipients and stabilizers, witch can interfere if you are also performing related substances analysis.
5. Low viscosity/surface tension solvents tend to transfer the highest energy, and also tend to be less pH buffered when extracting formulated materials, which may accelerate some degradation.

Use ultrasonication when it's most effective, but always be aware of the potential for harm, and revert to other techniques to confirm data if there is any doubt.

Please keep having fun,

Bruce Hamilton

[AdrianF]

I am aware that heat and light can degrade certain chemicals but can anyone offer any evidence that an ultrasonic bath extraction per se can cause degradation.

Or can anyone mention a specific drug/chemical which is degraded by ultrasonication.

[Peter Apps]

I vaguely remember seeing something about focussed ultrasound being able to generate so much energy by cavitation that you get flashes of light because the temperature gets up to the same as the surface of the sun. I doubt that any drug is going to put up with that for very long !

Peter

[Peter Apps]

Fun with ultrasound ........

http://www.sciencedaily.com/releases/20 ... 092605.htm

http://www3.interscience.wiley.com/cgi- ... 9/PDFSTART

Peter

[Bruce Hamilton]

Unfortunately, I can't specify the specific APIs and metabolites I've encountered ultrasonic degradation, but last year some retinoid drugs and metabolites showed degradation that was avoided by simple shaking of the volumetric..

I tend to avoid using ultrasonics for "at risk" compounds. As ultrasonication is effective because of the high localised energy, it would not be easy to separate out the effects of heating, especially as aqueous solvent misxtures can quickly transfer heat away

If you want specific published examples, you may have to go back to the 1960s and 1970s when ultrasonics were being considered.

" Ultrasonic degradation of aspirin in mixed solvent systems "
T. E. Needham Jr., Robert J. Gerraughty
J. Pharmaceutical Science v58 p62-64 ( 1968 )
Abstract
The effect of ultrasonic energy on the degradation of aspirin in ethanol-water, diethyl ether-water, and diethylene glycol-water solvent systems at various concentrations and temperatures was studied. It was found that the application of ultrasound to a system undergoing degradation would cause an increase in the rate, but would maintain the same kinetic order as in the control system. The heat of activation seems to be lowered by the mechanical vibrations of the ultrasonic energy. It is postulated that the ultrasonic vibration increases molecular collisions and the movement of the products away from each other, thereby producing a change in the overall rate of reaction. As the concentration ratio was increased in the diethylene glycol system, the subsequent increase in viscosity had a damping effect on the ultrasonic vibration.

I should note that many of the baths/probes from that era were much lower energy that current multiple-transducer ultrasonication systems.

Or you could look at the issue with automated sample preparation...

Automated Sonication and Sample Degradation; A Study of Two
Pharmaceutical Formulations. Peter J. Doyle
AstraZeneca Pharmaceutical & Analytical R&D
http://www.jasco.hu/konyvtar/Prelude-Ap ... n-AP13.pdf

As far as I'm aware, the plan to use ultrasonic compression to speed up the manufacture of pharmaceutical tablets hasn't been implemented which may partly be due to staility/degradation concerns.

I'm sure a WWW search would reveal many specific examples of ultrasonic degradation of chemicals, as it was proposed as a means of cleaning up process effluents and destroying toxins.

As I noted earlier, it is the analyst's responsibility to ensure that the sample preparation does not introduce artifacts.

Bruce Hamilton

[AdrianF]

Thank you for your answers. I will treat the ultrasonic bath with greater respect now. Clearly the effect of utrasonication should be part of method validation.

However I feel it is a mistake to go the other way and only use shaking which is relatively inefficient and very time consuming.

From the paper by Peter Apps it would appear that an Ultrasonic probe is likely to cause far more degrasation than an ultasonic bath. In the past I have used a poweful ulrasonic probe to break up bacterial cells.

[Dan]

The heating effect of ultrasonication has always been a concern where I have worked. However, we never tested its effects; if indeed there were any.

In one lab, we had cooling coils using cold water to keep the bath temperature around room temp. while sonicating.

I think that Rod made a good observation in that you should keep the sonication time to a minimum. For the preparation of tables, 10-15 minutes should be more than sufficeint sonication time. You would probably need twice that to have as efficient an extraction of the API (and other analytes) with a mechanical shaker.

Regards,
Dan