Avoiding Bad Habits in Dissolution

Avoiding Bad Habits in Dissolution

A recent article “Sources of dissolution variability into biorelevant media” (https://www.sciencedirect.com/science/article/pii/S0378517322003003?dgcid=author) found that location was the biggest factor in dissolution variability, and mentions other articles where location was found to be a main factor as well.?The study doesn’t get into why location is such a large factor – but I have some ideas based on my experiences in the industry.?In working with many customers all over, I have seen a lot of significant differences in how dissolutions are done from one lab to another.?I think these differences boil down to a couple of key issues, SOPs and training.?These two issues then lead to a wide variety of practices being followed and there being different ways of doing dissolution in different labs.?I’ll go over what I’m talking about, and point to some of my previous articles in this discussion.

As always, this article represents my views alone – and do not reflect the views of my employer.

SOPs written incompletely – or being too specific – Many times when I am working with a customer experiencing a challenge, I will ask to see the SOP that they are following.?I frequently will find methods which haven’t properly defined key parameters such as what filter to use and how to use it, degassing requirements, autosampler settings, cleaning protocols, etc.?I’ll also see challenges with the method being too specific and listing out a specific brand/part number item, which may not be made forever and cause challenges in the future.?When writing a SOP, you need to make sure that it captures all aspects of the method as it was validated.?You also need to ensure that the SOP is flexible enough to be able to change over time by allowing for other validated options should needs change in the future (for example using a different filter type).?I talk more about SOPs here:?https://www.dhirubhai.net/pulse/common-dissolution-sop-mistakes-ken-boda/

Inconsistent Training Plans – Dissolution Training is a hands-on effort.?As a result of this, dissolution training is often a grandfathered approach where one analyst trains another, who trains another, and so on.?As time goes on, more and more bad habits, short cuts, or even useless additional steps will creep into the dissolution procedure.?Sometimes, these bad habits will even make their way into the SOPs themselves and cement these bad habits.?To combat this, I would recommend that training should be periodically reviewed against the standards for dissolution testing such as USP <711>, <724>, <1092>, as well as regulatory documents that pertain to your region.?Secondly, I strongly recommend that part of the training be a standardized approach.?There are a lot of standardized training options out there, some with little to no cost.?Agilent offers one that is free to take at: https://www.coacssoftware.com/Dissolution2/

By standardizing part of the training, you can help to ensure that there is a correct foundation to build on in the lab, and limit potential sources of variability going forward.

So, what are some of the specific bad habits/procedures that can come up in the actual dissolution run?

Pre-stirring Dissolution Media – Pre-stirring dissolution media is often seen as a way to equilibrate the dissolution media more quickly so that you can start your run quicker.?This is a bad practice that I used to do, and it seems harmless.?There are 2 issues with this practice though that can lead to issues.?The first, is that by stirring the media you are likely speeding up dissolved gasses getting back into your dissolution media if you’ve degassed it.?

The second issue is that even if you stop the paddles before dropping your samples, you are dropping those samples into a media that is still rotating.?Media may continue to rotate several minutes after stopping the paddles.?This leads to greater variability in where your tablet lands in the vessel, which can cause a pretty dramatic impact with some dosage forms.?With the USP Prednisone test, a tablet landing off-center in the vessel can cause the tablet to disintegrate on the side of the vessel and forming a cone there – which then redistributes to the center of the vessel.?When that cone shifts from off-center to center, you see an increase in dissolution for that sample.?I saw this when the USP made the major changes to the PVT with the addition of the %CV requirement, and doing some investigation into causes of variability.?You can also get dramatic dissolution differences with off-center landings with products that stick to the vessel wall, such as a film coated tablet.?This can place the sample in an area of much higher hydrodynamics in the vessel and lead to variability.

Not Validating a Filter – Filtration is a key step which stops the dissolution process so that we can get an accurate picture of what has dissolved at that time.?If you aren’t using the proper filter, you can have results that are too high, too low, highly variable, etc.?You can find out more about proper filter validation here:?https://www.controlledreleasesociety.org/news/separation-done-right-selection-and-validation-best-dissolution-filter

Waiting to Filter- Another issue regarding filtration, is not filtering while sampling or immediately after.?This occurs a lot when it comes to use of syringe filters, since an analyst will first pull the sample (or all 6-8 samples) and then attach the syringe filter and push through it.?When you take a dissolution sample and pull it through a cannula and into a syringe, you are exposing an undissolved particles that have been pulled to very high hydrodynamic forces.?You can essentially force undissolved particles you have collected to dissolve in your syringe.?This effect gets worse if you wait several minutes to filter your sample.?This practice can lead to high values and high variability, sometimes with samples showing much higher than 100% dissolved values.

How can you limit these issues??First, I would recommend to use a cannula tip filter where possible.?Cannula tip filters are now available as low as 1 micron, and in many cases this will be the only dissolution filter that you need.?Even if you need finer filtration, use of a tip filter as a pre-filter will prevent most of the undissolved particles from making their way into the cannula and this will reduce the potential spike in values you might see.?Second, I would recommend sampling and filtering one sample at a time by staggering your drops and sampling.?Finally, this is something that autosamplers can really help with – as they can do immediate filtration while sampling with a wide variety of filters and filter types.

Not Validating a Cleaning Method for each Product – Cleaning is key.?Different cleaning methods may be needed for different formulations and different medias.?A little more info on that here: https://www.dhirubhai.net/pulse/cleaning-care-dissolution-components-how-save-lab-ken-boda/

Weighing your Products or Leaving them Out – Unless your sample has a direct correlation between weight and dose (such as powders, beads, semi-solids, etc.), weighing your sample likely will not add value.?In addition, weighing your samples or leaving them out exposes them to the laboratory environment.?Analytical balances often can still have drug residues on them which can contaminate your sample.?Laboratory air, especially near a dissolution unit, can be moist as well.?If your sample is hygroscopic (like prednisone is), then the moisture in the air can start working on your dissolution sample before you drop it.?It is good practice to not remove your samples from their container until it is time to start your dissolution run.

Not Quarantining Samples – If you’ve done a dissolution test and analyzed your samples, don’t throw them out.?Wait until the data has been reviewed so that you can re-analyze the samples in case an investigation is needed.

Not using a Sinker – If your product floats, dances, spins, etc., use a sinker.?The USP Capsule Coil Wire and JP Sinker basket are generally the best as they are heavy but don’t restrict media access too much. More on this in my previous article at: https://www.dhirubhai.net/pulse/dissolution-sinkers-101-ken-boda/

Using Accessories in Bad Shape – I frequently have found that failing dissolution runs are due to components being in bad shape.?Peeling PTFE paddles, bent or corroded baskets, basket shafts with loose clips, cracked vessels, etc. can all lead to variable mixing and contamination.?Every time you run on a dissolution system, you should evaluate whether the system is fit for use – including assessing these accessories.?Whether or not your lab is following the MQ, following the inspection elements in the FDA/ASTM/USP Toolkit is good practice.

Not Evaluating Vibration – Vibration con be continuous or periodic, and lead to variable dissolution data.?Reducing vibration with proper maintenance of equipment, keeping dissolution units away from sources of vibration, and putting the systems on an adequate bench is key.?Vibration should also be checked either by simply feeling it, or even better monitoring changes in vibration over time with a sensor.?I discuss this more here:?https://www.dhirubhai.net/pulse/vibration-dissolution-ken-boda/

Bad Sampling Location and Times – Proper sampling per USP takes practice and skill.?Sampling is also one of the largest causes of dissolution failures – so it is important to do it right.?I offer some suggestions here:?https://www.dhirubhai.net/pulse/how-manually-sample-ken-boda/

Not De-gassing Media Properly – Dissolved gasses can lead to variability with some dosage forms.?Determining if you need to degas and doing it the right way is very critical and another major source of dissolution failures.?I recently went into this topic at:?https://www.dhirubhai.net/pulse/overview-dissolved-gasses-dissolution-testing-ken-boda/

Not Validating the Automated Method – When automating a dissolution method, the method needs to be validated to show that a bias is not introduced when using the automation vs. the manual method.?USP <1092> has some guidance here on parameters to look at.?The most frequent issues I have seen are not properly defining how the automation needs to be programmed (prime, purge, and waste drop volumes for example) and improper cleaning.?The automation webinar presented here goes into more detail on what needs to be considered: https://event.on24.com/eventRegistration/EventLobbyServlet?target=reg20.jsp&referrer=&eventid=2959277&sessionid=1&key=5D056218CBE6F7987377DA871D36AB10&regTag=1971932&V2=false&sourcepage=register

Not Making Observations – Observations can help tell a lot about why the dissolution data looks the way that it does.?I strongly encourage taking observations at the beginning of the dissolution run to look at how the dosage form initially behaves and check for obvious analyst errors.?I also encourage observations be done at the end of the run before cleaning the dissolution unit, and while sampling when possible.?More on this at the dissolution method development webinar at:

https://event.on24.com/eventRegistration/EventLobbyServlet?target=reg20.jsp&referrer=&eventid=2959277&sessionid=1&key=5D056218CBE6F7987377DA871D36AB10&regTag=1971932&V2=false&sourcepage=register

and https://www.dhirubhai.net/pulse/first-2-minutes-dissolution-ken-boda/

While this article doesn’t include all of the bad habits I’ve seen in labs, I think it presents some of the more frequent root causes that I’ve seen.?I hope you find this article helpful, and please let me know what other articles might be of interest.?Thanks.