The First 2 Minutes of Dissolution

For those of you who have read my posts or attended one of my talks, you probably know that I am passionate about making observations of your dissolution run. Observations often can tell you as much about the product you are testing as the percent dissolved graph that you'll get at the end of analysis. In particular, watching the first couple minutes of the dissolution run can be incredibly helpful in diagnosing many common causes of failure in dissolution - and it requires so little of your time.

What information can be gained in a couple of minutes in dissolution? There are quite a few things we can see from aberrant product behavior to simple mistakes to needing to change the dissolution conditions. Here is a partial list of things that you may find:

Analytical Errors -

Nobody likes to admit they made a mistake, but they can be pretty common in dissolution testing. Some of these are mistakes I've made - others are customer reported, I won't say which is which. Not pouring enough dissolution media into a vessel, dropping 2 samples into the same vessel, not dropping a sample at all, setting the wrong RPM speed, a basket fell off, forgot to put the sample into a sinker, paddle/basket height isn't correct, and significant air bubble formation are all possible analytical errors. If you see any of these have occurred, then this will allow you to immediately abort the test and you can start a new one. No analysis and subsequent investigations needed - just a simple mistake.

Coning -

Disintegrating dosage forms will usually form a cone at the bottom of the vessels, and these cones typically will form within the first minute of the dissolution. Coning isn't necessarily a bad thing - and you can learn quite a bit by paying attention to how the cone is formed.

First, is the cone loose and moving somewhat or is it stationary and packed? If the cone appears to have some movement or particles surrounding it, then this is a good sign that the media is able to access the drug and would be able to dissolve it over time. If the cone looks packed down, not moving, few particles surrounding it, or is an odd shape then this could point to a coning problem. If there is a coning problem then this could indicate that you need a higher RPM speed or a formulation issue.

If you do have a loose cone, then next thing that I would look for is how the cones look between the 6-8 vessels. If all the cones look the same, then this is a good indicator that the products are behaving uniformly and that the dissolution unit is properly aligned and was set up properly. If the cones do not appear the same, then you need to take note of what is different and in which positions. If you see 1 position with a smaller cone than the others, then this could be an issue with that sample or something pertaining to the alignment of just that position. If you see a trend of cone sizes from left to right or front to back, then this is likely pointing to the system itself is misaligned and you have a trend of more centered to less centered shafts as you look across the unit.

Cross-linking -

Cross-linking of gelatin capsule shells is something else that you will see in the first 2 minutes of the dissolution. Usually, capsule shells will open within 1-2 minutes. If you find that one or more of the samples is taking longer to dissolve than 2 minutes then this could be an indicator that cross-linking is occurring with the sample. As it gets worse, you'll go from a delayed opening to formation of slimy balloons, tentacles, etc. which can restrict some or all of the drug from being exposed to the media for the duration of the run. The best time to observe cross-linking is at the beginning of the run.

Product movement -

Watching how the product behaves initially can be very important as well. For paddle methods, you want to make sure your product isn't floating - in which case you need a sinker. You should also use a sinker when you see dosage forms spinning, dancing, etc. as well. The more variable the movement of the sample is, the more variable your result will be too.

Samples in baskets should be watched as well. A recent lot of USP Prednisone tablets had a high rate of tablets floating in the baskets leading to % CV failures. These failures were not due to anything wrong with the apparatus or the chemist - it was just a quirk of the tablets themselves. Seeing this floating and aborting the test was the best practice and saved a lot of run and investigation time.

Disintegrating products in baskets you also should pay attention to the amount of powder which comes out of the basket initially. Excessive powder coming from one basket can cause lower results and may be due to vibration on that spindle or a worn/wobbling basket.

Air bubbles -

Deaeration can be critical for some dissolution products. Looking for air bubble formation can be very useful. A couple small air bubbles likely aren't an issue, but if you see several or large ones then there can be many potential issues. Blocking the basket mesh, causing floating or clumping of product, and even changing the mixing characteristics can occur.

I hope you take the time to watch these first couple minutes of your dissolution runs and write down a quick note about any observations you have. Those observations can be very valuable in helping with product development, explaining aberrant data, or aborting bad tests.