The following article has been authored by John Heaney.
Variability is a fact of life in any manufacturing process. That is the reason there are acceptance ranges and tolerances as well as QC departments to measure finished product ensuring that everything is acceptable. The tools used by any QC department need to be as consistent as possible. A pair of calipers that gives a slightly different reading each time when measuring an NIST standard block is not particularly valuable. The same is true of dissolution testers, or more specifically vessels, that have high variability. High variability in the vessel size and shape will increase the variability of the results.
Most accessories used in dissolution testing are machined which allows for the relatively tight tolerances of about 0.13 mm or 0.005 inches. Historically, the vessels have not fallen into this category. At the start of dissolution testing back in the 1960’s, vessels were hand formed from glass tubing by master craftsmen. A good craftsman would be able to keep the vessels similar, but they do this by working on the outside of the glass, not the inside where ultimately the tablet and dissolution media reside. And imperfections could form, whether it be to differences in craftsmen from the same facility, differences in the glass, or differences in how the flames were applied.
The hemisphere of the vessel is the most critical part of the process, but until the past 2 decades, has shown some of the highest variability. For Apparatus 2 especially, the hydrodynamics near the tablet would be determined by the hemisphere of the vessel. In some cases, deformities may be easy to find. One vessel has a shallow hemisphere compared to a deeper one, visibly obvious when the vessels are side by side. Or a vessel may have a slight bulge in one direction causing it not to match others that can be felt when inspected by hand. In other cases, it may not have been obvious until a performance verification test is done.
Vessel manufacturing technology has improved significantly though, and while higher variability was a requirement before, it is now optional. While the specifics of the process vary from manufacturer to manufacturer, high precision vessels can be manufactured using a process similar to molding. This allows for the dissolution vessels to move away from tolerances typically used for items made by hand, and closer to that of machined items.
And the results in many cases are obvious. Numerous studies have shown that vessels like QLA’s UltraCenter™ Precision Molded Glass Vessels are much more consistent both mechanically and during testing. In every case the adoption of high precision vessels has resulted in better centering results for ASTM based mechanical qualifications and lower variability with the USP Prednisone PVT. The reason for this is clear – the vessels are more similar, so the hydrodynamics are similar, so the results are similar.
In QLA’s own testing the variability dropped from over a %CV of 6 to a %CV below 3. That’s an immense change from altering a single component on a dissolution tester. It also further shows how critical the vessels are in dissolution testing.
Additional studies also show the benefits of these vessels:
- Effect of the Irregular Inner Shape of a Glass Vessel on Prednisone Dissolution Results (Makoto Tanaka, Hiroyasu Fujiwara and Morimasa Fujiwara, Dissolution Technologies November 2005, pgs 15-19)
- Dissolution Testing Variability: Effect of Using Vessels from Different Commercial Sources (Mark R. Liddell, Gang Deng and Walter W. Hauck- US Pharmacopeia. American Pharmaceutical Review)
- Evaluation of Glass Dissolution Vessel Dimensions and Irregularities (Mark R. Liddell, Gang Deng, Walter W. Hauck, William E. Brown, Samir Z. Wahab and Ronald G. Manning, Dissolution Technologies February 2007, pgs 28-33)
- Perturbation Study of Dissolution Apparatus Variables—A Design of Experiment Approach (Joseph Eaton, Gang Deng, Walter W. Hauck, William Brown, Ronald G. Manning and Samir Wahab, Dissolution Technologies February 2007, pgs 20-26)
The adoption of vessels similar to QLA’s UltraCenter™ Precision Glass Vessels are not just useful for passing the qualifications, but they show that the variability is present with the tablets or capsules rather than within the system. This makes determining if there’s a QC problem and if a batch needs to be stopped far easier and more reliable than handmade Standard Glass Vessels. They provide results you can count on.