(Developing) a discriminatory vs bio-relevant test

It appears that there is confusion in the description of these terminologies. In reality, these are one and the same thing. Let me explain:

A bio-relevant dissolution test is a test, which should be able to differentiate (discriminate) between the in vivo behaviour of two or more products. The in vivo behaviour means bioequivalency or bio-in-equivalency of the tested products. Therefore, by its very nature a bio-relevant test becomes a discriminatory test as well.

So, why are these two terminologies often referred to as different or separate? It is due to the fact that in the dissolution testing area, a discriminatory test is also described as, wrongly, an in vitro dissolution test, which may show formulation/manufacturing differences without their in vivo relevance or consequence. Such tests are often described as QC or consistency-check tests (e.g., in pharmacopeias). It is important to note that these tests do not relate to the in vivo characteristics of products, however, they are still expected to reflect quality of the products for humans use. How? It is not clear and is the most confusing part of current dissolution practices! In my opinion, these tests (QC or in vitro discriminatory), and their requirements, are not very useful and are conducted as a “tradition”.

It is like developing a (“discriminatory”) thermometer which will show differences of a couple of degrees of temperature from person to person (or within a person) and then, developing another (real/actual) thermometer which will reflect whether a person has a fever or not based on a difference in the temperature reading. In dissolution terminology the first type of thermometer would be called a “discriminatory” test or tester and the second type as “bio-relevant”. Can any one tell me, why should we have the first type of thermometer or test?

The purpose of this explanation is, if possible, to avoid using the word/terminology of a “discriminatory” test, as it takes an analyst away from the objective of drug dissolution testing. The only test required is the one which should be bio-relevant.

For developing such a test, one first has to define what a bio-relevant test is. I have explained this in one of my earlier posts (see Link). Briefly, a bio-relevant test is a test which not only provides physiologically relevant results, but these results must be obtained using physiologically relevant experimental conditions as well. Trying experimental conditions without their physiological significance or relevance would not be a useful exercise.

One main consideration in this regard is that as the human physiology remains the same, the experimental conditions should also remain the same as well. Therefore, working with different experimental conditions, in particular specific to your product, will be a violation of the fundamental requirements of (bio-relevant) dissolution testing.

The physiological environment dictates the following single set of experimental conditions. (1) Temperature 37 °C (2) Medium: aqueous buffer having pH between 5 and 7 (use of water can be a good choice or start), with or without solubiliser (3) Mixer: To provide gentle but thorough stirring and mixing. That is it!

One does not have an option of trying different experimental conditions. It is very important to note that, if one deviates from this testing requirement then that test may not be considered as a bio-relevant test, even if it provides matching bio results, as they are not obtained using bio-relevant experimental conditions.

Presently, paddle/basket apparatuses are used as mixers/stirrers, which have been shown to provide no or limited stirring and mixing. Therefore, one should NOT expect to obtain bio-relevant results using these apparatuses. If one obtains bio-relevant results using apparatuses, these should be considered as a match by chance.

The first thing in trying to obtain bio-relevant results, therefore, is to try a different stirring/mixing approach. There is no simple or practical option available, at least in my view, other than to try a different apparatus which shows gentle but thorough mixing and stirring environment.

Another important thing to consider is that one cannot develop a method using a product which is still under development (see link). One has to have a reference product with known drug dissolution characteristics which unfortunately is not available at present.

In the absence of such a reference product, what one may consider is to develop a method based on an approach of relative dissolution testing (as explained here).

In short, therefore, one needs to develop a bio-relevant dissolution test which by default will be discriminatory. Choice of experimental conditions should be based on the physiological environment. The experimental conditions should be established using well established products for human use and must not be based on a product which is under development.

As a starting point, the following may be considered: water as a medium (900 mL), with or without a solubiliser, maintained at 37 °C with a gentle but thorough stirring and mixing, perhaps using the crescent-shape spindle or another similar approach.

Links to two other articles which you may find useful as well (article1, article2)

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