This chapter appears quite popular and is often cited as a source for help and information concerning dissolution methods development and validation. However, if one evaluates it, even superficially, one should immediately realize that the chapter is based on invalid assumptions and false science. For example:

The chapter is meant to be helpful and useful in developing and validating a dissolution method. However, the problem is that for such a purpose a fundamental requirement is that one requires a reference product with known dissolution characteristics established independently. In this case, one requires a reference product, which should be approved for human use as the method is to be used for such a purpose, with known dissolution characteristics. The (dissolution) method development means that, using valid scientific principles and testers, the developed and validated method would be able to provide an expected answer for the reference product. This developed and validated method will then be used for evaluating the test products. As, at present, a reference product with known dissolution characteristics is not available, therefore, it is not possible to develop and validate a dissolution method. It is simply a scientific impossibility.

Furthermore, the valid scientific principles and testers mean that developed and validated method must be based on experimental conditions which are relevant to applications of the method. In this case, the relevancy aspect comes from the physiological environment of the GI tract in particular intestinal. The only purpose of the test/method is to evaluate dissolution characteristics of a drug product in the GI tract. It is important to note that even for QC purposes the method measures the dissolution characteristics for the GI tract that is why most, if not all, pharmacopeial tests are conducted using physiologically relevant conditions as well. Therefore, the choice of experimental conditions must be physiologically relevant.

A basic or fundamental requirement, in this regard, is that whatever experimental conditions one chooses to represent the GI tract environment, these should remain consistent from product to product or should be product independent, as does the GI tract environment. This is the second flaw (invalid science) of this chapter that it suggests and emphasizes selecting the test product dependent experimental conditions. It will be impossible to determine true and accurate dissolution characteristics of a test product using experimental conditions specific to the product itself. Furthermore, as the experimental conditions change from product to product, which is unlike the GI tract environment, therefore, such tests would be considered invalid for any purpose. No matter how one presents the argument, for product dependent experimental conditions, it will be an irrelevant evaluation method and test.

It is, therefore, critical to understand that the chapter cannot provide help or accurate information for developing or validating a scientifically valid dissolution method.

It is often suggested that to obtain appropriate dissolution characteristics of a product one may use or select an apparatus depending on the product attributes and/or desired release characteristics such as discriminating profiles, reproducibility, bio-relevancy etc. Such reasoning however, dictates that the analyst/formulator should have an idea about the expected outcome of the results, whether based on an educated guess or from prior experimentation. By selecting a particular apparatus and/or its associated experimental conditions, one is in fact trying to achieve the results reflecting one’s own expectation.

For example, when one conducts an experiment using the paddle apparatus and finds dissolution results of a tablet product, and their variability, higher than expected while observing that some, or all, tablets are floating within the vessel during testing. Such behavior or experiment is commonly considered flawed or inappropriate. A common practice to rectify this “problem” is to either use the basket apparatus, or a sinker, to restrict this floating behavior assuming that this may be causing the higher results and variability. This means that the analyst/formulator already has a preconceived idea/expectation about the results and variability of the product, and is trying to obtain those results by adjusting the means, in this case by using a different apparatus or a sinker. Obviously, the analyst is not determining dissolution characteristics of the product but achieving intended results by adjusting tester and/or associated experimental conditions. Continue reading →

Similar C-t (plasma drug concentration-time) profiles or BA/BE (bioavailability/bioequivalence) shows that the products (tablets/capsules) provide similar dissolution characteristics (all other things being equal). Therefore, for all practical purposes the C-t profiles or BA/BE studies are the measure of in vivo dissolution characteristics of the products. Thus, by definition, assessment of in vivo dissolution becomes a product assessment/development tool while the same assessment tool becomes a quality control/assurance tool as well. It is scientifically and logically incorrect to separate or differentiate dissolution tests on the basis of their use, i.e. as a product assessment/development tool and a “quality” control/assurance tool. The dissolution test remains exactly the same in both cases.

The same BA/BE test can be, and are, used during the product development stage as well as for comparing the performance of different batches of the same product. The BA/BE test does not change with the stages of product development and manufacturing.

Considering ethical reasons (testing in humans), cost and time, BA/BE tests can neither be conducted, nor conducted routinely, but only for confirmatory purposes. However, for all other purposes such assessments (during product development stage and as a quality control tool during manufacturing of products) dissolution characteristics of a product are evaluated by in vitro dissolution tests. For all practical purposes current drug dissolution tests are indeed used as a substitute of BA/BE, including for QC purposes such as pharmacopeial tests. Therefore, by definition dissolution tests conducted as recommended, are indeed bio-waivers. One does not require any further or special step to transfer a dissolution test to a bio-waiver status or vice versa. Stating otherwise would not change the reality or the fact.

If a dissolution test does not provide an in vivo relevant outcome, then the issue is with the dissolution test and such a test should not be used any further until corrected. Requiring the use of dissolution tests which do not provide bio-relevant results, for any purpose, cannot be justified on any basis, scientific or logical. It simply confuses reality, science and people, and furthermore hinders efficient product development and manufacturing.

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