An in vitro drug dissolution test is conducted to assess in vivo dissolution characteristics of products usually tablets and capsules. The reason or logic behind conducting this test is that if a drug is to exert its therapeutic effect after administration, it should be absorbed from the GI tract (mostly small intestine). Further, for a drug to be absorbed it should be available in dissolved (solution) form in the GI tract. Thus, measurement of the dissolution of a drug in the GI tract becomes one of the most critical steps for establishing and/or monitoring the efficacy and quality of the drug or its product.

Usually it is not possible that the in vivo dissolution of a drug be monitored directly. Therefore, it is monitored indirectly by measuring bioavailability of the drug, which is estimated from the drug concentrations in the blood or plasma, commonly known as plasma drug concentration-time profiles. On the other hand, as the in vitro dissolution test is used to evaluate in vivo dissolution which is monitored by bioavailability, the in vitro test dissolution test and bioavailability assessment thus becomes interlinked with each other.

It is very important to note that the only purpose or use of drug dissolution testing is to assess bioavailability of a drug from its product, which then reflects the quality of the product. It is also equally important to note that the link between dissolution testing and the quality of the product is through bioavailability assessment only. Otherwise, dissolution testing has no link to the quality of the product or its assessment. Often, it is promoted that dissolution testing is used and/or valuable for monitoring manufacturing efficiency/quality or its consistency. However, unfortunately, this is simply a false description or promotion of dissolution testing. A dissolution test has no ability to monitor anything but dissolution characteristics of a product, which then is used for bioavailability assessment.

It is now also well accepted that the current practices of dissolution testing have not been successful in predicting bioavailability assessment. Recently USP clearly described this situation by including the following statement in one of its general chapters, i.e. “Compliance with any of the [dissolution] tests does not assure bioequivalence or bioavailability” (link).

Obviously, it is clear that dissolution testing cannot be used for bioavailability assessment. What then is the purpose of such (pharmacopeial) dissolution tests? The answer is not much.

On the other hand, if one would address well known deficiencies of the currently suggested dissolution testers/apparatuses, in particular paddle/basket, then not only can dissolution testing be made bio-relevant, but also be vastly simplified and improved.

A modified apparatus/procedure has been suggested using the crescent-shape spindle, with a single set of experimental conditions, to address the above mentioned deficiencies. For further details in this regard, please follow the link.

In simple terms current practices of dissolution method development may be described as:

“A practice of selecting experimental conditions (e.g. apparatus, rpm, medium) to achieve or observe expected or perceived dissolution characteristics of a product.”

The selected methods (i.e. experimental conditions) are then “labelled” differently at one’s own choosing such as the QC-method, bio-relevant method, discriminatory method, etc. There are absolutely no differences in such methods and/or in their development approaches.

It is important to note that one never determines or establishes dissolution characteristics of any product, one just selects experimental conditions to achieve certain desired results. Therefore, one can never determine/establish quality, for QC, or bio-relevance (IVIVC, bio-waiver, product development etc.) for product development purposes. It has all been a serious and unfortunate marketing illusion.

Moreover, all the suggested or recommended apparatuses, e.g. compendial, have never been qualified and/or validated for dissolution testing purposes, for both bio-relevancy and/or manufacturing links. Therefore, dissolution results commonly obtained using these apparatuses, in particular using basket/paddle, are no different or better than those one may obtain using desk-top blenders, shakers, mixers etc. The point being that at present all the dissolution results, and their interpretations, reported have no meaning, use and/or relevance.

Considering the limitations of current practices, a new and very simple approach has been suggested which addresses issues described above. Further information in this regard can be obtained by visiting the site/blog (link).

I have had the opportunity to read the (review) article, titled

“In vitro models for the prediction of in vivo performance of oral dosage forms (2013), link”

and certainly it is quite (very) long article, but is it useful? In one way it might be, since it implies that the practices of dissolution testing have not been successful, at least from the in vivo perspective. It is claimed that for QC purposes, the practices may be successful (however, without going into details, I would argue against this view, see below).

My biggest surprise, a pleasant one, is that there is no or limited emphasis on the IVIVC aspect. I am assuming that lack of use or relevance of IVIVC for predictability of plasma drug levels has been recognised. This is great!

On the other hand, there is an emphasis on PBPK (physiologically based pharmacokinetics) modelling (perhaps starting of a new “fad”), with an underlying assumption that one requires complex instrumentation and mathematical modelling to predict plasma drug levels. In my view, such an approach may not be necessary as a simple convolution approach can predict plasma drug levels very well and easily.

Surprisingly (or perhaps not surprisingly), there is no mention of crescent shape spindle, convolution technique or the name Qureshi in the publication. This may reflect lack of credibility of the publication for the literature assessment/review.

In addition, in my view, the publication does not provide any suggestion as to how one should determine dissolution characteristics of a, or any, product (IR or ER). So, the question remains, if one cannot determine dissolution characteristics of a product (e.g. see link), one cannot move further, may it be for QC, PBPK modelling or prediction of plasma drug levels etc.

However, answers to such questions can easily be found as described in the following articles:

(1) Determining blood concentration-time (C-t) profiles from in vitro dissolution results and product evaluation – carbamazepine (link).

(2) A Simple and Unique Approach for Developing and Evaluating Products (link).