It is often noted that drug dissolution results fail to reflect the in vivo behaviour of a product, i.e., lack of relationship to bioequivalence of two test products. Therefore, it is usually inquired as to how one should explain the lack of relevance and/or how to address this issue.
There could be a number of potential causes for such a problem (lack of bio-relevance). In addition, the problem could only be related to the specific product. In such cases, it is difficult for others to provide suggestions without knowing the details about the formulation of the product, which are often not available because of the proprietary nature of the information. Therefore, it is almost impossible that one can obtain a direct and/or a correct suggestion to address the problem. The formulator should be aware that he/she might obtain completely un-related suggestions which may end up wasting a lot of time. Keeping these thoughts in mind, a few very general suggestions are provided here which may be helpful in such situations.
There are usually two potential outcomes in such situations (lack of bio-relevance): (1) in vitro dissolution tests show different (the so called “discriminatory”) results, but the in vivo results are similar; (2) in vitro dissolution test show similar results, but the in vivo results are not similar i.e. bio-in-equivalent.
In the first scenario, the most likely cause is that the test may have been conducted using much softer conditions (in particular, related to stirring/mixing) under the “requirements” of obtaining “discriminatory” results. For example, if the formulations of the two products are such that one hides the drug (API) better than the other at the bottom of the vessel then one will observe different in vitro dissolution results, but most likely similar in vivo results. Drugs with low aqueous solubility and/or of low content would show such a problem. This is the most commonly observed issue with the use of paddle/basket apparatuses as these provide poor, and/or lack of, stirring and mixing required. Commonly such tests are referred to as “overly discriminatory”, however, in reality these tests are incorrect tests, mostly because of the incorrect choice of a dissolution apparatus.
In the second scenario, the most likely cause would be of chemical nature, such as an interaction between a drug and an excipient. It is possible that during dissolution testing a complex has been formed, or dissociated, with much higher solubility, which may not be the case in vivo. The likely suspect in this case may be the pH of the medium. One should make sure that the pH of the medium has not been inadvertently increased as this will certainly cause this problem (use of larger amounts of SLS may be a prime suspect here). Some focus on the chemistry aspect of the product (drug excipient interaction) would be very helpful.
The next consideration should be given to the use of the paddle/basket apparatuses themselves. If possible, avoid using these apparatuses as these can be the main cause of the problem. Even if you are going to try the suggestions provided above, the use of paddle/basket may hinder in establishing cause of the problem. Consider using an apparatus which will provide efficient and reproducible mixing and stirring.
