An In-vitro in-vivo correlation (IVIVC) has been defined by the U.S. Food and Drug Administration (FDA) as “a predictive mathematical model describing the relationship between an in-vitro property of a dosage form and an in-vivo response”. For pharmaceutical products (tablets and capsules in particular) development purposes, in-vitro property and in vivo response mean in vitro drug dissolution/release characteristics and the plasma drug concentration profiles, respectively.

It is important to note that this relationship, or model, always exists between the two variables (dissolution vs plasma profile) for a given drug, which forms the basis for in vitro dissolution testing and its use for the assessment of quality of pharmaceutical products. Therefore, developing this relationship or modelling should have never been part of the practice of drug dissolution testing or its applications for products development or evaluation. However, this is precisely what has happened during the past two decades, i.e. repeated recommendations were made for correlating dissolution results with plasma drug levels. In fact, such developments have been suggested as regulatory requirements. Continue reading →

It is often suggested that to use an apparatus (or method) for dissolution testing, it must first be validated. There is nothing wrong with this statement or requirement. One should follow this requirement.

The question, however, is how should one validate a dissolution apparatus? This is where the problem is! In principle, validation means establishing that an apparatus is capable of measuring required characteristics. Here capability means ability of measuring relevant dissolution characteristics or results.

In the case of current practices of dissolution testing, however, there is an interesting twist in the validation requirement. Here, promoted validation means obtaining dissolution results similar to those one would obtain using one of the compendial apparatuses, in particular paddle or basket apparatus. It is important to note that the requirement is not that  of relevant and/or reproducible results, but similarity of results obtained using compendial apparatuses (read similar practices with vibration and de-aerations aspects). This would have been acceptable if compendial apparatuses were validated themselves against some relevant reference product or value. Unfortunately, the compendial apparatuses have never been validated. In fact, these apparatuses have been shown repeatedly to provide irrelevant and irreproducible results. As per current practices or requirements any new or different apparatus also become non-validated, by default, if it provide similar results as those of the compendial apparatuses. Therefore, current recommendations require developing and using non-validated apparatuses and methods. Continue reading →

To establish the quality of a product or bio-relevancy of dissolution results, obviously, one first has to determine dissolution characteristics of the product. To determine relevant dissolution results, one is required to have an agreeable or validated dissolution method (tester and experimental conditions).  The difficulty is that, at present, one does not have an agreeable or validated dissolution method or tester. Thus one cannot determine dissolution characteristics of a, or any, product, as a result its quality and/or bio-relevancy.

At present, people try to develop a dissolution method for the test product. However, it is not possible to develop a method using a product which itself is under development or evaluation. A (dissolution) method can only be developed using a product of known or agreeable dissolution characteristics (i.e. a reference product).

It is important to note that the current practices of method development for dissolution testing are not at all method development practices as one does not have a reference product with known dissolution characteristics. On the other hand, one cannot determine dissolution characteristics of any product, as one does not have a validated dissolution method or tester. Therefore, it is not possible to evaluate the quality of the product and/or relevancy of dissolution results to in vivo results. Continue reading →

A common query regarding drug dissolution testing is; how should I (scientist or analyst) get desired dissolution characteristics? The desired characteristics mean: (1) slower or faster dissolution results than observed; (2) discriminatory profiles; (3) bio-relevant or IVIVC results (4) QC- or batch-to-batch testing criteria, etc. Often such a question is not asked directly, but indirectly as to how should I (scientist or analyst) develop a dissolution method for my product, implying how to achieve a desired/expected dissolution characteristic of the product. It would be interesting to note that dissolution tests are conducted to evaluate impact of formulation/manufacturing on the drug release characteristics. Often the questioner does not provide (or cannot, because of confidential/proprietary reasons) the formulation/manufacturing attributes of the product. Then, how would someone be able to provide an appropriate response to such a question?

On the other hand, even without knowing the formulation/manufacturing attributes, people provide endless suggestions/recommendations of trying different experimental conditions (apparatuses, dissolution media, stirring speeds etc.) to achieve what a scientist or analyst is trying to achieve, i.e. desired dissolution results. How can such advice be considered valid or relevant? The current mindset, unfortunately, is to provide advice after advice as how to conduct dissolution tests – more appropriately how to play with experimental conditions to achieve certain desired dissolution results.

The purpose of dissolution testing and the queries, however, is very clear that the scientists/analysts would like to know dissolution characteristics of a product and not the available choices of experimental conditions.  Therefore, providing advice about selecting or playing with experimental conditions for dissolution testing, in particular product dependent, is clearly inaccurate and false help. One should be aware of such practices which may cause serious loss of time and resources.

To determine the value of a parameter/property, including dissolution, one requires a well-established and validated tester and method. Unfortunately, none of the apparatuses described including the associated methods (experimental conditions) are qualified and/or validated for the intended purposes i.e. to determine dissolution characteristics. Therefore, advices for conducting dissolution testing based on currently recommended apparatuses and/or experimental conditions become even more strange and a self-deceiving exercise. One should be extremely cautious in following such “help” or “advice”.

To conduct a dissolution test i.e. to evaluate dissolution characteristics of a product, one requires a common, and product independent, set of experimental conditions. The crescent shape spindle and associated experimental conditions have been suggested to address the difficulties and flaws of the current practices, thus providing an option for appropriate evaluation of dissolution characteristics of products.