It may be said that analysts performing drug dissolution tests are in a pretty difficult situation. They are expected to conduct appropriate dissolution tests to determine the quality of a product based on its in vitro drug release characteristics. However, procedures described in the literature (e.g. USP <1092>) or commonly taught in courses provide suggestions for choosing/selecting experimental conditions to achieve (match) a desired or pre-set dissolution outcome. These desired dissolution characteristics are commonly obtained by selecting apparatuses (mostly between basket and paddle) and/or by adjusting rpm, pH or molarity of medium/buffer and/or solubiliser (nature or amount). Therefore, it is important to note that the analyst, following the currently suggested procedures, will never know the true or actual nature of drug dissolution characteristics of the product, thus its quality.
A similar confusing situation exists when one is expected to establish bio or bio-relevant characteristics of a product. Here also the analyst does not determine the potential in vivo dissolution characteristics of a product but requires that in vitro dissolution results be match with those obtained from a bio-study by adjusting the experimental conditions. An even more confusing aspect of this practice is that the analyst is expected to describe this matching exercise as developing a bio predictable dissolution method. Sometimes such a confusion and misunderstanding is quite obvious, for example, as described in a recent publications.
“Adjusting dissolution testing conditions to match the behavior of the formulations in vitro with that in vivo by taking into account the properties of the drug and the formulation is a straightforward and useful approach in identifying a predictive method in the development of the IVIVC. These investigations will definitely help by derisking of new formulations as well as by rating changes in existing formulations with regard to their impact on bioavailability before entry into human”.
Such described methods are neither bio-relevant nor predicable, rather it is simply obtaining expected results by adjusted experimental conditions. A simple analogy to such an approach would be that one could start dissolution testing with a high speed stirrer (blender) and keep adjusting the stirring speed lower and lower until desired dissolution results are obtained. Obviously, this will not be considered a predictable of bio-relevant test. For appropriate testing, the analysts must work with a standard and common procedure independent of the test product. If a product does not provide relevant or expected dissolution characteristics then the product attributes (formulation/manufacturing) are to be changed not the dissolution method to achieve or match certain desired results. This is not a requirement for just dissolution testing, but a standard scientific principle and procedure of analytical chemistry. This is where current practices of dissolution testing have deviated from standard scientific principles.
The reason for this deviation is the recommended dissolution apparatuses, in particular paddle and basket, which are flawed. There are numerous examples/studies provided in the literature describing their flaws. These apparatuses are not capable of providing relevant and reproducible dissolution results. The analysts and manufacturers, however, are required to use these flawed apparatuses and experimental procedures to meet regulatory requirements. Thus, the dissolution results reported are often to fulfill the regulatory requirements. These results often do not reflect characteristics or quality of the products.
As it stands now, therefore, analysts face a very difficult situation where, in principle, s/he is expected to establish the quality of drug products, but with the use of apparatuses which are known to be flawed. A more detailed discussion on this topic is provided in literature and in various posts on this blog (please see under sub-menu “useful lists“).
A modified spindle has been proposed to address the flaws of the basket and paddle apparatuses. The use of the crescent-shaped spindle, with single set of product-independent experimental conditions simplifies the dissolution practice significantly and provides more appropriate and relevant dissolution characteristics of the products. The details about crescent-shaped based approach may be found in the literature (e.g. Link), on this website/blog and the upcoming course.
