In a recent article, titled “Stage Appropriate Dissolution Methods in Formulation Development,” published in the above-mentioned journal, the author presented a view as to how dissolution method requirements change as a project advances in time (link). Unfortunately, not only is this view logically flawed but scientifically invalid as well.
A dissolution method is used to estimate drug release characteristics of a product, mostly tablets, and capsules. Therefore, by definition, a method just like any other scale or measuring method (thermometer, weighing scale, density, etc.) must remain constant. A product, or stage, dependent scale/method will be considered scientifically invalid for this reason.
Further, during the product development stage, a dissolution method is used for evaluating the impact of different variables (formulation and/or manufacturing) so that a product with appropriate drug release characteristics is developed. Therefore, again, a constant method is required during the product development exercise. If the suggestion is to keep changing the methods (scales) at every stage, then one wonders how one would establish dissolution characteristics/rate of a product or any product. For a more detailed explanation and discussion on the topic, please follow the links:
(1) Limitations of Some Commonly Described Practices in Drug Dissolution Testing and Suggestions to Address These. (link).
(2) Blog (link)
In my view, the author had provided information that is not scientifically valid and would not help develop useful dissolution methods.
Note: This post has been shared with the author of the article, who provided the following response which is greatly appreciated. Also, I took the opportunity to introduce Dr. Hawley to the newly suggested crescent shape spindle which may help develop a “universal” dissolution tester. Saeed
I appreciate the thoughtful comments above, and especially the opportunity to respond to them. However, I do disagree that the article we published was logically flawed and scientifically invalid. The crux of the argument above is that the dissolution method should be an invariant test which is representative of the in-vivo system. This method should remain in place throughout the product’s development from pre-clinical studies to commercial. As such, it acts as an absolute arbiter of the performance of the formulations developed. I have been extremely fortunate to work with many excellent scientists in industry in my career. Unfortunately, I have not yet met any who have been able to easily identify a dissolution method to unfailingly predict the drug release characteristics of any drug product early in development. If we could, I would agree with the critique above, this article would not need to have been written, and I would use this defined dissolution method without alteration through development.
In the course of developing a drug product however, we go through several phases. In the early stage, when there is a large likelihood that the project will fail, we preserve our resource and may use something simple such as intrinsic dissolution or disintegration to assess the performance of our drug product. Admittedly crude, yes; not really representative of the in-vivo situation, yes also. However, these tests can identify critical flaws in the formulation approach which would impede the success of the clinical study, which is the real goal for the project. Later on, we may have a totally different formulation approach as, for example, we move from a powder in capsule dosage form to a tablet. If we had infinite resource to invest early on, we could develop the understanding to come up with a decent, representative method at this time. However, I do not think that is wise deployment of either formulation or analytical resources. Instead, much as many other analytical assays, as we progress the project, we learn and we revise our methods to enable us to measure the properties we are interested in. As the project team comes closer to defining a formulation, we do lock in our dissolution method as soon as it is practical. This paper was written to show what kinds of considerations should be taken into account when going through this process.
The purpose of this paper was really to discuss how to use different dissolution tests methods (rotating disk dissolution, USP Dissolution, multi-compartment dissolution) at different periods of the product development cycle to understand the mechanism by which the formulation works in order to design a better formulation (and we would argue – a better, final dissolution method). The clinical model is the true unwavering test that we all need to perform against and that is the standard by which the performance of our formulations are really measured, not by the in-vitro assay. When we reach the state where we have the ability to develop a representative dissolution method using little time, little resource and little API early in development, I will happily agree with the statements above and follow the protocol prescribed above. Until then, however, I respectfully dissent.
Michael Hawley, Ph.D.