By: Daniel Sironi, Annette Bauer-Brandl and Martin Brandl
Typically, tablets disintegrate and the drug substance dissolves before it will be absorbed across the gastrointestinal mucosa on its way to the site of action. Investigating the key steps of disintegration and dissolution in vitro is common practice for quality control of tablets. In drug development, however, the same methods are used to identify the most promising formulations for bioavailability studies in animals. Many years of experience indicate that the performance of formulations, as assessed by classical dissolution testing in different media, can indeed be indicative for the in vivo performance.
However, when it comes to poorly soluble drugs in enabling formulations, the standard dissolution experiment can be very misleading. Why? Enabling formulations (temporarily) increase drug solubility beyond its thermodynamic maximum, a phenomenon addressed as supersaturation. This being a metastable state, recrystallization will occur over time and the concentration of the drug will decrease again.
But this is not necessarily the case in vivo! The gastrointestine is a dynamic system where drug dissolution and drug absorption occur simultaneously. Thus, there is an interplay between these two processes: the continuous removal of dissolved drug by absorption into the blood circulation will circumvent the limitation of the drug dissolving in a closed system and may avoid reaching saturation concentrations at all. Therefore, absorption has a major impact on the dissolution process.
Together with many other research groups in the field, we postulate that for enabling formulations of poorly soluble drugs, static test systems should be replaced by dynamic ones that take this interplay into account. A dynamic approach will allow us to better understand enabling formulations and to replace today’s empiric formulation efforts (“trial and error”) with efficient formulation strategies that meaningfully compare different enabling for
A recent study compares a microparticle and a nanoparticle formulation of the poorly soluble drug substance fenofibrate. The results give insight into relevant processes related to drug absorption in this case. Only by combining dissolution and permeation testing was it possible to reveal that the underlying mechanisms of the enhanced bioavailability were rapid dissolution and true supersaturation. Furthermore, the study demonstrated that solubilization by the medium can create a drug reservoir from which drug molecules are absorbed once all drug particles are dissolved.
The focus of scientific effort now turns to developing a setup that can be used for routine testing of enabling formulations. This requires an experimental setup that is robust to the various components often used in enabling formulations (like surfactants) and that does not require extensive fine tuning of the parameters for each single drug. However, the biggest challenge is to design a new setup in which the permeation area and the dissolution volume better reflect human physiology.