editorial
`
`Oral Bioperformance and 21st Century Dissolution
`
`the oral bioperformance of a
`The ability to predict
`formulation from a laboratory based dissolution test is a long-
`term goal of the pharmaceutical scientist. This special issue
`is entitled “Oral Bioperformance and 21st Century Dissolu-
`tion”, and it demonstrates how far the science has progressed
`and yet how far it has to go to achieve this goal. Three keys
`to successful oral formulation design are stability, manufac-
`turability, and in vivo performance. Current industry stan-
`dards allow the pharmaceutical scientist to accurately predict
`the shelf life of a formulation under accelerated conditions.
`Similarly, recent advances even allow the manufacturability
`of formulations to be assessed using small amounts of
`material and lab sized equipment. The oral bioperformance
`of formulations, however, still remains a partially empirical
`art or mystery with dissolution testing at its core. USP
`Apparatus I was formally standardized and published in 1970
`with Apparatus 2 appearing in 1980. While there have been
`some additional advances in regulatory type dissolution
`testing, progress has been slow compared to other areas of
`science. USP dissolution has been very successful and has
`allowed dissolution testing to be standardized and used as
`an analytical and quality control tool. It is perhaps an
`outgrowth of the 20th century vision of applying analytical
`tools to control product development and manufacture, to
`minimize changes and, in a way, to test quality into a product.
`However, only in certain circumstances, or after a large
`collection of empirical data, does this type of dissolution
`test allow a scientist to accurately predict the performance
`of a dosage form or even predict the in vivo impact of
`changes in a dosage form. USP dissolution tests even led to
`an entire branch of research defining in vitro/in vivo
`correlations between USP dissolution results and pharma-
`cokinetic information.
`We believe the 21st century is starting off differently. The
`human genome has been mapped for most of this decade.
`Systems biology is advancing and emphasizing an integrated
`view and understanding of biological systems. A more
`thorough and integrated view of the dosage form and how it
`interacts with our biological system (the gastrointestinal tract
`in this case) is consistent with this vision. In this liminal
`period, we are seeing a shift in regulatory emphasis from
`control
`to quality by design (QbD) which emphasizes
`material, process and product understanding and their influ-
`ence on critical product attributes that impact performance.
`These changes are driving the movement toward an improved
`predictive capability of pharmaceutical science leading to
`
`improved oral bioperformance, but it necessitates a better
`understanding of the in vivo environment.
`In this special issue of Molecular Pharmaceutics, several
`areas of research are highlighted that relate to oral bioper-
`formance prediction. There are several
`innovative and
`nontraditional approaches to characterizing and understanding
`dissolution. Other topics address the simple, fundamental
`question of solubility, how to measure solubility in a way
`that
`is physiologically relevant, what
`is physiologically
`relevant media, and what are the proper methods for doing
`these studies. The question of supersaturation in vivo and
`modeling the impact of dynamic effects of solubility instead
`of using thermodynamic equilibrium solubility measurements
`is also discussed. The solid form is frequently key to all this.
`If the solid form and its solubility are understood, dissolution
`can be modeled successfully.
`One must also consider the impact of the formulation on
`the dissolution and solubility as well as their time depen-
`dence. As pointed out in this issue, current models do not
`handle these factors very well and additional work is needed
`to bring the models up to snuff. If we are able to employ
`the right techniques, this will allow us to choose the proper
`solid forms and formulations and to correctly and accurately
`predict how they will behave in an in vivo system. This will
`lead to more robust formulation performance as seen in
`improved fraction absorbed, reduced food effects and reduced
`variability. As pharmaceutical scientists, our job is frequently
`to control how the compound is delivered to the intestine
`and the intestinal membrane. If we do this well, we have
`done our job.
`The papers collected in this special issue show how much
`progress has been made recently in this area. But they also
`show how much more work is needed to achieve the vision
`of a lab based predictive system for oral bioperformance
`through better dissolution testing and modeling. Importantly,
`in this issue, there is a focus on models to try to convert
`laboratory data into pharmacokinetic profiles that enhance
`our understanding of what is actually happening in vivo. In
`QbD terminology: “process understanding”!
`Gregory E. Amidon
`College of Pharmacy, UniVersity of Michigan,
`Ann Arbor, Michigan 48109
`Michael Hawley
`
`Pfizer, Inc., Eastern Point Road, Groton, Connecticut 06340
`
`MP100275B
`
`10.1021/mp100275b  2010 American Chemical Society
`Published on Web 09/08/2010
`
`VOL. 7, NO. 5, 1361 MOLECULAR PHARMACEUTICS 1361
`
`Page 1
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