Biorelevant in-vitro performance testing of orally administered dosage forms Christos Reppas and Maria Vertzoni Department of Pharmaceutical Technology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece Keywords biorelevant hydrodynamics; biorelevant media; disintegration; dissolution; solubility Correspondence Maria Vertzoni, Department of Pharmaceutical Technology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis, 157 71 Athens, Greece. E-mail: vertzoni@pharm.uoa.gr Received November 18, 2011 Accepted January 5, 2012 doi: 10.1111/j.2042-7158.2012.01474.x Abstract Objectives This review focuses on the evolution and current status of biorelevant media and hydrodynamics, and discusses the usefulness of biorelevant performance testing in the evaluation of specific dosage form related lumenal processes. Key findings During the last 15 years our knowledge of the gastrointestinal envi- ronment (including the lower gut) has improved dramatically and biorelevant media composition and, to a lesser extent, biorelevant hydrodynamics, have been refined. Biorelevant dissolution/release testing is useful for the evaluation of formu- lation and food effects on plasma levels after administration of immediate release dosage forms containing low solubility compounds and after administration of extended release products. Lumenal disintegration times of immediate release dosage forms and the bile acid sequestering activity of resins in the lumen can also be successfully forecasted with biorelevant in vitro testing. Summary Biorelevant in-vitro performance testing is an important tool for evalu- ating intralumenal dosage form performance. Since the formulation of new active pharmaceutical ingredients for oral delivery is more challenging than ever before, efforts to improve the predictability of biorelevant tests are expected to continue. Introduction Oral dosing is the most popular route of administration because it is the most convenient. In order to be pharmaco- logically active after oral dosing, the drug must be released from the dosage form via disintegration, dispersion or other mechanisms into the lumenal contents in a timely and effi- cient manner. Whereas dissolution and permeation of the mucosa are prerequisites for systemic delivery, locally acting drugs must interact with lumenal components. During all these processes, the active pharmaceutical ingredient (API) must remain stable enough to elicit its desired action. New APIs tend to be less soluble, bigger and more sensitive to lumenal conditions [1] than their earlier counterparts. Knowledge of how a dosage form will behave in the gas- trointestinal (GI) lumen prior to its administration to humans will facilitate development of the optimum formulation and enable the API to be moved forward more quickly into clinical trials.For APIs already on the market,such knowledge will also facilitate the development of generic pharmaceutical pro- ducts. Intralumenal performance can be evaluated by using direct sampling or imaging techniques (M Vertzoni et al., unpublished data). [2–4] However,these techniques require spe- cialized procedures and are associated with high costs and/or ethical issues. If applied to animals in an attempt to gain information more efficiently, species differences in GI tract physiology may decrease the usefulness of the data obtained. Biorelevant dosage form performance testing refers to the in vitro testing of orally administered dosage forms under conditions simulating the intralumenal environment. It aims to forecast the intralumenal fate of the dosage form and of the API after oral administration. Simulation of the lumenal environment to evaluate the fate of the dosage form and API in the GI lumen has been a goal for several decades in the pharmaceutical sciences. However, it was a paper published almost 15 years ago by Dressman et al. [5] that practically initi- ated the systematic investigation of the subject. Perhaps the most important factor affecting dosage form and API perfor- mance after oral administration is lumenal composition. For example, thermodynamic drug solubility in GI lumenal con- tents, a key parameter affecting lumenal dissolution and maximum absorption rates of the API, is often significantly different in the GI environment than in water, and can vary dramatically with the region of the GI lumen (Table 1).Vari- ability even in just this one parameter is further increased by changing the dosing conditions. [8] And Pharmacology Journal of Pharmacy Review © 2012 The Authors. JPP © 2012 Royal Pharmaceutical Society 2012 Journal of Pharmacy and Pharmacology, 64, pp. 919–930 919 Downloaded from https://academic.oup.com/jpp/article/64/7/919/6135303 by guest on 12 June 2022