Accurate prediction of the in vivo biopharmaceutical performance of oral drug formulations is critical to efficient drug development. Traditionally, in vitro evaluation of oral drug formulations has focused on disintegration and dissolution testing for quality control (QC) purposes. The connection with in vivo biopharmaceutical performance has often been ignored. More recently, the switch to assessing drug products in a more biorelevant and mechanistic manner has advanced the understanding of drug formulation behavior. Notwithstanding this evolution, predicting the in vivo biopharmaceutical performance of formulations that rely on complex intraluminal processes (e.g. solubilization, supersaturation, precipitation…) remains extremely challenging. Concomitantly, the increasing demand for complex formulations to overcome low drug solubility or to control drug release rates urges the development of new in vitro tools. Development and optimizing innovative, predictive Oral Biopharmaceutical Tools is the main target of the OrBiTo project within the Innovative Medicines Initiative (IMI) framework. A combination of physico-chemical measurements, in vitro tests, in vivo methods, and physiology-based pharmacokinetic modeling is expected to create a unique knowledge platform, enabling the bottlenecks in drug development to be removed and the whole process of drug development to become more efficient. As part of the basis for the OrBiTo project, this review summarizes the current status of predictive in vitro assessment tools for formulation behavior. Both pharmacopoeia-listed apparatus and more advanced tools are discussed. Special attention is paid to major issues limiting the predictive power of traditional tools, including the simulation of dynamic changes in gastrointestinal conditions, the adequate reproduction of gastrointestinal motility, the simulation of supersaturation and precipitation, and the implementation of the solubility-permeability interplay. It is anticipated that the innovative in vitro biopharmaceutical tools arising from the OrBiTo project will lead to improved predictions for in vivo behavior of drug formulations in the GI tract.

Objectives The conventional dissolution test, particularly the USP apparatus I and II, remains an important tool in the armory of the pharmaceutical development scientist. For realistic dissolution characterization, sink conditions, where saturation solubility of a drug in the dissolution medium is at least three times more than the drug concentration, are critical. These conditions can be problematic to maintain with formulations containing poorly-soluble actives. This review summarizes the role of the dissolution test in the pharmaceutical industry, together with some traditional techniques/additives used to enhance solubility and facilitate the achievement of sink conditions. The biphasic dissolution system, an innovative model for the treatment of poorly-soluble species, will also be discussed. Key findings The biphasic dissolution model utilizes media comprising immiscible aqueous and organic layers whereby the drug, following initial aqueous dissolution, partitions into the organic layer. This step, which acts to remove all dissolved species from the aqueous layer, enables further aqueous dissolution to occur and hence the dissolution-partition cycle continues. Crucially, the aqueous layer does not saturate allowing sink conditions to be maintained and hence the experiment will, in theory, yield complete dissolution. Summary This review highlights important concepts regarding solubility/sink limitation and intends to provoke debate among analytical and formulation scientists as to the potential advantages, long-term development and widespread implementation of a biphasic dissolution system in drug development.

This article intends to summarize the current views of the IQ Consortium Dissolution Working Group, which comprises various industry companies, on the roles of dissolution testing throughout pharmaceutical product development, registration, commercialization, and beyond. Over the past 3 decades, dissolution testing has evolved from a routine and straightforward test as a component of end-product release into a comprehensive set of tools that the developer can deploy at various stages of the product life cycle. The definitions of commonly used dissolution approaches, how they relate to one another and how they may be applied in modern drug development, and life cycle management is described in this article. Specifically, this article discusses the purpose, advantages, and limitations of quality control, biorelevant, and clinically relevant dissolution methods.

The mechanical functioning of the stomach has been well researched (1). The contractions that mix, break up, and propel the gastric bolus in the main body and antrum have been described in detail and have been partially modeled mathematically. Because the antral forces are particularly important in the mixing and break up of food, they have been measured using manometers, pressure transducers, MRI imaging of agar beads of differing strength (2), and other methods (3, 4). The chemical and biochemical environment of the stomach, its acid and digestive enzymes, and their production and activity rates under different conditions have been studied for many years, and reference ranges established mainly for diagnostic purposes. All these areas have been extensively reviewed (5-7).Despite this understanding of gastric function, many in vitro digestion studies use grossly simplified systems that often include food homogenization, nonphysiological mixing and shear, and unrealistic acid and enzyme concentrations that do not change over time as happens in vivo.This paper describes the design and operation of a computer-controlled dynamic gastric model (DGM) that was built to investigate the effects of the biochemical and physical processing of foods and oral pharmaceuticals.Our intention was to draw together the physical and biochemical features of the human stomach with data on gastric residence time and emptying profiles and to design a computer-controlled mechanical stimulation that works in real time with realistic chewed foods or meals and oral pharmaceutical and nutraceutical products.

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