Development of a Continuous Dissolution/Absorption System—a Technical Note

Abstract

It has been several decades since the compendial dissolution technique has been used to characterize the performance of oral drug products and has attempted to serve as a surrogate for in vivo bioequivalence testing (1). Provided a validated in vitro–in vivo correlation (IVIVC) is established, the demonstrative bioequivalence test based on clinical trials could be waived. This regulatory benefit increases the interest in linking dissolution results with pharmacokinetic performance. However, the outcomes based on previous research indicate that only a small portion of drugs (in Biopharmaceutics Classification System (BCS) class I, high solubility, high permeability) are successful in establishing IVIVCs and subsequently obtaining waives for bioequivalence tests (2). The key parameters controlling oral drug absorption are the solubility/dissolution of the drug in the gastrointestinal (GI) track and the permeability of the drug through the GI membrane. The current compendial methods are simplified models to the human GI tract and are limited in their abilities to simulate the dynamic aspects of the in vivo processes that are associated with dosage form transit through a complex GI environment. Compartmental absorption and transit models have been developed for years (3,4). Some progress has been made to develop a dissolution apparatus based on multicompartmental models such as: (1) integrate dissolution testing with in vitro permeation process or (2) simulate drug dynamic transit in the GI tract. James Polli's group developed an integrated dissolution/Caco-2 system, which could be used to predict dissolution–absorption relationships, as well as the contributions of dissolution and intestinal permeation to overall drug absorption (2,5). The system has been applied to study piroxicam, metoprolol, and ranitidine formulations, and the results were in agreement with clinical studies. Some similar reports were also published recently by Makoto Kataoka's group on a novel dissolution/permeation (D/P) system (6–8). The D/P system included an apical side and a basal side with a Caco-2 monolayer in between. It was reported that drug dissolution and permeation could be simultaneously determined with this system. Another approach to assess bioavailability/bioequivalence in vitro is the TIM-1 system developed at TNO Nutrition and Food Research, Netherlands (9). This system is a multicompartmental, dynamic, computer-controlled system that closely simulates in vivo dynamic physiological processes in the human upper GI tract. Those efforts make it possible to better simulate the GI tract and correlate in vitro drug performance to in vivo clinical trials. However, because of the complexity of these systems, some limitations such as result reproducibility and repeatability, cost of each test, ease of use of the method, and high throughput may prevent the wide use of these systems. A new dissolution/absorption system that takes the advantage of current progress and improves the reproducibility and repeatability of test results, at a low cost, would be of benefit. This article is focused on the development of a new dissolution/absorption system. The system still depends on the idea of multicompartmental simulation and is able to link drug dissolution and absorption performance. On the other hand, the new system has some improvements: (1) it employs a dissolution section and an absorption section (two compartments) instead of using four compartments as in the TIM-1 system; (2) it applies an artificial membrane to link dissolution and absorption without using a Caco-2 monolayer; and (3) it accommodates current USP official dissolution apparatus easily into the system. Some preliminary tests with two drug products (Inderal propranolol capsule and Uricalm phenazopyridine tablet) have been done with this newly developed system. The results indicate that this new system is flexible and easy to use, has low cost and maintenance, and may have potential to better correlate in vitro testing with in vivo clinical trials than current dissolution configurations.