A Formulation Case Study Comparing the Dynamic Gastric Model with Conventional Dissolution Methods

Abstract

Even in the 21st century, conventional compendial dissolution testing remains a key cornerstone of the drug development process and quality control testing. However, opportunities exist with respect to in vitro technology developments that provide the potential for formulation and analytical scientists to exceed the capabilities of the conventional dissolution test toward a more biorelevant testing regime. This work presents a product development case study in which bioequivalence was observed between an immediate-release (IR) innovator product and a comparative singlelayer reference product. Despite this, when the constituent granule of the comparative single-layer reference product was formulated in a bilayer formulation with a nondisintegrating second layer, bioequivalence versus the innovator was not achieved. The use of USP Apparatus 2 dissolution testing failed to predict the bioequivalence failure, and hence an investigation was undertaken to develop a mechanistic understanding of in vivo behavior. Using both USP Apparatus 4 dissolution in the open-loop configuration and the dynamic gastric model (a novel in vitro model designed to mimic the human stomach), an understanding of the dissolution and disintegration properties of the reference product was established. The insights gained using novel technology facilitated the redesign and subsequent improvement in pharmacokinetic parameters of a complex pharmaceutical dosage form. INTRODUCTION The correlation of in vitro performance to in vivo behavior is a critically important and cost-effective objective for the drug development process within the pharmaceutical industry (1). It is imperative to work toward the development of a mechanistic understanding of the conditions of the gastrointestinal environment and its influence on drug liberation phenomena from the various oral pharmaceutical dosage forms (2). While fully characterizing the complexity of the gastrointestinal tract may remain an elusive goal (3), understanding the key parameters that can facilitate the prediction of dosage form behavior in vivo may be achieved. A key contributor to developing an understanding is the development of dissolution technologies that are designed to mimic the in vivo environment more closely. The noncompendial dissolution methods have been detailed in an excellent recent review (4). These include multicompartmental models such as the artificial stomach duodenal model (ASD), which has been used to evaluate the effect of gastric emptying on drug dissolution, solubilization, and precipitation in separate duodenal compartment in several studies (5–8). In addition, models exist that are designed to simulate GI physical stress forces such as the novel stress dissolution tester (9, 10) or the modified Apparatus 2 by Burke et al. (11). Systems that mimic absorption have been described, from the simple partitioning approach using USP apparatus with organic solvents (12–14) to the more complex models like the FloVitro Dissolution Testing system provided by Rohm and Haas (15). In addition, the human gastric simulator (HGS) is a recent technological advance that has been used to study the gastric digestion of foods (16), although this has yet to be applied in the pharmaceutical development space. The next evolutionary stage of dissolution technology comprises complex systems that are multicompartmental, not only mimicking the hydrodynamics and composition of media but also incorporating mechanical processing, digestion of real food, and gastric emptying. Examples of these systems are the TNO TIM–1 system (17) and the dynamic gastric model (DGM). The DGM, developed by the Institute of Food Research in Norwich, UK, is designed to simulate the human gastric compartment of the fundus and antrum (18, 19). It is the first “dynamic” in vitro model that replicates both the complex biochemical conditions and the array of gastric hydrodynamics, critical for the prediction of digestive processes and the bioperformance of pharmaceutical agents and dosage forms. The DGM is gaining increasing utility not only as a general biopharmaceutics tool for the evaluation of dosage form disposition and drug release characteristics, but also for the evaluation of (1) food effect potential, (2) dosage form integrity (especially the propensity for dose dumping), and (3) bespoke drug–alcohol interactions. This work reports a formulation development case study that utilized noncompendial in combination with traditional in vitro tools. The study has proved useful in gaining insight into the in vivo mechanisms of success and failure of the pharmaceutical product development of a complex multilayer pharmaceutical dosage form. *Corresponding author. e-mail: james_mann@merck.com dx.doi.org/10.14227/DT190412P14