Technical Note: Non-Sink Dissolution Media for Identification of Functional Formulation Excipients—The Case of a Precipitation Inhibitor

Abstract

INTRODUCTION Due to the abundance of dissolution methodology and media available to pharmaceutical development and quality scientists, it is advisable that method selection criteria be dictated by the purpose of the measurement. This is particularly important when dissolution is used as a tool to guide formulation design. These cases often require the use of conditions that are relevant to the in vivo situation, but most critically, they are chosen to tease out an excipient’s ability to perform its intended function. This note aims to illustrate how purposeful media selection can help probe the functionality of an excipient to be used in a solid oral dosage form of a low solubility compound. In this example, the active pharmaceutical ingredient (API) is a crystalline potassium salt of a weak acid with a pKa = 6.8, and the excipient in question is hydroxypropyl methylcellulose (HPMC). The API has relatively high solubility, 71 mg/ mL in water or at a pH > pKa, which drops to 0.01 mg/ mL (the equilibrium solubility of the protonated free form measured more than 24 h after the crystalline salt was introduced in aqueous medium) at pH < 6.8, the pH expected in the gastrointestinal (GI) tract (1). The HPMC excipient was chosen for its potential ability to act as an antinucleating agent (2), inhibit precipitation of the drug at a pH < pKa, and induce super saturation, thus enhancing in vivo solubility and absorption. To assess the utility of the excipient for an oral dosage form, in vitro dissolution of the neat API is carried out under non-sink conditions, at a pH < pKa and a dose-relevant concentration, in the presence and absence of HPMC. Next, dissolution of the formulated API is carried out under non-sink conditions, over a pH range that is GI relevant, at dose-relevant concentrations. Subsequently, preclinical models are used to assess further the in vivo utility of the HPMC excipient before defining a formulation for human trials. A range of drug and excipient concentrations may be explored in vitro depending on predicted clinical doses and dosage form considerations, respectively. Two examples of in vitro measurements of neat and formulated API are presented below.