Dissolution Testing for Bioavailability of Over-the-Counter (OTC) Drugs--a Technical Note.

Abstract

Over-the-counter (OTC) drug products are medicines that can be sold directly to a consumer without a prescription from a health-care practitioner. OTC drugs generally have these characteristics which have been summarized on FDA’s website “1) their benefits outweigh their risks; 2) the potential for misuse and abuse is low; 3) consumers can use them for self-diagnosed conditions; 4) they can be adequately labeled; and 5) health care practitioners are not needed for the safe and effective use of the product” [1]. OTC monograph drugs play an increasingly important role in the health-care system. There are more than 80 therapeutic categories and an estimated 100,000 OTC drug products in the US market. Because of the sheer volume of OTC drugs on the market in 1972, the FDA decided that a product-by-product application review process would be impractical and consequently created the OTC monograph system to review categories of drugs and make a determination as to their monograph status and whether they are generally recognized as safe and effective (GRAS/E). This means that certain active pharmaceutical ingredients (API) and/or categories of OTC drugs may be marketed without FDA pre-review that is typically expected for New Drug Applications (NDAs) and Abbreviated New Drug Applications (ANDAs). This regulatory pathway is available to industry if they conform to the OTC monograph guidelines for the API and conform to OTC labeling requirements. Since the OTC monograph system regulates the APIs, instead of the specific drug product, manufacturers are free to include any excipients that serve a pharmaceutical purpose, provided that those excipients are recognized by Center for Drug Evaluation and Research (CDER) to be safe. Recently there have been concerns within FDA regarding OTC monograph drugs, specifically low-solubility drugs, because their bioavailability can be formulation dependent. This paper presents results of solubility and dissolution testing of four OTC drug products for the purposes of exploring the possible impact of a drug product’s formulation and various biorelevant dissolution media on its bioavailability. We chose four drugs for testing and made preliminary determinations on their solubility in order to have a range of drugs with varying solubilities and dissolutions. Two highly soluble drugs (dextromethorphan HBr and guaifenesin) and two poorly soluble drugs (meclizine HCl and phenazopyridine HCl) were selected for study. The solubility of each API was measured and classified according to the Bioequivalence Classification System (BCS) Guidance [2]. Dissolution testing of these drugs was also conducted. The US Pharmacopeia (USP) dissolution methods for the four drugs call for water or acid (0.1 N hydrochloric acid) as the dissolution media. Water as a dissolution media is usually a poor choice because there is no control of pH. Furthermore some patients may have compromised digestive systems, and even for healthy people, the pH in the GI tract can range from a pH of 1.2 in the stomach to 6.8 in the small intestine. Therefore, dissolution profiles of these four drug products were presented at the recommended conditions in their corresponding USP monograph and at pH values of 1.2, 4.5, and 6.8 as suggested in a FDA BCS Guidance [2].