Chapter 6 A Staged Approach to Pharmaceutical Dissolution Testing

The complex and time-consuming process of drug development, from discovery of a new chemical entity (NCE) to the autho- rization of marketing for a new drug, can span a period of 12- 20 years.1 Undesirable physicochemical attributes are a major cause of attrition in the drug development process. In a typical physicochemical screening process (i.e., pKa, solubility, permeability, stability, and lipophilicity), poor solubility is a key factor limiting successful development.1,2 Compounds with insufficient solubility are more likely to fail during discovery and development as inadequate solubility not only impacts other property assays, masking additional undesirable properties, but also influences both pharmacokinetic and pharmacodynamic characteristics of the Table 2.1 The Biopharmaceutics Classification System (BCS) Biopharmaceutics class Permeability Solubility I High High II High Low III Low High IV Low Low compound.3 The Biopharmaceutics Classification System (BCS) is the scientific framework that allows the classification of drug sub- stances based on their dissolution, aqueous solubility, and intestinal permeability.1−4 A drug’s bioavailability depends primarily on its solubility in the gastrointestinal (GI) tract and its permeability across the cell membranes upon oral administration.5 This BCS systemwas proposed by the Food and Drug Administration (FDA) as a bioavailability/bioequivalence (BA/BE) regulatory guideline and assigns drugs into four groups illustrated in Table 2.1. According to the BCS framework, solubility is determined by obtaining the pH- solubility profile of the drug substance in question in an aqueous medium of pH range 1-8 at an established temperature of 37± 1◦C. A drug substance according to the solubility classification in the BCS is thus considered to be highly soluble when its highest dose strength proves to be soluble in 250 mL or less of an aqueous medium over the pH range of 1-8.6−8 If not, the drug substance is considered as poorly soluble. The 250 mL volume estimate is from bioequivalence study protocols which prescribe drug product administration with a glass of water to fasting volunteers.7 A drug substance is considered highly permeable when the extent of intestinal absorption is determined to be 90% or higher; if not, the drug substance is considered to be poorly permeable.7 Permeability classification is thus based directly on the extent of intestinal absorption of a drug substance in humans or indirectly on the measurements of the rate of mass transfer across the human intestinal membrane.7