Indomethacin Synthesis

INTRODUCTION POORLY SOLUBLE DRUGS

Poorly water soluble drugs are nowadays a great challenge in the pharmaceutical industry. Drugs classified in class II of the Biopharmaceutics classification system (BCS) exhibit good permeability, but poor solubility and hence poor bioavailability. (1) More than seventy percent of the new chemical entities are Class II drugs. One of the main reasons is the advent of high-throughput technology and the evolution to a target-based drug discovery. (2) For these drugs, solid state modification and the use of certain polymers are interesting approaches to enhance the solubility. The poorly soluble drug investigated in this master thesis is indomethacin. (3)

Indomethacin

Indomethacin is a non-steroidal anti-inflammatory drug (NSAID) with analgesic, antipyretic and anti-inflammatory properties. It prevents the synthesis of prostaglandins by inhibiting the activity of the enzyme cyclooxygenase (COX). Indomethacin is an indole derivative with the IUPAC name 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid, shown in figure 1.1. It is poorly soluble in water, but slightly soluble in alcohol. The solubility can be affected by the pH of the dissolution medium, because indomethacin is an acidic drug with a pKa of 4.5. (4) (5)

Indomethacin has polymorphic properties. Nowadays eight different polymorphic forms are known, namely α, β, γ, δ, ε, ζ, η and a crystal form that is still unnamed. The thermodynamically most stable form is the γ form and the α form is the most commonly observed metastable form. Depending on the preparation and the storage conditions, amorphous indomethacin often crystallizes to the metastable α and the stable γ form. (3) This will be explained in more details later on. Indomethacin is sensitive to light, therefore it has to be protected from light during storage