The Effects of Low Molecular Weight Polar Molecules on the Physical and Chemical Properties of Hard Gelatin Capsule Shells

Abstract

Liquid filled capsule formulations offer opportunities to enhance both solubility and the oral bioavailability of new chemical entities (1,5,7). Excipients used in liquid based formulations can range from lipophilic vehicles, solubilizing agents, surfactants, emulsifying agents and adsorption enhancers (2,3,4). Commonly used solubilizing agents in commercially available oral formulations are ethanol, propylene glycol (PG) and glycerin (11). These low molecular weight polar and hygroscopic molecules can penetrate and plasticize the capsule shell and affect the moisture content, compromising the capsule physical integrity and are therefore used in lower quantities (1,39). This research aims to investigate the effects of these commonly used low molecular weight polar solubilizing agents in lipophilic excipients (cremophors and miglyols) on the compatibility with hard gelatin capsules monitored over stress conditions for a 3 month period at 25C/60% RH, 30C/65% RH and 40C/75% RH storage conditions. The capsule physical properties such as brittleness and elasticity were determined by measuring the glass transition temperatures and the texture analysis of the gelatin films upon exposure to the solubilizing agents. Scanning Electron Microscopy (SEM) was used to document physical changes to the capsule shell. Additionally the extent of gelatin cross-linking upon exposure to the solubilizing agents was evaluated using dissolution testing and measuring the aldehydes content, a by-product of cross-linking, using p-amino benzoic acid (PABA) derivatization high-pressure liquid chromatography (HPLC) method. Results from this research suggest that propylene glycol and glycerin with two and three hydroxyl groups respectively are more incompatible with hard gelatin capsule shells than ethanol with one hydroxyl group.