An Investigation of the Influence of Rheological Factors on the Release of Drugs from Pharmaceutical Semisolids

Abstract

Many factors can affect the release of a drug from an ointment base. Some authors have suggested that rheological properties can be an important consideration. Unfortunately, the literature is not clear on this point. In all studies where 'viscosity' has been implicated, the formulated bases contained various complex components and it is not sensible to ascribe observed changes in release rate to rheological properties alone. In order to clarify the role of rheological factors, the release of salicylates from liquid paraffin-polyethylene gels (Plasti-bases) has been studied. These bases were chosen on the grounds that the drug-vehicle interactions were minimal and that bases of variable rheological properties were available. At a given concentration, the chemical potential of the drug in the base was constant and thus changes in release rate depended solely on rheological factors. The ointment bases were viscoelastic and rheological properties were characterised using continuous shear, creep, and oscillatory testing. Various relationships between apparent viscosity, yield value, dynamic viscosity, dynamic modulus, and polyethylene content of the bases were obtained. Methods of altering rheological parameters in the design of topical preparations were also investigated. The release of the drug in vitro into an aqueous sink was linearly related to the reciprocals of the apparent viscosity and the dynamic viscosity (measured at low test frequency) when the drug was in suspension in the base (salicylic acid). In vitro drug release was independent of viscosity when the drug was in solution in the base (methyl salicylate). These results were confirmed by in vivo studies on human volunteers from skin irritation and urinary excretion data. It was concluded that the viscosity of the base became an important factor when dissolution of the drug in the vehicle was a rate-determining factor. The rheological environment as seen by the diffusing drug molecule was different from that determined using a conventional viscometer or fundamental methods (creep and dynamic testing); however, simple relationships between micro viscosity and macro viscosity were derived.