Roxithromycin : a solubility and stability study

Abstract

Roxithromycin is a semi-synthetic, macrolide antibiotic, derived from erythromycin A. It acts as a bacteriostatic drug at low concentrations and a bactericidal drug at high concentrations. It binds to the 50S subunit of the 70S ribosome, which causes the reversible inhibition of RNA-dependent bacterial protein synthesis. It is well known that active pharmaceutical ingredients (APIs) may exist in numerous solid states. Differences in the solid state significantly influence the physical and chemical properties of an API. The in vivo performance of a dosage form will also be influenced by the solid state properties of a given pharmaceutical active. The amorphous characteristics of APIs have a significant impact on their performance and thus offer the potential for exciting new pharmaceuticals. Whilst amorphous forms of poorly soluble APIs are more soluble than their crystalline counterparts, they tend to be physically unstable, which makes their formulation into solid dosage forms quite challenging. Roxithromycin has only 50% oral bioavailability due to its poor aqueous solubility and for this reason, its potential for optimal therapeutic effect are limited. Poor solubility is thus an important obstacle in formulation development. During this study, amorphous forms of roxithromycin were prepared via quench cooling, and desolvation of chloroform- and ethyl acetate solvates. These amorphous forms were characterised by means of several techniques, whilst their solubilities and stabilities were also investigated. The outcomes of the solubility studies illustrated the complexity of this API and its amorphous forms with regards to their interactions with water. Solubility studies confirmed the superior solubility of the roxithromycin glass (prepared through quench cooling) and amorphous forms (desolvation of solvates) over the roxithromycin monohydrate in water. The solubility in water improved in the order of roxithromycin monohydrate < roxithromycin glass < roxithromycin glass powder < amorphous chloroform desolvate. The roxithromycin monohydrate, as well as the amorphous forms of roxithromycin demonstrated stability over a one-month period of exposure 40°C and relative humidity (RH) of 75%. The roxithromycin glass powder tended to revert to the more stable crystalline monohydrate after week 3 of stability testing. The roxithromycin glass at lower temperatures of 25°C and 30°C (both at 75% RH) tended to transform into the more crystalline form at week 4 of the study. These transformations were, however, not as significant as during the 40°C / 75% RH study. The conclusion could therefore be made that this transformation into the crystalline form was more temperature – than moisture dependant. At a higher temperature (at identical humidity conditions), the transformation into the crystalline form was much faster. Stability studies on the two roxithromycin desolvates were also performed in order to determine whether these amorphous forms, would differ, with regards to their stability, from the glass prepared through heating and cooling. It was determined that the desolvates were more stable than the roxithromycin glass.