Solution-mediated phase transformation of different roxithromycin solid-state forms: implications on dissolution and solubility

21 July 2015

The objective of this study was to describe the solid-state forms in which roxithromycin may exist and the significant influence of solution-mediated phase transformation on the dissolution and solubility behavior of these forms. Roxithromycin may exist as: Form I (monohydrate), Form II (amorphous), Form III (anhydrate) and a mixture of Forms I and III. Form III and Mixture I/III have not been reported previously, probably due to incomplete solid-state characterization or the use of a standard production method which consistently yielded the same solid-state form. Solution-mediated phase transformations of Forms II and III to the stable Form I were proved through dissolution studies and quantification of the phase proportions, as a function of time, utilizing XRPD. This study showed that pharmacopoeial identification methods for roxithromycin do not allow accurate identification of the different solid-state forms. The various forms differed significantly in terms of dissolution profiles, which could have a marked influence on bioavailability and performance of the final dosage form. It was demonstrated that solvent replacement, during dissolution testing, masks the characteristic profile usually obtained with a metastable form undergoing solution-mediated transformation. Finally, we propose that peak dissolution concentrations should be used to give a more exact indication of the aqueous solubility enhancement ratio obtained with metastable forms of APIs.