Physicochemical characterization of high- and low-melting phenylephrine oxazolidines

Abstract

Phenylephrine oxazolidine is a new prodrug of phenylephrine developed for improving ocular absorption and reducing systemic side effects. In the present study, high- and low-melting phenylephrine oxazolidines (HMP and LMP) were characterized in terms of their stereochemistry and crystal properties. It was found that the molecular configuration of the prodrug in the crystals of either HMP or LMP is identical (5R/2R). The two crystals were shown to have the same IR spectra and X-ray diffraction patterns but different crystal habits, thermal properties, solubilities and intrinsic dissolution rates. Single crystal X-ray structure analysis indicates that crystals of both HMP and LMP are orthorhombic and belong to the P2(1)2(1)2(1) space group with four molecules in a unit cell (a = 20.697 A, b = 7.065 A, and c = 9.304 A). The molecules in the crystal are held together by an intermolecular hydrogen bonding interaction between N(3) and O(13). The different physical properties observed for LMP result from crystal imperfections caused by the presence of trace amounts (often at levels < 0.5%) of an unidentified, structurally related synthetic impurity which can be dispersed in the prodrug. It was observed that both HMP and LMP can sustain thermal and mechanical treatment in the solid state. However, LMP was partially converted to HMP when suspended in certain solvents.