Solvatomorphism of codeine phosphate sesquihydrate—Vibrational spectroscopy and thermoanalytical characterization

Abstract

The detailed solvatomorphism study of codeine phosphate sesquihydrate – an important narcotic analgesic and antitusic active pharmaceutical ingredient (API) is reported. The extensive crystallization from a series of medium to high polarity solvents clearly exhibited the low affinity toward solvates building of this compound. The materials obtained after crystallization were investigated by vibrational spectroscopy (infrared and Raman) and thermoanalytical methods (DSC and TG/DTG). It was observed that after absolute ethanol, ethyl acetate, acetone and acetonitrile crystallization, direct solvent mediated phase transition of codeine phosphate sesquihydrate to anhydrous codeine phosphate was achieved. When N,N-dimethylformamide was used as crystallization medium, transformation to the hemihydrate form of codeine phosphate was induced. Only in the case of methanol solution, formation of mixed hydrate-methanolate solvate was observed. Compared to the commercial forms of codeine phosphate hydrates, according to the obtained spectroscopic and thermoanalytical data, the newly obtained compound has different molecular arrangement. Based on the data obtained from thermal analysis and water content study, tentative stoichiometry was established and the compound was labeled as codeine phosphate sesquihydrate methanolate. The X-ray powder diffraction (XRPD) measurements confirmed the spectroscopic and thermoanalytical findings about the existence of different crystal structures between the various obtained codeine phosphate solid forms.