PhD: Pseudopolymorphism and solid-state stability of some opiate alkaloids studied by vibrational spectroscopy and thermal analysis

Gjorgji Petrusevski
Institute of Chemistry, Faculty of Natural Sciences and Mathematics, Ss. Cyril and Methodius University, Skopje, Macedonia
November, 2013


The knowledge of the pseudopolymorphism and solid-state stability of each active pharmaceutical ingredient (API) is of crucial importance for selection of the most appropriate technological procedure for production of final pharmaceutical dosage form (further enabling its safe and efficient medical application). The PhD thesis comprises the results from the first detailed study related to the polymorphism of the commercial crystal hydrate forms of the narcotic-analgesic codeine phosphate. The phase transition interconversion pathway of codeine phosphate hemihydrate to sesquihydrate form, and vice versa, are thoroughly described. The obtained vibrational spectra and the results derived from the thermal analysis conducted on both studied API forms are elaborated. The existence of the metastable monohydrate and anhydrous form of codeine phosphate is also confirmed. Furthermore, solvatomorphism study governed by crystallization of the commercial form of codeine phosphate sesquihydrate from various organic solvents shows that sesquihydrate undergoes direct phase transition either to hemihydrate (by crystallization form dimethylformamide), or anhydrous form. The latter outcome occurs when absolute ethanol, acetone and ethyl acetate are used as crystallizing solvents. In addition, a formation of solvate in methanol solution is also observed. The new obtained compound was identified as codeine phosphate sesquihydrate methanolate by means of variuos solid-state instrumental techniques. Corresponding solid-state study is conducted for pholcodine monohydrate. The work revailed that after crystallization from various organic solvents, pholcodine monohydrate exhibits unique crystal modification identical to the commercial form. In addition, single-crystal X-ray diffraction on specimen obtained from acetone solution, enabled to solve the crystal structure of pholcodine monohydrate. In the determined structure, each water molecule is connected by two pholcodine molecules via three strong hydrogen bonds. The obtained results offer new prospects towards solid-state properties of pholcodine monohydrate that might result in extended medical application of this important API.