Crystallization of Metastable Orthorhombic Paracetamol by Specially Designed Seeding Technique

Elusive metastable orthorhombic paracetamol single crystals were obtained by specially designed seeding technique from conventional slow evaporation method. Seeds were prepared at optimized conditions under different cooling rates from seed preparation unit and Powder x-ray diffraction (PXRD) was performed to ensure the polymorphic form of seeds. Saturated paracetamol solutions with three different selected polar protic water, ethanol and aprotic cyclohexanone solvents were examined with and without seeding. All the three unseeded solutions and the seeded solution of polar protic water and ethanol yielded only stable monoclinic paracetamol whereas the seeded aprotic solvent cyclohexanone yielded metastable orthorhombic paracetamol single crystals. The effect of crystallization of polymorph is mainly attributed by the efficiency of seeding, metastable zone width of desired polymorphic region and by different types of intermolecular interaction of solute-solvent through hydrogen bonding. Morphology of the grown paracetamol single crystals was studied by optical goniometry. The difference in the stretching of specific bonding of few functional groups of the paracetamol molecule when it is stacked in mono and ortho crystallographic structures is evidently noticed from recorded FTIR spectra of both the polymorphs. Polymorphic transformation from ortho to mono at 89.44 °C was confirmed by DSC analysis.