A novel method for the separation of mono and ortho polymorphs of paracetamol in gel matrix

•First time, the mono and ortho paracetamol polymorphs were isolated in gel matrix.•Best solvent combination to attain necessary supersaturation is identified.•Supersaturation σ plays a key role behind the nucleation of paracetamol polymorphs.•Metastable ortho polymorph crystallizes at the top of the gel column at higher σ.•Stable mono polymorph crystallizes at the bottom of the gel column at lower σ.

The nucleation control and separation of mono and ortho polymorphs of the important pharmaceutical solid paracetamol were carried out through a crystallization process in gel media for the first time. Crystallization of mono and ortho polymorphic forms of paracetamol was achieved by optimizing the experimental parameters such as the specific gravity, pH, height of the gel column and solute concentration at ambient temperature. The optimized experimental conditions favor the generation of necessary supersaturation responsible for the nucleation of preferred polymorph at different levels in the gel column and also endure the stability of the grown orthorhombic polymorphs at ambient conditions. Accordingly the needle like metastable orthorhombic polymorph nucleates at the top portion of the gel column whereas the prismatic stable monoclinic polymorph nucleates mostly at the bottom level. Morphology of the nucleated polymorphs was analyzed and their crystalline structures were confirmed by PXRD. FTIR analysis revealed the shifting of absorption peaks of few functional groups corresponding to both the polymorphs due to the difference in their structural nature. DSC analysis revealed that the grown ortho polymorph form II transforms to mono form I at 89.47 °C while the grown mono form I retains its phase until melting.

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