Supersaturation dependent nucleation control and separation of mono, ortho and unstable polymorphs of paracetamol by swift cooling crystallization technique

A novel method for the separation and crystallization of all the three polymorphic forms of pharmaceutical solid paracetamol from pure aqueous solution is reported in this study. The polymorphic nucleation behaviour of the paracetamol has been investigated under different concentrations of the solute from pure aqueous solution by adopting swift cooling technique. With the variation in the concentration of the mother solution, the resulting effect of supersaturation on the nucleation rate of the three different polymorphic forms of paracetamol was studied. The variation in the induction period of nucleation at different supersaturation ranges was determined. The nucleation regions of three different polymorphs were separated in terms of supersaturation ranges at the end of the crystallization process. The form of crystallization of the nucleated polymorphs was confirmed by X-ray diffraction analysis. The main advantage of this technique is the achievement of the nucleation control without incorporating any nucleation selecting additives into the mother solution.