Polymorphism plays a significant role in pharmaceutics for drug designing because of their diversified properties. It has critical implications in pharmaceutical development as they impact the stability and bioavailability of the active drug ingredient. Paracetamol an excellent analgesic and antipyretic drug crystallizes in three different polymorphic forms mono, ortho and the unstable form. Crystallization of metastable orthorhombic and the unstable polymorph is highly elusive and moreover, the separation of these polymorphs remains as a challenging task today. In the present work, the polymorphic nucleation behaviour of pharmaceutical solid paracetamol has been investigated by performing cooling crystallization process at different cooling rates from 274-313 K with fixed agitation of the mother liquor at 100 rpm. Saturated pure aqueous solutions of paracetamol at fixed supersaturation conditions were stabilized for about 2 hours at 353 K and then swiftly cooled to a below ambient temperature of 274 K with continuous stirring by means of a DC micrometer with digital speed controlling facility. The resultant supersaturation generated in the mother solution favours the nucleation of desired polymorphs of paracetamol. The resulted nucleation in the solutions was investigated under in-situ optical microscopy and the type of polymorphs was identified according to their morphology. The phase diagram constructed to demonstrate the swift cooling experimental procedure clearly explains the reason for the occurrence of polymorphs and its stability by the movement of concentration position line into the metastable or labile zone region. The experiment was continued for different cooling rates in the range 274-313 K in steps of 1 K. The results elucidate a clear distinction of preferred nucleation regions of mono, ortho and unstable polymorph in the temperature range between 274 and 313 K. Very high supersaturation in the temperature range 274-281 K favours unstable polymorph with fibre-like morphology, the supersaturation generated in the temperature range 282-292 K yields orthorhombic polymorph with needle shaped morphology and the low supersaturation favours monoclinic polymorph with prismatic morphology in the temperature range 293-313 K. The nucleated metastable polymorph which possesses needle shaped morphology is quiet stable for about 10 minutes and after 15 minutes it undergoes dissolution. The nucleated unstable polymorph which possesses fibre-like morphology undergoes extensive dissolution within a short period and disappears within 7 seconds at that experimental condition. The form of crystallization of the obtained polymorphs was confirmed by PXRD. The type of nucleated paracetamol polymorphs in the solution is mainly influenced by the driving force created in the solution. Through swift cooling process the nucleation regions of the three different polymorphs were identified and separated for the first time. This novel specific cooling crystallization process seems as a promising one for the control of nucleation and separation of polymorphs.

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