Nucleation control and separation of paracetamol polymorphs through swift cooling crystallization process

• Preferred nucleation region of all the three paracetamol polymorphs were isolated.
• Supersaturation σ plays a key role behind the nucleation of paracetamol polymorphs.
• Swift cooling produces high σ region favorable for nucleation of form III.
• Intermediate σ range favours form II, while low σ range nucleates form I.
• Solution mediated transformation of form III–I and II–I are revealed.

Polymorphic nucleation behavior of pharmaceutical solid paracetamol has been investigated by performing swift cooling crystallization process. Saturated aqueous solution prepared at 318 K was swiftly cooled to 274 K in steps of every 1 K in the temperature range from 274 K to 313 K with uniform stirring of 100 rpm. The resultant supersaturation generated in the mother solution favours the nucleation of three different polymorphs of paracetamol. Lower supersaturation region σ=0.10–0.83 favours stable mono form I; the intermediate supersaturation region σ=0.92–1.28 favours metastable ortho form II and the higher supersaturation region σ=1.33–1.58 favours unstable form III polymorphic nucleation. Depending upon the level of supersaturation generated during swift cooling process and the corresponding solubility limit and metastable zone width (MSZW) of each polymorph, the nucleation of a particular polymorph occurs in the system. The type of polymorphs was identified by in-situ optical microscopy and the internal structure was confirmed by Powder X-ray diffraction (PXRD) study. By this novel approach, the preferred nucleation regions of all the three polymorphs of paracetamol are optimized in terms of different cooling ranges employed during the swift cooling process. Also solution mediated polymorphic transformations from unstable to mono and ortho to mono polymorphs have been studied by in-situ.