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

Abstract

This study explores the polymorphic control and separation of metacetamol in pure aqueous solution through swift cooling crystallization process. The impact of relative supersaturation

(σ = 0.76–16.19) created during crystallization process on the induction period, nucleation and morphology of metacetamol was investigated. Our findings demonstrate that lower relative supersaturation levels (σ = 0.76–2.84) facilitates the nucleation of only stable form I. At intermediate relative supersaturation levels (σ = 3.02–4.61), both form I and hemihydrate nucleated concomitantly, while at higher relative supersaturation levels (σ = 4.72–16.19) favoured only hemihydrate nucleation. Additionally, the induction time for nucleation decreased as relative supersaturation increased. External morphology of the nucleated form I and hemihydrate was examined using in-situ optical microscopy. Structural conformation and thermal behaviour of the grown polymorphs was determined by powder X-ray diffraction, differential scanning calorimetry analyses respectively. This method offers optimized nucleation regions for form I and hemihydrate of metacetamol.