Crystallization conditions and formation of orthorhombic paracetamol from ethanolic solution

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Abstract
Orthorhombic paracetamol exhibits far better tabletability than the monoclinic form and its bulk crystallization from solution attracts much interest. In this study, temperature changes in supersaturated ethanolic solution have been recorded after seeding with orthorhombic crystals under different cooling temperatures (TC) and agitation rates (AR). Average cooling rate (CR), time for maximum temperature deviation (tmax) and area confined between curves of measured and reference temperature plots (AUC) were calculated and correlated with crystal yield (Y). The micromeritic (size and shape) and the compression properties, the density and the orthorhombic content of the crystalline product were evaluated and related to the main crystallization conditions applied (TC and AR). Conditions for optimal crystal yield and orthorhombic content were elucidated. It was found that crystal yield (Y) increased with AR and decreased with TC. The ratio tmax/CR provided good prediction of crystal yield (Y = 58.92 −1.386 tmax/CR, r2 = 0.964 and P = 0.0001). TC and AR linearly affected crystal size and the size distribution, probably due to alterations in supersaturation, but they did not affect the crystal shape significantly. Density and compression properties (yield pressure and elastic recovery) were determined by the content of the orthorhombic form, which increased linearly with AR (P = 0.009) and with TC (P = 0.039) when agitation was between 300 and 500 rev min−1, while tmax decreased. At 700 rev min−1 orthorhombic content was maximized and became independent to TC. Higher orthorhombic content and crystal yield was expected for lower TC and for lower tmax, which corresponded to higher AR and might have also been affected by alteration of seeding and harvesting procedure.