Nucleation kinetics of clopidogrel hydrogen sulfate polymorphs in reactive crystallization: Induction period and interfacial tension measurements

Nucleation kinetics of clopidogrel hydrogen sulfate polymorphs has been investigated in the mixture of 2-butanol and ethyl acetate by reactive crystallization. The effect of supersaturation and temperature on the nucleation rate was researched by measuring the induction period. The results show that the induction period decreases with the increase of supersaturation and temperature. After identifying the form of nuclei, the results disclose the metastable form seems to favor generating at a high supersaturation level. The reasons have been explained from the view of critical nucleation size. The interfacial energy of two polymorphs (20 °C, γ_sl (I) = 4.49 mJ /m² , γ_sl (II) = 4.94 mJ /m² ; 25 °C, γ_sl (I) = 5.60 mJ /m² , γ_sl (II) = 6.27 mJ /m²) was also determined from induction time. The value calculated of Form II at 25 °C was close to the ones obtained from directly methods: by contact angle measurement (6.85 mJ /m²). The effect of different contents of ethyl acetate on the induction period at 20 °C was also explored. The results reveal the addition of a small amount of ethyl acetate can significantly promote nucleating.