Abstract 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 m J / m 2 , γ sl I I = 4.94 m J / m 2 ; 25 °C, γ sl I = 5.60 m J / m 2 , γ sl I I = 6.27 m J / m 2 ) 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 m J / m 2 ). 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.

中文翻译：

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反应结晶中硫酸氢氯吡格雷多晶型物的成核动力学：诱导期和界面张力测量

摘要 通过反应结晶研究了硫酸氢氯吡格雷多晶型物在 2-丁醇和乙酸乙酯混合物中的成核动力学。通过测量诱导期，研究了过饱和度和温度对成核速率的影响。结果表明，诱导期随着过饱和度和温度的升高而缩短。在确定原子核的形式后，结果显示亚稳态形式似乎有利于在高过饱和水平下生成。已经从临界成核尺寸的角度解释了原因。两种多晶型物的界面能（20 °C, γ sl I = 4.49 m J / m 2 , γ sl II = 4.94 m J / m 2 ; 25 °C, γ sl I = 5.60 m J / m 2 , γ sl II = 6.27 m J / m 2 ) 也由诱导时间确定。II 型在 25 °C 下的计算值接近直接方法获得的值：通过接触角测量 (6.85 m J / m 2 )。还探讨了不同含量的乙酸乙酯对 20°C 诱导期的影响。结果表明，加入少量乙酸乙酯可显着促进成核。