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Cooling Crystallization of Indomethacin: Effect of Supersaturation, Temperature, and Seeding on Polymorphism and Crystal Size Distribution
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2018-05-25 00:00:00 , DOI: 10.1021/acs.oprd.8b00078
Chandrakant R. Malwade 1 , Haiyan Qu 1
Affiliation  

In this work, the effect of crystallization parameters, i.e., supersaturation, seeding, and temperature, on the polymorphism and crystal size of a nonsteroidal anti-inflammatory drug, indomethacin (IMC), was investigated. First, several crystallization solvents (ethanol, methanol, ethyl acetate, acetone, acetonitrile, and dichloromethane) were screened through the measurement of IMC solubility at different temperatures. This was followed by the investigation of IMC nucleation through measurement of induction times in selected solvents at two supersaturations. Finally, seeded cooling crystallization of IMC in ethanol was performed with different process parameters to investigate the influence on the polymorphism and crystal size distribution. Remarkably long induction times were observed for IMC in ethanol and ethyl acetate solutions, while a shorter induction time was observed in acetone. Cooling crystallization of IMC from ethanol confirmed that supersaturation, operating temperature, and seeding do affect the polymorphism as well as crystal size distribution of IMC. Fine needle-shaped crystals of metastable α-IMC were obtained at 5 °C with high supersaturation even in the presence of γ-IMC seeds, while rhombic platelike crystals of thermodynamically stable γ-IMC were obtained in the remaining experiments. The seed loading only marginally influenced the crystal growth rate and median particle diameter. Particle size analysis of the crystals obtained showed a bimodal distribution in all experiments, and a larger median particle diameter was observed at 15 °C with high supersaturation.

中文翻译:

消炎痛的冷却结晶:过饱和度,温度和晶种对多态性和晶体尺寸分布的影响

在这项工作中,研究了结晶参数(即过饱和度,晶种和温度)对非甾体抗炎药消炎痛(IMC)的多态性和晶体尺寸的影响。首先,通过在不同温度下测量IMC溶解度来筛选几种结晶溶剂(乙醇,甲醇,乙酸乙酯,丙酮,乙腈和二氯甲烷)。随后通过测量在两个过饱和度下所选溶剂中的诱导时间来研究IMC成核。最后,以不同的工艺参数进行了IMC在乙醇中的晶种冷却结晶,以研究其对多态性和晶体尺寸分布的影响。在乙醇和乙酸乙酯溶液中,IMC的诱导时间非常长,而在丙酮中观察到的诱导时间更短。从乙醇中冷却IMC的结晶证实,过饱和度,操作温度和晶种确实会影响IMC的多态性以及晶体尺寸分布。即使在存在γ-IMC晶种的情况下,即使在存在γ-IMC晶种的情况下,也可在5°C时获得具有高过饱和度的细亚稳α-IMC针状晶体,而在其余实验中获得热力学稳定的γ-IMC菱形板状晶体。晶种负载仅略微影响晶体生长速率和中值粒径。所得晶体的粒度分析在所有实验中均显示出双峰分布,并且在15°C时具有较高的过饱和度,观察到较大的中值粒径。从乙醇中冷却IMC的结晶证实,过饱和度,操作温度和晶种确实会影响IMC的多态性以及晶体尺寸分布。即使在存在γ-IMC晶种的情况下,即使在存在γ-IMC晶种的情况下,也可在5°C时获得具有高过饱和度的细亚稳α-IMC针状晶体,而在其余实验中获得热力学稳定的γ-IMC菱形板状晶体。晶种负载仅略微影响晶体生长速率和中值粒径。所得晶体的粒度分析在所有实验中均显示出双峰分布,并且在15°C时具有较高的过饱和度,观察到较大的中值粒径。从乙醇中冷却IMC的结晶证实,过饱和度,操作温度和晶种确实会影响IMC的多态性以及晶体尺寸分布。即使在存在γ-IMC晶种的情况下,即使在存在γ-IMC晶种的情况下,也能在5°C的条件下获得具有高过饱和度的亚稳态α-IMC细针状晶体,而在其余实验中获得了热力学稳定的γ-IMC菱形板状晶体。晶种负载仅略微影响晶体生长速率和中值粒径。所得晶体的粒度分析在所有实验中均显示出双峰分布,并且在15°C时具有较高的过饱和度,观察到较大的中值粒径。即使在存在γ-IMC晶种的情况下,即使在存在γ-IMC晶种的情况下,也能在5°C的条件下获得具有高过饱和度的亚稳态α-IMC细针状晶体,而在其余实验中获得了热力学稳定的γ-IMC菱形板状晶体。晶种负载仅略微影响晶体生长速率和中值粒径。所得晶体的粒度分析在所有实验中均显示出双峰分布,并且在15°C时具有较高的过饱和度,观察到较大的中值粒径。即使在存在γ-IMC晶种的情况下,即使在存在γ-IMC晶种的情况下,也可在5°C时获得具有高过饱和度的细亚稳α-IMC针状晶体,而在其余实验中获得热力学稳定的γ-IMC菱形板状晶体。晶种负载仅略微影响晶体生长速率和中值粒径。所得晶体的粒度分析在所有实验中均显示出双峰分布,并且在15°C时具有较高的过饱和度,观察到较大的中值粒径。
更新日期:2018-05-25
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