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首页> 外文期刊>Crystal growth & design >Antisolvent crystallization using ionic liquids as solvent and antisolvent for polymorphic design of active pharmaceutical ingredient
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Antisolvent crystallization using ionic liquids as solvent and antisolvent for polymorphic design of active pharmaceutical ingredient

机译：使用离子液体作为溶剂和反溶剂的反溶剂结晶，用于活性药物成分的多晶型设计

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The applicability of ionic liquids to the polymorphic design of the active pharmaceutical ingredient adefovir dipivoxil (AD) was investigated in the case of antisolvent crystallization. When using 1-allyl-3-ethylimidazolium tetrafluoroborate (AEImBF_4) as the solvent and 1-butyl-2, 3dimethylimidazolium tetrafluoroborate (BDMImBF_4) as the antisolvent (AEImBF_4/BDMImBF_4), a new form (NF) of AD crystal was obtained at a crystallization temperature below 50 C and initial solute concentration of 25.6 mg/mL. However, when using 1-allyl-3-ethylimidazolium tetrafluoroborate/1,3-diallylimidazolium tetrafluoroborate (AEImBF _4/AAImBF_4) and 1-allyl-3-ethylimidazolium tetrafluoroborate/1-ethyl-3-methylimidazolium ethylsulfate (AEImBF _4/EMImEtSO_4), the conventional form-I polymorph was directly crystallized. No crystallization occurred in the ionic solutions of 1-allyl-3-ethylimidazolium tetrafluoroborate/1-allyl-3-ethylimidazolium bromide (AEImBF_4/AEImBr) and 1-allyl-3-ethylimidazolium tetrafluoroborate/1, 3-diallylimidazolium bromide (AEImBF_4/AAImBr). According to a spectroscopic analysis, the polymorphs were predominantly determined by the preorientation of the solute molecules in the ionic liquid solution (AEImBF _4/BDMImBF_4), and this preorientation varied according to the crystallization temperature. Thus, the pure form-X polymorph was nucleated at a crystallization temperature above 80 C. Plus, the polymorphic nucleation depending on the crystallization temperature was also combined with the crystallization concentration. Thus, the minimum crystallization temperature for the nucleation of the pure form-X polymorph was reduced to 40 C when decreasing the crystallization concentration to 15 mg/mL. The relationship between the polymorphic nucleation and the crystallization conditions was effectively predicted by a polymorphic supersaturation level diagram (S_(NF)-S _(form-X) diagram), where the formation of the metastable polymorph (NF crystals) was favored at a high supersaturation level (S_(NF) > 2.1), while the stable polymorph (form-X crystals) was preferentially nucleated at a low supersaturation level (S_(NF) < 1.6). Differental scanning calorimetry thermal analysis confirmed that the NF polymorph was the metastable phase and the form-X polymorph was the stable phase, and there was a monotropic relationship between the two polymorphs.
机译：在反溶剂结晶的情况下，研究了离子液体在活性药物成分阿德福韦酯（AD）多晶型设计中的适用性。当使用1-烯丙基-3-乙基咪唑四氟硼酸酯（AEImBF_4）作为溶剂和使用1-丁基-2,3-二甲基咪唑四氟硼酸酯（BDMImBF_4）作为抗溶剂（AEImBF_4 / BDMImBF_4）时，在结晶温度低于50℃，初始溶质浓度为25.6 mg / mL。但是，当使用1-烯丙基-3-乙基咪唑四氟硼酸酯/ 1,3-二烯丙基咪唑四氟硼酸酯（AEImBF _4 / AAImBF_4）和1-烯丙基-3-乙基咪唑四氟硼酸酯/ 1-乙基-3-甲基咪唑乙基硫酸乙酯（AEImBF _4 / EMImEtSO_4）时，常规的I型多晶型物直接结晶。在四氟硼酸1-烯丙基-3-乙基咪唑鎓/ 1-烯丙基-3-乙基咪唑鎓溴化物（AEImBF_4 / AEImBr）和1-烯丙基-3-乙基咪唑鎓四氟硼酸酯/ 1、3-二烯丙基咪唑溴化物（AEImBF_4 / AAImBr）的离子溶液中未发生结晶）。根据光谱分析，多晶型物主要由离子液体溶液中溶质分子的预取向（AEImBF _4 / BDMImBF_4）确定，并且该预取向随结晶温度而变化。因此，纯X型多晶型物在高于80℃的结晶温度下成核。另外，取决于结晶温度的多晶型核也与结晶浓度结合。因此，当将结晶浓度降低至15mg / mL时，用于纯X型多晶型物成核的最低结晶温度降低至40℃。多态过饱和能级图（S_（NF）-S _（form-X）图）有效地预测了多晶形核与结晶条件之间的关系，其中亚稳多晶形（NF晶体）的形成倾向于高过饱和度（S_（NF）> 2.1），而稳定的多晶型物（X型晶体）在低过饱和度（S_（NF）<1.6）时优先成核。差示扫描量热法分析证实，NF多晶型为亚稳相，X型多晶型为稳定相，且两种多晶型之间存在单向关系。

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