Resende de Azevedo Jacqueline, Espitalier Fabienne, Ré Maria Inês
Université de Toulouse, Mines-Albi, UMR-CNRS 5302, Centre RAPSODEE, Campus Jarlard, F-81013 Albi CT cedex 09, France; Univ Lyon, Université Claude Bernard Lyon 1, CNRS, LAGEPP UMR 5007, 43 boulevard du 11 novembre 1918, F-69100 Villeurbanne, France(1).
Université de Toulouse, Mines-Albi, UMR-CNRS 5302, Centre RAPSODEE, Campus Jarlard, F-81013 Albi CT cedex 09, France.
Ultrason Sonochem. 2019 Jul;55:32-43. doi: 10.1016/j.ultsonch.2019.03.011. Epub 2019 Mar 11.
This work deals with the antisolvent crystallization of LASSBio-294 (3,4-methylenedioxybenzoyl-2-thienylhydrazon) assisted by ultrasound. An ionic liquid (IL), 1-ethyl-3-methylimidazolium methyl phosphonate [emim][CHO(H)PO] was used as solvent and water as antisolvent. The influence of the following parameters on crystals properties (size distribution, morphology, residual solvent and in vitro dissolution) were studied with two mixing mode (quick and dropwise) of solution with antisolvent. The impact of washing and drying process was also evaluated. Comparative studies of conventional crystallization conditions (without ultrasound) were also performed. The effect of ultrasound on LASSBio-294 recrystallized properties was influenced by the add mode, water/IL ratio and drug solution concentration. As example, US promoted the formation of small crystals with high residual IL under the following conditions: quick addition, high drug solution concentration and high water/IL ratio. However, despite the decrease of elementary particle size, ultrasound did not avoid crystals agglomeration. The drug dissolution rate was affected by the physical structure of agglomerates. When employed as drying process of washed crystals, spray drying reduced this agglomeration and improved the dissolution of LASSBio-294 crystals.
本研究探讨了超声辅助下LASSBio-294（3,4-亚甲二氧基苯甲酰-2-噻吩腙）的抗溶剂结晶过程。以离子液体（IL）1-乙基-3-甲基咪唑甲基膦酸酯[emim][CHO(H)PO]为溶剂，水为抗溶剂。采用两种溶液与抗溶剂的混合方式（快速和滴加），研究了以下参数对晶体性质（尺寸分布、形态、残留溶剂和体外溶出度）的影响。同时评估了洗涤和干燥过程的影响。还进行了常规结晶条件（无超声）的对比研究。超声对LASSBio-294重结晶性质的影响受添加方式、水/离子液体比例和药物溶液浓度的影响。例如，在快速添加、高药物溶液浓度和高水/离子液体比例的条件下，超声促进了高残留离子液体的小晶体的形成。然而，尽管初级粒径减小，但超声并未避免晶体团聚。药物溶出速率受团聚体物理结构的影响。当用于洗涤后晶体的干燥过程时，喷雾干燥减少了这种团聚并提高了LASSBio-294晶体的溶出度。
