School of Pharmaceutical Sciences (Shandong Analysis and Testing Center), Qilu University of Technology (Shandong Academy of Sciences), Jinan 250014, PR China.
School of Pharmaceutical Sciences (Shandong Analysis and Testing Center), Qilu University of Technology (Shandong Academy of Sciences), Jinan 250014, PR China; School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, PR China.
Ultrason Sonochem. 2023 Jul;97:106475. doi: 10.1016/j.ultsonch.2023.106475. Epub 2023 Jun 9.
The objective of this research was to modify the crystal shape and size of poorly water-soluble drug ropivacaine, and to reveal the effects of polymeric additive and ultrasound on crystal nucleation and growth. Ropivacaine often grow as needle-like crystals extended along the a-axis and the shape was hardly controllable by altering solvent types and operating conditions for the crystallization process. We found that ropivacaine crystallized as block-like crystals when polyvinylpyrrolidone (PVP) was used. The control over crystal morphology by the additive was related to crystallization temperature, solute concentration, additive concentration, and molecular weight. SEM and AFM analyses were performed providing insights into crystal growth pattern and cavities on the surface induced by the polymeric additive. In ultrasound-assisted crystallization, the impacts of ultrasonic time, ultrasonic power, and additive concentration were investigated. The particles precipitated at extended ultrasonic time exhibited plate-like crystals with shorter aspect ratio. Combined use of polymeric additive and ultrasound led to rice-shaped crystals, which the average particle size was further decreased. The induction time measurement and single crystal growth experiments were carried out. The results suggested that PVP worked as strong nucleation and growth inhibitor. Molecular dynamics simulation was performed to explore the action mechanism of the polymer. The interaction energies between PVP and crystal faces were calculated, and mobility of the additive with different chain length in crystal-solution system was evaluated by mean square displacement. Based on the study, a possible mechanism for the morphological evolution of ropivacaine crystals assisted by PVP and ultrasound was proposed.
本研究旨在改变难溶性药物罗哌卡因的晶体形状和大小，并揭示高分子添加剂和超声对晶体成核和生长的影响。罗哌卡因通常呈针状晶体沿 a 轴延伸，通过改变溶剂类型和结晶过程的操作条件，很难控制其形状。我们发现，当使用聚乙烯吡咯烷酮（PVP）时，罗哌卡因结晶为块状晶体。添加剂对晶体形态的控制与结晶温度、溶质浓度、添加剂浓度和分子量有关。通过 SEM 和 AFM 分析，深入了解了晶体生长模式和表面的空腔，这是由高分子添加剂引起的。在超声辅助结晶中，研究了超声时间、超声功率和添加剂浓度的影响。在延长的超声时间下沉淀的颗粒表现出具有较短纵横比的板状晶体。高分子添加剂和超声的联合使用导致形成了稻粒状晶体，其平均粒径进一步减小。进行了诱导时间测量和单晶生长实验。结果表明，PVP 作为强成核和生长抑制剂发挥作用。进行了分子动力学模拟以探索聚合物的作用机制。计算了 PVP 与晶体表面之间的相互作用能，并通过均方位移评估了具有不同链长的添加剂在晶体-溶液体系中的迁移率。基于该研究，提出了 PVP 和超声辅助罗哌卡因晶体形态演变的可能机制。
