非光化学激光诱导乙酸钠结晶行为及机理研究

Non-photochemical laser-induced nucleation (NPLIN) is a new type of technique for crystallization, the relatively low power density of laser is chosen for crystal nucleation without photochemical reaction. This technique not only offers advantages to localizing temporally and spatially the point of nucleation, but also controls pharmaceutical crystal polymorphism through the transformation of laser polarization. As sodium acetate has a huge potential in energy storage, and in the initial work, the crystalized phenomenon of sodium acetate was suitable to observation under NPLIN with the application of different additives. In order to explore the underlying mechanism for NPLIN, this project will apply a single laser pulse to induce crystallization of sodium acetate with the combination of poly-(methacrylic acid) [PMA] solution and disodium hydrogen phosphate (DHP) as additives, video microscopy of laser-induced crystallization of sodium acetate will be more likely to reveal an alternative mechanism for NPLIN. Also, the effect of NPLIN on crystalline growth velocities and crystal morphology will be systematically investigated through experimental characterization and theoretical calculation. Solutions will be classified into three groups through the application of nanoparticle or filtration, and the quantities of bubbles and crystals induced by laser will be built in a mathematic function to deduce the feasibly of this mechanism underlying laser-induced nucleation. The research achievement gives a further understanding of inner mechanism and theoretical knowledge for NPLIN; The project offers an advantage with the meaning of practical instruction in the exploration of a new technique for pharmaceutical production. Also, the program brings some scientific research values for opening up a huge potential for NPLIN.

非光化学激光结晶（NPLIN）是一种新型结晶技术，即利用较低能量密度的激光在不引起光化学反应的同时诱导晶体结晶。该技术不仅对结晶的时间与形态具有可控性，还可通过改变激光偏振性控制药物晶体的多晶现象。基于乙酸钠在能源存储方面存在巨大潜力，且在初期NPLIN工作中，不同添加剂的使用会对乙酸钠形成易于观测的结晶现象，故本项目拟采用单个激光脉冲结合聚甲基丙基酸和磷酸氢二钠为添加剂诱导乙酸钠结晶来探索NPLIN的内在机理。利用视频显微镜记录的激光诱导结晶过程来揭示新机理，且系统性的结合实验与理论来研究NPLIN对晶体生长速度与形态的影响。溶液通过过滤或微米颗粒的加入将划分成三类样品，将激光诱导出的晶体与气泡数量建立成数学理论公式来推断新机理的可行性。研究成果可加深了解NPLIN技术内在机理与理论知识，项目对开拓药物新型生产技术具有实际指导意义，对发展与丰富NPLIN应有前景具有重要科学研究价值。

本项目采用的是非光化学激光诱导形核技术（NPLIN），该技术可在不发生光化学反应下诱导溶质分子或熔融物形核，该技术对形核的位置以及时间具有较高调控性。本项目的主要研究内容是采用NPLIN诱导无水乙酸钠结晶并验证相关机理，研究发现NPLIN作用下的无水乙酸钠晶体生长形态类似于蒲公英形态，NPLIN仅可对晶体形核阶段具有较好的控制性，在单个激光脉冲结束后，晶核形成后将进入生长阶段，在无任何添加剂作用下，晶体生长速度以及形态变得不均一且不受控制。为了使晶体生长阶段能得到有效控制，酸性聚合物作为添加剂被用于改变晶体溶液内部生长环境，在少量添加剂的作用下，晶体的数量、生长速度、形态以及大小都能得到有效的控制，这些优点可用于管控及生产高质量的晶体颗粒，且在晶体生长过程中无水乙酸钠晶体的形态以及大小也变得一致，这些现象也在NPLIN诱导氯化铯结晶中得到了验证。在NPLIN作用后，氯化铯晶粒在0.2wt%酸性聚合物（聚天冬氨酸或聚环氧琥珀酸）环境下生长速度将变得缓慢，晶粒形态大小变得统一；当聚环氧琥珀酸质量百分比在溶液中达到 0.3-0.4 wt%，生成的氯化铯晶体颗粒可以有效控制15个以内；当酸性聚合物的质量百分比增加到 5 wt%以上，NPLIN作用后的氯化铯晶体可由雪花状晶形生长成花状。然而在乙酸钠研究中，当酸性聚合物在溶液中成分占比超过0.441wt%以上，NPLIN无法诱导出无水乙酸钠晶体，研究发现酸性聚合物能增加乙酸钠的溶解度，这一发现可应用于难溶性药物生产，控制难溶性药物晶体的大小形态增加难溶性药物的溶解率；或应用于药物晶体的多晶现象，采用NPLIN协同酸性聚合物协调激光的偏振性来控制晶体的多晶现象将目标晶型诱导出来，这不仅提高了NPLIN的技术水平，也大大扩展了NPLIN的应用范围。