One challenge in the development of new drug formulations is overcoming their low solubility in relevant aqueous media. Reducing the particle size of drug powders to a few hundred nanometers is a well-known method that leads to an increase in solubility due to an elevated total surface area. However, state-of-the-art comminution techniques like cryo-milling suffer from degradation and contamination of the drugs, particularly when sub-micrometer diameters are aspired that require long processing times. In this work, picosecond-pulsed laser fragmentation in liquids (LFL) of dispersed drug particles in a liquid-jet passage reactor is used as a wear-free comminution technique using the hydrophobic oral model drugs naproxen, prednisolone, ketoconazole, and megestrol acetate. Particle size and morphology of the drug particles are characterized using scanning electron microscopy (SEM) and changes in particle size distributions upon irradiation are quantified using an analytical centrifuge. The findings highlight the superior fragmentation efficiency of the liquid-jet passage reactor setup, with a 100 times higher fraction of submicrometer particles (SMP) of the drugs compared to the batch control, which enhances solubility and goes along with minimal chemical degradation (<1%), determined by attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR), high-performance liquid chromatography (HPLC), and X-ray diffraction (XRD). Moreover, the underlying predominantly photo-mechanically induced laser fragmentation mechanisms of organic microparticles (MP) are discussed.

中文翻译：

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在液体喷射通道反应器中通过激光裂解有效合成亚微米级活性药物，降解程度最小

新药物制剂开发的一大挑战是克服它们在相关水介质中的低溶解度。将药物粉末的粒径减小到几百纳米是一种众所周知的方法，由于总表面积的增加，可导致溶解度增加。然而，最先进的粉碎技术（如冷冻研磨）会遭受药物降解和污染的问题，特别是当需要较长处理时间的亚微米直径时。在这项工作中，液体射流通道反应器中分散药物颗粒的液体中皮秒脉冲激光碎裂（LFL）被用作无磨损粉碎技术，使用疏水性口服模型药物萘普生、泼尼松龙、酮康唑和醋酸甲地孕酮。使用扫描电子显微镜 (SEM) 表征药物颗粒的粒径和形态，并使用分析离心机量化照射后粒径分布的变化。研究结果强调了液体射流通道反应器设置的卓越破碎效率，与批次控制相比，药物的亚微米颗粒 (SMP) 分数高出 100 倍，这提高了溶解度并伴随着最小的化学降解 (<1 %)，通过衰减全反射-傅里叶变换红外光谱 (ATR-FTIR)、高效液相色谱 (HPLC) 和 X 射线衍射 (XRD) 测定。此外，还讨论了有机微粒（MP）的主要光机械诱导激光破碎机制。