Department of Physics, Chemistry, and Pharmacy, University of Southern Denmark, Campusvej 55, 5230, Odense, Denmark.
AAPS PharmSciTech. 2024 Aug 13;25(6):185. doi: 10.1208/s12249-024-02907-6.
Aqueous suspensions containing crystalline drug in the sub-micron range is a favorable platform for long-acting injectables where particle size can be used to obtain a desired plasma-concentration profile. Stabilizers are added to the suspensions and screened extensively to define the optimal formulation composition. In the initial formulation screening the amount of drug compound can be limited, necessitating milling methods for small-volume screening predictable for scale-up. Hence, adaptive focused ultrasound was investigated as a potential milling method for rapid small-volume suspensions by identifying the critical process parameters during preparation. Suspensions containing drug compounds with different mechanical properties and thereby grindability, i.e., cinnarizine, haloperidol, and indomethacin with brittle, elastic, and plastic properties, respectively, were investigated to gain an understanding of the manufacturing with adaptive focused acoustics as well as comparison to already established milling techniques. Using a DoE-design, peak incident power was identified as the most crucial process parameter impacting the milling process for all three compounds. It was possible to decrease the sizes of drug particles to micron range after one minute of focused ultrasound exposure which was superior compared to other milling techniques (e.g., non-focused ultrasound exposure). The addition of milling beads decreased the drug particle sizes even further, thus to a lower degree than other already established milling techniques such as milling by dual centrifugation. This study thereby demonstrated that adaptive focused ultrasonication was a promising method for rapid homogenization and particle size reduction to micron range for different compounds varying in grindability without altering the crystalline structure.
含有亚微米级结晶药物的水混悬剂是长效注射剂的理想平台，可通过粒径来获得所需的血浆浓度曲线。混悬剂中添加稳定剂并进行广泛筛选，以确定最佳配方组成。在初始配方筛选中，药物化合物的用量可能受到限制，因此需要采用小体积筛选方法，且可预测放大后的情况。因此，研究了自适应聚焦超声作为一种潜在的用于快速小体积混悬剂的研磨方法，以确定在制备过程中的关键工艺参数。研究了含有不同机械性能（即脆性、弹性和塑性）药物化合物的混悬剂，如肉桂嗪、氟哌啶醇和吲哚美辛，以了解采用自适应聚焦超声进行制造的情况，并与已建立的研磨技术进行比较。采用设计实验（DoE）设计，确定峰值入射功率是影响三种化合物研磨过程的最关键工艺参数。经过一分钟的聚焦超声处理，药物颗粒的尺寸可减小到微米级，这优于其他研磨技术（例如非聚焦超声处理）。添加研磨珠甚至可以进一步减小药物颗粒的尺寸，但程度低于其他已建立的研磨技术，如双离心研磨。因此，这项研究表明，自适应聚焦超声处理是一种很有前途的方法，可用于快速均化和将不同可研磨性的化合物的粒径减小到微米级，而不会改变晶体结构。
