Abstract：
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.
摘要：
含有亚微米范围的结晶药物的水性悬浮液是长效注射剂的有利平台,其中粒度可用于获得所需的血浆浓度分布。将稳定剂添加到悬浮液中并广泛筛选以限定最佳制剂组成。在初始制剂筛选中，可以限制药物化合物的量，需要用于可预测放大的小体积筛选的研磨方法。因此，通过识别制备过程中的关键工艺参数，研究了自适应聚焦超声作为快速小体积悬浮液的潜在铣削方法。含有具有不同机械性能的药物化合物的悬浮液，从而具有不同的可磨性，即，桂利嗪,氟哌啶醇,和吲哚美辛，弹性，和塑料特性，分别,进行了调查，以了解具有自适应聚焦声学的制造以及与已经建立的铣削技术的比较。使用DoE设计，峰值入射功率被确定为影响所有三种化合物的研磨过程的最关键的过程参数。在聚焦超声暴露一分钟后，可以将药物颗粒的尺寸减小到微米范围，这优于其他研磨技术（例如，非聚焦超声暴露)。添加研磨珠进一步降低了药物的粒径，因此，其程度低于其他已经建立的研磨技术，例如通过双离心研磨。因此，这项研究表明，自适应聚焦超声处理是一种有前途的方法，可用于快速均质化并将不同化合物的可研磨性降低至微米范围，而不会改变晶体结构。
