Willmann Ann-Cathrin, Berkenfeld Kai, Faber Thilo, Wachtel Herbert, Boeck Georg, Wagner Karl G
Pharmaceutical Development, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 65, 88397 Biberach, Germany.
Department of Pharmaceutical Technology, University of Bonn, Gerhard-Domagk-Straße 3, 53121 Bonn, Germany.
Pharmaceutics. 2022 Jul 22;14(8):1528. doi: 10.3390/pharmaceutics14081528.
Nanocrystal suspensions proved to be a potent enabling principle for biopharmaceutics classification system class II drugs with dissolution limited bioavailability. In the example of itraconazole (ITZ) as a model drug combined with electrosteric stabilization using hydroxypropyl cellulose (HPC-SL), sodium dodecyl sulfate (SDS) and polysorbate 80 (PS80), the impacts of formulation and process parameters of a dual centrifugal mill on material attributes such as particle size, zeta potential, particle morphology, storage stability and especially solid-state characteristics were evaluated. A minimal concentration of 0.9% (/) HPC-SL, 0.14% (/) SDS and 0.07% (/) PS80 was necessary for sufficient nanoparticle stabilization. Despite the minor effect of PS80, its presence was beneficial for electrosteric stabilization. Choosing lower stabilizer concentrations resulted in a pronounced increase in particle size due to agglomeration, which was confirmed by SEM imaging and a decrease in zeta potential in combination with an amorphization of the particles. Milling temperature had no significant impact on the particle size, whereas milling speed and the size of the milling beads used were found to have a strong impact on the critical material attributes such as particle size and polydispersity index. The smallest particle sizes could be obtained by using the smallest milling bead size. However, the smallest obtainable particle size could only be achieved by using two-fold stabilizer concentrations, as smaller particles exhibit a larger specific surface area.
纳米晶体悬浮液被证明是生物药剂学分类系统中生物利用度受溶出限制的II类药物的一种有效促成原理。以伊曲康唑（ITZ）作为模型药物，结合使用羟丙基纤维素（HPC-SL）、十二烷基硫酸钠（SDS）和聚山梨酯80（PS80）进行电空间稳定化为例，评估了双盘式离心机的配方和工艺参数对材料属性（如粒径、zeta电位、颗粒形态、储存稳定性，尤其是固态特性）的影响。为了实现足够的纳米颗粒稳定化，HPC-SL的最低浓度为0.9%（/）、SDS为0.14%（/）、PS80为0.07%（/）是必要的。尽管PS80的影响较小，但其存在有利于电空间稳定化。选择较低的稳定剂浓度会由于团聚导致粒径显著增加，这通过扫描电子显微镜成像得到证实，同时zeta电位降低，颗粒发生非晶化。研磨温度对粒径没有显著影响，而研磨速度和所用研磨珠的尺寸对粒径和多分散指数等关键材料属性有很大影响。使用最小尺寸的研磨珠可获得最小的粒径。然而，只有使用两倍的稳定剂浓度才能实现可获得的最小粒径，因为较小的颗粒具有更大比表面积。
