Buyukgoz Guluzar G, Castro Jeremiah N, Atalla Andrew E, Pentangelo John G, Tripathi Siddharth, Davé Rajesh N
Otto H. York Department of Chemical and Materials Engineering, New Jersey Institute of Technology, Newark, NJ 07102, USA.
Pharmaceutics. 2021 May 29;13(6):812. doi: 10.3390/pharmaceutics13060812.
The impact of mixer type and critical process parameters (CPPs) on critical quality attributes (CQAs), including the drug content uniformity (CU) of slurry-cast polymer films loaded with micro-sized poorly water-soluble drugs were investigated. Previously untested hypothesis was that the best mixer at suitable CPPs promotes uniform drug dispersion within film precursors leading to acceptable dried-film CU at low, 0.6 wt% drug concentrations. Taguchi design was utilized to select the best of three mixers; low-shear impeller, high-shear planetary, and high-intensity vibrational, for dried-film drug concentration of ~23 wt%. As-received fenofibrate, a model poorly water-soluble drug (6 µm) was directly mixed with the hydroxypropyl methylcellulose (HPMC) and glycerin aqueous solution. Impeller and planetary mixers yielded desirable film relative standard deviation (RSD), while vibrational mixer could not. For the lowest dried-film drug concentration of ~0.6 wt%, only planetary mixer yielded RSD <6%. The precursor drug homogeneity was a sufficient but not a necessary condition for achieving dried-film RSD <6%. Thus, proper selection of mixer and its CPPs assured desirable film CQAs. However, minor drug particle aggregation was identified via re-dispersion testing which also led to incomplete drug release.
研究了混合器类型和关键工艺参数（CPPs）对关键质量属性（CQAs）的影响，包括载有微米级难溶性药物的流延聚合物薄膜的药物含量均匀度（CU）。此前未经检验的假设是，在合适的CPPs条件下，最佳混合器可促进药物在薄膜前驱体中均匀分散，从而在低药物浓度（约0.6 wt%）下获得可接受的干膜CU。采用田口设计从三种混合器中选出最佳混合器，即低剪切叶轮、高剪切行星式和高强度振动式混合器，用于干膜药物浓度约为23 wt%的情况。将市售非诺贝特（一种难溶性模型药物，粒径约6 µm）直接与羟丙基甲基纤维素（HPMC）和甘油水溶液混合。叶轮式和行星式混合器产生了理想的薄膜相对标准偏差（RSD），而振动式混合器则未达到。对于最低干膜药物浓度约0.6 wt%的情况，只有行星式混合器的RSD <6%。前驱体药物的均匀性是实现干膜RSD <6%的充分但非必要条件。因此，正确选择混合器及其CPPs可确保获得理想的薄膜CQAs。然而，通过再分散测试发现存在少量药物颗粒聚集现象，这也导致药物释放不完全。
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