Critical Analytics for Manufacturing Personalized-Medicine, Singapore-MIT Alliance for Research and Technology, Singapore138602, Singapore.
Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore117576, Singapore.
Mol Pharm. 2022 Nov 7;19(11):4345-4356. doi: 10.1021/acs.molpharmaceut.2c00714. Epub 2022 Oct 21.
Co-processing active pharmaceutical ingredients (APIs) with excipients is a promising particle engineering technique to improve the API physical properties, which can lead to more robust downstream drug product manufacturing and improved drug product attributes. Excipients provide control over critical API attributes like particle size and solid-state outcomes. Eudragit E100 is a widely used polymeric excipient to modulate drug release. Being cationic, it is primarily employed as a precipitation inhibitor to stabilize amorphous solid dispersions. In this work, we demonstrate how co-processing of E100 with naproxen (NPX) (a model hydrophobic API) into monodisperse emulsions via droplet microfluidics followed by solidification via solvent evaporation allows the facile fabrication of compact, monodisperse, and spherical particles with an expanded range of solid-state outcomes spanning from amorphous to crystalline forms. Low E100 concentrations (≤26% w/w) yield crystalline microparticles with a stable NPX polymorph distributed uniformly across the matrix at a high drug loading (∼89% w/w). Structurally, E100 incorporation reduces the size of primary particles comprising the co-processed microparticles in comparison to neat API microparticles made using the same technique and the as-received API powder. This reduction in primary particle size translates into an increased internal porosity of the co-processed microparticles, with specific surface area and pore volume ∼9 times higher than the neat API microparticles. These E100-enabled structural modifications result in faster drug release in acidic media compared to neat API microparticles. Additionally, E100-NPX microparticles have a significantly improved flowability compared to neat API microparticles and as-received API powder. Overall, this study demonstrates a facile microfluidics-based co-processing method that broadly expands the range of solid-state outcomes obtainable with E100 as an excipient, with multiscale control over the key attributes and performance of hydrophobic API-laden microparticles.
共加工活性药物成分（APIs）与赋形剂是一种很有前途的颗粒工程技术，可以改善 API 的物理性质，从而可以实现更稳健的下游药物产品制造和改善药物产品属性。赋形剂可以控制关键 API 属性，如粒径和固体状态结果。Eudragit E100 是一种广泛使用的聚合物赋形剂，用于调节药物释放。由于其带正电荷，主要用作沉淀抑制剂来稳定无定形固体分散体。在这项工作中，我们展示了如何通过液滴微流控技术将 E100 与萘普生（NPX）（一种模型疏水性 API）共加工成单分散乳液，然后通过溶剂蒸发固化，从而可以轻松地制造出具有扩展的固体状态结果范围的紧密、单分散、球形颗粒，从无定形到结晶形式。低浓度的 E100（≤26%w/w）可得到结晶微颗粒，其中 NPX 稳定多晶型体均匀分布在基质中，药物载量高（约 89%w/w）。结构上，与使用相同技术和原始 API 粉末制成的纯 API 微颗粒相比，E100 的掺入会减小组成共加工微颗粒的初级颗粒的尺寸。与纯 API 微颗粒相比，共加工微颗粒的这种初级颗粒尺寸的减小转化为内部孔隙率的增加，比表面积和孔体积约高 9 倍。这些 E100 实现的结构修饰导致在酸性介质中药物释放速度比纯 API 微颗粒更快。此外，与纯 API 微颗粒和原始 API 粉末相比，E100-NPX 微颗粒的流动性有了显著提高。总体而言，这项研究展示了一种简单的基于微流控的共加工方法，可以广泛扩展 E100 作为赋形剂获得的固体状态结果范围，并对载有疏水性 API 的微颗粒的关键属性和性能进行多尺度控制。
