The particles of phenytoin (Phe), a poorly water-soluble model drug, were bead-milled alone or co-milled with a hydrophilic waxy additive using an ultra cryo-milling technique in liquid nitrogen (LN₂) to improve its dissolution properties. However, the micronized drug particles adhered and aggregated, resulting in poor handling in manufacturing processes such as blending or tableting. To improve the dissolution profile and powder properties of the drug simultaneously, the milled products were secondarily processed together with larger spherical particles by mechanical powder processing. These secondary products were composite particles with a core-shell structure, with fine drug particles adhered and deposited on the core, based on order mixing theory. As a core, three types/sizes of spherical pharmaceutical excipient particles were applied. The resultant composite particles produced much faster release profiles than just milled or co-milled mixtures. In addition, the composite particles showed good micromeritic properties depending on the size of the core particles. These results indicate that the ultra cryo-milling and subsequent dry composite mixing is a potential approach for developing drug particles with improved dissolution.

苯妥英 (Phe) 是一种水溶性差的模型药物，在液氮 (LN _{2) 中}使用超低温研磨技术单独珠磨或与亲水性蜡状添加剂共同研磨) 以改善其溶解特性。然而，微粉化的药物颗粒会粘附和聚集，导致在混合或压片等制造过程中处理不当。为了同时改善药物的溶出曲线和粉末特性，通过机械粉末加工将研磨产品与较大的球形颗粒一起进行二次加工。这些次级产物是基于有序混合理论的具有核壳结构的复合颗粒，细小的药物颗粒粘附并沉积在核上。作为核心，应用了三种类型/尺寸的球形药用赋形剂颗粒。所得复合颗粒产生的释放曲线比仅研磨或共研磨的混合物快得多。此外，取决于核心颗粒的尺寸，复合颗粒显示出良好的微粒特性。这些结果表明超低温研磨和随后的干复合混合是开发具有改善溶出度的药物颗粒的潜在方法。