College of Pharmacy, Freie Universität Berlin, Kelchstr. 31, 12169 Berlin, Germany.
College of Pharmacy, Freie Universität Berlin, Kelchstr. 31, 12169 Berlin, Germany.
Eur J Pharm Biopharm. 2022 Jul;176:75-86. doi: 10.1016/j.ejpb.2022.05.011. Epub 2022 May 19.
Limited research has been performed on the downstream processing of nano-co-crystal suspensions into solid oral dosage forms. The objectives of this study were to evaluate the impact of three downstream processes (wet granulation, spray granulation and bead layering) on the performance of itraconazole-succinic acid (ITZ-SUC) nano-co-crystal suspension. An optimized ITZ-SUC nano-co-crystal suspension mixed with HPMC E5 was utilized for the downstream processing. The suspension was converted in the solid state either by wet or spray granulation (with microcrystalline cellulose or lactose as substrates) or by layering onto microcrystalline cellulose and sugar beads. The multiparticulate solid dosage forms were characterized by optical microscopy, differential scanning calorimeter (DSC), X-ray powder diffraction (XRPD) and in situ dissolution studies. Spray granulation and bead layering resulted in less particle aggregation, a faster dissolution rate, and higher kinetic solubility when compared to wet granulation. ITZ-SUC nano-co-crystals spray granulated with lactose resulted in higher kinetic solubility profiles compared to microcrystalline cellulose granules. The type of bead core had no impact on the dissolution behavior. A slower dissolution and decreased kinetic solubility were observed with increasing drug loading for sprayed granules when microcrystalline cellulose was used as substrate. All dosage forms were stable under accelerated storage conditions (40 °C/75% RH) when blistered. Nano-co-crystals incorporated in granules were less stable than layered beads under non-blistered condition. Nano-co-crystals layered sugar beads are an interesting alternative to amorphous solid dispersion; a comparable kinetic solubility but a faster drug release were achieved. This study identified bead layering as a superior downstream process approach for incorporating ITZ-SUC nano-co-crystals into an oral solid dosage form without compromising drug dissolution.
关于将纳米共晶体混悬剂下游加工成固体制剂的研究较少。本研究的目的是评估三种下游工艺（湿法制粒、喷雾造粒和丸芯上药）对伊曲康唑琥珀酸（ITZ-SUC）纳米共晶体混悬剂性能的影响。使用优化的 ITZ-SUC 纳米共晶体混悬液与 HPMC E5 混合进行下游加工。混悬液通过湿法制粒或喷雾造粒（以微晶纤维素或乳糖为基质）或通过上药到微晶纤维素和糖丸丸芯上药转化为固态多颗粒剂型。采用光学显微镜、差示扫描量热法（DSC）、X 射线粉末衍射（XRPD）和原位溶解研究对多颗粒固体制剂进行了表征。与湿法制粒相比，喷雾造粒和丸芯上药导致更少的颗粒聚集，更快的溶解速率和更高的动力学溶解度。与微晶纤维素颗粒相比，以乳糖喷雾造粒的 ITZ-SUC 纳米共晶体具有更高的动力学溶解度曲线。丸芯的类型对溶出行为没有影响。当以微晶纤维素为基质时，对于喷雾颗粒，随着载药量的增加，观察到溶解速度较慢且动力学溶解度降低。在加速储存条件（40°C/75% RH）下，所有剂型在泡罩包装时均稳定。在非泡罩条件下，与无定形固体分散体相比，纳米共晶体包埋在颗粒中的稳定性较差。包衣糖丸的纳米共晶体是无定形固体分散体的一种有趣替代物；达到了相当的动力学溶解度，但药物释放更快。本研究确定了丸芯上药作为将 ITZ-SUC 纳米共晶体掺入口服固体制剂的一种优越的下游加工方法，而不会影响药物溶解。
