Impact of Silica Dry Coprocessing with API and Blend Mixing Time on Blend Flowability and Drug Content Uniformity
Impact of Silica Dry Coprocessing with API and Blend Mixing Time on Blend Flowability and Drug Content Uniformity
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二氧化硅与 API 干法协同处理和共混物混合时间对共混物流动性和药物含量均匀性的影响
DOI：
10.1016/j.xphs.2023.05.016
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发表时间：
2023
影响因子：
3.8
通讯作者：
Davé, Rajesh N.
中科院分区：
文献类型：
--
作者：
Kim, Sangah S.;Seetahal, Ameera;Amores, Nicholas;Kossor, Christopher;Davé, Rajesh N.
本文以对乙酰氨基酚(MAPAP)和布洛芬(IBU)两种细粒模型药物(D50∼10µm)为研究对象，考察了API干法共处理对其多组分介质DL(30wt%)与精细辅料混合的影响。研究了共混时间对共混体系流动性、堆积密度、团聚等块体性能的影响。检验的假设是，在中等密度下，与细小原料药的混合物需要良好的混合流动性才能具有良好的混合均匀度(BU)。此外，通过用疏水性(R972P)二氧化硅干法包衣可以获得良好的流动性，这不仅减少了细API的团聚，而且在使用细赋形剂时也减少了其共混物的团聚。对于未涂覆的原料药，共混物的流动性较差，即在所有混合时间都存在粘结状态，共混物无法达到可接受的BU。相比之下，对于干涂层原料药，它们的共混流动性改善到易流动状态或更好，随着混合时间的延长而改善，正如假设的那样，所有共混物都达到了预期的BU。所有干涂层API共混物都表现出更高的堆积密度和更少的团聚，这归因于混合诱导的协同性能增强，可能是由于二氧化硅转移。尽管包衣了疏水二氧化硅，但由于细原料药的团聚减少，片剂的溶出度得到了改善。
This paper considers two fine-sized (d50∼10 µm) model drugs, acetaminophen (mAPAP) and ibuprofen (Ibu), to examine the effect of API dry coprocessing on their multi-component medium DL (30 wt%) blends with fine excipients. The impact of blend mixing time on the bulk properties such as flowability, bulk density, and agglomeration was studied. The hypothesis tested is that blends with fine APIs at medium DL require good blend flowability to have good blend uniformity (BU). Moreover, the good flowability could be achieved through dry coating with hydrophobic (R972P) silica, which reduces agglomeration of not only fine API, but also of its blends while using fine excipients. For uncoated APIs, the blend flowability was poor, i.e. cohesive regime at all mixing times, and the blends failed to achieve acceptable BU. In contrast, for dry coated APIs, their blend flowability improved to easy-flow regime or better, improving with mixing time, and as hypothesized, all blends consequently achieved desired BU. All dry coated API blends exhibited improved bulk density and reduced agglomeration, attributed to mixing induced synergistic property enhancements, likely due to silica transfer. Despite coating with hydrophobic silica, tablet dissolution was improved, attributed to the reduced agglomeration of fine API.