徐浩原1，任曼华1，何显洪1，陈 蕾2，张 欣1，关 健1，毛世瑞1
1. 沈阳药科大学 药学院，辽宁 沈阳 110016；2. 国家药典委员会，北京 100061
徐浩原，任曼华，何显洪，等. 原辅料粉体学性质对片剂连续制造的影响［J］. 中国粉体技术，2024，30（6）：1-22.
XU Haoyuan， REN Manhua， He Xianhong， et al. Influence of powder properties of pharmaceutical ingredients on continuous tablet manufacturing［J］. China Powder Science and Technology，2024，30（6）：1−22.
DOI：10.13732/j.issn.1008-5548.2024.06.009
收稿日期：2024-01-09，修回日期：2024-08-20，上线日期：2024-10-19。
基金项目：国家重点研发计划项目，编号：2020YFE0201700；国家药品标准修订研究课题项目，编号：2022Y15，2023Y38。
第一作者简介：徐浩原（2000—），男，硕士生，研究方向为缓控释递药系统与粉体学技术。E-mail：798449420@qq. com。
通信作者简介：
毛世瑞（1969—），女，教授，博士生导师，研究方向为以生物可降解高分子聚合物作为药物载体的药系统和缓控释递药系统。E-mail：maoshirui@vip. sina. com；
陈蕾（1975—），女，主任药师，硕士，研究方向为药用辅料和药包材标准管理。E-mail：chenlei@chp. org. cn。
摘要：【目的】 推进片剂连续制造技术的发展，分析粉体学性质在片剂连续制造中的重要性，进一步提升片剂连续制造的致密性和均匀性。【研究现状】综述物料输送、连续进料、连续混合、连续压片、连续辊压制粒、连续双螺杆制粒、连续流化床干燥等工艺过程，概括各工艺过程中使用的过程分析技术（process analytical technology， PAT）及监测工具，阐述原辅料粉末的关键原料特性对工艺过程和片剂关键质量属性的影响。【结论与展望】提出应当对具有多变性质的原辅料进行全面表征，预测流动性和成形性，建立物料库并进行分类，有利于选择工艺参数、优化工艺性能、完善处方设计；认为重视原辅料粉体性质并建立预测模型有利于减少裂片、含量不均匀等质量问题及堵塞、黏壁等生产问题。
关键词：片剂；连续制造；粉体学性质；单元操作；过程分析技术
Significance Continuous manufacturing is the future trend in tablet manufacturing. In order to accelerate the development of continuous tablet manufacturing， this article analyzes the influence of powder properties of pharmaceutical ingredients on continuous manufacturing. An in-depth understanding of powder properties enhances tablet quality， as well as the efficiency and homogeneity of continuous tablet manufacturing.
Progress So far， three main methods of continuous tablet manufacturing have improved production capability： continuous direct compression， continuous wet granulation， and continuous dry granulation. Among these， due to the limited number of unit operations involved， continuous direct compression has become the most popular method of continuous tablet manufacturing. Compared to batch manufacturing， continuous tablet manufacturing integrates unit operations， including loss-in-weight feeders，continuous mixers， continuous tablet press， roller compactor， twin-screw granulation （TSG）， and fluidized bed drying. The powder properties of pharmaceutical ingredients play a pivotal role in these unit operations， affecting flow behavior and tablet quality. During the continuous direct compression process， the physical properties of the powder， such as density， particle size，and particle shape， affect the flowability of powders， which in turn impacts feedability， mixing uniformity， and hence the drug content of the final tablet. Flowability can be characterized by emerging technologies such as shear testing or traditional static tests， such as the angle of repose and Carr's index. The compression mechanism of the material， such as brittle or plastic deformation， moisture content， and crystal habit， affects the compressibility and compactibility of the material. Powders with good compressibility and compactibility can be used to obtain tablets with a smooth appearance and sufficient hardness through appropriate process parameters. Compressibility and compactability can be evaluated using mathematical equations such as Heckel's equation， Shapiro's equation， Ryshkewitch-Duckworth's equation， and others. Continuous dry granulation is suitable for moisture- and heat-sensitive materials， and the effect of roller compactor process parameters on ribbon density and particle size needs to be emphasized. In addition， the process may lead to loss of tabletability. Continuous TSG has great potential due to its high efficiency， flexibility， and improved tabletability of granules. The properties of the binder and process parameters， such as screw speed and liquid-solid ratio， affect the particle size of the granules， as well as tablet porosity， disintegration time， and hardness. TSG is always integrated with a fluidized bed dryer， resulting in a controlled and homogeneous drying process， which greatly improves product quality and production efficiency. Process analytical technology （PAT） is a key technology for continuous manufacturing， including near-infrared spectroscopy， Raman spectroscopy， microwave resonance， focused beam reflectivity measurement， and other technologies. With PAT tools， the critical quality attributes of powders and tablets in each unit operation， such as drug content， moisture content， particle size， and other properties， can be monitored in real time.
Conclusions and Prospects Continuous tablet manufacturing is gaining increasing recognition in the pharmaceutical industry due to its high efficiency， flexibility， and reduced floor space. However， research on material properties has mainly focused on individual unit operations in batch manufacturing processes. Researchers have proposed requirements for the powder properties of materials， especially flowability. It is considered that， for pharmaceutical powders with variable properties， comprehensive powder characterizations should be carried out to predict their flowability and compression behavior during the process. A material property library needs to be established to classify the materials， which is conducive to selecting appropriate process parameters， optimizing process performance， and enhancing formulation design for continuous manufacturing. In addition， a complete material library facilitates the identification of materials with similar properties and reduces the workload of subsequent development. Modeling the predictive effects of powder properties on unit operations and end product quality can reduce various issues，such as sticking， capping， and bridging， that occur in continuous manufacturing due to poor powder properties.
Keywords：tablet； continuous manufacturing； powder properties； unit operation； process analytical technology
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