张晓阳^a, 应泽华^a, 郭抒博^a, 李文龙^{a, b}

(天津中医药大学 a. 中药制药工程学院, b. 现代中医药海河实验室, 天津 301617)

引用格式:

张晓阳, 应泽华, 郭抒博, 等. 固体分散体制备技术及质量控制研究进展[J]. 中国粉体技术, 2024, 30(2): 96-112.

ZHANG X Y, YING Z H, GUO S B et al. Research progress on the preparation techniques and quality control of solid dispersions[J]. China Powder Science and Technology, 2024, 30(2): 96-112.

摘要: 【目的】研究固体分散体 (solid dispersions, SDs) 制备技术和质量控制,分析 SDs 技术在药物制剂领域的发展现状,进一步推动 SDs 技术的推广应用。 【研究现状】总结熔融法、 溶剂法、 溶剂-熔融法、 机械分散法等固体分散体制备技术,其中熔融法又包括传统熔融法、 热熔挤出法、 熔融凝聚、 KinetiSol^® Dispersing、 3D 打印技术等,溶剂法又包括喷雾干燥、 冷冻干燥、 流化床干燥、 超临界流体法、 共沉淀法和静电纺丝法等;概括粉体学性质、 溶出度、 药物和聚合物之间的相互作用、 固态等固体分散体质量控制因素。 【展望】SDs 制剂的成功开发取决于正确的制备技术和全面、 准确的质量控制。 认为药物和聚合物的物理化学性质对于选择合适制备策略的重要性不容忽视,关系到最终产品的热稳定性和物理稳定性;应用于 SDs 的制备的技术需要解决有毒溶剂的使用和药物可能存在的热降解风险;应该尝试开发高效和扩展性好的 SDs 技术。 提出应对 SDs 的粉体学性质进行准确、全面的考察,具有优异流动性和溶解性能的 SDs 将会极大程度推动 SDs 产品的商业化发展。

关键词: 固体分散体; 热熔挤出; 热熔挤出; 3D 打印; 喷雾干燥; 流化床; 质量控制;粉体学性质

Abstrac

Significance Drug solubilization is an essential step for orally administered medications to be absorbed systemically. Unfortunately,many drugs have poor water solubility, which severely limits their clinical applications. During drug Research & Development,various methods have been tried to overcome the poor water solubility of drug candidates, including salt formation, micritization,solid-lipid nanoparticles, nanosuspensions, and solid dispersions (SDs). Among them, SDs technology stands out for the advantages of simplicity, rapidity, and maturity, making it oone of the most successful strategies for improving the dissolution properties of insoluble drugs. SDs. Hence, SDs have emerged as a hot research topic in the past decade.

Progress So far, many techniques have emerged for the preparation of SDs, which are derived from the following methods, including the melting method, solvent method, melt-solvent method, and milling-based method. Among them, melt-based hot melt extrusion technology (HME) has gained prominence as a solvent-free, commercially scalable method for various drug delivery systems. Additionally, spray drying technology known for its extremely fast solvent removal efficiencies and good scale-up capabilities, has become the most popular solvent method. The fluidized bed drying method stands out for its ability to prepare SDs with both good flowability and dissolution properties. Furthermore, 3D printing technology offers the advantages in personalization and dosage form customization for pharmaceutical production. Despite the availability of these techniques, the selection of appropriate preparation techniques for SDs remains a challenge due to the complex and variable physicochemical properties of APIs and polymers as well as the lack of in-depth knowledge of the preparation techniques. Although many drug products based on SDs technology have been successfully marketed since 1989, the current quality control of SDs was still limited to the solid state, drug -polymer interactions, and dissolution, neglecting the crucial powder properties of SDs. Notably, SDs serve as formulation intermediates and need further processing into tablets, pills, capsules, and granules for convenient consumption. The powder properties of SDs play a pivotal role in ensuring the smoothness of downstream processing and the overall quality of the final products.

Conclusions and Prospects It was the prerequisite for the correct selection of preparation techniques to have a deeper understanding of the application scenarios, advantages, and limitations of various preparation techniques. Furthermore, the significance of the physicochemical properties of drugs and polymers in selecting suitable preparation strategies should not be overlooked. These properties are related to the thermal and physical stability of the final product and should be thoroughly reviewed in the future.Although many techniques have been applied to prepare SDs, several challenges persist. Many issues such as the use of toxic solvents and the possible risk of thermal degradation of the drug still need careful addressing. In addition, the current choice of commercially viable SDs preparation techniques is still very limited. Future research endeavors should try to develop simpler, more efficient, and scalable techniques for the SDs preparation. In terms of quality control of SDs, in addition to examining the solid state, drug-polymer interactions, and dissolution, researchers are required to conduct accurate and comprehensive assessments of the powder chemistry properties of SDs. The creation of SDs with both excellent flowability and dissolution properties undoubtedly holds the promise to significantly contribute to the successful commercialization of SDs products.

Keywords: solid dispersion; preparation techniques; hot melt extrusion; melt agglomeration; three-dimensional printing; spray drying; quality control; powder properties

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