<br>冷冻过程会影响固体含量低、填充度高的冻干无定形蛋白制剂的饼状外观,International Journal of Pharmaceutics

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冷冻过程会影响固体含量低、填充度高的冻干无定形蛋白制剂的饼状外观
International Journal of Pharmaceutics ( IF 5.3 ) Pub Date : 2023-03-07 , DOI: 10.1016/j.ijpharm.2023.122803
Xiaofeng Lu ₁ , Shreya S Kulkarni ₁ , Hanmin Dong ₁ , Yongan Tang ₂ , Li Yi ₁ , Supriya Gupta ₁

Affiliation

低固体含量和高填充剂药品配置对冻干后获得优雅的蛋糕外观提出了特殊挑战。在这项研究中，蛋白质制剂的这种配置需要在狭窄的初级干燥操作空间内冻干以获得优雅的蛋糕。探讨了冷冻工艺优化作为一种解决方案。采用实验设计（DoE）方法评估货架冷却速率、退火温度及其相互作用对滤饼外观的影响。产品抗性斜率（Rp）与干燥层厚度（Ldry）的斜率用作定量响应，因为优雅的滤饼外观与较低的初始 Rp 和正斜率相关。由于可以在总初级干燥持续时间的前 1/6 内通过实验确定 Rp 与 Ldry 的斜率，因此进行了部分冻干运行，以便进行快速筛选。DoE 模型显示，缓慢的冷却速率（≤0.3 °C/min）和高退火温度（≥-10 °C）导致更好的滤饼外观。此外，X 射线显微计算机断层扫描显示，优雅的蛋糕表现出均匀的多孔结构和较大的孔隙，而不优雅的蛋糕表现出致密的表层和较小的孔隙。通过优化的冷冻工艺，扩大了初级干燥操作空间，改善了滤饼外观和批次均匀性。

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Freezing process influences cake appearance of a lyophilized amorphous protein formulation with low solid content and high fill configuration

Low solid content and high fill drug product configuration pose special challenges for achieving elegant cake appearance after lyophilization. In this study, such a configuration for a protein formulation required lyophilization within a narrow primary drying operating space to obtain elegant cakes. Freezing process optimization was explored as a solution. A Design of Experiment (DoE) approach was used to evaluate the effect of shelf cooling rate, annealing temperature, and their interaction on cake appearance. The slope of product resistance (Rp) vs. dried layer thickness (Ldry) was used as the quantitative response because elegant cake appearance correlated with a lower initial Rp and positive slope. As the Rp vs. Ldry slope can be experimentally established within the first 1/6th of the total primary drying duration, partial lyophilization runs were executed, allowing for rapid screening. The DoE model revealed that a slow cooling rate (≤0.3 °C/min) and high annealing temperature (≥-10 °C) resulted in a better cake appearance. Furthermore, X-ray micro-computed tomography showed that elegant cakes exhibited uniform porous structure and larger pores, while inelegant cakes showed dense top layers with smaller pores. With the optimized freezing process, the primary drying operating space was broadened with improved cake appearance and batch homogeneity.

更新日期：2023-03-07

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