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改善小瓶底部的传热,以实现单向结构化冰的一致冷冻干燥。

Improving Heat Transfer at the Bottom of Vials for Consistent Freeze Drying with Unidirectional Structured Ice.

作者信息

Rosa Mónica, Tiago João M, Singh Satish K, Geraldes Vítor, Rodrigues Miguel A

机构信息

Centro de Química Estrutural, Department of Chemical Engineering, Instituto Superior Técnico, University of Lisbon, Av. Rovisco Pais, 1049-001, Lisboa, Portugal.

Pharmaceutical Research and Development, BioTherapeutics Pharmaceutical Sciences, Pfizer Inc, Chesterfield, Missouri, 63017, USA.

出版信息

AAPS PharmSciTech. 2016 Oct;17(5):1049-59. doi: 10.1208/s12249-015-0437-3. Epub 2015 Oct 26.

Abstract

The quality of lyophilized products is dependent of the ice structure formed during the freezing step. Herein, we evaluate the importance of the air gap at the bottom of lyophilization vials for consistent nucleation, ice structure, and cake appearance. The bottom of lyophilization vials was modified by attaching a rectified aluminum disc with an adhesive material. Freezing was studied for normal and converted vials, with different volumes of solution, varying initial solution temperature (from 5°C to 20°C) and shelf temperature (from -20°C to -40°C). The impact of the air gap on the overall heat transfer was interpreted with the assistance of a computational fluid dynamics model. Converted vials caused nucleation at the bottom and decreased the nucleation time up to one order of magnitude. The formation of ice crystals unidirectionally structured from bottom to top lead to a honeycomb-structured cake after lyophilization of a solution with 4% mannitol. The primary drying time was reduced by approximately 35%. Converted vials that were frozen radially instead of bottom-up showed similar improvements compared with normal vials but very poor cake quality. Overall, the curvature of the bottom of glass vials presents a considerable threat to consistency by delaying nucleation and causing radial ice growth. Rectifying the vials bottom with an adhesive material revealed to be a relatively simple alternative to overcome this inconsistency.

摘要

冻干产品的质量取决于冷冻步骤中形成的冰结构。在此,我们评估冻干瓶底部气隙对于一致成核、冰结构和饼状外观的重要性。通过用粘合剂材料粘贴一个精馏铝盘对冻干瓶底部进行了改进。对正常瓶和改进瓶进行了冷冻研究,使用不同体积的溶液,改变初始溶液温度(从5°C到20°C)和搁板温度(从-20°C到-40°C)。借助计算流体动力学模型解释了气隙对整体传热的影响。改进瓶在底部引起成核,并将成核时间缩短了一个数量级。对于含有4%甘露醇的溶液,从底部到顶部单向结构的冰晶形成导致冻干后形成蜂窝状结构的饼状物。主干燥时间减少了约35%。与正常瓶相比,径向冷冻而非自下而上冷冻的改进瓶显示出类似的改善,但饼状质量非常差。总体而言,玻璃瓶底部的曲率通过延迟成核和导致径向冰生长对一致性构成了相当大的威胁。用粘合剂材料矫正瓶底被证明是克服这种不一致性的一种相对简单的方法。

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