Department of Chemical Engineering, Purdue University, West Lafayette, IN 47907, USA.
Department of Chemical Engineering, Purdue University, West Lafayette, IN 47907, USA.
J Pharm Sci. 2024 Sep;113(9):2699-2707. doi: 10.1016/j.xphs.2024.05.029. Epub 2024 May 31.
The purpose of this study was to investigate the mechanical stresses and strains acting on pharmaceutical glass tubing vials during freezing and thawing of model pharmaceutical formulations. Strain measurements were conducted inside of a laboratory-scale freeze-dryer using a custom wireless sensor. In both sucrose and trehalose formulations at concentrations between 5 % and 20 % w/v, the strain measurements initially increased before peaking in magnitude at temperatures close to the respective glass transition temperatures of the maximally freeze concentrated solutes, Tg'. We attribute this behavior to a shift in the mechanical properties of the frozen system from a purely elastic glass below Tg' to a viscoelastic rubber-like material above Tg'. That is, when the interstitial region becomes mechanically compliant at temperature above Tg'. The outputs were less predictable below 5 % w/v and tended to exhibit two separate peaks in strain output, one near the equilibrium melting temperature of pure ice and the other near Tg'. The peaks merged at concentrations between 4 and 5 % w/v where the largest strain magnitude was observed. The strain on primary packaging has traditionally been applied to evaluate the risk of damage or breakage due to, for example, crystallization of excipients. However, data collected during this study suggest there may be utility in formulation design or as a process analytical technology to minimize potentially destabilizing stresses and strains in the frozen formulation.
本研究的目的是研究在冷冻和解冻模型药物制剂过程中,药物玻璃管小瓶上的机械应力和应变。使用定制的无线传感器在实验室规模的冷冻干燥器中进行了应变测量。在 5%至 20%w/v 浓度的蔗糖和海藻糖制剂中,应变测量最初在接近最大冷冻浓缩溶质玻璃化转变温度 Tg'的温度下达到峰值之前增加。我们将这种行为归因于冷冻系统的机械性能从 Tg'以下的纯弹性玻璃转变为 Tg'以上的粘弹性橡胶状材料。也就是说,当间隙区域在 Tg'以上的温度变得具有机械柔韧性时。在 5%w/v 以下,输出结果不太可预测,并且应变输出往往表现出两个单独的峰值,一个接近纯冰的平衡熔点,另一个接近 Tg'。在 4%至 5%w/v 之间的浓度下,峰值合并,观察到最大应变幅度。传统上,对初级包装的应变施加压力是为了评估由于赋形剂结晶等原因导致损坏或破裂的风险。然而,本研究中收集的数据表明,在配方设计或作为过程分析技术中可能有用,以最小化冷冻配方中潜在的不稳定应力和应变。