Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar, Mohali, Punjab 160062, India.
Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar, Mohali, Punjab 160062, India.
Int J Pharm. 2015 Jan 15;478(1):46-52. doi: 10.1016/j.ijpharm.2014.11.002. Epub 2014 Nov 4.
In this study, the effect of four non-crystallizing sugars, namely fructose, trehalose, sucrose and raffinose, was assessed on the crystallization of gemcitabine hydrochloride (GHCl) in frozen solutions. Aqueous solutions containing GHCl (50 mg/mL) and a sugar at varying concentrations (10-60 mg/mL) were frozen in situ in DSC and analyzed in the subsequent heating run. Crystallization propensity of GHCl was quantified in terms of reduced crystallization temperature (RCT) as a function of sugar type and concentration. Multivariate analysis option in JMP(®) software was employed for calculating correlation between the variables. All sugars inhibited GHCl crystallization in a concentration dependent manner. At equal concentration, fructose (with the lowest Tg') exerted the strongest inhibitory effect, whereas raffinose (with the highest Tg') exerted the weakest inhibitory effect. Additionally, RCT showed a poor correlation with Tg' (r=0.2327). Thus, the inhibitory effect of sugars could not be described by their anti-plasticization effect. This counter-intuitive behavior was explained by the inhibitory effect of sugars on ice crystallization, which increased the unfrozen water content (UWC) in the freeze concentrate, thereby lowering the supersaturation of GHCl. This was established by observing a good correlation (r=0.9666) between RCT and ln(1/UWC). Additionally, reduced diffusion kinetics of GHCl in presence of sugar molecules was also postulated. This study highlights the importance of unfrozen water towards governing the crystallization behavior of solutes in multi-component frozen systems.
在这项研究中，评估了四种非结晶糖，即果糖、海藻糖、蔗糖和棉子糖，对盐酸吉西他滨（GHCl）在冷冻溶液中结晶的影响。在 DSC 中就地冷冻含有 GHCl（50mg/mL）和不同浓度（10-60mg/mL）糖的水溶液，并在随后的加热运行中进行分析。GHCl 的结晶倾向通过降低结晶温度（RCT）作为糖的类型和浓度的函数来定量。使用 JMP（®）软件中的多元分析选项计算变量之间的相关性。所有糖都以浓度依赖的方式抑制 GHCl 的结晶。在相同浓度下，果糖（Tg'最低）的抑制作用最强，而棉子糖（Tg'最高）的抑制作用最弱。此外，RCT 与 Tg'的相关性较差（r=0.2327）。因此，糖的抑制作用不能用其抗塑化作用来描述。这种违反直觉的行为可以通过糖对冰晶形成的抑制作用来解释，这增加了冷冻浓缩物中的未冻结水含量（UWC），从而降低了 GHCl 的过饱和度。通过观察 RCT 和 ln（1/UWC）之间的良好相关性（r=0.9666），证实了这一点。此外，还提出了糖分子存在时 GHCl 扩散动力学降低的假设。这项研究强调了未冻结水在多组分冷冻系统中控制溶质结晶行为的重要性。
