案例分析

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AccuSizer 780APS用于乳剂稳定性的检测

 

    An emulsion is usually comprised of two or more immiscible liquids where one liquid in the form of droplets is dispersed (the dispersed phase) in another liquid (the continuous phase).

 

    乳剂通常是有两种或三种不相溶的液体组成,其中一相液体(分散相)分散在另一相中。

 

    The surface of each droplet is an interface between hydrophilic and hydrophobic molecules and therefore thermodynamically unstable. The stability of an emulsion can also be affected by many external factors including storage methods (glass vs. plastic), time, and temperature. Light scattering techniques are the norm for determining the particle size distributions of emulsions. Oftentimes an emulsion that has become unstable will produce a shift in mean diameter of a light scattering PSD. However, the size and quantity of the particles which cause instability cannot be determined using these techniques.

 

    乳剂当中每个乳滴的表面都是亲水性分子和疏水性分子的交界面,因此热力学认为乳剂不稳定。而乳剂的储存方法(如玻璃容器和塑料容器)、储存时间和放置温度等也是影响乳剂本身稳定性的外在因素(客观因素)。目前应用于检测乳剂中乳滴粒径分布的标准方法是动态光散射法。当不稳定的乳剂在被检测时,时常会导致动态光散射的波动从而产生乳滴平均粒径的变化。然而,动态光散射法检测不出乳剂当中会对乳剂稳定性产生影响的的乳滴的体积大小和数量多少。

 

    This detail becomes extremely important when dealing with injectable fat emulsions. The coalescence of fat globules in intravenous lipid emulsions (IVLEs) can cause pulmonary embolisms in small blood vessels with diameters ranging between 4 and 9 µm and in larger blood vessels that have diameters ~20µm. Therefore the US Pharmacopeia contains a number of particle sizing procedures such as USP-788 and USP-729USP-729 requires that the mean droplet size as well as the extent of the large-diameter droplet tail (>5µm) be determined. The volume weighted percent of PFAT5 (percentage of fat greater than 5 microns) must not exceed 0.05%. A single particle counting technique such as SPOS is required to determine the PFAT5 in emulsions. For many years the Accusizer line of instruments has been the premier instrument for this determination. The figure below shows the volume-weighted distribution of an unstable emulsion that has become increasingly unstable over time.

 

     这一点尤其对于注射用脂肪乳来说极其重要。用于静脉注射的脂肪乳中乳滴一旦聚集不仅容易在直径在为-9微米的细小血管里形成栓塞,甚至也会在直径为20微米左右的血管中导致栓塞。因此美国药典制定了包括USP788和USP729在内的多个章节来规定测定乳剂中乳滴数目的检测方法。其中USP729不仅规定了对乳剂平均粒径的检测方法也规定了测定大粒子(直径大于5微米)数目的检测方法。乳剂中所含的大粒子(直径大于5微米)的体积所占比(PFAT5值)不得超过0.05%。而用于粒子大小检测并对粒子进行计数的方法是SPOS(单颗粒光学传感技术,或称“光阻法”),并可算出PFAT5值。PSS粒度仪公司的AccuSizer系列的仪器是最早用于乳剂的粒子计数和计算PFAT值的粒度仪,如下图所示的粒子体积径分布图可看出:不稳定的乳剂在被检测时,检测时间越长,其稳定性越差。

 

 

     Globule size distribution of a lipid emulsion after heat stress for 0 – 40 hours measured on the AccuSizer

 

     上图是用AccuSizer系列仪器对加热了0-40小时之后的脂肪乳进行检测后得出的乳滴粒径分布图。