胺类化合物在玻璃表面的吸附及其对分析方法和制药工艺发展的影响,Organic Process Research & Development

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胺类化合物在玻璃表面的吸附及其对分析方法和制药工艺发展的影响
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2022-01-31 , DOI: 10.1021/acs.oprd.1c00451
Xuejun Xu ₁ , Jennifer Lott ₁ , Kathleen A. Kelly ₁ , Zhongping Shi ₁

Affiliation

已证明二胺化合物 (3-{2-[2-(3-氨基丙氧基)乙氧基]乙氧基}丙-1-胺) 会影响药物合成过程中的下游步骤，并将该化合物控制在小于 0.015 wt% （或 150 ppm）是必要的。开发了一种无需二胺衍生化的新型、简单且灵敏的液相色谱/质谱 (LC/MS) 方法，用于过程控制 (IPC)，并证明适用于在小实验室规模进行实验时使用. 在LC-MS方法的开发过程中，发现二胺对玻璃器皿表面有显着的吸附作用，吸附常数估计为（5.4-10.4）×10 ⁸毫升/摩尔SiOH。这种现象影响了分析方法的回收率和过程中二胺的控制。研究了二胺吸附，并开发了减轻吸附的程序。发现在样品稀释剂中添加 0.1% 三乙胺可显着降低二胺的吸附并提高 LC-MS 方法的回收率。然而，在公斤级工厂规模上，出现了最初在开发工作中被抑制的杂质。已确定二胺吸附在玻璃器皿上的强度比先前预期的要强，包括反应器。本文将讨论为减少分析规模和植物玻璃反应器在玻璃上的吸附而采取的步骤。

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Adsorption of Amine Compounds on the Glass Surface and Their Impact on the Development of Analytical Method and Pharmaceutical Process

A diamine compound (3-{2-[2-(3-aminopropoxy)ethoxy]ethoxy}propan-1-amine) was demonstrated to impact downstream steps in a pharmaceutical synthetic process, and control of this compound to less than 0.015 wt % (or 150 ppm) was necessary. A novel, simple, and sensitive liquid chromatography/mass spectrometry (LC/MS) method without the derivatization of the diamine was developed for in-process control (IPC) and demonstrated to be suitable for use when experiments were run at a small lab scale. During the development of the LC-MS method, the diamine was found to significantly adsorb to the surface of glassware, and the adsorption constant was estimated to be (5.4–10.4) × 10⁸ mL/mol SiOH. This phenomenon impacted the analytical method recovery and the control of the diamine in the process. The diamine adsorption was investigated, and procedures were developed to mitigate adsorption. The addition of 0.1% triethylamine in sample diluent was found to significantly reduce adsorption of the diamine and improve LC-MS method recovery. However, at the kilo plant scale, the impurities that were initially inhibited in development work appeared. It was determined that the diamine adsorbed on glassware more strongly than previously expected, including the reactor. This paper will discuss steps taken to reduce adsorption on glass for both the analytical scale and the plant glass reactor.

更新日期：2022-01-31

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