Merck Research Laboratories, Merck & Co, Inc, RY818-C102, PO Box 2000, 126 E Lincoln Ave, Rahway, NJ 07065, United States.
J Pharm Biomed Anal. 2010 Jun 5;52(2):311-5. doi: 10.1016/j.jpba.2010.01.008. Epub 2010 Jan 15.
The pressure to reduce cycle times of sample analysis has made it increasingly important to improve sample throughput during pharmaceutical process development. For ICP-based analyses, sample preparation is often the bottleneck of the entire analytical scheme due to the tedious digestion procedure and lacking a universal diluent for organic compounds. In this work, N,N-dimethylformamide (DMF) was used as a "universal" organic diluent so that the sample preparation can be simplified as a "dilute-and-shoot" procedure. An optimized interface with a commercial membrane desolvation unit was implemented, which enabled the introduction of organic solvents into an ICP-AES without organic loading. Mixed standard solutions of 15 elements (Al, Co, Cr, Cu, Fe, Mn, Mo, Ni, Pd, Pt, Rh, Ru, W, Zn, and Zr), which covered the majority of processing metals routinely monitored in pharmaceutical development, were prepared for the study and stability of each element in a multi-element DMF solution was investigated. It was found that the addition of a stabilizing agent (EDTA) was necessary to ensure that all the elements at concentrations of 0.10-0.50 microg/mL remained physically stable in solution (recovery better than 95%) for 2 weeks. It was also important to use an internal standard (yttrium) in order to compensate for signal drift and matrix effects from different sample matrices. A 2-10-fold increase of sensitivity (due to enhanced analyte transport efficiency) and acceptable levels of precision (RSD<3%) and recoveries (91-111%) were achieved. The LOQs of all 15 elements were less than 10 microg/L in the solution, which translates to less than 5 microg/g or microg/mL in pharmaceutical samples tested. This technique would minimize the effort required for sample preparation, thus reducing the cycle time by approximately 60-90% in the entire analytical scheme for samples that are difficult to be dissolved in nitric acid. This will provide opportunities for a new level of sample handling and automation for metal analysis in pharmaceutical process development.
在药物研发过程中，为了缩短样品分析的周期时间，提高样品通量变得越来越重要。对于基于 ICP 的分析，由于繁琐的消解过程和缺乏有机化合物的通用稀释剂，样品制备通常是整个分析方案的瓶颈。在这项工作中，N,N-二甲基甲酰胺（DMF）被用作“通用”有机稀释剂，从而使样品制备可以简化为“稀释和进样”程序。采用了一种优化的接口，与商业膜去溶剂化单元相结合，实现了在不引入有机负荷的情况下将有机溶剂引入到 ICP-AES 中。为了研究，制备了 15 种元素（Al、Co、Cr、Cu、Fe、Mn、Mo、Ni、Pd、Pt、Rh、Ru、W、Zn 和 Zr）的混合标准溶液，这些元素涵盖了药物研发中常规监测的大多数加工金属。研究了每种元素在多元素 DMF 溶液中的稳定性，发现需要添加稳定剂（EDTA）以确保浓度为 0.10-0.50μg/mL 的所有元素在溶液中（回收率>95%）保持物理稳定 2 周。使用内标（钇）也很重要，以补偿不同样品基质的信号漂移和基质效应。灵敏度提高了 2-10 倍（由于分析物传输效率的提高），并且可以达到可接受的精密度（RSD<3%）和回收率（91-111%）。所有 15 种元素的 LOQs 在溶液中均小于 10μg/L，这相当于测试的药物样品中小于 5μg/g 或μg/mL。该技术将最大限度地减少样品制备所需的工作量，从而使难以溶解在硝酸中的样品的整个分析方案的周期时间缩短约 60-90%。这将为药物工艺开发中的金属分析提供新的样品处理和自动化水平的机会。
