Poronsky Christopher J, Cutrone Jingfang Qian
Bristol-Myers Squibb, Research and Development, Wallingford, CT 06492, USA.
J Pharm Anal. 2017 Aug;7(4):265-269. doi: 10.1016/j.jpha.2017.03.009. Epub 2017 Apr 3.
In drug discovery research, residual solvent measurement is an integral part of purity analysis for synthesis of a drug candidate before it is used for toxicity testing. This is usually carried out using gas chromatography (GC) with direct injection sample introduction. This method requires testing compounds to be soluble at high concentrations (>50 mg/mL, usually in DMSO) to achieve acceptable sensitivity, a hurdle which is not always achievable for some samples such as cyclic peptides and oligonucleotides. To overcome the limitation associated with the direct injection approach, a new method using the Chromatoprobe thermal extraction device was developed for quantifying residual solvents of drug discovery compounds. This method not only consumes significantly less material (less than 1 mg), but also shows higher sensitivity than the direct injection approach. In addition, because no diluent is required with the Chromatoprobe thermal extraction, all residual solvents can be detected and measured without further method optimization. In our study, we compared data from GC residual solvent analysis using the Chromatoprobe solid sample introduction to those of the direct injection method for seven in-house samples. Our results showed a good agreement between the data from these two sample introduction methods. Thus, the Chromatoprobe sample introduction method provided a sample-sparing alternative to the direct injection method for the measurement of residual solvents in drug discovery. This method can be particularly useful for residual solvent analysis in samples that are available only in limited amounts, poorly soluble, and/or unstable in the diluents used for the direct injection method.
在药物发现研究中，残留溶剂测量是药物候选物合成纯度分析的一个组成部分，在其用于毒性测试之前进行。这通常使用气相色谱法（GC）并采用直接进样方式来进行。该方法要求测试化合物在高浓度下（>50 mg/mL，通常在二甲基亚砜中）可溶，以实现可接受的灵敏度，而对于一些样品，如环肽和寡核苷酸，这一障碍并非总能克服。为了克服与直接进样方法相关的局限性，开发了一种使用Chromatoprobe热萃取装置的新方法来定量药物发现化合物中的残留溶剂。该方法不仅消耗的材料显著更少（少于1 mg），而且比直接进样方法具有更高的灵敏度。此外，由于使用Chromatoprobe热萃取不需要稀释剂，所有残留溶剂都可以在无需进一步方法优化的情况下被检测和测量。在我们的研究中，我们将使用Chromatoprobe固体进样的GC残留溶剂分析数据与七个内部样品的直接进样方法的数据进行了比较。我们的结果表明这两种进样方法的数据之间具有良好的一致性。因此，对于药物发现中残留溶剂的测量，Chromatoprobe进样方法为直接进样方法提供了一种节省样品的替代方法。该方法对于仅能获得少量、难溶和/或在直接进样方法所用稀释剂中不稳定的样品的残留溶剂分析可能特别有用。
