Analysis of Polar Drug Molecules and Excipients by Ultrahigh Performance Supercritical Fluid Chromatography - Mass Spectrometry

为了研究制药行业中使用超高性能超临界流体色谱-质谱仪(UHPSFC-MS)分析极性药物和高级配方辅料的情况，正在开发的分子类型正在进行演变。有一个转变，从基于利平斯基的“五规则”分类的可药物分子，到那些不再适合这一传统方法的分子。在分子(和配方)设计方面出现了三个值得注意的趋势：1.具有非常低或非常高疏水性(Log P)的分子，能够容易地穿透生理膜或增加作用部位的停留时间2.朝着更大和更复杂的生物分子实体的方向发展，例如寡核苷酸、肽、单抗等。开发复杂的药物制剂和载体，如脂质体、聚合物纳米粒子和药物-聚合物结合物。这些新的药物类型提出了不同的色谱挑战，这些挑战通常不能通过传统的方法如反相高效液相色谱、离子色谱(IC)或尺寸排除色谱(SEC)来解决。最近在SFC方面的进展为选择性识别、表征和定量极性化合物开辟了道路。SFC还证明了其在分析通常用作赋形剂的聚合物方面的适用性。除了MS检测外，还可以添加正交检测器，例如ELSD、CLND和CAD，以帮助检测和定量非发色物质。UHPSFC提供了一种额外的或替代的方法来分析其中一些新的药物分子，其中反相色谱方法可能是具有挑战性的。要实现这一仪器的全部潜力，将需要开发强大的新的UHPSFC方法，例如，除了低水平检测外，还需要了解MS电离响应、洗脱液分流比、离子抑制问题的变化，需要探索不同检测器的量化和校准。

To investigate the analysis of polar drugs and advanced formulation excipients by Ultrahigh Performance Supercritical Fluid Chromatography - Mass Spectrometry (UHPSFC-MS) Within the pharmaceutical industry, an evolution in the types of molecules being developed is underway. There is a move from drugable molecules based on Lipinski's 'Rule of Five' classification to those that no longer fit this traditional approach. There are three notable trends emerging in terms of molecular (and formulation) design:1. Molecules with very low or very high hydrophobicity (Log P) that enable facile penetration through physiological membranes or increased residence time at site of action 2. A move towards larger and more complex biomolecular entities, e.g. oligonucleotides, peptides, mAbs etc.3. Development of complex formulations and vehicles for drug delivery such as liposomes, polymer nanoparticles and drug-polymer conjugates.These new drug types pose different chromatographic challenges that are often not resolvable via traditional approaches such as reversed-phase HPLC, ion chromatography (IC) or size exclusion chromatography (SEC).Recent advances in SFC have opened the way to selective identification, characterisation, and quantification of polar compounds. SFC has also demonstrated its applicability in for the analysis of polymers commonly used as excipients. In addition to MS detection, orthogonal detectors, e.g. ELSD, CLND and CAD can be added to aid detection and quantification of non-chromophoric materials. UHPSFC offers an additional, or alternative approach to analysis of some of these new drug molecules where reversed-phase chromatographic approaches can be challenging. To realise the full potential of this instrumentation the development of robust new UHPSFC methodologies will be required, e.g. Understanding the changes in MS ionisation response, eluent flow split ratio, ion suppression issues, in addition to low level detection, quantification and calibration with different detectors requires exploration.