Moynihan Humphrey A, Armstrong Declan
School of Chemistry, Analytical and Biological Chemistry Research Facility, Synthesis and Solid-State Pharmaceutical Centre, University College Cork College Road Cork T12 K8AF Ireland
RSC Adv. 2019 Jul 9;9(37):21405-21417. doi: 10.1039/c9ra02781e. eCollection 2019 Jul 5.
Crystallisations are widely used in pharmaceutical and fine chemical manufacturing to control impurity levels, however crystallisations do not always reduce impurities to acceptable levels. Information on the location and distribution of impurities in crystallised materials would be helpful in such cases. A two phase dissolution medium featuring a fluorocarbon non-solvent vehicle and a aqueous ethanol solvent phase has been used to determine the composition of multi-particle crystalline samples through a partial dissolution approach combined with particle sizing and HPLC analysis. 4-Chloro-2-nitroacetanilide (1) was chosen as the host compound for this study, with 4-methyl-2-nitroacetanilide (2) and 4--butyl-2-nitroacetanilide (3) chosen as the guest impurities that were added to supersaturated toluene solutions of 1 at levels up to 5 mol%. The crystals that formed were subjected to a series of partial dissolution steps carried out using the biphasic dissolution medium composed of a 50% aqueous ethanol solvent phase and a perfluorohexane continuous phase. To inhibit particle agglomeration, the mixture also contained 13,13,14,14,15,15,16,16,17,17,18,18-dodecafluoro-2,5,8,11-tetraoxaoctadecane (4) as a non-ionic surfactant. The partial dissolution steps showed a relatively even dissolution with each sequential step as determined from particle sizing. Analysis of the solutions by HPLC from each partial dissolution step allowed the level of impurity to be determined, and when combined with the particle sizing data this allowed an impurity distribution to be generated. Impurity 2 was found to be relatively evenly distributed while impurity 3 was localised on or near the surfaces of crystals.
结晶在制药和精细化工生产中被广泛用于控制杂质水平，然而结晶并不总能将杂质降低到可接受的水平。在这种情况下，有关杂质在结晶材料中的位置和分布的信息将有所帮助。一种具有氟碳非溶剂载体和乙醇水溶液溶剂相的两相溶解介质已被用于通过部分溶解方法结合粒度分析和高效液相色谱（HPLC）分析来确定多颗粒结晶样品的组成。本研究选择4-氯-2-硝基乙酰苯胺（1）作为主体化合物，选择4-甲基-2-硝基乙酰苯胺（2）和4-丁基-2-硝基乙酰苯胺（3）作为客体杂质，将其以高达5 mol%的水平添加到1的过饱和甲苯溶液中。形成的晶体经过一系列使用由50%乙醇水溶液溶剂相和全氟己烷连续相组成的双相溶解介质进行的部分溶解步骤。为了抑制颗粒团聚，混合物中还含有13,13,14,14,15,15,16,16,17,17,18,18-十二氟-2,5,8,11-四氧杂十八烷（4）作为非离子表面活性剂。部分溶解步骤显示，根据粒度分析，每个连续步骤的溶解相对均匀。通过HPLC对每个部分溶解步骤的溶液进行分析，可以确定杂质水平，当与粒度数据结合时，这可以生成杂质分布图。发现杂质2分布相对均匀，而杂质3则集中在晶体表面或其附近。
