Evaluating a Crystal Energy Landscape in the Context of Industrial Polymorph Screening

To evaluate how the calculation of
a crystal energy landscape can
be used in the solid-form screening of pharmaceuticals, a Knowledge
Transfer Secondment between GlaxoSmithKline (GSK) and University College
London was established to carry out computational crystal structure
prediction (CSP) and further guided experimentation on a molecule
from GSK’s compound collection. The molecule chosen was 6-[(5-chloro-2-([(4-chloro-2-fluorophenyl)­methyl]­oxy)­phenyl)­methyl]-2-pyridinecarboxylic
acid (GSK269984B) since the preliminary thermodynamic form screening
had only identified one anhydrate, Form I. The calculations confirmed
that Form I is the most thermodynamically stable form. The thermodynamically
competitive computed structures all had very different conformations
of GSK269984B, and further experiments were designed to attempt to
generate these conformations in solution and hence the crystalline
solid. The experimental screening generated four novel solvates which
all eventually transformed to Form I, two of which could also be structurally
characterized by single crystal X-ray diffraction. The molecular conformation
(apart from the position of the polar proton) in all three crystal
structures was, however, very similar. GSK269984B appears to have
an unusually small number of solid forms because there is no kinetic
barrier to crystallizing in the most stable conformation which corresponds
to the most thermodynamically stable and densely packed structure.

为评估晶体能量景观（crystal energy landscape）计算在药物固体形式筛选中的应用潜力，葛兰素史克（GlaxoSmithKline, GSK）与伦敦大学学院（University College London）联合设立了知识转移借调项目，针对葛兰素史克化合物库中的一款分子开展计算晶体结构预测（computational crystal structure prediction, CSP）研究，并辅以定向实验验证。本次研究选取的分子为6-[(5-氯-2-([(4-氯-2-氟苯基)甲氧基]苯基)甲基]-2-吡啶甲酸（GSK269984B），此前的初步热力学晶型筛选仅发现了一种无水物——晶型I。计算结果证实，晶型I为该分子热力学最稳定的晶型。热力学竞争优势的计算所得结构均展现出与GSK269984B迥异的分子构象，研究团队据此设计后续实验，尝试在溶液中生成这些构象并最终获得晶体固体。实验筛选获得了四种新型溶剂化物，所有溶剂化物最终均转化为晶型I，其中两种可通过单晶X射线衍射（single crystal X-ray diffraction）完成结构表征。不过，三种晶体结构中（除极性质子的位置外）的分子构象高度相似。GSK269984B的固体形式数量异乎寻常地少，原因在于其以最稳定构象结晶不存在动力学壁垒——该构象对应热力学最稳定且堆积最致密的晶体结构。