Stanton Stephen A, Du Jonathan J, Lai Felcia, Stanton Gyte, Hawkins Bryson A, Ong Jennifer A, Groundwater Paul W, Platts James A, Hibbs David E
Sydney School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia.
School of Chemistry, Cardiff University, Cardiff CF10 3AT, U.K.
J Phys Chem A. 2021 Nov 18;125(45):9736-9756. doi: 10.1021/acs.jpca.0c09536. Epub 2021 Nov 3.
The charge density distribution in a novel cocrystal (1) complex of 1,3-dimethylxanthine (theophylline) and propanedioic acid (malonic acid) has been determined. The molecules crystallize in the triclinic, centrosymmetric space group 1̅, with four independent molecules ( = 4) in the asymmetric unit (two molecules each of theophylline and malonic acid). Theophylline has a notably high hygroscopic nature, and numerous cocrystals have shown a significant improvement in stability to humidity. A charge density study of the novel polymorph has identified interesting theoretical results correlating the stability enhancement of theophylline cocrystallization. Topological analysis of the electron density highlighted key differences (up to 17.8) in Laplacian (∇ρ) between the experimental (EXP) and single-point (SP) models, mainly around intermolecular-bonded carbonyls. Further investigation molecular electrostatic potential maps reaffirmed that the charge redistribution enhanced intramolecular hydrogen bonding, predominantly for N(2') and N(2) (61.2 and 61.8 kJ mol, respectively). An overall weaker lattice energy of the triclinic form (-126.1 kJ mol) compared to that of the monoclinic form (-133.8 kJ mol) suggests a lower energy threshold to overcome to initiate dissociation. Future work physical testing of the novel cocrystal in both dissolution and solubility will further solidify the correlation between theoretical and experimental results.
已确定了1,3 - 二甲基黄嘌呤（茶碱）与丙二酸形成的新型共晶体（1）配合物中的电荷密度分布。分子以三斜、中心对称空间群1̅结晶，不对称单元中有四个独立分子（Z = 4）（茶碱和丙二酸各两个分子）。茶碱具有显著的高吸湿性，并且许多共晶体在对湿度的稳定性方面有显著改善。对该新型多晶型物的电荷密度研究确定了与茶碱共结晶稳定性增强相关的有趣理论结果。电子密度的拓扑分析突出了实验（EXP）模型和单点（SP）模型之间拉普拉斯算子（∇ρ）的关键差异（高达17.8），主要围绕分子间键合的羰基。对分子静电势图的进一步研究再次证实，电荷重新分布增强了分子内氢键，主要是针对N(2')和N(2)（分别为61.2和61.8 kJ/mol）。与单斜晶型（-133.8 kJ/mol）相比，三斜晶型的晶格能总体较弱（-126.1 kJ/mol），这表明启动解离需要克服的能量阈值较低。未来对该新型共晶体在溶解和溶解度方面进行物理测试的工作将进一步巩固理论和实验结果之间的相关性。
