Conformational Polymorphism Analysis of Aspirin Crystal with a Crystal Calculation Method

Shigeaki OBATA and Hitoshi GOTO*

Toyohashi University of Technology
Tempaku-cho, Toyohashi, Aichi 441-8580, Japan

(Received: July 15, 2008; Accepted for publication: August 4, 2008; Advance publication: September 22, 2008)

In order to explore the possible polymorphs of aspirin crystal recently discovered in the subtle crystal packing form, conformational analysis of aspirin monomer and conformational polymorphism analysis of aspirin crystal were carried out using CONFLEX/KESSHOU (CONFLEX/K) which have implemented all functions of our crystal calculation program KESSHOU into our molecular mechanics program CONFLEX having an efficient conformational space search method. Ten conformers found by the exhaustive conformation search of a monomeric aspirin molecule (isolated in vacuum) were subjected to geometry optimizations and normal mode analyses using MMFF94 and ab initio (MP2/6-31+G**) calculations, and then, we examined the energy minima on the MMFF94 and MP2 potential energy surface, respectively. On the MM3 potential energy surface, nine conformers were also confirmed (energy minima), although one conformation was merged into another minimum by the geometry optimization. In comparison with the known aspirin conformations reported by Glaser, CONFLEX conformation search missed one of his conformations, but it is not an energy minimum of MMFF94 and MM3. To examine the accuracy of our CONFLEX/K crystal calculation, both known X-ray crystal forms of aspirin were subjected to crystal lattice optimization (LOPT) method by using MMFF94 and MM3 for intermolecular potential. It is surprisingly noted that MM3 can almost completely represent the observed crystal structures. In order to analyze the conformational polymorphism of aspirin crystal, twenty and eighteen trial crystal structures were generated by using ten MMFF94 and nine MM3 conformers, respectively, and applying form I and form II crystal structure information, and were optimized by LOPT optimizations with the corresponding force field. The results showed that 2SSc/I and 2SSc/II are the most stable crystal structures in both force fields and were in good agreement with the experimental crystal structures. The tautomeric conformational polymorphs, 1SAc/I and 1SAc/II, which can be formed from 2SSc/I and 2SSc/II, respectively, by proton exchange between the carboxylic groups of centrosymmetric aspirin dimer in the crystal, were also evaluated as stable crystal structures with both MMFF and MM3 intermolecular potential. On the other hand, the other conformational polymorphs have higher crystal energies than 10 kcal/mol from the lowest energy polymorph 2SSc/II. Therefore, we concluded that, except for two known polymorphs and their tautomers, there are extremely low probabilities for the existence of the artificial conformational polymorphs, at least, that we examined here.

Keywords: Aspirin, Polymorphism, Conformational polymorph, CONFLEX, MMFF94, MM3, Molecular orbital calculation


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