Methyl Geometry Explains Aspirin Polymorph Stability

For aspirin, the difference in how methyl groups pack into crystals may be the reason why one crystalline form of the pain reliever is more stable than another, according to a computational study (Phys. Rev. Lett. 2014, DOI: 10.1103/physrevlett.113.055701). Some molecules crystallize in different forms, or polymorphs, although the reasons for doing so are poorly understood. The difference can be important, however, because pharmaceutical polymorphs can have different bioavailability and therefore require different formulations. Anthony M. Reilly and Alexandre Tkatchenko of the Fritz Haber Institute of the Max Planck Society, in Berlin, looked at van der Waals interactions among atoms in the two known forms of aspirin. The researchers linked different geometric arrangements in the two forms to vibrational states in the crystal lattice. In form I, methyl groups in different layers of molecules are separated by 4.5 Å, whereas in form II, they are separated by 3.7 Å or 5.5 Å. Uniform separation in form I promotes coupling of electronic and lattice motion. That coupling lowers the energy of vibrational modes so they are more easily populated, which increases the entropy and lowers the free energy of the system so that form I is more thermodynamically stable than form II. Similar effects may also explain structural differences in other materials, the researchers suggest.