Can crystal structure prediction guide experimentalists to a new polymorph of paracetamol?

Abstract

The results of an extensive in silico polymorph screen with the program GRACE of paracetamol in all 230 space groups with one and two molecules in the asymmetric unit are presented. The three experimentally known forms I, II and III are found in the list of predicted crystal structures in the correct stability order with rank 1, 3 and 6, respectively. Structures with ranks 3 to 8 exhibit the same motif of 2-D hydrogen-bonded sheets. The hydrogen-bonding scheme of the rank 2 structure is markedly different from the known forms, consisting of two interpenetrating 3-D hydrogen-bonded networks. The excellent agreement with experiment and the prediction of one and only one new packing motif within the lattice energy window delimited by the known forms confirms the fitness for crystal structure prediction of the employed methodology. Analysis of the structure at rank 2 is used to propose experimental strategies that may lead to a new form IV of paracetamol.