How molecular interactions affect crystal morphology: the case of haloperidol

The tableting behaviour of drugs can be dramatically affected by changes in the crystal habit of the drug molecule. Pharmaceutical companies are therefore interested in the morphology prediction as a possible tool to optimise the industrial process. Molecular mechanics calculations embedded in dedicated software together with X-ray diffraction analysis were used to enlighten the structural properties of 4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-1-(4-fluorophenyl)butan-1-one-whose commercial name is haloperidol--an antipsychotic drug that contributed to the progress and revolution of psychiatric care. We defined, by means of X-ray powder diffraction, which--or how much--of the two crystallographic structures present in the Cambridge Crystallographic Database represents the commercial crystalline powder. Once the correct structure was selected, the whole structural analysis was carried out as a comparison with the already deposited structures. The available single crystal structure was used to model the X-ray powder diffraction pattern. The "real" structure was then optimised by means of molecular mechanics and the crystal morphology of the compounds was predicted with different computational methods. Analogies and differences among the different morphologies, together with the potential role of several solvents were used to try to bridge the gap between the molecular structure--that is, the atomic point of view--and the crystal habit.