Habit Modification of the API Lovastatin through a Predictive Solvent Selection Approach.

An analysis of the important intermolecular interactions of the active pharmaceutical ingredient (API) lovastatin which contribute to the surface chemistry and attachment energy morphology is presented. The analysis is supported by a recent redetermination of the single crystal structure (orthorhombic space group P212121) and targets the understanding and potential control of the morphology of lovastatin, which tends to crystallise in a needle-like morphology, where the aspect ratio varies depending on the nature of the solvent. The lattice energy was calculated to be -38.79 kcal mol-1 with a small contribution of -2.73 kcal mol-1 from electrostatic interactions. The lattice structure is significantly stabilised by the hexahydronaphthalene ring of the molecule, which contributes 43.39 % of the lattice energy. Synthon analysis shows that the dominant intermolecular interaction within the lattice structure of lovastatin is found to be along the a crystallographic axis, associated with a dispersive stacking interaction due to the close packing of two hexahydronaphthalene rings resulting in a total energy of -6.46 kcal mol-1 . The attachment energy morphology correlates well with the observed crystal morphology which exhibits a needle-like habit dominated by {0 1 1}, {0 2 0}, {0 0 2} and {1 0 1} crystal forms. The needle capping faces are found to contain the short stacks of hexahydronaphthalene rings where the strong intermolecular synthon is found to contribute positively to the attachment energy and hence growth at this surface. This dominant intermolecular synthon is concluded to be the major cause of enhanced growth along the crystallographic a axis leading to the formation of a needle-like morphology. A habit modification strategy is discussed which uses recrystallization from a-polar solvents to reduce the effective growth rate at the needle capping surfaces. This is supported through experimental data which shows that crystals obtained from crystallisation in hexane and methyl-cyclohexane have significantly reduced aspect ratios in comparison to those grown from methanol and ethyl acetate solutions. Crystals obtained from nitromethane solutions were found to have a very large reduction in aspect ratio to a prismatic morphology, critically with no polymorph change.