Additive crystallization routes to control the crystal habit of the active pharmaceutical ingredient (API) lovastatin are presented, at small scale up to 25 mL. Lovastatin is an archetypical example of an API that forms needle-like crystals via solution-based recrystallization, causing issues for downstream pharmaceutical processing stages. In this work, the size and shape of lovastatin needles are shown to be subtly influenced by the crystallization solvent, concentration and crystallization procedure, with moderately hygroscopic ethyl acetate solvent producing needles with improved aspect ratios in comparison to the acetone/water mixtures primarily used for industrial recrystallization. Further, the inclusion of soluble, non-size-matched polymer additives, at very low concentrations (0.5% wt/wt), into the solution has a pronounced impact on the crystal habit. While the inclusion of the hydrophilic polymer poly(ethyleneglycol) promotes the formation of even longer, thinner needles than those formed by non-additive routes, the use of hydrophobic poly(propyleneglycol) improves the habit from needles towards plate-like crystals. The product materials are analyzed by a combination of microscopy, thermal analysis and diffraction-based techniques, with the latter enabling rationalization of the habit control via identification of the prominent crystal faces and growth directions with respect to the underlying crystal structure.

Two Workflows are presented that are relevant to the design and construction of end-to-end pharmaceutiucal manufacturing processes. The Workflows target the very early stage crystallisation aspect of these processes –...