A framework for systematic crystal shape tuning – Case of Lovastatin's needle-shaped crystals.

One of the most important challenges in the pharmaceutical industry is to produce crystals with desired size and shape distributions, to enhance the critical quality attributes of the drug product, such as efficacy, and to improve manufacturability during downstream processing, such as filtration, drying and granulation. The paper provides a framework for effective crystal shape and size tuning, based on a systematic exploration of standard techniques, such as the linear cooling and supersaturation control (SSC), and novel methods based on the systematic combination of several techniques, namely direct nucleation control (DNC), wet milling, SSC and shape modification additives. The crystallization of lovastatin, which is notorious for its challenging needle-shaped crystals, with an extremely high aspect ratio, was used as a case study, and polypropylene glycol (PPG-4000), at different concentrations, was used as an effective shape modifier from small-scale tests studied previously. The proposed techniques were implemented in the case of seeded and unseeded systems. It was demonstrated that the combination of temperature cycling and polymer additive enhances greatly the control over the aspect ratio and crystal size distribution, compared to conventional linear cooling and SSC strategies. The implementation of wet milling at the beginning of the process, or the introduction of seeds, enhances even further the control of the critical quality attributes of the crystalline product. [Display omitted] • Developed and validated a new framework for systematic crystal shape and size tuning. • Standard cooling crystallization with a polymer additive was insufficient to improve the aspect ratio of lovastatin. • Crystal shape successfully modified using additives and Direct Nucleation Control (DNC). • The additive caused inhibition along the longest axis which resulted in an effective control of the aspect ratio. • The lowest aspect ratio was achieved using a combination of seeding, milling, additives and DNC. [ABSTRACT FROM AUTHOR]