Application of feedback control and in situ milling to improve particle size and shape in the crystallization of a slow growing needle-like active pharmaceutical ingredient

Control of crystal size and shape is crucially important for crystallization process development in the pharmaceutical industries. In general crystals of large size and low aspect ratio are desired for improved downstream manufacturability. It can be extremely challenging to design crystallization processes that achieve these targets for active pharmaceutical ingredients (APIs) that have very slow growth kinetics and needle-like morphology. In this work, a batch cooling crystallization process for a GlaxoSmithKline patented API, which is characterized by very slow growth rate and needle morphology, was studied and improved using process analytical technology (PAT) based feedback control techniques and in situ immersion milling. Four specific approaches were investigated: Supersaturation control (SSC), direct nucleation control (DNC), sequential milling-DNC, and simultaneous milling-DNC. This is the first time that immersion wet milling is combined with feedback control in a batch crystallization process. All four approaches were found to improve crystal size and/or shape compared to simple unseeded or seeded linear cooling crystallizations. DNC provided higher quality crystals than SSC, and sequential and simultanesou milling-DNC approaches could reduce particle 2D aspect ratio without generating too much fines. In addition, an ultra-performance liquid chromatography (UPLC) system was used online as a novel PAT tool in the crystallization study.