Abstract
When multiobjective particle engineering is needed,an extensive array of crystallization process development tools are necessary.An example of such an endeavor was reported by a team from Loughborough University and Takeda Pharmaceuticals(Sun,Z.;et al.Cryst.Growth Des.,DOI:10.1021/acs.cgd.lc01510).Compound X(a Takeda API) can crystallize as stable form A(desired) or as metastable form L exhibiting heavy agglomeration.A cooling antisolvent crystallization process was developed using solubility data and optimization of the solute concentration,antisolvent-cooling sequence,cooling protocol,seed amount(9.8-23.8%),and location.Process analytical technology(PAT) tools included calibrated UV-vis spectroscopy and focused-beam reflectance measurement(FBRM).Even though improvements in particle size and shape were observed,the specifications were not met,and wet milling was also employed.To remove the undesired fines obtained during wet milling,temperature cycling was included in the process,first in an open loop and then,for better results,in a closed feedback loop of direct nucleation control(DNC) using a target FBRM particle count.Utilizing suitable automated lab reactors,DNC allows for automated manipulation of heating/cooling and solvent/antisolvent addition.The API thus produced met specifications,showing a much lower degree of agglomeration than in the original process.
NSTL