Improving the Filterability of Particles by Healing the Seed Particles

A shift in particle size distribution toward smaller particle sizes has been observed in batches of Compound A Triethanolate, an isolated intermediate of a commercially available active pharmaceutical ingredient, leading to poor deliquoring of the filter cake and longer filtration times, which compromised the overall process cycle time. In the most extreme case, product breakthrough during filtration was observed, leading to significant yield loss. Compound A Triethanolate is crystallized through antisolvent addition/distillation/cooling crystallization in ethyl acetate/water/ethanol. Laboratory experiments were carried out using representative product streams in order to identify the cause for the shift in particle size distribution, which could be attributed to excessive secondary nucleation at an early stage of the process caused by the use of seed particles that have been previously dried under agitation. While statically dried particles exhibit a smooth surface, the surface of particles dried under agitation is severely damaged. Agitation during drying also leads to partial amorphization of the particles. Crystallization kinetics estimated in this work demonstrated that damaged seed particles led to an increase in the level of secondary nucleation. Analysis of historical data confirmed that the shift in particle size distribution coincided with the complete consumption of statically dried seed particles produced in pilot plant batches, thus requiring a switch in seed source to particles dried under agitation produced in manufacturing batches. As static drying is not a viable option in the production of Compound A Triethanolate because of cycle time constraints, a protocol was developed that aims at healing the seed particles to suppress secondary nucleation. Seed particles are slurried in antisolvent ethanol prior to being charged to the reactor as a slurry in order to decrease the level of amorphous content. The size of the particles produced by the subsequent crystallization increased with increasing amount of ethanol used, which can be explained by the increased capacity to dissolve amorphous content of the seed particles during healing. The increase in particle size is accompanied by reduced filter cake resistance and improved deliquoring of the filter cake. In laboratory experiments, the reduction in the filtration time achieved by using healed seed particles exceeded 1 order of magnitude.