Reducing the mean size of API crystals by continuous manufacturing with product classification and recycle

A continuous crystallization process is proposed that can produce active pharmaceutical ingredients with a small mean size and narrow distribution. The process flowsheet consists of a new product classifier configuration where the large crystals from the classifier are recycled to a dissolver along with the mother liquor from the filter. Crystallizer stability is explored and regions of sustained limit cycles are identified for the proposed kinetic models. Most industrial crystallizers are operated at low supersaturation; however, with this methodology the continuous crystallizer must be operated at high levels of supersaturation to promote nucleation and increase the number of small crystals in order to maintain a fixed desired production rate. The design and operating strategies presented can be implemented by simple modifications to most conventional continuous crystallization processes. This particle micronization technique may offer significant cost savings over other size reduction methods that utilize mechanical means.