Development of a Continuous Crystallization Process of the Spironolactone Hydrate Form with a Turbidity-Based Level Control Method

Abstract

In this study, a robust continuous antisolvent crystallization method was developed to produce the hydrate form of spironolactone. Continuous crystallizations were implemented in a one-stage mixed-suspension mixed-product removal crystallizer using a process turbidimeter as a fluid level sensor for the first time. The feed and removal rates were controlled by pumps using the signal of a turbidimeter in noncontact mode to maintain a constant fluid level and long-term steady-state operation. The chord length distribution of the crystal suspension was monitored online with a focused beam reflectance measurement probe in our custom-designed measurement cell in which the withdrawn suspension was representative of the crystallizer's content. The effects of process parameters on the particle size distribution of the products were investigated by full factorial design of experiments. Crystals were produced with monomodal distribution and with d 90 ranging from 7 to 62 μm. The temperature and antisolvent ratio were found to be significant process parameters. Compared to batch operation, these parameters had a larger effect on particle size; moreover, the antisolvent ratio became a key factor in the design of particle size distribution.