Continuous reactive crystallization of an API in PFR-CSTR cascade with in-line PATs

The continuous reactive crystallization of an active pharmaceutical ingredient (API) in a plug flow reactor (PFR)-continuous stirred tank reactor (CSTR) cascade system with in-line PATs was developed and investigated. Residence time distribution (RTD) measurements of the PFR (stage 1), the CSTR cascade (stages 2–6), and the combined PFR-CSTR cascade (stages 1–6) were performed to estimate the performance of the reactors. Several continuous reactive crystallization experiments were performed, and consistent reaction yields of 91.3 ± 0.5 and 89.6 ± 0.4% were obtained with and without the PFR, respectively. The integration of PFR (stage 1) created a very high level of supersaturation by itself, and ∼25% lower supersaturation and a 2.7% higher crystallization yield in the following vessel (stage 2). In stages 3–6, the supersaturation levels and crystallization yields were similar (with and without the PFR). With the PFR, the lower supersaturation in stage 2 resulted in lower nucleation rates and higher crystal growth rates, resulting in a larger crystal size distribution. Also, in-line ReactIR and focused beam reflectance measurement (FBRM) were used to monitor the reactant concentration and crystal chord length, respectively, during the reactive crystallization process. The ReactIR predicted reactant concentrations in the mother liquor that matched well with corresponding HPLC results (prediction error < 0.17%). The FBRM results showed a relatively stable mean square-weighted chord length of ∼150 μm. In addition, the process mass intensities (PMIs) for the batch process, the integrated continuous manufacturing (ICM) process without the PFR, and the ICM process with the PFR were 3.49, 1.99, and 1.97, respectively.