Polymorphic Control and Scale-Up Strategy for Antisolvent Crystallization Using a Sequential Supersaturation and Direct Nucleation Control Approach

In this work, a rapid direct design approach for crystallization processes was implemented using the novel Quality-by-Control (QbC) framework by sequentially applying antisolvent-based supersaturation control (AS-SSC) and temperature driven direct nucleation control (T-DNC) strategies. This novel strategy was used to optimize and scale up the batch crystallization of indomethacin (IMC) from a ternary solvents/antisolvent system, which enables the production of the desired polymorphic gamma form with significantly increased process yield. Sequentially applying the supersaturation control (SSC) and direct nucleation control (DNC) led to a combination of the advantages of the two feedback control strategies. SSC-based direct design and scale-up strategy showed high efficiency in providing high productivity (high process yield and shorter batch time), whereas DNC is advantageous in ensuring reproducible particle size distribution from processes at different scales. The combined AS-SSC and T-DNC strategy presented in this work showed a promising synergy, which enabled a good balance between the high productivity of the crystallization process and reproducible crystal properties from the processes at different scales. The results provide a proof-of-concept showing that the proposed QbC approach based on the sequential SSC-DNC implementation can be applied for rapid and successful scale-up, leading to similar particulate properties across scales.