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

Abstract

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 γ 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.

Risk-Based Operation of a Continuous Mixed-Suspension-Mixed-Product-Removal Antisolvent Crystallization Process for Polymorphic Control

“…Then, the γ-IMC seed is added corresponding to the theoretical yield obtained from a batch crystallization having an initial IMC concentration of 200.0 mg/g solvent. The later start-up conditions (experimental conditions 2 in Table ) imply adding 2.5% seed, which corresponds to the seed load used in previous work investigating the batch antisolvent crystallization of IMC. − Besides, the influence of the solvent/antisolvent ratio of the feed was also investigated on obtaining the desired γ-IMC throughout the process and on reaching a steady state. In the base case (experimental conditions 1), the ratio of solvent and antisolvent corresponds to the initial ratio within the MSMPR.…”

“…Antisolvent crystallization of IMC was studied in our previous work in a batch mode using acetone–methanol (66.5–33.5 wt %) as solvent and water as antisolvent, where two feedback strategies, supersaturation control (SSC) and direct nucleation control (DNC), were implemented. Implementation of the feedback control strategies ensured that solely the thermodynamically more stable γ-IMC was obtained. − In recent decades, the complexity of drugs increased and exhibits poor physicochemical properties presenting challenges in formulation and bioavailability . Due to the polymorphic behavior of IMC and poor water solubility, use of IMC and the aforementioned antisolvent system is a relevant case study for continuous crystallization.…”

Application of PAT-Based Feedback Control Approaches in Pharmaceutical Crystallization

“…The new image analysis based direct nucleation control (IA-DNC) is established by PVM to monitor particles in solution [37]. The combination of SSC-DNC [38] and the masscount (MC) framework approach was also established by ATR-FTIR and FBRM in the reported studies [39]. The active polymorphic feedback control (APFC) strategy is based on the use of a combination of Raman and ATR-UV/Vis spectroscopy [40].…”

Concomitant Polymorphism and Nucleation Control of DL‐Methionine Through Antisolvent Crystallization

“…In this aspect, during the antisolvent crystallization process, a model compound and an antisolvent that decreases the solubility are mixed. Notably, varying the initial supersaturation ratio and antisolvent fraction alters the nucleation rate significantly 4–6. More specifically, the addition of precise substances, i.e., drowning‐out antisolvent/salting‐out agents/precipitants, to the initial solution leads to the decrease of solubility, which consequently creates supersaturation 7, 8.…”

“…In particular, the metastable and stable polymorphs will have high and low solubilities, respectively. Recently, several reports described the formation of different polymorphs in the antisolvent crystallization process as a function of supersaturation 5–7.…”