Antisolvent crystallization of indomethacin (IMC) was investigated in this work by using an acetone-methanol (66.5-33.5 wt%) mixture as solvent and water as antisolvent. Selecting the binary mixture as the solvent led to an increased yield of the batch process as the solubility of IMC is higher in the mixed solvents. Adding methanol to the solvent system mitigated the nucleation of the acetone solvate, which is dominating in the acetone-water system. Process analytical technologies (PATs) were implemented to ensure that the desired polymorph was present throughout the process. Supersaturation control (SSC) was applied as a closed-loop feedback control strategy, to achieve a rapid direct design of the crystallization process using the principles of Quality by control (QbC). The antisolvent flowrate profiles obtained by the SSC, were implemented in open-loop and used for scaling up the process by one order of magnitude. The results show how feedback control of crystallization from a ternary solvent mixture increases productivity and simultaneously ensures suppression of nucleation to obtain the desired particle size distribution (PSD) and polymorph. The direct design approach can be applied in the design and development of crystallization processes to yield the chosen solid phase of IMC when scaling from small-to large-scale.

In this work, a scale-up strategy based on the principles of direct design and Quality-by-Control (QbC) was applied and investigated using direct nucleation control (DNC). Process analytical technologies (PATs) were implemented for process monitoring and control. Antisolvent crystallization of indomethacin (IMC) was performed in a ternary solvent and antisolvent system.Mixture of acetone-methanol (66.5-33.5 wt%) was used as solvent and water as antisolvent since the mixed solvent system provides increased process yield and facilitates the suppression of the undesired acetone solvates. The effect of different process parameters, such as seed load, seed size and initial concentration were investigated on process time, solid form and particle size distribution (PSD). The simplified solvent and antisolvent addition profiles obtained from the DNC were implemented directly in open-loop control to investigate reproducibility of the designed process.The open-loop operation was successfully scaled up by one order of magnitude, obtaining crystalline products with similar properties (solid form and PSD) as in the small-scale experiments.The results provide a proof-of-concept showing how the direct design approach can be applied in the rapid development of a robust crystallization process and efficient scale-up to yield the desired solid form with desired particulate properties (unimodal PSD and no agglomeration).

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.

Precompetitive collaborations on new enabling technologies for research and development are becoming popular among pharmaceutical companies. The Enabling Technologies Consortium (ETC), a precompetitive collaboration of leading innovative pharmaceutical companies, identifies and executes projects, often with third-party collaborators, to develop new tools and technologies of mutual interest. Here, we report the results of one of the first ETC projects: the development of a user-friendly population balance model (PBM)-based crystallization simulator software. This project required the development of PBM software with integrated experimental data handling, kinetic parameter regression, interactive process simulation, visualization, and optimization capabilities incorporated in a computationally efficient and robust software platform. Inputs from a team of experienced scientists at 10 ETC member companies helped define a set of software features that guided a team of crystallization modelers to develop software incorporating these features. Communication, continuous testing, and feedback between the ETC and the academic team facilitated the software development. The product of this project, a software tool called CrySiV, an acronym for Crystallization Simulation and Visualization, is reported herein. Currently, CrySiV can be used for cooling, antisolvent, and combined cooling and antisolvent crystallization processes, with primary and secondary nucleation, growth, dissolution, agglomeration, and breakage of crystals. This paper describes the features and the numerical methods of the software and presents two case studies demonstrating its use for parameter estimation. In the first case study, a simulated data set is used to demonstrate the capabilities of the software to find kinetic parameters and its goodness of fit to a known solution. In the second case study, the kinetics of an antisolvent crystallization of indomethacin from a ternary solvent system are estimated, providing a practical example of the tool.

Innovations in the continuous crystallization field are required for the pharmaceutical industry to go through the paradigm shift from batch to continuous processing. To do so, different risks associated with the continuous crystallization have to be identified and discussed. In this work, a continuous antisolvent crystallization of the model compound indomethacin (IMC) from a ternary solvent system in a mixed-suspension-mixed-product-removal (MSMPR) to produce the desired polymorphic γ-form is evaluated, and potential risks for process failure are identified. One of the main risks identified with the continuous crystallization is gaining a balance between the inlet and outlet flows. Two novel and different level controls are proposed in this work to overcome this risk, an ultrasonic sensor and image analysis based on a video recording of the level. These two methods demonstrate improved process robustness upon implementation. Additionally, different process parameters were investigated and showed that the seed load has a significant effect on maintaining the desired polymorph and avoiding process failure. To the best of our knowledge, this is the first study on continuous crystallization of IMC for the polymorphic control of γ-IMC.