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

Abstract

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.

Process Performance and Operational Challenges in Continuous Crystallization: A Study of the Polymorphs of L-Glutamic Acid

“…A check valve was installed at the outlet of the MSMPR1 to avoid the backflow of air during the pressurization of the MSMPR2. A level control was installed in each crystallizer, which triggered the pressurization once a specified fill level height was reached . This avoided a suspension overflow in the crystallizer, whereas the pressurization time was kept short enough to keep the variation of the suspension volume below 10% .…”

“…Three KPIs are defined to assess the process performance in both experiments and simulations. They are the polymorphic purity, w i , the solute yield, Y , and the process productivity, P , i.e., a key product specification, and the measures of how well the material to be crystallized and the crystallization equipment are exploited. , Yield and productivity can be considered proxies for operating costs and capital costs, respectively.…”

“…A level control was installed in each crystallizer, which triggered the pressurization once a specified fill level height was reached. 26 This avoided a suspension overflow in the crystallizer, whereas the pressurization time was kept short enough to keep the variation of the suspension volume below 10%. 27 The whole setup was automated by using an Arduino microcontroller.…”

Continuous Antisolvent Crystallization of L-Histidine: Impact of Process Parameters and Kinetic Estimation

“…Lai et al 6 studied the continuous cooling crystallization process of paminobenzoic acid and the influence of temperature and residence time on the product crystal forms in the experimental system, successfully controlling the two polymorphs of p-aminobenzoic acid. Ostergaard et al 7 researched the continuous antisolvent crystallization process of indomethacin (IMC) in a ternary solvent system. By altering the solvent-to-antisolvent ratio and crystal loading, they eventually achieved the control of γ-IMC.…”

Continuous Crystallization Process of Cefminox Sodium in MSMPR Crystallizer

“…[14] Ostergaard et al used MSMPR crystallizer to study the continuous crystallization of indomethacin, and explored the effect of different process conditions on the polymorphic 𝛾 crystal form. [15] Compared with batch crystallization, MSMPR crystallizer can produce narrow crystal size distribution (CSD), high yield and purity. Alvarez et al used a recycle stream to improve the yield and purity of cyclosporine in MSMPR crystallizer.…”