Designing Crystallisation Processes

Three recent papers from the groups of Nagy and Qu have discussed different options for designing and scaling up crystallisation processes to achieve polymorph control and obtain the correct particle size distribution (PSD). The first two papers^1,2 describe using PAT (online analysis) with feedback control to design an antisolvent crystallisation process for indomethacin.  Each paper describes a similar approach but using different feedback control algorithms (see Figure 1).

Figure 1: Outline of the approach to design and scale up an SSC process (exactly the same system is used for DNC, with DNC experiments replacing SSC experiments)

In each case you need to select your solvent system and determine the solubility curve and metastable limit and then carry out some scouting or Open Loop experiments.  The next step is to carry out the designed experiments using Supersaturation Control (SSC, in the first paper)¹ where the antisolvent addition is carried out at and the trajectory of the system through the metastable zone is measured using Focussed beam reflectance (FBRM), Particle Vision Monitor (PVM and Ultraviolet (UV) and this is fed back to the controller to adjust the antisolvent addition rate to ultimately achieve an antisolvent level of 40wt %.

The second approach² uses Directed Nucleation Control.  IN this case a similar approach s used except the feedback control is based on particle size and addition of antisolvent and solvent is alternated to allow the material to crystallise and recrystallise to achieve the desired PSD.

Once an optimised trajectory (antisolvent / solvent addition rate) for the process has been found the process is then scaled up using exactly the same trajectory, i.e. adding the antisolvent and/or solvent in the same order and at the same relative rates, but without the feedback control.

The third paper³ which also involves researchers from Takeda discusses and compares the difference between  model based approaches to crystallisation design as in QbD (Qualitry by Design), and QbC (Quality by Control) techniques using feedback algorithms such as SSC and DNC to dsign a crystallisation process.

1. I. Ostergaard, B. Szilagyi, Z.K. Nagy, H. Lopez de Diego and H. Qu, Cryst. Growth Des., 2020, 20, 1337-1346.
2. I. Ostergaard, B. Szilagyi, H. Lopez de Diego, H. Qu and Z.K. Nagy, Cryst. Growth Des., 2020, 20, 2683-2697.
3. B. Szilagyi, A. Eren, J.L. Quon, C.D. Papageorgiou and Z.K. Nagy, Cryst. Growth Des., 2020, 20, 2683-2697.