The versatility of the Secoya crystallization platform
Secoya’s crystallization technology allows a very wide range of different particle sizes whilst maintaining the same production yield. Moreover, all different important screening parameters for continuous nucleation can be performed on one single instrument, the SCT-LAB. And, all these parameters can be extrapolated to the same configuration at pilot scale and industrial production scale.
The SCT-LAB equipment for example, Figure 1, is accommodated to heat solution and antisolvent in place (and agitated) up to 85°C, which covers most of the organic solvents and solubilities of small molecules in solution. The syringes of the system are set at the same dissolution temperature, but also the antisolvent syringe can be cooled to 5°C. then, the inserts that are available for both antisolvent and cooling crystallization are placed on the SCT-LAB, it is a software choice to use only the solution syringe when cooling crystallization is performed. Also the different existing reactor types can be easily installed and uninstalled on the SCT-LAB so that in between testing different combinations of insert and reactor can be generated to help faster screening of different conditions.
These combinations have led to the development different crystallization processes and amorphous precipitations between several hundreds of micrometers and sub-micrometric particles. Evidently, to reach submicrometric particle sizes in suspension surfactants are needed to prevent aggregation. However – to the benefit of the technology – these surfactants can be mixed with either the solution phase or antisolvent phase. Thanks to the intense interaction between surfactant and recently created particles inside the mixers a number reported drastic drops in used surfactants as opposed to other ways fabrication have been published (https://doi.org/10.3390/pharmaceutics16030376).
Impact of nucleation temperature
Example 1: COOLING-0 + 3 mL reactor
We have developed a setup that enables both the finalization of the acetylation step of salicylic acid into acetyl salicylic acid or Aspirin. To do so a mixture of salicylic acid and acetic anhydride was preheated and flushed through a tubing at 90°C in oder to fully converse the reaction. Then, at the outlet of the heated reactor a mixture is obtained of 844 mg aspirin/mL acetic acid. With the used flow rate of 10 mL/min, the nucleation reactor of 3 mL was placed in water bath at different temperatures in between different productions. The crystal growth temperature was set at 25°C. this simple change in nucleation temperature has led to the crystal size curve as a function of the different nucleation temperatures, see Figure 3.
While the crystal growth phase is performed at room temperature there is a clear different between the tests performed at higher nucleation temperatures and the lower nucleation temperatures. One would expect that when the nucleation cannot take place at temperatures above 25°C, then these samples would all result in the same average particle size. However, the passage through the reactor enables indeed reaching spontaneous nucleation conditions; once again in the collection vessel the created crystals grow to equilibrium. Further lowering the nucleation temperature enables reaching very small particles. Details of this work can be found: https://doi.org/10.1039/C8RE00313K.
Example 2: CROSS FLOW MIXING INSERT + 0.5 mL reactor
An important feature of the use of the antisolvent mode is the possibility of the use of a cooled antisolvent to be mixed with the solution subsequently followed by a passage at cold temperatures inside the nucleation reactor. With Cross flow setup, cooled hexane at 5°C was mixed directly with a Brivaracetam/IsoPropyl Acetate (IPAc) solution at 30°C at different concentrations. Brivaracetam is known t have different polymorph of which one is an unwanted solvated structure, kinetically favoured at higher nucleation temperatures (https://pubs.acs.org/doi/abs/10.1021/acs.cgd.8b00928). Thanks to the mixing with cold hexane, the temperature is drastically decreased and therefore the wanted polymorphic form nucleates, as this is the metastable form at lower temperatures (https://pubs.acs.org/doi/abs/10.1021/acs.cgd.8b00930). The nucleation rate that was obtained is very high and therefore at very short residence times, small enantiopure crystals are obtained at different conditions (figure 3).
Table 1: Average particle sizes for antisolvent crystallization of Brivaracetam.
Impact of the nature of mixing together with antisolvent
Example 3: CO-FLOW MIXING INSERT + 1mL REACTOR
An important feature of the use of the antisolvent mode is the possibility of the use of a cooled antisolvent to be mixed with the solution subsequently followed by a passage at cold temperatures inside the nucleation reactor. With Cross flow setup, cooled hexane at 5°C was mixed directly with a Brivaracetam/IsoPropyl Acetate (IPAc) solution at 30°C at different concentrations. Brivaracetam is known t have different polymorph of which one is an unwanted solvated structure, kinetically favoured at higher nucleation temperatures (https://pubs.acs.org/doi/abs/10.1021/acs.cgd.8b00928). Thanks to the mixing with cold hexane, the temperature is drastically decreased and therefore the wanted polymorphic form nucleates, as this is the metastable form at lower temperatures (https://pubs.acs.org/doi/abs/10.1021/acs.cgd.8b00930). The nucleation rate that was obtained is very high and therefore at very short residence times, small enantiopure crystals are obtained at different conditions (figure 3).
Use of different flow rates inside antisolvent mixing conditions
Example 4: CO-FLOW MIXING INSERT + 1mL REACTOR
While using antisolvent additions many experimenters need to vary the particle size. It has been observed that the particle size can be altered by using higher flow rates inside the cross-flow mixer. The cross-flow mixer allows mixtures up to 1/3 to 1/4 in flow rate ratio between solution/antisolvent. Once the rate of the antisolvent goes higher, blockages may occur. To demonstrate this, in Figure 6 the flow simulations of a 1/1 and 1/2 flow rate ratio of solution and antisolvent are shown. Already at the 1/2 mixing ratio, the higher flow rate occupies the space inside the T-mixer. When this flow rate goes up, the solution end risks of becoming stagnant, which at the interface between both liquids provokes in stagnant solids that are formed with blockages as a result.
To enable higher mixing ratios, we recommend highly the use of the co-flow mixer, schematized in Figure 5, where the mixing is not chaotic as in the cross-flow mixer but purely diffusive as both solvents will gradually dissolve into one another. Playing with flow rate ratios there help to have a large excess in antisolvent but also aid in the particle migration towards the antisolvent rich phase (arrest of growth) or solution rich phase (resulting in larger particles). The example shown for Terephtalic acid is an example where the particles remain longer in the solution rich phase (1/2 mixing ratio) and therefore ‘larger’ crystals are found. In the next example, see Figure 7, a steroid compound with very low solubility of 20 mg/mL at room temperature was investigated, using the co-flow mixer and a 1 mL reactor in plain air. Also the antisolvent was kept at room temperature. Where the mixing in a 1/1 mixing ratio gave a wide variety in particle sizes, increasing the mixing ratio to 1/4 already drastically decreased the particle size to sub-20 µm particle sizes. A flow rate ratio of 1/5 and 1/6 not only decreased further the overall crystal size but it also homogenized the batch to batch variability. Then, with a mixing ratio of 1/8 particles of 3 µm in average size and low span value (indicator for diffence in smallest to largest particles). Please note that with the use of surfactant also submicrometric particles were retrieved.
