“Downstream processing (DSP) of biopharmaceuticals is dominated by chromatographic steps which suffer from low throughput, poor scalability and elevated energy consumption, as well as high equipment and materials costs. To this is added the low stability and high degradability of liquid formulations. The training program “”Crystallisation towards efficient and sustainable biomanufacturing”” (PROCRYSTAL) vision is that of crystallisation as a simple, sustainable, cost-efficient and scalable alternative to current DSP techniques and liquid formulations, once it allows to separate, purify and stabilise in single step. Nevertheless, integrated training to exploit biocrystallisation’s full potential is currently not available, only fragmented research activities. Within this training program, 13 Doctoral candidates (DCs) are expected to go beyond current practice to respond to the near future biopharma manufacturing needs. And only possible leveraged by the expertise conveyed in this consortium on biomolecules crystallisation, biochemistry, chemical and process engineering as well as advanced modelling. The PROCRYSTAL training program for the DCs has been framed with special attention to fundamental understanding of the underlying phenomena, from the molecular scale to process scale, and advanced experimental and modelling techniques specific to crystallisation technology. The DCs will acquire a wide range of subject-specific and general transferable skills, in an interdisciplinary and inter-sectoral environment and by multinational collaboration which enhances the early-career DCs long term employability and competitiveness.
Development of a complete process cycle from lab to pilot scale and beyond
In the previous blogs the focus was put on screening the parameters completely to let a molecule to crystallize to its desired critical material attributes (CMAs), most notably polymorphism, size and size distribution, and shape. Please note that our clients also investigate at this level the appearance of the powder to already give qualitative impressions on the flowability of the obtained powder, filtration behavior, compaction of the powder, etc. to already gain insight in the processability of the material. In general, you can create the following matrix valid for antisolvent crystallization with all parameters included.
Table 1: Parameter settings and results table for crystallization tests using the SCT-LAB equipment
Once this has been set, the user is ready for long-term testing at the pilot scale. One of the major benefits of Secoya’s Crystallization Technology is that the upscaling on the SCT-PILOT is performed using exactly the same parameter settings as for the SCT-LAB tests as pointed out in table 1. In this blog post, we elaborate on the example of lactose production, work that has been published as well: https://pubs.acs.org/doi/abs/10.1021/acs.oprd.3c00132
Lactose is extremely soluble in water, the solubility curve is shown in Figure 1. Several tests using our SCT-LAB instrument have demonstrated that the metastable zonewidth is very wide, at a concentration of 700 mg/mL nulceation has been observed inside the reactor at 5°C. This corresponds to a supersaturation value s of about 4. Compared to other molecules, this is not an extreme value, however, due to the large solubility of lactose, one cannot use a wide variation in temperatures to find different nucleation conditions: concentration higher than 1000 mg/mL are not workable, temperatures lower than 0°C become so viscous they do not run through the reactors anymore. Therefore the operational zonewidth is a small triangle between the orange dotted MSZW, 1000 mg/mL in concentration and about 2°C in temperature, indicated with the green zone in Figure 1. Nonetheless, using a specific execution of the reactor to cope with the high viscosity of the solution at low temperatures at 5°C nucleation temperature and a solution concentration of 850 mg/mL nucleation conditions have been found that result in the desired particle size and shape as was verified with laser particle sizing by our client. Microscopic images of the obtained crystals are shown in Figure 2. In Table 2 the corresponding SCT-LAB results table is found. This table is usually based on several repetitions of the same set of parameters to check the robustness of the methodology at lab scale.
Figure 1: Solubility of lactose in water as a function of temperature (blue), experimentally validated metastable zonewidth inside our reactors in orange.
This exact configuration was used for pilot testing, identical reactor conditions were set out on the pilot unit by connecting the SCT-PILOT unit to a IKA Easysyn 2000 system, set at 5°C, see Figure 3. The connection between both is simply made by putting the end of the Secoya reactor into the vessel and let the vessel fill up during production. 2 liter productions were performed a the start. Once all material was collected, the vessel was continuously stirring at 60 rpm during 18 hrs. At that point in time, the material was filtered using a stainless steel Nutsche cel from DrM, the lactose was washed with ethanol and evaluated for size and shape.
Figure 3: SCT-PILOT setup (left), IKA Easysyn 2000 unit (middle), and lab scale 100 mL Nutsche cell from DrM.
Weight calculation measurements of dried samples resulted in a 93% yield, holding the solubility of lactose in water into account. In the publication the study to reach equilibrium can be read in further detail. In Figure 4 two microscopic mages are shown for two different pilot productions. The typical tomahawk shaped crystals can be seen, there seems to be some coagulation, due to the large remaining part of lactose in solution. Washing with ethanol was performed to reduce this effect. Another test was performed as well to cross-check the effect of Secoya’s reactors. Identical quantities of product were dissolved and cooled down in the same vessel with the same residence time afterwards. The overall size of the product increased drastically to 90 µm average size, so 50% larger crystals are obtained. So, even though you can nucleate lactose in a vessel by cooling it down, the quality of product and the control in size is only guaranteed by the passage through the Secoya’s reactor. This size variation can be seen in Figure 5 where the lab tests, pilot test and batch test are compared in size, the d10, d50 and d90 values are shown in a spider-plot. This kind of plot makes it very easy to see true outliers of any test, and visibly the batch test is the one where the sizes are completely different as opposed to the tests using Secoya’s reactors, whether with the lab tests or pilot tests.
Figure 4: Microscopic image of two distinct sample originating from two different pilot test using the parameter settings from Table 2.
Figure 5: Spider-plot showing particle size attributes for different tests on lactose crystallization: LAB indicates test on the SCT-LAB instrument, PILOT on the SCT-PILOT unit, BATCH indicates the cross-test without a passage through our reactor, at pilot scale.
Further upscaling is then performed by placing the reactors parallel to each other. As the parameter settings at lab scale are completely identical to pilot scale productions, one just has to connect a second, third, fourth, or more reactor with its own flow control. In the next blog more information on this final step is shown.
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Aspen API – Crystallization with Secoya technology
Background
Aspen API, a global supplier of active pharmaceutical ingredients (APIs), conducted a research project in collaboration with Secoya Technologies to improve its crystallization process. The goal was to achieve a robust and reproducible particle size distribution (PSD) without the need for micronization, which has posed challenges due to the sticky nature of certain APIs.
Objectives
To determine whether Secoya’s crystallization technology can achieve optimal PSD during crystallization, reducing or eliminating the need for micronization.
Materials & Methods
API Selection and Solubility Curve Determination:
Initial API concentration: 72 mg/ml in a 7:3 ethanol-water solution.
Temperature range: Start at 70°C, cooling down to 5°C to determine the solubility curve.
Crystallization Setup:
Reactor: 3 mL reactor coupled with Secoya cooling blocks (Cooling-0 and later Cooling-2).
Cooling bath RS1050 maintained at 5°C.
Flow rate: 20 ml/min with material collected and stirred at 5°C to initiate crystallization.
Process Variables:
Temperature control was crucial, with temperatures varying between 0.5°C and 10°C.
Aging time in the reactor was also tested at intervals, such as 4½ hours and 24 hours, to observe PSD over time.
Antisolvent Crystallization Trials:
Concentration: 100 mg/ml in ethanol.
Different solute-to-antisolvent ratios were tested, ranging from 2:1 to 1:4.
Particle size and morphology were evaluated through visual inspection and PSD measuremen
Setup for cooling crystallization experiment
Results
Cooling Crystallization
Cooling crystallization gives a narrower distribution (PSD) than antisolvent for this AP (figure1)
PSD of cooling crystallization is better than regular production (figure 2)
Figure 1: Cooling crystallization versus antisolvent crystallization
Anti solvent Crystallization
Anti solvent gives a broader distribution (PSD) with smaller particles than cooling crystallization (figure3)
Figure2: Cooling crystallization vs commercial PSD
Figure3: PSD antisolvent vs cooling
Conclusion
Cooling crystallization using Secoya’s technology has demonstrated potential as a method to achieve the desired PSD without the need for micronization.
Erik ter Voert
Sr. Lab. Technician at Aspen Oss B.V.
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Versatile equipment for multiple crystallization modes and particle sizes range
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.
Figure 1: The SCT-LAB instrument
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.
Figure 2: Aspirin crystal size as a function of nucleation temperature as dissolved in acetic acid in a 844 mg/mL concentration (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).
Figure 3: Temperature evolution inside the cross-mixer for a Brivaracetam solution mixed with hexane at identical flow rates (https://pubs.acs.org/doi/abs/10.1021/acs.cgd.8b00930)
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.
Figure 6: Flow simulations inside the Cross-flow mixer for a 20 and 20 mL/min and 20 and 40 mL/min flow rates for solution and antisolvent.
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.
Figure 7: Co-fLow mixer insert crystallizations of a steroid compound at a concentration of 20 mg/mL, average particle size with standard deviations shown as a function of the mixing ratio.
Practical examples for the crystallization process development using the SCT-LAB instrumentation
A rapid process development using one single reactor configuration
As the technology is based on the use of one single reactor configuration from the lab equipment to the production scale, all exploration of process conditions is performed on the SCT-LAB equipment and then held constant. As such, all process development is done with a minimum quantity of product involved. At later stages of the increase in scale these process parameters are simply copy-pasted and used as such on both the PILOT unit as well as the industrial scaled ICE unit.
These parameters are:
Selection of mixer and reactor
Solution concentration and temperature
Flow rates of solution and antisolvent, when the latter is required
Nucleation temperature
The first filtration and drying steps.
To do so, a wide variety of different conditions is to be tested on the SCT-LAB equipment. A swift parameter testing sweep, typically performed on filtered and dried crystals gathered for each different test gives a in-depth insight in how the molecule is nucleating inside the reactor, and what sizes can be obtained by changing the thermodynamic conditions, i.e. playing around in the phase diagram, as shown here below schematically.
Once the optimal zone is reached, which means that upon retesting the exact same product is obtained, and this with a variety of different combinations of flow rate, residence time and nucleation temperature, one can fix the thermodynamic route for crystallization. Then, and this is a true benefit of the approach for controlled nucleation as done with this technology, one can use the influence of hydrodynamics to further refine the product up to final particle size that is desired. As an example for this approach for cooling crystallization, the molecule Brivaracetam was nucleated inside of these reactors to find an optimal size of 50µm average particle size with a d90 below 100 µm.
Brivaracetam has a particular behavior as it forms very easily a solvated crystal structure with different solvents. Nonetheless, a route was found in order to avoid the formation of the unwanted solvated polymorph using our technology.
To do so the following thermodynamic pathway was followed: using the
previously discussed fast cooling rates inside the reactors, the heated
solution is rapidly cooled down to temperatures inferior to the
enantiotropic point between 15 and 20°C, as shown with the blue arrow
numbered “1” in the next graphic.
Once the targeted nucleation temperature between 0 and 15 °C is reached, then we stay inside of the reactor at temperature to maximalise the nucleation rate. As such the overall concentration of solutes in solution drops as we are creating there already solid nuclei (arrow number 2 in the graphic). Then, the product exits the reactor. In this particular case, the product slurry has to be gathered at room temperature, therefore the slurry heats up to room temperature while still growing (arrow number 3). However, as the slurry has exited the reactor, no more nucleation of neither the wanted polymorph (cubic blocks as shown in the next figure) or the solvated structure occurs due to a lack of shear rate to overcome the metastable zonewidth as previously discussed.
At equilibrium, the product slightly grows for a few minutes to reach equilibrium state as stated by point number 4. In this way, the optimized thermodynamic route using the parameter settings as shown in the table is obtained.
Once this was achieved, we documented (doi/abs/10.1021/acs.cgd.8b00928) the use of static mixers before entering the cooling phase. This change un hydrodynamic conditions, as discussed previously has a drastic effect on the nucleation rate: up to a million of crystals is produced per mL per secod of slurry. Due to the conservation of the overall mass balance, this results then in a drastic decrease of the average particle size down to a average size of 45 µm and a very narrow particle size distribution as indicated by the error bars in the next graph where we have applied from 1 to 4 of these static mixers prior to cooling as opposed to the datapoint with no use of these mixers (point 0):
Therefore, for any crystallization based on cooling crystallization we recommend to first aim for a construction of the optimal thermodynamic pathway using our reactors focusing on stable and reproducible results. Once this is optimised, there is always the hydrodynamic optimisation that can be applied in order to finetune the eventual result.
A second degree of freedom in playing around with the hydrodynamics to have a big impact on the final crystal size is the use of antisolvents. A very good example is the crystallization of itraconazole, where an injectable formulation has been generated using our antisolvent setup in the SCT-LAB environment. While maintaining excellent crystal properties our technology allow to drastically reduce the used solvents and especially the surfactants needed to stabilize the product. Pinpointing the excellent mixing capacities achieved in our technology. This paper is open access and can be downloaded by clicking on this DOI: https://www.mdpi.com/1999-4923/16/3/376.
Screening crystallization parameters for targeted particle size distribution
Directly achieving the optimal crystal size for a solute in solution
Introduction
The development of a completely new technology does of course not come by itself. Many years on research on a specific molecule, Brivaracetam, has led to the creation of the understanding how to generate crystalline material while flowing heated solution through narrow capillaries. A large part of this research journey has been documented and published in Crystal Growth & Design, also a patent application WO2019215022A1 was submitted based on these results.
In general, our findings pointed out that solutes in solution can start to nucleate very rapidly inside reactors with reduced internal volume. More specifically, as Brivaracetam is a rather complex molecule to crystallize, we observed the possibility of selection a certain polymorphic form of Brivaracetam to nucleate preferentially. The benefits of these long, elongated reactors with narrow inner diameters and even smaller wall thickness are that the solutions are cooled down in a very controlled way from soluble conditions, through the metastable zone, and into the zone where spontaneous nucleation – whether homo- or heterogeneous – may take place. This cooling down is not affected by the fact that we use flow velocities inside these reactors from 10 to 100 cm/s; hence, the use of relevant flow rates – to obtain desired production rates of APIs – becomes possible. Together with the defined cooling of liquids flowing through our reactors, we have also observed to beneficial influence of occurring shear rate inside our reactors on the width of the metastable zone, resulting in a drastic increase in nucleation rates at identical conditions when increasing the shear rates inside the reactors. A side-effect was the observation of the absence of fouling during long-term productions of Brivaracetam from the start. On a side note, we have not considered fouling during the first years of research as we never encountered any blockages of the tubing, even during long runs. In the paragraph discussing fouling and blockages we will go deeper into the reasons behind the fact that blockages inside our reactors will only occur when several critical factors are or are not considered.
Developing a way to crystallize directly the correct crystal size for a solute in solution
From the start, our philosophy was based on the control of the number of nuclei appearing inside a crystallizing slurry. We had observed in literature several attempts to control crystal growth using difficult crystal growth models in different axes of a crystal, the use of CSTR tanks, etc. None of them we found satisfactory for this goal as it complexifies the process and you always rely on the use of solid seeds of some form and shape that results in a redundant process step if crystals are generated spontaneously. On the other hand, if one would be able to control how much nuclei are generated homogeneously while passing through a reactor, then in a simple, maybe even naïve, calculation, one would be able to predict their size once they have grown to their equilibrium state.
Suppose that you would have an initial solution concentration of 400 mg of solute per mL of solvent. And that at a low temperature solubility is 100 mg of solute per mL of solvent. That would mean that per mL of solvent you can crystallize – when performing for this example a cooling crystallization – 300 mg of crystals. Then, if you have 100 crystals in this slurry, or hundred thousand of crystals, this would then result immediately in completely different particle sizes once these crystals are fully grown.
Table 1: estimation of particle size of crystals as a function of the total amount of crystals present in a slurry for a given concentration and crystal density.
So, for an oral dosage form with average sizes preferentially below the 100 µm mark, anywhere between 105 and 106 crystals produced per mL solvent is to be achieved. Please note that in the above table we assumed both spherical and cubic particles leading to different expected crystal sizes. If we look at estimated nucleation rates for homogeneous crystallization at different conditions we will describe here below, in theory (Mersmann, Crystallization Technology Handbook, 2nd edition, ISBN 0-8247-05828-9, chapter nucleation) a nucleation rate can be expected in between 1012 and 1020 per cubic meter per second, which equals to 106 and 1014 of crystals produced per mL. Comparing both values indicates that whenever we can reach nucleation conditions as set out in Figure 1 and control their evacuation out of the reactors to let the freshly generated nuclei grow in non-nucleating conditions, we would be able to separate nucleation and growth of crystals and target exact reproducible size whenever the passage through our reactors is as homogeneous as possible.
Figure 1: Expected nucleation rates for homogeneous nucleation Bhom as a function of supersaturation and solubility, for molecules n=1, taken from 1
As stated in above figure, solubility and supersaturation are important parameters that rule the occurrence of nucleation. In fact, for a crystalline structure to appear, a treshold energy barrier needs to be overcome in order for the structured material to appear instead of molecules remaining disordered inside the solvent. The nucleation theory is of course already well described, but in general, for a molecule to start nucleating, this energy barrier is most easily depicted using the phase diagram of the solute in solution, as shown in Figure 2. This means that for a solute in solution, to the right of the solid line in Figure 2, needs to be cooled down in order to nucleate. The energy barrier is the most wide for primary homogeneous nucleation, which is nucleation from the solution without any other foreign material present. In the presence of foreign material – impurities, surfaces, etc. – but without any solute-own crystals, primary heterogeneous nucleation takes, with a lower energy barrier to be overcome as for homogeneous nucleation. Once crystals are present in the slurry, these may brake up due to fractures, shear effect, collisions, etc. These are grouped together as secondary nucleation – so with the presence of solute-own crystals in the slurry. Logically, these come at the lowest energy barrier to be overcome.
Figure 2: Solubility C* as a function of temperature T and the metastable zonewidths indicated for primary homogeneous and heterogeneous nucleation and secondary nucleation. Figure related to 1.
Following our philosophy to control the formation of crystals and to maintain the quantity of crystals nucleated, inside our reactors we aim for primary nucleation, whereas the gathering of the slurry coming out of the reactor has to be done in such a way that secondary nucleation is avoided.
To express this metastable zonewidth, at isothermal conditions supersaturation s is defined as the difference between the concentration C of a system and the solubility concentration at that temperature C*. To create a dimensionless number, this difference between C and C*, is divided by C*:
Once the metastable zonewidth is crossed for primary nucleation, the kinetics of nucleation – the number of nuclei generated – is increased by further cooling, generating a higher supersaturation value. As an example, in Figure 3 the difference in metastable zonewidth is shown between the compounds Brivaracetam and Aspirin in their proper solvents2.
Figure 3: Solubility diagrams of Brivaracetam (left) and Aspirin (right), with solubility (orange), experimentally established metastable zonewidth (blue) and indicated supersaturation at which crystallization tests are conducted .
The supersaturation value needed to obtain primary nucleation for Brivaracetam is of 0.6, and experiments can be conducted at concentrations as high as 400 mg/mL, resulting in very high supersaturation values and a large variability in crystal sizes while playing with different conditions can be obtained as published earlier (Rimez et al., Crystal Growth & design 2018, 18, 6431-6439 (doi: 10.1021/acs.cgd.8b00928)). For Aspirin, the metastable zonewidth when dissolved in water/ethanol is much larger, a supersaturation value of 5.7 needs to be overcome to observe nucleation in our reactors, making it for this example difficult to generate working conditions at supersaturations above the optimal value of Brivaracetam (σ = 6.7 instead of 4.6). However, both obtained supersaturations are high and it can indeed be expected that predicted nucleation rates and hence refined particles sizes can be obtained for both examples, with reported particle sizes between 50 and 200 µm for Brivaracetam3 and in used solvent between 400 and 800 µm for Aspirin2. Hence, the key factor to crystallize directly the desired particle size is to nucleate a certain amount of nuclei inside the solution and gather this liquid to let the crystals grow to their equilibrium state, independent of the time required to do so, as long as primary nucleation event only take place inside the specific nucleation reactor. As a side-note: all solution passing through such a reactor needs to undergo the exact same cooling pattern as to homogenize maximally the nucleation rate for the complete production liquid envisaged.
The use of capillary reactors to control the nucleation rate while maintaining uniformity
In order to cool a liquid down not only very rapidly but also in a uniform way, we opted for millifluidic tubing with maximally 1 mm inner diameter. We conclude this after an experimental study on Aspirin (Rimez et az., J Flow Chem 2019, 9, 237-249 (doi : 10.1007/s41981-019-00042-z)) where we experimentally and by simulation demonstrated how a liquid cools down when it is injected at a constant rate inside a tubular reactor of 1 mm having a wall thickness of 150 µm and being placed in a water bath of at least 100 times the volume as opposed to the volume of the reactor. For the study on Aspirin, we used a reactor of 3 m length which corresponds roughly to 3 mL of volume; this reactor was placed inside a 1 L water bath that was set at the desired temperature. Then we measured using thermocouples at different distances the temperature inside the reactor while liquid was flowing through the reactor. This liquid was preheated at the desired solution temperature for the Aspirin solution in ethanol/water (50/50 v/v). this overlapped with the simulate values for the tube center temperature. In the next figure, we show the simulated values for both the tube center and the simulated temperature at the tube wall.
In Figure 4 the liquid entering the reactor is indicated at distance zero. The temperature of the liquid drops drastically at the tube wall (dashed black lines), followed by the temperature in the center (solid black line). The dots in orange indicate when the liquid passes the solubility temperature of the concentration of 200 mg/mL; the blue dots correspond to the metastable zonewidth. It can therefore be observed that after a distance shorter than 50 cm inside the tubing the solution is already in conditions where spontaneous nucleation will take place, the remainder of the time inside the tubing, 4.7 s in total at ruling flow velocities, renders the possibility to produce a large quantity of nuclei in order to reach the desired amount of crystals. These short residence times prevent crystals to grow to sizes that might become difficult to handle.
Figure 4: Calculated spatial and temporal evolution of temperature (black lines) and supersaturation values s (green lines) at the centerline (solid lines) and at the wall (dashed lines) for an Aspirin solution of 200 mg/mL 50/50 vol% ethanol/water flowing at a rate of 30 mL/min inside a 1 mm ID tubing sitting in a water bath held at 10°C. Starting solution temperature was set at 60°C.
Any crystal growth is therefore also conducted outside of our reactors. In general, the next schematics represent very well how we perform crystallizations, see Figure 5: a heated liquid is injected at a constant rate inside a tubular reactor sitting at a low temperature at which the nucleation should take place. Before this cooling sown there is a possibility to alter flow hydrodynamics inside the tubing or add an antisolvent – these topics will be discussed later. While flowing through the tubing all liquid is always cooled down in exactly the same way: laminar flow conditions are reached for the combination of flow rates and tubing diameter we apply, therefore plug flow conditions are reached and all material is constantly moved forward through the tubing. Inside the phase diagram we go as fast as possible to the desired nucleation temperature (horizontal arrow from high to low temperatures in the phase diagram). At this point, the nucleation is already started, indicating a drop in solute concentration (vertical arrow in the phase diagram) while the liquid is still flowing throught the tubing. Then, at the end of the tubing, the slurry containing fast growing crystals can be gathered inside a waiting tank for the crystal growth to be fulfilled or, when the growth kinetics allow this, directly on a filtration unit. For crystal growth conditions, any temperature might be selected.
Figure 5: Schematic representation of the cooling crystallization approach of Secoya's Crystallization Technology (SCT).
Benefits of capillaries: solid particle mobility and shear rates
The uniformity in the cooling of liquids flowing through the tubing but also the development of a laminar flow regime inside the capillaries is beneficial for SCT. As the estimated Reynolds numbers are well below 4000, see Table 2, generally considered the threshold for turbulent flow, laminar flow behavior is to be expected. On the other hand, capillary reactors possess other beneficial aspects that are in use inside our reactors.
Table 2: typical flow rates with corresponding flow velocity inside capillary reactors and estimated Reynolds number using water at room temperature as basis for calculation.
Flow rate
mL/min
10
20
30
Flow velocity
cm/s
21,2
42,4
63,7
Reynolds number
20
400
600
Shear rate
s-1
1698
3395
5093
At usual flow rates inside the reactors, shear rates at the tube are above 1000 s-1. For other types of solid particles flowing through narrow channels under laminar flow conditions and elevated shear rates, it is known that these particles do not migrate towards the channel wall. Most famously is the Fåhræus–Lindqvist effect that describes the migration of erythrocytes to the center of the vessel, leaving only plasma neat the wall of the vessel (https://en.wikipedia.org/wiki/F%C3%A5hr%C3%A6us%E2%80%93Lindqvist_effect). In Figure 6 an artificial vein is shown with hemoglobin flowing through, showcasing the absence of hemoglobine at the tube wall.
When simulating the preferential position of solid particles inside circular tubings under constant flow conditions, Javier Rivero-Rodriguez and Prof. Benoit Scheid of the Université libre de Bruxelles (Rivero-Rodriguez and Scheid, J Fluid Mech 2018, 842, 215-247 (doi: 10.1017/jfm.2018.78)) discovered that small particles, when not subjected to gravity, will migrate under laminar flow conditions to a preferentially eccentric position, away from the tube center. At the tube wall the lowest probability to retrieve a solid particle is observed. This preferential position is shown in Figure 7. It is demonstrated that the difference in flow velocity in the laminar flow regime pushes the particle away from the tube center. On the other hand, the particles bounce off the tube wall, generating an equilibrium position off center. Therefore, as long as the particles are not subjected to gravity, the flow conditions inside of the reactors prevent collisions and deposition on the tube wall, resulting on blockages of the tubing.
Figure 7: Preferential position (black line) of a neutral bubble - solid particle - with particle diameter d (y-axis) inside a tubing with diameter ε (x-axis). Taken from Rivero-Rodriguez and Scheid (doi: 10.1017/jfm.2018.78).
Using Secoya’s Crystallization Technology, a large amount of nuclei are however formed at different conditions, which may provoke coagulation of these particles, very fast crystal growth, etc. Therefore, the use of a certain length for the reactor depends on the trade-off between sufficiently high nucleation rates and avoiding the possibility to block the tubing during operation due to too intense growth for example. The study to find the optimal reactor dimensions is an integral part of the development cycle of the process at the laboratory scale.
Another benefit of the tubular reactors is the high shear rates obtained inside. Mura and Zaccone have described mathematically the preferential nucleation conditions for particles under flow conditions and high shear rates (Mura and Zaccone, Phys Rev E 2016, 93, 042803 (doi: 10.1103/physRevE.93.042803)). in a joint study between Zaccone, ULB and Secoya, experimental data further evidenced this beneficial effect of shear rate in flow on the nucleation rate of a solute in solution (Debuysschère et al., Cryst Growth Des. 2023, 23, 4979-4989). In this work a cooling crystallization of Glycine in water was conducted. All Thermodynamic variables were kept constant (solution concentration and temperature, residence time at low temperature, nucleation temperature, etc.). The only variable was a change in shear rate while flowing through the reactor. This was achieved by varying the capillary diameter, flow rate and reactor lengths to obtain always the same thermodynamic conditions. The result was that the measured nucleation rate, shown in Figure 8a goes through an optimal value at a shear rate of 3000 s-1 and Reynolds number of 340 for 98% pure Glycine, whereas 99.5+ % pure Glycine had its maximum at a slightly lower shear rate of 1700 s-1. Other evidences on the influence of more localized shear rates generated inside the tubing in different studies (different studies already referenced here above) lead to further evidencing the large impact of shear rates on the nucleation rate of a solute in solution while cooling down. For any cooling crystallization study, the shear rate influence is part of the development cycle for optimization of the crystallization of any molecule.
Figure 8: a) Normalized nucleation rates (Jexp-Jthe) as a function of ruling normalized shear rate for 98% pure Glycine (left) and 99.5+ % pure Glycine (right). b) microscopic images of exemplary crystals obtained during experiments. Taken from Debuysschère et al. (DOI:10.1021/acs.cgd.3c00232)
Conclusions
Secoya’s Crystallization Technology is based on the adaptation of the size and shape of tubular reactors to the speed of nucleation of solutes in solution. The overall short residence times and uniform cooling conditions inside the reactors result in the control of primary nucleation, enabling a prediction of the final particle size of crystalline material after complete growth of the crystals, outside the reactor in a collecting vessel. Focusing only on nucleation in flow conditions also avoids blockages during production, as nuclei inside the reactors will not be able to migrate to the tube wall resulting in blocked tubings. The high shear rates obtained inside the reactors have an extra beneficial effect on the nucleation rate.
Understanding API crystallization process and its challenges
What is API Crystallization?
API crystallization refers to the process of transforming the active pharmaceutical ingredient (API) of a drug from a solution into a solid crystalline form. This is a crucial step in drug manufacturing because the crystalline form of an API can significantly influence its stability, solubility, uptake in the human/animal body and overall effectiveness. Crystallization also bridges the drug substance manufacturing and the drug product manufacturing towards its final application as a medicine. The process involves carefully controlling parameters such as temperature, solvent composition, and concentration to ensure the formation of crystals with desired properties (ex. crystals size, distribution).
Why crystallization is crucial in drug product manufacturing?
Crystallization is crucial as the final step in drug product manufacturing because it directly affects the purity, stability, and reproducibility in production.
Crystallization helps in purifying the active pharmaceutical ingredient (API) by removing impurities. It ensures that the drug substance is consistent in its chemical composition, which is essential for the safety and efficacy of the medication
Crystalline forms of APIs are generally more stable than their amorphous (non-crystalline) counterparts. A stable crystalline form ensures that the drug has a longer shelf life and maintains its therapeutic effectiveness over time. Also the selection of the most stable polymorphic state – when more than one crystalline structure exists for one single molecule – is important to reach the highest possible shelf life.
Crystallization processes can be standardized to produce consistent batches of the API. This reproducibility is critical for ensuring that every dose of the drug performs the same way, which is a key requirement in pharmaceutical manufacturing.
Batch crystallized drug substances from solution
Crystallization in a large batch reactor in a manufacturing process is conducted in such a way that any variability in between two produced batches is reduced to an absolute minimum. In order to achieve this feature inside large tank sizes, the API is dissolved at elevated temperatures. While gently cooling, a preset quantity of solid API is added as very fine sized particles – called “seeds” – already having the features of the desired polymorphic form. During cooling, the API in solution will adhere to the crystalline seeds to generate grown crystals at the lowest possible temperature. To maximalize the efficiency of the process at the end usually an antisolvent is added to promote adhesion of the remaining API in solution to the crystals.
If this is executed in a very standardized way, the variability in between different produced batches is acceptable to be further treated downstream in the drug product manufacturing process steps.
What are the important parameters for the crystalline API in drug product manufacturing?
Once the crystalline API from the drug substance production is generated, during the drug product manufacturing, focus is set on the actual application of the API and its formulation. Other parameters come into play like the physical properties size and shape of the crystals, making a large part of the critical material attributes (CMA) of a drug product. Size, size distribution and shape of the crystals determine the actual drug application, dissolution and bioavailablity, dose uniformity, processability of the drug product:
The size of the crystals determines how quickly they dissolve in the body. Smaller crystals generally dissolve faster due to their larger surface area relative to their volume, which can improve the drug’s bioavailability—how effectively it is absorbed and used by the body. A uniform size distribution ensures that the dissolution rate is consistent, leading to predictable drug performance and therapeutic outcomes.
In drug manufacturing, consistent crystal size and distribution help ensure that each dosage form (like a tablet or capsule) contains the same amount of active pharmaceutical ingredient (API). If the crystals vary widely in size, it can lead to uneven distribution of the API in the dosage form, resulting in variability in drug potency and potentially impacting patient safety.
Crystals with a narrow size distribution are easier to handle and process. They flow more uniformly through manufacturing equipment, mix evenly with excipients (inactive ingredients), and compress more consistently into tablets. This reduces the risk of production issues like segregation (where particles separate based on size), uneven tablet weights, or poor compaction, leading to more efficient and reliable manufacturing processes.
The size and distribution of crystals can affect the physical and chemical stability of the drug. For example, larger or irregularly shaped crystals might be more prone to breaking down or undergoing unwanted transformations, which could compromise the drug’s stability and shelf life. Consistent size and distribution help maintain the integrity and stability of the drug over time.
Crystallization conditions, including the size and distribution of crystals, can influence which polymorphic form of the API is produced. Different polymorphs can have different solubility, stability, and bioavailability. A controlled crystallization process that produces a uniform size distribution helps in consistently obtaining the desired polymorphic form, which is critical for maintaining drug efficacy and safety.
Challenges for batch produced crystalline API substances towards the change to drug product
While seeded batch crystallized APIs are in the correct polymorphic state and production is sufficiently consistent, the produced drug substance usually needs to be re-engineered towards its desired size and shape for its application. Hence, the addition of one or more additional process steps besides classic seeding, growing, filtration and drying are necessary: changes in shape and size are done with different grinding and milling techniques- wet or dry – followed by seeving steps to obtain the desired size and particle size distribution, avoiding a too large variability in between the smallest and largest crystals present in the drug product powder prior to final formulation.
Although applied consistently for nearly every produced API substance, any additional process step is very costly due to inherent losses of drug product for each different additional step. Also recycling of lost material during these steps comes at a high cost to work up this product to desired properties, if even possible.
At Secoya, we have developed a unique crystallization process that allows to reduce the total number of process steps to its bare minimum from drug substance to drug product. We bring the drug substance in solution, and we generate the final CMAs of the drug product in one single process step; followed by filtration and drying. No hustle anymore to generate correctly sized seeds, no more grinding, milling and sieving of the drug products. As a true benefit, our technology bridges completely the drug substance manufacturing with the drug production facility with the direct use of the manufactured API powder.
Join Secoya Technologies at CPHI Milan from October 8th to 10th.
Secoya Technologies has confirmed its participation in the upcoming CPHI set to be held in Milan from October 8th to 10th.
Meet Bertrand Loriers and Bart Rimez to discover our latest API encapsulation and crystallization improvements.
About CPHI
The exhibition, which will take place from 8-10 October 2024, is being hosted in Milan for the second time in three years in recognition of the massive pharmaceutical ingredients and manufacturing industry in the region.
Italy is one of Europe’s largest producers and exporters of ingredients – exporting around 85 percent to North America, the EU and Japan, according to CPHI research. The Milan region is at the centre of Italy’s pharmaceutical base, with over 50 facilities in the Lombardy region alone.
Read more
WEBINAR: Transforming your crystallization process (Recording available)
Screening crystallization parameters for targeted particle size distribution might be challenging and time-consuming.
Join this webinar to discover how Secoya’s Crystallization Technology transforms the process with spontaneous nucleation, making it faster and more efficient. During this LIVE session, the setup of the instrument will be shown for both cooling and antisolvent crystallization. At the end of this webinar, Bart Rimez our technology lead will explain the overall philosophy of Secoya.
Book your seat and learn how the SCT technology can be extrapolated to other molecules, how to obtain the required particle size distribution with the setup of experimental designs and how to upscale it using the SCT-PILOT unit.
Speakers
Bart Rimez, Secoya Co-Founder and Crystallization Tech Leader
THIS WEBINAR HAS ALREADY TAKEN PLACE
If you couldn’t join us for our live webinar “Transforming your crystallization process” or if you just want to experience it again, you can watch it again!
PUBLICATION: Continuous Microfluidic Antisolvent Crystallization as a Bottom-Up Solution for the Development of Long-Acting Injectable Formulations
Nandi, S. et al. Continuous Microfluidic Antisolvent Crystallization as a Bottom-Up Solution for the Development of Long-Acting Injectable Formulations. Pharmaceutics 2024, 16, 376. https://doi.org/10.3390/pharmaceutics16030376
Abstract
A bottom-up approach was investigated to produce long-acting injectable (LAI) suspension-based formulations to overcome specific limitations of top-down manufacturing methods by tailoring drug characteristics while making the methods more sustainable and cost-efficient. A Secoya microfluidic crystallization technology-based continuous liquid antisolvent crystallization (SCT-CLASC) process was optimized and afterwards compared to an earlier developed microchannel reactor-based continuous liquid antisolvent crystallization (MCR-CLASC) setup, using itraconazole (ITZ) as the model drug. After operating parameter optimization and downstream processing (i.e., concentrating the suspensions), stable micro suspensions were generated with a final solid loading of 300 mg ITZ/g suspension. The optimized post-precipitation feed suspension consisted of 40 mg ITZ/g suspension with a drug-to-excipient ratio of 53:1. Compared to the MCR-CLASC setup, where the post-precipitation feed suspensions contained 10 mg ITZ/g suspension and had a drug-to-excipient ratio of 2:1, a higher drug concentration and lower excipient use were successfully achieved to produce LAI microsuspensions using the SCT-CLASC setup. To ensure stability during drug crystallization and storage, the suspensions’ quality was monitored for particle size distribution (PSD), solid-state form, and particle morphology. The PSD of the ITZ crystals in suspension was maintained within the target range of 1–10 m, while the crystals displayed an elongated plate-shaped morphology and the solid state was confirmed to be form I, which is the most thermodynamically stable form of ITZ. In conclusion, this work lays the foundation for the SCT-CLASC process as an energy-efficient, robust, and reproducible bottom-up approach for the manufacture of LAI microsuspensions using ITZ at an industrial scale.
WEBINAR: Case study – Single crystal formation in core-shell microcapsules
This webinar introduces the latest advances in core-shell microcapsule technology. Discover how microcapsules are used as a versatile tool in drug delivery, encapsulation, crystallization, compound characterization, and more.
Explore the challenges of traditional microencapsulation methods and the transformative potential of microfluidic technology in producing precise, uniform microcapsules. Gain insights into the advantages of UV light crosslinking for rapid and solvent-free capsule production (Methacrylate-based resins, PEGDA, PEGDMA).
In the case study discussion of the program, a particular emphasis will be placed on the use of microcapsules for the screening of crystallization conditions.
Learn how to generate hundreds of identical UV-crosslinked microcapsules per second, produced by Secoya Technologies’ RayDrop and its all-in-one platform.
Speakers
Joseph Farah : Microfluidic Application Engineer·
Marie Mettler : R&D Engineer – Secoya Technologies
Meet us at the Flow Chemistry Pavilion at ACHEMA 2024, 10 – 14 June 2024 Frankfurt am Main (hall 8 booth E64-020)
Join us for the 3rd edition of the Flow Chemistry Pavilion at ACHEMA 2024!
The Flow Chemistry Pavilion brings together 25+ Companies working in the area of Flow Chemistry & gives visitors the opportunity to meet the Flow Community at a Global Tradeshow. Alongside the five-day exhibition will be a two-day Symposium, enabling visitors to learn what’s new in the area of Continuous Manufacturing.
Where to find us: hall 8 booth E64-020.
Secoya at Formulation & Delivery to present Crystallization and Encapsulation technologies
Secoya Technologies has confirmed its participation in the upcoming Formulation and Delivery Congress set to be held in London from April 26th to April 28th.
Meet Diala Youssevitch, Adrien Dewandre and Bart Rimez to discover our latest API encapsulation and crystallization improvements.
About Formulation and Delivery
Formulation & Delivery 2024 aims to connect pharmaceutical & biotech representatives as well as academia for high-level discussions on the latest innovations in pharmaceutical drugs formulation, drug delivery, inhaled therapeutics & RNA development.
ACS publication: Parameter Optimization from Laboratory- to Kilogram Pilot-Scale Operations in Crystallization
BREAKING NEWS! Our recent work on the continuous nucleation process of lactose and adipic acid has been published on the American Chemical Society website.
Read our publication (https://doi.org/10.1021/acs.oprd.3c00132) to discover how Secoya Crystallization Technology (SCT) and its equipment allow crystallization experts to obtain a set of optimal parameters from a small amount of material to be used seamlessly at a pilot scale. A scalable process enabling full continuous production of nucleated slurry.
Secoya is at BioFit Event in Marseille at a fantastic booth organised by the AWEX! Great opportunity to see and discuss the benefits of our technologies!
The BioFit event serves as an ideal platform for Secoya to network with industry leaders, investors, and fellow innovators, fostering collaborations that could pave the way for transformative advancements in biotechnology.
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CRYSTA’DAYS – Two-day Crystallization dedicated event hosted by Secoya Technologies
In November 2023, a two-day event orchestrated by Secoya gathered a community of experts in crystallization in Louvain-La-Neuve. During these two dedicated days technology leads, esteemed researchers and academics showcased their groundbreaking work captivating an audience of industry experts coming from all around Europe.
Title
Speaker
From microfluidics at TIPs to Secoya
Prof. Benoit Scheid (ULB)
Introduction to Secoya
crystallization technologies and crystallization
Complete the form to unlock access to all the presentations!
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BACTERIA AND YEAST ENCAPSULATION METHOD IN SMALL DOUBLE EMULSIONS
Abstract
The precise manipulation, quick cultivation, and delicate detection of yeast and bacteria are crucial in microbiology and biomedicine for behavior monitoring, identification of phenotypes, physiological assessment, and molecular analysis.
Microfluidic droplets have proven to be an effective method for encapsulating yeast and bacteria in highly monodisperse droplets for high-throughput screening and analysis of their phenotypes, subcellular structures, genes, and metabolites.This application note details the encapsulation of the yeast strain S. cerevisiae CEN.PK 113-7D and the bacterial strain L. cremorsi MG1363_GFP in double emulsions of 42 µm size using the Cell Encapsulation Platform, resulting in Microencapsulation of Bacteria and Yeast.
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Single crystal formation in core-shell capsules (ChemComm Oct.23)
Imagine, that you can easily produce solid microcapsules acting as independent crystallization vessels for both small and macromolecular molecules. Even more, imagine their remarkable stability allows you to handle those microcapsules and transport them without any limitations or constraints.
This is exactly what has been demonstrated by our team in this new publication entitled: “Single crystal formation in core-shell capsules” (ChemComm Oct.23). A unique process made possible only with Secoya’s Raydrop® innovative device.
Curious about this breakthrough microfluidic process? Download the publication or contact us: https://lnkd.in/e76faVcc
BREAKING NEWS: Secoya Technologies and ULB achieved a patent milestone in India.
This momentous achievement allows Secoya Technologies to explore and expand into new markets.
NEW Application Note: A quick and efficient double emulsion generation method for flow cytometry droplet sorting
In this paper, we describe the encapsulation of a fluorescent strain of Escherichia coli bacteria in w/o/w double emulsions and flow cytometry droplet sorting using a flow cytometry cell sorter (also commonly known as FACS). The Secoya’s RayDrop platform (including the RayDrop® device and distributed by Fluigent) allows the bacteria to be compartmentalized within a protective shell and ensures compatibility with the sorting device. The platform generates double emulsions in one step, scaling the production of common two-step double emulsion generation methods by up to ten times. Several hundred microliters of emulsions can be produced in 30 minutes, and multiple conditions can be tested within a single day, compared to a week with traditional methods. In addition, the platform integrates fluidic, pneumatic, and optic solutions, and does not require complex fabrication steps nor surface treatment. This application note was written in collaboration with Delphine Lestrade (head of the flow cytometry platform at Toulouse White Biotechnology, TWB) and Sophie Lajus (researcher at the Toulouse Biotechnology Institute, TBI)
WEBINAR: Upscaling of the crystallization process towards a full continuous crystal production
About this Webinar:
During this webinar, Bart Rimez our expert in Crystallization, demonstrated how the Secoya Crystallization Technology (SCT) process can be seamlessly scaled up from laboratory to production scale by tightly controlling various parameters.
At the laboratory scale, a set of parameters is identified and enables the production of the desired particle sizes and distributions. This same set of parameters can then be directly transferred to pilot-scale or production-scale processes, thus providing a reliable and efficient means of scaling up the SCT process.
Speakers:
Bart Rimez, PhD | Co-owner And Technology Lead at Secoya Technologies Diala Youssevitch | Technical Sales Manager
Invited speaker: Jan Vogeleer | Managing Director, Fette Compacting
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NEW White paper: The upscaling of lactose crystallization towards a full continuous crystal production
This white paper offers valuable insights into the upscaling of lactose crystallization for achieving fully continuous crystal production. By downloading it, you’ll discover how to optimize the parameters at the lab scale, enabling labs to achieve consistent results in terms of particle size and distribution at the pilot and even production scale when reactors are placed in parallel.
Secoya will be attending Formulation & Delivery 2023 (25 – 26 May) | London, UK to present Crystallization Technology
Our particle engineering experts will be in London end of May with other leading experts in pharmaceutical science to present Secoya’s Crystallization Technology (SCT) during the Formulation and Delivery addressing the critical strategic advances and technical innovation in formulation, drug delivery and drug product development. Also, attending the Formulation and Delivery Congress? Stop by our booth (#17) to discover our unique technology that enables a fast and easy scale-up of the crystallization process thanks to tight control of specific parameters such as particle size or distribution and that remain the same from lab to production scale.
SCT Family: equipments from lab to industrial scale
From the laboratory setup to the industrial-scale equipment, Secoya Technology has developed a full range of products that use the same parameters set all along the scale-up process:
SCT-LAB
This bench equipment has everything to make your life easy for fast crystallization screening. The batch type approach allows fast screening whilst assuring low product consumption.
SCT-PILOT unit allows to fully explore the design space of a crystallization process, performing controlled long-term runs on one single reactor on the same experimental conditions as the SCT-LAB equipment.
The cGMP SCT-ICE unit is designed for easy access and exchange of modules, depending on the customers needs. Versatile, it enables the production of different compounds by simply exchanging the modules in between production runs.
Unlike any alternative process, the Secoya crystallization technology is based on the precise control of spontaneous nucleation through the use of millifluidic tubular reactors upon cooling and different antisolvent addition possibilities. Using such capillaries, any parameter influencing the nucleation is ideally optimized and controlled.
Secoya’s crystallization technology is unique, enabling crystallization of molecules in a single process step avoiding difficult work-up when performed with conventional batch systems.
New White paper: 5 USE CASES OF CONTROLLED DOUBLE EMULSIFICATION PROCESS FOR ENCAPSULATION
By presenting five various possibilities for microcapsules production (Chitosan, PLGA, Polymethacrylate resin, Alginate, Agarose) using the double emulsion Raydrop® integrative platform, this white paper outlines the versatility of Secoya encapsulation technology.
Secoya Technologies raised €1M to commercialize its next-gen microfluidic equipment
We are delighted to announce the completion of our fundraising for an amount of €1million.
Bertrand Loriers, CEO commented: “This is a new milestone for Secoya. It will allow us to move to a new level of growth while we have a better knowledge of our customers and potential markets. These resources will indeed be allocated in a relevant way to our commercial deployment and to the operational reinforcement required to support our development. We seize the opportunity to thank our shareholders for trusting us.”
With a board of industry veterans, including former Delphi Genetics CEO Cédric Szpirer, Univercells co-founder Jose Castillo, Jean-Marie Solvay, and Stéphanie Hoffmann-Gendebien, Secoya already counts several major pharma companies among its clients in Europe and is expanding to the US.
Secoya Technologies announces the coming release of the InstaDrop
All the team is thrilled to announce in the coming weeks the release of the 𝗜𝗻𝘀𝘁𝗮𝗗𝗥𝗢𝗣, the most versatile instrument to set up precise, repeatable and cost-effective API encapsulation processes.
Broadly used in the pharmaceutical industry, encapsulation of active ingredients in microparticles allows to improve their delivery and absorption. Nevertheless, not all solutions guarantee a high control of the particle size Aand a robust long-run production process.
By its conception, the 𝗜𝗻𝘀𝘁𝗮𝗗𝗥𝗢𝗣 allows the easy control of flow and particle size. And as it includes our 𝗥𝗮𝘆𝗱𝗿𝗼𝗽® technology, the 𝗜𝗻𝘀𝘁𝗮𝗗𝗥𝗢𝗣 is perfectly suited for bead and capsule microencapsulation, preformulation screening and small batch production.
WEBINAR: Double emulsion production compatible with FACS for cell sorting application
How to efficiently encapsulate biological materials such as cell inside double emulsions, in an easy and robust way, which are totally compatible with (FACS) Fluorescence- Activated Cell Sorting.
FACS appears as a convenient tool to indicate the production of a molecule of interest. Combined with Combined with Raydrop® and LineUp® microfluidics technologies and more exactly encapsulation of cells in double emulsion, it offers a lot of potential to study single cell expression.
If you are looking for solutions and metod to improve performance in generating double emulsion compatible with FACS for your applications, this online workshop may be of benefit to you.
Meet Secoya’s team at CESPE conference, September 15th!
Secoya Technologies will participate at the next CESPE (CENTRE OF EXCELLENCE SUSTAINABLE PHARMACEUTICAL ENGINEERING & MANUFACTURING) conference titled Manufacturing Innovations For a Sustainable (Bio)pharmaceutical Industry.
If you want to discover more about our technologies or meet our microfluidics experts, do not hesitate to contact us at info@secoya.com.
Secoya Technologies exclusive presentation at the CGOM14 conference
We are delighted to announce that Secoya Technology has been selected to present its work on the high throughput single crystal formation in core-shell capsules.
Our R&D engineer Marie Mettler will present a new approach based on the use of the Raydrop®, our emulsification generator capable of producing highly controlled double emulsions of core-shell type 3,4. This system allowed us to produce microcapsules with an undersaturated liquid core confined in a solid polymer shell at a rate of several hundred capsules per second, each acting as an independent vessel for the crystallization of single crystals.
About CGOM14
The International Conference on Crystal Growth of Organic Materials (CGOM) brings together scientists already experienced or beginners, to present and discuss their current work and also to identify new challenging research fields of industrial interest. The CGOM14 offers an informal atmosphere for networking and meeting international scientists from industry and academia.
WHEN?
Sunday, 11 sept 2022 – Wednesday, 14 sept 2022
WHERE?
VUB building Pleinlaan 2, 1050 Brussels
WEBINAR: SCT-LAB laboratory setup (LIVE DEMO), the first step to optimize your crystallization process
About this Webinar:
This webinar aims to present the SCT-LAB laboratory setup which has everything to ease the fast crystallization screening. Indeed, using the SCT-LAB allows the study of correct polymorph nucleation, operational zonewidth determination, test reproducibility and influence of parameter variability, robustness of ruling conditions, yield, and many more.
DATE: Wednesday May 25th TIME: 5 pm CET
Speakers:
Bart Rimez, PhD | Co-owner And Technology Lead at Secoya Technologies Bertrand Loriers | CEO at Secoya Technologies
During this Webinar you will discover…
– How easy is the SCT-LAB setup
The SCT-LAB setup is fast, simple and fits in all classic fume hoods, isolators, confined spaces, and so on. Inter-test cleaning of the reactor setup is easy and straightforward. Different types of mixers exist for cooling and antisolvent crystallization experiments.
– How you can optimize and control the nucleation by using the SCT-LAB
Unlike any alternative process, the Secoya crystallization technology is based on the precise control of spontaneous nucleation through the use of millifluidic tubular reactors upon cooling and different antisolvent addition possibilities. Using such capillaries, any parameter influencing the nucleation is ideally optimized and controlled.
Secoya Technologies will participate at the next CPhI Summit in Milan from November 9 to 11, 2021. If you want to discover more about our technologies or see our products in real life, come and meet us at out booth 10K90 (Pavillon PMEC)!
If you would like to meet with one of our technology experts on site, do not hesitate to contact us at info@secoya.com.
Looking forward to meeting you!
Secoya celebrates its 2nd anniversary!
Happy birthday to Secoya! It has already been 2 years since the founding fathers of Secoya officially dived into the thrilling adventure of a spin-off company!
This is a prefect occasion to recognize all the hard work that allowed the launch of this innovative project. But it does not end with that as Secoya would not be the rising company it is today without all the persons who contributed to its growth. We celebrated this occasion by presenting the products we have developed over the last two years to all our investors, family, friends and partners. To every single one of you: thank you!
We are very grateful for having celebrated our birthday with all of you on a wonderful location, accompanied with bubbles, sunshine and a rainbow
The SCT approach to crystallization
In a White Paper we described earlier what the advantages of the use of Secoya’s Crystallization Technology (SCT) are to tame the nucleation of a material in solution inside a crystallization reactor as designed by Secoya [1]. Several advantages do exist: control of final crystal size, correct crystal form, inherent narrow size distributions, etc. But how exactly do you start using the technology, and how long does it take to develop a crystallization routine using the SCT technology?
Secoya Technologies will participate in the next CCP Summit from March 23 to 25, 2021. Bart Rimez, co-founder and Technology Lead, will give a presentation on the Secoya Crystallization technology.
Publication on Raydrop
Adrien Dewandre and Youen Vitry, Technology leads at Secoya, and Benoit Scheid, Chairman of the Board of Secoya and Maître de Recherche FNRS at ULB, were involved in an experimental and numerical study of the Secoya droplet generator, the Raydrop. Their work on “Microfluidic droplet generation in a non-embedded co-flow-focusing using 3D printed nozzle” is published in the journal Scientific Reports.
Secoya-Fluigent Webinar on double emulsion
28/10/2020
On November 17rd at 5 pm, Youen Vitry, co-founder and Encapsulation Technology Lead, will give a Webinar in collaboration with Fluigent on the Raydrop technology for the generation of double emulsion.
Secoya-Fluigent Webinar on the Raydrop technology – Replay
28/10/2020
On June 23rd, Adrien Dewandre, co-founder and Encapsulation Technology Lead, has given a Webinar in collaboration with Fluigent on the Raydrop technology for the droplet generation.
Secoya at CPHi Festival of pharma 5-16 October 2020
26/08/2020
Secoya Technologies will participate in the next CPHi Festival of Pharma from October 5 to 16, 2020. If you would like to know more about one of our technologies, do not hesitate to request a virtual meeting through the CPhI platform.
Publication of complex systems modeling
26/08/2020
Jean Septavaux, Technology lead at Secoya has been involved in the modelling of complex molecular systems with the CSAp lab from the University of Lyon. Their work on “The dark side of disulfide-based dynamic combinatorial chemistry” was published in the journal Chemical Science.
Secoya at Virtual Process Show 8-11 September 2020
26/08/2020
Please find below the timeslots and links to which the Secoya webinar on our crystallization technology will be broadcasted at the Virtual Process Show.
The webinar describes in detail the principles and the unique benefits of this new crystallization technology. It includes also the presentation of the latest results on the technology.
Would you be interested in this new technology ? Please join us at one of the three webinar time slots.
Secoya signs a collaboration contract with a top 5 pharma
03/06/2020
We are pleased to announce that Secoya Technologies has signed an important collaboration contract with a world top 5 pharmaceutical company. The collaboration focuses on the joint use of intensified chemical synthesis and pervaporation technologies developed by Secoya and aims to develop a prototype that fits into the client’s production process.
Hydrodynamics matters to control the crystallization of API
3/02/2020
Dr. Bart Rimez, co-founder and Crystallization Technology Lead, was invited to publish in the Emerging Scientists issue of Journal of Flow Chemistry, coming out beginning 2020. The paper deals with our findings on the synergistic effect of nucleation thermodynamics and hydrodynamics to increase nucleation rate. Read more
Secoya at Flow Chemistry Europe 2020
29/01/2020
Dr Rimez, co-founder and Crystallisation Technology Lead, will be present at the forthcoming conference, Flow Chemistry Europe 2020, 3-4 March 2020, Cambridge (UK). Dr Rimez will give a lecture on the development of capillary crystallisation reactors.
Worldwide distribution of the droplet generator RayDrop by Fluigent
28/01/2020
On 28Th January 2020, Fluigent and Secoya Technologies signed an exclusive distribution agreement under which Fluigent is responsible for the marketing and the sales of the RayDrop®, an innovative technology of Secoya dedicated to the production of droplets or particles for multiple applications. More information on the RayDrop on www.fluigent.com.
Intensification for sustainability
13/01/2020
Would it be possible to valorise a waste stream… by purifying another ? Dr. Jean Septavaux, co-founder of Secoya Technologies, co-authored a paper in Nature Chemistry describing a methodology for the convergent purification of electronic and gas waste streams. By using the unique properties of polyamines solutions upon capture of CO2 from car exhaust fumes, the authors manage to separate with a high selectivity the valuables metals contained in a dissolved car battery electrode.
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