EncapsDays 2025 by Secoya

Encaps’Days 2025 is an exclusive gathering of droplet microfluidics experts from across Europe and offers a unique opportunity to exchange insights, address challenges, and share best practices in emulsion production and applications

Louvain-La-Neuve | 10-11 April

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During this two-day event, you will have the opportunity to:

• Find out about the latest advances in the field through talks given by guest speakers from a wide range of research areas.
• Discover droplets microfluidics applications, from biology to fundamental physics, through short technical talks given by Raydrop users from academia and industry.
• Innovations update: Discover the latest advancements in Secoya’s Encapsulation Technology and its transformative potential.
• Hands-on demonstration: Participate in a live demonstration of the fully integrated InstaDrop equipment, showcasing its capabilities and practical applications with single and double emulsions (drugs formulation screening, cells encapsulation,…).
• Networking: Connect with a diverse panel of droplet microfluidics experts for insightful discussions.

Agenda

• DAY 1
• DAY 2

Time	Event
12:00 PM	Welcome and Lunch
1:00 PM	Introduction and Roundtable Discussion (Bertrand / Adrien / Benoît)
1:15 PM	Benoît: Presentation on the History of the Raydrop
1:30 PM	High throughput single crystal formation in core-shell capsules - Prof. Johan Wouters | University of Namur This work extends the scope of microfluidic-based crystallization methods by introducing solid microcapsules. Hundreds of perfectly similar microcapsules can be generated per second, allowing a fast screening of crystallization conditions. X-ray Diffraction analyses can be performed directly on encapsulated single crystals demonstrating the potential of this process for the characterization of compounds, including screening of polymorphism.
2:15 PM	Coffee Break
2:30 PM	Showcase of the Platform and InstaDrop
3:15 PM	Application Talk 1
3:30 PM	Application Talk 2
3:45 PM	Application Talk 3
4:00 PM	Coffee Break
4:15 PM	Generation and dynamics of droplets in microfluidics - Prof. Benoit Scheid | ULB (Brussels) We present and discuss the non-embedded co-flow-focusing configuration for microfluidic emulsification. Experimental results demonstrate the universality of the configuration in terms of the variety of fluids that can be emulsified, as well as the range of droplet size that can be obtained, without neither the need of surfactant nor coating. In a first part, a quasi-static model is developed and shows excellent predictive capability for the size of the droplets. Our results also demonstrate that the mechanism for the dripping-to-jetting transition in this quasi-static limit is intrinsically nonlinear and differs from the absolute-to-convective transition of the Rayleigh-Plateau instability for a jet. In a second part, we focus on the dynamics of droplets and bubbles in microchannels, and present stability maps for the centred position showing that non-deformable objects dominated by inertial effects are only stable if large enough, whereas deformable objects dominated by capillary effects can be stable for much smaller sizes.
5:00 PM	Spatial and temporal control over mechanics in soft dynamic biomaterials - Prof. Roxanne Kieltyka | Leiden University The natural extracellular matrix (ECM) provides a myriad of biophysical and biochemical cues to cells to instruct their behaviour throughout life. While stiffness is widely recognized for impacting fundamental cellular processes ranging from spreading to differentiation, there is a growing appreciation of other mechanical properties that are either time- or strain-dependent such as viscoelasticity, plasticity, or strain stiffening. Dynamic hydrogels consisting of non-covalent or dynamic covalent bonds exhibit these complex properties which are essential to develop synthetic 3D culture substrates that more accurately represent the in vivo condition. In my talk, I will share our efforts in developing supramolecular polymer materials whose mechanics can be controlled in a user-defined manner for various 3D cell culture applications. I will show that the mechanics of these materials can be modulated in space and time with light in different forms to influence the behavior of several cell types commonly used to model development and disease in vitro.
5:45 PM	Closing Remarks and Networking Drink
7:30 PM	Dinner @ Musée Hergé The Hergé Museum, located in Louvain-la-Neuve, Belgium, is a must-visit destination for fans of Tintin and the legendary Belgian cartoonist Hergé (Georges Remi). Designed by architect Christian de Portzamparc, the museum offers an immersive journey into Hergé’s life and artistic legacy, featuring original drawings, personal artifacts, and interactive exhibits. Visitors can explore the creative process behind The Adventures of Tintin and discover Hergé’s impact on comic art and storytelling. Set in a modern and visually striking building, the museum is a tribute to one of Belgium’s most iconic cultural figures.

Time	Event
9:00 AM	Welcome and Coffee
9:30 AM	Benoît / Adrien – Wrap-up of Day 1
9:45 AM	Alexandre Baccouche (Lille) – 30 minutes + Q&A (15 minutes)
10:30 AM	Short Application Talks 4, 5, 6
11:15 AM	High-throughput microfluidic analysis of multicellular spheroids - Léon Rembotte, PhD Student  | CNRS This work extends the scope of microfluidic-based crystallization methods by introducing solid microcapsules. Hundreds of perfectly similar microcapsules can be generated per second, allowing a fast screening of crystallization conditions. X-ray Diffraction analyses can be performed directly on encapsulated single crystals, demonstrating the potential of this process for the characterization of compounds, including screening of polymorphism.
12:00 PM	Closing and Lunch-to-go

Guest Speakers

Benoit Scheid, PhD

A professor at Université Libre de Bruxelles, he earned his PhD in 2004 on hydrodynamic instabilities and received the Ilya Prigogine Prize in 2005. After a postdoc at Harvard on glass processing with Saint-Gobain, he joined ULB in 2011 through FNRS. His research focuses on interfacial dynamics and surface rheology, with applications in material processing, microfluidics, and various scientific fields.

Johan Wouters, PhD

Dr. Johan Wouters is a professor at the University of Namur, leading the Laboratory of Structural Biological Chemistry. His research focuses on structure-based drug design, particularly in cancer and infectious diseases, using X-ray crystallography. He is a member of NAMEDIC and NARILIS, with expertise in enzyme study, pharmaceutical cocrystals, and metabolic pathway inhibitors. With over 8,300 citations and an h-index of 49, he is a recognized expert in crystallography and biochemistry.

Roxanne Kieltyka, PhD

Dr. Roxanne Kieltyka is a professor in the Department of Supramolecular and Biomaterials Chemistry at Leiden University. Her research focuses on developing dynamic biomaterials with spatial and temporal control over their mechanical properties. She has presented her work internationally, including a seminar at Kyoto University’s Institute for Integrated Cell-Material Sciences in June 2024.

Alexandre Baccouche, PhD

Dr. Alexandre Baccouche is a researcher in synthetic biology and molecular programming, specializing in developing molecular approaches to analyze and manipulate biological systems. Based at the Institute of Electronics, Microelectronics, and Nanotechnology (IEMN) at the University of Lille, his work focuses on creating intelligent biosensors and artificial cells that mimic cellular behaviors. His interdisciplinary research integrates microfabrication, microfluidics, and bioengineering, contributing to advancements in biotechnology and materials science.

 

Léon Rembotte, PhD Student

Léon Rembotte is a PhD student at the University of Bordeaux and the French National Centre for Scientific Research (CNRS), focusing on microfluidics and biophysics. Since November 2022, he has been developing microfluidic sorting devices for spheroids and organoids, aiming to create an integrated platform for their production and analysis. His recent work includes a novel drop millifluidic approach for screening and sorting large populations of multicellular aggregates.

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The event is hybrid, offering both in-person and remote participation options. To ensure a friendly and engaging atmosphere with high-quality interactions, we’ve limited the number of spots available. This allows for meaningful discussions, where everyone can actively participate. We encourage you to confirm your attendance promptly to secure your spot.

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The venue

We will be delighted to welcome you to THE GATE, a conveniently accessible venue near the University of Louvain-la-Neuve, located in the vibrant Axis Parc.

The Gate

Rue du Fond Cattelain 2, 1435 Mont-Saint-Guibert

Upscaling the crystallization technology from lab to production scale

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 reactors with its own flow control to generate a productive environment that produces sufficient crystalline material per hour of operation. For example, there is no work-up necessary for the upscaling towards kg productions for lactose. Even more, productions have been performed using two reactors in parallel with the same execution, on 12 liter of solution, with the same setup as mentioned in the previous blog. After filtration and drying the material attributes are exactly in line with previous findings.

         Figure 1: Microscopic images of a Lactose production using two parallel reactors operating at the same time.

Characteristics
Average	54 µm
Standard Deviation	16 µm
D10	37 µm
D50	52 µm
D90	73 µm
Span	0,71
Maximal obtainable yield	82 %
Process yield	95 %
Overall yield with 1 passage	78 %

Table 1: Material attributes of a Lactose Production using 2 parallel reactors.

Lactose is due to its high solubility in water, 150 mg/mL at 5°C an exceptional molecule as the theoretical yield one can obtain is bu 82% for any crystallization process not using antisolvents to pump out any remaining solute in solution. With this in mind, the process itself has a very respectable 95% mass yield. At this production scale, knowing that there are relatively large losses in the growth tank, transfer lines, etc. This is a good value for any process. Lactose comes as a very pure product ad requires only water as solvent so direct recycling of filtered product is absolutely a possibility. The following production design is therefore proposed:

Figure 2: Process Design for the continuous crystallization of Lactose

Batch size determination, production strategy and the resulting construction decide then on the total reactors present on the machine. For Secoya, these reactors are regarded as single-use reactors during one single batch production with no events occurring. The cleanability of these reactors, especially when PFA polymer is chosen as reactor material is considered to be insufficient. For other reactor materials like Stainless Steel a full Clean in Place (CIP) strategy can be put in place.

The production strategy in a company depends then on the annual requested volume and prospection. In this example 100 tonnes of dry product is required per year. The particular client demands batch productions split per week, in three shifts, full arrest over the weekend. A maximum of 40 production weeks is foreseen, the batch size is defined by what is weekly produced, hence 40 batches will be produced per week. One such a production consists of 3 days of passage through the Secoya’s crystallization reactors, followed by a crystal growth cycle inside a waiting tank at 5°C, after which a fully sied candle filter and fluid bed dryer setup finish the product to its dry state.

Now, with a cautious estimation of a full yield – holding recycling into account – of 92 mass%, each production reactor produces 0.75 kg/hr at current set conditions – holding the density of the solution into account. Therefore a total of 47 reactors in parallel are capable of producing sufficient amount of material. Secoya limits to 50 of these reactors in parallel as otherwise the control and monitoring of flow rate and temperature could be at risk, however we are inside this limit for this specific application. The client would use 3 crystal growth tanks for completion. We have demonstrated that the addition of one or more production lines to the growth tank is independent of the final result. This is clearly due to the fact that there is no secondary nucleation occurring once the product exits our reactor: the crystals that have nucleated inside the reactor are simply grown to their equilibrium state.

Production parameters
Solution concentration	850 mg/mL
Total process yield with recycling	92 %
Yield per mL of water	782 mg/mL
Flow rate per reactor	20 mL/min
Density solution	1,25 kg/L
Production rate per reactor per min	12,5 g/min
Production rate per reactor per hour	0,75 kg/hr
Demanded production per year	100 000 kg/year
Production hours all reactors	133 206 hr of production
Weeks of production	40 weeks
Production hours per week for simulation	72 hr/batch
Number of reactor required	47
Batch size dry powder	2600 kg
Treated liquid	4500 L

Table 2: Production parameters at production scale

Conclusion

In conclusion, API crystallization presents multifaceted challenges, including controlling particle size and shape, managing polymorphism, and ensuring purity. Secoya Technologies addresses these complexities by offering versatile equipment capable of handling multiple crystallization modes and a range of particle sizes. Our solutions facilitate the development of complete process cycles from lab to pilot scale and beyond, enabling the direct achievement of optimal crystal sizes for solutes in solution. By leveraging our expertise and advanced technologies, we empower pharmaceutical manufacturers to overcome crystallization challenges, ensuring consistent quality and efficiency in API production.

Blog

Upscaling the crystallization technology from lab to production scale

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22 January 2025

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Development of a complete process cycle from lab to pilot scale and beyond

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20 November 2024

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Versatile equipment for multiple crystallization modes and particle sizes range

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30 October 2024

Training program: Crystallisation towards efficient and sustainable biomanufacturing PROCRYSTAL

Details
Projectcode	3E241077
Acronym	PROCRYSTAL
Period	January 1, 2025 - December 31, 2028
Job Offer	Process development of Biomolecule Crystallization

Project summary

“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.

Financing

Funder

European Union

 

Program

HE-p1-MSCA Collaborative Marie Sklodowska Curie Actions

 

Reference

101169471

 

Promotor

Bart Rimez

Crystallization Technology Lead

Job offer

https://euraxess.ec.europa.eu/jobs/298688

Website

https://procrystal.csic.es/

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.

SCT-LAB Parameters
Solution concentration
Solution temperature
Antisolvent
Antisolvent temperature
Flow rate solution
Flow rate antisolvent
Mixing insert
Reactor volume
Post treatment
Growth temperature
Growth time
Filtration conditions

Results
Crystal size
Crystal appearance
Crystal shape
Crystal size distribution
Powder appearance
Filterability
Powder flow appearance

 

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.

SCT-LAB Parameters
Solution concentration	850 mg/mL
Solution temperature	85 °C
Flow rate solution	20 mL/min
Mixing insert	Specific execution
Reactor volume	7 mL
Reactor temperatue	5 °C
Post treatment	Vessel at 60 rpm
Growth temperature	5 °C
Growth time	18 hrs
Filtration conditions	No washing at present Filter funnel

Results
Crystal size
D10	32 µm
D50	60 µm
D90	90 µm
Standard deviation in between repeated tests	2.1 µm
Crystal appearance	Individual crystals Distinct aspects Transparent surface
Crystal shape	‘tomahawk’ shaped crystals
Powder flow appearance	Some agglomeration Fluffy powder
Filterability	Vacuum filtration fast
Powder flow appearance	Nicely flowing powder

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.

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.

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.

Discover the Secoya Crystallization Technology

Blog

Upscaling the crystallization technology from lab to production scale

Read More

22 January 2025

Blog

Development of a complete process cycle from lab to pilot scale and beyond

Read More

20 November 2024

Blog

Versatile equipment for multiple crystallization modes and particle sizes range

Read More

30 October 2024

7th Annual Inhalation & Respiratory Drug Deliver Conference

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)

Anti solvent Crystallization

• Anti solvent gives a broader distribution (PSD) with smaller particles than cooling crystallization (figure3)

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.

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).

Crystallization mehtod	Initial concentration	Reactor volume	Average particle size
	mg.mL-1	mL	μm
Casted	150	0.5	10 ± 5
	200	0.5	9 ± 5
Filter paper	150	0.5	9 ± 4
	200	0.5	7 ± 3
	300	0.5	8 ± 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

When performing crystallization tests on terephtalic acid dissolved in DiMethyl SulfOxide (DMSO), the cross-flow mixer where both flows are mixed perpendicular to each other, instantaneous demixing occurred immediately leading to instant blockages inside the mixer. The only way to avoid these blockages was the use of a co-flow mixer. When the 70°C solution is injected at a rate of 10 mL/min inside a 30 mL/min water flow a very homogenous crystalline product is obtained at exactly the same average particle size as the wanted benchmark. Specific to our products is the obtained narrow particle size distribution in our setup (the red blocks in the size diagram) as opposed to the benchmark product which has a large amount of big particles (blue blocks), as observed in Figure 4.

Figure 4: detail of the co-flow mixing insert, microscopic images of the Terephtalic acid powder, obtained particle size diagram and average size compared to the benchmark material.

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.

Blog

Upscaling the crystallization technology from lab to production scale

Read More

22 January 2025

Blog

Development of a complete process cycle from lab to pilot scale and beyond

Read More

20 November 2024

Blog

Versatile equipment for multiple crystallization modes and particle sizes range

Read More

30 October 2024

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.

Parameter	Optimal value
Concentration	400 mg/mL
Solution temperature	45 °C
Flow rate	20 mL/min
Reactor volume	7 mL
Reactor temperature	5 °C
Residence time inside reactor	21 s
Hydrodynamic coupling	Straight
Obtained polymorphic form	100 % pure anhydrous, non-solvated structure
Obtained average particle size	190 µm
Calculated nucleation rate	10 000 crystals/mL/s

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

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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.
Mass to crystallize	300 mg
Density of a crystal	1 g/mL
	1 mg/µL
	1 mg/mm3
Number of crystals	volume / mm3	Spherical average length / µm	Cubic average length / µm
100	3	895	1442
1000	0,3	415	669
10000	0,03	193	311
100000	0,003	89	144
1000000	0,0003	42	67
10000000	0,00003	19	31

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.

 

 

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.

 

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.

[1] Rimez at al. J Flow Chem 2020, 10, 241-249 (doi: 10.1007/s41981-019-00069-2)

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.

 

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.

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.

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.

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.

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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.

Purity and Consistency

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

Stability

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.

Reproducibility

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:

Dissolution Rate and Bioavailability

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.

Dose Uniformity

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.

Manufacturing Process Efficiency

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.

Product Stability

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.

Control of Polymorphism

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.

Secoya Crystallization Technology’s unique proposition

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.

Discover the Secoya Crystallization Technology

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30 October 2024

Join Secoya Technologies at CPHI Milan from October 8th to 10th.

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!

WATCH THE RECORDING

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.

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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

Adrien Dewandre : Technology Lead – Emulsification & Droplet generation – 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.

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ACS publication: Parameter Optimization from Laboratory- to Kilogram Pilot-Scale Operations in Crystallization

Secoya at Bio Fit Event (Marseille)

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	Dr. Bart Rimez
The theoretical and mathematical description of nucleation in shear flow conditions	Prof. Alessio Zaccone
The nucleation of molecules in solution using shear flow	Robin Debuysschère
API crystallization with Secoya Technology	Erik ter Voert
Introduction to the new SCT-LAB instrument	Dr. Bart Rimez
Filtration by DrM, Dr. Müller AG	Patrick Morsch
High throughput single crystal formation in core-shell capsules	Marie Mettler
From lab to pilot to scale-up ICE version: translation of conditions + case studies	Bart Rimez

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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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Crystallization

Emulsification

Pervaporation

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Single crystal formation in core-shell capsules (ChemComm Oct.23)

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

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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Crystallization

Emulsification

Pervaporation

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NEW White paper: The upscaling of lactose crystallization towards a full continuous crystal production

Secoya will be attending Formulation & Delivery 2023 (25 – 26 May) | London, UK to present Crystallization Technology

New White paper: 5 USE CASES OF CONTROLLED DOUBLE EMULSIFICATION PROCESS FOR ENCAPSULATION

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.

Read the full article (in French): https://www.lecho.be/entreprises/pharma-biotechnologie/secoya-revisite-les-procedes-de-production-en-biopharma/10448380.html

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

Meet Secoya’s team at CESPE conference, September 15th!

Secoya Technologies exclusive presentation at the CGOM14 conference

WEBINAR: SCT-LAB laboratory setup (LIVE DEMO), the first step to optimize your crystallization process

Secoya at CPhI WW, November 9-11, 2021

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!

The SCT approach to crystallization

Secoya at CPhi discover 17-18 May 2021

Would you like to learn more about our innovative technologies? Join us at the CPhi Discover and come to our virtual booth for a discussion.

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Secoya at CCP Summit 23-25 March 2021

20/01/2021

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.

Register to the webinar : https://www.fluigent.com/resources/webinars/

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.

Access now to the replay : https://webikeo.com/webinar/raydrop-a-universal-droplet-generator-based-on-a-non-embedded-co-flow-focusing/replay

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.

11.09.2020 at 10:00 CET
11.09.2020 at 18:00 CET
12.09.2020 at 02:00 CET

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 28^Th 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.

 Read the article