0:00
So thank you very much for the introduction and the invitation to have a talk here.
0:05
So I think I'm going to fit in right.
0:07
Well after the very interesting talk of Jerome as I think we would fit in more or less into your workflow at some point in time.
0:15
So I'm happy to discuss with you maybe, yeah, maybe later on just maybe as an introduction for Secoya technology on its own.
0:25
So in 2012, I myself and other colleagues joined as postdocs the TIPs laboratory at the Université Libre de Bruxelles, which is a service really focusing on flows, flow chemistry and all kinds of thermophysical changes occurring to flow interfaces surrounding that.
0:47
And so there was several topics that were addressed during those researches that we have done together.
0:56
And all those things culminated in fact into the development of some technologies which we were able to patent and then in 2019 to create the company Secoya Technologies, grouping these technologies together.
1:11
So basically we focus around 4 pillars, of which three of them we have propriety IP, and we sell equipment and perform services from.
1:22
So which one of those is crystallisation, which is on the topic of today.
1:25
The other one is emulsification and encapsulation technology that we have developed.
1:31
And the third one is the pervaporation unit.
1:34
And for process intensification, it's much more a service based approach where we also try to combine those different technologies together into one step to intensify your processes.
1:47
Basically what we try to focus on is to develop technologies that from the start will render you the parameter set that you would need in the end for the upscaling parts during the complete development phase into production of any molecule, of which I'm going to show you an example on later on.
2:05
But you know all that, the moment that you can reduce drastically the complete development time to put a molecule into production will render you a lot of savings in the end.
2:17
Basically our units to do so, our units can be subdivided into two parts.
2:24
So encapsulation and emulsification, divide is really something that we focus on for early stage development like morphologies, compatibilities, solvent screenings, all that kind of stuff in which we did some rather nice effects like doing crystallisation inside of capsules like shown there on the bottom right.
2:45
But for today we will more focus on the crystallisation part in which you really aim to develop a system that from the lab scale will generate you effectively the kind of critical material attributes that you would need in the end for your product.
3:01
So like Jerome has said, we are able with our technology for crystallisation to particle engineer directly during the crystallisation, the kind of particle size distribution, but also density, flowability, et cetera, during the passage through our reactors, which gives us a unique position within inside of the pharmaceutical market as a tech provider.
3:29
Basically at the beginning of the at the beginning of those projects that we did, we only had one prerequisite and that was to be able to perform a crystallisation of any molecule in solution in a continuous flowing system.
3:44
Not directly aiming for continuous manufacturing but being able to perform a crystallisation inside the continuous flowing system.
3:53
And in the end what we ended up with after trying numerous of different technologies already available on the market, et cetera, is in fact the point that we have reduced the scale of a reactor and the residence time inside of the reactor to this to the speed and the kinetics of the nucleation effect itself.
4:13
So rather than going for a seeded crystallisation and just perform the growth of those crystals in a batch and then later on having them to grind and mill and to reshape them back to the size and shape that you want, we really aim for.
4:27
And I don't know how this marker works, but so what we really aim for is to perform spontaneous nucleation inside of the reactor.
4:37
By cooling the reactor very fast, we can in fact have a full control of the temperature revolution of the liquid inside of our reactor.
4:47
And therefore the solute will start to nucleate deep inside the super saturated zone inside its phase flow diagram.
4:54
And therefore as depending then on concentration but also nucleation temperature, we really can determine and control as a function of time the amount of crystals that are produced per millilitre per second.
5:08
So it can range within anything of 50,000 to up to 1 million crystals produced per millilitre per second.
5:14
And because of that constant production rate of those crystals, when we let them grow to equilibrium, in some cases it's so fast that you can immediately filter them out.
5:24
In other cases, you have to gather your material, put them in the CSTR tank to let them grow to equilibrium.
5:31
We can determine the size and the particle size distribution of the materials that come out.
5:40
So basically, what are the important parameters here?
5:46
Of course, like I said, temperature concentration, but also, and that's one of the major benefits of the system is there is an influence of shearing inside of the tubing itself that enhances the nucleation part.
5:59
And we only not only do cooling crystallisation, but we also have a system that can add anti solvents to that to even more steer and to generate also particles and that are less big in size.
6:12
And so therefore we were able already for the same molecules, for example, to control the crystallisation as such that just depending on the parameter set that we put onto that system, we can generate particles of one micrometre up to 400 micrometres with at all cases a very nice controlled polymorphism and the PSD of the system as well with products having excellent flow abilities.
6:36
Now how do we do that exactly?
6:39
Well, this is the case of a molecule Brivaracetam.
6:43
And that's also a very complex molecule because in this case we also required a polymorph selectivity for that molecule because the blue solubility curve represents A solvated crystalline structure, whereas the mid, the stable form and the desired crystalline form is the orange solubility curve there.
7:04
Now what happens inside of our reactors is that we can cool down so fast inside of our reactors that by following arrow one you don't give enough time to the system to nucleate inside of the unwanted solvated polymorphic form.
7:18
But humidity can go down to temperatures below the enantiotropic point at 15 or 10°C Generate there a sufficient amount of crystals that will start to grow.
7:29
You come out of the reactor, the system will glow and gradually heat up again, but you will retain only the right crystal morphism.
7:38
And so for all different projects.
7:41
Sorry for all different projects.
7:43
We really focus then on what is the operational zone with that we can achieve what is the highest possible concentration to avoid blockages of the tubing, what is the lowest possible temperature rendering A sufficient amount of crystals et cetera.
8:00
But then on top of that, we have this 3D approach knowing that shear rates would have a big impact on the crystallisation are the nucleation rates themselves.
8:09
And so by playing around with the hydrodynamics inside of these reactors, we can still play around with the particle size.
8:17
Just to give you an example on Brivaracetam, if you look at the zero point is the point where you have a straight tubing, nothing at all happening inside of the reactor.
8:27
And then we ended up with a good polymorphic form, 200 micrometres average particle size, but too large for a normal or a dosage form.
8:36
And then by introducing a flow perturbations inside of the reactor when we are able to drastically decrease in fact the average particle size.
8:45
So the thermodynamics stay exactly the same throughout all those experiments.
8:49
It's all only the hydrodynamics here that play a role and that enables you to decrease the particle size in the end.
8:56
And so for this particle where AD 90 of another micrometre was required, we were able to do such test.
9:05
So rendering first we generate a stable operational zone window of combining concentration and temperatures and then we put a layer on top of that playing around with the hydrodynamics enabling us to really steer the eventual particle size of the product that comes out.
9:26
Now when you add an anti solvent to the system, we retain polymorphic control, but you also are able to decrease very rapidly and easily the particle, the crystalline particle size of the product that you want.
9:39
In this case again Brivaracetam is used.
9:42
And now to be able to polymorph selective we needed to add hexane as an anti-solvent but cooled at 5°C again because we wanted to have the interfaces in blue and the solute soluting solution in green.
9:58
There we wanted to have those interfaces temperatures that are underneath this antennal and anthropic point, meaning that at these interfaces your material will start to nucleate in the right polymorphic form.
10:11
Coming out of the reactor could be immediately filtered because the complete crystallisation was done coming out of the filter, coming out of the reactor filtered immediately.
10:21
And then you see that as opposed to the 50 micrometre market we had with only cooling crystallisation, we are able to decrease this two values of 7 to 8 micrometre in particle size.
10:35
So for different molecules, different solubilities, different BCS classes, we are already able to demonstrate using both cooling crystallization but also anti solvent crystallisation with different modes of mixing the anti-solvent together with the soluting solution that we can achieve a complete wide range of applications in thanks to the fact that you can steal those particle sizes.
11:02
So we can easily go down to 1 micrometre to obtain a crystalline material and sub micrometric parts.
11:10
Then it's more used for to produce something like nano emulsions and other applications.
11:18
So, but it's good to have a technology and yeah, there's also a panel discussion this morning on how to implement new technologies inside of pharmaceutical companies.
11:29
So we decided it's not sufficient, only sufficient to have a good working technology, but we try to translate this technology into workable instruments so that we can install these instruments at customers that you can have their own go with their own recipes, their own molecules on those systems as from the laboratory scale, meaning that you would use very small injections of a couple of millilitres of product.
11:57
We're really working at the gramme scale to develop your recipe.
12:01
So in this part, so the SCT lab value a lab instrument which is also in display here at our booth.
12:08
There you will completely set up the recipe, meaning you select your way of mixing it with the anti-solvent or any other insert that you would need to generate these hydrodynamic effects.
12:19
You select also the reactor size, the reactor type all the flow rates are determined at the lab scale.
12:26
And then the box containing these inserts and reactors are put on the pilot unit.
12:30
And that's an already a unit that's producing fully continuously litres on end of crystalline ancillary using exactly the same parameters.
12:39
So the gain that you will have here and that's something we have done before is that once the parameters are completely set on the lab scale, upscaling to pilot scale and then eventually putting those reactors in parallel on one big instrument is no effort at all.
12:57
To give you an example on that, this is an actual testing of we did on lactose for a customer where we have developed this complete recipe for lactose to be able to generate particles in between 50 and 60 microns as average particle size with a narrow span value.
13:24
And so we developed a reactor with several of those hydrodynamic perturbations, a 7 millilitre long reactor, a rather high solution concentration, so 850 milligramme per millilitre sitting at a rather high temperature as well.
13:38
We only apply cooling crystallisation applied, nucleation temperature of five degree C flow rate applied is 20 millilitre per minute.
13:48
And then very specific for lactose is that it's a very slow growing system.
13:53
So we can produce a huge amount of nuclei, but they take a very long time to grow.
13:58
And so therefore we need to gather all that material and keep that for 18 hours at 5°C to grow to its equilibrium.
14:06
Now these tests that you see on the bottom lab one to lab 5 are the same repetitions of exactly the same test with rather homogeneous evolution in size which rather symmetrical this image.
14:19
Then we put this thing into test on a 2 litre batch.
14:24
So we inject the two litres of material with using exactly the same conditions and this renders you as well exactly the same material attributes.
14:33
So average particle size stays the same, excellent flowability of the systems et cetera.
14:39
Everything that we want.
14:41
Now just to compare with a batch crystallisation because you have to look at it that these tests were done it the residence time inside of the reactor is about 30 seconds in this case.
14:53
And so we still need to keep the system for 18 hours at 5° C.
14:56
Now, if we don't do this injection inside of the reactor and we just cool the system down at the same conditions, then you end up with an average particle size of about 90 micrometres.
15:07
So you have a 50% increase in particle size just so the passage through the reactor makes it that you have a very constant production of the same material at all times.
15:17
And I'm just doing the same thing in a batch condition just gives you a complete wrong result.
15:22
So that's more or less showing you how with the capabilities could be of this kind of technology when you do your in this case cooling crystallisation.
15:33
So how do we look at the unit itself to be set up in a company?
15:38
So our industrialised unit containing 5 to 10 or even more of those reactors placed in parallel running constantly there in the middle and then coming out of the reactor.
15:50
In some cases for like for example for lactose gathered in a tank to grow to equilibrium.
15:56
Then later on filtered into the system.
15:59
The filtrate can be put aside.
16:01
You can work up the mother liquor anything that you would like.
16:05
Now we know that for several customers different approaches are required.
16:09
So sometimes fast growing systems you can go immediately to a direct filtration, slow growing systems there eventually you have the CSTR set up, but we have a different approach based on the customer with also based on molecule per molecule.
16:25
Now one of the major parts that we have been working on for the industrialised equipment is the stability of both the reactor temperature of course and the flow rate because those two are the ones that the only variables in fact that are important.
16:40
So we really wanted to have this quality by design that the moment that you select your insert your reactor, the other two major parameters which are then if like shown here reactor temperature but also reactor flow rate are the ones that we need to look at.
16:55
So if we set up the big industrialised equipment, after some time you evolve to a stable temperature, nothing happens anymore and that's then the point in time.
17:04
After about 100 minutes, all the other temperatures are settling as well.
17:08
At the same time we open reactor per reactor and there you see the evolution in flow rate as a function of time, in this case for a couple of hours.
17:19
And you see that looking at the scale there is that there is a very small variation of the total flow rate as a function of time.
17:26
If I zoom in fact, you would see that on the axis there is a variation which is sub the 0.05 millilitres per minute because it's the stability and the quality of the flow rate of all the reactors at the same time that determine the quality of the product and that you would generate in the end.
17:48
And that guarantees then as well the stability of the crystalline product that comes out of the reactor.
17:55
So here there is an example of adipic acid running through the reactor, in this case, immediate filtration after coming out.
18:03
And you see that after different times of running the unit, you always obtain exactly the same product quality.
18:10
And so you have a full continuously nicely working unit with let's say up to now that we found 0 flaws.
18:20
So we demonstrated it on obviously BCS Class 1 molecules.
18:24
So there's, those are the most easy to work with.
18:26
Typically there we can do a lot with cooling crystallisation only because typically they have a higher solubility inside of their solvents.
18:36
So they're easy, more easily to steer, let's say.
18:39
And therefore also class 3 molecule.
18:41
BCS class 3 molecules are also easy to handle.
18:44
We demonstrated a lot already as well on Class 2 molecules, but they're typically there, we select more anti solvent crystallisation parts and so most probably that would be accounting the same for the class 4 as repeated there.
19:00
Now what we are looking at and it's also something that Jerome has been introducing is that we really wanted also ourselves when we want to position ourselves onto the market, it's really good to try to more bridge what is DS and DP development because we can indeed provide not only the crystals of the good polymorphism, but directly we can steer the size, the density, the flowability, compactability of all of that.
19:28
And so we're really happy to announce that we are working now together with Fette compacting group, which have developed now also a continuous direct compaction unit that they are really investigating us to be able to provide them directly for their continuous direct compaction dry powder of the size, the shape, the density, the compact ability and what they call the ‘feederability’ of the product in one go.
19:55
So no more particle engineering anymore except during the crystallisation step as we are doing it.
20:03
So a little bit more rectification on the laboratory scaled unit which is on display here.
20:09
So we are also working on an evolution of this.
20:13
But you always aim as a company to have an as open platform as possible, meaning that you have all the possibilities to change all sorts of parameters that are necessary to you.
20:23
And we're also, as a small company, we are really flexible in the way that we can work together with you to find a solution to be able to implement not only our technology into your companies, but also to be able to find the correct parameter set for your system.
20:39
So generally, if you look at the unit itself, and that's the specifications for the SCT lab, but in fact, those can be regarded as a specifications of the technology as a whole as well, is that you have three different temperature zones.
20:55
So your solution can be applied from room temperature to 85°C anti-solvents can be applied from 5 to 85.
21:04
And so that's really important to have this polymorph selectivity is that your anti solvent can be heated as at the same temperature as your solution to in some cases avoid ordering out of the system.
21:15
But also in some other cases, like I've shown for video or acetone to be to have the to retain this polymorph selectivity on the reactor end, you can cool that virtually down to be temperatures below 0.
21:26
But we did some examples already where the crystallisation took place at 70°C.
21:30
So we kept that open just for the case.
21:34
And any a molecule comes by that requires this kind of temperature.
21:39
So the flow rates that we apply, that's also important.
21:43
Typically we have an optimum we found in nucleation rates anything between 20 and 30 millilitres per minute, meaning that generally if you calculated if you continuously operate the system you can do about 1 to 1.5 tonne per year if you fully produce only on that molecule per reactor.
22:01
So that means that we can calculate them as a function of the productivities, but also the way that you would attack your production strategy, how much reactors we need to put in place.
22:11
If you look at the true production.
22:13
So there are different inserts for cooling anti-solvent crystallisation.
22:17
So the way that you mix the way that you play with the hydrodynamics of the systems is really important.
22:24
And also there's a wide variety of different reactor volumes and the reactor lengths, let's say just to be able to shorten or elongate as a function of the nucleation rate that you want to obtain for that specific system.
22:39
So there is also a specific reactor execution for highly viscous solutions.
22:43
So we can go up to 1000 centipoise now.
22:46
So these three really nice.
22:47
So also very tough solutions can be attacked from now on.
22:54
And there will be a simplified collection studies as well.
22:57
And all the other things are quite logical.
23:00
So I'm a bit early, but I think that's OK.
23:02
So this gives us some time for some questions.
23:06
So you can visit us at our booth.
23:07
We are at booth 11.
23:09
Also rather important to tell you is that on the 15th of June, I will be giving a seminar together with my colleague Diyala on the upscaling of the processes.
23:19
So going much more into detail, what's our approaches, how you can implement it on the production scale and how do we see that with some true examples.
23:29
And there would be also an in person seminar in October where we will be having on display our SCT lab unit, pilot unit, but also the industrialised equipment.
23:38
So if you want to be part of that, please contact us and we can send you an invitation for that.
23:45
And what's also important is that we do live demos on site on your molecules.
23:51
We can do proof of concepts as a service inside our laboratories, do complete feasibility studies, but also install the equipment at your site, rentals, leasing, all of that is possible just to be able to accommodate you as much as possible in introducing this technology into your company.
24:10
And with that, I would like to end my talk and thank you for your attention.
