Drug Development Small Molecule Formulation |

Navigating You Through Drug Development: Improving the Bioavailability of BCS Class II and IV APIs

Giulia Milanesi, Group Leader - Formulation Development and Production

| Technology Showcase

21 August, 2025

Watch time: 31 Minutes

Giulia Milanedi began her presentation by introducing herself and the topic of formulation strategies to improve the viability of APIs with BCS classification II and IV. She provided an overview of Ardena, a Europe-based company with facilities across the continent, including drug substance facilities in the Netherlands and Sweden, a bio-analytics facility in the Netherlands, and drug product manufacturing sites in Belgium and Spain. Ardena supports customers from early drug substance development to GMP manufacturing for clinical trials, with analytical and regulatory services to aid in drug substance and product characterisation and regulatory submissions. Milanedi highlighted the challenge of poor solubility and low bioavailability of new chemical entities classified as BCS class II or IV. She explained that conventional dosage forms were insufficient for these molecules, necessitating the use of enabling technologies to improve solubility and bioavailability. Ardena employs a screening tool to apply different enabling technologies, focusing on nanosuspension, amorphous solid dispersion manufacturing via spray drying, and lipid formulation. She elaborated on nanosuspension, describing it as a colloidal dispersion of hydrophobic particles in a hydrophilic medium, usually water. The manufacturing methods included top-down processes like media milling and bottom-up processes like precipitation. Ardena primarily uses milling devices to achieve nanosuspension, starting with small batch sizes for screening and development before scaling up to larger batches. Milanedi presented a case study involving an API with poor water solubility, detailing the screening and development process, including the use of polymers and surfactants to stabilise the nanosuspension. Milanedi then discussed amorphous solid dispersion, focusing on spray drying as the primary method. She explained the process of solubilising the API and polymer in organic solvents, atomising the solution into small droplets, and drying them to form amorphous solid dispersions. She provided an example of a project where they screened polymers for precipitation inhibition and upscaled the process for larger batch manufacturing. Finally, Milanedi covered lipid formulations, particularly self-emulsifying drug delivery systems suitable for APIs soluble in lipids. She described the screening process for solubility in oils and surfactants and the evaluation of emulsification properties. She concluded by summarising the importance of enabling technologies for improving bioavailability and the need to screen multiple technologies in parallel.

00:06

Oh, good morning, everybody. Thank you for the nice introduction. I'm in Giulia Milanedi, and I will discuss about formulation strategy to improve the viability of API with BCS classification II and IV.

00:20

First of all, I would like to give a small introduction of Ardena. We are a Europe based company with different facilities all over Europe. We have, indeed, two drug substance facilities, one in the Netherlands and one in Sweden. We have also in the Netherlands, a facility more focused on bio analytics, and we have then two drug product manufacturing site, one located in Belgium. I'm from Belgium, actually, and one in Spain, in Pamplona.

0:51

As Ardena, we support our customer from the early development for drug substance manufacturing, up to GMP manufacturing of drug substance and in parallel, we also support the development of drug product for the development part and also for the GMP manufacturing for clinical trial. In parallel, we have analytical department that support both the drug substance and drug product characterization. And lastly, but not less important, we have a regular regulatory service that support our customer for submission of IND, INPD or dossier development.

1:34

But let's go back to the topic of my presentation of today. For many of you, probably this is a very well known slide, as you know, nowadays, most of the new chemical entities that are synthesized are classified as BCS class two or four, meaning with very poor solubility, which leads then to low bioavailability. And this is indeed what is a challenge from a formulation point of view, as for this type of molecule, the standard and conventional dosage forms, such as a simple tablet or capsule or solution, are then not sufficient to reach the therapeutic effect that we desire to have.

2:14

Therefore we have to introduce some enabling technology to improve the solubility of API, and therefore the bioavailability. As Ardena, we offer a screening tool. So in parallel, we try to apply different enabling technologies to the API that we work with in order to be able to understand which one is the technology that is more promising for a certain API. And mainly we focus our attention on nanosuspension, amorphous solid dispersion manufacturing, mainly via spray drying and lipid formulation.

Of course, if characterization of the API is well done since the beginning and we know already information, such as the solubility, for example, if the solubility of the molecule is very high in lipid so the product has very high LogP maybe the way to go forward can be a lipid formulation. While, if the solubility is very well, very good in organic solvents, sometimes, then the spray, dry approach can be the preferred technology. While, if we have, for example, issue with very high dose to be administered, and the limiting factor for the bioavailability is the dissolution rate of the molecule, then nanosuspension can be the way to go forward.

But of course, sometimes in early stage, the characterization of the drug substance is not fully completed, and it's very difficult to select which one is the preferred strategy to go forward. That's why we screen in parallel multiple technique to see which one is then more performing for our APIs.

3:55

Let's discuss about nanosuspension. As many of you know, nanosuspension is a colloidal dispersion with hydrophobic particle dispersing a hydrophilic medium, most of the time water with the size below one micron. And this is a very important aspect of nanosuspension, because in the nanometer range, then dissolution rate of the API is enhanced. Of course, as you know, these systems are by definition, not stable because of the high surface area of the particle and high interfacial tension, therefore, to reduce the energy of the system, phenomena like flocculation, aggregation or crystal growth can occur over the stability of the product, and it is then essential to introduce in the formulation some key excipient that can then provide electrostatic or steric stabilization. And for that, I'm mainly talking about surfactant and polymers. It is, of course, very challenging to select the right concentration and the right combination of this excipient to be sure to avoid, for example, Ostwald ripening or have the correct steric hindrance, for example.

Regarding the manufacturing method for nanosuspension, we can classify the technology into two main class, the top down process technology, where we start from particle that are in macro range, so large particle with large diameter. And thanks to this technology, for example, media milling, we can then reduce the particle size into the nano range. Or we have a completely different approach, which is part of the bottom up process technology, where we then start from normally a solution, and then we create the nanocrystal via precipitation. So the starting point is different in this case.

5:45

In Ardena, we mainly focus the nanosuspension manufacturing with the first classification. So we use a milling device to obtain nanosuspension. And in this case, milling media, normally, we use zirconium beads, are introduced together with the suspension, and these create high energy, which is then sufficient to break down the particle and reduce the size into the Nano range.

We have in house multiple techniques that can be used to achieve this goal. And we start, for example, with a very small batch size using a roller mill. And this is used mainly for screening and development purpose, because we can use very small batch size and consume very little amount of API. And then we move over the development and the upscaling to larger batch manufacturing, introducing the high energy milling.

6:41

I have also here a schematic representation of our Dynomill device, so high energy milling device, where we have, indeed a milling chamber where the suspension is introduced together with the beads, and thanks to the presence of a shaft equipped with ceramic blades, we can then introduce high energy in the process, and the impact that is generated from the beads on top of the crystal then is sufficient to reduce the particle size and obtain a nanosuspension.

Of course, for upscaling process is very important to optimize the milling process, to reduce the milling time and have a very efficient process. So many parameter has to be adjusted and controlled, such as the shaft speed, pump speed, bead size. It's possible to use different size of beads and also combination of different size together to improve the process, and also how much you're filling your chamber with the beads itself.

7:37

I have here a case study that was involving an API that was very poorly soluble in water. So the challenge we are all having nowadays. So for the development, we decided to proceed with nanosuspension manufacturing, and we use our small roller mill device for that. The target concentration for the product was 60 milligram per milliliter. But we started with a more concentrated nanosuspension at 150 milligram per milliliter, in order to be able to improve the milling process and also reduce the bulk volume of product to be milled. And we then started with the development. So we selected some polymer and surfactant, and we combined, we decided to combine them in a different concept to have a full screening. And for all the concept, we use 0.3 millimeter beads for the milling using the roller mill.

And I have here one of the most promising concept out of this screening, which is concept six that was made of HPMC as a polymer combined with SLS as a surfactant. You can see, wait, let's see if I can point out, sorry, we can see that the particle size was measured with laser diffraction at the beginning of the milling. So actually, this is the suspension prior to the milling started. And then over time, sample of the suspension were taken to monitor the evolution of the particle size and the reduction. And indeed, after 10 days of milling, we were able to obtain the desired particle size with a D50 distribution below 200 nanometer and D90 below 500 nanometer.

After that, the product were harvested from the beads and diluted to the final concentration. And you see, after dilution with placebo, there was no alteration of the particle size. And then the concept were placed on a screen stability program for two weeks at different temperature, 25 and 40 degrees, and also in a temperature cycle program. So the temperature was changed from five degrees to 40 degrees to induced shock in the composition, in the formulation, sorry. And indeed, you see that over the stability program, the particle style stays unchanged. You can also see that from the graph, the red curve is at time zero. So just. After dilution, and the green curve is after stability of two weeks at 40 degrees.

But of course, not all concepts were successful. For example, this concept was very nice after milling, because we managed to obtain at time zero, a nice distribution of particle but over stability after two weeks at 40 degrees, you see that there is agglomeration and crystal growth.

10:23

So the concept that was more promising was an upscale with our Dynomill device using a 0.3 liter chamber. And at this stage, our goal was also to improve the milling process and reduce the milling time. So we tested different pump speed and shaft speed to reduce the milling time. This combination of setting was the most performing. And later on, we upscale the process even further, manufacturing a 50 liter batch using our 1.4 liter chamber. And at this stage, we also try to improve the process as much as possible to reduce the milling time. And you can see here that after 10 minutes of milling.

So at the beginning of the milling, the particle size distribution was quite large. So the red curve. And then over time, the particle size distribution is changing. The peak is shifting towards the left. And only after 106 hour of milling, we were able to obtain a monomodal distribution of particle all in the Nano range. So, yeah, the most challenging part is to get rid of this tail in the peak with large particle. And this require quite some time.

11:30

Regarding amorphous solid dispersion, I was saying that in Ardena, we mainly focus ourselves on spray drying. As you know, amorphous solid dispersion are dispersion of amorphous API into a solid matrix, mainly composed by a polymer. And thanks to the amorphous state of the API, then the solubility of the product is improved. This system are also, by definition, not stable, because the high energy of the system, therefore, over time, the amorphous form will tend to convert back to the crystalline form. And for this reason, it is essential to include in the formulation a stabilizer, which is normally a polymer which has, as you can see here, multiple function inside the formulation, not only stabilizing but also, well prevent the crystallization, but also maintaining the super saturation upon administration.

Regarding the manufacturing method, we mainly focus ourselves on solvent based evaporation methods, so mainly spray drying. But of course, we also have melting based methods such as automatic extrusion.

12:37

As I said, we focus ourselves on spray drying. I have here small schematic representation of how the process is happening. We have normally a feeding solution where the polymer and the API are solubilized together, mainly using organic solvent. This solution is then sprayed through a nozzle that then atomized the droplets into very small droplets. And thanks to the drying gas, which is most of the time air, actually hot air that is blowed through the drying chamber, then the small particle are dried very fast, and we are then able to collect thanks to this cyclone, the amorphous solid dispersion, the fine are removed from the collection and take into a filter.

13:25

For spray drying, we also have different capabilities going from small R&D device: we have a Buchi B-290 in-house that we use to produce this screening concept. So with small amount of API, we can produce multiple type of formulation. And then later on, we upscale the process on ProCept. And for large batch, we have a GEA Mobile Miner in-house that we can use for large GMP manufacturing.

13:54

I have an example of a project that had also very poor solubility. Therefore we decided to screen for amorphous solid dispersion via spray drying. So the first step of the development is always performing a solubility screening of the API in organic solvent, because these are essential for the process. But also we have to assure that there is stability of the API in this solution.

After that, we select the polymer that we want to screen as a stabilizer and we test them in a solvent shift method to understand which polymer are the most promising in terms of precipitation inhibition. In this case, multiple polymer were tested, and HPMCAS, Kollidon VA64, and SOLUPLUS provided the best performance in terms of anti-precipitation, inhibition. So, these three polymers were then chosen for the later stage, where we indeed run some feasibility concept with our Buchi device.

14:53

So the very small device. And we also produce different concepts at different drug loading: 20:80, and 50:50 API-polymer as kind of bracketing approach. The solid content was selected as 10% to reduce the time required for the spraying and the manufacture were then placed on a screen stability study to evaluate the amorphousity over time and see if the polymer were able to maintain the API in the amorphous state. This concept was actually the most performing one, including HPMC-AS as a polymer.

And you can see this concept was characterized with XRPD, and you see that both drug loading, so also the 50:50 ratio, after two months of stability of 40 degrees, is still fully amorphous without crystallinity present.

16:00

We then decided to upscale this concept on larger batch manufacturing, using the ProCept, and at this stage, is very important for us to also put attention on the particle size and particle engineering, because most of the time spray dried products are very poorly in terms of flowability. So most of the time, if we want to move to a capsule or tablet formulation, a dry granulation step is required to improve the flowability. So we try, already in this phase, to improve the flow ability to, yeah, be able to introduce the granulation in a much later stage, to reduce costs and time needed for the development.

And we indeed, we were able to improve the particle size from the reference. So the red curve, which is the one produced with the Buchi in the initial trial, by changing the settings, we were able to increase the particle size. Indeed, concept ARD004 was the preferred selected one. And you can see that, compared to the reference, the particle size measured via laser diffraction was increased, so the flowability of the powder was much better compared to the reference. It was more cohesive.

17:10

But then, of course, we need to upscale even further the process. So we produce a batch of 3.2 kilo with the process, and we focus then on the upscaling of the process and also comparing direct blend versus granulation for the flowability. For this specific project, we proceed with direct blend because we were able to obtain a desired particle size, and the final product was then filled into capsules.

17:35

Regarding lipid formulation. With lipid formulation, I'm mainly talking about self emulsifying drug delivery system, which are then system that self emulsify in situ, when dispersed with gastrointestinal fluid. These systems are more suitable for API that are very soluble in lipid with high LogP and in general this system are isotropic mixtures, so they are very stable. The water is not included in the formulation, so we don't have the stability issue normally linked to emulsion. And thanks to the large surface area and they produce emulsion upon dispersion in gastrointestinal fluid, we are able to obtain very small droplets, which then increase the contact with the site of absorption, and also the presence of the oil is helping to keep the API in the solubilized phase.

It's also interesting to have oil in the formulation, because this can promote the uptake of the drug real lymphatic system. So it helps us to bypass the first pass effect, so to increase also, thanks to this way the bioavailability. And in general, these are very simple and stable formulation to prepare. So the technology required is less complex, let's say.

So depending on the size of the emulsion that is created in vivo, upon dispersion, we can have microemulsion or nanoemulsion. And in general, the composition of this kind of formulation are mainly lipids, so medium or long chain triglyceride combined with surfactant or emulsifier or a combination of two emulsifiers reduce the interfacial tension and promote the emulsification.

19:14

I have an example of an API that was also, in this case, poorly soluble. So we decided to proceed with the lipid formulation approach, because we screen solubility in oil surfactant and mixture of them, you see that multiple mixture with surfactant and oil were prepared and for example, for concept five, six and seven, over time, there was recrystallization and precipitation of the API. So these were not successful for this type of application, while the other concepts were then kept and diluted into simulated gastric fluid to evaluate the emulsification property of the formulation and to understand if there was phase separation or precipitation of the API. And you see that upon dilution with SGF for concept one, two and three, we had very nice milky like emulsion, without phase separation or precipitation. While for concept four and eight, immediately after dispersion, we had precipitation of the API. You see all this crystal present on the surface of the wall of the vial.

So this concept were discarded. While for this concept, we then perform a screen stability study to understand which one was more stable over time and a different storage condition. And we also perform a PK test in rats and dog to understand which one was better in terms of bioavailability, and the one that was selected was concept two actually, which was then produced for in a larger batch. And this formulation, so this lipid formulation was then filled into hard gelatin capsules using this CFS1200 device, which is quite interesting for small space, because you can feel and seal at the same time the capsules. So you don't need to technology for filling and bending of the capsules to avoid leakages. So this is quite interesting. So yeah, of course, this type of technology can then be upscale later on to soft gel capsules, for example.

21:14

So yeah, I will summarize a bit what we discussed. We know that most of the new chemical entity are nowadays classified as BCS class II or IV, so with very poor solubility and therefore low bioavailability. So it is essential to introduce some enabling technology to improve the bioavailability. And nanosuspension, amorphous or dispersion or lipid formulation are nice option to achieve that goal, and for us, is very essential to screen in parallel different technology, because it's very hard, sometimes, especially in the early phase, to pick a technology and be sure that this will be the successful one. So our strategy is always to screen small batch in parallel to understand which technique is then the best performing one.

22:02

Thank you so much. If you have question, we are also outside at the booth. You can join us, and we will be happy to help you.

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