Q&A: How can we overcome the challenges of suspension formulations in drug delivery?

Suspension formulations offer exciting opportunities in advanced therapies but also pose complex challenges.

In a conversation between TTP’s Drug Delivery Innovation Lead Matthew Parker, Engineering Lead Alastair Gregory, and Project Lead Benjamin Hatton, we explored the rising demand for suspension formulations in drug delivery, the challenges they pose, and the innovations required to overcome these hurdles. From the need for finely tuned release rates to the intricate balance between usability and device complexity, this conversation explores how cutting-edge innovations—and close collaboration—are key to unlocking the potential of suspension-based therapies.

In this in-depth Q&A, we dive into the key trends, challenges, and future possibilities in this space.

Benjamin Hatton: One of the major trends is the need to tune the release rate of drugs. The release rate needs to be optimised for each drug to achieve the desired pharmacokinetics (PK). For instance, if a drug has a higher-than-desired release rate, you may need to adjust the formulation—perhaps moving from a PLGA microsphere solution, which is highly bioavailable, to a fat-based solution for a slower release, longer-acting effect. The move toward long-acting formulations, like oily dispersions, is increasingly common as the industry seeks to deliver drugs more conveniently and sustainably.

Benjamin Hatton: It’s really a mix of both. There’s definitely a push to reduce the number of injections, shifting from daily or weekly doses to monthly injections. This is largely patient-driven, as fewer injections mean less hassle and better adherence to therapy. In addition, sustainability is a growing concern—pharma companies are becoming more conscious of reducing the number of devices required, which has a positive environmental impact.

Alastair Gregory: Suspensions have a tendency not to stay suspended. You often have to find a way to resuspend them before use, which can complicate the device design. For instance, one option is to mix the drug right before it’s injected, but that can add extra steps for the user, making the device more complex and potentially more error-prone.

There’s also the issue of particles settling or agglomerating over time. If the particles stick together, it’s difficult to resuspend them, and you could end up with clogs in the needle or reduced bioavailability. The challenge is to design devices and formulations that prevent these issues.

Benjamin Hatton: Shaking is one solution, but it’s not always reliable. Requirements are not necessarily common across products. A study by Zoetis, for example, looked at three similar suspension products. For two of them, 90% homogeneity was achieved after 10 seconds of shaking, but the third took over 90 seconds to reach the same level. That variability poses a challenge—especially since different people may shake in different ways or at variable accelerations. In our work, we’ve seen some users shake up to 35G, while others may shake as gently as 5G. You also have to consider the physical capabilities of patients, especially those with comorbidities. Without very clear messaging to the user and feedback, it is highly possible to be in a situation where poorly homogenous solutions are being injected. This brings concerns in achieving correct PK characteristics, needle clogging and dose variability.

Alastair Gregory: There are existing theories, like DLVO theory, that help us understand how particles behave in suspensions. This theory balances attractive van der Waals forces with and double-layer forces. By considering factors like particle size, charge, and the solution’s pH, we can estimate how long particles will take to agglomerate and how much energy is needed to break them apart.
However, these theoretical models have limitations. For example, DLVO theory assumes particles are rigid spheres, which isn’t always the case with complex formulations. So, while these models give us a rough idea of how a suspension will behave, experimental validation is still critical.

Benjamin Hatton: A mixed-methods approach works best here. Experimental methods help us understand the overall real-world performance, while simulations give us insights into why something works the way it does. We can use these iterative loops to refine the formulation and the delivery device.

Alastair Gregory: It’s absolutely crucial. Some challenges are incredibly difficult to overcome with just a device solution, and others are tough from a formulation perspective. Close collaboration between the two teams allows us to understand these trade-offs and create more effective solutions. It’s really the combination of the two that makes these projects successful.

Benjamin Hatton: I agree. From the moment we get involved as a device developer, we’re dealing with certain constraints imposed by the formulation. Understanding these early on is key to coming up with the right solution. More and more, we’re also looking at platform devices, where we’re not just dealing with a single formulation but a range of them. This requires us to understand the full scope of what’s possible—such as viscosity ranges, particle sizes and formulation sensitivities—so we can develop devices that accommodate multiple formulations.

Alastair Gregory: Yes, there are several options. Ultrasonic or vibrational methods, for instance, can help mix the suspension without changing the primary drug container, which simplifies validation. You could also introduce stirrers or create vortices inside the container to mix the drug. However, adding these features increases the complexity of the device, and verifying that they work as intended can be difficult.

There are also more experimental approaches, like using bubbles to move particles around within the fluid, but each of these methods comes with its own set of challenges.

Benjamin Hatton: I’d add that any strategy needs to be contextualised within the formulation technology. For example, using ultrasonic cavitation could damage biologics or other sensitive drugs, while high-shear mixing could break down the lipid-encapsulation of mRNA, greatly reducing bioavailability. Each approach needs to be carefully considered based on the formulation and the device.

Alastair Gregory: Yes, I’m optimistic. The physics behind suspensions is well-understood, even if applying it to drug delivery is a newer challenge. The key to success is collaboration between the formulation and device teams. It’s not just a technical challenge—there’s a lot of fun and creativity in figuring out how to apply these principles to develop effective solutions.

Benjamin Hatton: I share that optimism. With a clear understanding of the constraints and close collaboration between teams, these challenges can definitely be overcome. The benefit to patients—particularly in terms of reducing the frequency of injections and enabling at-home treatments—is tremendous. It’s exciting to be a part of this journey and help shape the future of drug delivery.

Benjamin Hatton: Issues with particle agglomerates, especially in small microparticles and crossing into the larger range of nanoparticles can be seen in dry powder inhalers. Over the past 35 years, TTP has been at the forefront of the dry powder space and has developed a significant toolkit for analysis and optimisation of factors such as agglomerate breakup. We commonly combine simulation tools including CFD and particle transport models to study particle impact trajectories, turbulence intensity and stagnation regions with in-vitro testing to fine tune devices. Many of these tools have direct relevance no matter the fluid medium.

The future of drug delivery will increasingly depend on innovative suspension formulations, but with close collaboration between formulation scientists and device engineers, these challenges can be met. From advanced modelling techniques to experimental methods, the path forward is clear—and the potential benefits for patients are significant.

When you work with TTP, you’re partnering with experts who understand the drug delivery market inside out. When success is critical, having the right team on your side makes all the difference. We solve complex challenges with scientific and engineering rigor, ensuring high-impact, user-centric results. Whether navigating uncharted territories or accelerating time to market, we combine strategic insight with an agile approach to find and retire risks early, ensuring that every decision and trade-off is made with confidence. We think boldly, helping you deliver solutions confidently and ensuring market success.