Future-Proofing the Small-Molecule Pipeline with Spray Drying

With industry reaching the limits of traditional formulation techniques, to overcome solubility and bioavailability challenges, spray-drying is increasingly emerging as a primary development pillar.

As the modern drug development pipeline becomes ever more saturated with complex molecules and targets shift toward ‘undruggable’ protein–protein interfaces, formulators are facing a solubility crisis that traditional formulation approaches can no longer solve. To explore why spray drying has moved from a specialized niche to a foundational development pillar, The Pharma Navigator spoke with Mark Macdonald, Technical Sales Director, Codis.

Pushing Formulation Limits

TPN: With estimates suggesting that up to 90% of new chemical entities (NCEs) now suffer from poor solubility, what are the primary chemical drivers behind this shift, why are traditional formulation approaches falling short, and at what point does a candidate become too insoluble to progress?

Macdonald (Codis): At a very broad level, I like to consider this trend along the lines that the ‘easier’ therapeutic indications have historically been addressed and progressed to commercial solutions, and what we have been experiencing more recently (and will continue to face moving forwards) are some of the challenges associated with developing more nuanced and complex therapies. This issue is therefore not necessarily a factor of pure solubility, but more of bioavailability, specifically looking at whether the compound can reach the target receptor or desired site of action in order to maximize effectiveness and benefit to the patient.

Increasingly drug discovery is moving beyond the traditional well-defined, rigid binding pockets to more complex targets that are flexible, dynamic, and historically thought to be ‘undruggable’. These modern targets are often shallow, highly polar or amphiphilic, have large surface areas located at protein–protein interfaces, or only appear transiently. An important consequence of this evolution is the generation of physically larger and more complex molecules which are inherently less soluble, or molecules which may need to act in a specific way, for example demonstrating hydrophobic or lipophilic qualities to reach a target site, which again, can affect solubility.

While traditional formulation approaches can be investigated as part of initial development work, some of the more complex compounds can push the limits of techniques, such as salt formation and micronization, and increasingly lead formulators to turn to more complex drug delivery systems.

Although not a ‘magic wand’, the generation of amorphous solid dispersions via spray drying can be a powerful tool to give hope to compounds which would otherwise not be able to progress to the clinical phases. The approach also has the added benefit of being a long-established technology with strong evidence of scale-up capability, providing reassurance to formulators and investors that successful compounds can have a viable route to commercial processing.

Spray drying has a wide operating range, and Codis has extensive experience in spray drying ‘insoluble’ compounds at commercial scale, so, in essence, if the material can be mobilized it could be a candidate for consideration with spray drying.

Versatile Enabling Approaches

TPN: What enabling technologies are currently available for developers to overcome the poor solubility issues? Are there any novel approaches that are yet to be implemented that you believe could be game-changing for industry?

Macdonald (Codis): There are a number of enabling technologies available to address solubility and bioavailability challenges, spanning particle engineering, amorphous form generation, complexation approaches, lipid-based formulations, and more traditional crystallization or salt-form optimization. Each technology class offers distinct advantages and limitations, and selecting the most appropriate route is a critical part of early formulation development.

Within this landscape, spray drying provides a uniquely versatile platform. It can combine the particle-size control typically associated with micronization with the generation of amorphous forms, enabling significant improvements in dissolution and bioavailability. Modern spray-drying approaches also allow the processing of thermally sensitive compounds, expanding into areas that were historically dominated by lyophilization.

Spray drying is therefore a strong candidate for early-stage evaluation. It offers well-established scale-up pathways, compatibility with a wide range of excipients and solvents, and a clear route to commercial-scale manufacturing if the technology proves suitable for the molecule.

Building on this versatility, several emerging approaches extend the capabilities of spray drying. Spray-freeze drying (SFD) integrates the benefits of atomization with low-temperature drying, aligning aspects of spray drying and lyophilization. Amorphous nanosuspensions represent another evolution, combining amorphous-state generation with the performance advantages of nanoparticle-based delivery.

Guiding Choices Early On

TPN: With so many enabling technologies available what does a robust technology selection framework look like today? Is there a technical filter to use to help decide whether a physical approach or a chemical approach is required? How can developers weigh the benefits and limitations of various enhancement strategies to ensure success?

Macdonald (Codis): With the number of enabling technologies available, formulators often use a flow-chart-style selection process to guide early decision-making. This typically begins with simple solubility assessments, evaluation of potential formulation systems (such as solvent–polymer combinations), and an understanding of the compound’s lipophilicity and other physicochemical properties. Advances in ever-increasing computational power are also beginning to offer a molecular-based first-principles approach.

These early assessments usually culminate in positioning the molecule within the Developability Classification System (DCS). This system provides an early indication of which enabling technologies are most appropriate. For example, spray drying is frequently explored for DCS Class IIb compounds, where solubility limits absorption, and for DCS Class IV compounds, where multi-modal enhancement strategies are required.

Even at this early stage, it is valuable to consider the long-term implications of formulation selection. While there is often pressure to ‘get something working’ to advance to the next clinical or funding milestone, early consideration of processability, operability, and scalability can provide significant advantages. Choosing a technology with a clear path to commercial manufacturing such as spray drying can accelerate development and reduce the risk of needing to reformulate later.

Scale Up Surprises

TPN: A common bottleneck is the inability to scale a specialized solubility-enhancing technology from the bench to CGMP manufacturing. What are the most frequent scale-up surprises you encounter, and how can developers mitigate them?

Macdonald (Codis): Scale-up is a critical element of the compound lifecycle, and because toxicology studies often require relatively large quantities of material, scale-up considerations can arise surprisingly early in development. Selecting an enabling technology with well-defined, proven, and commercially established scale-up principles — such as spray drying — allows teams to scale confidently and to demonstrate a robust, reproducible process suitable for later registration and commercial launch.

As a commercially focused spray-drying partner, we often see that early scale-up efforts can overlook the importance of associated unit operations. While early development rightly concentrates on the core spray-drying step, successful commercialization requires equal attention to feed preparation, process hold times, solution handling, and secondary drying. These elements become increasingly significant as throughput increases, and they must be assessed both individually as well as holistically to ensure a robust end-to-end process.

Maintaining a commercial mindset during early scale-up is also valuable. There is often a natural drive to push a formulation to its limits — for example, maximizing solids loading — to achieve short-term efficiency. However, this activity can introduce operability challenges, yield loss, or process instability at larger scales.

In many cases, accepting a modest reduction in solids loading for example to achieve a more stable, reproducible, and operator-friendly process delivers far greater value at commercial scale. With Codis’ flexibility in throughput and equipment configurations, any perceived loss in efficiency can often be offset without compromising long-term manufacturability.

Particularly Valuable Tool

TPN: As we look toward the end of the decade, which emerging technology/approach do you believe will become a standard tool for overcoming the industry's solubility crisis?

Macdonald (Codis): Although spray drying is not an emerging technology in the historical sense — with its origins dating back more than a century — it is increasingly emerging as a critical platform for enabling the commercial realization of today’s more complex compounds that face solubility and bioavailability challenges.

Its scope, versatility, and reliability are largely unmatched when tackling the formulation issues now common in modern drug pipelines. Spray drying’s ability to combine particle engineering with amorphous form generation makes it particularly valuable for DCS Class IIb and Class IV molecules.

With the continued development of cutting-edge augmentations — such as spray-freeze drying (SFD), and amorphous nanosuspensions — spray drying is well positioned to remain a versatile, future-proof solution into the 2030s and beyond.

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