Rethinking the Path from Spray-Dried Dispersions to Tablets: The Role of Continuous Direct Compression

Amorphous solid dispersions (ASDs) have become a leading formulation approach for oral drug candidates whose absorption is limited by poor aqueous solubility.¹ By dispersing the API in a polymeric matrix, spray drying can generate an amorphous form of the API that improves solubility and dissolution behavior.² This has made spray-dried dispersions (SDDs) an important enabling technology for many small-molecule development programs.

While spray drying enables the generation of ASDs that enhance solubility and bioavailability, it can also produce powders that are challenging to convert into tablets. SDD powders often exhibit low bulk density, fine particle size, cohesive behavior, and electrostatic sensitivity.³ Some of these attributes may influence dissolution performance, but they are primarily relevant due to their impact on downstream manufacturability. These characteristics can challenge downstream feeding, blending, powder transfer, tablet weight control, and content uniformity. As a result, the downstream development path for SDD-based tablets has historically included an intermediate granulation step before final blending and compression.

That choice is understandable: a key driver for selecting granulation is to improve powder density, flow, and handling.⁴ Further, it provides a familiar and predictable route for processing challenging powders. Granulation can reduce the impact of variability in certain powder properties and powder-handling challenges; although, it introduces its own sources of variability that must also be controlled and understood. However, reliance on granulation as the default means of compensating for powder-property variability may become less important when spray drying is operated within a robust and well-controlled design space and the resulting particle properties are consistently achieved at the intended manufacturing scale. As continuous manufacturing platforms mature and material characterization becomes more predictive,⁵ it is worth asking whether granulation should remain the default pathway for all SDDs or whether selected systems can move directly from spray drying to tableting.

Why Granulation Became the Default Route

Granulation has historically played a practical role in tablet development. When powders flow poorly, segregate, or compress inconsistently, dry or wet granulation can convert them into a more processable intermediate. For SDDs, dry granulation is often attractive because it can improve density and handling while avoiding the intentional liquid exposure and drying steps associated with wet granulation. This can be important for amorphous or moisture-sensitive systems, ^2,3 where exposure to water or other liquids may increase the risk of phase behavior changes or chemical instability.

In early development, the decision to granulate may also be influenced by pragmatic constraints. API availability can be limited, powder properties may not yet be fully optimized, and development teams often need a robust pathway that can support rapid progression.⁶ Specifically, this can routinely require spray drying at very small scales, where it becomes challenging to fully optimize spray-drying parameters and particle engineering strategies to achieve the powder properties that may be representative of future larger scale batches. Consequently, roller compaction may be selected as a purposeful risk-mitigation strategy to compensate for sub-optimal powder properties, even though subsequent optimization could potentially enable direct compression.

Although direct compression is typically the preferred tablet manufacturing route because it provides the simplest path from blend to final dosage form ⁷, its practical operating space in batch mode can be constrained by evolving API or intermediate properties during early phase development, as well as by flow, segregation, discharge, or transfer risks that emerge during scale-up or between batch variability. For SDD products, better control of the engineered intermediate can buffer API variability, but it may not always address the batch-specific handling and scale-up risks that often push development teams toward granulation.

The challenge is that early process choices can strongly shape the development path^5,7 and become increasingly difficult to change within a highly regulated framework for pharmaceutical development and manufacturing. Once a granulation-based process is established, substantial process development work, analytical strategy, equipment selection, supply chain planning, and control strategy development accumulate around the granulation route. Even when product or process technology improvements later make a direct compression route technically possible, these opportunities may not be pursued because changing a mature processcan trigger regulatory refiling and disruption across multiple parts of the current manufacturing system for the intended product. A process pathway initially selected to manage uncertainty can easily become the default manufacturing strategy.

The Additional Cost and Complexity of Default Granulation

Granulation remains valuable when technically required but should be adopted based on demonstrated need rather than by default as it can add complexity across development, manufacturing, and lifecycle management. Additional unit operations introduce more process parameters, sampling points, equipment transfers, cleaning considerations, and quality controls. They can also create new sources of variability, including granule particle size distribution, density, lubrication sensitivity, compactability, fines management, and dissolution behavior.

For SDD-based products, this complexity is amplified because the SDD is already an engineered API-containing intermediate, designed to stabilize the amorphous form and enhance bioperformance. Granulating the SDD with excipients creates a second API-containing intermediate before final compression. When needed, this transformation is justified ⁶; when unnecessary, it adds another layer of material attributes, process variables, and quality considerations that must be developed, controlled, and understood.

Every additional powder transformation can also complicate root-cause analysis. If a tableting in-process control trends unexpectedly beyond its limits, an investigation must consider not only the SDD and final compression step, but also compaction, milling, intermediate blending, lubrication, hold conditions, and transfer between operations. In programs where speed, API conservation, and process understanding are critical, this added complexity can be significant.

The issue, therefore, is not whether granulation is useful. It is whether granulation is necessary for a given SDD product. If an SDD formulation can be fed, blended, lubricated, and compressed directly with adequate robustness, the development team may be able to remove a process step rather than optimize around it. This contrast between a default granulation-based pathway and a simplified CDC pathway is summarized in Figure 1.

Continuous Direct Compression as a Simplified Pathway

Continuous direct compression (CDC) integrates continuous feeding, blending, lubrication, and compression into a seamless powder-to-tablet process. Compared with a process that includes intermediate granulation, CDC can offer a shorter process train and a clearer link between input material attributes and final tablet performance. This is particularly relevant for SDD products because CDC may preserve a more direct path from an engineered amorphous dispersion to final tablet, avoiding conversion into a separate granule intermediate when direct processing is feasible.

Against this backdrop, CDC can be viewed as a way to reopen the direct-compression option for selected SDD products. By reducing dependence on batch powder transfer, large-scale intermediate handling, and post-blending holds or discharge behavior, CDC may mitigate some of the material-handling and process-integration challenges that constrain batch direct compression, thereby expanding the practical operating space for selected formulations. In this sense, CDC does not replace the logic of direct compression; it extends it by making the simplest route more robust to development and scale-up realities.

Film coating, when required, is often the final processing step and may be performed using batch, continuous, or semi-continuous approaches; it is not discussed further here because the focus of this article is the SDD-to-core-tablet process selection.

Regulatory and technical guidance for continuous manufacturing has also evolved.⁸ The International Council for Harmonisation (ICH) published ICH Q13, which describes continuous manufacturing as a scientifically supportable approach when sustained by appropriate process understanding, control strategy, and lifecycle management. For oral solid dosage forms, this broader environment makes it increasingly practical to consider CDC not only as a manufacturing technology, but also as a development strategy that can reduce the gap between clinical and commercial process design.

For selected SDD formulations, CDC can provide a pathway in which the key development challenge shifts from “How do we granulate this material?” to “Can we design and control the material-process interaction well enough to avoid granulation?” This shift is important. It changes granulation from a default assumption into one of several processing options evaluated through evidence.

Material Attributes That Influence CDC Feasibility

A material-property-driven approach begins with the recognition that SDDs are not a single class of powders with uniform behavior. Their downstream processability depends on multiple interacting attributes, including particle size distribution, bulk and tapped density, particle morphology, surface properties, powder rheology, electrostatic behavior, compressibility, and segregation tendency.⁵ These attributes are influenced by formulation composition and spray drying conditions, and they can change as development progresses. Figure 2 provides a practical decision framework for assessing whether an SDD formulation is suitable for CDC, requires optimization, or should proceed through granulation.

Feeding is often the first major challenge. A continuous process depends on stable and accurate delivery of each component into the line. Low-density, cohesive, or aeratable SDD powders may require careful understanding of how they behave under gravimetric feeding conditions. However, feedability cannot be assessed from bulk density or particle size alone. A powder that appears challenging by one metric may still be processable when equipment configuration, refill strategy, and downstream blending dynamics are considered together.

Blending introduces a second layer of process behavior. Variability from feeding may be dampened by the residence time distribution that results from the material hold-up, and blender configuration. However, blending must also manage separate risks such as segregation tendency and insufficient mixing or dispersion. Therefore, an appropriately designed continuous blending process should mitigate these risks because they can affect blend uniformity and downstream tablet quality. Compression then adds additional constraints related to tablet weight control, compactability, ejection behavior, and final tablet attributes. The feasibility of CDC therefore depends on the integrated performance of the system, not on a single powder property or unit operation.⁹

Connecting Particle Engineering with Downstream Performance

One of the most important opportunities in SDD development is to treat spray drying and tableting as connected activities rather than sequential handoffs. Spray drying conditions influence particle formation, morphology, density, and surface behavior.^10,11 These attributes, in turn, influence whether the material can be fed, blended, and compressed directly. If downstream manufacturability is considered only after the SDD is fixed, the development team may discover tableting challenges too late, when formulation or process changes are more difficult.

A more integrated approach considers the SDD as a designed input to the drug product process. The objective is not only to produce an amorphous dispersion with suitable biorelevant dissolutionbehavior and stability, but also to generate a material whose physical attributes are compatible with the intended downstream operations ^2,5. In this context, particle engineering becomes a bridge between bioavailability enhancement and manufacturability.

This integration is particularly relevant for organizations that have experience across both spray drying and oral solid dosage manufacturing. Knowledge generated during SDD development can inform early process selection, and downstream process requirements can feed back into particle design. The result is a more deliberate development strategy in which the process pathway is selected based on material behavior rather than historical convention. ^5,7 Figure 3 illustrates how feedback from downstream CDC performance can inform particle engineering and SDD process design.

A Structured Development Methodology for Assessing CDC

A practical CDC assessment begins with targeted characterization of the SDD and formulation blend. Rather than relying on traditional flow tests alone, the evaluation should consider attributes that are relevant to continuous feeding, powder transport, blending dynamics, and compression. The objective is to understand how material properties translate into process behavior.

Importantly, granulation should not be viewed as the immediate next step when an SDD formulation shows feedability or handling limitations. The first response should be to determine whether the limitation can be addressed through ASD particle-property optimization, spray-drying process adjustment, or formulation design. If those changes are insufficient, targeted use of flowability-enhancing excipients, such as colloidal silica, may provide a comparatively low-burden way to improve feedability, blend behavior, or process robustness while preserving the simplicity advantages of direct compression.Only when these approaches do not provide an adequate operating space should dry granulation or roller compaction be considered as the preferred risk-mitigation strategy.

The assessment should therefore define whether the material issuitable for CDC as-is, requires targetedparticle or formulation optimization,or should bedirected toward granulation. This decision should be based on material characterization, process risk assessment, and targeted experimentation, while accounting for dose, drug load, tablet size, excipient selection, and intended manufacturing scale.

Predictive tools can further strengthen this development strategy by providing informed starting points for feeder selection, blending conditions, and compression development. The intent is not necessarily to replace experimentation, but to reduce trial-and-error and focus experimentation on the most relevant risks. This is especially valuable in early development, where API may be limited and each experiment must generate meaningful process understanding.

Benefits for Development and Manufacturing

When CDC is feasible, the benefits extend beyond process simplification. Development effort can shift from optimizing an additional granulation intermediate to understanding the direct relationship between SDD attributes, CDC performance, and final tablet quality. This shift can make experiments more targeted, reduce avoidable process-development burden, and support earlier, better-justified process route decisions.^12,13 In practice, this means pursuing CDC where the material-property assessment supports it, while proceeding with granulation when the underlying limitations make it necessary. By reducing the need to develop, characterize, and justify an additional granulation intermediate, a feasible CDC pathway may shorten the path to a filing-ready process and supporting control strategy.

For manufacturing and lifecycle management, process simplicity can have strategic value. Fewer unit operations may mean fewer scale-up transitions, fewer equipment interfaces, less subdivision and handling of intermediate material, fewer potential failure modes, and a more direct control strategy. CDC can also align well with broader continuous manufacturing goals, including flexible production, integrated monitoring, and science-based control of connected unit operations.^14,15

Practical Considerations and Limitations

CDC should not be presented as a universal solution for all SDD products. Some formulations will still require granulation when material behavior, product requirements, or robustness expectations cannot be adequately managed by direct compression. In those cases, granulation remains the justified and reliable manufacturing route.

The value of a CDC-focused development methodology is that it makes this decision more deliberate. Rather than assuming that SDDs must be granulated, teams can assess the material, understand the process risks, and select the manufacturing process that best fits the product. This approach expands the development toolbox without dismissing established technologies.

Equally important, the assessment should be performed early enough to influence development strategy. If CDC feasibility is evaluated too late, the program may already be committed to a more complex processing route. Early evaluation allows teams to either pursue a simplified pathway with confidence or proceed with granulation based on evidence rather than assumption.

From Default Granulation to Deliberate Process Selection

Spray-dried dispersions have transformed the formulation options available for poorly soluble molecules, but downstream tablet development remains a critical part of product success. The historical reliance on granulation reflects real material challenges, yet it should not prevent the industry from reassessing what is possible as continuous manufacturing platforms, powder characterization, and particle engineering capabilities advance.^5,11

For selected SDD systems, continuous direct compression offers a pathway to simplify development and manufacturing by linking spray drying, material attributes, and tablet process performance in a more integrated way. The central shift is from default granulation to deliberate process selection:^5,7 evaluate the material, understand the process, and choose the simplest robust pathway that the product can support. When spray drying development and continuous tableting expertise are connected early, SDD attributes can be intentionally guided toward a manufacturable CDC pathway where product requirements allow it and without compromising the intended performance of the SDD-based tablet.

As more technical evidence becomes available through scientific conferences and peer-reviewed publications, the industry will be better positioned to define when SDD products can move directly into continuous tableting and when granulation remains justified. That more nuanced view can help development teams reduce unnecessary complexity, conserve valuable material, and accelerate the path from enabling formulation technology to robust oral solid dosage products.

Acknowledgements

The author gratefully acknowledges Claudia Moura for leading this work and the broader Oral Product Development Team for their collaboration, technical input, and support. This article reflects the benefit of their collective expertise and ongoing efforts to advance robust oral solid dosage development, including continuous tableting.

References

1. Ueda K, Porter CJH, Goodwin A., et al. The expanding role of formulations to enable oral delivery of poorly water-soluble drugs. Nature Reviews Drug Discovery, 2026 25, 553–575. doi: 10.1038/s41573-026-01407-5
2. Gao Y, Qiu Y, Indulkar AS, Purohit HS, and Zhang GGZ.Rational design of amorphous solid dispersions. In Developing Solid Oral Dosage Forms. Elsevier, 2025.
3. Szabó E, Démuth B, Galata DL, Vass P, Hirsch E, Csontos I, Marosi G, and Nagy ZK. Continuous formulation approaches of amorphous solid dispersions: Significance of powder flow properties and feeding performance. Pharmaceutics, 2019 11(12), 654. doi: 10.3390/pharmaceutics11120654
4. Kleinebudde P. Improving process understanding in roll compaction. Journal of Pharmaceutical Sciences, 2022 111, 552–558. doi: 10.1016/j.xphs.2021.09.024
5. Leane M, Pitt K, Reynolds G, Tantuccio A, Moreton C, Crean A, Sheehan S. Ten years of the manufacturing classification system: A review of literature applications and an extension of the framework to continuous manufacture. Pharmaceutical Development and Technology, 2024 29(5), 395–414. doi: 10.1080/10837450.2024.2342953
6. Henriques J, Moreira J, and Doktorovová S. QbD approach to downstream processing of spray-dried amorphous solid dispersions – a case study. Pharmaceutical Development and Technology, 2021 26(3), 269–277. doi: 10.1080/10837450.2020.1863985
7. Leane M, Pitt K, Reynolds, G. The Manufacturing Classification System Working Group. A proposal for a drug product Manufacturing Classification System (MCS) for oral solid dosage forms. Pharmaceutical Development and Technology, 2014 Early Online, 1–10. doi: 10.3109/10837450.2014.954728
8. International Council for Harmonisation. Q13 Continuous manufacturing of drug substances and drug products. ICH, 2022.
9. Laki S, Ervasti T, Tajarobi P, Wikström H, Fransson M, Karttunen, AP, Ketolainen J, Folestad S, Abrahmsén-Alami S, and Korhonen O. Provoking an end-to-end continuous direct compression line with raw materials prone to segregation. European Journal of Pharmaceutical Sciences, 2017 109, 514–524. doi: 10.1016/j.ejps.2017.09.018
10. Al-Zoubi N, Gharaibeh S, Aljaberi A, bad Nikolakakis I. Spray drying for direct compression of pharmaceuticals. Processes, 2021 9(2), 267. doi: 10.3390/pr9020267
11. Baumann JM, Adam MS, and Wood JD. Engineering advances in spray drying for pharmaceuticals. Annual Review of Chemical and Biomolecular Engineering, 2021 12(1), 217–240. doi: 10.1146/annurev-chembioeng-091720-34106
12. Almaya A and Hanson J. Continuous manufacturing enables speed of development and commercialization. American Pharmaceutical Review. March 29, 2021. Accessed August 25, 2026. https://www.americanpharmaceuticalreview.com/Featured-Articles/574696-Continuous-Manufacturing-Enables-Speed-of-Development-and-Commercialization/
13. Vanhooren M. Drug product continuous manufacturing - Daurismo™ case study Conference presentation. CMC Strategy Forum Europe 2020, CASSS. May 12, 2020. Accessed August 25, 2026. https://www.casss.org/docs/default-source/cmc-strategy-forum-europe/2020-cmc-europe-speaker-presentations/speaker-presentation-vanhooren-meike-pfizer-2020.pdf
14. Rosas JG, Brush P, Thompson B, Miller C, Overton P, Tugby N, Stoliarskaia D, Hurley S, Ramasamy M, and Conway SL. Implementation of a fully integrated CM direct compression and coating process at a commercial pharmaceutical facility – Part 2: PAT and RTD results for normal operational conditions batches. International Journal of Pharmaceutics, 2023 636, Article 122814. doi: 10.1016/j.ijpharm.2023.122814
15. Conway SL, Rosas JG, Overton P, Tugby N, Cryan P, Witulski F, Hurley S, Wareham L, Tantuccio A, Ramasamy M, Lalloo A, Gibbs M, and Meyer RF. Implementation of a fully integrated continuous manufacturing line for direct compression and coating at a commercial pharmaceutical facility – Part 1: Operational considerations and control strategy. International Journal of Pharmaceutics, 2023 642, Article 122820. doi: 10.1016/j.ijpharm.2023.122820

About the Author

Anthony Tantuccio is a fellow scientist at Hovione and CT R&D program manager, with significant expertise in oral solid dosage forms, continuous tableting, PAT, and advanced control strategies. He previously held technical and innovation leadership roles at Bristol Myers Squibb and Merck & Co., where he contributed to the development and commercialization of continuous manufacturing platforms. At Hovione, Anthony helps shape the continuous tableting strategy by identifying and advancing projects that strengthen capability, reduce adoption barriers, and support business growth. His work connects technology development, client engagement, strategic partnerships, external scientific communication, and data-driven comparisons of continuous and batch operations to support broader adoption of continuous manufacturing.