The advantages and challenges of spray drying

Spray drying, a widely used processing technology in the food sector, has been increasing in popularity within the pharmaceutical manufacturing industry

Spray drying offers multiple opportunities for the formulation development of tablets, powder-filled capsules and inhaled drug products. It is highly scalable and offers high precision control of particle engineering, such as particle size, bulk density, degree of crystallinity and levels of both organic volatile impurities and residual solvents.

Both amorphous and crystalline powders are possible. The discussion in this article will focus on amorphous solid dispersions.

Benefits of pharmaceutical spray drying

An amorphous solid dispersion contains the active pharmaceutical ingredient (API) in its amorphous state (rather than the crystalline form produced during API purification) dispersed in a matrix comprising a hydrophilic polymeric carrier excipient.

The presence of the excipient(s) is critical; otherwise, the API would have a high tendency to recrystallise. As well as inhibiting recrystallisation, the excipient should also be chosen to improve both the solubility and dissolution rates of the API in the dispersion.

The higher energy, metastable amorphous state of the API has a higher solubility compared with the crystalline form, which is important, as increasing numbers of drug candidates have poor solubility in aqueous and gastrointestinal fluids. Poor solubility leads to lower absorption, poor bioavailability and increased pharmacokinetic variability. The end result is that poorly soluble drugs have suboptimal efficacy and safety profiles, which are likely to lead to failure in the clinic.

The time savings can also be significant: a study by scientists at GlaxoSmithKline showed that for Developability Classification System (DCS) IIb APIs (those with poor solubility but good permeability), it is not unusual for two additional years of clinical studies to be required just to prove that the compound does not have adequate exposure to reach the required efficacy.1

Spray drying amorphous formulations can increase both solubility and bioavailability while still permitting a traditional dosage form, such as a tablet or capsule, to be created.

Furthermore, an amorphous solid dispersion is a potential solution for APIs that have multiple polymorphs. Another advantage is in the formulation of products that have unusual or difficult characteristics. These products might be sticky or hygroscopic; they might be slow to crystallise or difficult to isolate. And, if the materials are particularly temperature sensitive, the rapid drying offered by the technique is a substantial advantage in terms of ensuring that the product is not degraded during processing.

Important processing parameters

In the spray drying process, the liquid feed is atomised into very small droplets through a narrow nozzle within a hot drying gas. The rapid evaporation of the droplets results in solid particles of amorphous API molecules dispersed in a polymeric matrix. The key to creating ideal spray dried particles is to control the critical processing parameters that influence the radial distribution of the components (API and polymer).2

During drying, the components tend to adsorb and diffuse on the surface of the droplet (often defined by Fick’s second law of diffusion). Solvent evaporation, a balance between the solvent’s vapour pressure and partial pressure, causes the droplet surface to recede, leading to the diffusion of components towards the interior.

It is important to model the diffusional movements within the droplet to predict the surface distribution of the components. There are several critical process parameters (spray rates, feed solution concentration, processing temperature), as evaporation must occur before either the API crystallises or phase separation occurs. Evaporation of the solvent must, therefore, be rapid if an amorphous dispersion is to be created.

The resulting particle size distribution is important for both the performance and powder handling of the dispersion. This is determined by the spray pattern and size of the droplets, tension and viscosity of the solution and its solids content, the spray rate, atomisation gas, inlet and outlet temperature, evaporation rate and residence time.

The particle size and morphology have an impact on both density and compressibility, both of which influence whether the powder can be formulated as a tablet.

The low density powder typically achieved from spray drying needs further development (such as roller compaction) before being compressed into tablets and filled into capsules.

Further development of spray-dried particles

It is important that the spray dried dispersion is both chemically and physically stable and provides adequate solubility enhancement. Some tests at this stage include X-ray powder diffraction and differential scanning calorimetry to assess the amorphous/crystalline content of the solid dispersion and its solubility and dissolution in biorelevant media.

Once benchmarks of stability and performance are met, the next step is to manufacture the solid dosage form.

Spray dried powders have low density, compressibility and poor powder flow. Additional excipients are required to add bulk and to aid processability. Whether manufacturing a tablet or capsule, any further excipients that may be required in production (roller compaction, tableting, capsule filling, etc.) should be selected and tested for compatibility with the spray dried powder. It is also essential to consider the manufacturability and disintegration properties of the powder blend and the final product.

When the compatibility of these excipients is being assessed, both binary mixtures and design of experiment (DoE) studies are appropriate. Any data that has previously been collected on the crystalline drug may not be applicable when working with amorphous material … but provides a reference point for comparisons.

It is important that the spray dried dispersion is both chemically and physically stable and provides adequate solubility enhancement

It is crucial that the final amorphous intermediate is used for these excipient compatibility studies, as amorphous forms are more sensitive to degradation. It is also important to consider moisture protection as amorphous APIs tend to be more hygroscopic than crystalline forms.

Formulation development efforts should be focused on creating dosage forms that have fast disintegration times; dissolution should also be monitored for gelling. It may be necessary to consider more aggressive disintegration approaches if the initial attempts produce long disintegration times or particularly slow dissolution rates. These approaches may include the incorporation of high levels of bicarbonate, an osmogen or highly water-soluble excipient, or a super-disintegrant.

Ensuring the rapid dissolution of solid dispersions

All this in vitro formulation development work should be confirmed with in vivo studies. Furthermore, the neat dispersion suspended in water and the formulated dispersion product should be compared in a relevant model. This will ensure that poor disintegration does not lead to exposure levels that are lower than expected.

If the disintegration of the final dosage form isn’t consistent, then the increased solubility imparted by the spray dried powder can rapidly be negated by the poor release of the spray dried intermediate. Formulation processes designed to increase density and reduce surface area can also slow down the spray dried intermediate’s wetting rate. This will allow the final dosage form to disintegrate fully without forming a gel.


Spray drying is widely applicable and commonly used to create dosage forms from powders and granules for oral delivery to powders for nasal and pulmonary delivery. Its primary advantage is in improving the bioavailability of poorly soluble drugs, but it also offers the developer other significant advantages.

It is not a trivial exercise to identify a suitable dispersion quickly. There are several reasons for this, but particularly notable is the fact that disintegration, flow and density challenges are amplified when developing a spray dried amorphous product, which may extend timelines and introduce complexities that are not commonly seen with more traditional tablets and powder-filled capsules.

However, the implementation of DoE strategies can help to avoid bottlenecks and programme delays. Importantly, if the API falls into DCS IIb as it is highly insoluble, the development savings can be substantial if bioavailability challenges are addressed ahead of first-in-human studies, as this will minimise the chances that a reformulation will be necessary after trials have started.


  1. M.M. Hann and G.M. Keserü, “Finding the Sweet Spot: The Role of Nature and Nurture in Medicinal Chemistry,” Nat. Rev. Drug Discov. 11(5), 355–365 (2012).
  2. R. Vehring, “Pharmaceutical Particle Engineering via Spray Drying,” Pharm. Res. 25(5), 999–1022 (2008).

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