Why Spray Drying Has a Thirty-Year Track Record in Pharma
Spray drying is not a new technology. It has been used in the food industry for over a century and in pharmaceutical manufacturing since the 1980s. What makes it particularly relevant to modern drug development is the growth of the BCS Class II molecule pipeline: drugs that are highly permeable but poorly soluble, and for which dissolution in the gastrointestinal fluid is the rate-limiting step in absorption.
For these molecules, converting the crystalline API into an amorphous form and dispersing it within a polymer matrix by spray drying provides a dissolution advantage that can increase oral bioavailability by two to tenfold or more, depending on the molecule and the formulation. The first spray-dried amorphous dispersion approved for a major indication was the HIV protease inhibitor ritonavir in Norvir capsules in the late 1990s. Since then, the technology has been applied to dozens of approved products across oncology, virology, and other therapeutic areas.
The Spray Drying Process: What Happens Inside the Dryer
In a spray drying process for amorphous solid dispersion (ASD) manufacture, the API and polymer are co-dissolved in an organic solvent, most commonly acetone, ethanol, methanol, dichloromethane, or a mixture of these. The solution is pumped to an atomiser, typically a two-fluid nozzle or a rotary atomiser, which breaks the solution into fine droplets that are sprayed into a heated drying chamber. Hot nitrogen or air flows through the chamber, evaporating the solvent from the droplets within milliseconds and leaving behind solid particles of the ASD.
The speed of solvent evaporation is what creates the amorphous state. The molecules do not have time to organise into a crystal lattice before the solvent is gone, so they are locked in a disordered, amorphous arrangement within the polymer matrix. The quality of that arrangement, specifically the degree of molecular dispersion of the drug within the polymer, depends on the polymer, the drug loading, and the processing conditions.
Key Process Parameters and Their Effects
| Process Parameter | Effect on Spray-Dried Dispersion | Typical Optimisation Approach |
| Inlet temperature | Drives solvent evaporation rate; affects particle temperature and morphology | Optimise to achieve residual solvent below ICH Q3C limits without thermal degradation of API |
| Feed concentration | Higher concentration increases throughput; affects particle size and morphology | Balance between yield, particle size target, and solution viscosity |
| Atomisation rate and type | Controls droplet size and therefore particle size of the SDD | Nozzle type and pressure optimised for target particle size distribution |
| Outlet temperature | Indicates drying efficiency; must be above glass transition temperature of wet cake | Typically 10-15 degrees C above Tg of formulation; controlled by inlet temperature and feed rate |
| Nitrogen flow rate | Affects residence time in drying chamber; closed loop systems recover solvent | Matched to feed rate for consistent outlet temperature |
| Secondary drying | Removes residual solvent to below specification limits | Fluid bed drying or tray drying post-spray; temperature and time optimised by residual solvent measurement |
Polymer Selection for Spray-Dried ASDs
The choice of polymer is the single most important formulation decision for a spray-dried ASD. The polymer must be miscible with the drug in the amorphous state, must dissolve in a common solvent with the drug, must form a rigid matrix with a sufficiently high Tg to prevent recrystallisation under storage conditions, and must release the drug appropriately when the dosage form contacts gastrointestinal fluid.
HPMC-AS (hypromellose acetate succinate) is the most widely used polymer for spray-dried ASDs in commercial products, offering good drug stabilisation, pH-dependent dissolution (releasing the drug in the upper small intestine at pH above approximately 5.5), and a well-established regulatory track record. PVPVA (polyvinylpyrrolidone-vinyl acetate) offers faster dissolution and is used where rapid drug release is needed. PVP-K grades and Eudragit systems are also used depending on the molecule and the target release profile.
From Spray Drying to Final Dosage Form
The spray-dried intermediate (the SDD powder) must be converted into a tablet or capsule for clinical and commercial use. The SDD typically has poor flow properties and low bulk density, which can make direct compression challenging. Granulation, either wet granulation or roller compaction, is often required to improve the powder properties before tabletting. The downstream processing step must preserve the particle size of the SDD and avoid conditions that would cause recrystallisation of the amorphous drug.
Ardena’s Spray Drying Capabilities
Ardena operates spray drying capability at its Somerset, New Jersey facility and at Pamplona (Idifarma) in Spain. Both sites provide spray drying for ASD development and GMP clinical manufacturing, with solvent handling systems, closed-loop nitrogen operation, and secondary drying capability. The formulation teams at these sites have developed spray-dried dispersions across a broad range of BCS Class II molecules and polymer systems.
