ARTICLE

A comprehensive approachto improving solubility andbioavailability: Spray drying
Spray drying is a well-established manufacturing process with applications in foods, industrial
products, and pharmaceuticals. Having come a long way from the first patent in 1865 (US patent
51,236),1 spray dryers today support the development of some of the most advanced drug
formulations, meeting the most precise morphological requirements to ensure performance,stability and manufacturability.

Stabilizing amorphous form: Worth the effort
Amorphous form materials have high levels of free energy andrequire a driving force to ensure their stability. Spray drying is
one method of stabilizing the amorphous form via amorphoussolid dispersions (ASDs). ASDs improve availability of poorly
water-soluble molecules.2 In these systems, drug-polymer

interactions inhibit recrystallization both in a solid state and ina dissolving media. In the latter, drug-polymer interactions canincrease free drug in solution which in most cases results in ahigher in vivo exposure. Thus, one of the initial steps in spraydrying is to identify the optimal drug-polymer combination forthe most successful levels of interaction.

Computational modeling programs, such as the Patheon™
Quadrant 2™ program, can predict optimal drug-polymer
combinations and ratios by assessing compatibility between
functional groups. This process generally yields four to fivedrug-polymer combinations from which a series of prototypes
are developed and evaluated at different drug loadings todetermine which one(s) provide the best combination of solubility
enhancement and stability.

Spray drying is one method of stabilizing theamorphous form via amorphous solid dispersions(ASDs).

as either formulation-dependent or process-dependent.
Formulation-dependent attributes depend on type of polymer
selected and the relationship of the drug to the polymer. These
include amorphicity, dissolution performance, physical stability,purity, and potency.
Process dependent attributes are directly influenced by theequipment used and include yield, particle size, flow properties,
residual solvent content, and particle morphology. Importantly,process-dependent attributes can be engineered to take on
specific properties by adjusting various processing conditions
and equipment parameters.
Comprehensive spray drying services from early development
through commercialization

Overview of the spray drying process
Once identified, the optimal drug-polymer system is dissolvedin an appropriate solvent and this solution is introduced into thedrying chamber of the spray dryer. The spray solution (or slurry) isthen atomized with an appropriate spray nozzle along with a hot
drying gas (e.g. nitrogen) being introduced co-currently. Due tocoupled heat and mass transfer, the solvent evaporates, causing
the droplets to dry and resulting in a spray-dried solid dispersion
powder. The particle morphology and particle size can be highly
controlled throughout the entire spray drying process. The spraydried powder typically undergoes a secondary drying step where
the solvent content is reduced to meet ICH guidelines.
Keeping an eye on the critical quality attributes of the productSeveral quality attributes of the product are monitored
throughout the spray drying process and can be categorized

An experienced spray drying manufacturer will be able
to contribute to all stages of drug development—fromformulation to clinical trial manufacturing to commercialization.
Comprehensive spray drying services also should also include
downstream processing of the spray-dried materials, including
further conversion, compacting, and spray coating of the spraydried powder into tablet or capsule formulations. Coating forclinical trial blinding purposes should also be available.
Specialized equipment is designed to support varying batchsizes. Smaller dryers are used in early development to conserve
material, and larger dryers support commercialization withbatch sizes measured in megatons. Having the right equipment
saves time and resources. For example, smaller equipment
is used to help understand the sensitivity of the product toprocess parameters prior to investing in the larger batches
necessary at scale-up.

2Considerations for scale-up and technology transfer
Scale-up and technology transfer between sites is typicallydone by a combination of thermodynamic process modelingand targeted statistical experiments relating the critical quality
attributes of the drug with the critical process parameters. The
design space is established by studying the scale independent
process variables that are verified at the new scale. Thesestudies can also serve as a basis for process validation.
In addition to the obvious requirement of having equipment
capable of handling larger batches of material, several factors
should be considered prior to scale-up. These include analyticalmethod validation, process fit/cycle time optimization, cleaningvalidation (including studies and method validation), vendor
qualification, shipping qualification, stability, etc. An experienced
spray-drying service provider needs to understand the impact ofeach of these factors before initiating scale up to prevent costly
errors and delays.
Analytical and downstream capabilities
Spray drying services need to include specific analyticalcapabilities for characterization of the spray-dried products.
A well-equipped characterization lab includes comprehensive
analytical testing of the product. These include differential
scanning calorimetry, X-ray powder diffraction, particle

size analysis, residual moisture/solvent, moisture sorption,
dissolution testing, ICH storage stability and other analytical
tools to fully characterize the products. Having these capabilities
onsite increases speed and streamlines development.
Downstream processing to convert the spray-dried intermediates
into solid oral dosage forms involve manufacturing capabilities
such as blending, roller compaction, milling, tablet compression
or encapsulation, and coating.
The benefit of a streamlined, comprehensive approachto spray drying
The poor water solubility of many of today’s new chemical entities3
in pharmaceutical research requires enabling technologies suchas spray drying to achieve the desired bioavailability. CDMOs
such as Thermo Fisher Scientific who have breadth and depthof experience in spray drying formulation and processes can
expedite product development along with successful technology
transfer and scale-up. In-house analytical and solid-state
capabilities allow for rapid development and release testing.
Spray-dried amorphous dispersions expand the possibilities
for therapeutic options for patients by making otherwise poorly
soluble compounds suitable for drug delivery. A detailed
understanding of the complexities associated with spray drying
coupled with in-house expertise and capabilities can leverage
this enabling technology to speed drug development.

References
1. Santos D, Maurício AC, Sencadas V, Santos JD, Fernandes MH, Gomes PS. Spray Drying: An Overview. InTechOpen Book Series. 2017. Available at: https://www.
intechopen.com/chapters/58222
2. Pandi P, Bulusu R, Kommineni N, Khan W, Singh M. Amorphous solid dispersions: An update for preparation, characterization, mechanism on bioavailability, stability,regulatory considerations and marketed products. Int J Pharm. 2020;586:119560. doi:10.1016/j.ijpharm.2020.119560
3. Ibid.

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Published 1/22