Spray Drying

Several approaches can be taken to overcome the poor solubility of oral drugs, including particle size
reduction, salt or cocrystal formation, lipid-based self-emulsification and the formation of amorphous solid
dispersions (ASDs). ASDs, which are prepared by combining drug substances with polymeric materials, are effective
because the drug substance exists in an amorphous state and is therefore more readily dissolved and absorbed. It is
reported that over 80% of ASDs offer improved bioavailability. Spray drying, hot melt extrusion and coprecipitation
are the three most used techniques for the manufacturing of ASDs.

Spray drying is a suspended particle processing (SPP) technique that utilizes liquid atomization to create
droplets that are dried to individual particles when moved in a hot gaseous drying medium, usually air. It is a one-
step continuous unit processing operation. The spray drying process transforms a pumpable fluid feed into a dried
product in a single operation. The fluid is atomized using a rotating wheel or a nozzle, and the spray of droplets
immediately comes into contact with the flow of hot drying medium. The resulting rapid evaporation maintains a low
droplet temperature so that high drying air temperatures can be applied without affecting the product. The time of
drying the droplets is very short in comparison with most other drying processes. Low product temperature and
short drying time allow spray drying of very heat-sensitive products.

The liquid is pumped from the product feed tank to the atomization device, such as the rotary disc atomizer,
pressure nozzle, pneumatic nozzle, or ultrasonic nozzle, which is usually located in the air distributor at the top of the
drying chamber. The drying air is drawn from the atmosphere through a filter by a supply fan and is passed through
the air heater (e.g oil furnace, electrical heater, steam heater) to the air distributor. The droplets produced by the
atomizer meet the hot air and the evaporation takes place cooling the air in the meantime (the air is cooled down
because it takes a lot of energy to evaporate the solvent, for instance water, and therefore we visualize a decrease in
temperature). After the drying of the droplets in the chamber, the majority of the dried product falls to the bottom of
the chamber and entrains in the air. Then they pass through the cyclone for separation of the dried particles from
the air. The particles leave the cyclone at the bottom via a rotary valve and are collected or packed later in the
cyclone and/or filter bag. The fine particles will remain entrained in the air and then this air passes through scrubbers
to wash out the fine particles. The air passes from the scrubber to the atmosphere via the exhaust fan.

The automatic controls often are to maintain the inlet temperature by altering the heater operating
parameters (such as the steam pressure, the amount of oil to the heater…) and the outlet temperature by adjusting
the amount of feed pumped to the atomizer.

The “liquid line” is usually made of stainless steel, since it is resistant to corrosion, resistance to high
temperatures, easy to sanitize, and because of the crystallization processes.

The following components can be found in a

spray-dryer: a feed solution, a pump (which
allows to feed the solution), a hot air inlet
(supplier for heat), an atomization device (nozzle
atomizers/ rotary atomizers), a drying chamber, a
product collecting system, an air heating system,
and a cyclone separator - ensures good
circulation of air, facilitates heat transfer and
mass transfer and encourages the separation of
dried particles from the moving air by the
centrifugal action. The spray-dryer provides a
large surface area for heat and mass transfer by
atomizing the liquid feed into small droplets.
 Spray drying stages:

1. Atomization

It is the most critical step in the spray drying process and consists of the conversion of the fluid into a fine
spray comprising high surface area droplets. The breakup of bulk liquid into a large number of droplets drives the
rest of the spray drying process by reducing the internal resistances to moisture transfer from the droplet to the
surrounding medium. This is because of the enormous increase in surface area of the bulk fluid as the droplet fission
proceeds, with its instability increasing in accordance with the intensity of atomization.

Atomization is central to the spray drying process, owing to its influence on shape, structure, velocity and size
distribution of the droplets and, in turn, the particle size and nature of the final product. This greater surface ‐to ‐
volume ratio enables spray drying to achieve a faster drying rate (as drying time is proportional to the square of the
particle dimension). Consequently, there is minimal loss of heat sensitive compounds and, eventually, particles of the
desired morphology and physical characteristics are obtained.

As the hot air rushes through the nozzle, it creates a low-pressure region behind it, which pulls the solution
along. As the solution is forced out of the nozzle, it breaks into small droplets and is atomised (aerosol). Whenever
aerosolised, the droplets of a liquid form spheres (smallest surface area to volume ratio).

The particle size of the final dry powder is primarily controlled by the initial feed droplet size. The type of
atomizer not only determines the energy required to form the spray but also the size and size distribution of the
drops and their trajectory and speed, on which the final particle size dep ends. The chamber design is also influenced
by the choice of the atomizer. The drop size establishes the heat transfer surface available and thus the drying rate.

Particle size

Successful prediction of droplet size enables one to control the powder properties as desired.

The Sauter mean diameter characterizes the droplet cloud together with the size distribution. This is defined
as the ratio of the total droplet volume to the total drop let surface. The Sauter mean diameter corresponds to the
particle diameter with the same volume-to-surface ratio as the entire spray or powder sample.

Rotary Atomizers: Allow centrifugal atomization. Driven by high

velocity discharge of liquid from the edge of a wheel or disc. Feed liquid is
centrifugally accelerated at high velocity to the centre of a rotating wheel with
a peripheral velocity of 200 m/s. The outward flowing feed with respect to the
rotating wheel surface accelerates to the periphery and then disintegrates into
a spray of droplets.

Wheel Atomizers: Liquid is fed into the centre of a rotating wheel,

moves to the edge of the wheel under the centrifugal force, and is disintegrated at the wheel edge into droplets. The
spray angle is about 180 ᵒC and forms a broad cloud. The wheel atomizer produces a spray of high homogeneity
within a wide range of mean droplet size. The size distribution of droplets can be controlled by changing the wheel
speed.

Pressure nozzle (hydraulic) atomization (single-fluid nozzle): In this type of atomization, a spray is created by
a consequence of pressure to velocity energy conversion as the liquid passes through the nozzle under pressure
within the usual range of 5–7 MPa. The required pressure is supplied by the spray-dryer feed pump, with spray
pressure having an influence on droplet size. The liquid enters the nozzle core tangentially and leaves the orifice in
the form of a hollow cone with an angle that varies from 40 to 140ᵒC. The orifice diameter is usually small, from 0.4
to 4 mm, and the usual capacity of one nozzle does not exceed 100 l/h. The dried particles are usually hollow
spheres. Pressure nozzles are not suitable for highly concentrated suspensions and abrasive materials because of
their tendency to clog and erode the nozzle orifice. (more appropriate for industrial scale)
 Pneumatic nozzle (two-fluid nozzle atomization): The source of
atomization energy is compressed gas with a spray created by a high-
speed gas steam (either air or nitrogen) blasting the liquid into droplets.
Briefly, it involves the use of two separate fluid streams: one carrying the
liquid to be atomized, and the other carrying a high-velocity gas or air
stream. These two streams are typically mixed at a nozzle or injector, and
the kinetic energy of the high-velocity gas stream imparts energy to the
liquid, breaking it up into small droplets. Compressed air creates a shear
field, which atomizes the liquid and produces a wide range of droplet sizes. Sprays of less viscous feeds are
characterized by low mean droplet sizes and a high degree of homogeneity. With highly viscous feeds, larger mean
droplet sizes are produced but homogeneity is not as high. These types of nozzles have the highest energy
consumption. (more appropriate for lab scale)

Ultrasonic nozzle (monodisperse nozzle): The liquid feed is

converted into a fine mist by high-frequency sound vibrations (high-
frequency sound waves, typically in the ultrasonic range, which can
break up a liquid into very fine droplets or a mist). These nozzles are
widely used in various industrial applications where precise and
controlled atomization of liquids is required. Droplet size is influenced
by the frequency of vibration, viscosity of the feed, and surface tension.
The range of frequencies used for ultrasonic nozzles is from 20 kHz to
180 kHz, with the smallest droplet size produced with the highest
frequency. However, ultrasonic atomization technology is effective only
for low‐viscosity Newtonian fluids as it demands large quantities of air. These nozzles can offer precise droplet size
control, efficiency, reduced agglomeration and wide range of viscosities.

2. Droplet drying and particle formation

Drying process: The removal of solvent occurs at the material's surface (saturated phase) to the
surrounding environment (unsaturated phase). In other words, as the solvent is removed from the surface, it
migrates from the core of the particles through diffusion to the surface. It is important to understand that if this
diffusion is too rapid, there is the possibility of obtaining roasted surfaces (cases in which an impermeable layer
forms). Temperature significantly influences the drying process (if the temperature is too high, particles may also
segregate). The particle size itself influences the drying process, in that the larger the specific surface area of the
particles (smaller particle size), the larger the interface surface area, and the faster the drying process. Due to the
latent heat of vaporization of water, during its vaporization, there is a cooling of the surface where it occurs. The
temperature difference results in a heat transfer from the air to the liquid at a rate that increases with the increasing
temperature difference.

The amount of easily removable water (unbound water) is known as the free moisture content, and the
moisture content of the water that is more difficult to remove in practice (bound water) is the equilibrium moisture
content.

Absolute humidity (AH) - AH is independent of temperature. It represents the mass of water vapor in the air
without considering the air's temperature or its capacity to hold moisture. It tells you how much water vapor is in the
air at a specific moment.

Relative humidity (RH) - RH is highly dependent on temperature. It indicates how close the air is to being
saturated with moisture at a specific temperature. It is a measure of the moisture content in the air relative to the
maximum amount of moisture that air could hold at a given temperature.
 Dry bulb temperature - Is the temperature of air, which is not saturated with water vapor, as measured by an
ordinary thermometer.

Wet bulb temperature - Is a characteristic of moist air of a given dry bulb temperature, expressing the
saturation temperature of that air with the same enthalpy, i.e. obtained by evaporation of 0°C water under adiabatic
conditions. The difference between dry and wet bulb temperatures is a measure of drying capability (driving force).

Usually, in the spray drying, the air enters the chamber tangentially and rotates the drying droplets around
the chamber to increase their residence time and therefore the time available for drying. For pharmaceutical
purposes, it is usual to filter the incoming air and to heat it indirectly by means of a heat exchanger. The rate of
drying of atomized droplets is extremely fast because of the very large total surface area of the droplets, which
facilitates fast evaporation of the solvent. The time taken to dry the particles in spray drying is within the range of
milliseconds to a few seconds.

The particles have a characteristic shape, in the form of hollow

spheres sometimes with a small hole. This shape arises from the drying
process because the droplet enters the hot air stream and dries from the
outside to form an outer crust with liquid still in the centre. The internal liquid
then vaporizes and the internal vapor escapes by blowing a hole in the sphere.

Diffusion: Diffusion is the process by which solute molecules move

from regions of higher concentration to lower concentration.

Convection: Convection, driven by hot air in the spray dryer, can carry
away moisture from the droplet's surface quickly, leaving behind a concentrated solution within the droplet.

The most critical step in particle formation, this process step is associated with the morphology of the final
product. Evaporation of moisture during spray drying can be visualized as two stages: constant rate period and falling
rate period.

Examining the drying kinetics of the spray drying

process is critical in predicting the heat and mass transfer
in the drying material. Initially, when the droplet is
exposed to hot gas, rapid evaporation takes place. During
this exposure, the droplet is heated from its initial
temperature (T0) to the temperature of equilibrium
evaporation temperature (Teq) (Figure 1.11, AB). During
this period, the removal of moisture follows the constant
rate period of the drying rate curve as the moisture is
removed constantly from the surface of the droplet
keeping it sufficiently cool. The droplet surface remains
saturated with moisture at this stage and its temperature
is constant at the wet‐bulb temperature.

As the moisture removal from

the droplet proceeds, the solute
dissolved in the liquid reaches a
concentration beyond its saturation
concentration and tend to form a thin
shell at the droplet surface described
as “crust formation” (step 2, Figure 1.12). The commencing of crust formation event is an important kinetic
characteristic of the spray drying process as it transforms from low to high temperature drying. After the crust
formation, the moisture removal turns into a diffusion‐controlled process, and the evaporation rate is dependent
upon the rate of water vapor diffusion through the dried surface shell (Figure 1.12, step 3). This constitutes the
falling rate period. During the falling rate period, although the particle will begin to heat (Figure 1.11, CD), it is
almost at the coolest part of the dryer, where the drying gas is at or near the outlet temperature of the dryer.
Consequently, the particles are never heated above the outlet temperature of the dryer, even though the inlet
temperature may be considerably higher. The final dried powder will be at a temperature approximately 20°C lower
than the air outlet temperature. An interesting phenomenon that happens during the falling rate period is “bubble
formation” (Figure 1.12, step 4, and Figure 1.13). When the partial pressure of moisture vapor at the droplet centre
exceeds ambient pressure, it results in bubble formation and a subsequent increase in temperature.

A considerable amount of energy is required for this vaporization, which halts the sensible heating ( Figure
1.11, DE). The droplet inflates to the outer
radius and finally results in irregular
randomly shaped particles (Figure 1.13). As
mentioned above, a crust is formed as the
moisture content decreases, and the
droplet temperature ultimately rises
towards the dry‐bulb temperature of the air
(Figure 1.11, EF).

Following the crust formation, the droplet may follow one of the two principal pathways, leading either to
small, solid particles or large, hollow particles. The first is the “dry shell” route, which is similar to a shrinking core,
producing particles which are susceptible to shattering when dried at high temperature. The second route is the “wet
shell” type, which tends to form hollow particles which may inflate when subjected to higher drying temperature.

In a rapid evaporation scenario, there may not be sufficient time for the solute to diffuse uniformly to the
surface of the droplet before it dries. Instead, a microencapsulation effect can occur (hollow spheres). As a result,
you get a core-shell structure, where the solute is concentrated at the core of the particle, and the outer layer
consists of the shell formed by the rapidly drying solvent. In this case, convection phenomenon is dominant towards
the diffusion phenomenon.

On the other hand, in a slow evaporation scenario, the drying process occurs gradually, allowing more time
for the solute to diffuse from the interior of the droplet to the surface. In this, solute molecules have sufficient time
to migrate to the droplet's surface as moisture evaporates slowly (diffusion). As a result, the solute is evenly
distributed throughout the particle, and there is no clear core-shell structure. In this case, diffusion phenomenon is
dominant towards the convection phenomenon.

Peclet number is depicted as the

main controlling parameter of
the droplet drying process and,
hence, the particle formation.

For Peclet numbers smaller

In the absence of other driving forces, the solutes remain evenly distributed in the droplet during the evaporation.
The surface enrichment is small. If the solutes are freely soluble in the solvent, the initial saturation is also small and
the characteristic time for the solutes to reach saturation at the surface is close to the droplet lifetime. In this case,
solid particles with a particle density close to the true density of the dry components are likely to form.

In the case of Peclet numbers larger than 1, the surface moves faster than the dissolved or suspended
components. The result is that the surface becomes enriched with the component associated with the high Peclet
number. Solutes may not have sufficient time to crystallize during the precipitation window. Instead, a shell may be
formed due to the increase in viscosity as the solution transitions to a wet glass at the surface. Molecules with high
initial saturation and fast crystallization kinetics may separate into a crystalline phase. Suspended material may form
a composite shell. Regardless of the nature of the shell formation mechanism, the process is initiated at the surface.
The resulting particles can have a range of different morphologies, depending on their size and the properties of their
shells in the final stages of the drying process. Solid hollow spheres can be formed, if the shell becomes rigid quickly
and does not buckle or fold. Otherwise, dimpled or wrinkled particles are formed. With increasing Peclet numbers
the time to reach the critical concentration for shell formation at the surface decreases, that is shell formation occurs
earlier in the evaporation process on a larger droplet. Hence, the density of the particle decreases.

A molecule with low solubility is dried that has a

large diffusion coefficient, so its Peclet number is low
initially. The concentration increases without much surface
enrichment until supersaturation is reached and
precipitation of a separate phase is initiated at the surface or
throughout the bulk of the droplet. At this point the mobility of
this component is no longer determined by the diffusion
coefficient of the dissolved molecule, but rather by the much
lower mobility of the phase separated domains. The Peclet
number associated with this component is now very large and the phase separated domains accumulate at the
surface and merge to form a shell which may deform in various ways, subsequently.

During spray‐air contact, the droplets usually meet hot air in the spraying chamber, either in co ‐current flow
or counter‐current flow or a mixed mode in relation to the droplets. In the pharmaceutical industry, co-current mode
is the most suitable method of supplying hot air.

→ Co-current contact occurs when the droplets fall down the chamber with the air flowing in the same
direction. It is the most common system with both wheel and nozzle atomization. In this arrangement, the
atomized droplets entering the dryer are in contact with the hot inlet air, but their temperature is kept low
due to a high rate of evaporation taking place and is approximately at the wet‐bulb temperature. The cold air,
in turn, pneumatically conveys the dried particles through the system. The contact time of the hot air with
the spray droplets is only a few seconds, during which drying is achieved, and the air temperature drops
instantaneously. The final product-temperature is lower
than the inlet air temperature. The air enters the
chamber tangentially and rotates the drying droplets
around the chamber to increase their residence time and
therefore the time available for drying.
→ Counter-current contact is achieved when the drying air
flows counter-current to the falling droplets or particles.
Here, the outlet product temperature is higher than the
exhaust air temperature, and is almost at the feed air
temperature, with which it is in contact. This type of
arrangement is used only for heat‐resistant products.
→ Mixed-flow contact is employed when the size of the drying chamber is limited. This type of arrangement is
used for drying coarse free‐flowing powder, but the drawback is the higher exit temperature of the product.

3. Product collection and air discharge system

Usually, the larger particles drop to the bottom of the drying chamber and are collected (drug product).
Smaller particles will be suspended in the air and must be removed somehow. The separation of fine particles from
the air is achieved by use of a special separation device, such as a cyclone or bag filter. A cyclone will have a column
of air spinning round and round. Since solids are denser than liquids, under a centrifugal force they will move to the
outside of the cyclone chamber. The air is exhausted to waste while the particles run down the side of the chamber
and are collected at the bottom.
 A cyclone consists of an upper cylindrical part,
referred to as the barrel, and a lower conical part, referred
to as the cone. The gas stream, loaded with solid particles,
leaving the spray dryer enters tangentially at the top of the
barrel and travels downward into the cone, forming an
outer vortex. The increasing air velocity in the outer vortex
exerts a centrifugal force on the particles, separating them
from the gas stream. When the gas stream reaches the
bottom of the cone, an inner vortex is created, thus
reversing its direction and exiting out at the top as clean
gas. The particulates fall into the collection chamber
attached to the bottom of the cyclone.

In a spray drying process, high flow rates of drying air are generally obtained using centrifugal fans. The fan
is a key component of the hot air circulation system, and its primary purpose is to ensure efficient drying by
facilitating the movement of hot air within the drying chamber. The fan draws in ambient air and directs it through a
heating system, where it is heated to the desired temperature. This hot air is then blown into the drying chamber.
The circulation of hot air within the chamber is essential for evaporating moisture from the atomized droplets and
transforming them into dry particles. Wet scrubbers are often used to purify and cool the air so that it can be
released to atmosphere.

As the drying chamber capacity is proportion al to the temperature difference of the inlet and outlet air over
the chamber, it is desirable to achieve the highest possible value, which are the highest inlet air temperature and the
lowest outlet air temperatures.

Spray drying can have many applications namely, it enables direct compressibility by manufacturing granule-
sized particles that can be directly compressed, enhances the bioavailability of poorly water-soluble drugs by
converting them into the amorphous form, enables modified release and taste masking, enables the production of
dry powders for inhalation by producing spherical particles in the respirable range, enables aseptic production and
enables the production of microencapsulated particles.

Process layouts and applications

The spray drying process can be an open or closed system. In an open system the drying gas is air. In an open
cycle the gas is not recirculated but enters the atmosphere. Open system spray drying is cost-effective but may not be
suitable for pharmaceuticals sensitive to oxygen. In a closed system, nitrogen is used as the drying gas. It is recycled,
with the evaporated solvents being recollected.
 Open-cycle layout: This
and conveying it through the chamber once, and then exhausting it back to the
atmosphere.

Closed-cycle layout: Closed

relatively inert gas such as nitrogen, or air
in special cases. A closed cycle dryer is
used when the feedstock is prepared by
dissolving the solids in flammable solvents, in order to reduce the explosion
risk and to obtain a complete recovery of the solvent. When the spray dried
product is susceptible to oxidation, then a closed cycle dryer is the most
appropriate choice. It is also advantageous to use this type of dryer when a
toxic feed is subjected to drying.

Semi closed-cycle layout: This dryer design is a cross between open and closed cycle dryers. A direct ‐fired
heater is used, and the air entering the system is limited to that required for combustion. An amount of air equal to
the combustion air is bled from the system at the other end of the process. The gas (mainly products of combustion)
is recycled through the dryer. The recycled gas has very low oxygen content.

Spray drying process parameters and their influence on product quality

The following factors will influence the final product quality, mainly in terms of residual moisture, particle size
and morphology, namely atomization pressure, feed flow rate, feed viscosity and feed surface tension. These
parameters have influence on the droplet size.

→ Atomization pressure

With the same type of nozzle and feed material, as the atomization pressure is increased, droplet size decreases
according to the relationship below:

Where D1 and D2 are the initial and final droplet sizes on changing the atomization pressure from P 1 to P2,
respectively. This is due to the requirement of an efficient delivery of the atomization energy to the bulk liquid to
drive droplet fission.

→ Feed flow rate

At constant atomization pressure, increasing the flow rate increases the droplet size, since the nozzle’s
hydraulic energy has to atomize more liquid. As the liquid interaction with the atomization energy is minimal, the
droplet fission is insufficient to reduce its size. Feed rate is associated with the peristaltic pump speed which feeds to
the spray solution to the rotary or nozzle atomizer. As the atomization pressure is for the nozzle atomizers, wheel
rotation speed and diameter are for the rotary atomizers. The wheel rotation speed and wheel diameter have an
inverse relationship to the droplet size.
 → Feed viscosity

The feed viscosity has a direct relationship to droplet size. As the feed viscosity increases, the atomization energy
supplied to the nozzle must overcome large viscous forces to achieve smaller droplet sizes. Viscous forces tend to
reduce the energy available for breaking the droplets, thus resulting in larger droplets. The equation describing the
relationship between droplet size and feed viscosity is given below. The same principle also applies to that of feed
density.

Where D1 and D2 are the initial and final droplet sizes on changing the feed viscosity from
μ1 to μ2, respectively.

→ Feed surface tension

Surface tension of the liquid plays an important role in the extent of atomization. To achieve atomization, the
atomizer should overcome the surface tension of the feed liquid. Hence, a liquid having higher surface tension is
difficult to atomize. This necessitates the preparation of an emulsion with the aid of emulsifier addition, and a
homogenization step prior to spray drying in certain cases, in order to combat the surface tension of a feed,
especially that involving multiple components.
NOTE: Higher surface tension means that the liquid molecules are more strongly attracted to each other and tend to
resist breaking apart into smaller droplets. As a result, it requires more energy or force to overcome these cohesive
forces and disintegrate the liquid into finer particles.

Optimizing the spray-dryer

To increase production, we can increase the flow in three ways, namely:

→ Increase flow by increasing the nozzle’s orifice size - Increasing the orifice size while maintaining pressure
increases flow rate. Be sure to check that the dryer has enough evaporative capacity to handle the higher
flow rates and enough residence time to handle the larger drops that will be produced.
→ Increase flow by increasing pressure - One option is to use the same nozzle but beware that higher pressure
will result in smaller drops. Another option is to use a different nozzle type – or a different orifice and
core/swirlchamber/whirlchamber combination – to maintain the same drop size at a higher pressure and
flow.
→ Increase flow by using a multi-orifice nozzle - The same size orifice and operating pressure will produce the
same droplet/particle size. Or use a multi-orifice nozzle that produces smaller drops when splitting the flow
rate through two, three or four orifices. This results in smaller drops that evaporate more quickly and will
increase the rate of powder production.

NOTES:

 Widening the spray angle, increases the liquid tangential velocity to reduce the droplet size. The choice of
spray angle is related to the type of air flow, namely co-current and counter-current, with the wider angle
being used with the former and the narrow angle with the latter.
 Very small droplets result in fines of powder which can overload cyclones, causing dusty emission and
product loss. To address this problem, it is important to check heat setting to make sure particles are not
over-dried, causing fractured particles; use larger capacity nozzles at lower pressure; consider nozzles that
provide a narrower drop size distribution.
 Smaller spray droplets (and particles) are obtained by using smaller capacity nozzles (expressed in terms of
flow rate) and/or by spraying at higher pressures.
 Larger spray droplets (and particles) are produced by larger capacity spray nozzles and/or spraying at lower
pressures.

 The speed at which the drying air travels through the chamber affects particle residence time and drying
rate.
Process factors

Feed concentration – The feed concentration is the solid particle fraction in the volume of the solution. A
higher feed concentration corresponds to less solvent in each droplet. This leads to higher Peclet values, shorter
evaporation times and porous particles with less density in the final stage. Higher feed concentrations increase the
chance of agglomeration or formation of multimers between polymer chains or API molecules which result in more
porous particles with lower density and rougher surfaces.

Feed rate – Is reported as the mass of transferred powder per unit of time. It controls the amount of solvent
and solid content entering the drying chamber. Thus, physicochemical properties such as solvent evaporation rate,
morphology, particle size and density can be altered by varying the feeding rate. Higher feed rates result in higher
moisture content in final particles. Higher yields were reported at decreased feed rates. Increased feeding rate of
the feedstock at the same atomizing gas flow rate leads to enlarged droplets due to lower atomization energies.
However, very high feeding rates might result in overloading the condenser in closed loop setup.

Inlet temperature – Inlet temperature has a direct effect on heat and mass transfer during the droplet drying
process and is significant in cooling the atomized feed droplets to their wet ‐bulb temperature. Higher inlet
temperatures influence the particle formation process due to high rate of solvent evaporation. This process can lead
to a pressure gradient inside and outside the droplet with subsequent effects on the final morphology of the powder
such as surface roughness. A higher inlet temperature leads to rapid formation of a solid skin on the outer surface
of the droplet which entraps the solvent vapours. Depending on the type of API and excipient polymer used, the
solvent vapour pressure may collapse the whole particle, or result in a particle with a porous surface. Slower drying
rates, caused by lower temperatures, can result in low Tg products having stickier particles which reduce the final
yield due to wall deposition. This will in turn increase the stickiness of the powders to the cyclone and lower the
final yield of the spray-dried material. Inlet temperature is often associated with dryer evaporative capacity and
thermal efficiency.

Outlet temperature - The temperature of the air laden with solid particles before entering the cyclone is
defined as the outlet temperature. This temperature is a result of the heat and mass balance in the drying cylinder,
and therefore cannot be regulated. Striking the optimum temperature difference between the inlet and outlet
temperature is most critical in a spray drying process. Outlet temperature correlates with the final moisture content
and surface topography of the final product. For instance, operation at high outlet temperature is carried out to
achieve high moisture content to obtain agglomerated “instant” powdered products. This is because higher outlet air
temperature promotes rapid crust formation while the drying of the inner core is still not complete. Furthermore, an
increase in the outlet temperature also increases the particle temperature by shifting the wet ‐bulb lines on the
psychrometric chart.

Atomization and drying gas (type and flow rate) – Atomization gas properties such as density and specific
heat capacity are decidedly important in defining the final properties of spray-dried powders. For instance, N 2 with
lower density has been shown to produce smaller particles with different surface morphologies compared to CO 2.
Moreover, an inert gas like N2 is typically used with non-aqueous solutions (organic solvents) and for solutions
containing easily oxidized solutes. According to a study, the order of most crystallinity to least is N 2 > air > CO2. A
possible reason for this is due to the higher temperature and mass transfer of CO 2 compared to N2 and air which in
turn provides better conditions for production of amorphous materials. It was reported that higher efficiency in the
drying process with CO2 compared to air is due to its higher heat transfer rate.

Atomization device – The type of atomization device also affects the droplet size distribution, velocity, spray-
cone diameter and incident angle. One-fluid nozzles can produce larger particles compared to the other types of
atomizers. However, these nozzles are not compatible with high-viscosity non-Newtonian feed stocks. The most
common type of atomizer used in production and research of amorphous solid dispersions is the two-fluid nozzle. In
these systems, the atomizing gas and solution feed rate are the main factors in defining final particle size distribution
thereby permitting a high level of control of the atomization process. Higher gas flow rates in tandem with lower
feed rates typically result in smaller particle sizes.

Residence time of particles in the spray chamber - Longer residence times can lead to over-drying, while
shorter times can result in under-drying. This parameter is important from two perspectives – namely, with respect
to complete drying of feed droplets to achieve optimum product specifications, and in the control of particle
temperature to minimize aroma loss and thermal degradation of heat sensitive materials. The particle residence time
(RT) also affects product quality indices such as solubility and bulk density. RT is divided into two parts: primary and
secondary residence times. The primary RT is calculated from the time taken for droplets leaving the nozzle to impact
on the wall or leave at the outlet. The secondary residence time can be defined as the time taken for a particle to
slide along the wall from the impact position to the exit.

Glass transition temperature (Tg) - Tg is the temperature above which the matrix shifts from the structurally
rigid glassy state to a rubbery state, which is associated with product stickiness on the spray chamber wall in spray
drying. Stickiness is one of the major process challenges in spray drying. It leads to product agglomeration and poses
problems of caking and lumping of the product during packaging of the spray dried products. Tg of feed depends on
the constituent solutes present in the feed.

Critical Quality Attributes

Particle size distribution – Higher solid contents in tandem with higher Peclet number leads to lower particle
size distribution.

Yield – The process yield is highly affected by two main factors, namely loss due to the non-optimal process
factors and the material formulation. This could be prevented by selection of an appropriate spray dryer with optimal
design features such as wide drying chamber for rotary atomizers or high efficiency collection cyclone in tandem
with clearly defined and optimised processing factors. In addition, wall deposition during spray drying due to low Tg
of the sprayed formulation decreases the yield. This can be avoided by spray drying at lower outlet temperatures or
introduction of polymeric excipients (maltodextrin) with higher Tg to the formulation. Low drying temperatures can
cause incomplete drying of the particles (residual solvent in the particles) and stickiness of the particles to the drying
chamber. Thus, optimising the drying conditions improves drying resulting in higher yields.

Morphology – Formulations factors such as solvent evaporation rate and diffusion rate of solute from inner
core to the outer crust of the particles has been shown to significantly affect the final morphology of the particles. It
is well known that the higher the feeding rate, the larger the particle size. Moreover, lower solid contents and
smaller nozzle tips (typically in two-fluid nozzle) lead to smaller droplets and thus finer final particles.

Ten guidelines on the choice of spray drying process parameters

1. The inlet temperature must be as high as possible in order to achieve a final product with low residual
moisture and a higher thermal efficiency (choice of inlet temperature should take into account the heat
sensitivity of the feed components to prevent thermal degradation).
2. Increasing the feed flow rate lowers the outlet temperature and thus increases the temperature difference
between the inlet temperature and the outlet temperature. This results in product with higher residual
moisture content.
3. High aspirator speed leads to higher degree of separation in the cyclone.
4. Lower aspirator speed leads to lower residual moisture content.
5. The higher the feed flow rate, the larger is the size of the particles in the final product.
6. The higher the feed concentration, the greater is the moisture content of the particles and, hence, the
greater the possibility of agglomeration and the occurrence of irregular particle shapes.
7. The drying air temperature should be below the glass transition temperature in order to prevent product
collapse and stickiness in the spray chamber.
8. The Tg of the feed material can be made higher for a convenient spray drying operation by the addition of
high molecular weight components such as maltodextrin.
9. The percentage of water content in the feed is also a significant parameter in controlling the Tg, since water
depresses Tg considerably.
10. A shorter residence time (RT) (10–15 sec) is recommended for fine particles containing an ample amount of
free surface moisture content, enabling easy evaporation. A medium RT (25–35 sec) should be applied for
fine to semi‐coarse sprays that needs to be dried to low residual moisture content. A longer RT is needed for
drying coarser sprays in order to achieve lower residual moisture content.