Review

pubs.acs.org/OPRD

The Pharmaceutical Drying Unit Operation: An Industry Perspective

on Advancing the Science and Development Approach for Scale-Up
and Technology Transfer
Edward W. Conder,† Andrew S. Cosbie,‡ John Gaertner,§ William Hicks,∥ Seth Huggins,‡
Claire S. MacLeod,∥ Brenda Remy,¶ Bing-Shiou Yang,# Joshua D. Engstrom,*,¶ David J. Lamberto,*,⊥
and Charles D. Papageorgiou*,▽
†
Small Molecule Design & Development, Eli Lilly & Co., Lilly Corporate Center, Indianapolis, Indiana 46285, United States
‡
Drug Substance Technologies, Process Development, Amgen Inc., 1 Amgen Center Drive, Thousand Oaks, California 91320, United
States
§
Process Research and Development, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States
∥
Pharmaceutical Development, AstraZeneca, Hulley Road, Macclesfield SK11 2NA, U.K.
¶
Drug Product Science & Technology, Pharmaceutical Development, Bristol-Myers Squibb Co., 1 Squibb Drive, New Brunswick,
New Jersey 08901, United States
#
Material and Analytical Sciences, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06488,
United States
⊥
Chemical Engineering R&D, Merck & Co., Inc., 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States
▽
Process Chemistry, Takeda Pharmaceuticals International Co., 40 Landsdowne Street, Cambridge, Massachusetts 02139, United
States

ABSTRACT: The drying unit operation is used extensively in the pharmaceutical industry, but often a lack of understanding of
the impact of the drying process parameters on active pharmaceutical ingredient critical quality attributes can create challenges
during development. A working group within the Enabling Technologies Consortium identified common challenges in
pharmaceutical drying development, including material constraints for scale-up studies and transferring to different equipment
types and sizes. This manuscript surveys current practices within the industry for drying development related to chemical and
physical stability, drying kinetics, and powder properties and highlights common development gaps for improving drying
development workflows within the industry. The ultimate goal is to encourage further fundamental research and technological
advancements for improving the drying development workflow.

■ INTRODUCTION
In the pharmaceutical industry, the goal is to produce a drug
product (DP) that is efficacious and safe for the patient in a
cost-effective and timely manner. To this end, a target product
profile (TPP) is created to define the critical quality attributes
(CQAs) of the DP that then guide the determination of the
active pharmaceutical ingredient (API) CQAs. For synthetically
produced small molecular weight drug substances, in particular
those formulated in oral solid dosage forms, the CQAs include
aspects related to both purity and chemical and physical
stability as well as those associated with powder properties,
which can affect DP processing and performance. To ensure
that the API CQAs are met, it is crucial to understand the
impact of the processing parameters on these attributes.
Typically, much time and effort are needed to develop an
API manufacturing process to improve product purity and
optimize the isolation steps to ensure proper form control is
achieved and the required powder properties are met. Although
a critical step of the synthesis compared to other unit
operations, drying is often overlooked and not fully understood
until later in the development cycle. This frequently occurs
because many of the issues are only discovered when
manufacturing occurs at larger scale or the process is
transferred to a different equipment train. Unfortunately, this
approach carries high risk because the API drying step, which is
normally the last step in the synthesis, can greatly impact the
API CQAs. To mitigate this risk, it is important to have a firm
understanding of the impacts of the drying process parameters
on the API CQAs early in the development process.
Development of an optimum drying protocol for an API
involves having an in-depth understanding of the elements
associated with the chemical and physical stability of the
compound, the drying kinetics, and the physical properties of
the isolated solids as illustrated in Figure 1. In the
pharmaceutical industry, it is critical that all three elements
are considered during processing including how they are
impacted during scale-up and by the choice of equipment.1
Optimization of the processing parameters with focus on one
element without considering the impact on the others can
Received: December 1, 2016
Published: February 3, 2017

© 2017 American Chemical Society 420 DOI: 10.1021/acs.oprd.6b00406

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Figure 1. Elements of API drying key to the development of an
optimum drying protocol.
create unintended risk on the API CQAs. Often, changes that
are beneficial for one are detrimental to another. For example,
increasing the processing temperature or agitation rate to
achieve faster drying kinetics can have a negative effect on
maintaining product purity and desired physical attributes.
Therefore, in addition to understanding each element, it is
important to understand how each is interconnected with the
other elements through the drying process parameters (e.g.,
temperature, agitation protocol, vacuum, dryer type) and how
each is related to the API CQAs. Under ideal circumstances,
the connections between the processing parameters and each
drying element are fully understood and fed into the design so
that the optimum drying protocol is achieved. Having this
knowledge helps ensure that the drying protocol is robust and
able to reliably deliver API with the desired attributes. It should
be noted that the same elements presented in Figure 1 also
apply to the drying of intermediates, but physical property
control is typically less critical.
Achieving the understanding needed to design and scale-up
an optimum API drying protocol has many challenges.
Typically, only limited material quantities are available in
early development, and in most cases, surrogate materials
capable of fully capturing the powder properties of the API are
nonexistent. Unlike liquid systems, solids are discontinuous,
and there is not a universal theory for their behavior. As an
example, there is no set of material properties that can be
measured and used to determine the response of a compound
to mechanical stress.2 There has also been limited work to
characterize the processing environments that the compounds
are exposed to during drying at scale, and novel approaches are
needed to project performance and behavior observed at
smaller to larger scales. Typically, connections between small
and large scale have been made primarily through empirical
testing with results having limited applicability across
compounds and dryer types.2,3
Other challenges include the utilization of several different
dryer types when moving from laboratory to pilot to
commercial scales and between commercial facilities.4 Often,
the knowledge gained from processing in one dryer type is not
applicable to another, and each dryer type has unique features
that can impact the final API CQAs in different ways.5 Dryer
options that are commonly used in the pharmaceutical industry
include variations of vacuum contact dryers where the outer
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wall and perhaps agitator are heated and the dryer is maintained
under vacuum to allow solvent to evaporate (e.g., filter dryer,
conical dryer, or rotary dryer).3f,6 Although it would be ideal to
complete all development and manufacture work with one
dryer type at a physically representative scale, it is normally not
realistic or feasible to achieve this, as material is scarce and the
choice of dryer and/or dryer type is often dictated by
equipment availability at the particular processing facility as
well as the stage of development. For example, wet-cakes at the
lab scale are dried statically in tray dryers, whereas agitated
dryers are only used upon scale-up into the kilo-lab and pilot
plant.
The Enabling Technologies Consortium (ETC)7 was formed
to support improvements in the development and manufactur-
ing of pharmaceuticals by addressing common development
and manufacturing issues experienced throughout the industry
in a precompetitive manner. Within the ETC, a drying working
group (WG) composed of representatives from eight
pharmaceutical companies was organized to focus on advancing
the drying unit operation of APIs and intermediates. The aims
of the ETC Drying WG are to “identify, evaluate, develop, and
improve scientific tools and techniques for efficient develop-
ment and manufacture of pharmaceuticals”.7a For the drying
unit operation, this will be accomplished first by identifying
current industry practices utilized in drying development and
then by articulating and helping address ongoing knowledge
and technology gaps that hinder development efficiency, scale-
up predictability and success, as well as robustness.
The goal of this manuscript is to provide a survey of the
current state and to encourage future fundamental studies and
technology development for the drying of pharmaceutical
compounds. Current industry approaches to drying develop-
ment for each of the three drying elements shown in Figure 1
will be discussed, and each section will include lab scale
development approaches, relevant process analytical technology
(PAT) and modeling tools, as well as scale-up considerations.
The hope is that sharing the current industrial drying practices
and highlighting the current gaps and shortcomings will
stimulate technological and product innovations that will
improve the way that drying is carried out within the
pharmaceutical industry.
Chemical and Physical Stability. When developing a
drying process for an API or an intermediate, the chemical and
physical stability of the compound must be understood to
ensure that purity and form criteria are met; otherwise, batch
failure may result, or reprocessing may be required, leading to
significant development delays and added costs. Development
studies to better understand the impact of drying process
parameters on chemical and physical stability can greatly reduce
this risk.
Chemical stability of the API during drying is most often
impacted by the drying temperature. To understand a
compound’s degradation with temperature, thermal stability is
typically assessed in a lab dryer by heating the compound in
both the wet and dry state at several different temperatures for
a duration exceeding the greatest potential drying time at scale.
The highest reasonable dryer temperature, safely below the
melting point or the highest temperature at which there is no
significant degradation, is then selected for large-scale drying to
apply the highest possible temperature driving force while
avoiding compound degradation.
To address compound-specific physical stability, a solid form
phase map as a function of solvent/water composition and
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Figure 2. Possible crystal form transition pathways during drying of a hypothetical compound.
temperature is typically generated that guides the identification
of the crystallization, isolation, and drying design spaces.1,8 The
complexity of the form phase map helps determine the control
efforts needed in the drying process.9 In the simple case
consisting of only one known form and assuming that the risk
of amorphous formation is low, the crystal form remains stable
over a wide range of drying process parameters, thus
simplifying the strategy to deliver the specified form. In other
cases, the form phase map may be more complicated (Figure
2). For example, compounds isolated from an aqueous/organic
solvent mixture may exhibit multiple hydrate, solvate, and/or
anhydrate forms in which dehydration, desolvation, and
changes in crystallinity can be the most common changes in
the crystal form during drying.10
For the study of physical form stability, commonly applied
PAT includes hygrometers, near-infrared (NIR) spectrometry,
mass and Raman spectrometry, as well as gas chromatography
(GC).11 In the case of a hydrate, it is often sufficient to monitor
the humidity of the dryer effluent using a cost-effective dew
point hygrometer.1 Although NIR has also been applied to
analyze the dryer effluent, it may be more powerful when used
in direct contact with the cake as it has been shown to be
capable of quantitatively differentiating between free and bound
water in the solids and is therefore a suitable methodology for
monitoring and controlling a compound’s form.12 However,
online mass spectrometry is perhaps the most versatile and
commonly used methodology for monitoring the dryer effluent
stream, giving an indirect indication of form change by
desolvation or dehydration, as it does not require the
development of complex chemometric models to obtain
quantitative data, greatly facilitating process optimization.
Although these instruments have limitations, they have been
successfully used to ensure that form control is maintained
throughout the drying process.
Upon scale-up, the area for specific heat transfer relative to
product volume is typically reduced. As a result, mass transfer
rates also decrease, often leading to an increase in drying time
and a decrease in the rate of solid conversions of crystal forms.
Residual solvent and internal temperature profiles observed at
the lab scale may differ at large scale and between dryer types,
and the spatial temperature profiles in the cake can be difficult
to measure or compute. Also, existing computational dryer
models generally require experimentally determined process
parameters that can be difficult to generate, and the models are
generally insufficient to accurately calculate the temperature
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profiles. Therefore, an empirical approach is generally
employed for scale-up to ensure chemical and physical stability
requirements are met.
During drying scale-up, a jacket temperature or pressure
ramp is frequently employed to help avoid overloading the
condenser/vacuum system at the start of drying and minimize
agglomeration that can result from liquid condensation on the
dryer surfaces.13 A high initial temperature can also result in
partial dissolution of compound at the start of drying. The
durations of these ramps are often extended during scale-up
due to the typical increase in drying time with scale, but the
same final jacket temperature and pressure is maintained across
scales to ensure that chemical degradation and form are
controlled. For form control, drying can be closely monitored
during scale-up by means of simple sensors and PAT (e.g.,
internal thermocouple, hygrometer, mass spectrometry, and
Raman) as well as by offline sample analysis including GC and
X-ray powder diffraction (XRPD). The change in crystallinity
of the API should also be monitored due to the increased
normal and shear forces experienced at increased scales.11c,14
If the target form is a hydrate, a common scale-up approach
is to apply staged humidified drying.12,15 Initially, either a dry
nitrogen sweep may be applied to remove most of the water
not incorporated into the crystal structure or a fully humidified
sweep may be used to accelerate the removal of organic solvent
and/or convert the solvate to the hydrate. As the water (or
organic solvent) level of the solid approaches the level
corresponding to the desired hydrate, a switch is made to a
nitrogen sweep with controlled humidity. This staged
humidified nitrogen approach has the advantage of improving
the efficiency of the drying process with careful dryer humidity
control. If multiple hydrate forms exist, then it may be
necessary to precisely control the humidity within a certain
range defined by simple lab scale dynamic vapor sorption
experiments.
When a solvate (e.g., ethanolate) is the target form, a drying
approach similar to that used to stabilize hydrates with
humidified nitrogen may not be possible. In these cases, the
drying temperature and pressure profiles are maintained in a
range to prevent desolvation. This same approach can also be
used when the target form is a hydrate in the event that
humidified nitrogen is unavailable. For drying crystals
containing two or more solvents, it is important to understand
the impact of the relative removal rates of the different solvents.
In some cases, preferential removal of an individual solvent can
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cause crystal structural change that slows or prevents removal
of the other solvent from the interior of the crystal. In this case,
an improper temperature/drying profile may result in slow
drying or failure of the residual solvent specification. For poorly
crystalline compounds, the drying profile can impact the degree
of crystallinity of the dried compound, which can lead to an
XRPD analytical result that does not meet the product
identification specification. As a result, the rate of desolvation
must be controlled within an acceptable range to achieve a
consistent degree of crystallinity.
For cases in which the amorphous state is the target form,
conditions need to be selected to prevent the compound from
crystallizing and/or chemically degrading. Although isolation of
amorphous solids is beginning to become more prevalent, it has
not been typically accomplished in the pharmaceutical industry.
Therefore, it is currently premature to generalize industry
approaches for development and scale-up.
Drying Kinetics. Once thermodynamic conditions for
maintaining chemical stability and form have been identified,
the process can be further optimized within these defined
boundaries (i.e., temperature, humidity, moisture or solvent
content, etc.) to ensure all CQAs of the drug substance are met
while improving process robustness, increasing drying rate, and
reducing process cycle time. To achieve this, a detailed
understanding of the system drying kinetics is required.3f
Processing parameters such as temperature, pressure, inert gas
flow through the solids, as well as the applied agitation
protocol, agitator design, and effective dryer heated surface area
can greatly influence the drying kinetics.
During drying there will typically be at least two distinct
drying regimes or periods, which include the so-called “constant
rate period” associated with removal of the unbound free liquid
and the “falling rate period” associated with removal of the
more tightly bound liquid from within the solids (Figure 3).
Figure 3. Typical drying curve.
During the “constant rate” period, the solvent or moisture
content in the solids decreases linearly and is limited by the rate
at which heat is added to the solids. The slope of this curve and
hence the drying rate can be affected by the conditions in the
dryer including agitation, operating pressure, and the presence
of an inert gas sweep. In the falling rate period, there is a more
gradual decrease in solvent content as solvent concentration
decreases, and the path for diffusion increases resulting in a
slower drying rate. Additional drying regimes can be present
including the rising rate period associated with the initial
heating of the solids as well as multiple falling rate periods
associated with, for example but not limited to, a change in the
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drying mechanisms from diffusion limited to the breaking of a
solvate or hydrate.16
At a minimum, the initial and final amount of residual liquid
on the solids is needed to determine an average drying rate.
However, additional data should be collected throughout the
drying process to capture more details about the overall
mechanism, and ideally the process should be monitored
continuously to allow for real-time optimization and end point
determination. There are many approaches for generating
kinetic drying data spanning from the use of commercial
equipment to custom chambers, depending on the material
quantities available. A few approaches used within the
pharmaceutical industry are described below.
When material quantities for development are limited
(milligram to gram scale), drying kinetic data can be generated
by static methods assuming uniform drying across the sample
using, for example, vacuum dynamic vapor sorption (DVS)
techniques.1,5,17 These studies can be useful for understanding
the impact of temperature, pressure, and solvent partial
pressure on the drying kinetics and to elucidate the drying
mechanism. In many drying studies, custom chambers, such as
those shown in Figure 4, have also been used to gather
information and data beyond what DVS can provide, such as
information on the solid state.
In the design shown in Figure 4A,18 solids are loaded onto a
drying pan mounted on a high precision analytical balance or
load cell within a drying chamber. The system temperature,
pressure, and composition of the gas sweep through the
chamber can be controlled, and the loss of weight is measured
over time as the solids are exposed to specified drying
conditions. Mass spectrometry can be employed to determine
the vapor composition of the effluent gas stream and, in some
cases, form conversion can be monitored using analytical
technologies such as noncontact Raman spectrometry.
The flow cell (or drying chamber) shown in Figure 4B
consists of a jacketed glass vessel connected to a drying
manifold equipped with instrumentation for monitoring the
inlet nitrogen flow rate, temperature, pressure, humidity of the
inlet and outlet streams, and concentrations of individual
solvents of the outlet gas stream. If desired, a NIR, Raman, or
temperature probe can also be installed through the top of the
flow cell to monitor the solid state.
When quantities are not limiting, drying experiments can be
performed at larger scales in agitated dryers from which the
impact of agitation on the overall drying kinetics can be
determined. For instance, experiments of this type have been
performed in an ∼8 L agitated dryer that required 0.2−1.0 kg of
solids for mixing to be reasonably representative of perform-
ance at larger scale19 and allow for multiple samples to be
collected over time to generate suitable drying curves. PAT can
be used to improve the accuracy of the profile and greatly aid
the ability to predict performance and complete scale-up
successfully. Processing at the multikilogram scale in a pilot
plant offers further opportunities to confirm results obtained at
smaller scale, assess the impact of specific dryer configurations,
and verify drying time predictions.
Once drying kinetics data have been collected, scale-up can
be performed using various commercially available or custom
models to predict drying cycle times and process perform-
ance.20 Drying times can be estimated relatively accurately from
laboratory scale data using heat and mass balance equations
along with the known batch size at each scale. In the simplest
models, the loss of liquid per time per heated surface area is
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Figure 4. Examples of types of custom drying chambers developed by (A) Bristol-Myers Squibb Co. (New Brunswick, NJ, USA) and (B) Merck &
Co., Inc. (Kenilworth, NJ, USA).
determined in each distinct drying regime. These rates can then
be applied for scale-up using the heated surface area of the
larger scale dryer, the batch size, and the known starting and
transitional compositions for the compound. This assumes that
the highest resistance to heat transfer is defined by the
properties of the solids, which is independent of scale. Accuracy
of these predictions requires the application of consistent
drying conditions (T, P, sweep rate, initial solvent content) and
comparable mixing efficiencies within similar dryer types
between scales.
More sophisticated models have been developed and are
available within commercial software packages. For instance,
models and tools exist within DynoChem (Scale-Up Systems)
that use a mass and energy balance by assuming a moving
drying front based upon the heat penetration theory described
by Schlunder.20a,b,d−f The front moves from the jacketed wall,
where solids are dry, to the bulk cake bed, where solids are wet
in a mixed bed of solids. Process Systems Enterprise includes a
population balance in addition to the mass and energy balance
and has the capability of modeling agglomerate formation and
breakage as well as accommodating custom modifications.
Several options are also available for calculating the mass
transfer coefficient from the dimensionless Sherwood number
using external diffusion limitations. Typically, kinetic data from
smaller scale experiments are used to fit model parameters to
estimate performance at scale.19,21 Complications can arise
when the compound is a hydrate/solvate that can dehydrate/
desolvate or the required data for the compound and/or the
processing equipment are not available.
Powder Bulk Property Control. A significant risk in using
agitated dryers to isolate powders is the potential that they may
cause agglomeration and/or attrition, which could adversely
impact the target powder bulk properties of the API. This is of
particular concern for APIs being developed as oral
formulations because both the downstream DP manufacturing
process and the API bioavailability can be severely impacted.
The lack of fundamental understanding of agglomeration and
attrition during drying can lead to issues with process transfer
between different dryer types, identification of key process
parameters, and scale-up.
During drying there is a complex interplay between agitation
protocol, agglomeration, and attrition.22 Agitation is necessary
to improve the heat and mass transfer rates by redistributing
particles inside the dryer because the wet-cake in the dryer is
heterogeneous with material near the dryer edge drying faster
and containing less solvent than the material near the dryer
center. Therefore, in the absence of agitation, drying times
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would be prohibitively long, and inhomogeneities in the
material would be present. In general, agglomeration becomes
dominant in the early stages of drying in which the onset of
particle−particle cohesion can occur. Therefore, agitation
during this drying stage should be minimized.23 Furthermore,
as the scale and/or bed height changes, the powder flow
dynamics can vary. Attrition can dominate in the areas of the
dryer where particles tend to have the greatest flow velocity,
namely, at a lower bed height and in areas near the impeller,
whereas agglomeration tends to prevail in the other areas.13
Once agglomerates are formed, because of their spherical
nature, they tend to experience lower shear from the agitator
blade as they tend to roll over the blade, especially for batches
with low fill volume where the hydrostatic pressure from the
bulk is low. To better understand the challenges with studying
agglomeration and attrition, the current methodologies used to
investigate each one as well as the common strategies to
address each one upon scale-up are discussed.
Agglomeration Control and Scale-Up in Agitated Dryers.
Although agglomeration can be observed during filtration as a
result of agitation and/or compression of the wet-cake, it is
most prevalent during drying. Agglomerates are defined as
clusters of particles that are fused together, typically through
the formation of solid bridges, and are differentiated from
aggregates that are held together by weak interparticular forces
and readily dissociate. To identify and study the key process
parameters resulting in agglomeration, it is critical to measure
both the extent, such as relative quantity of agglomerated
material in the batch, and severity of agglomeration as
determined by agglomerate hardness. Sieving, particle size,
and texture analysis have all been used for the quantification
and characterization of agglomeration.3a,c,d,g,13 In sieving, the
percentage of a compound retained on the sieve after a defined
period of shaking at a defined amplitude is used as a
comparative measure of the extent of agglomeration. This
methodology has recently been extended to determine
agglomerate hardness by measuring the rate of decrease of
the percentage of powder retained on this sieve through
successive cycles.3d
Three main empirical tools are used within the pharmaceut-
ical industry to study the agglomeration potential in agitated
dryers including a mixer torque rheometer (MTR), an acoustic
granulator, and a small-scale agitated filter dryer (Figure
5).3a,b,d,g The MTR is used to determine the onset of
particle−particle cohesion, which is the region of temperature
and moisture/solvent combinations where aggregates are held
together by forces resulting from the presence of mobile liquid
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Figure 5. Empirical tools used for the study of agglomeration during
drying: (A) mixer torque rheometer (MTR), (B) acoustic granulator,
and (C) small-scale agitated filter dryer (AFD).
between the particles that upon drying give rise to solid
bridges.23 In this region, the force required to rotate a blade
through the wet-cake increases markedly relative to that in a
wetter or dryer state, resulting in an increase in the torque
registered by the MTR. The acoustic granulator can also be
used to independently identify the onset of particle−particle
cohesion3d or as a small-scale method to verify the MTR
findings.3g Lastly, the small-scale agitated filter dryer is used to
aid in the determination of the key process parameters.
Using these tools, it has been shown that particle size,
particle size distribution (PSD), and morphology can all have a
significant impact on a compound’s agglomeration potentia-
l.3a,b,d,g,13,24 In general, small acicular crystals exhibit a high risk
of agglomeration as a result of their high specific surface area,
which enables effective contact between each particle.25 Broad
PSDs and irregularly shaped crystals can allow for efficient
packing of the particles by filling available voids and therefore
result in the formation of strong agglomerates.
Solvent choice has also been shown to be critical as crystals
in wet-cakes are held together by liquid bridges, the strength of
which are dependent on the surface tension of the
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solvents.3a,g,22,24 Furthermore, greater solubility of the com-
pound in the final wash solvent results in a greater number of
crystalline bridges forming during drying and hence more
severe agglomeration. Therefore, a final wash solvent with poor
product solubility should be selected, and when a solvent
mixture is used, both solvents should be evaluated independ-
ently as one solvent may become enriched during drying.
Solvent viscosity will also impact the wet-cake’s deliquoring
efficiency and ability to navigate through the onset of particle−
particle cohesion with minimal agitation. Typically, lower
viscosity solvents deliquor much more efficiently.
For scale-up, agitation is typically initiated below the critical
moisture content at which the onset of agglomeration can
occur,3a,g which is often challenging to accomplish in practice
due to the heterogeneity of the wet-cake prior to agitation. The
initial solvent composition of the wet-cake is typically
determined by the deliquoring efficiency during the filtration.
Although some compounds deliquor very efficiently (with a
solvent content of 25% or less), those of higher agglomeration
potential (e.g., those with a broad and/or small PSD) tend to
retain significant solvent. This can be mitigated to some extent
by solvent and/or equipment selection (e.g., use of a lower
viscosity solvent and/or a centrifuge for the filtration). To
reduce the risk of agglomeration, a nitrogen blow-through is an
option that, as long as the wet-cake does not crack or pull away
from the filter walls, can reduce the residual solvent levels
below the onset of particle−particle cohesion before agitation is
initiated. In case of cracking, smoothing of the wet-cake should
take place, which will improve the deliquoring efficiency.
Equivalent blow-through conditions between the laboratory
and the plant can be maintained by using the Carman−Kozeny
equation.3c In cases where a nitrogen blow-through is not
possible and an agitated filter dryer is used, the solvent content
of the wet-cake can be reduced by pressing the wet-cake with
the agitator.3a This is achieved by smoothing the wet-cake (i.e.,
operating the agitator in a counterclockwise fashion) while
progressively lowering the agitator. However, care is needed to
avoid particle breakage as particles are exposed to higher
mechanical stress when agitation is operated in this manner.
In many cases, scale-up in the plant relies upon visual
observation, especially during the initial stages of the process
and upon performing a number of full-scale engineering runs.3a
Processing parameters such as agitator speed, height (i.e.,
vertical depth of penetration into the cake), frequency, and
direction of agitation are manually adjusted to control and
break down agglomerates, which can introduce operator-to-
operator and plant-to-plant variability. However, this strategy is
not always successful as in some cases small agglomerates are
formed that are not easily visible to the operator. Therefore,
there can often be some trial and error in identifying the
optimal drying protocol to prevent agglomeration. Predictive
tools for determining the agglomeration potential of a
compound as well as suitable scale-up conditions that will
minimize and/or control agglomeration are not yet robust, and
until there is further improvement, empirical approaches will
continue to be the standard practice for studying and
understanding agglomeration during development.
Attrition Control and Scale-Up in Agitated Dryers. It has
been shown that laboratory scale dryers designed to use small
quantities of material (10−100 g) are not capable of
reproducing the shear stresses and hence the attrition observed
at scale.2,3e This is primarily a result of the hydrostatic pressure
being lower in the lab scale dryer than that in the plant. To
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Figure 6. Laboratory setups for the study of attrition designed and used by (A) Merck & Co., Inc. (Kenilworth, NJ, USA) and (B) Bristol-Myers
Squibb Co. (New Brunswick, NJ, USA).
overcome this limitation, attrition has been studied in small
cylindrical vessels mechanically agitated by an impeller in which
suitable normal loads have been applied by placing a weight on
top of the particle bed (Figure 6).2,3e These scale-down setups
have been used to study the propensity of attrition during the
different stages of drying.
Using such laboratory-scale equipment, it has been shown
that in general particles with large aspect ratios (e.g., rod and
needle particles) are highly susceptible to attrition with the
particles breaking mostly along the major axis.3e On the other
hand, “platelike” particles tended to be much less susceptible to
attrition in which the particles experience attrition through
chipping rather than fracturing.2,26 Particles with secondary
structures, such as agglomerates, can sometimes lose these
structures when agitated, as the solid bridges holding the
primary particles together are broken. In these instances, the
strength of these solid bridges is significantly lower than the
strength of the primary particles, such that little, if any,
breakage of the primary particles is observed.
The liquid content of the particle bed during agitation has
also been shown to affect the degree of attrition.2 For some
particles, higher levels of attrition were observed when agitated
dry than when wet, suggesting that the solvent acted as a
lubricant.3e,27 In other cases, as the solvent content of the
particle bed was reduced, so was the extent of attrition.2 This
highlights the complexity and the lack of understanding of the
mechanism of particle attrition that is not only dependent on
the process and a particle’s physical properties but also on its
material properties.
Finally, the equipment configuration, such as impeller blade
design and angle of the walls, can also have a significant impact
on the extent of attrition, and simple geometrical arguments
have been used to attempt to predict the extent of attrition
expected for a particular compound in different dryers.28
However, these arguments are often an oversimplification of
the complex mechanism occurring during drying and fail to
provide accurate predictions.
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Review
A more rigorous approach has been recently reported in the
literature that used the bulk friction coefficient and the total
amount of work done by the impeller to predict the degree of
attrition expected during scale-up.3e Laboratory-scale experi-
ments were conducted during which the impeller torque was
measured and used to calculate the average shear stress during
agitation. The bulk friction coefficient was then determined by
measuring the shear stress under different hydrostatic pressures.
Finally, the total work done by the impeller was determined
from knowledge of the measured torque, impeller speed, and
agitation time and plotted against the corresponding particle
size. The anticipated work done during scale-up was then
calculated to estimate the resulting product particle size.
The risk of attrition during scale-up is most commonly
mitigated empirically by using “standardized” agitation
protocols that have shown minimal attrition as experienced in
batches for a wide range of compounds.19a Although these
protocols can assist in decreasing the amount of attrition during
agitated drying, they rely on operator experience and judgment
to control a key attribute of the API and do not result in an
efficient and robust process.
Current Technology and Knowledge Gaps. It is clear
from the preceding sections that although many tools and
practices have been developed to aid the study and scale-up of
drying, there are still many knowledge and technology gaps that
inhibit the creation of standardized work-flows and allow for
the seamless scale-up and process equipment transfer. In an
effort to advance the pharmaceutical industry’s drying develop-
ment capabilities and unit operation process understanding, the
ETC Drying WG identified the following as the most important
current knowledge and technology gaps relating to drying:
1. Limited real-time drying process understanding due to
limitations of PAT tools and/or material sampling.
2. Lack of effective and efficient universal mathematical
models able to describe and scale-up the unit operation
accounting for chemical and physical stability, drying kinetics,
and physical property control.
DOI: 10.1021/acs.oprd.6b00406
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Organic Process Research & Development
3. Lack of standardized, commercially available scale-down
equipment.
The following subsections expound on these gaps with the
intent to encourage further research and development in these
areas for the common benefit of the pharmaceutical industry
and any industry with interests in drying.
Drying Evaluation by PAT and Material Sampling. As
discussed in the previous sections, many PAT tools are available
and utilized in the pharmaceutical industry for both drying
process development and batch monitoring. Unfortunately,
current PAT technologies such as NIR or mass spectrometry
are limited to single point assessment or determination of
average compositions, respectively. Probe applications are
hindered by the need to avoid contact with mechanical
agitators and often suffer from loss of contact with the solids,
blinding, or limited penetration depth, which provides only a
limited view of dryer contents.29 Furthermore, because of the
heterogeneous nature of the wet-cake prior to agitation, the
data from the current probes are not representative of the
whole batch. These limitations make it unfeasible to effectively
incorporate data for model verification or pursue the design of
scale-down equipment.
The ideal PAT solution for drying would allow for real-time
monitoring of lab to commercial scale vessels throughout the
entire volume of the cake during the drying process and would
not require significant retrofitting of the existing large scale
equipment. This capability would be beneficial to more fully
verify models or design scale-down equipment that help
identify and properly simulate dominant forces experienced by
materials during drying. PAT that could provide a three-
dimensional profile of the dryer to determine spatial
heterogeneity of solvent content for drying kinetics, powder
properties, and form visualization are desired to simultaneously
assess impacts on all three of the key drying elements. Electrical
impedance, capacitance, inductance tomography, and other
technologies look promising but may currently be too difficult
or costly to fit to existing equipment. Furthermore, an
evaluation would need to be made on the effectiveness of
these techniques to monitor solvent composition, particle size,
and form. If further developed, the advantages of such
capabilities would allow for the design of suitable process
controls with feedback and/or forward capabilities to improve
product quality, consistency and optimize cycle times.
To complement the PAT approach, techniques for
representative sampling of materials within the vessel during
drying would further improve drying process understanding.
Currently, retrieving representative quantities of material from
the dryer or sampling while drying is in progress is difficult or
impossible in many large scale dryers. Having these capabilities
would allow for better characterization of materials during
drying using standard characterization techniques to assess
solvent content (e.g., gas chromatography), powder properties
(e.g., particle size by laser light scattering, specific surface area,
bulk density, scanning electron microscope, etc.), and form
(e.g., XRPD). This approach would still offer an opportunity to
give a coarse representation of material changes that occur
throughout the drying process and validate real time analysis.
Modeling. Models have a key role in drying process
understanding, optimization, and scale-up and are central to
the development of appropriate process control strategies.
General purpose models are needed that can reliably predict
both drying times for cycle time optimization and the impact of
various process parameters to the API CQAs over a wide range
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Review
of scales and equipment configurations. Ultimately, a universal
model should be able to address the issues for each drying
element including drying kinetics, chemical and physical
stability, and powder properties. Although a general purpose
model would be ideal, it is understood that first principle
models are lacking in key areas such as desolvation or
dehydration kinetics as well as agglomeration and attrition. It
is expected that further advances in these areas are required that
will further support the development of a more robust drying
model.
Modeling desolvation and dehydration kinetics are currently
challenging because there are complex resistances to heat and
mass transfer that are not fully captured in existing models.
Some models include the impact of mixing the powder bed but
only by approximating spatial redistribution of solvent
concentration and thermal gradients. The models generally
do not include the thermodynamics of desorption and the mass
transfer resistances needed to simulate breaking of a hydrate or
solvate.3f This lack of understanding can greatly impact the final
drying time end point to meet form or solvent content
specifications.
It was demonstrated earlier that agglomeration and attrition
can have profound impacts on powder property behavior.
Although recent studies are beginning to elucidate the key
mechanisms that induce agglomeration and attrition during
agitated drying, many gaps still exist, and robust models are
absent. The role of particle morphology on the tendency for
agglomeration and/or attrition to occur at the different stages
of drying is still not fully understood. Recent studies performed
with particles of high aspect ratio have provided some insights
into how agglomeration and attrition can be impacted by the
aligning and stacking of rodlike particles during drying.3e
However, it remains unclear whether the trends observed with
high aspect ratios apply to particles with different morpholo-
gies. The effect of liquid content during agitation on particle
agglomeration and/or attrition is also not well understood.
Additionally, a multivariate interaction between particle
morphology, degree of wetness, and the intrinsic mechanical
properties of the materials may exist, but no theory is currently
available that can explain this relationship. Lastly, it is not
uncommon for a product during its development lifecycle to be
transferred to a new manufacturing facility and concurrently to
a different size and/or a different type of agitated dryer (e.g.,
from agitated filter drying to conical dryer). Therefore, it would
be of extreme value if powder property outcomes could be
simulated across different equipment and in silico predictions
conducted to more effectively match operating conditions
between dryers.
Although complex models can be helpful, the predictive
models also need to be computationally efficient. For instance,
although discrete element method (DEM) simulations have
furthered our understanding of stress generation and attrition
during agitation, this technique cannot simulate realistic
industrial dryers in whole or in compartmental regions
consisting of millions or billions of particle−particle contacts.
Mechanistic models that can take into account the effect of key
material properties and process parameters can provide a
theoretical framework for the design and optimization of these
unit operations. The accuracy of the developed models relies
directly on the type and quality of data used to train or calibrate
the models. In the process development space, these data sets
will ideally come from both scale-down experiments and pilot
or production scale runs.
DOI: 10.1021/acs.oprd.6b00406
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Organic Process Research & Development
In some cases, models may require input data that are
currently not gathered in the pharmaceutical industry. As an
example, DEM simulations have shown that the surface
roughness of particles will affect stress generation and attrition
during agitation.30 These simulations have also shown that the
aspect ratio and the mechanical strength of the crystal will
significantly influence the degree of attrition observed.30f These
microscopic material properties cannot be determined from the
traditional bulk property tests performed. The ability to
measure these microscopic properties can facilitate the
construction of mechanistic models that support more efficient
and reliable design of agitated drying processes to ensure PSD
targets are met. For any model that is developed within the
pharmaceutical industry, attention will need to be given to the
capabilities of generating certain data inputs that are critical to
the model. If the model requires data that are not currently
feasible to attain, the model will likely have limited benefit to
the industry.
Scale-Down Equipment. Standardized laboratory equip-
ment for scale-down experimentation that accurately mimics
the scale-up conditions is critical to enabling the study and
successful scale-up of the drying unit operation. Most of the
scale-down equipment used to date is custom-made and ranges
from small agitated filter dryers to vapor sorption chambers.
Current setups that mimic heat and mass transfer characteristics
as well as the normal and shear forces encountered on the
manufacturing scale require the use of hundreds of grams of
material per experiment that is not often available during the
early stages of process development. They may also not be able
to incorporate the PAT needed for process understanding and
modeling.
Having standardized, commercially available equipment that
improves upon custom approaches will reduce the barrier to
performing some of these studies, allowing data on more
compounds to be collected, ultimately advancing the current
state of the art. It will also avoid continuous reinvention of the
wheel, allowing researchers to focus on studying the unit
operation rather than designing drying equipment.
Ideally, this equipment will require only limited amounts of
material, account for important scale-dependent processes
including resistances to heat transfer, mass transfer, and mixing,
and would allow for adequate in-process monitoring of the
headspace, powder, and system as a whole. Scale-down
equipment that can measure in real time key properties such
as solvent content, particle size, and impeller torque will aid
process design in a material-sparing way. This will then enable
better process design earlier in development when only small
quantities of API are available for lab studies.
Looking Forward. The future state of drying development
would include robust scale-down equipment with PAT that can
enable modeling for predictive process scale-up and/or
equipment transfer. Unfortunately, this has been difficult to
achieve in practice because the necessary components for
effective development (scale-down equipment, PAT, modeling)
are interrelated. For example, modeling improvements may
require improved PAT and scale-down equipment. Although
simultaneous independent efforts to address specific gaps may
be a necessity as a result of resource constraints, it is expected
that advances in one area will have an influence on others. It is
our opinion that greater effort should be invested in improving
the current state of the art in monitoring the real time behavior
of powders during drying and developing suitable PAT that can
be easily integrated with existing large-scale processing
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equipment. These data will provide immediate insight on
relating drying process parameters to API CQAs and will be
essential in designing and validating improved models that are
robust and practical. Ideally, PAT and model development
should occur concurrently to be able to satisfy modeling data
requirements and ensure that desired data can be effectively
collected. These coordinated efforts would greatly aid the
design of more effective lab scale-down equipment.
It is the aim of the ETC Drying WG to initiate research
efforts through collaborating with relevant technology
companies, academics, and funding independent research to
address the identified knowledge and technology gaps to
advance the current state of the art and ultimately develop a
robust work flow for the study and scale-up of the drying unit
operation. Updates on progress made toward this end as well as
opportunities for collaboration will be communicated in
subsequent publications and on the ETC Web site (www.
etconsortium.org). Any comments or suggestions to the ETC,
and the drying WG in particular, are welcome and any inquiries
can be made directly to info@etconsortium.org.
■ AUTHOR INFORMATION
Corresponding Authors
*E-mail: joshua.engstrom@bms.com.
*E-mail: david_lamberto@merck.com.
*E-mail: Charles.Papageorgiou@Takeda.com.
ORCID
Joshua D. Engstrom: 0000-0002-4496-1191
David J. Lamberto: 0000-0001-9529-9559
Charles D. Papageorgiou: 0000-0001-7959-6289
Notes
The authors declare no competing financial interest.
■ ACKNOWLEDGMENTS
The ETC Drying WG would like to thank the ETC Secretariat
and ETC Board for providing the forum and guidance for this
work to be accomplished.
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