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DOI 10.1007/s12247-009-9064-4
RESEARCH ARTICLE
# The Author(s) 2009. This article is published with open access at Springerlink.com
Introduction
Spray-drying is a widely used unit operation for pharmaceutical
applications. In addition to its use in preparing solid amorphous
D. E. Dobry (*) : D. M. Settell : J. M. Baumann : R. J. Ray :
L. J. Graham : R. A. Beyerinck
Bend Research Inc.,
64550 Research Road,
Bend, OR 97701, USA
e-mail: dobry@bendres.com
J Pharm Innov
Solvent
Polymer
Active
Process Heater
System Gas
Blower
Condenser
System Gas
Blower
Solvent Tank
Solution Tank
Drying
Chamber
Cyclone
Baghouse
Feed Pump
Product
Collection
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Pressure-Nozzle
Atomization Image
FEED SOLUTION
Solution Feed Rate (Msoln)
DRYING GAS
Pressure
Nozzle
DROPLETENVIRONMENT
CONTROL
VOLUME
Drying Chamber
MACROSCOPIC /
THERMODYNAMIC
CONTROL VOLUME
Initial
Solution
Droplet
10-6 sec
Drying Gas
Contacts
Droplet
Skinned
Droplet
10-2 sec
SPRAY-DRIED
PRODUCT:
Dryer Outlet Temperature (Tout )
Relative Saturation of Solvent (%RSout )
Dried SDD
Particle
~1 sec
Fig. 2 Physical situation and key control volumes of the spray-drying process
Within the macroscopic control volume, the dropletenvironment control volume comprises individual droplet
formation, droplet interaction with the drying gas that
immediately surrounds the droplet, and solvent evaporation
to form dry particles. Droplet-drying kinetics is defined in
the droplet-environment control volume. Several key events
occur within this control volume. First, on the scale of
microseconds, droplets are formed via the atomization
process. Second, on the scale of milliseconds, droplets in
the atomization plume contact the hot drying gas and
solvent evaporation begins. Solvent evaporation occurs
quickly, increasing the concentration of solids at the surface
of the droplet and forming a polymer skin. The polymer
skin resists solvent evaporation because the solvent must
diffuse through the viscous skin. This entire droplet-drying
process happens quickly; typically, dried particles are
formed within approximately 1 s. Within the context of
process definition, this paper will address experimental and
modeling approaches to gain insight into each of the events
occurring within the droplet-environment control volume,
both on an individual droplet level and across a distribution,
as appropriate.
Understanding the key control volumes is critical to
quantifying the multivariate relationship between product
attributes and process parameters. Use of models and
process-characterization tools aid in the quantitative understanding of the key control volumes, leading to rational
definition of process parameters.
J Pharm Innov
1. FORMULATION
SCREENING/
DEFINITION
DEFINE:
PROCESS
Stability
Performance
Solvent Selection
[Cmpd.] (g/mL)
70
HPMCAS-Dispersion
60
50
40
PVP Dispersion
30
Amorphous Drug Crystalline Drug
20
10
0
0
30
60
PRODUCT ANALYSIS
90
Time (min)
ITERATE
2. PROCESS
CONSTRAINTS
Drying-gas flowrate
Drying-gas inlet
temperature
4. DRYING
KINETICS
Target Droplet Size
temperature
Graphical Thermodynamic
Model:
CFD Models:
Temperature Contours
Particle Tracks
5. ATOMIZATION
Nozzle Operating
Conditions
6. VERIFICATION
RUN
(Optional)
Nozzle
Test
Stand:
(Liquid/Gas)
3. THERMODYNAMICS
Outlet
temp
50C
60C
70C
180
170
160
150
140
130
120
110
80C
Wet droplet
Skinned droplet
Dry particle
(Temperature in oC)
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Msoln;
drying-gas flow rate (Mgas);
Tin;
Tout; and
relative saturation (or humidity) of the solvent at
spray-dryer outlet conditions (%RSout).
1
For spray dryers operating in recycle mode, the relative saturation at
the inlet of the dryer must also be considered. Additional factors
such as heat loss to the ambient surroundingswould need to be
added if a poorly insulated spray-dryer system is used.
and:
Tout f Msoln ; Mgas ; Tin :
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Tout (C)
Tin (C)
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Particle Tracks
Wet dropl
droplet
Skinned dro
droplet
Dry particle
properties of commonly used polymers. Particle morphology can be related to process parameters using dimensionless correlations such as the Peclet number [16]. These
correlations can define when a skin is likely to form at the
particle surface during droplet drying. This phenomenon
can also be studied experimentally using an individual
droplet apparatus [12, 13].
Figure 6 shows the effect of drying conditions (i.e., hot/
fast and cold/slow) on particle morphologies. This example,
for demonstration purposes, varies based on solution
properties for a given formulation. In the case of hot/fast
drying, the droplet temperature is near or above the boiling
point of the solvent when droplet skin forms. This causes
the vapor pressure in the particle to keep it inflated when
it dries, producing a hollow-sphere morphology. In the case
of cold/slow drying, the droplet temperature is below the
boiling point of the solvent when the droplet skin forms,
causing the particle to collapse into a raisin morphology.
These kinetic morphology considerations can be combined
with the thermodynamic operating space defined in step 3
and mapped within the design space.
Drying-kinetic considerations are particularly important
during spray dryer scale-up where additional factors must
be considered [17]. Key scale-up considerations include the
presence of solvent vapor in the inlet drying gas and less
mixing of the droplets and drying gas [18]. In practice, it is
common to see a distribution of particle morphologies.
However, drying parameters may be tuned so that the
majority of the dried particles are of a specific desired
morphology.
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Fig. 6 High-speed images of
pressure-nozzle atomization and
droplets suspended on thermocouples subjected to various
drying conditions, showing
images for individual dropletdrying experiments for a hot/fast
drying conditions and b cold/
slow drying conditions when a
film-forming polymer is used in
acetone solution
100
90
80
Nozzle B
70
1. Formulation screening/
definition
API/polymer ratio
Spray solvent
xsolids
Tin
Mgas
Msoln
Upper and lower limit of
Tout and %RSout
Tout
RSout
Nozzle size
Atomization pressure
Atomizer droplet size
Confirmation that spraydrying process meets formulation targets
60
50
Nozzle A
40
30
2. Process constraints
20
10
3. Thermodynamic design
space
0
700
Nozzle A
600
Flowchart step
4. Drying kinetics
500
5. Atomization parameter
selection
Nozzle B
400
300
200
100
0
80
100
120
140
160
180
200
220
240
Fig. 7 Example PDPA output from a nozzle test stand for two
pressure nozzles of different dimensions
145
50b
1c
3d
500c
11
645
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(3) successful completion of an SDD clinical manufacturing campaign in <3 months from initial processdevelopment activities; and
(4) replication of key product attributes (e.g., bulk
properties and bioperformance) between development
and clinical scales.
Conclusions
The outcome of the spray-drying process-development flowchart methodology allows formulation and process definition
using time and resources similar to those required for
conventional immediate-release crystalline formulations. The
methodology, which is based on fundamental engineering
models and state-of-the-art process-characterization tools, can
be used as an alternative to traditional empirical spray-drying
process-development methods, resulting in streamlined and
robust process development.
This model-based process development represents a
QbD approach that lays the groundwork for continuous
improvement and eventual design-space process regulatory
filings. This approach is in alignment with the current
guidance on Pharmaceutical Development Q8(R1). Many
aspects of this approach can be directly translated to other
atomization/evaporative processes, such tablet-coating and
fluid-bed processes. A similar strategy can also be applied to
many other pharmaceutical-processing unit operations.
Acknowledgments We would like to acknowledge the contributions
of Pfizer, Tim Hagen, Ravi Shanker, and our colleagues at Bend
Research for their support of this work. We would also like to thank
the reviewers for their input into this manuscript.
Open Access This article is distributed under the terms of the Creative
Commons Attribution Noncommercial License which permits any
noncommercial use, distribution, and reproduction in any medium,
provided the original author(s) and source are credited.
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