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Spray Drying Scale-up Approaches

Fundamentals and Case Studies


João Vicente APS Amorphous by Design
April 29th, 2014
Overview

Spray Drying fundamentals

Setting a stable lab scale process

Scale-up methodology

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Spray Drying
How it works

Feed atomization
produces small
droplets
with the target
size distribution

Droplet evaporation takes place within


the drying chamber
contraction

Dry product
collection

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Mechanistic approach

Thermodynamics
• to calculate of RS_out, T_dew, dgas
hot drying gas
• detect abnormal conditions of operation
Feed • a tool for development & scale-up
Gas
Tank
Recycling
wet gas Unit
Drying chamber
Cyclone Atomization
• a tool for scale-up
• to achieve target particle size distribution
hot drying gas

Gas
Recycling
Unit
Drying Kinetics
wet gas
Drying chamber
Cyclone
Product
• to control particle morphology
(very fine particles) • to optimize powder performance
• identify pitfalls

Product
(very fine particles)
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Thermodynamics

• Thermal conditions in a spray dryer are determined through heat and mass
balance so that Qin  Qfeed  Qloss  Qout
Qin  FdryingTin   Cp
i
g
i
g
i

Qloss  UA Tout  Troom 

Q feed  Ffeed 1  C feed    H  Cp T


l
i i
l
i bi  Tfeed 
i Pv i
y condi  i xi
  Cp
P
Qout  FdryingTout g
i
g
i
i

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Thermodynamics
• If Qloss is known the model is scale and product independent
• Determination of T_out, T_dew and RS_out

200 Buchi B-290 Adv. Niro PSD1 Niro PSD2

Portugal & USA Portugal & USA Portugal

+10%
160
T_in (predicted)

-10%
120

Niro PSD3 Niro PSD4 Niro PSD5

Portugal Portugal Ireland


80
y = 1.00x
R² = 0.99
40
40 80 120 160 200
T_in (observed)

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Atomization
• Considerable differences among published models
• Droplet size correlations based on experimental data (Phase Doppler
Interferometer) are the most straightforward tools to generate the required data

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Atomization
• Particle size is typically dictated by the droplet size
• Atomization model can be used to select the nozzle and atomization conditions that
best suit the targets of particle size and process throughput

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Drying Kinetics

• Fast drying promotes the production of spherical particles; Slow drying results in the
production of shriveled particles; Solids concentration impacts shell flexibility
• Drying time depends on relative saturation and droplet size
• Bulk density is typically dependent on RS_out

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Drying Kinetics

• Ballooning is associated with flexible polymers, dried at temperatures above boiling


point
• Friable material may break when dried at high temperatures

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Case-study

• Solids: API + HPMCP - Solvents: DCM and ethanol


• Data is available from trials executed in two different scales
• Particle size, bulk density and residual solvents predicted by scale-independent
parameters

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Overview

Spray Drying fundamentals

Setting a stable lab scale process

Scale-up methodology

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Setting a stable lab scale process

Most relevant parameters for SD process

Feed properties
• Feed chemical and physical stability
• Solvent system, concentration, viscosity, etc...

Product attributes
• Stickness, tendency to agglomerate
• Residual solvents
• Chemical/physical stability, hygroscopicity, etc…

Process:
• Edge of failure
• Reprocessability Where everything starts!
• Process yield
• Ability to post-dry the SD powders
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Setting a stable lab scale process
Solution stability - Temperature

• Affects surface tension / viscosity / density and therefore droplet size


• Seldom used to optimize powder properties
• Strict control is required when operating close to solubility limits
• Often used to increase chemical stability

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Setting a stable lab scale process
Solids concentration

• Large effect on particle size and process throughput.


• Avoid extremely viscous feeds since they are difficult to atomize
• Stay away from saturation limit (target 80-85%)

m (cP)

T_feed
(ºC)
C_feed (%)

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Setting a stable lab scale process

Summary (Lab-scale work)

 Set a process stable at lab conditions (assure good atomization and select
adequate T_in, T_out)

 Select T_feed based on feed stability and control it during scale up

 Select C_feed to maximize throughput but avoid very viscous solutions and keep
some distance from saturation.

 Once the process seems stable, run it with extended processing time; check
the yield and the occurence of bearding problems

 Use a close-loop system to get representative values for the residual solvents;
evaluate the feasibility of the solvent/post-drying step

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Scale-Up
Taking advantage of scale-up to optimize powder properties

Buchi B290/295 (two-fluid nozzle) Niro PSD4 (pressure nozzle)

Dv50 = 2.4 mm Dv50 = 70 mm


span = 2.6 span = 1.6
bulk density = 0.19 g/ml bulk density = 0.35 g/ml
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Scale-Up Method
Similar powder properties can also be obtained at different scales

ProCepT Micro-Spray (ultrasonic nozzle) Niro PSD4 (pressure nozzle)

Dv50 = 83 mm Dv50 = 82 mm;


span = 1.5 span = 1.7
bulk density = 0.34 g/ml bulk density = 0.29 g/ml
tap density = 0.42 g/ml tap density = 0.40 g/ml
solvent = 7% w/w solvent = 5% w/w
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Overview

Spray Drying fundamentals

Setting a stable lab scale process

Scale-up methodology

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What is important in scaling-up?

Nozzle and process conditions Product attributes


• Thermal conditions • Particle size
• Atomization / Droplet size • Bulk density
• Dew point • Glass transition temperature (Tg)
• Bearding • Solvent content
• Spray plume
• Yield

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Tg and solvent content

• The relation of Tg with RS_out enables the anticipation of the impact of the spray
drying operating conditions on the SDD amorphous stability

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Solvent content and residence time

• The extended residence time in larger units provides a safety margin


• Drying curve determined at lab scale can be considered the worst case scenario

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Scale-up
Thermodynamic space

• Conservative approach: Maintain relative saturation


• Consider equipment and process limitations

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Scale-up
Atomization

• Use droplet size correlations to select the nozzle

100
95 140
Droplet Size (mm)

Feed Flow (kg/h)


90
85 120

80
100
75
70
80
65
60 60
55
50 40
30 40 50 60 70 80 90 100

Pressure (bar)

Droplet Size 61/21 Feed Flow 61/21

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Typical challenges

• Atomization issues
• Yield/agglomeration/stickness
• Bearding
• Chemical stability / degradation
• Solvent condensation

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Conclusions

• Useful information can be gathered in laboratorial work minimizing the use


of large scale testing
• Powder properties can be well described through scale independent
parameters
• With the right tools, scale up can be a straightforward and predictable task

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Thank you for your attention

João Vicente
Drug Product Development
+351 21 982 9502
jvicente@hovione.com

www.hovione.com

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