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# Spray Drying Scale-up Approaches

## Fundamentals and Case Studies

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

## Setting a stable lab scale process

Scale-up methodology

## 2 | João Vicente | April 2014 | Confidential Hovione © 2014

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

## 3 | João Vicente | April 2014 | Confidential Hovione © 2014

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)
4 | João Vicente | April 2014 | Confidential Hovione © 2014
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

## 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

## 5 | João Vicente | April 2014 | Confidential Hovione © 2014

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

+10%
160
T_in (predicted)

-10%
120

## Portugal Portugal Ireland

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

## 6 | João Vicente | April 2014 | Confidential Hovione © 2014

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

## 7 | João Vicente | April 2014 | Confidential Hovione © 2014

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

## 8 | João Vicente | April 2014 | Confidential Hovione © 2014

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

Drying Kinetics

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

point
• Friable material may break when dried at high temperatures

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

Overview

## Setting a stable lab scale process

Scale-up methodology

## 12 | João Vicente | April 2014 | Confidential Hovione © 2014

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
13 | João Vicente | April 2014 | Confidential Hovione © 2014
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

## 14 | João Vicente | April 2014 | Confidential Hovione © 2014

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 (%)

## 15 | João Vicente | April 2014 | Confidential Hovione © 2014

Setting a stable lab scale process

## Summary (Lab-scale work)

 Set a process stable at lab conditions (assure good atomization and select

##  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

## 16 | João Vicente | April 2014 | Confidential Hovione © 2014

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

## 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
17 | João Vicente | April 2014 | Confidential Hovione © 2014
Scale-Up Method
Similar powder properties can also be obtained at different scales

## 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
18 | João Vicente | April 2014 | Confidential Hovione © 2014
Overview

## Setting a stable lab scale process

Scale-up methodology

## 19 | João Vicente | April 2014 | Confidential Hovione © 2014

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

## 20 | João Vicente | April 2014 | Confidential Hovione © 2014

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

## 21 | João Vicente | April 2014 | Confidential Hovione © 2014

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

## 22 | João Vicente | April 2014 | Confidential Hovione © 2014

Scale-up
Thermodynamic space

## • Conservative approach: Maintain relative saturation

• Consider equipment and process limitations

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)

## 24 | João Vicente | April 2014 | Confidential Hovione © 2014

Typical challenges

• Atomization issues
• Yield/agglomeration/stickness
• Bearding
• Solvent condensation

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