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7th Training School on Microencapsulation – Strasbourg
Februar 2015
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Pellet Layering and Coating Processes
Dr. Anne Ettner, Glatt Pharmaceutical Services
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1. Introduction
2. Fluid bed equipment
3. Basics of fluid bed Wurster technology
4. Characteristics of Bottom spray processes
5. Formulation and process parameters
6. Case Studies
Overview
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Pellet Layering and Coating Processes
1. Introduction: Pharmaceutical Pellets
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Pellet Layering and Coating Processes
1. Introduction: Pharmaceutical Pellets
• Spherical particles with smooth and uniform surface
• Particle size range: 50 – 2000 µm
• Narrow particle size distribution
• Layering of active pharmaceutical ingredients and coating
(functional) excipients
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1. Introduction: Pharmaceutical Pellets
• Formulation concepts for modified release preparations
Matrix approach
uniform and homogenous matrix
Membrane approach
multi-layer composition
Pellet Layering and Coating Processes
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1. Introduction: Pharmaceutical Pellets
• Formulation concepts for modified release preparations
Coating of pellets required for:
- Delayed release preparations
- Extended release products
- Taste masking
Pellet Layering and Coating Processes
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Pellet Layering and Coating Processes
1. Introduction: Pharmaceutical Pellets
• Benefits
- reduced variability in dosage (low intra- and inter- individual
variability)
- controlled onset time of drug release
- delivery of API to distal sites within GI tract
• Pellets can be administered as capsules, tablets, sachets and oral
suspensions
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Pellet Layering and Coating Processes
1. Introduction: State-of-the-art Pelletization Technologies
• Extrusion / Spheronization
- Multitude of manufacturing steps Multitude of manufacturing equipment
(mixing, wet granulation, extrusion, spheronization, drying, sieving, coating)
- Particle size > 500 µm
- Broad particle size distribution
- Mostly particles not totally spherical
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Pellet Layering and Coating Processes
1. Introduction: State-of-the-art Pelletization Technologies
• Fluid Bed Layering (e.g. Wurster)
- Drug layering onto starter material
- Could be time consuming process for high drug loaded products
- Narrower particle size distribution compared to
extrusion/spheronization
• Direct pelletization: Rotor fluid bed granulator
- Broad particle size distribution
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Pellet Layering and Coating Processes
1. Introduction: Fluid bed process for pellets manufacturing
• starting beads
• (drug layering liquid)
• coating liquid(s)
application of liquid(s) on pellets
no losses
no agglomerates
specified dissolution profile to be achieved
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Pellet Layering and Coating Processes
1. Introduction: Fluid bed process for pellets manufacturing
• Pellet drug layering and coating principle
Starting beads + liquid to be processed
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Pellet Layering and Coating Processes
1. Introduction: The coating zone principle
Core
Coalescence
of droplets
Penetration
Spray
nozzle
Contact / spreading
Spray drying
Evaporation of solvent
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1. Introduction
2. Fluid bed equipment
3. Characteristics of Bottom spray processes
4. Formulation and process parameters
5. Case Studies
Overview
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Pellet Layering and Coating Processes
2. Fluid bed equipment: Fluid bed unit in bottom spray configuration
Downbed
Upbed
Spray nozzle position:
Bottom-spray (“Wurster“)
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Pellet Layering and Coating Processes
2. Fluid bed equipment: Fresh-air system vs. closed-loop system
Fresh air system
Water based systems
Organic solvent based
systems
Closed-loop system with N2
inertisation and organic solvent
recovery system (SRS)
Organic solvent based
systems
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Pellet Layering and Coating Processes
2. Fluid bed equipment: Fresh-air system vs. closed-loop system
Pellet surfaces
Organic solution coating Aqueous dispersion (film
condensation not completed)
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1. Introduction
2. Fluid bed equipment
3. Characteristics of Bottom spray processes
4. Formulation and process parameters
5. Case Studies
Overview
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Pellet Layering and Coating Processes
3. Characteristics of Bottom spray processes
HS collar
Wurster partition
HS nozzle
Inlet air dis-
tribution plate
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Pellet Layering and Coating Processes
3. Characteristics of Bottom spray processes
HS collar
Wurster partition
HS nozzle
Inlet air dis-
tribution plate
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Pellet Layering and Coating Processes
3. Characteristics of Bottom spray processes:
Inlet air distribution plate
The air flow in the upbed
zone is most important for
the homogenous application
of the film.
The most feasible
configuration is selected for
each product quality
(particle size of substrate).
Downbed
zone
Upbed
zone
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Pellet Layering and Coating Processes
3. Characteristics of Bottom spray processes:
Inlet air distribution plate
Plate type
A B C D
Inlet air volume in downbed
Upbed zone Downbed zone
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Pellet Layering and Coating Processes
3. Characteristics of Bottom spray processes
HS collar
Wurster partition
HS nozzle
Inlet air dis-
tribution plate
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Pellet Layering and Coating Processes
3. Characteristics of Bottom spray processes: Wurster Partition
h
h
downbed upbed downbed upbed
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Pellet Layering and Coating Processes
3. Characteristics of Bottom spray processes:
High Speed (“HS”) nozzle system
HS nozzle HS nozzle + collar
+ Collar
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Pellet Layering and Coating Processes
3. Characteristics of Bottom spray processes
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1. Introduction
2. Fluid bed equipment
3. Characteristics of Bottom spray processes
4. Formulation and process parameters
5. Case Studies
Overview
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Pellet Layering and Coating Processes
4. Formulation and process parameters
Formulation • specified, no further
optimisation possible
Inlet air volume • temperature and
moisture adjustable
Atomization air • pressure and spray
rate adjustable
Drying
capacity Fluidization
pattern
Agglomeration
or spray drying
Product: • moisture
• temperature
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Pellet Layering and Coating Processes
4. Formulation and process parameters: hx diagram (Mollier diagram)
For understanding the modifications in terms of HUMIDITY
in the process air (inlet and outlet) and in the product, you may use the
Mollier-Diagram = the psychrometric chart
• You can read relative and absolute values for:
• the inlet air humidity conditions and temperature
• the outlet air humidity conditions and temperature
• the product humidity conditions and temperature
…and you can predict the overwetting condition:
when the product temperature reaches the 100 %
relative humidity curve.
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Pellet Layering and Coating Processes
4. Formulation and process parameters: hx diagram (Mollier diagram)
Moisture can be present at different amounts in air, but the air becomes saturated at
some point
Air cannot contain more moisture than the saturated amount
Hot air can contain more moisture than cold air before saturation is reached - air
expands when heated
The saturation point depends on the temperature of the air
At saturation point, the Relative Humidity is 100% and the temperature is said to be
the Dew Point
% RH values show the % saturation of air at that temperature
If the temperature of a sample of air is increased, its
relative Humidity will decrease
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Pellet Layering and Coating Processes
4. Formulation and process parameters: hx diagram (Mollier diagram)
0 10 20 30 40 50 water content x
[ g water / kg dry air]
0
-10
10
20
30
40
50
Tem
pera
ture
[°C
]
20
40
60
80
100
120
140
100
80
60
relativ humidity [%]
The diagram shows the correlation of
• evaporation capacity
• relative humidity in exhaust air
• product temperature / moisture
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Pellet Layering and Coating Processes
4. Formulation and process parameters: hx diagram (Mollier diagram)
Fluid Bed Layering and Coating in moderate climate conditions
Ambient air :
• temperature 10 °C
• relative humidity 40 %
What is the dew point of the air ?
Heated to 55 °C for processing, what will the inlet air relative
humidity be ?
Passed through a bed of wet product, what will the product
temperature be?
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Pellet Layering and Coating Processes
4. Formulation and process parameters: hx diagram (Mollier diagram)
0 10 20 30 40 50 water content x
[ g water / kg dry air]
0
-10
10
20
30
40
50
Tem
pera
ture
[°C
]
20
40
60
80
100
120
140
100
80
60
relativ humidity [%]
Ambient conditions:10°C
40% rel. humidity: A
heating to 55°C inlet
inlet air temp.: A-B
B
by spraying the drug layering or coating
liquid: a defined product moisture
expressed as product / exhaust air
temperature is achieved in the example:
product temperature ~ 30°C
rel. humidity ~ 45%
stable process
good product quality
C
x = 3 g / kg dry air
x = 3 g / kg dry air
rel. hum.: 3,5 % 30
A
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Pellet Layering and Coating Processes
4. Formulation and process parameters: hx diagram (Mollier diagram)
60
0
-10
10
20
30
40
50
Tem
pera
ture
[°C
]
20
40
60
80
100
120
140
0 10 20 30 40 50 water content x
[ g water / kg dry air]
100
80
60
relative humidity
[%]
but:
do not drive too fast !!
Process speed is limited by
specific qualities of coating
formulations (temperature +
moisture induced sticking) !!
in the “too fast example”
product temperature ~ 23°C
rel. humidity ~ 80%
“catastrophe”
3
!
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Pellet Layering and Coating Processes
4. Formulation and process parameters: hx diagram (Mollier diagram)
Now what about drying in hot and
humid summer times ?
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Pellet Layering and Coating Processes
4. Formulation and process parameters: hx diagram (Mollier diagram)
• de-humidification by cooling (10 +/- 2 °C)
• de-humidification +/-
re-humidification
absorption dryer with desiccants
in combination with a de-humidifier +
re-humidifier
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Pellet Layering and Coating Processes
4. Formulation and process parameters: hx diagram (Mollier diagram)
0 10 20 30 40 50 water content x
[ g water / kg dry air]
0
-10
10
20
30
40
50
Tem
pera
ture
[°C
]
20
40
60
80
100
120
140
100
80
60
relativ humidity [%]
Dehumidification of inlet air
Ambient conditions:
37°C, 90% rel. hum.: A
Cooling to 6°C inlet
air temp.: A-B
A
B
x = 38 g / kg dry air
38
rel. hum.: 100 %
x = 6 g / kg dry air
6
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Pellet Layering and Coating Processes
4. Formulation and process parameters: hx diagram (Mollier diagram)
38 – 6 = 32 [g water/kg dry air]
37°C, 90% rH
38 g water/
kg dry air
6°C / 100 % rH
6 g water/
kg dry air
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1. Introduction
2. Fluid bed equipment
3. Characteristics of Bottom spray processes
4. Formulation and process parameters
5. Case Studies
Overview
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Pellet Layering and Coating Processes
Summary and Conclusion
The WURSTER fluid bed technology is a feasible process for highly efficient
and reproducible pellet processing.
It is a complex, but very logical and comprehensive process technology
which provides stable conditions for particle coating
(of pellets, micropellets, crystals …).
The understanding of potential interactions of fluid bed equipment
configuration and processing parameters is a prerequisite in order to achieve
stable processes in development and industrial production.
Development is ongoing in order to improve efficiency, stability and safety
of processes – PAT (Process Analytical Technology).
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Thank you!
Dr. Anne Ettner, Pharmacist
Qualified Person
Glatt GmbH