7th training school on microencapsulation...

1 Textmasterformat in Mastervorlage eingeben 1

7th Training School on Microencapsulation – Strasbourg

Februar 2015

2 Textmasterformat in Mastervorlage eingeben 2

Pellet Layering and Coating Processes

Dr. Anne Ettner, Glatt Pharmaceutical Services

3 Textmasterformat in Mastervorlage eingeben 3 3

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

4 Textmasterformat in Mastervorlage eingeben 4

Pellet Layering and Coating Processes

1. Introduction: Pharmaceutical Pellets

5 Textmasterformat in Mastervorlage eingeben 5

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

6 Textmasterformat in Mastervorlage eingeben 6

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

7 Textmasterformat in Mastervorlage eingeben 7

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

8 Textmasterformat in Mastervorlage eingeben 8

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

9 Textmasterformat in Mastervorlage eingeben 9

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

10 Textmasterformat in Mastervorlage eingeben 10

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

11 Textmasterformat in Mastervorlage eingeben 11

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

12 Textmasterformat in Mastervorlage eingeben 12

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

13 Textmasterformat in Mastervorlage eingeben 13

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

14 Textmasterformat in Mastervorlage eingeben 14 14

1. Introduction

2. Fluid bed equipment

3. Characteristics of Bottom spray processes

4. Formulation and process parameters

5. Case Studies

Overview

15 Textmasterformat in Mastervorlage eingeben 15

Pellet Layering and Coating Processes

2. Fluid bed equipment: Fluid bed unit in bottom spray configuration

Downbed

Upbed

Spray nozzle position:

Bottom-spray (“Wurster“)

16 Textmasterformat in Mastervorlage eingeben 16

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

17 Textmasterformat in Mastervorlage eingeben 17

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)

18 Textmasterformat in Mastervorlage eingeben 18 18

1. Introduction

2. Fluid bed equipment

3. Characteristics of Bottom spray processes

4. Formulation and process parameters

5. Case Studies

Overview

19 Textmasterformat in Mastervorlage eingeben 19

Pellet Layering and Coating Processes

3. Characteristics of Bottom spray processes

HS collar

Wurster partition

HS nozzle

Inlet air dis-

tribution plate

20 Textmasterformat in Mastervorlage eingeben 20

Pellet Layering and Coating Processes

3. Characteristics of Bottom spray processes

HS collar

Wurster partition

HS nozzle

Inlet air dis-

tribution plate

21 Textmasterformat in Mastervorlage eingeben 21

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

22 Textmasterformat in Mastervorlage eingeben 22

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

23 Textmasterformat in Mastervorlage eingeben 23

Pellet Layering and Coating Processes

3. Characteristics of Bottom spray processes

HS collar

Wurster partition

HS nozzle

Inlet air dis-

tribution plate

24 Textmasterformat in Mastervorlage eingeben 24

Pellet Layering and Coating Processes

3. Characteristics of Bottom spray processes: Wurster Partition

h

h

downbed upbed downbed upbed

25 Textmasterformat in Mastervorlage eingeben 25

Pellet Layering and Coating Processes

3. Characteristics of Bottom spray processes:

High Speed (“HS”) nozzle system

HS nozzle HS nozzle + collar

+ Collar

26 Textmasterformat in Mastervorlage eingeben 26

Pellet Layering and Coating Processes

3. Characteristics of Bottom spray processes

27 Textmasterformat in Mastervorlage eingeben 27 27

1. Introduction

2. Fluid bed equipment

3. Characteristics of Bottom spray processes

4. Formulation and process parameters

5. Case Studies

Overview

28 Textmasterformat in Mastervorlage eingeben 28

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

29 Textmasterformat in Mastervorlage eingeben 29

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.

30 Textmasterformat in Mastervorlage eingeben 30

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

31 Textmasterformat in Mastervorlage eingeben 31

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

32 Textmasterformat in Mastervorlage eingeben 32

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?

33 Textmasterformat in Mastervorlage eingeben 33

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

34 Textmasterformat in Mastervorlage eingeben 34

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

!

35 Textmasterformat in Mastervorlage eingeben 35

Pellet Layering and Coating Processes

4. Formulation and process parameters: hx diagram (Mollier diagram)

Now what about drying in hot and

humid summer times ?

36 Textmasterformat in Mastervorlage eingeben 36

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

37 Textmasterformat in Mastervorlage eingeben 37

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

38 Textmasterformat in Mastervorlage eingeben 38

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

39 Textmasterformat in Mastervorlage eingeben 39 39

1. Introduction

2. Fluid bed equipment

3. Characteristics of Bottom spray processes

4. Formulation and process parameters

5. Case Studies

Overview

40 Textmasterformat in Mastervorlage eingeben 40

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).

41 Textmasterformat in Mastervorlage eingeben 41 41

Thank you!

Dr. Anne Ettner, Pharmacist

Qualified Person

Glatt GmbH

anne.ettner@glatt.com