Maroglou, 1986
EQUIPMENT AND PROCESSING
Fluid Bed Granulation
Global Technical Research & Development
40
40
50
50
60
60
e
W
ulb
tB
80
%
70
80
90
DRY BULB TEMPERATURE (F)
)
(F 70
80
90
60
%
EQUIPMENT AND PROCESSING
Psychrometric Chart
Global Technical Research & Development
100
%
20%
40
120
.004
.008
.012
.016
.020
.024
.028
HUMIDITY RATIO (Lbv/Lba)
•
•
•
•
– rotary granulation
Particles are suspended in the hot air stream.
The atomized liquid is sprayed
Top spray granulation
Tangential spray granulation
EQUIPMENT AND PROCESSING
Fluid Bed Granulation Process
Global Technical Research & Development
Glatt Company Brochure
EQUIPMENT AND PROCESSING
Fluid Bed Top Spray Granulation Process
Global Technical Research & Development
Vector Inc
EQUIPMENT AND PROCESSING
Top Spray Fluid Bed Granulation Process
Global Technical Research & Development
Glatt Brochure
EQUIPMENT AND PROCESSING
Fluid Bed Rotor (Tangential Spray) Granulation Process
Global Technical Research & Development
Glatt Brochure
Glatt GRG 120/200 Rotor
1400 mm dia disc
5 - 25 m/s circumf. Speed
70 - 340 rpm
6000 m3/h air flow
EQUIPMENT AND PROCESSING
Fluid Bed Rotor (Tangential Spray) Granulation Process
Global Technical Research & Development
– cohesive material
– dust explosion potential
• Limitation:
• Single process step for mixing, granulating, drying
• Relative ease of process control and validation
• Lighter granules (dissolution, chewable tab.)
EQUIPMENT AND PROCESSING
Assessment of Fluid Bed Granulation
Global Technical Research & Development
Nucleation
Transition
Ball growth
Binder
Characteristics of primary particles
Process parameters of the Fluid Bed
Granule growth stages
• Balance between bonding forces and breakup force to control
growth
•
•
•
•
EQUIPMENT AND PROCESSING
Bonding of Granules in Fluid Bed Granulation
Global Technical Research & Development
• Fliter Bag Shaker
• Granulator Bowl Geometry
– low density drug requires low fluidizing velocity
• Air Distributor Plate
EQUIPMENT AND PROCESSING
Fluid Bed Granulation Equipment Variables
Global Technical Research & Development
Inlet Temperature
Air Volume
Dew Point
Droplet size
Spray rate
Atomization air pressure/volume
• Solids content
• Product Temperature
• Exhaust Temperature
•
•
•
•
• Granule size increases with increasing binder concentration
• Linear relation between size of granules & droplets
EQUIPMENT AND PROCESSING
Fluid Bed Granulation Process Variables
Global Technical Research & Development
Combination of:
• Exhaust temperature
• Bed temperature
• Drying time
EQUIPMENT AND PROCESSING
Fluid Bed Granulation End Point
Global Technical Research & Development
– Produces fluidization pattern
– Delivers heat to the product
– Changes should be at the same time and magnitude (batch to
batch)
• Process air volume
– Selected to achieve desired product temperature
– Adjusted with process air volume
• Process air temperature
EQUIPMENT AND PROCESSING
Scale-Up Fluid-Bed Processes
Global Technical Research & Development
Spray drying is instant moisture removal
Process to convert pumpable liquid into a free flowing powders
EQUIPMENT AND PROCESSING
Spray Drying Granulation Process
Global Technical Research & Development
4. A device to separate the powders
3. A place to mix them in
2. Atomized liquid
1. Source of hot gas
1
EQUIPMENT AND PROCESSING
Spray Drying Granulation Process
Global Technical Research & Development
3
2
4
EQUIPMENT AND PROCESSING
Spray Drying Co-current Process
Global Technical Research & Development
Quantity and pressure of atomization
air controls particle size
Good for small particles 5 - 50µm
Two Fluid Nozzle
EQUIPMENT AND PROCESSING
Spray Drying Two Fluid Nozzle
Global Technical Research & Development
EQUIPMENT AND PROCESSING
Spray Drying Two Fluid Nozzle
Global Technical Research & Development
May need a larger tower for larger particles
High pressure pump required (500-2000 psi)
Large particles, less fines (30->100µm)
Narrow particle size distribution
Pressure Fluid Nozzle
EQUIPMENT AND PROCESSING
Spray Drying Pressure Nozzle
Global Technical Research & Development
Good Scalability
Less potential for plugging
More complex system
Largest particle size range (15-100µm)
Narrowest particle size distribution
Rotary Nozzle
EQUIPMENT AND PROCESSING
Spray Drying Rotary Nozzle
Global Technical Research & Development
EQUIPMENT AND PROCESSING
Spray Drying Rotary Nozzle
Global Technical Research & Development
Rotary 30 um
2 Fluid Nozzle 30 um
Rotary 40-50 um
2 Fluid Nozzle 60-80 um
Rotary 80-100 um
2 Fluid Nozzle 80-100 um
Press Nozzle >100 um
Size 1
Size 2
Size 4
EQUIPMENT AND PROCESSING
Particle Size From Spray Drier - Nozzle Type Combination
Global Technical Research & Development
• Controlled Particle Size Distribution
• Dust Free
• Free Flowing
EQUIPMENT AND PROCESSING
Spray Dried Powder
Global Technical Research & Development
Enhanced Physical Properties
Flow
Compressibility
Molecular to Colloidal Drug Substance Dispersion
Dissolution/Bioavailability
Content Uniformity
Amorphous Powders
EQUIPMENT AND PROCESSING
Spray Drying Advantages
Global Technical Research & Development
Modified Release
Taste Masking
Enhanced Solubility/Bioavailability
Solid Dispersions
Solids Solution
Drug Matrix Formation
EQUIPMENT AND PROCESSING
Spray Drying Applications
Global Technical Research & Development
Microwave Drying
Fluid Bed Drying
Tray Drying
EQUIPMENT AND PROCESSING
Drying Unit Operation
Global Technical Research & Development
• bonded on the surface of the granules
• bonded inside the granules (capillary
attraction)
• hygroscopically / chemically bonded ...
Moisture bonding mechanisms
EQUIPMENT AND PROCESSING
Characteristic Drying Curve
Global Technical Research & Development
• Heated, inlet air enters
chamber from bottom
• Paper-lined trays hold
granules
- Spread evenly to
promote uniform drying
• Perforated trays to improve
air flow through granule bed
• Exhaust air emitted
through top
EQUIPMENT AND PROCESSING
Tray Drier
Global Technical Research & Development
• Filter Housing
Traps product which has become
entrained in the exiting air stream
Agitated to allow particles to return
to the product container
• Expansion Chamber
Cylindrical in shape
Area of fluidization/drying
• Product Container
Conical in shape
Bottom screen to retain product
while allowing air flow through
the product bed
EQUIPMENT AND PROCESSING - Fluid Bed Drier
Global Technical Research & Development
• Humidity of Inlet Air
• Inlet Air Volume
• Inlet Air Temperature
EQUIPMENT AND PROCESSING
Critical Process Parameters
Global Technical Research & Development
[°C]
60
60
60
60
60
60
0
15
30
50
60
62
24.0
27.1
36.3
47.4
47.9
Product
Incoming Air
Temperature Temperature
[min]
Drying
Time
24
24
24
24
24
24
[°C]
Wet Bulb
Temperature
0
3.1
12.3
23.4
23.9
Product
Temperature
Difference
[°C]
39.0
27.9
17.4
7.5
4.5
4.1
[%]
LOD
• From Development Work It’s Been Established That a ∆t of
Correlates to an Acceptable Endpoint LOD
• In Example, the Product Is Dried to a Product Temperature
of 47.9°C to Achieve an LOD of 4.1%
EQUIPMENT AND PROCESSING
∆T Drying
Global Technical Research & Development
Microwave - Vacuum Drying
Combination of Microwave Plus Gas Assisted Drying
•
•
EQUIPMENT AND PROCESSING
Microwave Drying Techniques
Global Technical Research & Development
At this rate, the orientation polarization
effect gives rise to internal friction
phenomena, producing heat.
At 2450 MHz, the field is alternating at a
rate of 2450 million times per second.
The used microwave frequency (2450 MHz)
creates a rapidly alternating electric field.
In an electric field, the charges of dipolar
material are polarized and oriented according
to the direction of the field.
EQUIPMENT AND PROCESSING
Microwave Drying Principles
Global Technical Research & Development
P= k • loss factor
transparent material: low loss factor
absorbers: high loss factor
e.g. Rubber
e.g. Metals
P = 2π f v 2 E0 Er tan δ
EQUIPMENT AND PROCESSING
Microwave Drying Principles
Global Technical Research & Development
known as :
LOSS FACTOR
For a given electrical
field strength (v)
2πfv2Eo is constant and
P (power absorbed) is
proportional to:
Er tan δ
P = energy absorbed by
material exposed to
microwave energy
(Watt/m3)
Methanol
Ethanol
Water
Isopropanol
Acetone
ice
2.9
6.1
8.6
13.6
Corn starch
Mc cellulose
Mannitol
Ca phosphate
Ca carbonate
Lactose
0
0.15
0,41
Commonly used excipients
0,05 0,1 0,15 0,2 0,25 0,3 0,35 0,4 0,45
0,06
0,06
0,03
0,02
Result : faster evaporation, reduced drying times
Commonly used solvents
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
1.3
0,003
Loss factors
Preferential heating of products with a high loss factor (water,
solvents), negligible heating of products with a low loss factor
(most pharmaceutical excipients)
Additional energy supply by microwaves:
EQUIPMENT AND PROCESSING
Microwave Drying Principles
Global Technical Research & Development
Lower energy supply and lower temperatures
needed for drying
By applying vacuum in the bowl, the boiling point of
the granulation liquid used is significantly
decreased.
The boiling point of liquids is lower at lower
pressures.
EQUIPMENT AND PROCESSING
Vacuum Drying Principles
Global Technical Research & Development
-80
-60
-40
-20
0
20
40
water
EQUIPMENT AND PROCESSING
Vacuum Drying - Temperature and Pressure Relationship
Global Technical Research & Development
Methylene chloride
Acetone
Methanol
Ethanol
Isopropanol
Water
water 20 mbar
0
500
1000
1500
2000
2500
organic solvents will evaporate
4 to 5 times quicker than water
(on fixed energy input)
Enthalpy of vaporization (kJ/kg)
Is Influenced by the Solvent Used
EQUIPMENT AND PROCESSING
Vacuum Drying Principles
Global Technical Research & Development
– Limited energy supply and thus long drying time
– scale up of drying time not linear due to difference in ratio of
working volume and contact surface
EQUIPMENT AND PROCESSING
Vacuum Drying Scale-up
Global Technical Research & Development
y Mix the Product Gently When It
Becomes Dry and Fragile
y Improve the Heat Transport Through
the Bed
y Increase the Partial Pressure Drop
Across the Vessel
y Improve the Transport of Moisture
From the Granules to the Vacuum
System
During Vacuum Drying, Inert Gas Is
Passed Through the Product in Order
To:
EQUIPMENT AND PROCESSING
Gas Assisted Drying
Global Technical Research & Development
0
2
4
6
8
10
12
0
15
30
45
60
75
90
105
120
135
Pure Vacuum
150
165
180 time
17.5%
Water
Gas Assisted, and
Vacuum
9.1%
Prejel PA5
16
Microwave
18.2%
Corn Starch
18
14
72.7%
Lactose
Composition:
20
LOD [%]
EQUIPMENT AND PROCESSING
End-Point Analysis
Global Technical Research & Development
* The roots blower is integrated for machines ≥ ULTIMA 75
production area
CONDENSER 1
technical area
BLOWER
ROOTS
• Liquid recovery unit (1or 2 condensers)
• Energy supply through heated jacket of lid and bowl
PUMP
VACUUM
• Highly efficient vacuum system (roots blower + vacuum pump)*
EQUIPMENT AND PROCESSING
Characteristics of the Collette Vacuum System
Global Technical Research & Development
2
CONDENSER
EQUIPMENT AND PROCESSING
Collette Vacuum System
Global Technical Research & Development
EQUIPMENT AND PROCESSING
Collette Vacuum System
Global Technical Research & Development
Product
water jacket
Removable
inserts
Control of drying process by
means of product temperature
and power detection
EQUIPMENT AND PROCESSING
End-Point Analysis
Global Technical Research & Development
Melt Extrusion is relatively new to the pharmaceutical
industry
- Feeding
- Melting Temperature control
- Mixing
Melt Extrusion is a versatile application with precise
monitoring systems
Melt Extrusion is a suitable process for preparation of
solid dispersions and for the enhancement of
dissolution for poorly water-soluble drugs
EQUIPMENT AND PROCESSING
Melt Extrusion
Global Technical Research & Development
Serajuddin, 1999
EQUIPMENT AND PROCESSING
Melt Extrusion
Global Technical Research & Development
Antioxidants: BHT, BHA
Surfactants: Sodium Lauryl Sulfate, Poloxamer
Plasticizers: Water, PEGs, triethyl citrate (TEC), Sorbitol
Lower Tg of material and torque
Polyvinylpyrrolidone (PVPs) - Amorphous
Molecular weights of 2500 to 3000000 (K value)
Polyethylene Glycols (PEGs) - Crystalline
Molecular weights of 4000 - 6000 are most common
Carrier materials: PVP, PEG, Eudragit, HPMC, etc.
EQUIPMENT AND PROCESSING
Melt Extrusion
Global Technical Research & Development
EQUIPMENT AND PROCESSING
Melt Extrusion
Global Technical Research & Development
EQUIPMENT AND PROCESSING
Melt Extrusion
Global Technical Research & Development
EQUIPMENT AND PROCESSING
Melt Extrusion - 16 mm Twin - Screw Extruder
Global Technical Research & Development
EQUIPMENT AND PROCESSING
Melt Extrusion - 16 mm Clam Shell Design
Global Technical Research & Development
• Layering Spheres with Drug Substances
Layered with Drug
• Applying Polymeric Coating to Spheres Containing or
EQUIPMENT AND PROCESSING
Particle Coating - Fluid Bed
Global Technical Research & Development
EQUIPMENT AND PROCESSING
Particle Coating - Coating
Global Technical Research & Development
Polymer Film
water evaporation
droplet coalescence
Close Packed Spheres
water evaporation
Substrate Contact
water evaporation
Coating Droplets
EQUIPMENT AND PROCESSING
Particle Coating - Layering
Global Technical Research & Development
water evaporation
polymer film formation
Layered Particles
water evaporation
Substrate Contact
water evaporation
Layering Particles
EQUIPMENT AND PROCESSING
Particle Coating - Coating/Layering
Global Technical Research & Development
Coating
Drug Layer
16 - 18 mesh (1000 um)
60 - 80 mesh (215 um),
(Nu-Pareils)
Sugar Starch Spheres
EQUIPMENT AND PROCESSING
Particle Coating - Fluid Bed Basic Design Layout
Global Technical Research & Development
Ebey, G., Pharm. Tech., April 1987, pages 40-50
ma1ha1 + mv1hv1 + mliqhliq = ma2ha2 + mv2hv2
ma1 = mass of dry air in
hliq = enthalpy of water in
ha1 = enthalpy of air in
ma2 = mass of air out
mv1 = mass of water vapor in
ha2 = enthalpy of air out
hv1 = enthalpy of water vapor in mv2 = mass of water vapor out
mliq = mass of water in
hv2 = enthalpy of water vapor out
Coating Equations ∆H = 0
EQUIPMENT AND PROCESSING
Particle Coating - Theoretical Considerations
Global Technical Research & Development
•
•
•
•
•
•
Substrate (Sugar/Starch Spheres)
Substrate Particle Size
Substrate Density
Coating Composition (latex, suspension, solution)
Coating Concentration
Coating Viscosity
EQUIPMENT AND PROCESSING
Particle Coating - Formulation Variables
Global Technical Research & Development
•
•
•
•
•
Inlet temperature
Outlet temperature
Inlet/Outlet Air flow
Spray Rate
Atomization Pressure
EQUIPMENT AND PROCESSING
Particle Coating - Process Variables
Global Technical Research & Development
Width of Column Partition
Length of Column Partition
Gap of Column Partition
Bottom Plate Design
Bottom Spray -
Tangential Spray - Size of Disc
Texture of the Disc
Speed of the Disc
Nip between Disc and Wall
Location in Expansion Chamber
Design of the expansion Chamber
Top Spray -
Type Spray (Top, Bottom & Tangential)
EQUIPMENT AND PROCESSING
Particle Coating - Equipment Variables
Global Technical Research & Development
Glatt Company Brochure
EQUIPMENT AND PROCESSING
Particle Coating - Top Spray Process
Global Technical Research & Development
Glatt Company Brochure
EQUIPMENT AND PROCESSING
Particle Coating - Top Spray Process
Global Technical Research & Development
Glatt Company Brochure
EQUIPMENT AND PROCESSING
Particle Coating - Bottom Spray (Wurster) Process
Global Technical Research & Development
Glatt Company Brochure
EQUIPMENT AND PROCESSING
Particle Coating - Bottom Spray Process
Global Technical Research & Development
Glatt Brochure
EQUIPMENT AND PROCESSING
Particle Coating - Tangential Spray Rotor Process
Global Technical Research & Development
Glatt Brochure
EQUIPMENT AND PROCESSING
Particle Coating - Tangential Spray Rotor Process
Global Technical Research & Development
Glatt Company Brochure
EQUIPMENT AND PROCESSING
Particle Coating - Top Spray Process
Global Technical Research & Development
Glatt Company Brochure
EQUIPMENT AND PROCESSING
Particle Coating - Bottom Spray (Wurster) Process
Global Technical Research & Development
Novartis
EQUIPMENT AND PROCESSING
Particle Coating - Bottom Spray (Wurster) Process
Global Technical Research & Development
Novartis
EQUIPMENT AND PROCESSING
Particle Coating - Bottom Spray (Wurster) Process
Global Technical Research & Development
Glatt Brochure
EQUIPMENT AND PROCESSING
Particle Coating - Tangential Spray Rotor Process
Global Technical Research & Development
Glatt Training Manual
EQUIPMENT AND PROCESSING
Particle Coating - Spray Systems
Global Technical Research & Development
EQUIPMENT AND PROCESSING
Particle Coating - Nozzle Droplet Size Distribution
Global Technical Research & Development
Rubino, O., Pharm. Tech., June 1999
Machine Space
Equipment Capacity
Equipment Cost
Economic:
Film Quality
Coating Uniformity
Coating Efficiency
Layering Capacity
Product:
Simplicity
Nozzle Access
Scale-Up
Mechanical Stress
Process:
Property
2
3
3
1
2
1
2
3
3
3
3
Top
1
2
2
3
3
3
1
2
1
2
2
Bottom
3
1
1
3
3
3
3
1
2
1
1
Tangential
EQUIPMENT AND PROCESSING
Particle Coating - Equipment Application Assessment
Global Technical Research & Development