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