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GRANULATION PROCESS TECHNOLOGY

Granulation and Coating Seminar Freund-Vector Corporation

Freund Group Companies

Over 40 Representatives Worldwide:

Service Centers in South America, Europe, USA, and Japan

Iowa, USA

Tokyo, Hamamatsu, and Osaka, Japan

FREUND

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Japan

FREUND-VECTOR

FREUND-VECTOR

european laboratory

Villasanta, Italy

What is Granulation?

Granulation is a process where small particles are integrated into a larger, permanent mass in which the original particles can still be readily identified.

This can be accomplished by applying mechanical energy, binding agents, or a combination of both.

Why Granulate?

• Improve Flow – Reduce Weight Variation

– Improve Content Uniformity

• Improve Tableting Properties – Compaction

• Prevent Segregation

• Increase Density of Product

• Minimize Dust (increasing particle size) – Reduce Exposure

– Improve Yield

Characteristics of Pharmaceutical Raw Materials

• Small Average Particle Size (<100µm)

• Wide Particle Size Distribution (PSD)

• Poor Flowability and Difficult to Compress

• Dusty and Subject to Segregation

• Difficult to Control Dosing

• APIs Display some level of Toxicity

Characteristics of Granulated Materials

• Larger Average Particle Size (>150µm)

• Tight/Narrow Particle Size Distribution (PSD)

• High Level of Content Uniformity

• Low Dust and Improved Flowability Tailored for: – Tablet Compression

– Capsule Fill

– Coating

– To Matching other Ingredient Particle Size for Improved Blending

Dry Granulation • A Three Step Process

• Materials are Pre-Blended, Compressed tightly together and then Milled.

– Slugging • Usually large compacts with variable density

– Roll Compaction • A compressed sheet of uniform density

Fully Pre-gelatinized Corn Starch Hypromellose

Typical Dry Granulating Equipment

Roll Compactor • For Compressible and some Poorly Compressible Materials

• Often used to densify API and blends with high active loading

• Excellent for Moisture Sensitive Products

• Continuous Process, up to 600 kilograms per hour or more

• Granule Size is primarily controlled by the Milling step

Compaction Process

• Three Regions

– Slip Zone

– Nip Zone

– Release Zone

Slip Zone

Nip Zone

Slip & Nip Zones

Nip Angle

Process Variables

• Roll speed

• Screw feeder speed

• Compaction pressure

• Deaeration pressure

Wet Granulation • Generally a Four Step Process

• Liquid is introduced in to a mass of API and Excipients and Mixed, Dried and Milled.

• Depends on the Formation of Liquid Bridges

• Particles are drawn together via Capillary Force

• The Liquid Bridges contain a Binder material or a Solvent for a portion of the Formulation

Three Simultaneous Granulation Sub-Processes

– Wetting and Nucleation

– Consolidation and Growth

– Attrition and Breakage

Hapgood et al., J.Coll.Int.Sci., 253, 353-366, 2002

Wet Granulation

Depends on The Formation of Liquid Bridges

These bridges may or may not contain a binder material

Wet Granulation Methods

• Low Shear

• High Shear

• Fluidized Bed – Top Spray

– Rotor Granulation

Wet Granulating Equipment High Shear Mixer

• Advantages:

– Fast Granulating step

– Simple Process

– Good Mixing

– Wide Range of Batch Sizes up to 1900 Liters

• Potential Disadvantages:

– High Moisture content

– Issues of Repeatability with bowl temperature

– Requires wet milling, drying and dry milling

– Granule Size is Primarily controlled by Milling step

High Shear Advantages

• Granulation Phase is Simple – API – Binder – Liquid

• Fast • High Bulk Density Granulations • Easy to Scale up

– Maintain Tip Speed – Maintain Liquid Addition Time – Maintain Liquid Addition Percent

High Shear Disadvantages

• Moisture-sensitive products often cannot be processed with aqueous binders.

• Distribution of binder solutions is less uniform than with other processes.

• Wide particle size range in unmilled granulation.

• Requires multiple handling and processing steps to achieve dry finished granulation.

Mixing Blade or Impeller

Top Drive High Shear Granulator/Mixers

Chopper Impeller

Bottom Drive High Shear Granulator/Mixers

Wet Granulating Equipment Top Spray Fluid Bed

Advantages: – Relatively Fast Granulation

– Good Control of Particle size

– Excellent Content Uniformity

– Precise Temperature control

– Process includes drying step

– May not need milling, so total process time and number of process steps can be less than that of a High Shear process

– Available in wide range of batch volumes up to 8,400 liters

– Multi-functional (drying, granulation, & coating)

Wet Granulating Equipment Fluid Bed Rotor: Granurex (GXR)

• Advantages

– Relatively Fast Granulation, Spheronization and Powder Layering

– Produces a Granulation with a Very Uniform Particle Size, never needs a Milling step

– Process include the Drying step

– Capable of producing a Very Spherical, Very Dense Granulation

• Potential Disadvantages

– More Complex Process than Top Spray

– Batch sizes are not as large as with other methods, less than 500 Liters depending on the process

Granulation Applications

• Improve Compression Characteristics – Improve/Narrow Particle Size Distribution to Increase Tabletability and

Decrease Tablet Friability by adding Binders

– Increase Granulation Density to Improve Tableting Speed and Reduce Capping (less air to expel during compression).

• Mix Multiple Components for Improved Content Uniformity — Formulation

— Comparisons

• Instantizing (Sufficient Dispersibility in a relative time frame)

Unprocessed Top-Spray Fluid Bed

Rotary Fluid Bed

Tryptophane 0.13 g/cc 0.24 g/cc 0.43 g/cc

Sulfamethazine 0.31 g/cc 0.43 g/cc 0.60 g/cc

Lactose 0.50 g/cc 0.49 g/cc 0.60 g/cc

Ascorbic Acid 0.46 g/cc 0.56 g/cc 0.63 g/cc

Increasing Granulation Density Top Spray and Rotor Granulation Density Examples

GXR: Spherical Granulation

• Starting with a powder blend inside the rotor disc, a binder solution is sprayed onto the powder to form granules

• The rotor imparts force onto the powder, forming a more spherical granule than with top spray processing

GXR: Spherical Granulation Why is it done?

• Creates a very narrow particle size distribution (PSD) • Granules are much more spherical than other granulation methods • Very few excipients are required, so each granule can have up to

97% active content • Achieves excellent content uniformity from granule to granule

Wet Granulating Equipment Process Time Comparison

10-15 Minute Granulation

5-20 Minute Mill

20-60 Minute Dry

5-15 Minute Mill

40-110 minute Total, 4 Steps

20-60 Minute Granulation

15-30 Minute Dry

0-15 Minute Mill

35-105 minute Total, 3 Steps

30-50 Minute Granulation

5-15 Minute Dry

35-65 minute Total, 2 Steps

COATING PROCESS TECHNOLOGY

Granulation and Coating Seminar Freund-Vector Corporation

Terms

• Tablets, Larger than 2000µm

• Multiparticulates, 10 – 2000µm.

Tablet Coating Equipment

Side Vented Fully or Partially Perforated Coating Pan

• Side Vented Coating Pans handle wide ranges of tablet sizes and tablet characteristics.

• They are well suited to apply Aqueous and Solvent based polymeric systems as well as the high weight gain of Sugar Coatings.

AT - FILM COATING SPRAY GUN

ATOMIZATION AIR ADJUSTMENT

PATTERN AIR ADJUSTMENT

SOLUTION RECIRCULATION

NEEDLE ADJUSTMENT

ORFICE SELECTION

AIR CAP SELECTION SOLUTION IN

NEEDLE (CYLINDER) AIR.

PATTERN AIR ATOMIZATION AIR

Film Coating Procedure

Localized over wetting

60 g/min

140 g/min

80 g/min

120 g/min

Under spray

Examine spray pattern width as the source of over wetting

Localized over wetting

Film Coating

Overlapping the spray pattern creates the potential for localized over wetting of the tablets (red zones)

Film Coating

Film Coating Procedure

100 g/min

100 g/min

100 g/min

100 g/min

The goal of solution calibration is to create

a uniform “curtain” of spray.

Multiparticulate Coating Equipment

Fluid Bed Wurster • Wurster coaters handle the widest

range of product sizes,

• They are well suited to apply Aqueous and Solvent and Hot Melt based coating systems.

• Systems such as the Accelerator greatly improve the coating speed and minimum particle size that can be coated.

Multiparticulate Coating Equipment

Fluid Bed Rotor, Granurex

• Standard Aqueous and Solvent

polymeric coatings.

• Polymeric coatings with separate application of glidants.

• High solids application of cellulosic and methacrylate based coatings.

• Powder Layering of actives and finely divided polymers.

GXR: The Conical Rotor Insert

GXR: Dry Polymer Layering Powder Layering Ethylcellulose

Core API Layer Polymer coating