Freund Group Companies
Over 40 Representatives Worldwide:
Service Centers in South America, Europe, USA, and Japan
Iowa, USA
Tokyo, Hamamatsu, and Osaka, Japan
FREUND
FREUND-TURBO
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
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 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.
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
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
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.