A Discussion on Granulation

API: The substance in a pharmaceutical drug that is biologically active EXCIPIENTS: A pharmacologically inactive substance used as a carrier for the active ingredients BINDER: A liquid added to a dry substance in order to hold solids together

GRANULATION

What is Granulation?
Granulation is a size-enlargement process in of which small particles are formed into larger, physically strong agglomerates in which the original particles can still be identified.

Why do we do it?
Increase the uniformity of the active ingredients distribution Improve flowability properties Densify the materials Ensure optimal particle size distribution and reduce dust.

GRANULATION

DRY GRANULATION

WET GRANULATION

DRY GRANULATION
Process to form granules without using a liquid solution because the product to be granulated may be sensitive to moisture and heat.

WET GRANULATION

Technique whereby a liquid is used to transform small solid particles into clusters of larger ones

RMG/HSG/HSMG

WORKING PRINCIPLE
Dry powder mixing 3-5 min

 Liquid binder addition

5-10 min

 WET MASSING

5-10 min

PROCESS

PROCESS

STAGES OF GRANULES

WET MILLING
Wet milling is a process defined as the size reduction of wet granulation prior to a fluid bed dryer.

 REASONS Reducing fluid bed drying time Improving moisture uniformity across a dried product BENEFITS: Mixing and granulation can form lumps of irregular shapes and size To create homogenous and uniformly sized wet particles for drying

VARIABLES IN WET GRANULATION

PROCESS PARAMETERS
Impeller Speed Higher Impeller speeds generally results in denser and smaller granules. Low impeller speeds generally result in more porous, large granules. Binder Addition Rate and Method Binder addition rate is chosen such that local over wetting of the powder mass is not a concern and at the same time the addition rate is fast enough to accommodate processing times.

OPERATING CONDITIONS
Amount of binder added
An increased granulation rate is also observed when the liquid-solid ratio increases If the liquid-solid ratio becomes too high, a phenomenon called overwetting may occur, which results in paste Saturation: ratio of liquid volume to granule-interstitial volume The minimum amount of liquid needed for granulation increased when the size of the constituent particles decreased.

Method of binder addition

2 ways: Pouring & Spraying

If liquid was added very fast the resulting in overwetting & forming of Paste. This led to the local formation of large granules or lumps, whereas a gradual liquid addition (i.e. spraying) led to a more uniform distribution of the binder The spray-on technique

EFFECT OF AGITATION
2 ways of increasing the amount of energy : IMPELLER & CHOPPER High Impeller speeds limits granules growth because of granule breakage & decrease in granule size vice versa High chopper speed improves homogeneity & decreases granule size

Effect of feed material properties

Binder properties
Binder viscosity
Increased binder viscosity increased average granule size.

Binder Surface Tension When using binders with lower surface tension, a larger of amount of binder is required.

Primary particle size

More liquid is used when the primary particle size decreases Less liquid is required to obtain an identical average granule size when a larger size is used for granulation

GENERAL RULES OF GRANULATION

Drug Substance Particle Size Granulation time Amount of Binder Solution Granulation time and/or Granule size Drug Substance Particle Size (Drug Substance Surface Area) Binder solution required and/or Granulation Time

 Granulation time/Binder solution Densification (to a point) Wettability Binder solution required and/or Granulation Time

GOOD GRANULE
Granule size Shape Density distributions

END POINT
End-point can be defined by the formulator as a target particle size mean or distribution. Most challenging task while performing wet granulation in high-shear mixers, is the detection of end point and reproducibility of same end point by controlling various process variables.

TRADITIONAL/OLD METHODS
Power Consumption: Power consumption of the mixer motor for end-point determination and scale-up is widely used because the measurement is economical, does not require extensive mixer modifications and is well correlated with granule growth.

 Impeller Torque: Direct torque measurement requires installation of strain gauges on the impeller shaft or on the coupling between the motor and impeller shaft. Since the shaft is rotating, a device called a slip ring is used to transmit the signal to the stationary data acquisition system.

 Reaction Torque: As the impeller shaft rotates, the motor tries to rotate in the opposite direction, but does not because it is bolted in place. The tensions in the stationary motor base can be measured by a reaction torque transducer.

Emerging Technologies
Near-Infrared (NIR) Use of a refractive NIR moisture sensor for endpoint determination of wet granulation. There are technological challenges associated with this approach, as the sensor can only measure the amount of water at the powder surface

 Acoustic: Applicability of piezo-electric acoustic emission sensors to endpoint determination has been studied since the beginning of this century. The technique is very promising, especially since it is non-invasive, sensitive and relatively inexpensive. Granulation process signatures obtained with an acoustic transducer can be used to monitor changes in particle size, flow and compression properties

FBRM: Focused beam reflectance measurement (FBRM) is a particle-size determination technique based on a laser beam focusing in the vicinity of a sapphire window of a probe.

 PVM:
Particle Vision Microscope (PVM) is a probe-based vision tool that provides immediate, critical insight into crystal, particle, and droplet systems. Visualize and Understand Particles and Droplets - By capturing thousands of images per experiment without the need for sampling, PVM helps to immediately visualize changes to particles and droplets and gain early insight into process challenges. High Resolution Images - PVM provides microscope quality images in real time to characterize particle systems from 2m to 1mm at full process concentrations.

Thank you