Granulation Presentation

8/2/2019 Granulation Presentation

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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 tohold solids together







GRANULATION



What is Granulation?

Granulation is a size-enlargement processin of which small particles are formed intolarger, physically strong agglomerates in

which the original particles can still beidentified.



Why do we do it?

• Increase the uniformity of the activeingredients distribution

•

Improve flowability properties• Densify the materials• Ensure optimal particle size distribution

and reduce dust.



GRANULATION

DRYGRANULATION

WETGRANULATION



DRY GRANULATION

Process to form granules without using aliquid solution because the product to be

granulated may be sensitive to moistureand heat.





WET GRANULATION

Technique whereby a liquid is used to transformsmall 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 processdefined as the size

reduction of wetgranulation prior to afluid bed dryer.



• REASONS

Reducing fluid bed drying timeImproving moisture uniformity across a driedproduct

• BENEFITS:Mixing and granulation can form lumps of

irregular shapes and sizeTo create homogenous and uniformly sized wet

particles for drying



VARIABLES IN WET GRANULATION



PROCESS PARAMETERS

• Impeller SpeedHigher Impeller speeds generally results indenser and smaller granules. Low impellerspeeds generally result in more porous, large

granules.• Binder Addition Rate and MethodBinder addition rate is chosen such that local

over wetting of the powder mass is not aconcern and at the same time the addition rateis fast enough to accommodate processingtimes.



OPERATING CONDITIONS

Amount of binder added

• An increased granulation rate is also observed when theliquid-solid ratio increases

• If the liquid-solid ratio becomes too high, a phenomenoncalled overwetting may occur, which results in paste

• Saturation: ratio of liquid volume to granule-interstitialvolume

• The minimum amount of liquid needed for granulationincreased when the size of the constituent particlesdecreased.



Method of binder addition

• 2 ways: Pouring & Spraying

• If liquid was added very fast the resulting inoverwetting & forming of Paste. This led to the local

formation of large granules or lumps, whereas a gradualliquid addition (i.e. spraying) led to a more uniformdistribution 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 propertiesBinder 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 particlesize decreases

• Less liquid is required to obtain an identicalaverage granule size when a larger size is usedfor 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 SubstanceSurface 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 asa target particle size mean or distribution.

• Most challenging task while performing wetgranulation in high-shear mixers, is thedetection 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-pointdetermination and scale-up is widely used because themeasurement is economical, does not require extensive mixermodifications and is well correlated with granule growth.



• Impeller Torque :

Direct torque measurement requiresinstallation of strain gauges on the impellershaft or on the coupling between the motor

and impeller shaft. Since the shaft is rotating,a device called a slip ring is used to transmitthe signal to the stationary data acquisition

system.





• Reaction Torque :

As the impeller shaft rotates, the motor triesto rotate in the opposite direction, but doesnot because it is bolted in place. The tensionsin the stationary motor base can be measuredby a reaction torque transducer.



Emerging Technologies

• Near-Infrared (NIR)Use of a refractive NIR moisture sensor forendpoint determination of wet granulation.There are technological challenges associatedwith this approach, as the sensor can onlymeasure the amount of water at the powder

surface



• Acoustic:Applicability of piezo-electric acousticemission sensors to endpoint determinationhas been studied since the beginning of thiscentury. The technique is very promising,

especially since it is non-invasive, sensitiveand relatively inexpensive. Granulationprocess signatures obtained with an acoustictransducer can be used to monitor changes inparticle size, flow and compression properties



FBRM:Focused beam reflectance measurement

(FBRM) is a particle-size determinationtechnique based on a laser beam focusing inthe vicinity of a sapphire window of a probe.



• PVM:

Particle Vision Microscope (PVM®) is a probe-basedvision tool that provides immediate, critical insight intocrystal, particle, and droplet systems.

•

Visualize and Understand Particles and Droplets - Bycapturing thousands of images per experiment withoutthe need for sampling, PVM® helps to immediatelyvisualize changes to particles and droplets and gainearly insight into process challenges.

• High Resolution Images - PVM® provides microscopequality images in real time to characterize particlesystems from 2μm to 1mm at full processconcentrations.



Thank you

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Granulation Presentation