Pilot scale up of tablets

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www.ijpbs.com (or) www.ijpbsonline.com IJPBS |Volume 2| Issue 3 |JULY-SEPT |2012|223-239

Review Article
Pharmaceutical Sciences
REVIEW: SCALE UP PROCESS OF TABLET PRODUCTION: A PROSPECTIVE DISCUSSION

Kamya Chaudhary*, A.C.Rana, Rajni Bala, Nimrata Seth

Department of Pharmaceutics, Rayat College of Pharmacy, Ropar, India
*Corresponding Author Email: kamya0058@gmail.com

ABSTRACT
Scale up is generally defined as the process of increasing batch size. In process scale up a formula is transformed into a viable,
robust product by the development of a reliable and practical method of manufacturing that effect the orderly transition from
laboratory to routine processing in a full-scale production facility. It must include a close examination of the formula to
determine its ability to withstand batch-scale and process modification. In moving from R&D to production scale, it is sometimes
essential to have an intermediate batch scale. This is achieved at the so-called pilot scale, which is defined as the manufacturing
of drug product by a procedure fully representative of and simulating that used for full manufacturing scale. In tableting
applications, the process scale-up involves different speeds of production in what is essentially the same unit volume (die cavity
in which the compaction takes place). So process scale up of tablets includes Trial Batches, Exhibit Batches and Validation Batch.
After these batches produce large scale up of tablets. During the scale up process controls are evaluated, valuated and finalized
in addition, appropriate records and report are issued to support good manufacturing practices and to provide the historical
development of the production, formulation, process equipments train, and specification.

Pilot Plants are the part of the pharmaceutical plant model. Pilot plant studies must includes a
industry where lab scale formula is transformed close examination of formula to determine its
into viable product by the development of liable ability to withstand batch-scale and process
practical procedure for manufacture. modifications; it must includes a review of range
Pharmaceutical pilot plants that can quickly of relevant processing equipment also availability
numerous short-run production lines of multiple of raw materials meeting the specification of
batches are essential for ensuring success in the product and during the scale up efforts in the
clinical testing and bougainvilleas study phases. pilot plant production and process control are
Drug formulation research time targets are met evaluated, validated and finalized. In addition,
by having a well-designed facility with the appropriate records and reports issued to support
appropriate equipment mix, to quickly move from Good Manufacturing Practices and to provide
the laboratory to the pilot plant scale 1. In pilot historical development of the production
plant, a formula is transformed into a viable, formulation, process, equipment train, and
robust product by the development of a reliable specifications2. A manufacturer’s decision to scale
and practical method of manufacture that effects up / scale down a process is ultimately rooted in
the orderly transition from laboratory to routine the economics of the production process, i.e., in
processing in a full scale production facility where the cost of material, personnel, and equipment
as the scale up involves the designing of associated with the process and its control. [1]
prototype using the data obtained from the pilot
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International Journal of Pharmacy and Biological Sciences (e-ISSN: 2230-7605)

Kamya Chaudhary* et al Int J Pharm Bio Sci
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Why conduct pilot plant studies? the same process to different output volumes.
• A pilot plant allows investigation of a product There is a subtle difference between these two
and process on an intermediate scale before definitions: batch size enlargement does not
large amounts of money are committed to always translate into a size increase of the
full-scale production processing volume. In mixing applications, scale-
• It is usually not possible to predict the effects up is indeed concerned with increasing the linear
of a many-fold increase in scale. dimensions from the laboratory to the plant size.
• It is not possible to design a large scale On the other hand, processes exist (e.g.,
processing plant from laboratory data alone tableting) for which “scale-up” simply means
with any degree of success.[3] enlarging the output by increasing the speed. To
Pilot plant can be used for: complete the picture, one should point out
• Evaluating the results of laboratory studies special procedures (especially in biotechnology) in
and making product and process corrections which an increase of the scale is
and improvements counterproductive and “scale-down” is required
• Producing small quantities of product for to improve the quality of the product. In moving
sensory, chemical, microbiological from R&D to production scale, it is sometimes
evaluations, limited market testing or essential to have an intermediate batch scale.
furnishing samples to potential customers, This is achieved at the so-called pilot scale, which
shelf-life and storage stability studies is defined as the manufacturing of drug product
• Providing data that can be used in making a by a procedure fully representative of and
decision on whether or not to proceed to a simulating that used for full manufacturing scale.
full-scale production process; and in the case This scale also makes possible the production of
of a positive decision, designing and enough product for clinical testing and samples
constructing a full-size plant or modifying an for marketing. However, inserting an
existing plant. [3] intermediate step between R&D and production
Pilot plant design for tablets: scales does not in itself guarantee a smooth
• Each stage considered carefully from transition. A well-defined process may generate a
experimental lab batch size to intermediate perfect product in both the laboratory and the
and large scale production. pilot plant and then fail quality assurance tests in
• Same process, same equipment but different production.[2]
performance when amount of material It is procedure of transferring the results of R&D
increased significantly. obtained on laboratory scale to the pilot plant
• May involve a major process change that and finally to production scale. Process scale up
utilizes techniques and equipment that were can also be viewed as procedure for applying the
either unavailable or unsuitable on a lab same process to different output volume. Process
scale.[3] of changing the equipment ,machine speed or
Process scale up: process steps to enable large scale manufacturing
Scale-up is generally defined as the process of scale up of a process that involve powder
increasing the batch size. Scale-up of a process handling is especially difficult because the
can also be viewed as a procedure for applying
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dynamic behavior of powders is not very well formulation - decide criticality. E.g.a) HPMC film
understood. coating material or rate controlling polymer in
Process scale up is done to give the quality to the matrix. b) Starch- diluents or disintegrate. c)
product and for extensive scientific knowledge of Aesthetic or reservoir CR system. Scale up provide
the physiochemical process that transform the us the process monitoring and its control like
incoming materials into the finals products, hence complex city of process/formulation, process time
Scale up gives a clear cut idea about the limit, reproducibility, Simplicity for execution and
formulations and help us to control the critical Identifying processing stress on product quality,
process parameters by proper process example a) Loss of viscosity during colloid milling,
optimization. b) Evaporation of alcohol during processing. c)
When scale up is applied to granulation process, Capping during high speed compression.[2]
the effects of the operational variable on powder Stages of production of tablets:
properties and granule growth is not clearly  Material handling
known. So, scale up process of material in the  Dry blending
solid state can be based on dimensional analysis,  Granulation
mathematical modeling, and computer  Drying
simulation, most of the work in this field still  Reduction of particle size
depends on trial and error and the principles of  Blending
geometric similarity. Ratio of some variables in  Dry blending
small scale equipment should be equal to that of  Direct compression
similar variables in equivalent larger-scale  Slugging (dry granulation)
equipment. Dimensional analysis is a algebraic Material handling: In laboratory, materials are
treatment of variables affecting a process. It does scooped, dumped or poured by hand. It may work
not result in a numerical equation, but well for small or intermediate scale productions.
experimental data are fitted to an empirical For large scale productions, mechanical means is
process equation that result in scale up being necessary. The simple means are: post hoist
achieved more readily. devices, devices for lifting and tilting drums but
Scale up give us the various information about the the sophisticated ones are: vaccum loading
product like physically and chemically stable systems, screw feed system and meter pumping
therapeutic dosage forms, evaluate the systems. The type of system selected depends
formulation and process suitability for large scale, upon the characteristics of the material e.g.
review of processing equipment, to identify the density. Material handling system should cause
production and process control parameters, to no/minimal loss of material. The lengthy the
identify the critical features of product and transfer, the more is material loss. If one system
process, to provide the master formula and being used for more than one material cross
formulation evaluation for assessing criticality of contamination should be avoided, accomplished
ingredients. Identify the role of ingredient in by using validated cleaning procedures.[4]
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Dry blending process:

Figure 1: Dry blending method

In the dry blending process using a binary  Ribbon blender
cohesive-powder mixture which contains two  Slant cone blender
different sizes, it is well known that finer particles  Bin blender
adhere preferentially on the surface of the coarse  Orbiting screw blenders vertical and
particles. This type mixture has been called an horizontal high intensity mixers [2]
interactive mixture. The blending of fine and Scale up considerations:
coarse particles breaks down the agglomerates of  Time of blending
fine and coarse powders, and produces an electric  Blender loading
charge by contact and collision between particles.  Size of blender [2]
Fine and coarse particles do not revert to the Granulation: Granulation process is a ‘‘process
former agglomerates. The blending operation whereby small particles are gathered into larger,
produces new agglomerates in which fine permanent masses in which the original particles
particles are adhered to the surface of the coarse can still be identified.’’ Pharmaceutical
particles. In the first step, however, the coating granulation is the rapid breakdown of
particles randomly adhere onto the surface of the agglomerates is important to maximize the
core particles.[4] available surface area and aid in solution of the
Problems of improper blending: active drug. In ancient times the granulation
 Flow problem through the equipment process used within the pharmaceutical industry
 Non- reproducible compression but in modern time, granulation technology has
 No content uniformity been widely used by a wide range of industries,
Screening and/or milling of the ingredients prior such as Pharmaceutical. ‘‘granulated’’ material is
to blending done to make the process more derived from the Latin word ‘‘granulatum,’’
reliable and reproducible. The equipments used meaning grained. The fundamental research on
for blending are: mixing, segregation mechanisms of powder,
 V-blender surface chemistry, and material science are
 Double cone blender necessary to develop the theoretical framework
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of granulation technology. The granulated 1. To increase the uniformity of drug distribution
material can be obtained by direct size in the product
enlargement of primary particles, or size 2. To densify the material
reduction from dry compacted material. These 3. To enhance the flow rates and rate uniformity
industries employ agglomeration techniques to 4. To facilitate metering or volumetric dispensing
reduce dust, provide ease of handling, and 5. To reduce dust
enhance the material’s ultimate utility. 6. To improve the appearance of the product.
Granulation is process of particle designing.[3] 7. Granulation encountered the incomplete
Granulation methods: Two types description behavior of powders in general.[5]
1. Wet methods which utilize some form of liquid Various Drying Techniques for Granulation
to bind the primary particles. Sr. Granulation Drying techniques
2. Dry methods which do Granulation Minimizes No. Techniques
the technical risks. 1 Wet Tray or fluid-bed dryer
1. Wet granulation technology: It is employed granulation Tray or fluid-bed dryer
low-shear mixers or the mixers/blenders normally Vacuum/gas
used for dry blending such as ribbon mixers. stripping/microwave
There are a number of products currently Spray dryer
manufactured using these low-shear granulators. Extrusion/
The process control and efficiency has increased Spheronization
over the years; however, the industry has /Pelletization
embraced high-shear granulators for wet 2 Dry Direct compression
granulation because of its efficient and granulation Slugging Mill
reproducible process and modern process control Process Roller compactor
capabilities.[11] Compacts milled
2. Dry methods: Dry compaction technique like
roller compaction is commonly used in the Granulation Mechanisms: These include wetting
Pharmaceutical industry. There are a number of and nucleation, coalescence or growth,
drug substances which are moisture sensitive and consolidation, and attrition or breakage. Initial
cannot be directly compressed.[5] wetting of the feed powder and existing granules
Application of Granulation technology in by the binding fluid is strongly influenced by spray
Pharmaceutical Industry: Pharmaceutical rate or fluid distribution as well as feed
granulation process is used for tablet and formulation properties, in comparison with
sometimes capsule dosage forms; however, in mechanical mixing.
some applications the process is used to produce Role of Binders in wet-granulation
spherical granules for the modified release process: Binders are adhesives that are added to
indications or to prepare granules as sprinkles to solid dosage formulations. The primary role of
be used by pediatric patients. binders is to provide the cohesiveness essential
Granulation of Pharmaceutical for the bonding of the solid particles under
Compounds: Pharmaceutical compounds are compaction to form a tablet. In a wet-granulation
granulated due to:
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process, binders promote size enlargement to  High- and low-shear granulation
produce granules and thus improve flowability of  Roller compaction
the blend during the manufacturing process.  Spray drying
Binders may also improve the hardness of the  Fluid-bed granulation
tablets by enhancing intragranular as well as  Extrusion spheronization
intergranular forces. In a direct compression  Melt granulation and Pelletization
process, binders often act as fillers and impart  Effervescent Granulation
compressibility to the powder blend. The Granulation Characterization: Granulation is a
cohesive properties of binders may reduce process used to prevent segregation of
friability of the tablets and thus aid in their formulation components in a powder blend, bulk
durability and elegance. volume of granulation, improve blend flow,
Examples: content uniformity, compressibility, and other
Natural Polymers: Starch, Pregelatinized Starch properties. Chemical properties are equally
Synthetic polymers: PVP, Methyl cellulose, HPMC important due to their impact on specifications of
New Natural and Synthetic binders: Khaya gum, a dosage form such as content uniformity,
Leucaena leucocephala seed gum, Anacardium chemical purity, and in vitro performance. In vivo
occidentale gum, Gellan gum, Combination of performance such as bioequivalence done
detarium gum and veegum. because it determines whether a
New synthetic binders: Maltrodextrins, Chitosan pivotal bioequivalency batch passes or fails.
derivatives [11] Granule Size affect the dissolution performance
Granulation techniques: The choice of which ultimately affect bioequivalence study.
granulation technique depends on various factors Physical characterization can be performed at
such as chemical and physical stability of the final molecular, particulate, or bulk (macroscopic)
dosage form, intended biopharmaceutical levels. [5]
performance.

Different Parameters and Methods for Characterization of Granules
Sr. No. Parameters Method
1 Particle Morphology Optical microscopy
2 Particle Size Distribution Sieve analysis, laser light scattering
3 Nature Powder X-Ray Diffraction
4 Thermal Analysis DSC, TGA, DTA
5 Identification Near-infrared (NIR) spectroscopy
6 Surface Area Gas adsorption
7 Granule Porosity Mercury intrusion methods
8 Granule Strength Development of a Formulation
9 Granule Flowability and Density Mechanical Method, Hopper Method,
Density Appratus
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Drying: It is the most common conventional  The very fine particle size leads to the
method. It involves circulating hot air oven, flowabilty problem that results in the weight
which is heated by either steam or electricity. variation of the tablets.
Scale up considerations for oven drying  Capping (also occurs if the speed of the
operation are: press is increased)
 Airflow Equipments used are:
 Air temperature  Oscillating granulator (for not too hard
 The depth of the granulation on the trays oversize granulation)
Too deep or too dense bed makes the drying  Hammer mill
process inefficient and if soluble dyes are  Mechanical sieving device
involved, migration of the dye to the surface of  Screening device
the granules. Drying times at specified Determining factors for a particle size: Particle
temperatures and air flow rates must be size distribution needs to be small enough to go
established for each product and for each through an 18 mesh screen yet big enough as to
particular oven load. Fluidized bed dryers are an not go through a 200 mesh screen. While
attractive alternative to the circulating hot air machine type and condition play a role, the
ovens. The important factor considered as part following list of items should also considered.
of scale up fluidized bed dryer are optimum Flowability: Generally speaking the smaller the
loads, rate of airflow, inlet air temperature and particle the worse the flow. Compare powdered
humidity. sugar with granular sugar. The fine small
Reduction of particle size: particles in powdered sugar aide dissolution but
Particle size influences many properties of not flow.
particulate materials and is a valuable indicator Feeder clearance: Particle size must be larger
of quality and performance. This is true for than the feeder clearance to prevent leakage.
powders, suspensions, emulsions, and aerosols. Die table run-out: If die table run-out increases,
The size and shape of powders influences flow feeder clearance and particle size must also
and compaction properties. Larger, more increase proportionately. To check run-out, use
spherical particles will typically flow more easily a dial indicator to determine the variation of the
than smaller or high aspect ratio particles. die table.
Smaller particles dissolve more quickly and lead Die fill: Wide variations in particle sizes can
to higher suspension viscosities than larger cause inconsistent fill volumes.
ones. Smaller droplet sizes and higher surface Weight control: Final volume is final weight.
charge (zeta potential) will typically improve Larger particles pulled out of the die can reduce
suspension and emulsion stability. Powder or the final weight. Fine particles require more
droplets in the range of 2-5µm aerosolize better precise scrape-off and increase the need for a
and will penetrate into lungs deeper than larger good scraper blade.
sizes. For these and many other reasons it is Compressibility: Improves with increased
important to measure and control the particle particle size and decreases as particles become
size distribution of many products. [6] smaller and smaller. Small particles have less
Problems encountered due to improper ability to lock together during compaction.
particle size are: Hardness: Smaller particles are more sensitive
 Too large particle size leads to the to over-compression.
insufficient filling of the die cavity that Ejection force: Small particles decrease
results in weight variation of the tablets. interstitial space and increase drag and friction.
 In case of colored granulation the coarser Lubrication levels: In general higher
the granulation, greater are the chances of percentages of small particles require increased
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mottling. quantities of lubricant. Magnesium stearate is
the most commonly used lubricant and should
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be de-agglomerated before use.




Disintegration & Dissolution: Small particles introduce the proper particle profile within a
decrease disintegration time, and increase range; between 40 – 180 mesh for most oral
dissolution. solid dosages. We do not want any particles
Friability: Larger particles usually lock together larger than 20 mesh and try hard to limit the
better which results in reduced friability while percentage of fines to less than 20% smaller
small particles often increase the potential for than 200 mesh. The next step is to complete
failure (higher friability). pre-blending steps in a carefully planned order
Electro Static effects: Electro static charge is of addition.[7]
increased as the percentage of small particles Characteristics of material:
increases.  Fragile particles or agglomerates: more
Dust control: Fine particles create a dusty readily abraided – more fines – improper
operation, creating a need for frequent mixing – flow problems; fill problems,
production stoppages and press clean-ups. content uniformity problems.
Environmental conditions: Many products are  Particle abbraision is more when high shear
hygroscopic and sensitive to heat. Variations in mixing with spiral screws or blades are used.
room conditions can result in poor flow,  Tumble blenders: for prolonged mixing.
compression and ejection conditions.  Bulk density of raw materials considered in
Lamination & Capping: Small particles are the selection of the blender and determining
heart of the most common defects. optimum blender load.
Punch lubrication: Dust and super fine particles  Excessive granulation: poor content
become airborne and combine with the oils and uniformity, poor lubrication, & improper
greases which can produce black specks in color dispersion.
tablets. Direct compression: The term “direct
Tooling condition: Punch tip & die clearance are compression” is defined as the process by which
designed to control air release allowing for tablets are compressed directly from powder
improved compaction. mixture of API and suitable excipients. No pre-
Machine condition: Cleaning and maintenance treatment of the powder blend by wet or dry
are downtime issues. A high percentage of fine granulation procedure is required.[8]
particles and dust increases the potential for Merits
greater wear, increased cleaning frequency,  Direct compression is more efficient and
reduced yield, greater particle segregation, and economical process as compared to other
more tablet defects. processes, because it involves only dry
Cost: Fines (small dusty particles) increase blending and compaction of API and
operating costs, require increased levels of dust necessary excipients.
collection, decreased yields, increased  The most important advantage of direct
frequency of cleaning, and generate greater compression is economical process.
machine & tool wear. Reducing fines will Reduced processing time, reduced labor
improve tablet quality.[7] costs, fewer manufacturing steps, and less
Blending: Blending in solid dose manufacturing number of equipments are required, less
has two objectives; process validation, reduced consumption
1) To achieve blend uniformity and of power.
2) to distribute the lubricant.  Elimination of heat and moisture, thus
In (objective 1) the blend step(s) are designed increasing not only the stability of the
to achieve homogeneity of all components prior process for thermolabile and moisture
to the final blend of the lubricant (objective 2). sensitive API’s.
blending powders is more of a challenge due to  Particle size uniformity.
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particle size, moisture content, structure, bulk
 Prime particle dissolution.
density and flow characteristics. The first step in
 The chances of batch-to-batch variation are
achieving predictable results in a blend is to
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negligible, because the unit operations



required for manufacturing process is
fewer.
 Chemical stability problems for API and
excipient would be avoided.
 Provides stability against the effect of aging
which affects the dissolution rates.[8]
Demerits Figure 2. Manufacturing Steps for Direct
Excipient Related Compression
 Problems in uniform distribution of low Control factors:
dose drugs.  Particle characteristics (mixing and
 High dose drugs having high bulk volume, segregation): size, size distribution, shape,
poor compressibility and poor flowability static charge
are not suitable for direct compression.For  Blender load
example, Aluminium Hydroxide, Magnesium
 Optimum mixing speed
Hydroxide.
 Blending time
 The choice of excipients for direct
 Optimizing the process and validation of its
compression is extremely critical. Direct
performance
compression diluents nad binders must
Aspects for optimization:
possess both good compressibility and good
 Order of addition of components to the
flowability.
blender
 Many active ingredients are not
 Mixing speed: can be varied with the
compressible either in crystalline or
original direction as necessary
amorphous forms.
 Mixing time: excessive mixing may fracture
 Direct compression blends may lead to
the fragile excipients and ruin their
unblending because of difference in particle
compressibility
size or density of drug and excipients.
Similarly the lack of moisture may give rise  Use of auxiliary dispersion material within
the mixer (chopper blade within a twin shell
to static charges, which may lead to
mixer):
unblending.
a) Increase efficiency
 Non- uniform distribution of color,
b) Reduce agglomerates
especially in tablets of deep colors.[10]
Mixing action: The mixing action is determined
Process Related
by the mechanics of the mixer. It is changed by
 Capping, lamination, splitting, or layering of
converting from one blender to the other or by
tablets is sometimes related to air
modifying the blender through addition of
entrapment during direct compression.
baffles or plates, which would alter the mixing
When air is trapped, the resulting
characteristics.
tablets expand when the pressure of tablet
Blender load: The size of blender load affects
is released, resulting in splits or
the efficiency to greater extent. The blender
layers in the tablet.
overload reduces free flow of granules and
 In some cases require greater sophistication
reduced efficiency. The localized concentration
in blending and compression equipments.
improves the content uniformity where as the
 Direct compression equipments are small loads improves sliding and rolling of
expensive.[10] powders in the blender, no proper mixing &
increased time for mixing.
Slugging (dry granulation): when tablet
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ingredients are sensitive to moisture or are
unable to withstand elevated temperatures
during drying and when the tablet ingredients
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have sufficient inherent binding or cohesive needed to form initial liquid bonds between
properties,slugging may be used to form the particles to enable agglomerative
granules. This method is reffered to as dry growth. The feed powder must have
granulation, pre-compression or double reasonably good wetting properties if there
compression. The active ingredient, diluents (if is to be uniform granulating liquid
required) and the part of the lubricant are distribution. In fluidized bed granulation,
blended. One of the constituents either the the initial spreading of the binder in the
active ingredient or diluents, must have powder bed is very crucial (Faure et al.,
cohesive properties. Powdered material 2001). This is because of the rather low
contains a considerable amount of air;under shear forces present in the fluidized bed and
pressure this air is expelled and a fairly dense liquid within agglomerates would be less
piece is formed. The more time allowed for this likely to be squeezed out for growth by
air to escape, the better the tablet or slug.[13] coalescence. The initial wetting conditions
Diameter of slugs: therefore determine the size distribution of
 1 inch for more easily slugged material the granule batch. The important role of this
 ¾ inch for materials difficult to compress interaction has been emphasized by
Materials of very low density require roller different groups of researchers in literature.
compaction to achieve a bulk density sufficient Pont and co-workers (Pont et al., 2001;
to allow encapsulation or compression. E.g. Hemati et al., 2003) have illustrated that
densification of aluminium hydroxide. granule growth was favoured with an
Parameters influencing the process and increase in interfacial tension and a
granule quality: The micro-level interactions decrease in contact angle between the
between the powder particles and liquid binder particles and the liquid binder. Danjo et al.
have been shown by many researchers to play (1992) reported that harder and less porous
important roles in granulation phenomena granules were formed when the adhesion-
(Ennis et al., 1991; Iveson and Litster, 1998a; Liu tension of the liquid binder was increased.
et al., 2000; Simons and Fairbrother, 2000; Spreading coefficients of the liquid binder
Iveson et al., 2003). over the particles were similarly observed
Fluidized bed granulation is an intricate process by Planinsek et al. (2000) to be in good
and the factors affecting the process and correlation with granule friability.
granule quality are classified into three  Solubility of powder particles: Surface
categories for discussion below. The first dissolution of lactose was proposed to
category involves the nature and characteristics behave as a secondary binder after
of the ingredients in the formulation. Even solidification upon drying, and contributed
though the discussed scope on this category is to the sphericity of the granules (Wan and
focused on fluidized bed granules, the findings Lim, 1989). An increase in granule hardness
for this category are generally applicable to all with a decrease in pore volume was
other wet granulation processes. Process factors reported by Danjo et al. (1992) with
during liquid binder addition phase and process increased solubility of lactose particles in
factors during the drying phase constitute the the solvent used to prepare the liquid
second and third categories respectively, and binder. Rohera and Zahir (1993) also found
are more specific to the fluidized bed that part dissolution of excipients being
equipment.[14] granulated was desirable for granule growth
Material related factors: The properties of the and affected granule size distribution.
raw materials involved in granulation, namely  Type of powder: The different deformation
the feed powder, binder and granulating liquid, behavior during coalescence exhibited by
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will affect granule formation and growth. different types of powder was shown to
 Ability of powder particles to be wetted: influence the kinetics of the process
Wetting is an essential phenomenon (Abberger, 2001). Powder load: Due to a
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larger load to binder ratio, whereby a  Mode of binder addition: Binder addition,
smaller extent of wetting took place, an either suspended in the spray liquid or dry
increment in feed load resulted in more of mixed in the powder was shown to affect
the smaller size granules being produced the granular characteristics of the end
(Wan and Lim, 1988; Cryer and Scherer, product. Binder distribution was found to be
2003). more uniform when suspended in the spray
 Powder particle size: It was implied by liquid with a smaller amount of oversized
Hemati et al. (2003) that an increase in the granules produced (Kokubo et al.,1995,
initial particle size led to an increment in 1998; Wan and Lim, 1988).
particle growth rate and affected the  Volume of liquid binder: The volume of
mechanism of growth. Powder particle granulating liquid needed depends primarily
shape: Contact surface between the less on the solubility of the drug and/or
spherical particles was reportedly enhanced components of the binder. Larger granules
as compared to the highly spherical resulted when bigger volumes of binder
particles. This resulted in different growth solution were used (Rohera and Zahir, 1993;
kinetics (Hemati et al., 2003). Merkku et al., 1994; Wan et al., 1996). This
 Powder particle surface roughness: Growth was likely to be due to promoted wetting of
kinetics was also found to have a strong particles during growth.[14]
dependence on the surface roughness of Process related factors during the liquid binder
the particles by Stepanek et al. (2009). addition phase: The sensitivity of the process to
 Type of binder: Binder is an essential part of its bed humidity has been identified by many
the granulating fluid. Yuksel et al. (2003) researchers, and control of this bed condition is
reported that granules prepared using primary for process reliability (Kokubo and
polyvinylpyrrolidone were observed to have Sunada, 1997; Watano et al., 1997; Hu et al.,
lower mechanical strength than those 2007). Bed humidity is an indication of the
prepared using pregelatinized starch and availability of liquid binder at the particle
gelatin. In another study by Rohera and surfaces. A more humid bed indicates wetter
Zahir (1993) where polyvinylpyrrolidone, conditions, more liquid binder is available to the
acacia, and gelatin were investigated, it was surfaces of the particles and this enhances
found that different binders had different nucleation and growth. However, if the
influences on granule growth. moisture content in the granule bed is too high,
 Binder concentration and viscosity: In excessive granule growth can result and the bed
general, increasing the concentration and can even collapse by wet quenching due to the
viscosity of the liquid binder increased mean poor fluidizing capacity of the wetted mass
granule size and increased granule strength, (Schaafsma et al., 1999). Accordingly,
as reported in several studies. The types of parameters that affect the temperature and
binders investigated in these reports moisture content of the powder bed play
included gelatin, acacia, important roles in influencing process and
polyvinylpyrrolidones and cellulosic binders granule quality.
(Davies and Gloor, 1972; Alkan and Yuksel,  Binder spray rate: An increase in binder
1986; Lim, 1989; Rohera and Zahir, 1993; spray rate availed more liquid binder to the
Ling,1995; Wan et al., 1996; Kokubo et al., particles and resulted in a more humid bed.
1995, 1998; Bouffard et al., 2005). Other Thus, granules of larger size and lower bulk
physical properties such as drug release density typically formed as reported by
(Haldar et al., 1989), granule morphology many researchers (Rankell et al., 1964;
and porosity (Rajniak et al., 2007) were also Davies and Gloor, 1971; Lipps and Sakr,
233

found to be influenced by binder 1994; Wan et al., 1995; Menon et al., 1996;
concentration. Gao et al., 2002; Cryer and Scherer, 2003;
Hemati et al., 2003; Bouffard et al., 2005).
Page




Pulsed spraying of the liquid binder had also Particle flow pattern and distribution were
been tried by Ehlers et al. (2009) as a shown to be affected by the shape of the
method to control granule growth. product chamber, and is an important factor
 Binder droplet size: A direct relation to consider during process design (Yang et
between droplet size and granule size at the al., 1992; Schaafsma et al., 2006).
early stage of the growth process was  Airflow rate: Smaller granules were
reported by Schaafsma et al. (2000). Bigger observed when the airflow rate was
spray droplets were found to produce more increased (Cryer and Scherer, 2003;
granules in the larger mass size fractions. Bouffard et al., 2005). This was explained by
 Atomizing air pressure: The degree of a more rapid removal of water from the
atomization of the liquid binder depended wetted particles by the air that caused
on the air to liquid mass ratio at the nozzle slower growth kinetics with higher airflow
head. A decrease in atomizing air pressure rate. It was also found by Wang et al. (2003)
was extensively shown to result in granules that airflow rate affected granule size and
of larger size and lower bulk density. This is process yields.
because of the resultant decreased air-to-  Inlet air temperature: As the inlet air
liquid mass ratio that caused the formation temperature increased, there was faster
of bigger spray droplets (Davies and Gloor, mass transfer of water from the wetted
1971; Merkku et al., 1994; Gao et al.,2002; particles to the air (i.e. evaporation). This
Rambali et al., 2001; Bouffard et al., 2005). reduced the binder layer surrounding the
An optimum pressure was found to be powder particle, created fewer
necessary for promoting uniform opportunities for coalescence and resulted
distribution of a low dose drug, when the in smaller granules (Lipps and Sakr, 1994;
drug was incorporated in the granulating Schinzinger and Schmidt, 2005).
liquid (Wan et al., 1992). The degree of Process related factors during the drying
atomization was also observed to affect phase: After complete spraying of the liquid
granule structures and consequently, binder, the granules formed are dried for a
granule strength by Wang et al. (2003). further period of time. This is to remove
 Spray nozzle position from bed: The remaining moisture contained in them down to
position of the spray nozzle in TG was a moisture level best suited for the stability of
reported to significantly influence granule the constituent actives and requirements of the
growth and granule friability (Rankell et al., ensuing downstream process. Inefficient or poor
1964; Davies and Gloor, 1971; Rambali et process control of this drying phase will lead to
al., 2001). The nearer the nozzle was placed inconsistent end product quality. For instance,
to the powder bed from the top, the larger attrition of the formed granules was reported to
were the granules formed.[4] occur paradoxically, resulting in unwanted size
 Spray nozzle tip protrusion from air cap: reduction (Niskanen and Yliruusu, 1994).
This determined the angle at which the Formation of fines by attrition is, in practice, an
binder solution was sprayed onto the important parameter because excessive fines
powder bed by changing the airflow rate generation can affect granule flow and should
through the nozzle. Rambali et al. (2001) be avoided (Nieuwmeyer et al., 2007b).
found that a higher protrusion resulted in  Inlet air humidity: Zoglio et al. (1975)
more granules in the smaller mass size reported that the humidity of the drying air
fractions and higher process yield. strongly impacted the drying rate for
 Spray nozzle tip diameter: A wider nozzle aqueous based granulations. This was
tip diameter caused larger spray droplets to attributed to the diffusion of water vapor
234

be formed, promoted granule growth and through the stagnant air film surrounding
resulted in bigger granules (Rambali et the granule and into the neighboring
al.,2001). Product chamber geometry: fluidizing air - the rate-limiting step in the
Page




drying phase. Based on the findings that an found to affect the hydrodynamic behavior
increase in inlet air humidity resulted in (Wormsbecker and Pugsley, 2008) and
higher product temperatures (Lipsanen et granule size (Nieuwmeyer et al., 2007b).
al., 2007, 2008), concern in scenarios where  Duration of drying phase: The duration of
a fixed product, temperature was used as a drying was widely shown to affect granule
drying end-point criterion was highlighted size properties (Banks and Aulton, 1991).
by the authors. This is because the residual Extended duration of drying may result in
moisture content in the dried granules could excessive granule attrition. The drying time
vary between batches if the inlet air was recently shown by Tomuta et al. (2009)
humidity is not controlled and this would to influence the residual moisture content,
affect the quality of the product attained at bulk and tapped density of the granules.[4]
the end of processing. Their findings also Fluidized Bed Granulation:
implied stability issues when using a fixed Fluidized bed technology has its origins from the
product temperature as a drying end-point petroleum industry in the 1940s. Since its
criterion for granulating moisture sensitive successful implementation for coating in the
and heat sensitive materials.[4] pharmaceutical industry by Wurster (1959), this
 Inlet air temperature: Reductions in drying air suspension technique has been used widely
time was reported to be possible with in coating, granulating, pelletizing and drying
employment of higher inlet air processes. As shown in Figure 1, a fluidized bed
temperatures, and the lower temperatures processing system typically consists of a Inlet air
were found to cause higher equilibrium filter, Condenser, Humidifier, Inlet air Heater,
moisture content in the granules. HEPA filter, Inlet air, Inlet air plenum, Gas
 Airflow rate: Increments in airflow rate was distributor plate, Product container, Conical
observed to lead to the enhancement of expansion zone, Filter housing, Product filter,
evaporation rates (Hlinak and Saleki- Outlet air, HEPA filter, Fan and a Spray gun. In-
Gerhardt, 2000) and possibly drying. line monitoring of process conditions is also
However in practice, practical use of airflow often possible to facilitate process control. In
rate to enhance the evaporation rate might this system, a bed of powder particles,
be limited due to its potential influence on supported over a fluid distribution plate, is
the particle size distribution of granules made to behave like a liquid by the passage of
(Faure et al., 2001). Too high an airflow rate the fluid, typically air, at a flow rate above a
may result in an unacceptable level of certain critical value. The phenomenon of
attrition. imparting the properties of this fluid to the bed
 Atomizing air pressure: High atomizing air of particulate solids by passing the fluid through
pressure, especially when maintained the latter at a velocity which brings the
during the drying phase was shown to stationary bed to its loosest possible state just
contribute substantially to granule breakage before its transformation into a fluid-like bed is
(Bouffard et al., 2005). As the atomizing air termed fluidization (Gupta and Sathiyamoorthy,
is counter-current to the fluidizing air, it is 1998).
best switched off after completion of liquid During granulation, the powder particles
addition. The atomizing air may also disrupt circulate within the product chamber and
the fountain like flow of the granules in the provide a constant flow of bed particles through
fluidized bed. a defined spray granulation zone. At the spray
 Liquid binder: Niskanen and Yliruusu (1994) granulation zone, a fine spray of liquid binder is
observed that attrition was dependent on usually atomized and deposited onto the
both the amount and the wetting tendency fluidizing particles. Particle wetting brings about
235

of the liquid binder. granule formation. Partial drying of the wetted
 Moisture content: The moisture content of particles by the fluidizing air occurs continuously
granules during fluidized bed drying was during granulation. When the spraying of liquid
Page




binder is completed, the granules are quickly the solids, the fluidized bed typically provides
dried by the hot air stream and complete drying high rates of heat and mass transfer, leading to
is achieved.[14] uniform temperature distribution within the
bed and relatively short processing times(Turton
et al., 1999). High process yields of 97 to 100 %,
w/w with typically less than 1 %, w/w fines and
3 %, w/w lumps can be attained (Olsen, 1985).
In comparison to high shear granulation, a
popular wet process to employ for granulation
in the industry, the size distribution of fluidized
bed granules is often narrower with the absence
of large size compact granules. This indicates a
less frequent need for re-granulation and a less
problematic drying step. Fluidized bed granules
have also been generally shown to be more
porous, less dense, and more compressible than
high shear granules (Tobyn et al., 1996;
Horisawa et al., 2000; Gao et al., 2002;
Hausman,2004). As mixing and fluidization
quality in the fluidized bed is highly dependent
Figure 3: Fluid bed granulator on the characteristics and properties of the
1. Inlet air filter powder particles, the process is more sensitive
2. Condenser to the filler characteristics and properties. The
3. Humidifier filler type was reported to have a more
4. Inlet air Heater pronounced effect on granule properties in the
5. HEPA filter conventional fluidized bed granulator than in
6. Inlet air the rotary processor (Kristensen and Hansen,
7. Inlet air plenum 2006). It has also been shown that a wider
8. Gas distributor plate selection of feed material can be used in rotary
9. Product container processing (Kawaguchi et al., 2001) and high
10. Conical expansion zone shear granulation (Stahl, 2004). The mixing
11. Filter housing effect in a fluidized bed is generally good for
12. Product filter particle sizes between 50 to 2000 μm. However,
13. Outlet air for fine particles less than 50 μm and particles
14. HEPA filter which are difficult to fluidize when wet,
15. Fan vibratory forces have to be applied to the
16. Spray gun powder bed, increasing equipment, cleaning
Advantages and challenges and maintenance costs (Law and Mujumdar,
Fluidized bed granulation is efficient and 2007). A lower critical size where the usual
convenient to use, offering many advantages pharmaceutical powders can be discretely
over the multistage process of conventional wet processed will be around 20 μm. Lower than
granulation (Banks and Aulton, 1991). Powder this size, steady fluidization without any
can be mixed, granulated and dried in a single retardation is difficult as indicated by Geldart’s
container, thereby avoiding cross- fluidization map (Geldart, 1973). To process
contamination. Since fluidized bed granules are powder mixture containing components of
formed and dried within the same piece of vastly different densities is another difficult
236

equipment, it cuts cost by saving time needed task, as the different fluidization behaviour of
for transfers and greatly simplifies the process. the individual components may result in bed
By virtue of the air or gas required to fluidize segregation and non-uniform mixing. Without
Page




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238
Page




*Corresponding Author:
Kamya Chaudhary*
Department of Pharmaceutics,
Rayat College of Pharmacy, Ropar, India
239
Page



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