Clarification

and Filtration

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 Clarification and Filtration

Clarification may be defined as the process that involves the removal or

separation of a solid from a liquid, or a fluid from another fluid. The term “fluid”
encompasses both liquids and gases. Clarification can be achieved using either
filtration or centrifugation techniques. Filtration is mainly required to remove
unwanted solid particles from a liquid product or from air and centrifugation is
normally used to separate fluid from another fluid or to collect the solid as the
product

Filtration is defined as the process in which particles are separated from a liquid
by passing the liquid through a permeable material. The permeable medium is a
porous material that separates particles from the liquid passing through it and is
known as a filter.

Thus, filtration is a unit operation in which a mixture of solids and liquid, the feed,
suspension, dispersion, influent or slurry, is forced through a porous medium, in
which the solids are deposited or entrapped. The solids retained on a filter are
known as the residue. The solids form a cake on the surface of the medium, and the
clarified liquid known as effluent or filtrate is discharged from the filter. If
recovery of solids is desired, the process is called cake filtration.

There are numerous applications of filtration in pharmaceutical

processing which mainly include:
(i) clarification of products to improve their appearance, i.e. to give them „sparkle‟
or „brightness‟,
(ii) removal of potential irritants e.g. from eye drop preparations or solutions
applied to mucous membranes,

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(iii) filtration for recovery of desired solid material from a suspension of slurry,
e.g. to obtain a drug or excipient after a crystallization process,
(iv) production of water of appropriate quality for pharmaceutical use,
(v) meeting sterility specification (removal of microorganisms) required for some
products using sterile filtration or aseptic filtration
(vi) Sterilization of solutions and vehicles of suspensions that are chemically or
physically unstable under heating conditions
(vii) detect ion of microorganisms present in liquids by analyzing a suitable filter
on which the bacteria are retained and
(viii) assessment of the efficacy of preservatives. Recently, techniques such as
nanofiltration, ultrafiltration, and microfiltration have been used to recover
colloidal delivery systems from mother liquor.
MECHANISMS OF FILTRATION
Four different mechanisms of filtration according to the way in which the
suspended material is trapped by the filter medium are as follows:
1)Surface Straining
In surface straining, any particle that is larger in size than the pores of the medium
deposits on the surface, and stays there until it is removed. Particles that are
smaller in size than the pores pass quickly through the medium
2) Depth Straining
Depth straining is also governed by particle size or shape. For filter media that are
relatively thick in comparison with their pore diameters, particles will travel along
the pore until they reach a point where the pore narrows down to a size too small
for the particles to go any further, so that they become
trapped
3)Depth Filtration

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In depth filtration, the particles becomes entrapped in the depth of the medium,
even though they are smaller in diameter, and possibly much smaller, than the pore
at that point, They become attached to the pore wall, or to another particle already
held by means of van der Waals and other surface forces (entanglement).

4)Cake Filtration
Cake filtration (which is a development of surface filtration) begins with the
formation of a layer of particles on the surface of the filter medium, with larger
pores bridged by a group of smaller particles. On this layer, a cake of particles
accumulates to act as the filter medium for subsequent filtration. Cake filtration in
which solid recovery is the goal is an important pharmaceutical process.
These definitions emphasize that the mechanisms of filtration may result in the
trapping of far smaller particles than might be expected from the size of the pores
in the medium. The actual mechanism or combination of mechanisms in any
specific instance is dependent on the characteristics of both the medium and the
suspension being filtered

THEORY OF FILTRATION
The flow of liquid through a filter follows the basic rules that govern flow of any
liquid through a medium offering resistance. The rate of flow may be expressed as:

The rate may be expressed as volume per unit time and the driving force as a
pressure differential. The apparent complexity of the filtration equations arises
from the expansion of the resistance term. Resistance is not constant since it
increases as solids are deposited on the filter medium. An expression of this
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changing resistance involves a material balance as well as factors expressing
permeability or coefficient of resistance of the continuously expanding cake.

These factors have been taken into account in the formation of the Darcy‟s
equation:

where, A = Filter area

P= total pressure drop through cake and filter medium
V = volume of filtrate
T = time
η = filtrate viscosity
L = bed thickness in direction of fluid flow
K = permeability coefficient

It is convenient to summarize the theoretic relationship as:

Interpretation of the basic equations, however, leads to a general set of rules:

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1)Pressure increases usually cause a proportionate increase in flow unless the cake
is highly compressible. Pressure increases on highly compressible, flocculent, or
slimy precipitates may decrease or terminate flow.
2)An increase in area increases flow and life proportional to the square of the area
since cake thickness and thus resistance, are also reduced.
3)Cake resistance is a function of cake thickness, therefore, the average flow rate is
inversely proportional to the amount of cake deposited.
4) The filtrate flow rate at any instant is inversely proportional to viscosity so,
filtration efficiency also may be affected by changes in temperature.
The viscosities of most liquids decrease with increase in temperature. Increasing
the temperature of heavy pharmaceutical syrups lowers the viscosity and increases
filtration rates
5) The permeability coefficient may be examined in terms of its two variables:
porosity and surface area,the cake porosity depends on the way in which particles
are deposited and packed. A fast deposition rate, given by concentrated slurries or
high flow rates, may give a higher porosity because of the greater possibility of
bridging and arching in the cake Surface area
,
unlike porosity, is markedly affected by particle size and is inversely proportional
to particle diameter. Hence, a coarse precipitate is easier to filter than a fine
precipitate even though both may pack with the same porosity.
Most clarification problems can be resolved empirically by varying one or more of
these factors

FILTER MEDIA
The surface upon which solids are deposited in a filter is called the filter
medium. For the pharmacist selecting this important element, the wide range of
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available materials may be bewildering. The selection is frequently based on past
experience, and reliance on technical services of commercial suppliers is often
advisable. The ideal filter material should have the following characteristics:
1)A medium for cake filtration must retain the solids without plugging and without
excessive bleeding of particles at the start of the filtration. In clarification
applications in which no appreciable cake is developed, the medium must remove
all particles above a desired size.
2)It should offer minimum resistance and the resistance offered by the medium
itself will not vary significantly during the filtration process.
3)It allows easy discharge of cake.
4)It should be chemically and physically inert.
5)It should not swell when it is in contact with filtrate and washing liquid.
6)It should have sufficient mechanical strength to withstand pressure drop and
mechanical stress during filtration.
There are a variety of different depth filter and membrane filter materials used in
pharmaceutical processes. Depth filters are mainly polymeric fibrous materials.
The filter fabrics are commonly woven from natural fibers such as cotton and from
synthetic fibers and glass.
Filter cloth, a surface type medium, is woven from either natural or synthetic fiber
or metal. Cotton fabric is the most common and is widely used as a primary
medium, as backing for paper or felts in plate and frame filters, and as fabricated
bags for coarse straining. Nylon is often superior for pharmaceutical use, since it is
unaffected by molds, fungi, or bacteria, provides an extremely smooth surface for
good cake discharge, and has negligible absorption properties. Both cotton and
nylon are suitable for coarse straining in aseptic filtrations, since they can be
sterilized by autoclaving. Monofilament nylon cloth is extremely strong and is
available for openings as small as 10 μm. Teflon is superior for most liquid
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filtration, as it is almost chemically inert, provides sufficient strength, and can
withstand elevated temperatures.
Woven wire cloth, particularly stainless steel, is durable, resistant to plugging, and
easily cleaned. Metallic filter media provide good surfaces for cake filtration and
are usually used with filter aids. As support elements for disposable media, wire
screens are particularly suitable, since they may be cleaned rapidly and returned to
service. Wire mesh filters also are installed in filling lines of packaging equipment.

Non-woven filter media include felts, bonded fabrics, and kraft papers. A felt is a
fibrous mass that is free from bonding agents and mechanically interlocked to yield
specific pore diameters that have controlled particle retention. High flow rate with
low pressure drop is a primary characteristic.
Felts of natural or synthetic material function as depth media and are
recommended where gelatinous solutions or fine particulate matter are involved.
Porous stainless steel filters are widely used for the removal of small amounts of
unwanted solids from liquids (clarification) such as milk, syrup, sulfuric acid, and
hot caustic soda. Porous metallic filters can be easily cleaned and repeatedly
sterilized
Membrane filter media are the basic tools for microfiltration, ultrafiltration,
nanofiltration and reverse osmosis, Membrane filters, classified as surface or
screen filters, are made of various esters of cellulose or from nylon, Teflon,
polyvinyl chloride, polyamide, polysulfone, or silver.
Because of surface screening characteristics, prefiltration is often required to avoid
rapid clogging of a membrane. The selection of a membrane filter for a particular
application is a function of the size of the particle or particles to be removed.
Surface-type cartridges of corrugated, resin-treated paper are common in hydraulic
lines of processing equipment, but are rarely applied to finished products. Ceramic
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cartridges have the advantage of being cleanable for reuse by back-flushing.
Asbestos and porcelain filter candles are acceptable for some sterile filtrations
along with membrane filters.

FILTER AIDS
Usually, the resistance to flow due the filter medium itself is very low, but
increases as a layer of solids builds up, blocking the pores of the medium and
forming a solid, impervious cake. Poorly flocculated solids offer higher resistance
than do flocculated solids or solids providing high porosity to the cake. In the case
of cake filtration, the rate varies with the square of the volume of liquid. When the
volume of the filter cake solids per unit volume of filtrate is low, the solids
deposited on the filter medium may penetrate the void space, thus making the filter
medium more resistant to flow. At a higher concentration of solids in a suspension,
the bridging over of openings over the void space, rather than blinding of the
openings, seems to predominate.
The filter medium becomes plugged or slimy with the accumulation of
solids, and the flow of filtrate stops. A filter aid acts by reducing this resistance.
Filter aids are a special type of filter medium. Ideally, the filter aid forms a
fine surface deposit that screens out all solids, preventing them from contacting
and plugging the supporting filter medium.
Usually, the filter aid acts by forming a highly porous and non-compressible
cake that retains solids, as does any depth filter. The duration of a filtration cycle
and the clarity attained can be controlled as density, type, particle size, and quantity
of the filter aid are varied.
The quantity of the filter aid greatly influences the filtration rate. If too little
filter aid is used, the resistance offered by the filter cake is greater than if no filter
aid is used, because of the added thickness to the cake. On the other hand, if high
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amounts of filter aid are added, the filter aid merely adds to the thickness of the
cake without providing additional cake porosity
.

typical plot of filter aid concentration versus permeability. In the figure, flow rate
and permeability are directly proportional to each other. At low concentrations of
filter aid, the flow rate is low because of low permeability. As the filter aid
concentration increases, the flow rate increases and peaks off. Beyond this point,
the flow rate decreases as the filter aid concentration is increased
The ideal filter aid performs its functions physically or mechanically and no
absorption or chemical action is involved in most cases.
The important characteristics for filter aids are the following:
1)It should have a structure that permits formation of pervious cake.
2)It should have a particle size distribution suitable for the retention of solids, as
required.
3)It should be able to remain suspended in the liquid.

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4)It should be free of impurities.
5)It should be inert to the liquid being filtered.
6)It should be free from moisture in cases where the addition of moisture would be
undesirable
Filter aids are considered to be equivalent in performance when they produce the
same flow rate and filtered solution clarity under the same operating conditions
when filtering a standard sugar solution.
Diatomite (diatomaceous earth) is the most important filter aid. Processed from
fossilized diatoms, it has irregularly shaped porous particles that form a rigid
incompressible cake. Since diatomite is primarily silica, it is relatively inert and
insoluble
Cellulose, asbestos, filter aids are also commercially available. Cellulose is highly
compressible and costs two to four times more than diatomite or perlite. It is
reserved for applications where the liquids may be incompatible with silica
compounds. Cellulose is used as a coarse pre-coat
Asbestos has good retention on coarse screens, but has limited application because
of its high cost, and leaching of fibers into the filtrate that might be toxic. Asbestos
filters may be used in pharmaceutical industry if their application is followed by
membrane filtration.
Filter aids may be applied by precoating or body-mix techniques.
Precoating requires suspending the filter aid in a liquid and recirculating the slurry
until the filter aid is uniformly deposited on the filter septum Body mix (direct
addition of filter aid to the filter feed) is more common in batch pharmaceutical
operations.
Filter aids are chosen by trial and error in either laboratory or plant. Within the
ranges previously indicated, the filter aid is usually selected to give acceptable
filtrate at the highest flow rate; however, in pharmaceutical operations in which
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quality is a primary consideration, the selection usually favors‟ the fine grades,
which yield low flow rates.
The most important pharmaceutical factor is inertness. A filter aid may have such
extensive absorption properties that desired coloured substances and active
principles are frequently removed. The total quantity of any ingredient absorbed
may be small, but it may be a considerable portion of the original concentration.

FILTRATION EQUIPMENT
Commercial filtration equipment is classified by the end product desired (filtrate of
cake solids), by the method of operation (batch or continuous), by type of
operation (non-sterile filtration, sterile filtration, centrifugation filtration,
centrifugation sedimentation), but most importantly by the type of driving force
(gravity, vacuum, pressure and centrifugation)

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Gravity Filters
Gravity filters rely on gravity generated low operating pressure (usually less than
1.03 × 104 N/m2) and give low filtration rates unless very large surfaces areas are
used, which limits their use on a large scale However, these are simple and cheap,
and are frequently used in laboratory filtration where volumes are small and low
filtration rate is relatively insignificant. Gravity filters employing thick, granular
beds are common in water treatment, where clarification of water is done prior to
deionization or distillation
Small-scale purification of water may use porous ceramics as a filter medium in
the form of hollow “candles”. The fluid passes from the outside through the porous
ceramics into the interior of the hollow candles
Various new gravity filter systems are available commercially such as cylindrical
gravity filters, rectangular gravity filters, and hydro-clear gravity filters which
utilize granular particles in a basin. Fluid streams pass through the basin and
particles are physically and/or chemically captured by the media.

Vacuum Filters
These are employed on a large scale, but are rarely used for the collection of
crystalline precipitates or sterile filtration
Vacuum filters are simple and reliable machines, and therefore have gained wide
acceptance in the chemical, food and pharmaceutical industries. For large-scale
operations, continuous vacuum filters are the most widely used
Rotary Drum Filter
The rotary drum vacuum filter is divided into sections, each connected to a
discharge head

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Each filter unit is rectangular in shape with a curved profile so that a number can
be joined up to form a drum. Each unit has a perforated metal surface and is
covered with filter cloth

The slurry is fed to a tank in which solids are held in suspension by an agitator. As
the drum rotates, each section passes through the slurry and vacuum draws filtrate
through the filter medium at the drum surface (pick-up zone).
The suspended solids deposit on the filter drum as a cake, and as rotation
continues, vacuum holds the cake at the drum surface. This is followed by washing
and further drainage in the drying zone. As the cake moves towards the discharge
point, it may be scraped from the drum or it may be supported by strings until it
breaks free under gravitational forces (cake removal zone).

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The cake discharge may be done through a scraper, belt, roll or a string. Scraper
discharge mechanisms will suit cakes that could be scraped readily and roller
discharge mechanism are better for thixotropic cakes.
For solids that tend to block the filter cloth, a precoat of filter aids such as
diatomaceous earth, perlite and cellulose is deposited on the drum prior to the
filtration process.
Precoat filters are generally used where a very high degree of clarity is required
and solids content is very low (less than 2– 3%) or where solids are sticky and
would otherwise clog the filter cloth.

Rotary Disc Filter

It consists of several discs, up to 15 in the larger machines, each made up from
sectors which are clamped together to form the disc .
Each sector is connected to a vacuum system, compressed air, and appropriate
receivers, in the correct sequence, by means of special rotating valve. The
operation sequence of a disc filter is similar to a drum filter. The main feature of
disc filter is less floor space and the lowest cost of filtration when compared to
other vacuum filters.

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Pressure Filters
Most of the pressure filters are batch operated but continuous filters are also
available. However, owing to the difficulty in removing the cake they are
mechanically complex and expensive so mainly used where the added value to the
product is high. The filtration rate is influenced, in broad terms, by the properties
of the slurry. The trend is that the rate goes up with increased
pressure, coarser particles, particle distribution with high uniformity, nonslimy or
non-gelatinous solids, noncompressible cakes, lower liquid viscosity and higher
temperatures.

Plate and Frame Filter Press

The plate and frame filter press is the simplest of all pressure filters and is the most
widely used.

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Filter presses are used for a high degree of clarification of the fluid and for the
harvesting of the cake. When clarity is the main objective, a “batch” mode of
operation is applied.
As the name implies, the plate and frame filter press is an assembly of hollow
frames and solid plates that support filter media.
One side of the plate is designed for the flow of the feed. After passing the filter
media, the filtrate is accommodated on the other side. The solids collect in the
frames, and filtrate is removed through place conduits. In cake filtration, the size of
the frame space is critical, and wide sludge frames are used
The filter press is the most versatile of filters since the number and type of filter
sheets can be varied to suit a particular requirement. It can be used for coarse to
fine filtrations, and by special conduit arrangements, for multistage filtration
within a single press
The filter press is the most economical filter per unit of filtering surface, and its
material of construction can be chosen to suit any process conditions.
Disc Filters
The term disc filter is applied to assemblies of felt or paper discs sealed into a
pressure case.

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The discs may be preassembled into a self-supporting unit, or each disc may rest
on an individual screen or plate. Single plate or multiples of single plates may be
applied. The flow may be from the inside out wards or outside in wards. The disc
filter overcomes some deficiencies of the filter press. Compactness, portability, and
cleanliness are obvious advantages for pharmaceutical batch operations.

Centrifugation Filtration
In filtering centrifuges, centrifugal force is used to affect the passage of the
liquid through the filter medium. This type of filtration is particularly advantageous
when very fine particles are involved. Whenever solids recovery is the primary
goal, filtering centrifuges must be considered as an alternative to filtration.
The advantages of the process are effective washing and drying. Residual
moisture after centrifugation is far less than in cakes produced by pressure or
vacuum filtration.
By this method the moisture content of a cake of coarse crystals can be
reduced to as low as 3%., This facilitates the drying operation which normally
follows. The process is widely used for separating granular products from liquors,
but is less effective for concentrated slurries containing smaller particles.
Perforated Basket
The device consists of a perforated metal basket mounted on a vertical axis
by means of which it can be rotated at a speed of 20 to 25 revolutions per second.

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 The cloth used to retain solids is often supported on a metal screen and the
outer casing collects the liquid thrown out from the perforated basket by
centrifugal force.
Baskets mounted are emptied by shoveling the cake. If, however, top
suspension is used, the cake can be more easily withdrawn through traps in the
base of the basket.

Laboratory Filtration Equipment

Laboratory equipment catalogs offer a wide choice of funnels and flasks
adaptable to pharmaceutical filtration studies
For gravity filtration, conventional glass percolators are applicable, in which case
the bottom tube is covered with fibrous material. The filtering funnel is the most
common of all laboratory filter devices. Filter paper is used with funnels.
Sometimes, a plug of fibrous material may be used instead.
Filter bags for laboratory use are made of fabric and are mounted for gravity
filtration. The uncertainty of adequate clarification with glass beads or sand has
restricted their use as gravity filters for certain operations in the laboratory.

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Suction filters are greatly utilized in the laboratory. Usually, a conical funnel and
the Buchner funnel are used for suction filtration, as are immersion and suction-
leaf filters. Immersion filter tubes, also known as filter sticks, are generally used
for small-scale laboratory operations.
Filter paper in circular form is the most common medium for laboratory filtrations.
Filter papers are available in a wide variety of textures, purities, and sizes and are
available for different uses. They may be circular (1 to 50 cm in diameter), folded,
or arranged in sheets or rolls. Some of the special types of laboratory filter papers
for pharmaceutical industry are:
1)Filter papers impregnated with activated carbon for the adsorption of colours and
odours in pharmaceutical liquids.
2)Filter paper impregnated with diatomaceous earth for the removal of colloidal
haze from liquids with low turbidity
Minimum laboratory equipment includes a plate and frame press, a membrane
filter holder, and a single-element housing for disposable cartridges.
SPECIALIZED FILTRATION
Sterile/Aseptic Operations
Filtration may be used to clarify and sterilize pharmaceutical solutions that
are heat-labile. Membrane filters have become the basic tool in the preparation of
sterile solutions
A sterility requirement imposes a severe restraint on filter selection. All sterility
tests are presumptive, and one must rely upon total confidence in the basic process,
and economics becomes a secondary factor. Membranes with porosity ratings of
0.2 or 0.45 μm are usually specified for sterile filtrations.
In this porosity range, membrane filters may clog rapidly, and a prefilter is used to
remove some colloidal matter to extend the filtration cycle.

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 The FDA allows the use of 0.45 μm filters only in cases of colloidal
solutions in which 0.2 μm filters have been shown to clog very rapidly.
Simple formulations such as intravenous solutions, ophthalmics, and other
aqueous products may be filtered directly through membranes in an economical
manner. Heat-labile oils and liquids containing proteins require pretreatment, e.g.
centrifugation or conventional filtration, prior to sterilization filtration, The
objective is removal of gross contamination that would rapidly plug the finer
membranes
The use of filtration to remove bacteria, particulate matter from air, and other gases
such as nitrogen and carbon dioxide is widespread in the pharmaceutical industry.
The following are some common applications employing initial gas filtration:
1)Vent filtration
2)Compressed air used in sterilizers
3)Air or nitrogen used for product and in process solution transfers and at filling
lines
4)Air or nitrogen used in fermentation
Filtration should be the last step in processing, and the filter should be
placed as close as possible to the point of use of final packaging. In serial
filtrations, only the final unit needs to be sterile, but minimal contamination in
prior steps increases the reliability of the total process. Sterile filtration should
always be a pressure operation; a vacuum is undesirable since bacteria may be
drawn in at leaky joints and contaminate the product.
Membrane Ultrafiltration
Unlike conventional filtration, ultrafiltration is a process of selective molecular
separation.
It is defined as a process of removing dissolved molecules on the basis of
membrane size and configuration by passing a solution under pressure through a
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very fine filter. Ultrafiltration membrane retains most macromolecules while
allowing smaller molecules and solvent to pass through the membrane
The difference between microfiltration and ultrafiltration is significant. The former
removes particulates and bacteria; the latter separates molecules
Separation of a solvent and a solute of different molecular size may be achieved by
selecting a membrane that allows the solvent, but not the solute, to pass through.
Alternatively, two solutes of different molecular sizes may be separated by
choosing a membrane that allows the smaller molecule, to pass through but holds
back the larger one.

The selectivity and retentively of a membrane are characterized by its

molecular weight cut off. Applications in the pharmaceutical industry are
predominantly in the concentration of heat-labile products, such as vaccines, virus
preparations, and immunoglobulins. Ultrafiltration also has been used to recover
antibiotics, hormones, or vitamins from fermentation broths, to separate cells from
fermentation broth, to clarify solutions, and to remove low-molecular-weight
contaminants prior to using conventional recovery techniques. The most important
application of ultrafiltration is the removal of pyrogens.

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Integrity Testing
An important feature of filtration system is its ability to be tested for
integrity before and after each filtration, which is of high importance especially in
sterilization filtration.

Integrity test is nondestructive test used to predict functional performance of a

filter.
Each filter has characteristic bubble point and diffusion rate of air through water in
wetted filter as function of porosity.
Integrity test detect a damage membrane, system leak and ineffective sealing.

Bubble point test is direct measure of largest pore in filter. Failure to hold rated
pressure is indicator of inefficient membrane or improper assembly.

Diffusion test is recommended for high volume system like multi- cartilage or
other system with high filtration area. The diffusion test measure the volume of air
that flow through a wet filter membrane from pressurized site to the atmospheric
site.

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 FILTER SELECTION
Once the purpose of the process has been determined, the selection of the
filter medium can be made. For example, for a sterilizing filtration, a 0.2 μm pore
size is used; for clarification, a plate and frame filter or woven-fiber filter may be
used. In general, a pore size smaller than the smallest particle to be removed is
selected. The filter medium should be compatible with the liquid or gas to be
filtered. It is advisable to check the chemical compatibility charts provided by the
vendors for selection of filter type.
Filtration surface area is calculated after the filter media, pore size, required
flow rate, and pressure differentials are established. For a liquid having a viscosity
significantly different from that of water (1 cp), the clean water flow rate is divided
by the viscosity of the liquid in centipoises to obtain the approximate initial flow
rate for the liquid in question.
The broad span of pharmaceutical requirements cannot be met by a single
type of filter. The industrial pharmacist must achieve a balance between filter
media and equipment capabilities, slurry characteristics, and quality specifications
for the final product. The choice is usually a batch pressure filter, which uses either
surface or depth filtration principles.

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