Filtration and clarification

Hasan Muti

1
 Filtration
•Is defined as the process in which particles are
separated from a liquid by passing the liquid
through a permeable material.
•The porous filter medium is the permeable
material that separates particles from the liquid
passing through it and know as a filter.
•Thus filtration is a unit operation in which a
mixture of solids and liquid, the feed, suspension,
dispersion, influent (flowing in) or slurry is forced
through a porous medium, in which the solids are
deposited or entrapped.

2
 Filtration System
Funnel Filtration

3
 Filtration System

Diagram of simple filtration: oversize particles in the feed cannot

pass through the lattice structure of the filter, while fluid and
small particles pass through, becoming filtrate.
4
 Filtration System

5
 Clarification and filtration
•The preparation of pharmaceutical dosage
forms frequently requires the separation of
particles from a fluid.
•The usual objective is a sparkling liquid that is
free of amorphous or crystalline precipitates,
colloidal hazes or insoluble liquid drops.
•Sterility specifications may expand the
objective to include removal of microorganisms.

6
 Clarification and filtration
•The solids retained on the filter are known as
the residue.
• a cake is the solids form retained on the
surface of the medium.
•effluent or filtrated is the clarified liquid
discharged from the filter
•If recovery of solids is desired, the process is
called cake filtration

7
 Clarification and filtration
•Filtration is frequently the method of choice
for sterilization of solutions that are
chemically or physically unstable under
heating conditions (sterile filtration is an ideal
technique, provided that a process validation
is conducted on the product and area)
•Today filtration is an art than science

8
 General rules
1. Pressure increases usually cause a proportionate
increase in flow unless the cake is highly compressible.
2. Pressure increases on highly compressible, flocculent,
or slimy precipitates may decrease or terminate flow
3. An increase in surface area increases flow and life
proportional to the square of the area since cake
thickness, and thus resistance, are also reduced
4. The filtrate flow rate at any instant is inversely
proportional to viscosity
5. Cake resistance is a function of cake thickness,
therefore, the average flow rate is inversely
proportional to the amount of cake deposited

9
 Rate of filtration

Rate of filtration = (area of filter) x (pressure difference)

(viscosity)x(resistance of cake and filter)

10
 Filter Aids
•An inert powder or granules such as diatomaceous earth
(Siliceous sedimentary rocks), fly ash, or sand added to a
solution that is to be filtered in order to form a porous bed
on the filter and increase the rate and improve the quality of
filtration.
•The rate of filtration is inversely proportional to the
resistance of the solids cake.
•Therefore the pressure drop across the system is directly
proportional to the filtration rate, the thickness of the cake
and the liquid viscosity for flow through porous media when
laminar flow conditions exist in the filter media or cake.
•It is also inversely proportional to the density of the liquid
and square of the particle diameter.
11
 Filter Aid
•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 quantity of the filter aid greatly influences
the filtration rate
12
 Filter aid
•If too little filter aid is used, the resistance
offered by the filter cake is greater than if no
filter is used of because of the added
thickness to the cake.
•On the other hand if high amounts of filter
aid are added, the filter aid merely(nothing
more) adds to the thickness of the cake
without providing additional cake porosity

13
 Typical plot of filter aid concentration
versus permeability

14
 Concentration of filter aid
•The previous figure is a typical plot of filter aid
concentrations versus permeability.
•The flow rate and permeability are directly
proportional to each other
•At low concentration of filter aid, the flow rate is
slow 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.
15
 Filter aids
• The ideal filter aid performs its functions
physically or mechanically; no absorption or
chemical reaction is involved in most cases.
• It should have a structure that permits
formation of pervious (permeable) cake
• It should have a particle size distribution
suitable for the retention of solids, as
required.
• It should be able to remain suspended in the
liquid.
16
 Filter Aids continued
• It should be free of impurities.
• It should be inert to the liquid being filtered.
• It should be free from moisture in cases where
the addition of moisture to the fluid would be
undesirable.

17
 Aids to Filtration
• 1. Talc- Non absorbent material , chemically
inert for filtering any liquid.
• 2. Kieselguhr- is pure silica. It is as applicable
as talc. It is non adsorbent.
• 3. Charcoals- It possess adsorptive properties
not only toward color but for many active
constituents of medicinal preparations, e.g.
alkaloids and glycosides.

18
 Filter particles
• The particles must be inert, insoluble,
incompressible and irregularly shaped.
• Filter aids are classified from low flow rate (3-
6 micron) to fast flow rate (20-40 micron).
• Clarity of the filtrate is inversely proportional
to the flow rate.

19
 Advantages and disadvantages of
filter aids

20
 Filter Selection
• The following questions should be answered
before any assistance is requested from the
manufacturers of filtration equipment.
• What is to be filtered - liquid or gas?
• What liquid or gas is to be filtered?
• What is the pore size required to remove the
smallest particle?

21
 Filter Selection

• What is the desired flow rate?

• What will the operating pressure be?
• What are the inlet and outlet plumbing
connections?
• What is the operating temperature?
• Will the process be a sterilizing filtration?
• What is the volume to be filtered?
• What time constraints will be imposed, if any?
22
 Sterile Operation
• Filtration may be used to clarify and sterilize
pharmaceutical solutions that are heat-labile.
• Membranes with porosity ratings of 0.2 or
0.45 microns are usually specified for sterile
filtration.
• It is highly advisable to use prefilters to
prevent clogging of filters.

23
 Diameter of filters and prefilters

24
 Sterile Operation
• In selecting a filtration system for sterilization
of any growth-supporting medium, the
following precautions must be kept in mind:
• 1. Identify the potential sources of adverse
biochemical and chemical contamination at
each point of the system.

25
 Sterile Operation
• 2. Identify the control points necessary to
eliminate possible contamination and
decrease cost.
• 3. Identify the hazards associated with each
control point, I.e. airborne contamination
and protein denaturation.
• 4. Establish a protocol for monitoring the
hazards at control points of the system.

26
 Illustration of the basic filtration
system
•The following figure illustrates the basic filtration
system for nonsterile filtration of serum, water and
salts to reduce the microbiological and particulate
matter, followed by final filtration through the
sterile membrane
•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
27
 Schematic representation of operational
sequence

28
 Integrity Testing
• An important feature of a filtration system is
its ability to be tested for integrity before and
after each filtration.
• This process is very important in sterilization
filtration, where even a few microorganisms
passing through a crack in the filter could be
disastrous.

29
 Integrity Test
• Integrity test is a nondestructive test used to
predict the functional performance of a filter.
• Each membrane has a characteristic bubble
point, diffusion rate, or diffusion rate of air
through water in a wetted filter, which is a
function of the porosity rating and predicts
the performance of the filter.

30
 Bubble Point Test
• Bubble test should be conducted prior and after
filtration , as this the requirements of cGMP
• This test can be run during filtration as an IPC test
• The bubble point test is based on the fact that
when these capillaries are full of liquid, the liquid
is held by surface tension.
• The minimum pressure required to force the
liquid out of the capillary must be sufficient to
overcome surface tension.
• The capillary pressure is higher in the case of a
small pore than in that of a large pore.
31
 Principle of bubble point test

32
 Bubble point performing
• The membrane is wetted and usually has a
liquid above and a gas below.
• Since the pores are full of liquid, there is no
passage of gas at zero pressure. There is still
no passage of gas if the pressure is increased
slightly.
• When the bubble point pressure is reached, a
small bubble forms at the largest opening.

33
 Bubble point performing
• As the pressure is further increased, rapid
bubbling begins to occur.
• Bubble point pressure for a given membrane
is different for different liquids.
• Filtration should normally be performed at
pressures lower than the bubble point of a
membrane.

34
 Filtration failure
• When failure occurs, filtration should be
discontinued, and material already processed
should be refiltered.

35
 Equipment Used
• Commercial filtration equipment is classified
by type of driving force (gravity, pressure,
centrifugal, or vacuum).
• Or by method of operation (batch or
continuous), and by end product desired
(filtrate or cake solids).
• Sand filters , plate and frame filter press and
disc filter and cartridge filters.

36
 Membrane 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
fine filter. E.g. filters for pyrogens
• Ultrafiltration membrane retains most
macromolecules while allowing smaller
molecules and the solvent pass through the
membrane.

37
 Ultrafiltration continue
• The difference between microfiltration and
ultrafiltration is significant. The former
removes particulates and bacteria , the latter
separates molecules.
• Ultrafiltration is similar in process to reverse
osmosis.
• Ultrafiltration is different from R.O in the
sense that it does not separate on the basis of
ionic rejection.

38
 Dust filters
• The GMP guidelines insisted that the
pharmaceutical industry should have an air
handling filters to filter the air enters the
production areas and to filter also the outlet air
to protect the environment form the wastes and
dusts of the chemicals.
• In sterile areas they use HEPA (High Efficiency
Particulate Air) filters (these types of filters
prevents the entrance of particles larger than 0.2
microns).

39
 Air handling system
• In other parts of production areas of
pharmaceutical industry, less efficient filters
are used with an efficiency of 99,97%.
• The same HEPA filters are used with less
efficiency as mentioned above.
• Air changes per hour depending on the area
e.g. Sterile area is 60 times and production
area is around 14 times

40
 Centrifugation
• A mixture of solid and liquid, or of two liquids
is rotated at high speeds so that the mixture is
separated into its constituent parts by the
action of centrifugal force.
• Centrifugation is useful when separation by
filtration is difficult, e.g. in separating a highly
viscous mixture.

41
 Centrifugation
• Centrifugation has a wide use in the
pharmaceutical laboratories and it is used for
predicting emulsion stability.
• Two types of centrifuges are available:
• 1. Sedimentation, depends on differences in
the densities of the mixture.
• 2. Filtration, is limited to the separation of
solid-liquid mixtures only.

42
 Sedimentation Centrifuges
• Bottle Centrifuge- Consists of a vertical spindle
that rotates the containers in a horizontal
plane. It is commonly used to separate
materials of different densities.
• It is used for separation of blood from serum.

43
 Sedimentation Centrifuges
• Ultracentrifuge- when extremely fine solid
matter must be separated from a liquid ,e.g. in
colloid or biological research, the
ultracentrifuge is employed.
• It is operated at a speed of more than 100,000
rpm and forces up to one million times gravity
are exerted.

44
 Sedimentation Centrifuges
• Ultracentrifuges are employed in the
determination of particle size and molecular
weight of polymeric and other high-
molecular-weight materials such as proteins
and nucleic acid.

45
 Filtering Media
• The filtering medium, whether a filter paper,
synthetic fiber, or porous bed of glass, sand ,
or stone, is composed of countless channels
which impart porosity to the medium.
• These channels or pores are nonuniform and
possess a rather tortuous (full of twists) nature.

46
 Filtering Media
• The mechanism of filtration basically involves a
two-step process:
• 1. The filter medium itself resists the flow
of solid material.
• 2. The suspended, solid material builds up
on the filter medium and thereby forms a
filter bed which acts as a second, and
often more efficient, filter medium.

47
 Filtering Media
• Retentive(power or capacity) ability of a filter
medium and filtration rate are dependent on
the porosity of the medium. These are
influenced by :
• 1. The viscosity of the liquid
• 2. The proportion of solid matter in liquid.
• 3. The size, shape, and physical nature of
the suspended solids.

48
 Sterile Operations

49
 Sterile Operations

50
 Membrane Filters
• These are produced from pure cellulose,
cellulose derivatives, and polymeric materials.
• All these have an extremely uniform
micropore structure as well as exceptionally
smooth surface.

51
 Membrane Filters
• The pore size, of different types of these
filters, ranges from 10 nm to 10m and 0.2
m.
• The thickness of these membrane filters
ranges from 50 to 200 m.

52
 Filter Paper
• Is most frequently employed in clarification
process of the pharmacy practitioner.
• High quality filter paper should be used to
assure maximum filtering efficiency.
• The first few drops should be discarded in
order to eliminate as possible contamination
of pharmaceutical product by free fibers
associated with the paper.

53
 Other Filtering Media
• Cotton Filters- a small pledget (A small flat
absorbent pad used to medicate, drain, or
protect a wound or sore) of absorbent cotton,
loosely inserted in the neck of a funnel.
• It is necessary to return the liquid a number of
times to secure perfect transparency.

54
 Other Filtering Media
• Glass-wool Filters- used for highly reactive
chemicals, such as strong acids.
• Sintered Glass Filters- consists of a flat or
convex plate of particles of Jena glass
powdered as sifted to produce a uniform size
which are molded together.
• These are useful in the filtration of solutions
intended for parenteral injection.

55
 Rapid Filtering Apparatus
• 1. Vacuum Filtration-
– a. Pump Acting by Water Pressure.
– B. Filtration under Pressure.

56
 Buchner funnel

57
 Filter pore size reference guide
Pore size (micron) Particle removed

0.2 (0.22) All bacteria

0.45 All coliform group bacteria

0.8 All airborne particles

1.2 All nonliving particles considered dangerous in i.v fluids

5 All significant cells from body fluids

58
 Decoloration
• Is the process of depriving (to take something away
from) solutions of color by use of an
appropriate adsorptive medium.
• Decoloration is used for removal of coloring
matter from a number of raw materials, both
natural and synthetic.
• Animal charcoal (carbonized bone) , wood
charcoal, and activated charcoal are
frequently used as decolorizing agents.

59