Industrial pharmacy

Industrial pharmacy
8/22/20171
 Industrial pharmacy is a discipline which includes
manufacturing, development, marketing and
distribution of drug products including quality
assurance of these activities
 The reasons for the increasing of large scale
manufacturing
 Economic – As the scale of manufacturing batches
increases so, proportionally, does the cost of
production decreases
 Accuracy – The larger the quantities of materials
involved so, proportionally, is the accuracy of
measurements increased

The Fundamentals unit operations
8/22/20172
 In a pharmaceutical industry a unit operation is a
basic step in a process
Eg. tablet processing: mixing, milling, drying
and sifting
 It is convenient to break down the processes for the
manufacture of pharmaceutical products into unit
operations
those unit operations are not fundamental
 All unit operations involve and are controlled, to a
greater or lesser extent, by one or more of the
following basic processes.
Fluid flow

Fluid flow
8/22/20173
 Fluids are a form of matter that cannot achieve
equilibrium under an applied shear stress but
deform continuously, or flow, as shear stress is
applied.
 Certain aspects of all the unit operations employ
the movement of a fluid through pipes or
between or around particles, etc
Mechanism of Fluid Flow
 When a fluid flows through a pipe , the character
of the flow can vary according to the conditions

Reynolds’ experiment
8/22/20174
 a long glass tube was connected to
a reservoir providing a constant
head of water, with the control
valve at the outlet so that the rate of
flow could be varied
 In the inlet of the tube a jet was
inserted which allowed a colored
liquid to be injected into the center
of the tube for the visualization of
the flow behavior

Cont…
8/22/20175
When the velocity is low, the thread of colored liquid remains
undisturbed in the center of the water stream and moves steadily along
the tube, with out mixing, this condition is known as streamline or
laminar flow (a)
 At moderate velocities, a point is reached (the critical velocity) at which
the thread begins to waver, although no mixing occurs. This is the
phase of transitional flow.
As the velocity is increased to high values eddies begin to occur in the
flow, so that the colored liquid mixes with the bulk of the water
immediately after leaving the jet. Since this is a state of complete
turbulence, the condition is known as turbulent flow.

Cont…
8/22/20176
Reynolds found that flow conditions were affected by four factors
 Diameter of pipe
Velocity of fluid
 Density of fluid
 Viscosity of fluid
Re = ρvd/μ
 where Re = Reynolds Number
ρ = density of fluid (kg/m3)
v = velocity of fluid (m/s)
d = diameter of pipe (m)
μ = viscosity of fluid (kg/m. s)
 Reynolds number is just a number and it has no

Distribution of Velocities Across the Tube
8/22/20177
 When a fluid flows along a tube, not all parts
are moving at the same velocity
 The fluid in the center travels at the highest
velocity and that at the walls at the lowest
 In laminar flow; Fluid in the centre can move
at highest velocity with frictional force causing
a continual decrease in the velocity towards
the walls

Boundary Lines
8/22/20178
 whether flow in the tube is laminar or turbulent, the
velocity reaches very low values near the walls
ultimately, it becomes zero at the wall itself
 Reynolds Number is proportional to the velocity
 So similar decrease in the value of the local Re.
 This means that there will be a change from
turbulence, through a transitional region to a
sluggish streamline region and finally, to a stationary
film on wall.
 that boundary layers can never be eliminated
 Increasing the velocity of the fluid over the surface
will reduce the thickness of the layer

1.2 Heat Transfer
8/22/20179
 Heat is a form of energy.
 It can only be transferred from a region of higher
temperature to a region of lower temperature
 Many pharmaceutical unit operations like
distillation, drying, evaporation, sterilization etc
involve the application of heat
Heat is transferred by three mechanisms
 Conduction: is the transfer of heat through a static
material by direct contact of particles of matter
is greater in solids, where atoms are in constant
contact
is limited to solids and to fluids that are ‘bound’ in

Cont…
8/22/201710
 Convection: is the transfer of heat from one point to another
within a fluid (gas, liquid) by the mixing of one portion of the
fluid with another
 In convection, the heat flow results from mixing or turbulence,
which can occur in fluids only
 Radiation: is the transfer of heat energy through empty space
 No medium is necessary for radiation to occur

Heat transfer by conduction
8/22/201712
 Conduction is the most familiar and widely
understood mechanism of heat transfer
 When heat is flowing under steady-state
conditions, the quantity of heat transferred is
given by:

8/22/201713
 k ,which is characteristic for any material, is known
as the coefficient of thermal conductivity
 Thermal conductivities vary considerably, ranging
from metals that have high values to gases that
have the lowest values
Material Thermal conductivity
(J/sm°c)
Copper 379
Aluminum 242
Steel 43
Glass 1
Water 0.6
Air 0.03

1.3 Mass transfer
8/22/201714
involves the movement of material from one
phase to another
Eg. in drying a wet solid, the liquid is
converted to vapor and carried away in that
form
when a drug is extracted with a solvent,
soluble material passes from the solid phase
into solution and is taken away in the liquid
phase

Solid fluid mass transfer
8/22/201715
 Consider a crystal of a soluble material immersed in
a solvent in which it is dissolving
 transport of the molecules of the dissolving solid will
take place in two stages
 First the molecules move through the boundary layer
by molecular diffusion, with no mechanical
mixing
 Once material has passed through the boundary
layer, mass transfer takes place by bulk movement of
the solution, known as eddy diffusion,
 the controlling factor in the rate of solution of the
crystal will be the molecular diffusion through the
boundary layer

Cont…
8/22/201716
 Eddy diffusion will not be considered further
since, in general, molecular diffusion is the
controlling process
 Equation for mass transfer by molecular
diffusion

Factors affecting Solid fluid mass transfer
8/22/201717
 Agitation, which reduces the thickness of the
boundary layers and disperses any local
concentrations of solution, so increasing the
concentration gradient.
 Elevated temperatures which increase the diffusion
coefficient and decrease the viscosity of the liquid,
so reducing boundary layer thickness.
 Size reduction of the solid, which increases the
area over which diffusion can occur.

Unit operations
8/22/201718
 Unit operations:- are different processes and
equipments required in the manufacturing of
pharmaceuticals
Size reduction
Mixing
Drying
Filtration
 Crystallization

Drying
8/22/201719
 Removal of water or other liquid from a solution,
suspension or solid –liquid mixture to form a dry
solid
 involves heat transfer and mass transfer
 Drying and evaporation are distinguishable merely
by the relative quantities of liquid removed from the
solid
Purpose of drying/Application of Drying
 In the preparation of granules
Stabilizes moisture sensitive materials :-Aspirin
& penicillin

Factors affecting drying
8/22/201720
The critical factor in drying operations is the
vapor - carrying capacity of the air, nitrogen,
or other gas stream passing over the drying
material
 The vapor - carrying capacity determines both
rate and extent of drying
Heat sensitivity of the product
Physical characteristics of the product
Nature of solvent to be removed

Convective Driers for Wet Solid
8/22/201721
Tray Drier
 Air flows in the direction of
the arrows over each shelf
in turn
 The wet material is spread
on shallow trays resting
as the shelves
 The required latent heat
of evaporation is
transferred convectively
from the air
 Slow heat transfer=> slow
rate of drying

Dynamic Convective Driers
8/22/201722
Fluidized Bed
Drier(FBD)
 There is an excellent
contact between the warm
drying air and the wet
particle
 The material to be dried is
contained in a vessel, the
base of which is
perforated enabling a fluid
(air) to pass through the
bed of the solid from the
bottom

Advantages of Fluidized Bed Drying
8/22/201723
 Efficient heat and mass transfer. This
attributes to
 Short drying time (20-30 min)
Good for thermolibile materials
 Drying occurs from the surface of the individual
particles
 No migration of soluble API & Expients
 The temperature of the fluidizing bed is uniform
throughout and can be controlled precisely
 Turbulence cause attrition – More spherical free
flowing particles
 The container can be mobile, good for material

Disadvantages of FBD
8/22/201724
 Turbulence – Excessive attrition
 Production of too much dust –> too fine –> flow
problem
– >segregation
 Generation of static electricity
 Mixture of air with organic materials (starch and
lactose) can cause explosion
 The danger is increased if the fluidizing material
contains volatile solvents such as isopropyl
alcohol
 Therefore, adequate electrical earthing is

Conductive Drying of wet solids
8/22/201725
 The wet solid is in thermal contact with a hot surface
and heat transfer mainly occurs by conduction
 Vacuum Oven
 Consists of a jacketed Vessels sufficiently strong in
construction to with stand vacuum and steam pressure in
the jacket
 Operating pressure can be as low as 0.03-0.06 bar,H2O
boils at25-350c
[[[
 Commonly used in pharma R & D`s
 Advantages:
 For thermolibile products
 Minimum oxidation

Radiation drying of wet solid
8/22/201726
Microwave (MW) Radiation
 Microwave radiation in the Wave length of 10nm-
1nm penetrates much better than IR
 More application in pharma than IR dries does
Microwaves are produced by an electronic
devices known as magnetron
 When MW falls on substances of suitable electronic
structure (Polar molecules e.g. water), the electrons
in molecules attempt to resonate in sympathy with
the radiation and the resulting molecular friction
which in turn causes generation of heat

Advantage of MW drying
8/22/201727
 Rapid drying at fairly low Temp.
 Thermal efficiency is high
 most of the MW is absorbed by the liquid
No heating of the air
 The bed is stationary avoiding the problem of dust
generation
 Solute migration is reduced as there is uniform
heating of the wet mass.
 Equipment is highly efficient and refined
All product and operators safety have been
incorporated
CGMP compliant
 Drying end point detection is possible

Disadvantages of MW drying
8/22/201728
 Smaller batches sizes are used as compared to FBD
 Safety issues.
Care should be taken to shield operators from the MW
radiation
 which can cause damage to the eyes and testes

Driers for Dilute solutions and suspensions
8/22/201729
 Objective
 To spread the liquid to a large surface area for heat and
mass transfer and to provide an efficient means of
collecting the dry solid
 Two main types are used
 Spreading the liquid to a thin film on a drum
 Dispersing the liquid to a spray of small droplets

Drum driers
8/22/201730
 consists of a drum 0.75-1.5m
in diameter and 2-4m in length
 It is heated internally by steam
 The liquid is applied to the
surface of the drum and
spread to a film
 This is usually performed by
Deeping the drum in the
feeding pan
 Drying rate is controlled by
 Manipulating the speed of the
drum
 Manipulating Temp.
 The product is scraped from

Advantages of the drum drier
8/22/201731
 gives rapid drying =>rapid heat and mass transfer
 The equipment is compact less space than spray
drier
 Heating time is short (a few sec)
 The drum can be enclosed in vacuum =>the drying
Temp. can be reduced
 The product is obtained in flake form which is
convenient for many purposes

Disadvantages
8/22/201732
 Operation conditions are critical i.e. it is
necessary to impose careful control on
 Feed rate
Film thickness
Speed of drum
 Drum Temperature
 Pharmaceutical applications
Drying of starch products
 Ferrous salt
 Suspensions of Zn oxide

Spray Driers
8/22/201733
 Provides a larger surface area for heat and mass
transfer
Works by atomizing the liquid to small droplets
The liquid is sprayed into a stream of hot air
 Each droplet dries to an individual solid particles
Mechanism of drying
 The air enters the chamber tangentially and rotates the
drying droplets around the chamber to increase their
residence time
 The air is heated by heat exchangers
 Dust carried over in the air is recovered by cyclone
separator of filter
 Physical characteristics of spray dried products

Advantages of the spray Drying process
8/22/201735
Rapid drying (fraction of sec)
 Evaporation is rapid =>the droplets do not attain
high Temp.
 good for thermolibile products
High bulk density=> rapid dissolution due to
increased surface area
Uniform and controlled particle size
The product is free flowing as the particles are
spherical in shape
Low labor costs. No human handling

Disadvantages
8/22/201736
 The equipment is very bulky
 Thermal efficiency is low as the air is still hot when it
leaves the drier
 Pharmaceutical Application
 Gelatin
 Starch
 Some powdered antibiotics for reconstitution into
syrup
 Particles in 1-7mm can be dried and used in DPI
(dry powder inhalers)
 Can be operated with inert gases for 02 sensitive

Freeze drying (lyophilization)
8/22/201737
 Many products of pharmaceutical lose their viability
in the liquid state and readily deteriorate if dried in
air at normal atmospheric pressures
 It works by freezing the material and then reducing
the surrounding pressure and adding enough heat to
allow the frozen water in the material to sublime
directly from the solid phase to gas

Advantages
8/22/201738
1. Drying takes place at low Temp., so that enzymes
action is inhibited and chemical decomposition,
particularly hydrolysis, is minimized
2. The solution is frozen such that the final dry product
occupy the same volume as the original solution
3. Fast solubility due to high porosity
4. The process takes place under high vacuum; there
is little chance for oxidation

Disadvantage
8/22/201739
1. Very hygroscopic substance.
 The products should be dried in their final
containers and sealed in situ
2. The process is very slow and uses complicated
plants and not universal method.
 Uses
For drying of Biological products
Such as Antibiotics, blood products and
vaccines, and enzyme preparations

Size Reduction
8/22/201740
 is the mechanical process of reducing the particle
size of a substance to smaller pieces, to coarse
particles, or to powder
 Various terms have been used synonymously with
size reduction depending on the product, the
equipment, and the process
Crushing , Grinding, Milling, Pulverization and
Dispersion
 particle size affects a number of characteristics in
the manufacturing process
 controlling the particle size helps assure that the
milled material will be consistent and repeatable

the most common reasons for reducing material sizes
8/22/201741
Create appropriate particle sizes for subsequent
processing or end use
 Color - uniform particles assure batch-to-batch colo
consistency /less chance for mottling/
Improve material blending and prevent segregation
by making different sized products with similar particle
size distributions
Increase the material’s surface area to improve a
material’s solubility
Examples:- decrease particle size of griseofulvin
decreased oral dosage regimen half.
To facilitate drying of wet masses
 reduces the distance the moisture must travel to

Factors affecting size reduction
8/22/201742
Hardness
 Hard materials are difficult to comminute
Toughness
 It is often more important than hardness, so that a soft
but tough material may present more problems in size
reduction than a hard but brittle substance.
Ex. - Rubber - Fibrous drugs
Rubber are capable of absorbing large amount of
energy through elastic and plastic deformation
 Such materials can be milled by cooling
Stickiness
 It may cause difficulty in size reduction, since a material
acts as a lubricant & lowers efficiency of the grinding
surfaces.
 Example:- Grinding of gummy or resinous

Cont…
8/22/201743
 Softening Temperature
 The heat during size reduction processes softens and
melts materials with a low melting point.
 Ex. – Synthetic gums and resins
- Heat-sensitive drugs may be degraded or even
charred
 Moisture content
 An increase in moisture can decrease the rate of size
reduction to a specified product size
 The presence of more than 5% water hinder comminution
and often produces a sticky mass upon milling
 Only a small amount of energy put into a milling
operation actually effect size reduction (2%)

Methods for size reduction
8/22/201744
There are four main methods of effecting size
reduction
 Cutting:- the material is cut by means of a sharp
blade or blades
 Compression:- the material is crushed by
application of pressure
 Impact:- material is hit by an object moving at a
high speed or it strikes a stationary surface and
the material is broken down into small places
 Attrition:- the pressure is applied to the material
as in the case of compression, but the surfaces
are in motion relative to each other.

Cutting
8/22/201745
 The cutter mill consists of a series of knives attached on
a horizontal rotary which act against a series of
stationary knives attached to the mill casing.
 Size reduction occurs by fracture of particles between
the two sets of knives which have a clearance of a few
millimeters
Application
 To produce a coarse degree of size reduction of dried
granulation prior to tableting
 To mill fibrous crude drugs such as roots or barks prior
to extraction

Compression
8/22/201747
 Size reduction range 10-100μm
 Direct-pressure milling occurs when a particle is
crushed or pinched between two hardened surfaces
 Two rotating bars or one rotating bar and a stationary
plate generally produce this milling action
 Used in small scale by using a mortar and pestle
 In large scale there are:
 End runner mill- a weighted pestle is turned by
friction of material passing beneath it- a mortar rotates
under the powder
 Edge runner mill -a pestle rotates against a bed of
powder

Alternative technique/Roller Mill/
8/22/201748
 Compression mill which uses two cylindrical rollers
mounted horizontally and rotated about their long axes
 In rollers, one of the rollers is rotating and the other one
is rotated by friction.
 This are not like ointment mills where both rolls are
driven at different speed and size reduction occurs by
attrition
 The commonest method in the pharmaceutical industry
 USE - used for crushing, such as cracking the seeds
of fixed oils to aid solvent penetration in extraction

Attrition milling (1-100μm)
8/22/201749
 Is used for the Size reduction of solids in
suspensions, pastes and ointments
Roller Mill
 Two or more metal rolls are mounted horizontally with
an adjustable gap which can be as small as 20 μm
 The rollers rotate at different speeds so that the
material is sheared as it pass though the gap
 The material is transformed from the slower to the
faster roll
 The material (milled) is removed by scraper

Impact milling (1-10000μm)
8/22/201750
A hammer mill
 A hammer mill consists of a four or more hammers
hinged on a central shaft which is enclosed in a rigid
metal case
 During milling, the hammer swing out radially from
the central shaft
 As size reduction continues the inertia of particles
hitting the hammer reduces and sequentially fracture
is less probable
 Hence, hammer mill tend to produce powders with
narrow size distribution

Cont …
8/22/201753
 Example-2 Alternative Technique (Vibration
Milling)
 Uses a drum where 80% of the content is filled with
porcelain or steel balls
 During milling, the whole body of the mill is vibrated
and size reduction occurs by repeated impaction
 Comminuted particles fall through a screen at the
base of the mill
 The efficiency of vibration milling is greater than
that of the conventional ball mill

Combined impact and attrition Method
8/22/201754
Ball mill
 Both impact and attrition methods are used
 Consists of a hollow cylinder containing balls (30-
50%) of its space
 The amount of material in a mill is considerable
important
 Speed of ball mill has a considerable effect on
grinding
At low speed – balls will slide or roll over each
other

Advantages of ball mill
8/22/201756
 It is capable of grinding a wide variety of materials
 It can produce very fine powders
 It is economical and simple to operate
 It can be used for batch or continuous operation
 It can be used in completely enclosed form, which
makes it especially suitable for use with toxic
materials
 Disadvantages
 Contamination may happen because of wearing of
balls and partially from casing.
 Soft materials may stick on the sizes of the mill.

Fluid Energy Mill
8/22/201757
 Utilizes particle impaction and attrition
 Consists of a hallow tube with a diameter of 20-200mm
 A fluid (air) is injected as a high pressure jet through
nozzles at the bottom of the loop
 The high velocity of the air gives rise to zones of
turbulence into which solid particles are fed
 The high kinetic energy of air causes the particles to
impact with each other
 A particle size classifier is incorporated so that particles
are retained in the tube until sufficiently milled

Advantages Fluid energy mill
8/22/201758
 The particle size of the product is smaller than that
produced by any other method of size reduction
 Is used for thermolabile substances because the
cooling effect counteracts the heat generated by milling
 There is no abrasion of mill so virtually no
contamination of the product
 For very sensitive materials it is possible to use inert
gases
 Having a classifier as an integral part of the system
permits close control of particle size and of particle size
distribution
 Use:- used for obtaining very fine powders, e.g.

SIZE SEPARATION
8/22/201759
 In pharmaceutical industry, the control of particle size
and size range has great importance
 Standards for sieves
 There are different standards of sieves for
standardization of particles size of powders
 Number of sieves:- this is the number of meshes in a
length of 25.4 mm (1 inch), in each direction, parallel to
the wires
 thus a number 10 sieve has 10 meshes in 2.54cm in
each direction
 Nominal size of aperture:- this is the distance
between the wires, so that it represents the length of the
side of the square aperture

Size separation by sieving
8/22/201760
 There are several techniques for encouraging particles
to separate into their appropriate size fractions
efficiently
Agitation methods
A. Oscillation:- The sieve is mounted in a frame that
oscillated back and forth
B. Vibration:- the mesh is vibrated at high speed,
often by means of an electrical device
 Brushing methods
 A brush can be used to move the particles on the
surface of the sieve and to keep the meshes clear.

Cont …
8/22/201761
Centrifugal methods
This type of sieve used a vertical cylindrical sieve
with a high speed rotor inside the cylinder, so the
particles are thrown outwards by centrifugal force
Wet sieving
 Wet sieving is more efficient than the equivalent dry
process, particles being suspended readily and
passing easily through the sieve with less blinding of
the meshes.

Mixing
8/22/201762
 is a process in which two or more components in a
separate or roughly mixed condition are treated so that
each particle lies as nearly as possible in contact with a
particle of each of the other ingredients
 Purposes of pharmaceutical mixing
To ensure even distribution of the API
 To ensure even appearance
To ensure the release of the drug at the correct site
and at the desired rate

Types of Mixtures
8/22/201763
 There are three types of mixing based on their
behavior:-
 Positive mixtures
 These mixtures are formed when two or more miscible
liquids are mixed together by diffusion process.
 Irreversible mixing would take place.
 Negative mixtures
 Hence insoluble solids are mixed with the vehicle to form
a suspension or two immiscible liquids are mixed to form
emulsion.
 require energy for their formation
 The components of which will separate unless work is
continually expanded on them.

Cont…
8/22/201764
 Neutral Mixtures
 Here mixing of pastes, ointments takes place.
 When two powders are mixed, then it forms a
neutral mixtures
 Components of the mixture have no tendency to
mix spontaneously, nor do they segregate when
mixed
 They are static in their behavior

Mechanisms of solid mixing
8/22/201765
 Convective mixing
 Arises when there is the transfer of relatively large group
of particles from one part of the powder bed to another as
might occur when a mixture blade or paddle moves
through the mix
 In order to achieve a random mix an extended mixing time
is required
 Shear mixings
 When a layer of material moves / flow over another layer

Cont..
8/22/201766
 Diffusion mixing
 When the powder bed is forced to move or flow
 This is because the powder particles will become
less tightly packed and there is an increase in the
voids space between them
 Under this circumstance, there is a potential for the
particles to fall under gravity through the void
created
 results in low rate of mixing
 N.B all three mixing mechanisms are likely to occur
in a certain mixing operation

Mechanisms of Mixing for Liquids
8/22/201767
 Bulk transport
 involves the movement of a relatively large amount
of materials from one position in the mix to another
 It tends to produce a large degree of mixing fairly
quickly
 Turbulent mixing
 Arises from the haphazard movement of molecules
when forced to move in a turbulent manner
 Molecular diffusion
 Occurs with miscible fluid whenever a concentration
gradient exists and will eventually produce a well
mixed product

Powder Segregation /demixing/
8/22/201768
 Segregation is the opposite effect to mixing i.e.
components tend to separate out
 is very important in pharmaceutical preparations
as it causes a non random mixing
 Effects of segregation
 Increased content variation
 Un acceptable variation in weight
 Processing difficulties
 Non uniform drug release rate

Causes of powder segregation
8/22/201769
 Particle size effect
 It is the main cause of segregation
a. Percolation segregation
 Smaller particles tend to fall through the void between
larger ones and moves to the bottom of the mass.
 Example - during vibration, Stirring or poring
b. Trajectory segregation
 During mixing larger particles will tend to have greater
kinetic energy imparted to them and therefore will tend
to move greater distance than smaller particles before
come to rest

8/22/201770
C. Elutriation segregation/Dusting out/
 When a material is discharged from a container, very
small particles dust in a mix may tend to be blown
upward by turbulent air current as the mass tumbles
and remains suspended in the air
 Particle –density effect
 If component are of different density, the more dense
materials will have a tendency to move downward even
if the particles size are similar
 Particle shape
 Spherical particles exhibit the greatest flow ability and
are therefore more easily mixed, but they also
segregate more easily than non spherical particles

Approach to Rectify Segregation
8/22/201771
Selection of particle size fractions
 E.g. sieving to remove fins or lumps to achieve drug
and excipients within narrow particles size
distribution range
Milling of components followed by sieving
To reduce particle size range
Controlled crystallization
 Selection of excipients which have densities similar
to the API
Avoid vibration /proper material handling/
 Use of filling machine hopers designed so that

Powder mixing equipment
8/22/201772
Tumbling mixer equipments
 Used for mixing /blending of granules of free flowing
powders
 There are many designs
 Examples :Double cone mixers, Twin shells ,Cube
mixers , y- cone mixers, Drum mixers
 Too high mixer speed
 Will cause the material to be held on the wall by the
centrifugal force
 Too low mixer speed
Will generate insufficient bed expansion and little
shear mixing

8/22/201774
 High speed mixer granulator( Rapid mixer
granulators)(RMG)
 It both mixes and granulates
 Fluidized Bed mixers
 Used for mixing of powders prior to granulation
 Agitator mixers
Eg -ribbon mixers

Mixing of Miscible Liquids and Suspensions
8/22/201775
 Propeller mixer
 It has angled blade which cause the fluid to circulate in
both axial and radial directions
 Turbine Mixer
 Used for more viscous fluids
 The impeller has four flat blades surrounded by
perforated inner and
outer diffuser rings

Mixing of Semi solids
8/22/201777
 The problem with semi solids is that they are
not free flowing
 For this reason, mixers with rotating
elements and narrow clearance between
themselves and mixing vessels wall
 they must produce a high degree of shear
mixing
 Sigma blade mixer /- mixer/

Clarification (Filtration)
8/22/201779
Filtration is process that involves the removal or
separation of a solid from a fluid or a fluid from
another fluid
The preparation of pharmaceutical dosage forms
frequently requires the separation of particles from a
fluid
Objectives
 Sparkling liquid that is free of
 Crystalline precipitates or amorphous
Colloidal hazes
 Insoluble liquid drops
Removal of microbes or sterilization

Terminologies in Filtration
8/22/201780
 Filters: - the porous (permeable) material that
separates particles from the liquid passes through it
 Residue: - solids retained in the filter
 Effluent filtrate:-the classified liquid
 Cake filtration:- The solid forms a cake on the medium
and if the recovery of this cake is required the process is
called cake filtration
 Clarification: - When the solid to be filleted is not
exceeding 1.0% and the filtrate is the primary product
 Ultra filtration- separation of inter molecular liquid from
solids by the use of pressure in on a semi permeable

Principles of Filtration
8/22/201781
 It is more of an art than a science
 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
 Rate = driving force
Resistance
 The rate is expressed as volume per unit time & the
driving force as a pressure differential
 Rate of filtration:- ( dv) (area of filter) x (pressure
difference)
( dt) (Viscosity) x (resistance of

Factors Affecting Filtration rate
8/22/201782
The area available for filtration (A)
 The pressure difference across the filter bed (filler
medium and any cake formed)
The viscosity of the fluid passing through the filter i.e.
the filtrate( μ pas) increase viscosity =>greater
resistance for movement
The thickness of the filter medium and any deposited
cake (L)
Increased Cake = >decreased rate of filtration

Mechanisms of Filtration
8/22/201783
 Straining (sieving)
 the pores are smaller than the particles to be filtered,
and this results the particles to be retained on the filter
medium.
 Example – Removal of bacteria and fibers from parental
preparation
Impingement -A liquid following pattern is disturbed
eg. Used mainly for removal of materials from gases
 Entanglement
 If the filter medium consists of a cloth with a nap or is a
porous , then particles become entangled in the mass of
fibers

Filtration Equipment
8/22/201784
•Equipment selection
 Equipment should
 Allow a fast filtration rate
 Minimize production cost
Cheap to buy and to run
 Be easily cleanable
 Be resistant to corrosion
Be capable of filtering large volumes

Industrial Filtration Equipments
8/22/201785
Gravity Filter
 Filter that relay solely on gravity generate low
operating pressure
 They are very simple and cheap and used in
laboratories
Are common in water treatment Ex - Sand filter
Vacuum Filters
The rotary Vacuum Filter
 is continuous in operation and has a system for
removing the cake
 up to 2m in diameter and 3.5m in length with a
filtration area of 20m2
 Used for continuous filtration of slurry containing 15-

Advantages
8/22/201787
1. It is automatic and continuous in operation
2. It has a large capacity
3. Varied speed of rotation enables the cake thickness
to be controlled
 Disadvantage
1. It is complex and expensive
2. Ancillary equipments like
vacuum pump
 Vacuum receivers
Slurry pumps are required
3. Less satisfactory for solids that forms impermeable
cake

Pressure filters
8/22/201788
 The product is fed to the filter at a high pressure
 Most commonly used for processing of pharmaceuticals
I. The Meta filter
 The filter operates by pumping in the slurry under
pressure
 Advantages
1. High strength and no fear of bursting
2. No filter medium (stainless steel). This makes it
economical
 Application
 The small surface area restricts the amount of solid that
can be
collected.

Cartridge filter
8/22/201789
 Commonly used in the
preparation of
pharmaceutical products
 It poses a very large
filtration surface area in a
small unit and is easy and
cheap to operate
 The cartridge is then fitted
in a metal supporting
cylinder and the product is
pumped under pressure
into one end of the

Air Filtration (High Efficiency Particulate Air (HEPA) filter)
8/22/201790
 HEPA is a type of highly efficient filtration media that
removes microscopic particles from air which
passes through the filter
 The most efficient HEPA filter removes 99.7% of
particles with a size of 0.3η that enter the filter.
 Such particles include tobacco smoke, household
dust, and pollen.
 ULPA filters, or "Ultra-HEPA" filters, are designed to
trap 99.999%
 Usually Microban is used in HEPA filters which is
used to treat the HEPA filter

8/22/201791
 In most industries HEPA filters work along with
Dehumidifiers or humidity controllers and also along
with steam line and chillers which controls the
temperature in such cases the system is termed as
Heating, Ventilation and Air conditioning system
(HVAC system)

Crystallization
8/22/201793
 Crystallization refers to the formation of solid crystals
from a homogeneous solution
 It is essentially a solid-liquid separation technique
 The processes by which a crystal forms are called
nucleation and growth.
 Nucleation is the formation of a small mass on to which
a crystal can grow.
 Growth is the addition of more solute molecules to the
nucleation site
 In order for crystallization to take place a solution must
be "supersaturated“
 Supersaturation refers to a state in which the solvent
contains more dissolved solute

Cont…
8/22/201794
 Primary nucleation is the first step in crystallization.
 Simply defined, it's the growth of a new crystal
 The second chief mechanism in crystallization is called
secondary nucleation requires "seeds" or existing
crystals to achieve crystal growth
 The four most common methods of reaching
supersaturation in industrial processes are:
Cooling (with some exceptions) Ce2(SO4)3
Solvent Evaporation
 Drowning :addition of a nonsolvent to the solution
which decreases the solubility of the
solid
Chemical Reaction: alter the dissolved solid to

Figure 3: Solubility's of Several Solids
8/22/201795

Equipment Used in Crystallization
8/22/201796
 Tank Crystallizers
 the oldest and most basic method of crystallization
 saturated solutions are allowed to cool in open
tanks
 After crystallization, the mother liquor is drained and
the crystals are collected
 The crystallization is essentially just "allowed to
happen“
 Heat transfer coils and agitation can be used
 high operating costs

Forced Circulating Liquid Evaporator-Crystallizer
8/22/201797
 These crystallizers combine crystallization and
evaporation
 The circulating liquid is forced through the tube side of
a steam heater
 The heated liquid flows into the vapor space of the
crystallization vessel
 flash evaporation occurs, reducing the amount of
solvent in the solution
 The supersaturated liquor flows down through a tube,
then up through a fluidized area of crystals and liquor
where crystallization takes place via secondary
nucleation.
 Larger product crystals are withdrawn while the liquor
is recycled, mixed with the feed, and reheated.

Industrial pharmacy

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