INDUSTRIAL PHARMACY

February 2, 2025 1
 Introduction
 Pharmaceutical industry- is a commercial business
licensed to research, develop, market and/or
distribute drugs.

 Is a complex organization that constitutes different

units (departments), personnel, equipments and
processes.
Particle size reduction
 Objectives of size reduction
o The dimensions of particulate

solids are important in achieving

optimum production of efficacious

medicines

o Influences the subsequent physical

performance of the medicine and

the pharmacological performance

of the drug
 Objectives of size reduction…

 Following administration of the medicine, the dosage

form should release the drug into solution at the
optimum rate
This depends on several factors, one of which will
be the particle size of drug as predicted from the
Noyes and Whitney equation
 Influence of material properties on size reduction

Crack propagation and toughness

 Size reduction or comminution is carried out by a process of

crack propagation, whereby localized stresses produce strains in

the particles which are large enough to cause bond rupture and

thus propagate the crack

Once a crack is initiated the crack tip propagates at a velocity

approaching 40% of the speed of sound in the solid

 Thus a cascade effect occurs and an almost instantaneous brittle

fracture occurs
Influence of material properties on size reduction…
 Not all materials exhibit this type of brittle behavior

and can resist fracture at much larger stresses

 This occurs because these tougher materials can

undergo plastic flow, which allows strain energy

relaxation without crack propagation

When plastic flow occurs, atoms or molecules slip

over one another and this process of deformation

requires energy
Influence of material properties on size reduction…

Surface hardness
 The hardness of a material can be described by its
position in Mohs’ scale
 Mohs' scale is a table of materials
 at the top of which is diamond with Mohs hardness >7
 at the bottom of the table with Mohs hardness <3 is talc
Influence of material properties on size reduction…
 Generally, harder materials are more difficult to
comminute and can lead to abrasive wear of metal
mill parts, which then cause product contamination

 Conversely, materials with a large elastic component,

such as rubber, are extremely soft yet difficult to size
reduce
 Influence of material properties on size reduction…
 Some materials are capable of absorbing large amounts of energy

through elastic and plastic deformation without crack initiation and

propagation
 Materials (e.g. rubber) which are soft under ambient conditions

 waxy substances (e.g. stearic acid) which soften when heated,

and
 'sticky' materials (e.g. gums)

Can be more easily size reduced by lowering the

temperature below the glass transition point of the material

Influence of material properties on size reduction…

Moisture content
 In general, a moisture content below 5% is suitable
for dry grinding and greater than 50% if wet grinding
is to be carried out
 Energy requirements of size reduction process
 Only a very small amount of the energy put into a

comminution operation actually effects size reduction and

other lost in d/f ways

 Elastic deformation of particles

 plastic deformation of particles without fracture

 deformation to initiate cracks that cause fracture

 deformation of metal machine parts

 interparticle friction and particle-machine wall friction

 heat, sound and vibration

 Energy requirements of size reduction process…
 There are hypotheses and theories that attempt to relate
energy input to the degree of size reduction produced
Rittinger's hypothesis
 the energy, E, used in a size-reduction process, is

proportional to the new surface area produced, Sn

 where Si; is the initial surface area and KR is Rittinger's

constant of energy per unit area

 Energy requirements of size reduction process…

Kick's theory
 states that the energy used in fracturing a set of particles
of equivalent shape is proportional to the ratio of the
change in size, or:

 where KKis Kick's constant of energy per unit mass,

 di is the initial particle diameter and

 dn the new particle diameter

 Energy requirements of size reduction process…
Bond's theory
 states that the energy used in crack propagation is proportional
to the new crack length produced, which is often related to the
change in particle dimensions

 KB is known as Bond's work index and represents the variation

in material properties and size-reduction methods with

dimensions of energy per unit mass
 Energy requirements of size reduction process…

 When designing a milling process for a given particle, the

most appropriate energy relationship will be required in order

to calculate energy consumptions

 the most appropriate values for n are 1 for coarse particles > 1 μm

where Kick-type behaviour occurs,

 2 for Rittinger-type milling of particles <1 μm.

 The third value of n = 3/2 is the average of these two extremes and

indicates a possible solution where neither Kick's nor Rittinger's

theory is appropriate
Influence of size reduction on size distribution

 During a size-reduction process the particles of feed

material will be broken down and particles in

different size ranges undergo different amounts of
breakage
This uneven milling leads to a change in the size

distribution
Particle-size separation
 Introduction
o The aim of size separation is to classify powders into

separate particle size ranges or 'cuts', and is

therefore linked to particle-size analysis
However, an important difference exists between

size separation, and size analysis: following size

separation, powder in a given particle size range is
available for separate handling or subsequent
processing
 Size-separation efficiency
o The efficiency with which a powder can be separated into
different particle size ranges is related to
 the particle and fluid properties and the separation method
used

o Separation efficiency is determined as a function of the

effectiveness of a given process in separating particles into
oversize and undersize fractions
 Size-separation efficiency

 In a continuous size-separation process

the production of oversize and undersize
powder streams from a single feed
stream can be represented as

o where Ff, fo and fu are functions of the

mass flow rates of the feed material,

oversize product and undersize product
streams, respectively
 Size-separation efficiency

o If the separation process is 100% efficient then all

oversize material will end up in the oversize product

stream and all undersize material will end up in the

undersize product stream

 Size-separation efficiency

o Considering the oversize material,

 a given powder feed stream will contain a
certain proportion of true oversize
material, δf,
 the oversize product stream will contain a
fraction, δ0, of true oversize particles, and
 the undersize stream will contain a
fraction, δU, of true oversize material
 Size-separation efficiency
 The efficiency of the separation of oversize material,
can be determined by considering the relationship
between mass flow rates of feed and product streams
and the fractional contributions of true size grade in
the streams
 Size-separation efficiency
o the efficiency, Eo, of a size-separation process for
oversize material in the oversize stream is given by

o the separation efficiency for undersize material in the

undersize stream is given by
 Size-separation efficiency

 The total efficiency, Et, for the whole size separation

process is given by

 Separation efficiency determination is often referred

to as 'grade efficiency'
 Size-separation efficiency
o In some cases a knowledge of grade efficiency is
insufficient
o A 'sharpness index' can be used to quantify the
sharpness of cut-off in a given size range
o A sharpness index, S, can be determined in several
different ways, for example by taking the percentage
values from a grade efficiency curve at the 25 and 75%
levels (L)
 Size-separation efficiency

or at other percentile points, such as the 10 and 90%

levels:
 Size-separation methods
Size separation by sieving
 There may be some differences in the methods used to

achieve size separation from that of size analysis

 it is more common and more suitable to use stainless

steel meshes for size separation where as for size

analysis are brass and bronze
 The sieves used for size separation are often larger in

area than those used for size analysis

 Size-separation methods

Separation ranges
 Size-separation methods

Principles of operation

Agitation methods

o Size separation is achieved by

 electrically induced oscillation or

 mechanically induced vibration of the sieve meshes, or

 by gyration, in which sieves are fitted to a flexible

mounting which is connected to an out-of balance flywheel

 Size-separation methods

Brushing methods

 A brush is used to reorientate particles on the surface of a

sieve and prevent apertures becoming blocked

 A single brush can be rotated about the midpoint of a circular

sieve

 For large-scale processing, a horizontal cylindrical sieve, is

employed, with a spiral brush rotating about its longitudinal

axis
 Size-separation methods

Centrifugal methods
 Particles are thrown outwards on to a vertical
cylindrical sieve under the action of a high-speed
rotor inside the cylinder

 The current of air created by the rotor movement also

assists in sieving, especially where very fine powders
are being processed
 Size-separation methods

o Wet sieving can also be used to effect size separation

and is generally more efficient than dry sieving
methods.
 Standards for powders based on sieving

o Standards for powders used

pharmaceutically are
provided in pharmacopoeia
o indicate that 'the degree of

coarseness or fineness of a
powder is differentiated and
expressed by reference to the
nominal mesh aperture size of
the sieves used'
 Size separation by fluid classification

Sedimentation methods
Separation ranges
 Size separation by fluid classification
Principles of operation(Size separation by sedimentation)
o Size separation by sedimentation utilizes the differences in settling

velocities of particles with different diameters, and these can be

related according to Stokes‘ equations
o One of the simplest forms of sedimentation classification uses a

chamber containing a suspension of solid particles in a liquid

(usually water)
o After predetermined times, particles less than a given diameter can

be recovered using a pipette placed a fixed distance below the

surface of the liquid.
 Size separation by fluid classification
 Alternatively, a single separation can be carried out
simply by removing the upper layer of suspension fluid
after the desired time.
Disadvantages of these simple methods are that they
are batch processes and
discrete particle fractions cannot be collected, as
samples contain every particle diameter up to the
limiting diameter and not specific size ranges
 Size separation by fluid classification

Alternative techniques
 An alternative technique is to use
a continuous settling chamber
so that particles in suspension
enter a shallow container
 The particle Reynolds' number of
the system is below
approximately 0.2, so that
streamline flow occurs
 Size separation by fluid classification
 Particles entering at the top of the chamber are acted
upon by a driving force which can be divided into
two components:
a horizontal component of particle velocity which
is equal to the suspension fluid velocity, and
a vertical component which corresponds to Stokes'
settling velocity
 Size separation by fluid classification
 These two components are constant for each particle,
so that the settling path will be given by a curve
whose slope depends on particle diameter
 The coarsest particles will have the steepest settling
paths and will sediment closest to the inlet
 the finest particles with low Stokes velocity
component will have the shallowest settling paths and
will sediment furthest from the fluid suspension feed
stream
 Size separation by fluid classification
 In order to increase the driving force of sedimentation,
centrifugal methods can be used to separate particles of
different sizes in the submicrometre region

 Simple cylindrical centrifuges can be used to remove

single size cuts from a fluid stream

 but where separation is required over a wider number of

size ranges multiple-chamber centrifuges can be used.
 Size separation by fluid classification
o In multiple-chamber

centrifuges there are a

number of spinning

cylinders of different

diameters set inside a closed

chamber

o Fine particles in liquid

suspension are fed in

through the top of the inner

 Size separation by fluid classification

 the particles are acted on by two component forces

 The coarsest particles will have the shallowest

trajectories and will be carried to the walls of the inner

cylinder

 All other particles remain entrained in the liquid and

flow out at the base of the cylinder and via a baffle or

weir into the top of the next cylinder out, where the

centrifugal force is higher

Size separation by fluid classification
 Elutriation methods
Separation ranges
 Elutriation methods
Principles of operation
o Elutriation is a technique in which the
fluid flows in an opposite direction to
the sedimentation movement, so that in
gravitational elutriators particles move
vertically downwards while the fluid
travels vertically upwards
 Elutriation methods
 Particles are divided into different size fractions
depending on the velocity of the fluid
If the upward velocity of the fluid is less than the
settling velocity of the particle, sedimentation occurs
and the particle moves downwards against the flow
of fluid
If the settling velocity of the particle is less than the
upward fluid velocity, the particle moves upwards
with the fluid flow
 Elutriation methods
o Separation of powders into several size

fractions can be effected by using a

number of elutriators connected in

series

o The suspension is fed into the bottom of

the narrowest column, overflowing from

the top into the bottom of the next widest

column and so on

o As the column diameter increases the

fluid velocity decreases and therefore

particles of decreasing size will be

separated.
 Elutriation methods
Alternative techniques
o Air may be used as the counterflow
fluid in place of water for elutriation
of soluble particles into different size
ranges
o There are several types of air
elutriator
o One type is upward airflow elutriator
o Particles are held on a supporting
mesh through which air is drawn
 Elutriation methods

o Classification occurs within a very short distance of

the mesh and any particles remaining entrained in the
air stream are accelerated to a collecting chamber by
passage through a conical section of tube.
 Elutriation methods
o It may be required to separate finer particles than can be

achieved using gravitational elutriation, and in these cases

counterflow centrifugal methods can be used
o Particles in air suspension are fed into a rotating hollow torus

at high speed, tangential to the outer wall

o Coarse particles move outwards to the walls against the

inwardly spiralling air flow, which leaves the elutriator in the

centre
o The desired particle size fraction can be separated by selecting

the appropriate airflow rate and rotor speed

 Cyclone methods
Separation range
 Cyclone methods
Principle of operation
o The most common type is the reverse-

flow cyclone

o particles in air or liquid suspension are

often introduced tangentially into the

cylindrical upper section of the

cyclone, where the relatively high fluid

velocity produces a vortex that throws

solid particles out on to the walls of the

cyclone
 Cyclone methods
 The particles are forced down the conical section of the cyclone
under the influence of the fluid flow - gravity interactions are a
relatively insignificant mechanism in this process
 At the tip of the conical section the vortex of fluid is above the
critical velocity at which it can escape through the narrow outlet
and forms an inner vortex which travels back up the cyclone and
out through a central outlet or vortex finder
 Coarser particles separate from the fluid stream and fall out of the
cyclone through the dust outlet, whereas finer particles remain
entrained in the fluid stream and leave the cyclone through the
vortex finder
 Mixing
Definition and objective
 Mixing is a process where two or more components are
treated so as to lie as nearly as possible in contact with
a particle of each of the other component

 The process that results in a randomization of a

dissimilar particle within a system
 The objective of mixing is to produce:
A blend of solid particles (powder mixing)
A suspension of an insoluble solid in liquid
A mixture of immiscible liquids (Emulsions)
A dispersion of particles as semisolid as in the
preparation of ointments or pastes
Types of mixing
 There are three types of mixing based on their behavior

Positive Mixing
 Is a process where by substances will in time completely mix

spontaneously and no energy needs to be used for this to occur

 Irreversible mixing occur

E.g.: miscible liquids, gases

These types of material do not create any problem in

mixing
 Negative Mixing
 Are mixtures that require work for their formation and
the components of which will separate unless work is
done by stirring to keep them dispersed.
 If segregation occurs quickly, then energy must be
continuously input to keep the components adequately
dispersed
 e.g. with a suspension formulation in less viscous
liquids
 Mixing...
 With some negative mixtures the components tend to

separate very slowly

 e.g. emulsions, creams and viscous suspensions

 Negative mixtures are generally
more difficult to form and maintain and
require a higher degree of mixing efficiency than
do positive mixtures
 Neutral Mixing
 Work must be done to mix them initially but usually
there is no tendency for de-mixing to occur
spontaneously
 They are static in their behavior
i.e. the components of such products don’t have any
tendency to mix spontaneously but once mixed they
do not separate out easily
E.g. pastes, ointments and mixed powders
 Mixing...
 The type of mixture might change during processing
For example
If the viscosity increases the mixture may
change from a negative to a neutral mixture
If the particle size, degree of wetting or liquid
surface tension changes the mixture type may
also change
 Process of mixing

 To simplify discussion of the principles of the mixing

process, a situation will be considered

where there are equal quantities of two powdered

components of the same size, shape and density that

are required to be mixed

the only difference between them being their

color
 Mixing process
 Ideal situation or 'perfect mix’ be

produced

 when each particle lies as closely as

possible in contact with a particle of

the other component

 Powder mixing is a 'chance' process the

odds against ideal mixing are so great

that for practical purposes it can be
considered impossible
 Mixing process

 In practice, the best type of mix likely to be obtained is

random mix
a mix where the probability of selecting a particular
type of particle is the same at all positions in the mix,
and is equal to the proportion of such particles in the
total mix
 Scale of scrutiny
 Mixing process produces a large 'bulk' of mixture that

is subsequently subdivided into individual dose units

 Each dosage unit should contains the correct

amount/concentration of active component(s)

 It is the weight or volume of the dosage unit that

dictates how closely the mix must be

examined/analysed to ensure it contains the correct

dose/concentration
 Scale of scrutiny
 Scale of scrutiny

 The number of particles in the scale of scrutiny will

depend on the sample weight, particle size and

particle density
 will increase as the sample weight increases and the

particle size and density decrease

 Another important factor to consider when carrying

out a mixing process is the proportion of the active

component in the dosage form/scale of scrutiny

 Scale of scrutiny

 The lower the proportion of active component present in

the mixture the more difficult it is to achieve an

acceptably low deviation in active content

 The more particles there are present in a unit dose/scale

of scrutiny the lower the deviation in content

 One way of reducing the deviation would be to

increase number of particles in the scale of scrutiny

by reducing particle size

 Mathematical treatment of the mixing process
o Simplified statistical approach
illustrate some of the factors that influence dose
variation within a batch of a dosage form, and
demonstrates the difficulties encountered with
potent drugs
 Mathematical treatment of the mixing process
 The variation in the proportion of a component in samples

taken from the random mix can be calculated from:

(1)

 where SD is the standard deviation in the proportion of the

component in the samples

 p is the proportion of the component in the total mix and

 n is the total number of particles in the sample

 Mathematical treatment of the mixing process…
 As p is decreased the value of the content standard
deviation decreases, which may lead to the incorrect
conclusion that it is beneficial to have a low
proportion of the active component
 Mathematical treatment of the mixing process

o A more useful parameter to determine is the

percentage coefficient of variation (%CV), which

indicates the average deviation as a percentage of

the mean amount of active component in the

samples

%CV = (content standard deviation/mean content) x

100 (2)
The value of %CV will increase as p decreases
 Mathematical treatment of the mixing process

Example
1. consider the situation where n=100 000 and P=0.5
and calculate SD and %CV
2. If p is reduced to 0.001 and n remains at 100 000,
what is SD and %CV
 Evaluation of the degree of mixing
o Manufacturers require some means of monitoring a

mixing process for a variety of reasons

 To indicate the degree/extent of mixing

 To follow a mixing process

 To indicate when sufficient mixing has occurred

 To assess the efficiency of a mixer

 To determine the mixing time required for a

particular process
Factors affecting mixing

Mixing affected by:

 Particle size

 Percolation segregation : Smaller particles tend to fall

through the voids between larger ones and so move to the

bottom of the mass, during vibration, stirring or pouring

 Trajectory segregation : larger particles will tend to have

greater kinetic energy imparted to them, therefore move

greater distances than smaller particles

 Factors affecting mixing…

 Elutriation segregation /dusting out: very small

particles ('dust') in a mix may tend to be 'blown'

upwards by turbulent air currents as the mass

tumbles, and remain suspended in the air

 When the mixer is stopped or material discharge is

complete, these particles will sediment and

subsequently form a layer on top of the coarser

particles
 Factors affecting mixing…

 Density:
 If components are of different density, the more dense
material will have a tendency to move downwards
even if the particle sizes are similar.
 The effect of density on percolation segregation may
be potentiated if the more dense particles are also
smaller
 Factors affecting mixing…
o Shape

 Spherical particles exhibit the greatest flowability and are

therefore more easily mixed, but they also segregate more

easily than non-spherical particles

 Irregularly particles may become interlocked, reducing the

tendency to segregate once mixing has occurred

 Non-spherical particles will also have a greater surface area to

weight ratio , which will tend to decrease segregation by

increasing any cohesive effects

 Factors affecting mixing…
 Length of time for which mixing occur
 Non-segregating mixes will improve with continued
increases in mixing time
 This may not, however, occur for segregating mixes,
where there is often an optimum mixing time
 This is because the factors causing segregation generally
require longer to take effect than the time needed to produce a
reasonable degree of mixing.
 Approaches to minimize segregation
o Selection of particular size fractions to achieve drug and
excipients of the same narrow particle size range
o Milling of components (size reduction)
 to reduce the particle size range (this may need to be
followed by a sieving stage to remove fines) or

 to ensure that all particles are below approximately

30 μm
 Approaches to minimize segregation

 Controlled crystallization during production of the

drug/excipients to give components of a particular

crystal shape or size range

 Selection of excipients which have a density similar

to the active component (s)

 Reduce the extent to which the powder mass is

subjected to vibration or movement after mixing

 Approaches to minimize segregation

 Use filling machine hoppers designed so that powder

residence time is minimized
 Use equipment where several operations can be
carried out without transferring the mix, e.g. a
fluidized-bed drier or a high-speed mixer/ granulator
for mixing and granulating
 Production of an 'ordered' mix
 Classification of mixing
 Based on the state of existence mixing can be classified into

Liquid Mixing
o Mixing of liquids and liquids
 Mixing of two miscible liquids  solution
 Mixing of two immiscible liquids  emulsion

o Mixing of liquids and solids

 Mixing of liquids and soluble solids  solution
 Mixing of liquids and insoluble solids  suspension
 Powder Mixing

 Neutral type of mixing in which two or more solid

substances are intermingled in a mixer by continuous

movement of the particles

 The degree of mixing will increase with the length

of time for which mixing is done

 Powder mixing is employed in formulation of

powders, capsules and tablets

 Classification of Mixing

Semisolid Mixing
 Many semisolids form neutral mixture because they
have no tendency to segregate but sedimentation
occur in certain circumstances
 Mixing mechanisms
Powder Mixing
o There are three main mechanisms by which powder
mixing occurs
convection
shear
diffusion
 Con't

Convective mixing

 arises when there is the transfer of relatively large groups

of particles from one part of the powder bed to another

 contributes mainly to the macroscopic mixing of powder

mixtures and

 tends to produce a large degree of mixing fairly and quickly

 E.g. Occur when a mixer blade or paddle moves through

the mix
 Shear mixing
 occurs when a layer of material moves/flows over another
layer
due to the removal of a mass by convective mixing
creating an unstable shear/slip plane, which causes the
powder bed to collapse.
 It may also occur in high shear mixers or tumbling mixers,
where the action of the mixer induces velocity gradients
within the powder bed and hence 'shearing' of one layer
over another
 Con't

Diffusive mixing

 When a powder bed is forced to move or flow it will 'dilate',

i.e. the volume occupied by the bed will increase

 Under these circumstances there is the potential for the

particles to fall under gravity, through the voids created

 diffusive mixing

 Diffusive mixing having the potential to produce a random

mix

 generally results in a low rate of mixing

 Con't

 All three mixing mechanisms are likely to occur in a

mixing operation
 Which one predominates and the extent to which each
occurs will depend on
the mixer type
mixing process conditions (mixer load, speed etc.)
the flowability of the powder components
 Con't
Liquid mixing
 The three main mechanisms by which liquids are
mixed are
bulk transport
turbulent mixing and
molecular diffusion
Bulk transport
 Movement of a relatively large portion of the material
being mixed from one location in the system to another
constitutes

 tends to produce a large degree of mixing fairly

quickly,
but leaves the liquid within the moving material
unmixed
Turbulent mixing
o arises from the haphazard movement of molecules when
forced to move in a turbulent manner
o The constant changes in speed and direction of
movement means that induced turbulence is a highly
effective mechanism for mixing.
o Within a turbulent fluid there are, however, small groups
of molecules moving together as a unit, referred to as
eddies
 Con't

 Turbulent mixing alone may leave

small unmixed areas within the eddies and
in areas near the container surface which will exhibit
streamlined flow
Molecular diffusion
 The primary mechanism for mixing at molecular level
 will occur with miscible fluids wherever a concentration
gradient exists and will eventually produce a well-
mixed product
 considerable time may be required if this is the only
mixing mechanism
 Con't
 In most mixers all three mechanisms will occur, bulk
transport and turbulence arising from the movement
of a stirrer or mixer paddle set at a suitable speed and
diffusive mixing from concentration gradient
 Mixing Equipments
In small scale
 Ointment tile and spatula
 Mortar and pestle

In industrial scales
 Impeller/propeller mixer
 Tumbling mixer (V-shape, Y cone, etc)
 Fluidized bed mixer
Impellers/propellers
 A propeller has angled blades,
which cause the fluid to
circulate in both an axial and a
radial direction

 The distinction b/n impellers

type is made on the basis of
type of flow pattern they
produce or on the basis of the
shape of the blades
 Con't
 A vortex forms when the centrifugal force imparted to the

liquid by the propeller blades causes it to back up around the

sides of the vessel and create a depression at the shaft

 As the speed of rotation is increased air may be sucked into

the fluid by the formation of a vortex; this can cause oxidation

 vortex is suppressed by fitting vertical baffles into the vessel

 divert the rotating fluid from its circular path into the

centre of the vessel, where the vortex would otherwise

form
Tumbling mixer
o Common type of mixer consists of a container of one

of several geometric forms, which is mounted so that

it can be rotated about an axis
o Mixer of this type takes the form of cylinder, cubes,

or hexagonal cylinders and may be rotated about any

axis depending on the manufacturer
o Eg: - V-shape, Y-shape
 When rotated, material is alternately collected in the
bottom of the V and then split into two portions when
the V is inverted.

 This is effective b/c the Convective and shear which

occur in tumbling mixers generally accelerated by
this design.
Con't
 The efficiency of tumbling mixer is highly

dependent on the speed of rotation

 Too slow => doesn’t produce desired intense tumbling

nor does it generate rapid shear rates

 Too rapid => produce centrifugal force sufficient to hold

powder to the side of mixer and reduce efficiency

 The optimum rate of rotation depends on the size

and shape of the tumbler and also on the type of

material being mixed.
 Con't
o Other types of mixers
Agitator mixers
Fluidized-bed mixers
Turbine mixers
Planetary mixers
Sigma-blade mixer
Factors considered to select type of mixer
 The physical property of material to be mixed

E.g.: density, Viscosity, Miscibility

 Economic consideration
time required for mixing
power consumption
the cost of the equipment and its maintenance
 Drying
Definition
 Drying is the removal of a liquid from a material by
the application of heat and
 is accomplished by the transfer a liquid from a
surface into an unsaturated vapor phase
 Drying involves both heat and mass transfer
 Drying and evaporation are distinguishable merely by

the relative quantities of liquid removed from the solid

 To be considered drying, the final product must be a

solid
 To achieve this there must be a source of heat and a

sink of vapor thus produced

Purpose of drying
 To prepare granules
 To prepare certain product such as powdered extracts,
dried anhydrous lactose and dried vegetable drugs
 To reduce bulk and weight, lowering the cost of
transportation and storage
 To preserve products
 To minimize chemical reaction
 To facilitate size reduction
 Factors affecting drying
o The vapor carrying capacity of the air or gas stream
passing over the drying material
o This carrying capacity determines
the rate of drying
the extent of drying
 Con't

 Driving force

 Humidity differential => diffusion of moisture

 Temperature differential => for heat transfer

 air flow and inlet air temperature

 rate of convection and radiation heat transfer

 Thickness of the material being dried

 Air velocity

Increased air velocity speed up rate of drying by

increasing coefficient of mass transfer

 Dehumidification of inlet air

 Molecular and capillary structure of the solid affects

drying
 The drying of wet solids

Moisture content of wet solids

 The moisture content of a wet solid is expressed as
kilograms of moisture associated with 1 kg of the
moisture-free or 'bone-dry' solid
 It is sometimes calculated as a percentage moisture
content
%MC = weight of water in sample X100
Weight of dry sample
 Con't
Total moisture content
 the total amount of liquid associated with a wet solid

 The easily removable water is known as the free

moisture content (unbound water) and

 the moisture which is more difficult to remove

in practice is the equilibrium moisture content

(Bound water)
 Con't
Equilibrium moisture content
 The moisture content present in a solid under steady-
state ambient conditions

 Its value changes with temperature, humidity and the

nature of the solid
 Con't
Moisture content of air
o the moisture content expressed as kg of water per kg
of 'bone-dry‘ air
o Unlike RH, Moisture content is not altered by change
of temperature alone, only if further moisture is taken
up by the air
Loss on drying (LOD)
 Is an expression of moisture content on a wet weight
basis which is calculated as follows.
% LOD = Wt. of water in sample X 100
Total wt. of wet sample
 A weighed sample is placed on the balance and

allowed to dry until it is at constant weight and the

water lost by evaporation is calculated by subtracting
dry weight of sample from the wet weight of sample.

Wt of water in sample = wt of wet sample – wt of

dry sample

Note: It is assumed that there are no other volatile

materials in sample.
Example
 If exactly 5 gram of moist solid is brought to a
constant dry weight of 3 gram, compute
%MC
%LOD
 Con't
MC = [(5-3)/3] x100% = 66.7%
LOD = [(5-3)/5] x100 = 40%
 Con't
Loss of water from wet solids
 unbound water is easily lost by evaporation until the
equilibrium moisture content of the solid is reached
 The only way to reduce the moisture content of the solid
is to reduce the relative humidity of the ambient air
 On a large scale with an air-conditioning system
 On a small scale with desiccators
 Con't
o Moisture may be regained very quickly from the

atmosphere if a 'dry' solid is exposed to ambient air

it is unnecessary to 'overdry' a product

o If a low residual moisture content is necessary because

of hydrolytic instability in the material

the dried product must be efficiently sealed
 TYPES OF DRYING METHOD

 When considering how to dry a material, the following

points should be considered:
Heat sensitivity of the material being dried
Physical characteristics of the material
The necessity for asepsis
Nature of the liquid to be removed
The scale of the operation
Available sources of heat (steam, electrical).
 Con't

 The general principles for efficient drying

Large surface area for heat transfer

Efficient heat transfer per unit area

Efficient mass transfer of evaporated water through

any surrounding boundary layers

Efficient vapour removal, i.e. low relative humidity

air at adequate velocity

 Convective drying of wet solids

Fixed (or static) bed convective drying

 There is no relative movement among the solid particles

being dried but there may be bulk motion of the entire

drying mass

Only a fraction of the total number of particles is

directly exposed to heat source

 The exposed surface can be increased by decreasing the

thickness of the bed

a) Tray Dryers
 shelf, cabinet, or

compartment dryers

 consists of cabinet in which

the material to be dried is

spread on tiers of trays

 Con't
Tray dryer classified into

 Direct tray dryer: in which heating is accomplished by

the forced circulation of large volume of heated air

 Indirect tray dryer: utilizes heated shelves or radiant

heat sources inside drying chamber to evaporate the

moisture which is then removed by either vacuum

pump or small amount of circulating gas

 Con't
 To achieve uniform drying there must be a constant
temperature and a uniform air flow over the material
being dried
 Con't
b) Truck dryer

o A truck dryer is one in which the trays are loaded on

truck (racks equipped with wheels) which can be

rolled into and out of the drying cabinet

o Truck dryer preferred over tray dryer because it

offers greater convenience in loading and unloading

o Both tray and truck dryers are batch procedures

 Con't
c) Tunnel and Convey dryers
 Tunnel and conveyor dryer are another static bed dryer
which are semi continuous and continuous respectively

 Conveyor dryer is more suitable to handle large

volume of materials
 Dynamic convective driers

Fluidized bed dryers

 It comprises of a top fluidizing chamber and a bottom air
distribution chamber separated by a special designed
perforated plate
 System in which the solid particles are partially
suspended in an upward moving gas stream
 The feed of wet materials is dried by intimate contact
with hot air when the material is in a fluidized state
 Con't
 Classified into

Vertical fluidized bed dryer

Horizontal vibrating conveyor dryer

 Con't

Advantages of fluidized-bed drying

 Efficient heat and mass transfer give high drying rates

 The fluidized state of the bed ensures that drying occurs from the

surface of all the individual particles and not just from the surface

of the bed.

Hence, most of the drying will be at constant rate and the

failing-rate period is very short

 The temperature of a fluidized bed is uniform throughout and can

be controlled precisely.
 Con't
 The turbulence in a fluidized bed causes some attrition
to the surface of the granule.
 This produces a more spherical free-flowing
product
 The containers can be mobile, making handling and
movement around the production area simple and so
reducing labour costs
 Short drying times mean that the unit has a high output
 Con't
Disadvantages of fluidized-bed drying

 The turbulence of the fluidized state may cause excessive

attrition of some materials, with damage to some granules

and the production of too much dust

 Fine particles may become entrained in the fluidizing air

and must be collected by bag filters

 The vigorous movement of particles in hot dry air can

lead to the generation of static electricity charges

 Conductive drying of wet solids
 the wet solid is in thermal contact with a hot surface and

the bulk of heat transfer occurs by conduction

Vacuum oven
 The vacuum oven consists of a jacketed vessel

sufficiently stout in construction to withstand vacuum

within the oven and steam pressure in the jacket
 The supports for the shelves form part of the jacket,

giving a larger area for conduction heat transfer.

 Con't
 The oven is connected through a

condenser and liquid receiver to a

vacuum pump

 If the liquid to be removed is water

and the pump is of the ejector type

that can handle water vapour, the

pump can be connected directly to the

oven.
 Con't

 The main advantage of a vacuum oven is that drying

takes place at a low temperature, and as there is little
air present there is minimum risk of oxidation

 The temperature of the drying solid will rise to the

steam or water temperature at the end of the drying
 Con't
Vacuum tumbling drier

 One design of tumbler drier resembles a large Y-cone

mixer

 The vessel is steam jacketed and is connected to a

vacuum

 Heat transfer rates in this equipment are much higher

than in a conventional vacuum oven

 Radiation drying of wet solids

Radiant heat transmission

 Heat transmission by radiation differs from heat transfer

by conduction or convection in that no transfer medium

need be present
 Heat energy in the form of radiation can cross empty

space or travel through the atmosphere virtually without

loss
 If it falls on a body capable of absorbing it then it appears as heat
 Con't

Use of infrared radiation

 Infrared heating has been used in the past to dry

pharmaceutical products such as wet granules

 It suffers from the disadvantage that it is absorbed very

quickly and does not penetrate far into the wet mass

 The surface layers dry quickly and the absorption of further

energy then raises the temperature of the dry material to a

high value, which is often detrimental to the product.

 Con't
The use of microwave radiation
 Microwave radiation in the wavelength range 10 nm to
1 nm penetrates much better than IR radiation

 Microwave driers are finding some application in the

pharmaceutical industry
 Con't

Generation and action of microwaves

 Microwaves are produced by an electronic device

known as a magnetron

 Microwave energy can be reflected down a rectangular

duct (termed a waveguide)

 The penetration of microwaves into the wet product is

so good that heat is generated uniformly within the

solid
 Con't
 When microwaves fall on substances of suitable
electronic structure (small polar molecules, such as
water)
the electrons in the molecule attempt to resonate in
sympathy with the radiation and the resulting
molecular 'friction' results in the generation of heat
 Dry solids do not resonate as well as water, so further
heating may be avoided once the water is removed
Advantages of microwave drying

 It provides rapid drying at fairly low temperatures

 The thermal efficiency is high, as the drier casing and the air remain

cool

 The bed is stationary, avoiding the problems of dust and attrition.

 Solute migration is reduced as there is uniform heating of the wet

mass.

 Equipment is highly efficient and refined

 Granulation end-point is possible by measuring the residual

microwave energy
 Con't
Disadvantages of microwave drying
 The batch size of commercial production microwave
driers is smaller than those available for fluidized-bed
driers.

 Care must be taken to shield operators from the

microwave radiation
 Driers for dilute solutions and suspensions

 The objective of these driers is

– to spread the liquid to a large surface area for heat and

mass transfer and

– to provide an effective means of collecting the dry solid

 Two main types are used

– the first spreading the liquid to a thin film on to a drum

– the second dispersing the liquid to a spray of small

droplets
 Con't
Drum drier (film drier)

The drum dryer consists of a drum,

0.75-1.5 m in diameter which heated

internally, usually by steam and rotate

on its longitudinal axis

The liquid is applied to the surface

and spread to a film

The product is scraped from the

surface of drum by means of knife

 Con't
Advantages of the drum drier

The method gives rapid drying

The equipment is compact, occupying much less space

than the spray-drier

Heating time is short, being only a few seconds

The drum can be enclosed in a vacuum jacket, enabling

the temperature of drying to be reduced

The product is obtained in flake form

 Con't
 The only disadvantage is that operating conditions are
critical and it is necessary to impose careful control on
feed rate, film thickness, speed of drum rotation and
drum temperature.
 Con't

Spray dryer
 provides a large surface area for heat and mass transfer by
atomizing the liquid to small droplets
The droplets are sprayed into a stream of hot air so
that each droplet dries to solid particles
 The sprays are produced by either rotary or nozzle
atomizer
 Con't

 The character of the particles is controlled by

the droplet size, and so the type of atomizer is

important

 Jet atomizers are easily blocked by rapid

evaporation and deposition of solid on the

nozzle, and the droplet size is likely to vary

 This is not the case with rotary types of atomizer
 Con't…

 Spray-dried products are easily recognizable, being

uniform in appearance.

 The particles have a characteristic shape, in the form

of hollow spheres sometimes with a small hole

Advantages of the spray drying process

 Millions of small droplets give a large SA for heat and mass

transfer

 the droplets do not attain a high temperature

 The characteristic particle form gives the product rapid

dissolution

 The resulting powder will have a uniform and controllable particle

size.

 The product is free flowing, with almost spherical particles

 Labour costs are low

 Con't
Disadvantages of the spray drying process
 The equipment is very bulky, and with the ancillary
equipment is expensive
 The overall thermal efficiency is rather low
 Con't

Freeze-drying
 lyophilisation or cryodesiccation or drying by sublimation

 Involves freezing the material and then reducing the

surrounding pressure to allow the frozen water in the material to

sublime

 The theory and practice of freeze drying is based on an

understanding and application of the phase diagram for the

water system
 The phase diagram for water

In a typical phase diagram, the boundary

between gas and liquid runs from the triple point
to the critical point. Freeze-drying (S to G) brings
the system around the triple point, avoiding the
direct liquid-gas transition seen in ordinary drying
(L to G).
 Con't

Application of the phase diagram of water to freeze

drying

• the solution must be cooled to well below the normal

freezing temperature for pure water

 b/c of the depression of the freezing point caused by the

presence of dissolved solutes

o It is usual to work in the range -10 to -30°C

 Con't
 Sublimation can only occur at the frozen surface and is
a slow process
the SA must be increased and the liquid thickness prior to
freezing be reduced in order to reduce the thickness of ice
to be sublimated

 At low pressures large volumes of water vapour are

produced which must be rapidly removed to prevent the
pressure rising above the triple point pressure
 Freeze drying equipment
 Freeze dryers are composed of four basic components

o Chamber for vacuum drying

 Continuous or batch operation

o Vacuum source
 Vacuum achieved by pumps, steam ejectors

o Heat source
 Heat provided by conduction or radiation

o Vapor removal system


 Con't
Stages of the freeze drying process
Freezing stage
 The liquid material is frozen before the application of
vacuum to avoid frothing

 several methods are used to produce a large frozen

surface
 Con't

Shell freezing

Employed for fairly large volumes

The bottles are rotated slowly and almost

horizontally in a refrigerated bath

The liquid freezes in a thin shell around the

inner circumference of the bottle.

Freezing is slow and large ice crystals form

 Con't
Vertical spin freezing
 In vertical spin freezing the bottles are spun
individually in a vertical position so that centrifugal
force forms a circumferential layer of solution, which
is cooled by a blast of cold air.

 The solution supercools and freezes rapidly, with the

formation of small ice crystals
 Con't
Centrifugal evaporative freezing
 prevents foaming when a vacuum is applied
 The vacuum causes boiling at room temperature and this
removes so much latent heat that the solution cools
quickly and snap freezes
 About 20% of the water is removed prior to freeze
drying and there is no need for refrigeration.
 Ampoules are usually frozen in this way
 Con't
Vacuum application stage
 The containers and the frozen material must be

connected to a vacuum source sufficient to drop the

pressure below the triple point and remove the large
volumes of low-pressure vapour formed during
drying
 An excess vacuum is normal in practice, to ensure

that the product in question is below its triple point

 Con't
Sublimation stage
 Heat of sublimation must be supplied.

 Under these conditions the ice slowly sublimes, leaving a

porous solid which still contains about 0.5% moisture after
primary drying

 During the primary drying, the latent heat of sublimation

must be provided
 Con't
 Heat transfer is critical: insufficient heat input prolongs the

process and excess heat will cause melting

 Prefrozen bottles are placed in individually heated cylinders,

or are connected to a manifold when heat can be taken from

the atmosphere.

 Shelf-frozen materials are heated from the drier shelf

 ampoules may be left on the centrifuge head or may be

placed on a manifold, but in either case heat from the

atmosphere is sufficient
 Con't

Vapour removal
 The vapour formed must be continually removed to avoid a

pressure rise that would stop sublimation.

 To reduce the pressure sufficiently it is necessary to use

efficient vacuum pumps, usually two-stage rotary pumps on

the small scale, and ejector pumps on the large scale

 On the small scale, vapour is absorbed by a desiccant or is

cooled in a small condenser with solid carbon dioxide

 Mechanically refrigerated condensers are used on the large

 Con't

Secondary drying

 The removal of residual moisture at the end of

primary drying is performed by raising the

temperature of the solid to as high as 50 or 60°C.

 A high temperature is permissible for many

materials because the small amount of moisture

remaining is not sufficient to cause spoilage.

 Con't
Packaging
 Attention must be paid to packaging freeze-dried

products to ensure protection from moisture

 Containers should be closed without contacting the

atmosphere , if possible, and ampoules, for example, are

sealed on the manifold while still under vacuum
 Con't
Advantages

 Drying takes place at very low temperatures, so that enzyme

action is inhibited and chemical decomposition, particularly

hydrolysis, is minimized

 the product is light and porous

 The porous form of the product gives ready solubility

 Salts do not concentrate and denature proteins, as occurs

with other drying methods.

 there is little contact with air, and oxidation is minimized

 Con't

Disadvantages

 The porosity, ready solubility and complete dryness

yield a very hygroscopic product.

 The process is very slow and uses complicated plant,

which is very expensive.

It is limited to certain types of valuable products

which cannot be dried by any other means

 Con't

Uses of freeze drying

 The method is used for products that cannot be dried by
any other heat method.

biological products, for example some antibiotics,

blood products, vaccines, enzyme preparations and
microbiological cultures
BLESS YOU!!!!