Industrial Pharmacy I
Text books
The science of dosage form design (ed. Aulton)
The theory and practice of industrial pharmacy (ed. Leon
LACHMAN)
Main topics:
Mixing
Milling
Drying
Clarification and filtration
Sterilization
Preformulation study
Pharmaceutcial dosage form development.
Mixing
Mixing is one of the most common pharmaceutical
operations.
Mixing may be defined as the process in which two or
more than two components in a separate or roughly
mixed condition are treated in such a way so that each
particle of any one ingredient lies as nearly as possible
to the adjacent particles of other ingredients or
components
This process may involve the mixing of gases, liquids
or solids in any possible combination
examples of large scale mixing practiced in pharmacy
1. Mixing of powders in varying proportions prior to
granulation or tabletting
2. Dry mixing of the materials for direct compression in
tablets
3. Dry blending of powders in capsules and compound
powders (insufflations).
4. Blending of powders in cosmetics in the preparation of
face powders, tooth powders
5. Dissolution of soluble solids in viscous liquids for
dispensing in soft capsules and in the preparation of syrups
6. Mixing of two immiscible liquids for preparation of
emulsions
solids are divided
Depending on the flow properties of materials:
1- Cohesive materials - These are characterized by
their resistance to flow through openings for e.g. wet
clay.
2- Noncohesive materials - These materials flow
readily such as grain, dry sand, plastic chips etc.
Objectives of mixing
Mixing can be done for the following reasons:
•1- To ensure that there is uniformity of composition
between the mixed ingredients which may be
determined by taking samples from the bulk material
and analyzing them, which should represent overall
composition of the mixture.
•2-To initiate or to enhance the physical or chemical
reactions e.g. diffusion, dissolution etc.
mixing is carried out to obtain following
type of products
• When two or more than two miscible liquids are
mixed together, this results in to a solution known as
true solution.
• When two immiscible liquids are mixed in the
presence of an emulsifying agent, an emulsion is
produced.
• When a solid is dissolved in a vehicle, a solution is
obtained
• When an insoluble solid is mixed with a vehicle, a
suspension is obtained.
• When a solid or liquid is mixed with a semisolid
base, an ointment or a suppository is produced.
• When two or more than two solid substances are
mixed together, a powder is obtained which when
filled into capsule shell is known as capsules and when
compressed under heavy pressure is called tablet.
Types of Mixtures
Mixtures may be classified as follows:
-1. Positive mixtures
-2. Negative mixtures
-3. Neutral mixtures
I. Positive Mixtures – These types of mixtures are formed
when two or more than two gases or miscible liquids
are mixed together by means of diffusion process. In
this case no energy is required provided the time
allowed for solution formation is sufficient.
II. Negative Mixtures – These types of mixtures are formed
when insoluble solids are mixed with a vehicle to form a
suspension or when two immiscible liquids are mixed to
form an emulsion. These mixtures are more difficult to
prepare and require a higher degree of mixing with external
force as there is tendency of the components of these
mixtures separate out unless they are continuously stirred.
III. Neutral Mixtures – Many pharmaceutical products such
as pastes, ointments and mixed powders are the examples
of neutral mixtures. They are static in their behavior. The
components of such products do not have any tendency to
mix spontaneously but once mixed, they do not separate
out easily.
Rate of Mixing
In the early stages of mixing, the rate of mixing is very
fast because the mixing particles change their path of
circulation quickly and find themselves in different
environment
whereas at the end of the process rate of mixing
reaches to almost zero because the particles do not
find different environment.
Evaluation of mixing for 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.
Sampling for test
Evaluation methods of mixing:
1. Electrical conductivity of the
samples
2. Specific gravity of the samples,
3. X-ray fluorescence,
4. Emission spectroscopy,
5. Flame spectrometry
6. Radioactive tracer method.
7. The scale of segregation represents average value of
the lumps present.
8. The intensity of segregation is expressed as the
measurement of the variation in composition among
the various portions of the mixture.
In practical degree of mixing is defined by its
standard deviation σ which is equal to (xy/N)1/2 where
x and y are the proportions of the components and N is
the number of particle in the sample taken.
Liquid Mixing
Flow characteristics
Liquid may generally be classified as Newtonian or
non-Newtonian
In Newtonian flow of liquid, the rate of shear is
proportional to the applied stress (linear relationship)
such as water, glycerin, chloroform, syrups
Non-Newtonian liquids are categorized as plastic,
peudoplastic and dilatant flow exhibit nonlinear
relationship such as emulsions, suspensions and
semisolids.
Liquid mixing may be divided according to
properties
1. Mixing of liquids and liquids
a) Mixing of two miscible liquids
b) Mixing of two immiscible liquids
2. Mixing of liquids and solids
a) Mixing of liquids and soluble solids
b) Mixing of liquids and insoluble solids
Mixing of two miscible liquids
mixing of two miscible liquids is quite easy and occur
by diffusion.
does not create any problem
if the liquids are not readily miscible or if they have
very different viscosities then turbulence may be
created in the liquids to be mixed.
Turbulence is a function of velocity gradient between
two adjacent layers of a liquid which cause eddies or
vortex formation.
Mixing of two immiscible liquids
eg. of such type of mixing is the extraction of
penicillin
When two immiscible liquids are mixed together in
the presence of an emulsifying agent an emulsion is
produced.
For the production of a stable emulsion, the mixing
must be very efficient i.e. continuous
2(a) Mixing of liquids and soluble solids
when insoluble solids are mixed with a liquid a
suspension is produced which is an unstable system
Thus a suspending agent is required to produce a
stable suspension.
On small scale, suspensions may be prepared in a
pestle and mortar.
three velocity components
The movement of the liquid at any point in the vessel
will have three velocity components
Radial components, acting in a direction vertical to
the impeller shaft.
• A longitudinal (Axial)component, acting parallel to
the impeller shaft.
• A tangential component, acting in a direction that is
a tangent to the circle of rotation round the impeller
shaft.
Liquid flow pattern
A satisfactory flow pattern will depend on the
balance of the 3 components.
If the tangential component is dominant, a vortex
forms and may deepen until it reaches the
impeller, when aeration occurs.
If the longitudinal component is inadequate,
liquids and solids may rotate in layers without
mixing.
factors effect on flow pattern
The form of the impeller and its position:
for example, whether it is high or low in the
vessel, whether mounted centrally or to one
side, or whether the shaft is vertical or
inclined.
Container shape and the presence of baffles
will have an effect also.
Mixing mechanism of liquids
Usually more than one of these processes is operative in
practical mixing situations.
1.bulk transport,
2.turbulent flow,
3.laminar flow, and
4. molecular diffusion
Bulk transport
the movement of a relatively large portion of the
material being mixed from one location in the system
to another constitutes bulk transport.
For bulk transport to be effective it must result in a
rearrangement of the various portions of the material
to be mixed.
This can be accomplished by means of paddles,
revolving blades, or other devices within the mixer
Turbulent Mixing
Characterized by the fluid having different
instantaneous velocities at the same instant of time.
With turbulence, these directional components
fluctuate randomly about their individual mean values,
as does the velocity itself.
Turbulent flow can be conveniently visualized as a
composite of eddies of various sizes
An eddy is defined as a portion of fluid moving as a unit
in a direction often contrary to that of the general flow
The size distribution of eddies within a turbulent region
is referred to as the scale of turbulence
3. Laminar mixing
Fluid flow characterized by long, smooth flow
currents, mainly in the same direction as the bulk of
the flow with little interaction between them.
Laminar flow is frequently encountered when highly
viscous liquids are being processed.
When two dissimilar liquids are mixed through
laminar flow, the shear that is generated stretches the
interface between them.
4. Molecular diffusion
The primary mechanism responsible for mixing at the
molecular level is diffusion resulting from the thermal
motion of the molecules.
The process is described quantitatively in terms of
Fick’s law of diffusion: Dm/dt = -DA dc/dx
Dm/dt = rate of transport of mass
A= area of interface
D=diffusion coefficient
dc/dx=concentration gradient
the scale of segregation
Through the mixing of fluids, the scale of segregation
is reduced (in regions of bulk transport and turbulent
mixing) with a resulting increase in the molecular
diffusion when reach the end of the mixing operation
and the intensity of segregation become zero
Liquid mixing Equipments
A. Batch Mixing
A system for batch mixing commonly consists of two
primary components:
Tank or container suitable to hold the material being
mixed, and
Supplying energy to the system to cause reasonable
rapid mixing.
Power may be supplied to the fluid mass by means of an
impeller, air stream, or liquid jet.
1.Impeller
The types of impeller depend on the basis of the shape
and pitch of the blades. Three basic type of flow may
be produced: radial, axial, and tangential (Figure).
Three basic type of flow may be produced: radial, axial, and tangential
(Figure). These may occur singly or in various combinations.
RADIAL FLOW: The movement of a fluid generally from the center of
the tank to the wall.
AXIAL FLOW: The movement of a fluid generally from the top to the
bottom of the tank.
types of impeller
There are three types of impeller that include:
Propeller, Paddles and Turbines.
a. Propellers mixers
A three or four-bladed Axial Flow Impeller, having helically
shaped blades. Although some tangential flow occurs, they
induced primary effect with axial flow for low viscosity of
liquid
Disadvantages: Propellers are not effective with liquids of
viscosity greater than 200 cP for example, glycerin and castor
oil.
b. Paddle mixers
Paddle mixers – A two-flat bladed Impeller whose
diameter is usually greater than 60% of the tank
diameter and rotate at low speed of 100 rpm. or less.
The blades have a large surface area in relation to the
container. Effectively mix the viscous liquids or semi-
solids.
Uses of paddle mixers: paddles are used in the
manufacture of antacid suspensions, anti-diarrheal
mixtures such as bismuth-kaolin mixture.
Advantage: Since mixers with paddle-impellers have
low speed, vortex formation is not possible with such
mixers.
c. Turbine mixers
Turbine mixers – turbine mixers consist of a circular
disc impeller to which a number of short, straight or
curved blades are attached (usually 4 or more).
These mixers differ from propellers in that they are
rotated at a lower speed than propellers and the ratio of
the impeller and container diameter is also low.
they are used for mixing liquids of high viscosity and has
a special application in the preparation of emulsions.
Baffles are often used to prevent vortexes.
Uses of turbine mixers: Turbines are effective for high
viscous solutions.
Advantage: Turbines give greater shearing forces than
propellers
Blending capabilities of different
impellers
BAFFLE:
BAFFLE:
A stationary device usually installed at, or near tank walls to
prevent liquid swirl and promote vertical flow in the vessel.
Baffles are typically introduced to prevent vortex formation
and convert tangential (rotational) flow into axial (vertical)
flow
Baffles are always used in turbulent flow systems (low
viscosity fluids)
Baffles are not used in laminar flow (high viscosity fluids)
Typically four baffles are used (occasionally three) in fully
baffled tanks
A gap between the baffles and the wall is introduced to
prevent stagnation behind the baffles and accumulation of
material (e.g., solids)
2.Air jets (gas)
They are effective mixing evices for certain liquids that
have characteristics ads low viscosity, nonfoaming,
unreactivity with gas and reasonably nonvolatile.
The air jets are usually arranged to induce an upward
fluid flow in the tube.
This flow tends to circulate fluid in the vertical tank.
Turbulent Draft tube
region
Air jet
3.Fluid jets
The fluids are pumped through the nozzles arranged
to permit good circulation of material throughout the
tank.
For mixing, the fluid jets behave somewhat like
propellers in that they generate turbulent flow in the
direction of their axes. However they induced
tangential flow as do propellers.
4. Sonic and ultrasonic devices
Application of intense vibration by causing
equipment producing sonic or ultrasonic
frequencies, can effect vibration in some
cases causing emulsification.
These equipments are widely used for large-
scale emulsification and are known as
rapisonic homogenizers.
factors to be considered in the choice of
ultrasonic
The amount of emulsion to be prepared.
• The rheological characteristics of the final
emulsion.
• The need to incorporate ingredients such as
powders.
• The operation temperature and
• Whether the processing is batch wise or a
continuous operation.
B. Continuous Mixing
It is often desirable when very large volumes of
material are to be handled. It can be accomplished
essentially in two ways:
1. In a tube or pipe through which the material
flows and in which there is very little recirculation,
or,
2. In a chamber in which a considerable amount of
holdup and recirculation occur
A, baffled pipe mixer; B, mixing chamber
Mixer Selection
One of the most important considerations in any mixing
problem is equipment selection. Factors that must be
taken in consideration include:
the physical properties of the materials to be mixed
such as density, viscosity, and miscibility,
Economic considerations regarding processing (e.g.
time and power), and cost of the equipment.
II. Solid-Solid Mixing (Powder mixing)
Powder mixing importance
Product with too low an active ingredient will be
ineffective and a product with too high active
ingredient may be lethal.
good solid mixing to overcome the tendency of the
particles to segregate.
Segregation occurs when a system contains particles
with different sizes, densities, etc.
The degree of mixing will increase with the length of
time for which mixing is requires.
Powder mixing is a neutral type of mixing.
Mechanism of Powder mixing
solid mixing is achieved by a combination of one or
more of the following mechanisms:
Convective mixing – In convective mixing transfer of
groups of particles takes place from one location to
another by means of blades or paddles of the machine.
Shear mixing – In shear mixing, slip planes are set up
within the mass of material
Diffusive mixing – During this mechanism, mixing
occurs by diffusion process by random movement of
particles within a powder bed and cause them to
change their relative positions.
Physical properties affecting powder mixing
1. Material density: If the components are of different density, the denser
material will sink through the lighter one, the effect of which will depend
on the relative positions of the material in the mixer.
2. Particle size: Variation in particle size can lead to segregation also since
smaller particles can fall through the voids between the larger particles. It is
easier to mix two powders having approximately the same particle size.
3. Particle shape: The ideal particle is spherical in shape and increase of
irregularity results in increase the difficulty of mixing.
4. Particle attraction: Some particles exert attractive forces due to
electrostatic charge on them.
5. Proportions of materials to be mixed: The proportions of materials to
be mixed play a very important role in powder mixing. It is easy to mix the
powders if they are available in equal quantities.
Equipments for solid mixing
Batch mixing
There are several types of solids-mixing machines. Mainly divided
into 2 classes:
1. Rotating containers (Tumbling mixers)
In this machines the container rotate cause tumbling of the
materials.
2. Stationary container
In these machines, there is internal device rotates within a
stationary container.
1. Rotating containers (Tumbling mixers)
mixer consists of a container of different shapes, which is mounted to rotate
about an axis called tumbler and included twin-shell (V-shape mixer), cubic,
cylindrical, and double cone
Figure: types of tumblers shown mounted on a common shaft, A, twin-shell; B,
cubic; C, cylindrical; D, double cone.
There is also baffled tumbler like double cone revolving
around long axis with baffle
The efficiency of tumblers is highly dependent on the
speed of rotation.
The optimum rate of rotation (common in range of 30 to
100 rpm) depends on the size and shape of the tumbler
and also on the type of material being mixed.
2. Stationary container
This class of mixer employs moving screws, paddles or blades .
1. Ribbon mixer (Figure) is more popular consists of a horizontal
cylindric tank usually opening at the top and fitted with helical blades.
The blades are mounted on the shaft through the long axis of the tank
and often of both right- and left-hand twist.
It is accommodated to fibrous and sticky materials.
2.Helical flight mixer (vertical screw mixer-Figure)
consists of vertical screw that rotate about its own axis.
It is primarily suitable for free-flowing dry solids.
3.Hammer mill operates by swinging hammerheads
attached to a rotor that rotates at high speed inside a
hardened casing. It is roughly mixed the materials by
breaking up the aggregates.
4.Muller mixer consists of the pan with rotating
turret which the pan and muller turret rotate in
opposite directions. The muller is useful for mixing of
materials requiring certain types of aggregate
breakdown.
Batch muller: shows pan rotates clockwise, muller turret
rotates counter clockwise.
Continuous mixing
Although batch mixing has been the predominant method of mixing
solids, consideration is being given to the use of continuous mixing in
many industries.
Continuous-mixing operations are analogous to those of liquid mixers.
A continuous muller mixer has been developed for continuous mixer
III. Mixing of semi-solids
The mechanisms involved in mixing semi solids
depend on the character of the material which may
show considerable variation.
Three most commonly used semi solid mixers are
(a) Sigma blade mixer – Contains two blades which
operate in a mixing vessel which has a double trough
shape, the blades moving at different speeds towards
each other. Used for products like granulation masses
and ointments.
(b) Triple-roller mill
The differential speed and narrow clearance between
the rollers develop high shear over small volumes of
material.
The roller mills are generally used to grind and
complete the homogeneity of ointments.
(c) Planetary mixers
– it utilizes a mixing arm rotating about its own axis
and also about a common axis usually the centre of the
mixing wheel.
The blades provide the kneading action, while the
narrow passage between the blades and the wall of the
can provides shear.
