5 November, 2015 This is a part of our assignment in which we are told to pick one of the pharmaceutical engineering topics and make a paperwork + presentation out of it. Presentation slide can be found in: http://www.slideshare.net/annisahayatunnufus/power-point-mixing-pharmaceutical-engineering Recorded presentation can be found in: https://youtu.be/O4QvWmW37YA Students of Bachelor of Pharmacy Management & Science University

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PHARMACEUTICAL ENGINEERING
SPH2272
ASSIGNMENT NO. 1
MIXING
Name ID Number
Ahda Sabila Bt. Eddy Yusuf 012014052233
Annisa Hayatunnufus 012014052438
Chan Choon Jet 012014052225
Iffah Umaimah Bt. Rosli 012014052231
Muhammad Shafiq bin Shahidan 012014052491
Nurul Nabihah Bt. Abdul Rahman 012014052223
Programme : Bachelor of Pharmacy
DOS : November 3rd
, 2015
Lecturer : Dr. Jiyauddin Khan & Mr. Mohd. Kaleemullah

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Table of Contents
I. INTRODUCTION..................................................................................................3
II. OBJECTIVE ..........................................................................................................3
III. Types of mixing ......................................................................................................4
IV. Mechanism of mixing.............................................................................................5
V. Division of mixing ..................................................................................................6
1. Liquid Mixing................................................................................................................ 6
2. Powder mixing............................................................................................................ 10
3. Semi Solid................................................................................................................... 16

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INTRODUCTION
Mixing is an operation 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 ingredient. Mixing may be performed
between any two phases ranging from mobile liquids to viscous liquids, semi solids
and solids.
OBJECTIVE
1. To produce simple physical mixture:
This may be simply the production of a blend of two or more miscible liquids
or two or more uniformly divided solids. In pharmaceutical practice the degree of
mixing must commonly be of high order as many such mixtures are dilutions of a
potent substances, and correct dosage must be ensured.
2. To produce physical change:
Here mixing may aim at producing a change that is physical as clear from
chemical, e.g. solution of a soluble substance. In such cases, a lower efficiency of
mixing with often be acceptable because mixing merely accelerates a process that
could occur by diffusion, without agitation.
3. To produce dispersion:
This includes dispersion of two immiscible liquids to form an emulsion or
dispersion of a solid in a liquid to give a suspension or paste. Usually good mixing
is required to ensure stability.
4. To promote chemical Reaction:
Mixing usually encourage (and control at the same time) a chemical reaction.
So ensuring uniform product, e.g. products where accurate adjustment to pH is
required and the degree of mixing will depend on the process.

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Types ofmixing
Generally mixing can be divided into 3 types that are different fundamentally in their
behaviours, which are;
i) Positive mixtures
These types of mixture formed when two or more gases or miscible liquids are irreversibly
mixed together by diffusion process. In the case of positive mixtures, no energy is required
provided the time allowed for the solution to mix is sufficient. Besides, these types of
materials will not create any problem during mixing process.
ii) Negative mixtures
Negative 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. The components
of these mixtures have high tendency to separate out they are not continuously being stirred.
Thus, these mixtures are more difficult to prepare as they need high degree of mixing with
external force.
iii) Neutral mixtures
Pharmaceutical products such as pastes, ointments, and mixed powders are the examples of
neutral mixture. They are stable in behavior. The components of these mixtures do not have
tendency to mix spontaneously but once mixed, they do not separate out easily.

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Mechanism of mixing
In general, mixing can be done by applying one or more of the following mechanisms;
i. Convective mixing
In convective mixing, a process of transferring groups of particles in bulk takes
place from one part of powder bed to another. Convective mixing is also known as
macro mixing.
ii. Shear mixing
During this process, shear forces are created within the mass of the material by
using agitator arm or a blast of air.
iii. Diffusive mixing
In diffusive mixing, the materials are tilted to ensure the upper layer to slip and
diffusion of individual particles will take place at the new developed surfaces.
Diffusive mixing is also known as micro mixing.

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Divisionof mixing
1. Liquid Mixing
There are two stages occur in liquid mixing which are;
a) Localized mixing, in which shear is applied to the particles of the liquid.
b) A general movement which sufficient to take all the particles of the materials
through the shearing zone to produce a uniform product.
In addition, liquid mixing can be divided into two following subgroups;
1. Mixing of liquids and liquids
a) Mixing of two miscible liquids (homogenous mixtures)
These mixtures are produced through diffusion process by simple stirring or
shaking. Electric stirrer may also be used if the liquids are not readily miscible or
if they have different viscosities. Example of homogenous mixture is solution.
b) Mixing of two immiscible liquids (heterogeneous mixture)
When two immiscible liquids are mixed using emulsifying agent, an emulsion is
produced. In order to produce stable emulsion, the mixing must be efficient which
required continuous mixing because the components tend to separate out if they
are not mix continuously.
2. Mixing of liquids and solids
a) Mixing of liquids and soluble solids (homogenous mixtures)
During this process, soluble solids are dissolved in suitable liquids by simple
stirring to produce a solution.
b) Mixing of liquids and insoluble solids (heterogeneous mixtures)
When insoluble solids are dissolve in liquids, a liquid suspension will be produced
which is an unstable product. The ingredients of suspension might separate out
when allowed to stand for some time. Thus, it needs a suspending agent to
produce a stable suspension.

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The movement of the liquid at any point in the vessel will have three velocity components
and the complete flow pattern will depend upon variations in these three components in
different parts of the vessel.
The three velocity components are;
1. Radial components, acting in a direction vertical to the impeller shaft.
2. Longitudinal component, acting parallel to the impeller shaft.
3. Tangential component, acting in a direction that is a tangent to the circle of rotation
round the impeller shaft.
Mixing equipment
1. Shaker mixers
 The material present in the containers is agitated either by an oscillatory (for small scale
mixing) or by a rotary movement (large scale mixing).
 It has limited use in industry.
2. Propeller mixers
 Used for mixing relatively low viscosity dispersions like thicker solutions and
maintaining contents in suspension.
 The most widely used form of mixers for liquids of low viscosity.
 Mixing is in a short time
 Operate at a very high speed which is up to 8000 r.p.m.
Advantage:
 Used when high mixing capacity is needed.
 More effective in handling liquids having a viscosity of about 2.0 Pascal/second.
Disadvantages
 Not effective with liquids of viscosity greater than 5 pascal/second such as glycerin and
castor

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3. Paddle mixers
 Used as impellers that consisting of flat blades attached to a vertical shaft and rotating at low
speed (100rpm).
 Effectively mix the viscous liquids or semi-solids.
 A variety of paddle mixers having different shapes and sizes by depending on the nature
and viscosity of the product are available for use in industries.
 Used in the manufacture of antacid suspensions and anti-diarrhoeal mixtures such as
bismuth-kaolin mixture
Advantages
 Vortex formation is not possible.
 It has low speed.
 The width of the impellers is not more than 1/2 to 2/3 of the diameter of the vessel and
less power which is can improves the circulation and increases mixing efficiency.
 For more viscous liquids the paddle having number of blades fitted closely to the surface
of vessel to avoid dead spots and deposited solids.
Disadvantages
 Mixing of the suspensions is poor, thus, baffled tanks are required.
4. Turbine mixers
 It is consist of a circular disc impeller to which a number of short, straight or curved
blades are attached.
 They are rotated at a lower speed than propellers and the ratio of the impeller and
container diameter is also low.
 The former produces greater shear forces than propellers.
 Therefore they are used for mixing liquids of high viscosity and have a special
application in the preparation of emulsions.
 Baffles are often used to prevent vortexes.

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Advantages:
 Effective for high viscous solutions with a wide range of viscosities up to 7,00
pascal/seconds.
 Give greater shearing forces than propellers.
 They are more suitable for preparation of emulsions.

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2. Powder mixing
Powder mixing is a process in which two or more solid substances are combined together
to produce a homogenous mixture or continuous movement of the particles. The main
objective of this mixing is to produce a bulk mixture which when divide into different doses,
every unit of divided doses must contain the correct proportion of each ingredient. It is
critical process because the quality of the final product and its attributes are derived by the
quality of the mixing. Improper mixing process results in non-homogenous product that lacks
of consistency like chemical composition, texture, flavor, color, particle size and the most
important is pharmacological effect.
Powder mixing is a neutral type of mixing. It is one of the most common operations
employed in pharmaceutical industries for the preparation of different types of formulations
such as powders, capsules and tablets. To provide good solid mixing, the phenomenon to be
avoided or overcome is the tendency of particles to segregate. Segregation is a process when
a system contains particles with a different sizes and densities that preferentially accumulate
into one area over another. For the example, fines particles will be accumulated at the bottom
while course particles will be accumulated at the top.
In general, for powder mixing, the following physical particle properties should be
considered. Mono size particles are easy to mix and provide a free flowing, but segregation
by size, density and rotational inertia are possible with free flowing powders possessing
differences of these properties. In other words, even fine particle or powder also can have a
problem when mixing together, this can be overcome by applying a proper technique and
suitable equipment for the process of mixing that will be discussed later. Besides, it is easier
to mix equal weights of two powders of similar fineness than to incorporate a small
proportion of a fine powder in a large mass of a coarse powder. Apart from density and
particle size, the stickiness of the components to be mixed is also important. It will take a
longer time to mix substance which is wet and sticky.

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Mechanism of Powdermixing
It has been generally accepted that in all the mixtures, solid mixing is achieved by a
combination of one or more of the following mechanisms:
Convective mixing – The mechanism of convective mixing is analogous to bulk transport in
fluid mixing. It can be done by an inversion of the powder bed, blades or paddle, revolving
screw and any method of moving relatively large mass of material from one part of the
powder bed to another
Shear mixing – In shear mixing, slip planes are set up within the mass of material. This will
produces relative displacement of two regions. These two regions will reduce the scale of
segregation by thinning the dissimilar layers. Thus reduces the scale of segregation.
Diffusive mixing – Diffusive mixing occur when random motion of particles within a
powder bed causes them to change position relative to one another. This exchange positions
by the single particle results in reduction of intensity of the segregation. It occurs at the
interfaces of dissimilar regions that are undergoing shear and therefore results from shear
mixing.

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Factors Affecting Solid Mixing
There are few factors that can influence the efficient of mixing and it may lead to non-
uniform distribution which can result in inaccurate dosage production. These factors include
the following:
1. Material Density
Variant density of materials will affect the efficacy of mixing as the denser
materials will sink to the bottom. To maximize the mixing, the denser materials place
at lower layer of mixer during the mixing process. By these the degree of mixing will
increase gradually until it reached equilibrium state.
2. Particle Size
Different particle sizes of substances also can cause segregation lead to non-
uniform distribution as smaller particles can fall through the voids between the lager
molecules. Besides that, in mixing process the particles might dilate and the greater
porosity of open packing allows a large particle to slip into void. Eventually result in
non-uniform distribution.
3. Particle Shapes
The particle which is in spherical shape are more easier to mix thus other
shape apart from this shape will also increase in difficulty during mixing process.
4. Particle Attraction
Some substances which the particle consists of electrostatic charge exert
properties of attraction force that hold surrounding particles. As result the mixing
process is not effective. But since these are surface properties, thus reducing the
particles size will produce better outcome.
5. Proportion of materials
The proportion of difference substances are one of the crucial factor that result
in the efficacy of mixing process. The mixing outcome will be great if the mass of
difference substances is equal. In other hand, if the efficacy will reduce as the mass
difference of substances increase. However, to ensure uniform mixing, the substance
should be mixed in ascending order of their weights.

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6. Mixer Volume
In mixing process, the mixer must reserve sufficient space for dilation of bed
during mixing process. By this , the substances are enable to mix uniformly and
increase the efficacy.
7. Mixing Mechanisms
The suitable shear force and a convective movement is require for the mixer to
ensure that the bulk of material passes through entire area.
8. Mixing Time
The degree of mixing usually will approach its limiting equilibrium value
asymptotically, thus the mixing time must target at the optimum time for mixing of
the substances situation to prevent present of segregation.
9. Handling of Mixed Powder
When the mixing is completed, the product is required to handle according to
standard procedure to minimize the risk of segregation. A common factor that causes
segregation is vibration throughout the handling, transport, or packaging. Thus, all
bulk powder should undergo remixed before it take into use.

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Equipments use for solid mixing
There are plenty of mixing equipments used by different industries for mixing.
Choosing the right mixing equipment can avoid unwanted result such as cross contamination,
dust formation, aggregation, and others. The most common used mixers are agitator mixer
and tumbling mixer.
i) Agitator Mixers
These mixers contain agitator arms which can create a pulling and kneading
action that can clear the material from the surface or mixing vessel. The fitting helical
blades in the agitator can provide an End to End movement during mixing. But the
disadvantage is the shear force isn’t high result in present of aggregates, thus addition
of perforated baffles is require to break the aggregates. These mixer are commonly
use for free flowing materials with uniform size and density.
Beside mechanical agitator, air movement can be use to mixing powder too.
Inside a vertical cylindrical vessel, the air blasts admitted from the base intermittent to
impart spiral movement within the vessel.
Figure. Agitator Mixer

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ii) Tumbling Mixer
The mechanism of this mixer is tilting the materials by rotating the vessel until
the angle of surface exceeds the origin angle when the surface layers particles will
slide to the bottom area. The simple form of tumbler mixer uses cylindrical vessels
which rotating on its horizontal axis, but the shear force is not high and only produce
slightly end-to-end movement. To overcome this problem, the tumbler mixer is
designed in other shapes to avoid the symmetry. For instance, double cone mixer and
v-blender.
For tumbler mixer, the speed of rotation is important as low speed will cause
gliding; high speed will cause rise of centrifuging. Thus the speed should maintain at
the correct speed where both of the materials is proper mixed. Besides that the method
of charging the materials also can affect the mixing efficacy. The standard method is
to add the ingredients together in intermingling streams.
Figure. Double cone mixer

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3. Semi Solid
Semi solid mixtures are lying between solid and liquid. It also can be defined as mixing the
insoluble powder and liquid.
Theory
1. Pellet and powder state.
 Small amount amount of liquid is added to a bulk of dry powder it cause the solid to ball
up and form small pellets.
 The pellets are embedded in a matrix of dry powder, which has a cushioning effect and
makes the pellets difficult to break up.
 The solid is free-flowing and rate of homogenization is low.
2. Pellet-State:
 Further addition of liquids results in conversion of all the dry powder to pellets.
 The mass has coarse granular appearance but the pellet do not cohere and agitation will
cause aggregates to break down into smaller granules.
 Homogenization is even lower than in the pellet and powder.
 This stage is for moistening powders for tablet granulation.
3.Plastic State:
 Liquid content is increased further, the character of the mixture changes markedly:
 aggregates of the material adhere,
 The granular appearance is lost,
 The mixture becomes more or less homogeneous and of a day-like consistency.
 Plastic properties are shown,
 The mixture being difficult to shear, flowing at low stresses but breaking under high
stresses. Homogenization can be achieved much more rapidly than in previous cases.
 This is the state obtained when making a pill-mass.

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4. Sticky State:
 Continual incorporation of liquid causes the mixture to attain the sticky state;
 The appearance becomes paste-like,
 The surface is shiny
 The mass adheres to the solid surfaces.
 The mass flow easily even under low stresses, but homogeneity is attained only slowly.
 Kaolin Poultice exemplifies the sticky state
5. Liquid State:
 Addition of liquids results in a decrease of consistency until a fluid state is reached.
 In this state the mixture flows under its own weight and will drain off vertical surfaces.
 The rate of homogenization is rapid.

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Mixing equipment
i) Agitator mixers
Agitator mixtures have two types, which are;
a) Sigma mixers
 Use two mixer blades. The two blades rotate s towards each other and operate in a
mixing vessel which has a double trough shape each blade fitting into a trough.
 The two blades rotate at a different speeds, one usually about the twice the speed of the
other, Resulting in a pulling of material and division
 The blade shape and difference in speed causes End-to-End movement.
 Can handle heaviest plastic materials such as pill masses, tablet granule mass and
ointments.
 To avoid entrapment of air, the sigma arm mixers can be enclosed and operated under
reduced pressure.
 The vessel may be jacketed for heating or cooling
Advantages
 Creates a minimum dead space during mixing.
 There is close tolerance between the blades and the sidewalls as well as the bottom of the
mixer shell.
Disadvantage:
 Sigma mixers work at a fixed speed.
b) Planetary mixers
 Used for mixing and beating for viscous and pasty materials,
 Still often used for basic operations of mixing and blending in pharmaceutical industry.
 Low speeds are used for dry blending
 Faster speeds for the kneading action required in wet granulation.
Advantage:
 Work at varying speeds.
 More useful for wet granulation

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Disadvantages
 Planetary mixers require high power.
 Mechanical heat is built up within the powder mix.
 Use is limited to batch work only
ii) Shearmixers
Shear mixtures also have two types, which are;
a) Colloidal mill
 Useful for milling, dispersing, homogenizing and breaking down of agglomerates in the
manufacture of food pastes, emulsions, coatings, ointments, creams, pulps, grease, etc.
 The main function is to ensure a breakdown of agglomerates or in the case of emulsions
to produce droplets of fine size around 1 micron.
 The materials must be supplied at such a rate that the space between the rotor and stator
is kept entirely filled with liquid.
 Used in the production of ointment, cream, gels and high viscous fluids for grinding,
dispersing and homogenizing in one operation.
Advantages
 Extremely fine particle distribution through optimal shear force.
 High capacity with minimal space requirements.
 Rapid handling and easy cleaning.
 Virtually unlimited application due to highly flexible homogenization system.
b) Triple roller mill
 Various types of roller mills consisting of one or more rollers are commonly used but
triple roller mill is preferred.
 It is fitted with three rollers which are composed of a hard abrasion-resistant material.
 They are fitted in such a way that they come in close contact with each other and rotate at
different speeds.
 The material which comes in-between the rollers is crushed and reduced in particle size.

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 The reduction in particle size depends on the gap between the rollers and difference in
their speeds.
 Advantages:
 The triple roller mill produces very uniform dispersion and is suitable for continuous
processes.
iii) Ultrasonic mixture
The material is subjected to ultrasonic vibrations and is applicable in the preparation of
emulsion.