PHARMACEUTICAL ENGINEERING

SPH2272

ASSIGNMENT NO. 1

MIXING

Name ID NumberAhda Sabila Bt. Eddy Yusuf 012014052233

Annisa Hayatunnufus 012014052438Chan Choon Jet 012014052225

Iffah Umaimah Bt. Rosli 012014052231Muhammad Shafiq bin Shahidan 012014052491Nurul 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 ContentsI. 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 of mixing

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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Division of 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 Powder mixing

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 mixingThere 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 mixersAgitator 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) Shear mixersShear 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.

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