Pharmaceutical Mixing

 

Theory of
mixing

Mixing may be defined as a unit operation in which two or more
components, in an unmixed or partially mixed state, are treated so that each
unit (particle, molecule etc.) of the components lies as nearly as possible in
contact with a unit of each of the other components.

IMPOTANCE
OF MIXING

1.       To make simple physical mixture

In the production of tablets, capsules,
sachets and dry powders two or more powders or granules are mixed.

2.       Physical change

Mixing may aim at producing a change that is
physical, for example the solution of a soluble substance. In case of
dissolving a solid in a solvent mixing will take place by diffusion but the
process will be slow. In this case agitation makes the process rapid.

3.       Dispersion

In case of emulsions and creams two immiscible
liquids are mixed where one liquid is dispersed into other. In suspension and
pastes solid particles are dispersed in a liquid by mixing.

4.      
Promotion
of reaction

Mixing encourages and controls a chemical
reaction, so ensuring uniform products

Objective
of Mixing

·        
To ensure uniformity.

·        
To initiate or to enhance the physical or
chemical reactions e.g. diffusion, dissolution etc.

·        
To make the pharmaceutical products such as
Tablets, Capsules, Suspensions, Emulsions, Pastes, Creams,

Factors
affecting Mixing

·        
Nature of
product: For effective mixing particle surface should be smooth.

·        
Particle  size: 
It  is  easier 
to  mix  powder 
of  same  particle 
size.  Increasing the difference
in particle size will lead to segregation.

·        
Particle
shape: Particle should be spherical in shape to get a uniform mixture.

·        
Particle  charge: 
some  particle  due 
to  electrostatic  charge 
exerts  attractive  force which leads to separation.

·        
Proportion
of material: It is easier to mix powders if available in same quantities.

·        
Relative
density: If the components have a different density, the denser material
will sink through lighter material.

·        
Viscosity: An
increase in viscosity reduces the extent of mixing.

·        
Surface
tension of liquids: High surface tension reduces the extension of
mixing.

·        
Temperature:
Temperature also affects the mixing because viscosity changes with increase in temperature.

·        
Mixture
volume: Mixing efficiency depends on mixture volume.

·        
Agitator
type: The shape, size, location and type of agitator also affect
affects the degree of mixing.

·        
Speed/rpm
of the impeller: Mixing at less rpm is more homogenous than at
higher rpm.

·        
Mixing
time: Mixing time is also very important for appropriate mixing.

Types of
Mixers

There are 3 types of mixtures:

1.       Positive mixtures:

·        
Formed from materials such as, gases or
miscible liquids. The materials mix spontaneously and irreversibly by diffusion

·        
No 
input  of  energy 
if  time  of 
mixing  is  unlimited, although time will be shorten if
energy is supplied.

·        
Generally, these materials do not show any
problems during mixing.

2.       Negative mixture

·        
Materials have the tendency to separate out
from each other. Energy needs to be supplied to keep components adequately
dispersed.

·        
Some separate faster, while for others, the
separation is slower.

·        
In a suspension, there is the dispersion of
solid in the solution (fast separation)

·        
Emulsions, creams and viscous suspension have
a slow separation.

·        
Are more difficult to be formed and require
high degree of mixing efficiency.

3.       Neutral mixture

·        
Are static in behavior.

·        
Neither mixing nor de-mixing occurs, unless
acted upon by an external system of forces.

·        
Examples are: a) Mixed powders b) Pastes c)
Ointments.

Difference
between Solid and Liquid Mixing

Mixing
of Semi-solid

If the solid is not too coarse, the liquid is not too viscous and
the percentage of solids is not too great, solids can be suspended in liquids
by the use of a propellers or a flat- bladed turbine in a cylindrical
container.

Apparatus
used:

·        
Planetary mixers and sigma blade mixers used
as agitator mixers

·        
Triple roller mills used as shear mixers-size
reduction

Planetary
Mixers

·        
Planetary mixers are one of the most widely
used mixers in the pharmaceutical industry. 

·        
In the pharmaceutical industry, the planetary
mixer is often used for basic operations of mixing, blending, and low-shear
granulation.

·        
This machine is also used in other industries
like cosmetics and personal care products, food, glass, cements, ceramics,
metal industry etc.

·        
The Planetary Mixer have two blades which
rotate on their own axes, while they orbit the mix vessel on a common axis.

·        
The blades continuously advance along the
periphery of the vessel, removing material from the vessel wall and transporting
it to the interior.

·        
These mixers are ideal for mixing and kneading
viscous pastes or putty-like materials.

Uses of
Planetary Mixer

·        
Planetary mixers are ideal for mixing of
pharmaceutical creams, ointments, ceramics, color and pigments, resins, ink, cosmetic
creams, herbal creams etc.

·        
Planetary mixers are also ideal for mixing and
kneading viscous pastes under atmospheric or vacuum conditions.

·        
Used in the mixing of viscous, heat sensitive
and cohesive pastes, dough and moist etc.

Sigma Blade Mixer

·        
Sigma blade mixer is a common form used to
handle The two blades rotate 
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 different speeds, one
usually about twice the speed of the other, resulting in a lateral pulling of
the material and divisions into two troughs, while the blade shape and
difference in speed causes end- to-end movement semi-solids of plastic
consistency.

Working of Sigma Blade Mixer 

·        
It works on the principle of shearing and
convective in action.

·        
This mixer is designed for mixing, blending
and kneading of medium and heavy on- flowing pastes.

·        
The impellers and bowls are accurately
machined to close tolerances, eliminating build up and providing high shear and
rapid distribution of materials.

Homogenization

It is a process in which coarse globules in emulsion are converted
into smaller globules of uniform composition, so that each measured dose has
the same composition.

Principle:
It
is based on the principle that when large globules in coarse emulsion are
passed under high pressure through a narrow orifice are broken into smaller
globules having a greater degree of uniformity and stability.

Simple
homogenizer

·        
It 
consist  of  a 
pump  that  rises 
the  pressure  of  the
dispersion to a range of 500-5000psi.

·        
And an orifice through which the fluid strikes
upon the homogenizing valve.

·        
The homogenizing valve is held on valve seat
by strong spring.

·        
As the pressure increases some of the
dispersion escapes b/w valve and valve seat, and instantly pressure is released
which subjects the product to intense turbulence and hydraulic shear.

Silverson
homogenizer

·        
In silverson homogenizer the droplets are
subjected to a high shear rates.

·        
It consists of an emulsifying head to which
blades are attached, surrounded by a fine mesh sieve made up of a stainless
steel.

·        
The emulsifying head is immersed in the liquid
to be emulsified.

·        
The head is rotated by a small motor at very
high speed.

·        
The liquids to be mixed are sucked through
fine mesh into the base of the emulsifying head where they are subjected to
vigorous mixing by high speed rotation of blades.

·        
The mixed material is then expelled with a
great force through the sieve band.

·        
This 
sucking  in  and 
forcing  out  sets 
up  a  pattern 
of circulation, and thus large size globules are reduced to small size
globules.

Triple Roller Mill

Construction
and working principle

·        
It is fitted with three rollers, made up of
hard abrasion-resistant materials.

·        
Rollers are fitted in such a way that they
come in close contact with each other and rotate at different speeds.

·        
A scraper is used to remove the final ointment
of smooth and uniform texture.

·        
The feed enters through a hopper.

·        
The material passes through hopper A, in
between rollers B and C where size reduction occurs.

·        
Then the ointment is passed between the
rollers C and D, where it is further reduced in size and a smooth mixture is
obtained.

·        
The gap between rollers C and D is usually
less than the gap between B and C.

·        
The smoothened material is continuously
removed from roller D by means of scraper E, from where it is collected in a
receiver.

Advantage

·        
Produces a uniform dispersion and a continuous
process

·        
Material used: Stainless steel to prevent
contamination

·        
Applications: To mix paint, chemicals, glass
coatings, pigments

Solid- Solid Mixing

Mechanism of Solid Mixing:

Convective mixing, in which group of particles move from one position to another. It also referred to as macro mixing.

Shear mixing, in this, shearing force is created within the mass of material by the use of a stirring arm or a burst of air.

Diffusive mixing, During this mixing, gravitational forces cause the upper layers of material to slip and random motion of individual particles take place on newly developed surfaces. Also known as micro mixing.

Apparatus used:

Solid mixing equipment

• Tumblers/Blenders

• Agitator mixers

• Continuous mixers

Tumblers/Blenders

• Twin- shell (v shape)

• Double cone

• Ribbon mixer

Double Cone Blender

Principles

·         The Double Cone Blenders design is most often used for the intimate dry blending of free flowing solids.

·         The solids being blended in these units can vary in bulk density and in percentage of the total mixture. Materials being blended are constantly being intermixed as the Double Cone rotates.

·         Normal cycle times are typically in the range of 10 minutes; however, they can be less depending on the difficulty of blending.

·         The slant double cone design eliminates dead spots which occasionally occur in conventional double cone mixer.

·         The conical shape at both end enables uniform mixing and easy discharge.

Construction

·         The conical shape at both ends enables uniform mixing and easy discharge.

·         The cone is statically balanced which protects the gear box and motor from any excessive load.

·         Powder is loaded into the cone through a wide opening and discharged through a butterfly or a Slide valve.

·         Depending upon the characteristic of the product, paddle type baffles can be provided on the shaft.

·         Flame proof electricals can be provided as optional.

·         ‘Slant’ design (off centre) CLIN CONE BLENDER are also used.

·         Dust free bin charging system ensures minimum material handling.

·         Mixing, uniform blending and de-agglomeration.

Working

·         Double Cone Blenders are most often used for dry blending of free flowing solids.

·         The solids being blended in these units can vary in bulk density and in percentage of the total mixture.

·         Materials being blended are constantly being intermixed as the Double Cone rotates.

Uses

·         Double cone blender is used to produce homogeneous solid-solid mixture.

·         It is used for effective mixing of powder and granules.

·         The double cone blender machine is of canonical shape at both ends that provide uniform mixing of granules in bulk.

Advantage

·         If fragile granules are to be blended, double cone blender is suitable because of minimum attrition.

·         They handle large capacities.

·         Easy to clean, load, and unload.

·         This equipment requires minimum maintenance.

Disadvantage

·         Double cone blender needs high head space for installation.

·         It is not suitable for fine particulate system or ingredients of large difference in particle size distribution, because not enough shear is applied.

·         If powders are free flowing, serial dilution is required for the addition of low dose active ingredients.

Twin Shell Blender or V Cone Blender

Principle

The mixing occurs due to tumbling motion.

Construction

·         Twin shell blenders have two connected blending shells that are connected to form a V-shape. Intensifier bars are designed to break up clumps of solids while the product is separated in the two ends of the V (when the twin shell blender is upside down).

·         It consists of horizontal shaft rotated about an axis causing the particles within the mixer to tumble over each other onto the mixture surface.

·         The charging of materials into the V-Blender is through either of the two ends.

·         Batches from 20 kg to 1 tonne can be loaded for mixing depending upon the size of the equipment’s.

Working

·         The V-Blender (also known as a twin shell blender) is one of the most commonly used tumbling blenders.

·         The material is loaded into the blender.

·         As the V-blender tumbles, the material continuously splits and recombines, with the mixing occurring as the material free-falls randomly inside the vessel.

·         Tumble blenders rely upon the action of gravity to cause the powder to cascade within a rotating vessel.

·         The recommended filled-up volume for the V-Blender is 50 to 60% of the total blender volume.

·         The product is collected from the bottom of V.

·         Normal blend times are typically in the range of 5 to 15 minutes depending on the properties of materials to be blended.

Advantage

V Cone Blender without Baffle-

·         Have large capacities

·         Easy handling

·         Minimum maintenance

V Cone Blender with Baffle-

·         Wet and dry mixing

·         High shearing force

·         Serial dilution is not required

Disadvantage

V Cone Blender without Baffle-

·         High head space for installation

·         Not suitable for fine particulate system

·         Serial dilution is required

V Cone Blender with Baffle-

·         Size reduction

·         Cleaning problem

·         Sealing problem

Uses

·         V blenders are used for dry mixing.

·         It provides efficient blending in short time.

·         This blender is often used for pharmaceuticals. But not suitable for very soft powders or granules.

·         V blenders are generally used for the food products, milk products, dry flavors, pesticides and herbicides, animal feed, spice blends, baby foods and cosmetics.

Ribbon Blender

Principle             

·         The mechanism of mixing is shear which is transferred by moving blades (ribbon shaped) in a fixed (non-movable) shell.

·         Convective mixing is the macro movement of large portions of the solids.

·         Convection mixing occurs when the solids are turned over along the horizontal axis of the agitator assembly.

·         High shear rates are effective in breaking lumps and aggregates. An equilibrium state of mixing can be achieved.

Construction

·         A ribbon blender consists of a U-shaped horizontal trough (shell) containing a double helical ribbon agitator that rotates within.

·         The agitator’s shaft is positioned in the center of the trough and has welded spokes on which the helical ribbons (also known as spirals) are welded.

·         The blades have both right- and left-hand twists.

·         The blades are connected to a fixed speed drive.

·         The ribbon blender is top loading with a bottom discharge port.

·         The trough can be closed with a lid.

Working   

·         Different powders are introduced from the top of the trough.

·         The outer ribbon of agitator moves the material from the ends to center while the inner ribbon moves the material from the center to end.

·         Through the fixed speed drive, ribbons are allowed to rotate.

·         Radial movement is achieved because of the rotational motion of the ribbons.

·         The difference in the peripheral speeds of the outer and inner ribbon results in axial movement, homogenous blending is achieved in short time.

·         The powders are lifted by a centrally located vertical screw and allowed to cascade to the bottom of the container (tumbling action).

·         The counter acting blades set up high shear and are effective in breaking up lumps or aggregates.

·         Helical blades move the powders from one end to another.

·         The blend is discharged from the bottom opening.

Advantage

·         The  Ribbon  mixer  has  price  savings  as  a  result  of  the  thermal  treatment  is accomplished among a similar time and liner being utilized for combining step.

·         Correct management of batch thermal treatment time. Low opportunity cost because the drying is accomplished within the same time and vessel getting used for transferring and combining.

·         One of the most important benefits of using a ribbon mixer for any industrial project is that it blends nearly any material completely with nearly no flaws.

·         This comes in handy for producing any material that must be mixed well like paint, concrete, and foods.

·         These mixers are usually utilized in bakeries that require to blend large amounts of ingredients at only once.

·         They will additionally mix materials fairly quickly, although the ribbons themselves inch.

·         Finally, the common ribbon mixer features a very large trough, thus it’s ideal for big projects.

·         High shear is also applied by exploitation perforated baffles that create a rubbing and breakdown aggregates. Headroom needs less aera.

·         Protect the motor and ribbon mixer from overload.

·         Once the load is just too massive to the drum and rotates, the operating liquid is ejected from the liquid plug to separate the operating machine and therefore the load, in order that the motor and instrumentality won’t be broken once beginning and overloading.

·         The speed distinction caused by the impact is going to be mitigated by coupling.

Disadvantage

·         The hydraulic mechanical device isn’t loaded with the electrical converter generally, and may not modify the rotating speed of the ribbon mixer effectively, because the loading of hydraulic couplings is simple to make multiple transfer mechanical energy, leading to power consumption, thus it can’t improve the start-up performance of the ribbon mixer.

·         It is a poor mixer as a result of the movement of particles is two dimensional.

·         Shearing action is a smaller amount than in planetary mixer.

·         It has a set speed drive.

·         Rate  of  mixing  is  greater  at  the  surface,  causing  local  differences  in  mixture composition.

·         Attrition of particles may occur at the wall due to the higher forces present there.

·         Prone to dead spots, especially near the discharge valve, and along the central axis.

·         There aren’t many downsides to using a ribbon mixer to combine ingredients. the sole major disadvantage that you simply may realize is that a ribbon mixer takes large amounts of power to work properly, thus you must positively detain mind your energy desires if you’re about to use one in every of these machines.

Uses

·         Ribbon blender is used to mix finely divided solids, wet solid mass, sticky and plastic solids.

·         Uniform size and density material can be easily mixed.

·         It is used for liquid-solid and solid-solid mixing.

Mechanism of Liquid Mixing

Mechanism of liquid mixing are

Bulk transport: It is the movement of large portion of material from one location to another location. The movement is done
by rotating blades or paddles.

Turbulent mixing: In this mixing is due to turbulence. Turbulence is a function of velocity
gradient between
two adjacent layers
of a liquid.

Laminar mixing/Streamline mixing: When two dissimilar liquid are
mixed through a
laminar flow, the shear that is generated stretches the interface
between them. In this mechanism layers folds on themselves. As a result, the number of layers, and therefore
interfacial area between them, increases exponentially with
time.

Molecular
 diffusion:  The
 mechanism
 responsible  for  mixing  at
 molecular
 level
 is
 the
diffusion resulting from
thermal movement of molecules.

Primary mechanism responsible for mixing at the molecular
level is the thermal motion of molecules. Governed by Fick‘s
fist law of diffusion,

dm/dt
= – DA dc/dx

Where,

dm/dt –
rate of transport of mass
across a surface area

D
– Diffusion Co-efficient

A – Area across
which diffusion is occurring dc/dx – Concentration
gradient

PROPELLERS

Propellers are the mechanical device that are used to mix liquid materials
using blades

A three bladed design is generally used for liquids.

Principle

The propeller mixer mainly works on the principle of shearing
force.

Construction

·        
It consists of vessel and propeller.

·        
A propeller has angled blades, which cause the
fluid to circulate in both an axial and radial direction.

·        
Size of the propeller is small and many
increases up to 0.5meters depending on size of tank. Small size propeller can
rotate up to 8000 rpm.

Working

·        
A vortex forms when a centrifugal force is
imparted to the liquid by the propeller blades because it to backup ground the
sides of the vessel and creates a depression at the shaft.

·        
As the speed of the rotation is increased air
may be sucked in to the fluid by the formation of a vortex this causes frothing
and possible oxidation.

·        
Another method supressing vortex is to fit
vertical baffles in to the vessel.

·        
Installation of vertical propeller reduces the
vortex to considerable extent.

·        
Vertical propeller mixer consists of three
blades (4 ft long).

·        
Horizontal or Inclined Propeller or Marine
Propeller are also used on side entry mixers.

·        
They are mounted with the impeller shaft
inclined at an angle to the vessel axis to improve the process results.

·        
They provide good blending capability in small
batches of low to medium viscosity.

Advantage

·        
Propeller is effective when high mixing
capacity is required.

Disadvantage

·        
Propellers are not effective for liquids
having viscosity greater than 5.0 Pascal second.

·        
Equipment cost is high.

Uses

·        
Propeller mixer used  for mixing liquid  having 
maximum  viscosity of  2.0  Pascal
second, for mixing of low viscosity emulsions and also used in mixing
suspensions with particle size up to 0.1 to 0.5 mm.

TURBINES

Principle

·        
A turbine mixer is a mechanical device that is
used in mixing different type of liquids.

·        
The turbine mixer works mainly on the
principle of shearing action.

Construction

·        
Turbine consists of number of blades attached
to the circular disk.

·        
The blades used in the mixture are of various
types: flat blades, disk-type flat blades, inclined blades, curved blades,
arrow headed blades, and so on.

·        
The diameter of turbine varies from 30 to 50
percentage of the diameter of vessel.

·        
As compared to propeller turbines rotates at
lower speed.

Working

·        
When turbine mixer operates at sufficiently at
high rotational speeds, the radial tangential flow becomes pronounced with the formation of vortex.

·        
It is necessary to install baffles in the
vessel for the mixing process for uniform mixing.

·        
The radial flow of the impeller impinges on
vessel walls, where it slits in to two streams.

Advantage

·        
Turbines give greater shearing force than
propeller.

·        
Therefore, turbines are suitable for
emulsification.

Disadvantage

·        
Turbines have less pumping rate.

Uses

·        
A turbine mixer suitable for viscous fluids
(7.0 Pascal-second).

·        
Turbines used for thin paste and
emulsification.

·        
Turbines can also be used to handle slurries
with 60 percentage solids.

·        
Mainly used for semisolid materials.

PADDLES

 Principle

·        
Paddles consist of two long flat blades attached
vertically to a shaft.

·        
IT rotates at low speed.

·        
Paddle mixer is suitable to mix viscous
liquids or semisolids.

Construction

·        
Blades used in this mixer are dished or
hemispherical in shape.

·        
The diameter of paddle is 50-80 percentage of
inside diameter of vessel.

Working

·        
Paddles push liquid radially and tangentially.

·        
There is no axial movement of flow during
mixing.

Advantage

·        
Vortex formation is not possible.

·        
It has low speed.

·        
Mixing efficiency is better.

·        
No dead spots and deposited solids.

Disadvantage

·        
Here suspension mixing is poor.

·        
Baffled tanks are required.

Uses

·        
Paddles are used in the manufacture of antacid
suspensions (aluminum hydroxide gel and magnesium hydroxide), agar and pectin
related purgative, antidiarrheal mixtures such as bismuth-kaolin.

SILVERSON
EMULSIFIER

Principle

The  silverson  homogenizer 
works  on  the 
principle  that  the  large 
globules  in  a 
course emulsion are broken in to smaller globules by intensive shearing
forces and turbulence by high speed rotors.

Construction

·        
It consists of emulsifier head.

·        
The emulsifier head consist of a number of
turbine blades.

·        
The blades are surrounded by mesh which is
enclosed by cover having perforations.

·        
The blades are rotated by using electric motor
fitted at the top.

·        
There is 
also  one  shaft 
whose  one  end 
is  connected  to 
motor  and  other 
end  is connected to head.

Working    

·        
The emulsifier head is dipped in to the vessel
containing immiscible liquids.

·        
When the motor is started, shaft rotates the
head.

·        
Therefore, turbines blades also rotate at very
high speed.

·        
The liquids are sucked trough the fine holes.

·        
The complex flow pattern can cause droplet
break up under either laminar or turbulent conditions

·        
Centrifugal force expels the content through
mesh and then to cover and subjects them to mechanical shear.

·        
This is followed by intense hydraulic shear.

·        
The oil is reduced in to globules quickly
resulting in a homogenous uniform product.

·        
Then the fine emulsion emerge trough opening
of cover.

·        
As a result, bigger globules rapidly break in
to smaller globules.

Advantage

·        
Fast and efficient.

·        
They are used to get a fine droplet or
particle size (2-5 microns).

·        
Process efficiency is good.

·        
Low operating cost.

Advantage

·        
Chance of chocking of pores of mesh.

Uses

·        
Used in preparation of creams, ointments,
pharmaceutical suspension and emulsion of fine particle size.

  Mixing & Mixer Used in 

Pharmaceutical Industries Notes PDF

Drying and Dryers Used in Pharma Industries                   Size Reduction – Methods & Equipment