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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

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 pharmaceutical products such as Tablets, Capsules, Suspensions, Emulsions, Pastes, Creams,

Factors Affecting Pharmaceutical 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 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:

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 shortened if energy is supplied.

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

2. Negative mixture

· Materials tend 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

Solid Mixing	Liquids Mixing
In solid mixing two or more substances are Intermingled by continuous movement of particles.	This is achieved by mixing elements of Suitable shape to act as impeller to produce appropriate flow pattern in mixing vessel.
This is used for mixing of dry powders.	This is used in preparation of emulsion, suspension and mixtures.
Large sample size is required.	Small sample size is sufficient.
High power required for mixing.	Less power required for 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 into globules quickly resulting in a homogenous uniform product.
Then the fine emulsion emerges through the opening of cover.
As a result, bigger globules rapidly break into smaller globules.

Advantage