Mixing and Homogenization: Processes, Mechanism, & Equipments

Mixing

Mixing is a Pharmaceutical unit operation in which two components in a separate or roughly mixed condition are treated so that each particle lies nearly as close to each other ingredient. The attempt to achieve the most perfect mixture is often dependent on the objective of mixing.

Objective of Mixing

The objective of mixing may include:

1. To ensure simple mixture. This may include production of uniform blend of two uniformly dispersed solids or of two miscible liquids. This may involve blending for dosage formulation. High degree of mixing is required here
2. To ensure physical change. Here, mixing merely accelerates the process of chemical change which can occur as contact is made. It is often for solution of soluble substances and lower efficiency of mixing may pass.
3. Dispersion of two immiscible liquids or of solute and immiscible liquid to form emulsion and suspension respectively. Good mixing is required here.
4. Promotion of reaction such as chemical reaction to ensure uniform formation of product. The degree of mixing is dependent on the process.

TYPES OF MIXTURES

There are different types of mixtures depending on the arrangement of the mixed materials in the final blend.
Positive mixtures: here mixtures take place irreversible, spontaneously, and without expenditure of work if time is unlimited. Example is diffusion of gases or miscible liquids.
Negative mixtures: these mixtures are difficult to make, require high degree of mixing efficiency to effect and work to continually keep it mixed. Example is suspensions of solids in liquid.

Neutral mixtures: these mixtures are static. They have no tendency to mix, and when mixed remain mixed. Examples are pastes, ointments and mixed powders.

SCALE OF SCRUTINY

This is the weight or volume of the dosage unit that dictates how closely the mix must be examined/analyzed to ensure it contains the correct dosage/concentration. For example if a large mixture for preparation of tablet is made and the dosage for one tablet is 200 mg, then that quantity that should contain 200 mg is what should be taken for analysis and is what is ‘the scale of scrutiny’.
Reason for evaluating degree of mixing
To indicate the extent of mixing
To follow the mixing process
To indicate when sufficient mixing is done
To access the efficiency of mixer
To determine the mixing time required for a particular process

Factors that determines choice of mixing process and equipment

1. Properties of materials to be mixed:

The properties of materials to be considered include:

• Material density/ viscosity
• Particle size
• Particle shape
• Particle attrition
• Particle attraction (miscibility) proportion of materials.

2. Properties of the mixing equipment

These includes

• Mixer volume
• Mixer mechanism (type of force, direction, agitation)
• Mixing time
• Handling of mixed material in mixing and after.

3. The degree of mixing required

MECHANISM OF MIXING.

Solid

• Convection– when large group of material move from one part of powder bed to another like bulk transfer
• Shear– when one layer of material move over another layer of material
• Diffusion– when because a material is over stretch it creates space and hole for another material to fall through.

Liquid:

• Bulk transfer– this is like convection of solid. Large volume movement
• Turbulent mixing– this is the random mixing of materials when forced to move in turbulent manner
• Molecular diffusion– this occur wherever the is a concentration gradient of material and creates good mix

Types of mixers:

a) Solid (Powder mixing equipment)

Several types of blenders accomplish this task. The most common ones are:

• Tumblers,
• Agitators (ribbon/horizontal agitator blenders, and vertical agitator blenders),
• Tumble and agitator blenders
• Fluidized bed dryers, and
• High speed granulators:

Tumble Blender

This is characterized by a rotating vessel of different shapes but usually comes in a double-cone or V-shaped configuration, and involves tumbling of material in chamber to induce shear movement. Top material moves at high velocity, bed tumbles, dilates and allows particle move downwards by gravity, allowing diffusion and mixing. Asymmetric vessels designed to reduce blend times and improve uniformity are also available. Generally, tumble blenders operate at a speed of 5 to 25 revolutions per minute. Materials cascade and intermix as the vessel rotates. Mixing is very low-impact. The intensifier bar is a feature commonly seen on tumble blenders. Because the blending action is very gentle, this type of blender benefits from having a high speed intensifier bar with one or more chopper blades. The intensifier bar breaks up agglomerates and also provides a means for liquid addition.

Ribbon Blender and Horizontal Agitator mixers

The Ribbon Blender consists of a U-shaped horizontal trough and an agitator made up of inner and outer helical ribbons that are pitched to move material axially in opposite directions, as well as radially. The ribbons rotate with tip speeds of approximately 300 rpm. For blends that require a gentler mixing action, the same trough can be utilized but the ribbon assembly is replaced with a paddle agitator. A horizontal paddle blender has less surface area at the periphery of the agitator, providing lower shear and less heat development compared to the ribbon design. Rotation of blade or paddle movement inside the bowl filled with material ensures mixing on operation. It involves convective mixing by the blade, and shear and diffusion mixing by cascading materials as the fall downwards in the bowl.

Liquid addition is best accomplished through the use of spray nozzles installed in a spray bar located just above the ribbon or paddle agitator. This blender design is very efficient and cost-effective for dry mixing. Its attractive price makes it appealing and widely used for relatively low margin-high volume lines such as nutraceutical beverages, and whey supplements.

Vertical Blenders

In comparison horizontal/ribbon blenders, the blending action of a Vertical Blender’s slow turning auger is far gentler than that of a horizontal blender making it more suitable for delicate applications. The auger screw orbits a conical vessel wall while it turns and gently lifts material upward. As materials reach the upper most level of the batch, they cascade slowly back down in regions opposite the moving auger screw. Spray nozzles may also be installed in the vertical blender for liquid addition purposes.

A common use for vertical blenders is as vacuum drying where the starting material is in the form of wet granules or even a slurry, and the end product is typically a freeflowing powder. Requiring only low heat to drive off moisture or solvents, vacuum drying is an excellent method for drying heat-sensitive pharmaceutical products without fear of thermal degradation. The gentle and thorough agitation of the vertical blender promotes better heat transfer than simple oven drying operations wherein the product is stationary.

Comparative Advantages

1. Aside from level of shear, other factors such as space requirements, completeness of discharge, and batch size flexibility help determine which type of blender will work most efficiently in a certain application.
2. If floor space is tight, a vertical blender is ideal as it requires a much smaller footprint. If overhead space is limited, a horizontal ribbon blender allows the use of a low-profile loading system; a multi-level operation is usually not necessary. A tumble blender of a similar blend capacity will occupy the most space.
3. The vertical blender and tumble blender give virtually 100% discharge, but not a ribbon blender.
4. Ribbon blenders must be filled to at least 40% of the maximum working capacity while vertical blenders can efficiently handle as little as 10%. Tumble blenders are more sensitive to fill method – generally, it is more beneficial to add raw materials in layers rather than side by side and fill level is critical (minimum of around 70%) for applications that require maximum contact with the intensifier bar.

Tumbling and agitator mixers

It combines the powerful diffusion shear of tumbling bowl with the aggressive convective force of agitator blades.

Fluidized bed mixers

Explained under dryer. The high pressured hot air that is passed through the base of the bowl raises the wet material and ensures mixing as they are diffused and suspended in air.

High speed granulator mixers

The centrally mounted impeller at the bottom of the mixer rotates at high speed, throws material by centrifugal force towards the bowl wall. The side of the bowl throws them up and they descend towards the middle bottom again to continue the circle. High shear, diffusion, and mixing. Granulation can take place along mixing when granulation fluid is introduced tohe high speed impeller and the side chopper that chops the materials.

Liquid

Homogenizer

Blenders: Blade type and propeller homogenizer uses blade or propeller that is bottom or top driven. Agitators, propellers.
Propeller mixers: This stirs the liquids using propeller (different shapes can be seen) in axial and radial direction to ensure mixing. Disadvantage is that: At high speed, centrifugal force imparted on the liquid by the propeller blade causes it to back up around the sides of the vessel and create a depression at the shaft, and this may suck air to create vortex. Vertical baffles can reduce this

Turbine mixers

This is used for more viscous materials. This consist of four flat blades surrounded by perforated inner and outer diffuser rings. Rotating impeller draws liquid into the turbine head and forces liquid through the perforation at high velocity producing high shear forces for droplet formation and dispersion. This mixers cannot cope with high viscosity liquids

Inline Static Mixing

Static mixing is another technology employed in the preparation of pharmaceutical products and intermediates. It is used for continuous blending of fluid streams, emulsification, dispersion of gas(es) into liquid, pH control, dilution and heat exchange. A static mixer is unique in that there are no moving parts in this device and it relies on external pumps to move the fluids through it.
An array of static mixer elements or a central shaft with baffle plates is placed inside a pipe and the mixing operation is based on splitting and diverting input streams. Various designs are available for selection based on flow regime (laminar or turbulent), viscosity, allowable pressure drop, solubility and other factors.

Ultrasonic Homogenizers. Ultrasonic pressure waves, streaming of liquid, rapid formation of micro bubbles, growth and coalescence until they reach resonant size, vibrate violently and then collapse. Called cavitation process (formation and collapse of low-pressure vapor cavities in flowing liquid). Implosion of vapor phase bubble generates shock waves with sufficient energy to break covalent bonds. Shear from imploding cavitation bubbles as well as from eddying induced by the vibrating sonic transducer disrupt cells.

High Pressure Homogenizers: works by forcing suspension through a narrow orifice under pressure, and impinge at high velocity on a hard-impact ring or against another high velocity streaming liquid. Mixture may be pretreated with blade blender, rotor/stator homogenizer or paddle blender
High Shear Homogenizers or High Shear Mixers (HSM);
This includes (a) rotor-stator homogenizer for emulsions (b) rotor-stator homogenizer for suspensions.
Rotor-stator homogenizers for emulsions,
In rotor stator homogenizer, a rapidly rotating rotor blade is positioned within a stator head or tube that contains slots or holes. The rapidly rotating rotor draws in material into the stator, and with the aid of the rotor, forces same material after mixing through the orifices of the stator. They are used for High Shear Mixing and Emulsification. Throughout the pharmaceutical industry, rotor/stator High Shear Mixers (HSM) are widely used in the preparation of emulsions such as medicated lotions, balms, ointments, creams and eye drops. Available in batch (vertical) or inline (horizontal) configurations, high shear mixers are comprised of a rotor that turns at high speed within a stationary stator. As the blades rotate, materials are continuously drawn into one end of the mixing head and expelled at high velocity through the openings of the stator. The hydraulic shear generated promotes fast mixing, breaks down agglomerates and reduces the size of droplets. Rotor tip speeds between 3,000 to 4,000 rpm are typical.

Batch (vertical) mixer

The batch starts with heating mineral oil to 70oC followed by adding a surfactant in pellet form which dissolves easily through the high shear mixer. In a separate vessel, the water phase is prepared and also heated to 70oC. The water phase is poured into the oil phase and, keeping mixer speed constant, a sample is drawn at every time interval using a pipette.
The target droplet size for this intermediate is <12 microns. Particle size analysis revealed that this was achieved in 8-10 minutes of processing under a batch high shear mixer with slotted stator and four-blade rotor.

Inline high shear rotor-stator mixer

In an inline high shear rotor/stator mixer, the greatest extent of droplet size reduction occurs within the first few passes. This phenomenon is true for almost any emulsion. Past this phase of sharp decrease in droplet size, the emulsion hovers at an equilibrium size despite subsequent recirculation. The same trend applies to batch rotor/stator mixing systems although the actual number of product turnovers is not as easy to define. Identifying the number of passes that it takes to achieve the desired or equilibrium droplet size is very useful to avoid over-processing. Inline mixers; Mobile miscible liquids are fed through an online mixer to ensure continuous mixing.

High Shear Mixing and Powder Dispersion into Liquid
Different powders behave differently when added into liquid, and some require more coaxing in order to dissolve, hydrate or disperse completely than others. The ‘easier’ ones need only gentle agitation as provided by low speed propeller, turbine or paddle agitators. More challenging powders benefit from higher speed devices such as open disc type blades which generate a powerful vortex into which the powders are added for faster wet-out. When dealing with solids that tend to form tough agglomerates which do not easily break apart, a high shear mixer is often installed to replace or supplement the existing propeller or disc type disperser in the vessel. For this reason, many solutions and dispersions are made in high shear mixers, from tablet coatings and vaccines to pharmaceutical inks and disinfectants.
Adding hard-to-disperse powders slowly into a small batch of vigorously agitated liquid is not an issue in lab-scale batches. However, in a full-scale production setting, this method of addition is very costly and time-consuming. In addition, if powders are added too slowly, an uncontrolled viscosity build-up can occur mid-processing thus preventing the rest of the solids to be fully dissolved. On the other hand, charging too fast can cause some powders to clump up. These agglomerates can solvate to form a tough outer layer which prevents complete wetting of the interior particles. These “fish eyes” lead to solution defects such as grainy texture and reduced viscosity. The high shear conditions usually needed to break up these agglomerates may overshear the already hydrated or dispersed particles leading to a permanent loss in viscosity. In an effort to correct below-target viscosity, many will actually resort to adding more solids than is really needed and subsequently filtering agglomerates out of the mixture, which not only drives up raw material costs but also wastes power, lowers productivity and constrains over-all production.
A key development in HSM design is the SLIM (Solids/Liquid Injection Manifold) Technology, a high speed powder induction system available on Ross High Shear Mixers. The modified rotor/stator assembly is specially designed to create negative pressure (vacuum) behind the rotor, which can be used as the motive force to inject powdered (or liquid) ingredients directly into the high shear zone.

 Batch SLIM  Inline (Continuous) SLIM  

The SLIM is particularly useful in inducting hard-to-disperse powders such as fumed silica, carboxymethyl cellulose (CMC), hydroxyethyl cellulose (HEC) starch, pectin, talc, carbomers, xanthan gum, Agar, guar gum, carrageenan, tragacanth, etc. into a liquid phase. These powders are notorious for driving up processing costs in the form of labor and reduced production. Even with a strong vortex in an open vessel, they resist wetting out and often float on the surface for hours. In the SLIM system, solids are added not to the top of the liquid but right in the mix chamber where they are instantly subjected to intense shear. As solids and liquids are combined and mixed simultaneously, agglomerates are prevented from forming because dispersion is virtually instantaneous. The inline configuration of the SLIM is a superior design compared to earlier venturi or eductor systems. In eductor systems, the process liquid is pumped at high velocity into a venturi chamber and passes into a downstream inline mixer. The combination of the pump, venturi and the pumping action of the mixer creates a vacuum in the venturi chamber. Powder fed through an overhead hopper is drawn by this vacuum into the eductor where it joins the liquid flow. A rotor/stator then mixes the powder and liquid, and propels the flow downstream.
While this set-up eliminates the dusting and floating issues of batch systems, it also presents serious limitations. With three separate devices in series, maintenance is intensive. Balancing the performance of the pump, eductor and mixer is often difficult, and in many applications, downtime is quite high.
But the most serious limitation relates to the inherent operating limitations of the venturi or eductor. Clogging is routine. The system is temperamental and requires a lot of operator experience and attention to operate successfully. Since the feed rate of the eductor relies on the vacuum created by a fast-moving stream, it is also extremely viscosity-dependent. As the viscosity of the stream rises, velocity falls and the efficiency of the eductor drops offs steadily until it finally stops.
The Ross SLIM design is a breakthrough based on one simple idea — eliminate the eductor. In the older powder induction designs, solids are combined with the moving liquid stream in the eductor, and then mixed farther down the line. That distance between the eductor and the mixer is critical. Material that had been combined but not yet mixed intimately could clog the pathway before reaching the rotor/stator mixer where agglomerates could be disintegrated and small particles are forced into a dispersion that could flow quickly without problems. In addition, clumps produced in the venturi chamber would form that tough outer layer which will prevent interior particles from being wetted out.

Rotor heads

The QuadSlot mixing head is a multi-stage rotor/stator with a fixed clearance. This generator produces higher pumping rates and requires higher horsepower compared to an X-Series rotor/stator set running at similar speeds.
The MegaShear head (US Patent No. 6,241,472) operates at the same tip speed as the X-Series and QuadSlot heads, but is even more aggressive in terms of shear and throughput levels. It consists of parallel semi-cylindrical grooves in the rotor and stator towards which product is forced by high velocity pumping vanes. Different streams are induced within the grooves and collide at high frequency before exiting the mix chamber.
In certain cases, an ultra-high shear mixer will effectively replace a high pressure homogenizer or a colloid mill. Manufacturers that find this to be true for their particular formulations welcome the change because high pressure homogenizers and colloid mills are high maintenance machines; during crossovers of different batches, the clean-up procedure is labor-intensive. Also, throughput rates of a similarly-powered ultra-high shear mixer are far greater compared to that of a high pressure homogenizer or colloid mill. Lastly, ultra-high shear mixers cost less upfront.

Semisolid mixers
-Planetary mixers
This blade travels round the circumference of the bowl while simultaneous rotating around its axis. This creates a double rotation similar to planet rotating around the sun. The small clearance between paddle and vessel gives shear. Solids and semi solids can be mixed with this mixer.

High Speed Planetary Mixing
Some highly filled and highly viscous formulations benefit from a hybrid planetary mixer which combines the traditional thorough mixing action of a planetary mixer with the added advantage of a high speed disperser. Both the planetary blade and the high speed disperser rotate on their own axes while revolving around a central axis. The planetary blade orbits through the mix can continuously sweeping the vessel walls, as well as the vessel bottom, and carrying material toward the high speed disperser. The close tolerance sweeping action of the planetary blade also insures that the heat which can be created by the disperser blade is evenly distributed throughout the batch. Variable speed allows precise control of shear rates to minimize the degradation of any shear-sensitive components.

Dual-Shaft and Triple Shaft Mixers
These are used in the pharmaceutical industry for batching moderate to relatively high viscosity applications such as syrups, suspensions, pastes, creams, ointments and gels.
This type of mixing system is comprised of two or more independently-driven agitators working in tandem. A low speed anchor compliments one or two stationary high shear devices, such as an open disc style disperser blade or a high shear mixer rotor/stator assembly. On its own, a disperser blade will produce acceptable flow patterns in batches up to around 50,000 cP; the rotor/stator up to around 10,000-20,000 cP. Hence, for higher viscosities, there is a need for a supplemental agitator to improve bulk flow, deliver material to the high speed devices and constantly remove product from the vessel walls for better heat transfer.
The most common low speed agitator designs are the two-wing and three-wing anchor. For added efficiency, especially in terms of axial flow, a three-wing anchor can be modified to feature helical flights in between wings. In combination, stationary high shear devices and an anchor will process formulations that are several hundred thousand centipoise.
Another mixer design widely used in the pharmaceutical industry is the Counter-Rotating Agitator with bottom homogenizer (rotor/stator). In some of these machines, the agitation system is a fully top-supported coaxial shaft arrangement driving three simultaneous mixers, namely: (1) the outer anchor agitator with blades and wall scrapers; (2) the inner blades positioned inside the anchor, rotating in opposite direction to the anchor to create a contrasting series of flow patterns; and (3) the homogenizing head with rotor and stator, centrally positioned at the lowest end of the agitation system.
In other configurations, the rotor/stator assembly is bottom-entering and/or installed as an external inline unit designed for product recirculation.
Double Shaft Mixers
Other advantages of the double planetary mixer design include:
Ease of cleaning
A vertical mixer design has no shaft seals, bearings, packing glands or stuffing boxes submerged in the product zone. In addition, the agitators are raised and lowered in/out of the mix vessel by a hydraulic lift. This allows easy access for cleaning between batches. Mix vessels are interchangeable and can be dedicated to a particular formulation and/or color. There is less concern for cross contamination from batch to batch.
Ease of discharge
The ability to use a Discharge System is a big advantage to the DPM design. The platen-style hydraulic discharge system improves speed, efficiency and cleanliness of the discharge operation. With the mix can positioned beneath the discharge system, a platen is lowered hydraulically into the vessel. A specially-fitted O-ring rides against the vessel wall, literally wiping it clean. Product is forced out through a valve in the bottom of the vessel, or through the top of the platen. A Discharge System eliminates wasted hours of scraping heavy or sticky materials from a tilt-style sigma mixer.
Semi-continuous operation
With the use of extra mix vessels, the double planetary mixer can produce material in a semicontinuous basis: one vessel is being charged while other vessels in the loop are under the mixer, being discharged, and/or cleaned.
Floor space requirement
Footprint of the double planetary mixer is considerably less than that of a double arm / sigma blade mixer. Capital cost
Depending on specifications, a double planetary mixer is generally 1/2 – 1/3 the cost of a comparably sized new sigma blade mixer.
Energy savings
Since the double planetary mixer uses less motor horsepower to operate, everyday energy/operating costs will be less. This can be significant over time.
A lesser known fact is that double planetary mixers are not limited to processing viscous end products, but are also capable of gentle and thorough blending of low viscosity materials or even powders. This versatility makes them suitable for wet granulation and drying operations.

-Sigma-blade mixers
It is worth mentioning that not all viscous applications can be successfully made in a double planetary mixer. For these, there are Kneader Extruders (Sigma Blade Mixers), high torque machines that can muscle through blocks of rubbery or hard semi-solids. They remain to be the most powerful tools for manufacturing extremely viscous formulations. Sigma Blade Mixers is a strong mixer used for semi solids, stiff pastes and ointments. The sigma blades turn in opposite directions and clearance between sigma shapes blades and mixing trough is small. Blends may be subjected to colloid or roller mill to complete mixing. One of those considerations is that sigma blade mixers rely on the product being highly viscous at all times in order to mix properly – liquid components must be added very slowly, portion by portion, or else they can act like a lubricant and reduce shearing efficiency. While this issue is also present in a vertical double planetary mixer, its blades run at higher tip speeds than sigma blades making it less sensitive to liquid additions or shifts in viscosity.

SEGGREGATION AND TYPES OF SEGGREGATION

1. Percolation: falling and settling of powders into small spaces after mixing. This leaves large light particles on top and heavy, dense and small particles under. This demixes already mixed powder
2. Trajectory: this happens in the process of mixing, with dense particles developing higher force to fly off the edges.
3. Elutriation: This happens after mixing when the tiny particles agitated and blown into the air space begins to fall down on the mixed bulk after mixing.

WAYS TO AVOID POWDER SEGGREGATION/DEMIXING

1. Collection of particle fractions by sieving to achieve a size of granulating to even up
2. Milling of components to reduce some size to the uniform expectation
3. Selection of particle with same density.
4. Recrystallization and granulation to specified size, density and standard

Conclusion

There are two distinct approaches in the selection of mixing systems. One is to issue mechanical specifications (speed, blade diameter, power, etc.) based on previous in-house experience. The other is to supply the vendor with just the process specs including the engineering purpose for the mixer, as well as expectations of mixer performance. The ideal situation is somewhere in between these two approaches.
Cycle times, particle size distribution and other parameters are influenced not just by mixer design but also by product chemistry, operating temperature, pressure/vacuum conditions, quality of raw materials, presence of additives, etc. Process guarantees are really more misleading than helpful most especially in the absence of any empirical data gathered from mixer testing wherein your own formulation or a fairly similar one was actually utilized.
Ultimately, most of the mixer features will depend on the requirements of your specific process. Some aspects worth discussing in detail with your mixer manufacturer include construction and polish of wetted parts, sanitary connections and valves, CIP/SIP capability, batch size flexibility, sufficient horsepower(s), ease of discharge, level of maintenance, sealing arrangements and the degree of sophistication you expect to have in the mixer controls.
It is essential for R&D scientists and process engineers to be continually updated on new mixer systems and improved designs. In reality, many of today’s mixing technologies overlap in use and function such that certain applications can actually be successfully produced by two or more types of mixing systems. In these situations, economics rule out the more costly initial investments, but difference in efficiencies must also be taken into account. A trusted manufacturer that offers long-term experience, rental and testing resources will make for a very strategic partner whether you are selecting a mixer for a new product or simply updating an existing process.