Tech Tip Categories

Blending & Mixing
Formulation
Granulating & Drying
Milling
Tablet Coating
Tablet Compression
Tablet Defects
Tablet Printing
Weighing

Blending & Mixing
Final Blending for Solid Dosage

The final blending is actually a two part process: blending the components to as near a “perfect blend” as possible and then blending in the lubricant. Both sections of this process are important to understand. In order to achieve the "perfect blend," a sampling of each product being blended is necessary, watching for the time interval when the product is at its optimum. It is at the optimum time, i.e. when the samples have the tightest spread that the lubricant can be added. For solid dosage formulas, the best practice for adding lubricants is to adequately mix in the lube without over coating all the powders. Depending upon the type of mixer and the capacity, lubricating times will vary. We recommend adding the lube through a 30 mesh screen and blending for 3-5 minutes.
 

Over-blending and Under-blending

What Are The Symptoms of Over Blending And Under Blending?
Content Uniformity problems, Weight variation, and Hardness variation

There may be many pre-blending cycles in a process to combine and create uniform distribution of the powders. This is based on the characteristics of each ingredient. Some ingredients will naturally flow, but most will not. This is why some machines are simple tumble blenders and some have mechanical agitators.

Products that are Under-Blended demonstrate the same characteristics of products that are Over-Blended. Products that are friable may also produce more “fines” as a result of too much blending and potential to break up the granules.

Content Uniformity problems, Weight variation, and Hardness variation can be attributed to both over & under blending.

Final blending is the addition of the lubricant into the pre-blended mass. The final blend cycle time is usually 3-5 minutes. The purpose of adding a lubricant is to protect the granules from sticking and locking onto the steel components and punches & dies of the tablet press. Under-Blending the lubricant may result in some periodic sticking of powders to the punch faces resulting in a tablet defect. Over- Blending the lubricant can result in the same problem as under-blending. Over-blending a lubricant causes the lubricant to “hide” and not protect granules from contacting the punch faces and steel components impeding flow and causing sticking.

Blending is a critical unit operation. The powder characteristics, blender, blend time, blend volume and final blend times are all factors that must be considered to have a successful blend.
 

Formulation

Determining Factors for Particle Size of a Tablet Formulation

What are the determining factors for achieving the correct particle size distribution of a tablet formulation? I recall some 30 years ago being taught that the general rule of thumb is: particle size distribution needs to be small enough to go through an 18 mesh screen yet big enough as to not go through a 200 mesh screen. While machine type and condition play a role, the following list of items should also be considered.
Flowability: Generally speaking the smaller the particle the worse the flow. Compare powdered sugar with granular sugar. The fine small particles in powdered sugar aide dissolution but not flow.
Feeder clearance: Particle size must be larger than the feeder clearance to prevent leakage.
Die table run-out: If die table run-out increases feeder clearance and particle size must also increase proportionately. To check run-out, use a dial indicator to determine the variation of the die table.
Die fill: Wide variations in particle sizes can cause inconsistent fill volumes.
Weight control: Final volume is final weight. Larger particles pulled out of the die can reduce the final weight. Fine particles require more precise scrape-off and increase the need for a good scraper blade.
Compressibility: Improves with increased particle size and decreases as particles become smaller and smaller. Small particles have less ability to lock together during compaction.
Hardness: Smaller particles are more sensitive to over-compression.
Ejection force: Small particles decrease interstitial space and increase drag and friction.
Lubrication levels: In general higher percentages of small particles require increased quantities of lubricant. Magnesium stearate is the most commonly used lubricant and should be de-agglomerated before use.
Disintegration & Dissolution: Small particles decrease disintegration time, and increase dissolution.
Friability: Larger particles usually lock together better which results in reduced friability while small particles often increase the potential for failure (higher friability).
Electro Static effects: Electro static charge is increased as the percentage of small particles increases.
Dust control: Fine particles create a dusty operation, creating a need for frequent production stoppages and press clean-ups.
Environmental conditions: Many products are hygroscopic and sensitive to heat. Variations in room conditions can result in poor flow, compression and ejection conditions.
Lamination & Capping: Small particles are the heart of the most common defects.
Punch lubrication: Dust and super fine particles become airborne and combine with the oils and greases which can produce black specks in tablets.
Tooling condition: Punch tip & die clearance are designed to control air release allowing for improved compaction.
Machine condition: Cleaning and maintenance are downtime issues. A high percentage of fine particles and dust increases the potential for greater wear, increased cleaning frequency, reduced yield, greater particle segregation, and more tablet defects.
Cost: Fines (small dusty particles) increase operating costs, require increased levels of dust collection, decreased yields, increased frequency of cleaning, and generate greater machine & tool wear. Reducing fines will improve tablet quality.

Summary: Establishing an appropriate particle size distribution will improve tablet quality and will reduce overall costs in the long run. Fine dusty particles are the source of most tablet defects.

Stearic Acid, An Excipient

Stearic acid may be used as a lubricant and it may also be used as a binder. It is frequently added and used for both purposes, although one must be aware of the limits of using the material safely. Many companies have a top limit of around 4%. At levels much above this, the stearic acid starts to gum up the lower punches on a compressing machine and can actually bind the punches producing tablet defects.

Stearic acid is frequently used when the active material has a tendency to be brittle. In this case stearic acid acts as an anti-friability additive.

There have been instances when stearic acid may interact with an active ingredient and cause degredation on stability. Because of this many ethical pharmaceutical companies have stopped using it unless there is a specific technical reason for doing so. The additive stearic acid is now most often used by nutraceutical companies.
 

An Alternative Low Cost Filler For Hard Shell Capsules

Filler selection may sometimes affect the total cost of the product, especially where large quantities are required. Many firms continue to use established fillers such as lactose, but are others less costly and just as effective.

One example of a cost effective filler is rice bran. This product provides a convenient form of dietary fiber, it is relatively stable and performs well on most automated and semi automatic capsule fillers.

There Are Limits To What You Can Fit Into A Tablet!

There are many sizes and shapes of tablets to choose from when formulating. There are relationships between the diameter of any tablet and its thickness. Some formulators decide on what diameter tablet they want, then try and formulate around it. There is a limit of what can "fit" into any specific diameter of a tablet.

See the table below, there are recommended targets and limits associated with most any size and shape of tablet:

Round Tablets Caplet Shaped Tablets Oval Shaped Tablets

¼” 250 mg. .220 x .600” 700 mg .318 x .580” 525 mg.

5/16” 275 mg .250 x .750” 725 mg. .315 x .748” 900 mg.

3/8” 450 mg .312 x .750” 1,200 mg. .375 x .748” 1,200 mg.

13/32” 500 mg. .320 x 750” 1,300 mg. .375 x .875” 1,700 mg.

7/16” 650 mg .330 x .850” 1,450 mg. .400 x .900” 1,950 mg.

½” 1,250 mg.

What is formulating all about, why do we formulate?

Formulating: What is formulating all about, why do we formulate?

Tablet and Capsule Formulation is Driven by the Characteristics of the Active Ingredient
How well do they flow?
How well do they compress?
To what degree do they eject?
Are they dense enough to fit in the die?
Do they react with heat or moisture?
What percentage of the tablet is the active?

Non- Active components in the formula are called excipients. The right combination of excipients is ultimately what permits the development of a successful tablet.

The average tablet press makes 30,000 tablets per minute or 50 tablets per second. When the company makes the move to a higher speed press and spends a great deal of money…just to find out that the new press will not run any faster than the old press…why?

This is a very common problem that starts in R&D and is seen all the time on the production floor: products are sensitive to speed. When moving a formula to a higher speed press, expect an impact on flow rates & compression time (dwell time). Just because the press will run faster does not mean the formula will.

Granulating & Drying

Fluid Bed Granulating Basics

The Basics of Fluidized Bed Granulating

I. Introduction to the Technology
The fluidized bed process is basically the addition of a wet binding suspension into an actively moving bed of mixed powders. The binding suspension is reduced from a single solution stream into minute droplets by the application of compressed air; called atomizing air or air of atomization. This mist then combines with the randomly agitated powder to produce a granule that is both porous and free flowing. The powder is heated and agitated by the introduction of a filtered, heated variable mass of air generated by a single turbine on the exit side of the process. Combined together with a bag house (or scrubber on some installations) this system may take a non flowing powder and convert it into predictable well flowing powder required for high speed tablet compression.

II. The Basic Components of the Fluidized Bed Granulator
The Fluidized Bed Granulator is comprised of eight basic parts. These parts are: 1) the air treatment package, 2) the product bowl, 3) the expansion chamber, 4) the filter system, 5) the bag house, 6) the air turbine, 7) the suspension pumping system and 8) the control panel.

The air treatment package may vary somewhat depending upon the firm’s general need. A basic package is composed of set of paper and HEPA filters and a heating system. The incoming air stream is filter and heated before passing into the product bowl. Available options generally are either a dehumidifier a humidifier or both.
The product bowl is measured in liters for capacity planning and is made up of either a set of screens or a perforated plate. Product is retained by the screen/plate and is made free flowing and random by the incoming air stream. Below some product bowls one often finds a series of baffles designed to better center the air stream to the dead center of the screen.

The expansion chamber separates the product bowl from the filter system. The expansion chamber may vary in length on various models and product year and can range from a few feet to over 10 feet in length. The longer the expansion chamber the more room for the powder to flow and hence the more uniform the particle. Some expansion chambers are tapered to allow for both granulating and particle coating.

The filter system is usually composed of a filter bag or bags that are shaken during processing to free up any accumulated powder and return it to the product bowl. In some filter systems a single bag is shaken at one time while in others a dual split bag is shaken alternatively.

The bag house collects any powder that might have slipped by the filter bag during an upset condition, such as a bag tear, and protects the turbine. Bag houses vary from manufacturer and site and often are installed at a somewhat great distance from the actual processing unit. Figure 2 illustrates a typical laboratory unit showing the control panel, the product bowl, the plastic expansion chamber and the filter bag system.

The suspension pumping system takes a pre-formulated mixture of powder binder and vehicle and introduces it into the expansion chamber as an atomized mist. The system is usually composed of a tank, a pump, and gun boom and a nozzle head. The suspension may be kept at a constant temperature right up to the moment of introduction with available options.

The control panel is usually immediately adjacent to the central processing unit and is composed of a pneumatic control panel or a computer. In older units there may be miles and miles of pneumatic tubing used to transmit signals to the granulator while newer units have a computer recessed into a control area.

The Three Basic Processing Cycles of the Fluidized Bed Process

The pre-heat, the spray and dry cycles and an optional cooling cycle comprise the fluidized bed process. Their purpose and a general description follow.

The pre-heat cycle is generally used to both warm and mix the powder. Completing both requirements can take up to 20 minutes depending upon the material being processed and the size of the granulator. During this time the bag is shaken periodically while powder is kept fluid but at a “rolling boil” and generally out of the expansion chamber. If this is done correctly the powder should be both heated and mixed without having to shake the bag more than once or twice.

The spray cycle is used to construct the granule. During the cycle the atomized binding suspension meets the ascending and cascading powder creating granules of all sizes. The temperature of the incoming air may vary between 30 and 50 Deg. C depending upon the nature of the powder being processed and the vehicle used. Aqueous suspensions generally require a high air temperature to prevent powder from adhering to the granulator surfaces. The bag is also shaken more frequently to optimize the quantity of powder under the spray nozzle. After a predetermined quantity of suspension has been pumped into the bed, the spray cycle ends.

The dry cycle is engineered to dry the powder quickly and preserved the granules constructed during the spray cycle. The inlet air temperature is usually raised to between 60 and 90 Deg C, again depending upon the nature of the powder being processed. Because the powder bed is heaviest immediately after completion of the spray cycle, settings for quantity of air used to levitate the powder will change as the cycle progresses and the powder dries. The bag shaking cycle is usually minimal and approaches that used during the spray cycle but becomes more frequent as the powder dries and becomes lighter. When the powder has reached the required moisture, the dry cycle ends.

The optional cooling cycle is usually quite short using a reduced inlet air temperature. The cycle is usually engineered to return the powder to near room temperature preventing operator injury when evacuating the powder from the vessel. In come cases the cooling cycle is much longer and is designed to prevent product shock from sudden exposure to significantly lower room temperatures.

The Critical Operating Parameters Used in a Fluidized Bed Granulator
Critical operating parameters vary depending upon the cycle used. In the pre-heat we are concerning about the incoming air temperature, the quantity of air used and to some degree the bag shake cycle. In the spray cycle we are concerning with these items as well as powder bed height, spray rate, quantity of atomizing air, nozzle height and the bag shaking cycle. In the drying cycle we reduce the number of parameters back down to inlet air temperature and quantity, bed height and bag shaking cycle. A full and detailed understanding of these and other critical operating parameters is available from equipment vendors and in the literature.

Common Problems Observed in a Fluidized Bed Granulator
There are four general problems seen on the production floor.

1. Sticking powder is commonly observed when insufficient bed agitation, an excessive spray rate, an inadequate quantity of atomizing air or inadequate inlet air temperatures. Powder sticking to the product bowl screen can interfere with the intended air flow patterns and in extreme cases may even cause total bed failure. Powder sticking to the expansion chamber sides is common during the spray cycle and usually frees itself at some point during the dry cycle. On occasion it may be appropriate for the operator to use a mallet and strike the chamber side to free the powder. Powder may also stick to the spray nozzle causing a partial or a complete clog of the solution port. Most granulators have a compressed air purge so that solution is always free to flow. 2. Poor yields and content uniformity problems may result from excessive accumulation of powder in the filter bag. This is caused by a non optimized bag shaking cycle during the spray cycle, excessive atomizing air or an excessively high inlet air temperature. On occasion a combination of these three factors may in the aggregate cause the same condition. 3. An excessive quantity of fines in the finished product is usually a result of excessive inlet air temperature, excessive atomizing air, excessive bed agitation (too much CFM) or a combination of all the factors. 4. A non optimized moisture content, observed as an LOD result that is either too high or too low, may result from inattention to the drying curve, use of solvent vehicles, a badly calibrated moisture analyzer or a combination of all the factors. Incorrect sampling of the powder may also contribute to this problem by giving an erroneous value.

VI. Summary
The fluidized bed granulator is a complex option in the arsenal of powder preparation systems. Using a fluidized bed granulator properly can produce the most porous granule of any other the technologies while maintaining or even improving powder flow characteristics.

Fluidized Bed Granulating Bag Shaking Cycle

Fluidized Bed Granulators: The Bag Shaking During the Spray Cycle

The filter bag one sees in a fluidized bed granulator/drier plays a key roll in producing a uniform particle size distribution. The frequency with which one shakes this bag as well as the duration of the shake helps keep the powder bed flowing in a constant, random motion. Failure to shake the bag frequently may result in a large quantity of fine particle collecting in the bag area. This eventually may lead to a total bag clog which in effect gives the granulator/drier a “heart attack” which stops the flow of the powder resulting in a dead bed.

During the spray cycle, while the particles are the wettest they are going to be, it is important to shake the bag frequently. This should be something like 15-20 seconds every 2 minutes or so. You can see the bag as it begins to clog up by simply monitoring the magnehelic gauge for the filter bag and shaking the bag once the gauge indicates a significant pressure build up. Shaking frequently will bring the fines back down under the influence of the spray gun where they can continue to grow as granules.
 

Dry Granulating - roll chatter

Roll chatter is an undesirable condition that you can hear immediately when you enter the roller compactor/chilsonator area. It has a distinct a sound like a piano out of tune. It means that you have something wrong with the process; one of the four critical processing parameters is not optimized. In order to understand what the process is and possibly what has gone wrong; let’s look at an illustration of a typical process:

As you can see, there are four variables. The blue arrows indicate feed rates of powder while the red arrows indicate pressure roll pressure and roll turn or revolutions per minute (rpm). Of the four critical parameters, horizontal screw speed is the least critical for success. Roll chatter may occur when one or more of these four conditions do not match the other three settings. Usually roll chatter is caused by a variable powder feed rate into the rolls or a roll speed that is too fast.

Roll chatter may also be caused by air entrapment in the powder. Air may accumulate for more than one reason or for several reasons. Common reasons are a predisposition of the product to entrap air, a combination of natural fiber containing materials and heavier, denser minerals or simple transportation and agitation resulting in air entrapment.

When roll chatter does occur, there are several ways to fix this problem. Fix the powder flow problem first. Premix the powder to ensure standardized flow rates, slow down the vertical feed rate into the pressure rolls or slow down the roll speed. You may also want to purchase a powder de-aerator which will help eliminate excessive air build up.
So roll chatter is really a result of non optimized process settings or perhaps attempting to roller compact a powder that tends to entrap air.

What is Over-Granulating

What Exactly is “Over-Granulating?”

Over-Granulating results from using too much mechanical energy to mix the wet mass. It may also occur from mixing too long, past the end point. It may also occur from adding too much binding solution. Granules are created through a combination of mechanical energy and the quantity and addition rate of a binder. To some extent, it is also a result of the concentration of the binder in the solution. Over granulating is over processing or over working the powders while the liquid is being added and results in a having a negative impact on the final tablet. An over worked granulation my not flow well, compress or eject properly. It may impact hardness, disintegration and dissolution profiles.
 

What is Granulating?

The real final objective of granulating is to provide a tablet that has content uniformity, i.e. the same quantity of ingredients as every other tablet.

Primary reasons for granulating:
Granules may improve flow of fine powders
Granules may improve compression
Granule formation may improve control over disintegration and dissolution rates
Granule formation may improve the tablet appearance

There are two basic methods of granulating; Wet Granulating and Dry Granulating

Wet Granulating
Granules can be formed by adding a liquid into the dry powder mass, much like combining water, milk or egg to flour when cooking.

Dry Granulating
Granules can be formed through dry compaction; some powders are sensitive to liquid addition and must be dry compacted using a tablet press (called slugging), or using a roller compactor to densify the dry powders.


The Wet Granulating process can be used to form very light granules or very dense granules through the use of mechincal force. A granulating machine is catagorized as a High, Medium or Low Shear Energy mixing device that may or may not have drying capabilities.

The wet granulation process can produce a variety of granules. The type of granule produced depends of the nature of the powders, the binding solution, granulator and length of mix. Also, the drying process can influence the final granule. The end result depends on if the product is dried within the mixer or moved to a tray-drying oven or to a fluid bed drying process or some other means of drying away the excess binding solution.

Milling

Determining Factors For Particle Size of a Tablet Formulation

What are the determining factors for achieving the correct particle size distribution of a tablet formulation? I recall some 30 years ago being taught that the general rule of thumb is: particle size distribution needs to be small enough to go through an 18 mesh screen yet big enough as to not go through a 200 mesh screen. While machine type and condition play a role, the following list of items should also be considered.

Flowability: Generally speaking the smaller the particle the worse the flow. Compare powdered sugar with granular sugar. The fine small particles in powdered sugar aide dissolution but not flow.
Feeder clearance: Particle size must be larger than the feeder clearance to prevent leakage.
Die table run-out: If die table run-out increases feeder clearance and particle size must also increase proportionately. To check run-out, use a dial indicator to determine the variation of the die table.
Die fill: Wide variations in particle sizes can cause inconsistent fill volumes.
Weight control: Final volume is final weight. Larger particles pulled out of the die can reduce the final weight. Fine particles require more precise scrape-off and increase the need for a good scraper blade.
Compressibility: Improves with increased particle size and decreases as particles become smaller and smaller. Small particles have less ability to lock together during compaction.
Hardness: Smaller particles are more sensitive to over-compression.
Ejection force: Small particles decrease interstitial space and increase drag and friction.
Lubrication levels: In general higher percentages of small particles require increased quantities of lubricant. Magnesium stearate is the most commonly used lubricant and should be de-agglomerated before use.
Disintegration & Dissolution: Small particles decrease disintegration time, and increase dissolution.
Friability: Larger particles usually lock together better which results in reduced friability while small particles often increase the potential for failure (higher friability).
Electro Static effects: Electro static charge is increased as the percentage of small particles increases.
Dust control: Fine particles create a dusty operation, creating a need for frequent production stoppages and press clean-ups.
Environmental conditions: Many products are hygroscopic and sensitive to heat. Variations in room conditions can result in poor flow, compression and ejection conditions.
Lamination & Capping: Small particles are the heart of the most common defects.
Punch lubrication: Dust and super fine particles become airborne and combine with the oils and greases which can produce black specks in tablets.
Tooling condition: Punch tip & die clearance are designed to control air release allowing for improved compaction.
Machine condition: Cleaning and maintenance are downtime issues. A high percentage of fine particles and dust increases the potential for greater wear, increased cleaning frequency, reduced yield, greater particle segregation, and more tablet defects.
Cost: Fines (small dusty particles) increase operating costs, require increased levels of dust collection, decreased yields, increased frequency of cleaning, and generate greater machine & tool wear. Reducing fines will improve tablet quality.

Summary: Establishing an appropriate particle size distribution will improve tablet quality and will reduce overall costs in the long run. Fine dusty particles are the source of most tablet defects.

Checking the Fitzmill for Standardized Milling Speed

Not all mills are equipped with a tachometer in order to verify mill speed. In any case, it is ALWAYS important to verify that all three belts are in the same condition to insure standardized mill operation. The speeds "slow, medium and high" indicated on the batch record will not necessarily be achieved unless all three belts are in approximately the same condition.
 

What mill should be used in each unit operation?

Why mills are used in pharmaceutical manufacturing.

The four primary reasons for milling a powder and granulations are to;
Improve Flow
Reduce Segregation
Enhance Drying
Improve Particle Size Control

Mills are used in many steps with the manufacturing process:
Pre-Weighing/Dispensing to eliminate lumps- use a low shear mill
Pre-Blending to reduce agglomerates – use a low–medium shear mill
Post Wet-granulating to improve drying uniformity–low-medium shear
Post Dry-granulating for size reduction– high shear mill

Mills can be categorized from gentle (low shear) to aggressive (high shear).
If a product is soft and sensitive to compaction and densification the mill used and how the product is feed into the mill can be critical. A gentle low shear mill like a Comill or Oscillator maybe preferred to a high shear type mill like a Hammer mill.
 

Tablet Coating

Gun Calibration Before Coating

Gun calibration is important for top quality coated tablets. After the gun geometry check and before gun boom installation into the coating pan, a gun check should be performed to determine if all the guns are spraying the same amount of solution per minute. Ideally one would place a graduated cylinder beneath each of the guns to be tested and then run either a one or two minute spraying cycle to determine if the guns are spraying at the same rate. Keep the atomizing air off while doing this. The guns should not vary by more that +/- 10 ml/min. Any variation greater than this requires a gun adjustment.
You can fine tune the gun by turning the bolt or the spin dial at the rear of the gun. This adjusts the needle thrust and allows either more or less solution through the nozzle. Try altering this setting until you have all the guns spraying within the tolerances outlined above.

Particles Adhering To The Spray Guns

Particles adhering to the area of the gun near the solution port or the areas of compressed air egress can seriously alter spray patterns and ruin a pan of tablets in less than 5 minutes. It is important for the operator to constantly monitor the guns using a flash light to see in and around the guns. Any material adhering to these parts of the gun should be cleaned immediately.

Clean the gun using this procedure: stop spraying, keep the atomizing air on, take out the gun boom (or reach into the pan for the affected gun(s), clean off the guns using either a short plastic or brass bristled brush. After thoroughly cleaning the gun surface, return the gun to its position and then turn the gun back on. Never turn off the atomizing or pattern while cleaning the gun.
 

Aqueous Coating 101

Aqueous Tablet Coating 101


I. Introduction
What makes aqueous coating so dynamic? Once a we have a compressed tablet, we often need to add a coating. The coating can serve many purposes; it may make the tablet stronger and tougher, it may improve taste, it may add just a color, and may make the tablet easier to handle and package. The coating may be a thick sugar based coating or a very thin film. Most pharmaceutical tablets are coated with a thin film coating.

II. Before we Begin: A Short History of Tablet Coating
“Panning” was the original term for the process of adding a coating to a tablet. The term panning is still a common term used in the confectionary business. Ion years past coating began basically using a rotating drum (pan) on a stand. A coating solution was added using a ladle, while the rotation of the pan distributed the solution throughout the bed of tablets. This technology was slow waiting for the coating solution to dry; and the trick was to get it to dry evenly.
With the advent of film coating a film or thin membrane, usually representing 1-3% of the total tablet weight, was sprayed on using a perforated pan. To decrease the overall process time, holes where drilled through the pan so that treated air (hot or cold) could be pulled through the pan, much like a clothes dryer, allowing the tablets to dry more quickly. With this advent of improved drying came the ability to switch the film coating solution from a solvent based solution to a water based solution, thus the beginning of what we know today as aqueous film coating.

Many Pharmaceuticals manufacturers have moved to a water based solution replacing solvents. Exposing tablets to a water based solution presents a challenge in applying and quickly removing the water so it does not disrupt the integrity of the tablet. Tablet film coating equipment has evolved to enhance this drying capability.


III. Basic Aqueous Coating 101: The Basic Coating Process
Essentially a tablet coating system is much like a fancy clothes dryer. The water based solution is sprayed in a fine mist so as to dry almost immediately as it reaches the tablets. As the water dries it leaves the solids as a thin film on each tablet. The coating system continuously supplies hot air; at the same time it pulling air through small holes in the coating drum. Over time, the film builds into a layer of coating solids which is called the film coating. This process can take as little as 30 minutes or as much as several hours, depending upon the size and shape of the tablet and the size of the coating pan.
The length of time it takes to coat a batch of tablets depends on several variables: tablet quality, coating solution type (water or solvent), coating solution percentage of solids, rate of coating solution addition, the air volume and temperature control within the equipment and maintaining the proper balance of room to pan pressure. the tablets must be tough enough to tumble while the solution is added. The solution is distributed from tablet to tablet during the tumbling and drying process. The spraying, distribution and drying all takes place place at the same time. When you add still another factor that core tablet quality maybe somewhat variable, we have a collectively a condition that requires true operator skill and understanding.

Stated differently, vitamin or nutriceutical tablets having a high percentage of “natural” ingredients are more difficult to coat than products with a high percentage of excipients. Natural ingredients may have variations in moisture content, bulk density, granule structure, flow characteristics and compressibility. Therefore the consistency of tablet quality and its surface characteristics influence process setting to be used. The more inconsistent the surface of the tablet, the more likely the final tablet quality may not meet the desired quality level. Again, for this and other reasons, the tablet coating process is dynamic. There are various phyiscal actions taking place at the same time. Nevertheless, we must begin with a good core tablet in order to finish with a well coated tablet.

IV. Coating Equipment Used Today

Tablet coating equipment combines several technologies and is commonly referred to as a coating system. The system consists of a solution preparation tank, the air handling unit, the coating pan, the spraying system, the dust collector and a set of controls.

The solution preparation system usually consists of a solution preparation tank equipped with a mixing devise.
The air handling unit (AHU) is basically a way of heating and filtering the air. Dehumidification and humidification maybe be needed depending on your location and application requirements. This system is engineered to provide a consistent stream of treated air each time one uses the coating pan.

The coating pan is a perforated drum within a cabinet, allowing for control of air flow, air temperature and solution application.

The spraying system consists of a solution tank & mixer, a solution/suspension pump, a set of air assisted solution guns and air lines.
The solution is pumped into the guns and the air combines with the solution for atomization into a very fine mist.
The dust collector collects the dust during the preheat and tumbling cycles and the Controls connect all of the components creating a complete coating system.

V. The Eight Critical Process Variables in Aqueous Coating

There are eight critical process variables in aqueous film coating. A basic understanding of these variables is critical for successful tablet coating. The eight variables and a brief description of each follow:

(1) Gun Geometry: The placement of the guns inside the pan to obtain maximum exposure of the tablets to the solution spray without coating the pan surfaces.
(2) Atomizing/Pattern air: The compressed air used to convert a stream of solution into a pattern of small, flat droplets.
(3) Pan Pressure: The differential pressure between the pan and the room resulting in a slight negative pressure in the pan which in turn draws the coating solution into the bed of tablets.
(4) Pan Speed: The speed of the perforated rotating drum holding the tablets. The speed may be constant or variable throughout the length of the coating cycle.
(5) Spray Rate: Usually expressed as ml/min/gun or total quantity sprayed per minute, this is the amount of solution sprayed onto the tablets at any unit time.
(6) Inlet/Outlet Air Temperature: The temperature of the inlet air provided to the pan (a set point) and the temperature of the air after leaving the pan (a function).
(7) Total Air Volume: The quantity of air provided both to the pan and taken out of the pan.



(8) Adhesion of Particles to The Gun Surface: A non quantifiable operating parameter involving prevention of sprayed dried coating solution from adhering to the critical surfaces of the spraying gun(s).


VI. Basic Tablet Defects Seen in Aqueous Coating
There are several common defects commonly seen in the finished tablets as a result of non optimized or improper setting of the critical operating parameters. These are briefly described below.

Picking & Sticking are caused by over wetting of the tablets or by under drying.
Bridging or the filling in of lettering is caused by improper solution addition, poor tablet embossing design or high solution viscosity/percentage of solids.
Capping is often a problem that is created in tablet compression but not seen until the coating.
Erosion can be the result of soft tablets, over wetted surface, and inadequate drying and a lack of tablet surface strength.
Twinning is when to tablets stick together, a common problem with a caplet shaped tablet.
Peeling & Frosting is a defect where the coating peels away from the tablet surface in a sheet. The coating solution did not lock into the tablet surface. This can be from the coating solution, over wetting or from high moisture content within the tablet core.
Chipping can be caused by high pan speed, a friable tablet core or a poor coating solution.
Mottled Color is caused by improper solution preparation, spray rates, cold cores, and improper drying rates
Orange Peal is usually the result of high atomization pressure in combination with higher solution rates combined with tablets rubbing


VII. Putting It All Together: An Example of Coating A Typical Batch
After calibrating the spraying guns and loading a batch of tablets into the coating pan, we need to preheat and remove excess dust and tablet flash. Once the tablet bed reaches the 42°C- 46°C outlet temperature, the spraying process can begin. Soft tablets or tablets with high porosity may require an initial spray rate that is slower than the recommended average of 80-100 ml/minute/gun. Most tablets need an intial coating to protect them, and usually around the 20 minute mark the spray rate and pan speeds can be increased signiciantly. During coating it is important to monitor the spray pattern. Any changes in the pattern usually means buildup of solids on the tip of the gun and this must be corrected by stopping the spray addition and manually cleaning the guns. The operator must continuously monitor the pan/room magnehelic pressure gauge making certain that there is always a slight negative pressure. Once the spraying cycle is complete a cooling cycle is sometimes used to return the tablets to room temperature.

Automatic controls follow a menu that maintains most of the critcal paramters outlined above. But the computer cannot see everything. Gun geometry and particle build up on the spray guns will forever remain under the watchfull eye of the process operator.

IX. Summary: Aqueous film coating is a technically demanding, controllable process to seal core tablets with a clear or color coating. Understanding the eight critical operating parameters and the common defects encountered by using non optimized conditions or improper settings will greatly assist the manufacturer in achieving quality coated core tablets.
 

Tablet Compression

Tablet Press Overload Setting

Tablet Press Overload Setting: Is a protection device to protect the tooling from becoming damaged as a result of too much pressure while making tablets. Each set of tooling has a limit of how much pressure (force) they can take before bending or breaking. Tablet presses are built with a release system designed to allow the pressure rolls to “release” (spread apart) during operation when the limit of the tooling capacity is reached. Therefore, when you receive a set of tooling to install into the tablet press, one of the set-up procedures would be to identify the maximum load the tooling can take, and then set the press to match this limit. This can be accomplished by asking your tooling supplier to give you this value or you can look it up in the TSM (Tablet Specification Manual). Example per attached Table #13: A set of ¼” (6.350mm) round, standard cup tooling, made of S7 tool steel, has a maximum load rating of 14.0 Kilonewtons (1.4 tons). The TSM is a standardization of tooling & press specification, some refer to it as the “tablet press bible”, and it is a good guide (not a bible). The TSM is available from most punch & die suppliers. When a machine goes into “Overload” the capacity of the compression set point has been exceeded and the pressure rolls will move apart to protect the tooling. Some machines have very simple overload systems and others have very complex systems that are set to a computer which can track, reject, alert and stop the machine. Older machines that go into overload start to bang loudly.

Target Weight: Do GMP’s allow a tablet to be made off target?

Do GMP’s allow a tablet to be made off target within a weight range or must a tablet be made to target? The objective is to make a tablet within a weight range, where the center of that range is considered the target...or is it? This implies that a tablet made off target is not acceptable. If a tablet is made within an acceptable weight range but intentionally off target...is that OK according to GMP’s? Anyone who runs a tablet press knows that a press has two primary functions; Weight and Thickness. Hardness is a result of weight, thickness and dwell time. Therefore if the hardness target is low, weight can be increased within an acceptable range to increase hardness. Is the question can we make tablets within a range or is the question to define what target means? Weight is the single most important tablet attribute...go check your weights...AGAIN!
 

The Scraper Blade, a Critical Part

One of the cheapest parts on a tablet press that causes some of the most serious problems is an object called the scraper blade. Its task is simple, i.e. to scrape the excess powder away from the die and direct it into the recirculation channel towards the feed frame. While the part itself may only cost between $5.00 and $30.00, if allowed to wear out can cause thousands of dollars in machine damage and material loss.

The scraper blade can be a tricky part to adjust properly. It is also the only part on the entire press that comes in direct contact with the table.

Take the time to adjust the scraper blade properly! A correctly installed blade will ride on the table preventing powder from extruding under it, but it will not be so snug as to gouge the table and cause damage.


So take the time to install the scrape blade correctly!

Oil on the Press and Spots on the Tablets

Machine oil leaks are very common on older presses with an older style of lubrication system for the punches and main worm gear. Sometimes it may be that the resevoirs are overfilled, but more often than not the oilers (or drip cup) will have just come loose during the compression run. These are easy problems to fix and will prevent unnecessary rejects: tighten up the fittings and don't overfill the reservoirs.

Tooling Room

Tooling Room, unknown empire!


The tooling room in a pharmaceutical plant is an unknown empire. Most line managers we speak with know it exists, know where it is, know about what it does (“polishes punches”); but have no idea of its true role in the larger manufacturing picture. Neither does the FDA. In our experience we know of no inspector that has ever seriously visited a tooling room at a large pharmaceutical company and we rarely see a form 483 observation issued specifically for a tooling room deficiency. Our article discusses the role of the tooling room and provides a basic checklist of established equipment and practices used in this key manufacturing area.

The tooling room performs much more than the “punch polishing” function. There are many more operations performed than is commonly appreciated and, in fact; the more one understands about successful high speed tablet production, the more one appreciates the tooling room and its key place in the manufacturing department. For high quality tablets, in part, come from tooling room practices and procedures. In the article below, we discuss some of the tooling room activities commonly performed and their impact on the production floor.
I. Primary Function: Check in and Verification of New Tooling
A. Initial checking of tooling when received- Upon receipt and check in, the tooling first undergoes a comparison with the approved original drawing outlining verifying size, shape, type of punch surface and any identification wording. The tooling next undergoes an initial battery of standardized dimension checks. There are semi-automatic tooling dimension verification systems available on the market. The illustration below presents an example of one such test called the tip concentricity measurement.
B. Checking the Tooling Dies: Checking dies is performed to verify die tolerance and ware.
II. Primary Function: Checking Tooling after Each Use on the Press
A. Checks performed after each use- Dimension checks are performed to determine what, if any, changes have taken place as a result of exposure to active ingredients and the wear and tear that accompanies the tablet compression event. The degree of wear varies greatly depending upon the nature of the active ingredient, number of batches compressed, lubrication practices on the press and the method of handling.
B. Cleaning The Tooling- Tooling must first be cleaned of residual drug and granulation. In some operations this is achieved using an ultrasonic cleaner combined with tooling racks.
C. The polishing operation- Tooling usually dulls with use. At each inspection tooling will usually undergo a polishing to remove the dulled portion of the tooling cup and to standardize the cup finish prior to reuse.
D. The different kinds of polishing compounds- There are many polishing compounds available to the user. Some of the most popular types are diamond compound and Jeweler’s rouge.
E. The different methods of polishing punches: Generally, we use either a Duo Flex motor and/or a buffing wheel to polish tablet tooling. Both have their advantages and disadvantages.
F. The role of the optical comparator in checking head flats: Use the optical comparator to determine head flat type and condition.


III. Primary Function III: Understanding the Role of Worn and Damaged Tooling and Taking Appropriate Action
A. The Effect of using short or long punches- Short punches, assuming they are not received in this condition, always happen as a result of wear and/or polishing. Long punches, again assuming that they are not received in this condition, result when comparing to shorter punches. Using long or short punches is a discredited practice and creates problems on the tablet press. For example, a short upper punch creates thicker and in some cases softer tablets. A short lower punch creates a tablet with a heavier weight. Another discredited practice involves taking punches from different sets and creating a hybrid set of tooling. Doing this essentially may create a set of punches having multiple punch lengths and may result in an uncontrollable tablet weight for lower punches and an uncontrollable tablet hardness and thickness for upper punches.
B. Worn Tooling and appropriate remedial action- Press tooling, press cams, die lock screws, pressure rolls and other major press parts are all wear parts and must be replaced with time and wear. For press tooling the real question to ask is: “at what point does one replace these items and how does one measure tooling wear to predict the replacement point?”.
C. Damaged punches and appropriate remedial action- Damage to press tooling occurs as a result of many factors including handling, cams, set up and lubrication practices. Damage to tooling heads, bevels and shanks as well as tips have structured repair approaches depending upon the amount and type of damage incurred.

IV. Other Factors in the Tool Room Affecting Tooling Performance
A. Record Keeping- Record keeping is a cGMP requirement in all areas of tablet manufacturing. Record keeping begins with the initial tooling check in and ends with tooling destruction. A typical record packet will contain the initial tooling drawing along with the purchase order as well as dimensions found at check in. A second portion of the package will contain results of tooling inspection and dimension readings (both before and after reconditioning) each time the tooling is rechecked into the tooling room. A third portion of the record packet will contain any unusual condition in the tooling noted during the various inspections and what was done to correct any problem.
B. Cramped Conditions in the Tooling Room- The same standards for safety and cGMP compliance used on the tablet production floor should be used to evaluate the tooling rooms. Unfortunately, in our experience, the tooling room needs are all too often not well understood or receive a lower priority.
C. Overhead Lighting- There should be adequate lighting in the tooling room consistent with the lighting standard in the compressing cubicles. We note that many tooling rooms have inadequate lighting for the tasks required of the technician. If the technician doesn’t notice, no one else usually does either.
D. Inadequate or Inappropriate Work Tools-The concept that tool polishing alone prepares the press tooling for a manufacturing run simply does not allow the organization success on the production floor. Inspection equipment, as well as the two major polishing avenues, should be provided to the tool room technician.
E. Technician Training-All major tooling manufacturers provide technician training classes at a nominal charge. These courses are customarily given periodically throughout the year at the tooling factories or on a prearranged basis at the customer’s site. Most pharmaceutical sites send a technician to the tooling manufacturer for training.
Summary
The Unknown Empire helps keep the tablet manufacturing floor running efficiently and with a high degree of product confidence.
Tablet Press Overload Set Point

Is The Overload Set Point Really Important?

The overload set point is one of the most misunderstood concepts associated with tablet press operation. It is often mistakenly associated with tablet hardness, compression force and even tablet weight. Although considered an important machine parameter by compressing professionals, it is not in fact a process parameter. It generally does not appear on a batch record nor in many operating SOP’s; yet failing to set it correctly may lead to a costly and even dangerous outcome. This article discusses the importance of understanding the overload set point, how it is correctly used and what it does and does not do.

I. Introduction
What exactly is the overload set point? What is its purpose? Why is it important?
Why is it so misunderstood? Let us begin to explore the answer by asking a basic question: is it possible to place too much force on a set of punches in a tablet press? What happens when this event occurs?
An overload condition, sometimes called an event, occurs when too much material is placed in the die at one time, and amazingly, some of the material many not be the powder we are compressing. For example, suppose a bolt has shaken loose from a feed frame and entered into a die? The computer senses the difference, makes a decision and rejects the tablet. Product quality is preserved, but what potential effect does this upset condition have on the tooling? The tip of the tooling may fracture, or completely break off or the entire tool may fail.

How does one protect the tooling against this potentially fatal situation? By correctly setting the overload set point.

II. Understanding How a Tablet Is Made Is Key To Understanding What May Go Wrong

Powder is actually “squeezed” into a tablet by the action of one upper and one lower punch sliding along ever closing cam tracks and meeting together at a predetermined point in a die between the two main pressure rolls. The predetermined point may be altered and the width of the “squeeze” may change by moving the lower pressure roll upward or downward. We call this result tablet thickness. The force observed we call the “compressing force”. When an upset condition might occur, such as when an entire tablet sticks to the punch and fails to be ejected from the die, we have a potential for an overload condition. In this situation we have the die filled again followed by a double compressing event of the stuck tablet combined with the new material.

This results in a pressure far exceeding a normal situation and probably exceeding the maximum allowable for on the punch tip. Other similar events might also occur: a scraper bar comes lose and center itself over the die under the two punches, a bolt shakes loose off the press and enters the die cavity, a tablet jumps into a feed frame is torn apart by the feeder wheels and pieces enter multiple dies.

III. The Overload Event: When set correctly the machine will release separating the pressure rolls to prevent damage to the tooling. The press senses an excessive pressure through the release set point and reacts. The reaction is in fact a separation of the two main pressure rolls by momentarily moving the lower pressure roll downwards away from the other. Doing this relieves the pressure situation and protects the punch tips. How does the press sense this situation? How do we determine what is the maximum allowable tip pressure, where is this information located and how do we set this information on our tablet press?
IV. Determining The Maximum Allowable Tip Pressure and Setting This Value on The Tablet Press; The tablet actually compares an input pressure value to actual pressure value and makes a decision to accept the value or back the lower pressure roll away. This may be done in more than one way. Some systems are hydraulic; others act on a “carriage” value or “support” value through a spring. For example, on older presses this is done by adjusting a large spring at the back of the press. Some presses like the Manesty series, have a simple dial adjustment. All computerized presses accept a simple input value. So the overload set point has no relation to tablet weight, hardness or thickness except in the rare case that the overload is triggered. In this situation the tablet will be thicker and softer than the other tablets because the compressing process was stopped along the way when the lower pressure roll assembly pulled away from the upper. The overload system is simply like the presses relief valve one sees on a pressure cooker. There are various sources for the overload value we seek. Most tablet press manuals provide established calculations for many standard round tablets. In some manuals detailed rules accounting for various pressure discounts for letters, numbers and bisects are also provided. In most cases, all other type of tablets, such as capsule and oval shapes, are calculated on a case by case basis. Manuals are not the only source of this value. Most drawings generated after 1999 that accompany newly received tooling have the same values printed somewhere on the face. For all non round tablets the values are calculated on a punch by punch basis since even upper and lower punches with the same shape may vary somewhat if the combination of letters numbers and bisects are different. If you have two punches with different values you should use the lower number as the setting for both.

V. Setting The Overload Set point Value on The Tablet Press

The overload may be set in more than one way, depending upon which type of press you are using. Remember that the overload value is a one time setting or input to the press for any number of batches being processed. It does not change until the next product in placed on the tablet press. With tablet presses having computerized set up, this is a numerical value for input in a field. For older presses, a physical adjustment of a spring or counterbalance is required.

VI. Summary

The overload set point is a safety value that all tablet presses use to protect the tips of the punches. It is not a critical processing parameter but it is a very critical machine setting. It is not related to compressing force or tablet attributes and it has no influence on tablet quality. The overload values do not change using different types of tablet presses but it will vary from punch to punch depending upon the combination of letters, numbers and bisects used. Understanding and using the overload system correctly is one of many key factors involved in the overall tablet compressing operation.
 

Installing Dust Cups on Tablet Press Tooling

Proper installation of dust cups on tablet press tooling

Dust cups or oil cups? Depending on how dust cup are installed, they can be defined as either dust cups or oil cups. Rubber cups are placed on the punch tips to prevent product that has combined with the oil from dropping onto the die table and contaminating tablets with gray and black specks. If the dust cup is placed on the punch tip and seated by rotating the machine and allowing the upper punch to seat the dust cup against the die during compression, it will help prevent dust from puffing and becoming airborne during compression. If the dust cup is pushed up on the punch tip, and does not touch the die during compression, it is really only an oil cup.

Solutions:

Remember that dust cups should be punched-out upside down then turned over for use. This will assure that the dust cups lock onto the punch tip much more tightly. It is best to place the cups on the very edge of the punch tip and allow the upper punch penetration to seat them. This is done easily by just putting the cups on the very edge of the tip and rotating the machine. The cups will then all be in the same position on the punch tips.

Black & Gray Specks

Black & Gray Specks found on the surface of the tablet - a common problem found immediately after the tablet is made and ejects from the tablet press.


Black and Gray specks are often a problem. As tablets are made, fine dusty particles become air born and will often combine with the lubricating oils of the upper punches (make sure you are putting the dust cups on correctly and placing them in the correct position on the punch tip). Punch lubricating oils are dried up by this air born dust and will often turn gray or black and flake and fall from the punch barrel. Centrifugal force and vibration can distribute these gray and black flakes onto the feeder, die tablet and punch faces. Thus, finding their way into the tablet. Dust cups will help prevent some of the combined oil and dust falling on to the die table. Also, monitor the build up of oil and dust on the punch barrel. Quantities can build up and can be slung onto the feeder and die table, especially when running at higher rpm. Also, black and gray specks can occur from granulators, blenders and mills. Make certain where the source of the problem is before blaming the press.

Reader's Solutions:

Remember that an automatic lubrication system delivers a set amount of lubricant at timed intervals. The amount of oil and frequency is determined by the operator. Since pharmaceuticals are processed “batch to batch”, every batch is not exactly the same. The press operator must monitor that the proper amount of oil is being delivered. If the batch you’re working on is dustier than the previous batch then increase the frequency of the automatic lubrication system or manually over ride the auto system and activate the lubrication system.

We have also found that setting the feed frame too close or too far above the die table can allow product to compact on the die table, especially with waxy and oily products. Make certain to set up the feeders on the high spot of the die table. Every press has a die table high spot; the older the press the more likely the die table is not perfectly flat all the way around. Teach set up persons to position the high spot under the feeder while setting proper feeder height.
 

Tablet Defects

Target Weights

Do GMPs allow a tablet to be made off target within a weight range or must a tablet be made to target? The objective is to make a tablet within a weight range, where the center of that range is considered the target...or is it? This implies that a tablet made off target is not acceptable. If a tablet is made within an acceptable weight range but intentionally off target...is that OK according to GMPs? Anyone who runs a tablet press knows that a press has two primary functions: Weight and Thickness. Hardness is a result of weight, thickness and dwell time. Therefore if the hardness target is low, weight can be increased within an acceptable range to increase hardness. Is the question, can we make tablets within a range, or is the question to define what target means? Weight is the single most important tablet attribute...go check your weights...AGAIN!
 

Tablet Lamination

Lamination is when the tablet splits apart in single or multiple layers. Lamination is often blamed on over compressing - too much compression force flattens out the granules, and they no longer lock together. Lamination can also occur when groups of fine and light particles do not lock together. These groups of fine and light particles simply will not compress well. Reducing thickness and increasing dwell time will give these particles more of a chance. Dwell time can be increased by adding pre-compression or slowing the machine speed down. Adding a taper into the die will help eliminate lamination, however, many lamination problems are directly attributed to the formulation or to the preparation of the product.

Tablet Capping

Capping is often directly related to air entrapment. That is, the tooling (punches & dies) is designed to allow the air to escape between the upper punch tip and the die wall. The upper punch tip is smaller in diameter than the lower punch tip in order to allow the air to evacuate during compression. For this reason capping is often associated with air entrapment. Running a tablet press at 3,000 tablets per minute (50 tablets per second) may not allow enough time to evacuate the air completely. Compression can be so quick that when air is evacuated it also drives the fine, dry and light particles (non-compressible particles) to the caps edge, thus resulting in capping.

The first step to resolve capping is to increase dwell time. Dwell time is controlled by press speed, compression stations (main compression & pre-compression) and punch head flat diameter. Punch head flat diameter is often overlooked. As punches wear, the punch head flat usually becomes smaller and smaller (less and less dwell time). Variations in hardness tablet to tablet can be attributed to changes in punch head flat diameter. Also, worn dies (dies with a wear ring) will make the tablet split during ejection which gives the tablet the appearance that capping has occurred (replace the dies).

A "bad" formula can contribute to capping. Dry blends, particularly, are frequent victims in nutritional supplements in that all actives are force fit into a “boiler plate formula” with little fundamental research attached. Formulas that do not contain enough binder or have excipient ratios that are out of line with established guidelines will surely bring problems like capping to the production floor. Blending too fast or too long may introduce air, breakdown granules or over blend the mixture and spoil an otherwise perfectly good formula. Under mixing actually causes segregation and indirectly causes capping.

Sticking

Sticking occurs when granules attach themselves to the faces of tablet press punches. Picking is a more specific term that describes product sticking only within the letters, logos, or designs on the punch faces. This article explains the causes of sticking and picking and describes the steps you can take to resolve both problems.

Regardless whether it’s sticking or picking, the result is a defective tablet. To salvage the batch, you may have to visually inspect the tablets. This certainly will slow production and decrease yields, but there is no alternative. The formulation is completed; you can’t send it back down the hallway for reprocessing.

Sticking can happen at any time throughout a batch. It occurs most often at the initial setup of the tablet press, but it might just as easily appear randomly in a production run. It might also appear at regular, predictable times. With some products, sticking is so predictable that operators consider it a success when they can run for 2 hours without any sticking.

Knowing the moisture content, particle size distribution, and other product properties will help you predict whether a product will compress without sticking. However, even products that meet your specifications may stick and pick. The fact is, you may not know how well a product will compress until it is on the tablet press.

The source of the problem may relate to the product, the tooling, the upstream processes, or the operation of the tablet press. It might also be a combination of these factors.


Sticky granules make good tablets…right?

When a tablet press is set up for the first production run, the operator will first adjust the weight cams to get the correct tablet weights. (Actually, you adjust the position of the lower punch in the die. In doing so, you control the volume of the die cavity. At a given bulk density, the die volume will correspond directly to tablet weight.)

Once you have the weights right, adjust tablet thickness next. Tablet hardness is determined by a combination of variables, including tablet weight, tablet thickness, press speed, and the dwell time of the upper punch in the die at full compression force.

Products with granules that are super-sensitive to compression—call them sticky granules—can form excellent tablets. But they are also prone to sticking to the punch faces. If this is the problem on your press, you are likely to see the problem worsen over the course of the production run. That’s because granules super-sensitive to compression will readily compact as they flow through the hopper and into the feed frame.

If a powder compacts before it reaches the die cavity, the bulk density of the formulation increases, impeding your ability to control the tablet weights. As the weight of the tablets fluctuates, so does the compressive force. This variation in force, in turn, can exacerbate the product’s tendency to stick. That starts a downward trend, and that’s why the sticking gets worse and worse.

Experienced tablet press operators know a trick about compression: If sticking is a problem, they quickly over-compress the product and make very hard tablets for a few press revolutions. This quick action, known as “shocking the press” can work very well. Why? The answer is fairly simple: The stronger compaction forces cause the granules to bind with the tablet and pull the stuck granules away from the punch face. Be careful when using this method to shock the press. If you overload the punches, you will damage them or even break them.

Experienced operators can also “save” a sticking batch when inexperienced operators don’t know where to start. Experienced operators, for example, often hear changes in the sound of the press and know that the product is sticking. Their first action might be to change the compression settings, such as by increasing the force, reducing tablet thickness, or by decreasing pre-compression thickness (which makes the tablet thinner and harder). They may even slow the press. A good operator always pays attention to the tablet and the tablet press. The sooner you identify a sticking problem, the faster you can resolve it.

The P’s and Q's of Tooling:

Sticking and picking are usually the result of many factors, but because they happen on the face of the punch, it’s easy to blame the tooling. Sometimes the blame is placed there correctly, especially in the case of picking.

Picking occurs on the letters, logos, and other designs of the punch face. Usually you’ll find the picking within the “closed” numbers and letters that form “islands.” These numbers are 0, 4, 6, 8, and 9. Some of the letters are A, a, B, b, D, d, e, P, p, Q, q, and so on.

Tooling manufacturers know about these problematic numbers and letters and do a good job of making punch faces that prevent picking. You can even order tooling with a “pre-pick” feature. A pre-pick feature means that the punch face has islands that are not as deep as the rest of the embossing. Despite the shallower islands, the punch still makes a clean, legible indentation. Another strategy is to change the height and angle of the embossing. Doing so produces a tablet with the same appearance but without the picking problem.

Note that tablets destined to receive a coating will have lettering that is less severely angled, wider, and shallower than the lettering on non-coated tablets. Thus, the design of coated tablets helps reduced sticking and picking.

The choice of steel and the degree of polish on the punch will also affect picking. Type D2 and Type 440C steel contain more chromium than other steels, which reduces sticking and picking. High-chrome steels also allow you to achieve a mirror-like polish. Another option is to specify a chrome-plated finish for a hard-faced, wear-resistant surface. However, if the product is abrasive, the chrome-plated finish can wear away quickly. Ask your tooling supplier about these options.

In some cases, changing the tool design and its surface finish is enough to stop sticking and picking. But changing designs could well be a waste of time and money, because many products will stick and pick no matter what changes are made to the punch design.

Air Entrapment:

The act of compression can trap air in the concave cup of the punch face. The deeper the cup, the more likely it is to trap air. This trapped air creates a soft area on the very top of the tablet. In such cases, the granules don’t know whether to stick to each other or to stick within the punch cup. It is similar to making a tablet that is too soft: The granules aren’t sure where or what to stick to.

The solution here is to make certain the punch dwell time is correct and that air evacuation is adequate. The primary way to reduce entrapped air is to increase the force of the pre-compression stage so that there is less air to evacuate during final compression. You should also be certain that the tablet is compressed as high in the die as possible. This is referred to as the depth of upper punch penetration. The higher it is, the easier and faster the air can escape during compression.

If those adjustments are not possible, consider using tapered dies to help get the air out. Talk with your tooling manufacturer. Tooling manufacturers are specialists and they can probably help you solve the problem by adding a taper.

Another possible solution is to specify a tablet shape that uses a compound radius. Doing so “flattens” the very top of the tablet, eliminating the air pocket. The change is slight but effective. Furthermore, it will not cause a noticeable change in the tablet shape or design.

When making a compound radius change to tablet tooling (specifically small tip tooling) you should have the tooling manufacture evaluate the change for
additional compression force stress (tooling life) that may come about due
to a compound radius change. Otherwise, you maybe exchanging one problem for another.

It is also important to note that a slight change to a tablet shape (even a slight radius change) can negatively impact blister feeding and tablet count when packaging in bottles. This is especially true on high speed blister and bottle packaging lines. Go over this change with the packaging professionals before you committ your site to the new design.

You may discover that new punches are more likely to entrap air than used punches simply because of their tighter clearances. Tight clearances are good, but they can cause air to escape more slowly during compression. With the old tooling, air escapes more quickly so particle-to-particle bonding is more likely. When customers tell me that brand new tooling gives them more hardness, sticking, and capping problems than the older used tooling, I attribute the problems to the tighter clearances of the new tooling and a decrease in the evacuation of air.

Lubricating the Right Way:

The function of a lubricant in the product formulation is to prevent powder from sticking to the punches, dies, and other metal components of the tablet press. A lubricant also facilitates the ejection of compacted tablets. It is not a liquid or oil, but a light, fine powder. Typically, lubricants account for a small percentage of the formula’s content, from 0.25 percent to 2 percent. The most common lubricant in pharmaceutical formulations is magnesium stearate.

Despite the small particle size and the small quantity of the lubricants, they strongly affect your ability to make a good tablet. If they are not blended correctly in the mixture, they will not function as designed. There are two common errors when processing lubricants. The first error is neglecting to pre-screen the lubricants to remove the lumpy, over-size particles. The second error is failing to blend the lubricant evenly into the product formulation. The lubricant must be able to contact the metal parts to work correctly. However, it is better to under-blend the lubricant than to over-blend it. Over-blending will hide the lubricant within the other particles, rendering it useless.

If you run a press without lubricant, you may hear the powder squeaking as it compresses. You will also notice an increase in the force needed to eject the tablet. In fact, the increase may be so great that it damages the punches and the ejection cams. The absence of lubricant or the presence of incorrectly blended lubricant will also lead to sticking.

If you don’t recognize that poor lubrication is causing the sticking problem, you or your colleagues are likely to blame the tooling. The next step in this misdiagnosis is to stop the press, remove the stuck products, and polish the punches before restarting the press. Because polishing the punches can provide short-term relief from sticking, you may repeat this cycle throughout the production campaign. By the time you’re done, you’ll have convinced yourself and your team that the tooling’s loss of polish is the source of the problem. But that is incorrect.

True, polishing the punches can solve a sticking or picking problem temporarily, because many polishes act as mold-release agents. So the act of polishing did nothing more than work this mold-release agent into the surface of the punch. The satisfactory—but temporary—result is a successful production run. Then the product begins to stick again, and you re-polish. Sometimes polishing does no good whatsoever. Other times you might go for an hour or so before sticking resumes.

Some companies accept these short production runs as part of doing business. They expect some products to start OK, and then to stick eventually. They will remove the punches and polish them throughout the run. Ask your operator about the polishing routine. The secret that every press operator knows is that some polishing compound must remain on the punch tips for sticking to stop. They know not to clean the punch tips with isopropyl alcohol, as is standard. If they did, the sticking would return immediately. So is polishing really solving the problem? Not likely.

Even so, a combination of factors may convince you that poorly polished punches are indeed the source of the sticking. Recall that many sticking problems occur at startup, when all the metal components are clean and free of any lubricant. Thus, the punches are prone to sticking. The reaction of most operators when they see sticking is to stop the press, pull the punches, and polish again, even though the punches were just polished.

While they polish the punches, operators might give the press itself only a cursory cleaning. Excess powder is removed, but a thin dusting of the product is left behind. When the punches are reinstalled, the press runs without sticking. Thus, the operators walk away believing that polishing the punches solved the problem when the distribution of the lubricant within the product was actually the source of success.

To prevent sticking at startup, some companies routinely distribute lubricant by hand before tableting. This puts a dusting on the press that prevents sticking at the start. Excess lubricant is gone after the first few press revolutions. Some people think this is unacceptable. But is it any less acceptable than not cleaning the punches after polishing?

Process-Related Sticking:

Some sticking and picking relates to upstream processing. Improperly applying binders or poor drying of the product, for example, can make polishing the punches an hourly event at some companies.

Application of Binder:

During the granulation process, a liquid binder is often added to a powder blend, thus bonding (binding) the ingredients together to form granules. Binders are often called pharmaceutical glue, and to work as planned, the distribution must be even throughout the batch of product and the binders must be uniformly dried.

If binders are not distributed evenly and dried completely, some portions of the blend will contain concentrations of binder. In the drying process, these overly wet granules become dry on the outside, but not on the inside. This is called case-hardening.

Case-hardening can occur even when binder is added correctly but drying was too rapid. Removing the moisture too quickly causes some binder to move to the granule’s exterior. This migration of binder to the granule surface creates a hard shell around other material that may not be completely or evenly dry. This phenomenon leads to two possible causes of sticking: Entrapped moisture and concentrated binder on the granules’ surfaces. Slowing the drying process will sometimes eliminate both problems.

Changing the way you add binders or dry a granulation is easier said than done. Nonetheless, scrutinize all the steps of your methods to find and prevent problems. After all, proper granulating is a fundamental issue when sticking is the problem. Some of you may opt to polish the punches again and again instead of addressing the true cause. Sometimes a company buys new punches which may work better than the old ones, but often only because the new punches are very polished. As discussed earlier, new punches may create a bigger problem because their tighter clearances lead to air entrapment.

Milling:

Many times mills are viewed as ancillary pieces of equipment that you just roll into a vacant room to perform a quick task. That attitude raises several questions: Is this milling step controlled and predictable? Will the operators mill a batch on a Monday at 8 a.m. the same way they do on Friday at 4 p.m.?

Overly fine particles, known as fines, often exhibit poor compression characteristics and may cause sticking. The fines are usually the result of milling friable powders incorrectly or at inconsistent feed rates. With too many of these dust-like particles in the product formulation, it won’t flow or compress well. The fines also create a dusty atmosphere and cause tablet-to-tablet weight fluctuations. Furthermore, fines can get trapped within the logos and lettering on the punch face, especially if the punch design was made to handle a different particle size range.

Non-friable powders can also cause problems. Especially problematic are the powders that are readily compressible, because they can compact during the milling step. Furthermore, some products may re-agglomerate if they are stored too long. In that case, they will need to be de-agglomerated in a low-shear mill before going any further in the process. Products that have re-agglomerated flow poorly and cause weight fluctuations which, in turn, create hardness variations that increase the potential for sticking and picking.

Pinning the Problem on R&D:

Why do products compress into a tablet well in the lab but not on the production floor? We have all had this question at some time. More accurately, you might think that if only the product development team and the R&D people had developed the product correctly, we wouldn’t have sticking, picking, or other problems on the production floor.

There may be some truth to such thinking, but you should understand that identifying operational differences between lab and production equipment is difficult, especially when the product is still under development. Because of scale-up problems, many companies use production-capacity machines when developing products. The substitution of critical ingredients during product development can also hamper scale-up success.

Scale-up:

Some machines scale up better than others. Changing the batch size or a machine’s capacity may or may not give your product its intended attributes. Scale-up guidelines are general, and they don’t always work. I’ve seen plants that use identical or comparable processing machinery to make the same product, but the properties of the products at each plant differ. You can attribute these differences to environmental factors, the skill of the people who work at the plant, or both. There is still a lot of art in the science of tablet making.

Ingredient Substitution:

Many of the ingredients in tablet formulations are expensive, especially in the pharmaceutical industry. Therefore, sometimes a company substitutes a cheap ingredient for an expensive one during product development. Or the company may not have enough of the active pharmaceutical ingredient to make tablets and to perform all the developmental tests. In that case, the company will again use a substitute.

If the substitute doesn’t have the exact attributes of the true ingredient, then test results can lead you in the wrong direction. Time and storage conditions may also cause the ingredient to behave one way in the lab and another way on the plant floor. This may include more fines, de-mixing at the tablet press, and heat sensitivity, all or which may cause sticking.

Conclusion:

The one conclusion you should draw from this article is that a sticking or picking problem can have one or several causes. Polishing the punches during a production run is a temporary fix, not a long-term solution. Environmental factors can affect how well a tablet will form. Some products are so sensitive to temperature and humidity that they may compress differently or not at all with the slightest change in the environment.

If you’re the troubleshooter in charge of solving a sticking problem, evaluate the problem at the press and work upstream from there. Study all the process variables and record as much data as possible. Finally, if you make a change, try to make just one change at a time. This will help you link each change to a result.

Reader's Solutions:

1. Sticking can also be caused by an incomplete blend and not prescreening the lubricant before the final blend. No two blends are exactly the same! If lubricant is not prescreened then the problem is magnified. Lumps of lubricant will not be properly dispersed within the blend. This will definitely create a picking problem and a dissolution problem.

Also, sticking is not always caused by moisture. Many times the air becomes entrapped during compression, which creates a soft area on the top of the tablet where granules don’t know whether to stick to each other or to the upper punch tip. The solution here is to make certain dwell time and air evacuation is adequate. Increasing precompression hardness and getting the air out during compression is what will solve this problem. Using tapered dies will help get the air out. Sometimes talking to your tooling manufacturer about this problem can help. We see sticking in lettering, due to improper engraving angles, as a common issue. Using a compound radius to flatten out the very top of the tablet, will eliminate the air pocket. This change can be very slight but it can solve the problem without causing any noticeable change in the tablet shape or design.

2. While it may be impractical for a company to completely change their granulating and drying methods, they may be able to modify
it somewhat.The case hardening occurs when a granulation is dried too rapidly and the moisture is removed too quickly to carry some of the binder with it to the outside of the granule. This migrating binder is what forms the hard shell on the outside of the granule. This leads to two possible causes of material sticking to the punch faces - the entrapped moisture that Mike referred to and the concentrated binder on the surface of the granule. Sometimes slowing the drying process will eliminate the problem.

Tablet Printing

Ink Stabilization in the Printing Room

Ink stabilization during the course of tablet printing is not well understood. Of all the unit operations used to produce finished tablets, tablet printing is the most susceptible to variations in room conditions. Specifically, changes in room temperature, humidity or even the number of air changes per hour can alter evaporation rates of the printing ink. This is especially true of alcohol based inks. It is important to monitor both the incoming ink bottles and the ink in the ink well to assure standardized ink printing conditions.

In addition, ink bottles can sometimes lose their vehicle, whether water or alcohol during transit and storage. It is important to verify and, if necessary, re-dilute the concentrated ink back to its original consistency before using it on line.

It is important to keep room conditions constant when printing tablets. Usually a room in the mid 60’s to low mid 70’s is best with a constant humidity load is optimum for tablet printing. Don’t assume that any room in the facility may be used for tablet printing; choose a room that you would expect to compress or mill in, not an unused storage area or a part of a hallway blocked off for temporary manufacturing use.

Weighing

Common Causes of Weighing Errors

What should an ideal weigh off room look like? We need a small scale for items to be weighed in grams, a marble tablet for the intermediate scale, an intermediate scale from 500 gm to say 20 kg., a floor scale and magnehelic gauges monitoring the air pressure in different parts of the room and in relation to the hallway outside.

The room has minimum horizontal surfaces for dust to settle on. The floor is a sealed material non reactive to potential materials to be weighed. The walls are stainless steel for ease of cleaning. The room is very well lighted for easy reading of numbers posted on the digital readouts.

Even if you had that ideal weigh room to perform your weigh offs, you still face the possibility of a weigh off error. Following, is a list and discussion of some common root causes of weighing errors. Some errors occur primarily due to the conditions in the weighing room itself.


Wrong scale used: All scales have limits on the quantity of materials to be weighed. For companies that do not have SOP¡¦s for scale use, the scale chosen for weigh off by the operator may in fact not be capable of accurately weighing the material.

Objects near the scale: Take only what you need into the weighing area. Take a few pair of gloves; not boxes and boxes. Do not take tool boxes into the weighing area. You should have only the tools you need to weigh the material. Before weighing, make sure there are no objects under or near the scale to be used.

Wind currents: Are not really a factor with floor scales but are a critical factor when weighing small quantities of materials. In parts of the country where it gets warm the use of an electric fan in the room can produce a weighing error

Objects too large for scale: Even if the object is within the correct weighing range of the scale, it may have a bulk density so low that its mass is too large for the scale. Good examples of this are the flow enhancers used in solid dosage manufacturing.

Weighing off-center: The object to be weighed should be placed in the center of the tare vessel. Again, this is especially true of the smaller objects to be weighed. Never place the tare vessel or the material to be weighed toward the side of the weighing pan.

Tare vessel too small for its content: Plastic ¡§Weigh boats¡¨ commonly used as tare vessels come in a variety of sizes. Never use a tare vessel that is too small for its content. Doing will produce a weighing error if the material touches a non scale area.

Excessive vibration: A commonly overlooked and under appreciated weighing factor. Scales need to be placed on a solid object free from vibration. Modern scales will post an alarm if it cannot come to rest with a zero reading but older scales depend upon sound operator judgment for accurate read out.

Weighing material with an electrical charge in plastic containers: Some materials, such as natural fibrous materials or steroid like components, will generate electric currents in the weighing process. This causes some materials to stick to weighing containers, plastic bags etc. When the operator goes to transfer the materials, he or she should verify that there is no residual material left in the container.

Confusion between unit of measure: gm. Vs mg: Clear weigh off instructions in the SOP and batch record help prevent this type of error. Inadequate lighting in the scale areas may produce conditions where numbers and units are difficult to read. Always have one operator as the weigher and a second person as the checker. In most companies the checker bears ultimate responsibility for weighing errors, not the weigher!


By reviewing these simple tech tips for the Weighing Area, you should be able to avoid some of the common errors seen in the weighing operation.