Author Topic: Instruction for making tablets.  (Read 7402 times)

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Argox

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Instruction for making tablets.
« on: July 19, 2001, 07:02:00 PM »
A.  DISCUSSION:
Consumers prefer tablets over gel caps.  The tablet maker has a responsibility to make a safe product; since, once those tablets are delivered, there is no control over the end use.  One's karmic burden would be great, should one be responsible for an innocent's accident or illness.  Only pharmaceutical grade ingredients should be used.  Dosage must be carefully controlled.
In order to successfully compete against the myriad of products on the market, the tablet must be strong and have a good appearance.
Typical Amsterdam tablets are extremely well-made with creative logos; however, there is no reason a smaller producer cannot achieve similar results.
The active hydrochlorides that are discussed in this forum cannot be compressed by themselves.  One must mix the active ingredient with a binder and a lubricant in order to make a pill.  Binders, lubricants, coloring agents and any other non-active ingredients of a tablet are called excipients.

B.  TABLET INGREDIENTS:
1.  Active hydrochloride (your favorite honey) screened through a fine stainless steel screen, such as can be found in the kitchen section of most department stores.  The active MUST be screened into a fine powder.  1 kg will make about 10,000 tablets.
2.  Microcrystalline cellulose (MCC).  This is the best binder.  It compresses into a hard tablet.  It is insoluble, thus acting as a disintegrant as well as a binder.  It is used specifically for tablets.  Buy 2 kg for every 1 kg of active you plan to press.
3.  Lactose Powder.  (USP grade--any other grade will be off-white, almost yellowish, which only matters for esthetics)   This is a commonly used binder also known as milk sugar.  It has less compressibility than MCC, but provides a sweet taste and imparts a sheen to the tablet.   Buy 1 kg of lactose for every 1 kg of active you plan to press.
4.  Magnesium Stearate (NF grade).  This is a lubricant.  It is a fine white powder that looks and feels like corn starch.  One kg will be enough for 250,000 tablets.
5.  Stearic Acid powder.  (NF vegetable origin).  This is another lubricant.  The stearic acid we want is made from coconuts, not the stearic acid made from rendered cows (you'll thank me for this in ten years, when half the world will be dying of mad cow disease--at least you won't get it from a pill made by this recipe).  If you cannot find stearic acid in powder and what you find is granular or in small flakes, you will have to screen it, just as you screened the active.  1 kg will be enough for 125,000 tablets.

C.  SOURCES:
MCC can be obtained from the larger supply houses--the kind that supply pharmaceutical manufacturers.  Lactose powder can be purchased in a pharmacy without a prescription.  Mag stearate and vegetable stearic acid (aka stearin) can be found by calling around in the Yellow Pages to pharmacy supply houses and chemical companies.  Manufacturers and distributors can be found on the Web.  These excipients are not controlled, yet.  However, as in any procurement, it helps to have a legitimate reason for the purchase, to sound knowledgable when talking to suppliers, and to have shipping accounts, fax, e-mail, and other business accoutrements.  Please do not call up an industry rep with "Hey Dood!  Can you sell me that stuff to make pills?"   You'll just fuck it up for us legitimate guys.

D.  DOSAGE:
In a nutshell:  25% active.  50% MCC.  22% Lactose.  1% magnesium stearate.  2% stearic acid.
Your goal is to make a 400mg pill that contains 100mg of active ingredient.  A 400mg pill is larger than what comes from Europe, but the Europeans' main concern is lowering weight and volume for "transport," whereas your concern is hardness and durability.  Also, the Europeans have access to real punch and die sets made by real manufacturers.  You will have to make your own.  A 400mg punch set is pretty small for a non-expert lathe operator.  400 mg is roughly the size of a Bayer aspirin.  
Per 1000 g of active (for 10,000 pills @ 100 mg active each) use the following quantities of excipients:
2000 g MCC
880 g Lactose powder
40 g Magnesium stearate
80 g Stearic acid

(Tip:  If you cannot find MCC, it can be substituted with lactose powder.  In other words, you can make a passable pill entirely from lactose, lubricants, and active, without any MCC. However the calibration of your press will require more attention, since the lactose has less compressibility.)
Weigh the excipients into a large Tupperware bowl with an airtight cover.  Do not add the active ingredient, yet!  Mix the excipients by vigorous shaking for at least 15 minutes.  Really shake them up, until you are convinced they are thoroughly mixed.
Use 20 grams of this mixture to calibrate your tablet press, until you have a 400 mg pill that is hard and cannot be broken between your fingers without a real effort.  By calibration I mean adjusting the fill depth until you have a 400mg tablet and adjusting the top punch for hardness.  Bear in mind that you will have to re-adjust everything once you add the active, since it has a higher specific gravity than the excipients.
   IMPORTANT NOTE--If after making your test pills, you find that because of the shape or size of your punches and die that the optimum weight of your particular tablet is greater or less than 400mg, then adjust the amount of active that you add in the next step accordingly, so that each tablet has 100 mg of active.  Obviously, for higher or lower dosages, you add more or less active, or you adjust the tablet press to make a heavier or lighter pill.  Common sense and a calculator will be needed, since there are many factors to juggle when adding active to the excipients.
Add the active ingredient (it must be screened first) to the Tupperware bowl containing the excipients and thoroughly shake for 15 minutes.  The mixture must be as homogenous as you can make it.  Real pharmaceutical companies use a cone mixer to prepare tablet ingredients.  A cone mixer works on the same principle as you shaking a Tupperware bowl.  Just shake it up and down over and over and over, until your arms start to ache.  Then mix it some more.  The ingredients MUST as perfectly mixed as possible: the lives of users depend on your diligence.

E.  ADVICE:
   Wear disposable plastic gloves during the entire process of weighing, mixing, and tabletting.  Wear a dust mask over your mouth and nose (this protects you as much as it protects the quality of the tablets).  ALWAYS wash your hands.  Once opened, store excipients in airtight containers to avoid contamination--remember, people will be eating this stuff.  You might even consider a hair net while tabletting--you don't want your DNA in those pills.  Your burden will be great, if you scrape up the dirty powder that has fallen around your machine--powder that contains metal filings and lubrication oil--and press it into pills.  Just throw it away and call that the price of doing business.
   ALWAYS wear gloves when you put the tablets into plastic bags.  You do NOT want your fingerprints on those bags!  Experience shows that vacuum bagging the pills keeps everybody honest. 
   Good luck.

I'll follow up with photos of a tablet press and how to build.

Semtexium

  • Guest
Re: Instruction for making tablets.
« Reply #1 on: July 19, 2001, 07:26:00 PM »
This is much needed information for bees, I believe Osmium had a thread going where people were to try and build a pill press or something.  Perhaps you've won...?

Good work in any event...  :)


::)  ::)

Osmium

  • Guest
Re: Instruction for making tablets.
« Reply #2 on: July 19, 2001, 08:11:00 PM »
I have no experience whatsoever in pill presses  ;) , but I seem to remember that ready-made tabletting mixes contained spray dried, very fluffy lactose with a small particle size, since this can be easily compressed and sticks together very well.
Regarding the mixing of ingredients, if you can afford it and are planning to make bigger amounts a vibrating sieve should be used prior to pressing. Low amplitude and big enough sieve openings are important, otherwise you might separate your ingredients with those vibrations!
Real homogenity is hard to achieve by simple mixing. Smaller amounts should be prepared in a mortar by grinding the active ingredient with about the same amount of excipient. If you want to add pigments or dyes do it now, this will help with the homogenity (easy to spot inhomogenous areas later). Once this is well mixed, add more fillers. Grind well again, then mix with rest of fillers, sieve it a few times to assure homogenity, and there you go.
For bigger amounts a ball mill works best. This will assure you ultrafine particle sizes, very low density, perfect homogenity (since the falling balls will work the ingredients into each other) and a good quality product.
Centrifugal mills are another possibility to reduce particle size and mix stuff real good.

Commercial pharmaceutical pills are often made from two different mixtures, the inner phase (25% or so; containing the active ingredient, and some of the filler materials), and an outer phase (75% or so), consisting mainly of the excipients and having a bigger particle size. These two are uniformly mixed, and then pressed. The fine inner phase will fill all the voids between the outer phase. All these mixtures are optimised for the particular pill and press type, so it's very unlikely that people will even stumble across such ready-made mixtures at all. And if they do the result will probably less than perfect, because you don't know the optimum parameters.

dirtybastard

  • Guest
Re: Instruction for making tablets.
« Reply #3 on: July 20, 2001, 07:49:00 AM »
Lets see those pictures of the press. SWIM has always hated caping up the goods. takes such a waste of time.


I have no data to actually back up what I say.

yellium

  • Guest
Re: Instruction for making tablets.
« Reply #4 on: July 20, 2001, 08:14:00 AM »
>Real homogenity is hard to achieve by simple mixing.

Yup. Experience in this lab has shown that from the users of gelcaps containing a thoroughly mixed dextrose/goodies mix  25% are complaining about `does nothing for me' whereas 25% of the others are complaining about unexpectedly tripping their balls off. Resulting 50% has a good time.

dirtybastard

  • Guest
Re: Instruction for making tablets.
« Reply #5 on: July 20, 2001, 08:39:00 AM »
Ol'dirty loves it when the phrase "rolling my balls off" is used. his friends say that often, especially at the point when the eye-wiggles are at there peak.


I have no data to actually back up what I say.

lugh

  • Guest
Tablet patents
« Reply #6 on: July 20, 2001, 02:53:00 PM »
The first patent related to pill manufacture was granted to William Brockedon,

Patent GB9977

, "Shaping Pills, Lozenges and Black Lead by Pressure in Dies:" Other early patents of interest are:

Patent US152666

;

Patent US156398

;

Patent US168240

;

Patent US174790

;

Patent US189005

;

Patent US215452

;

Patent US251678

;

Patent US256573

;

Patent US260828

&

Patent US276828

 8)


goiterjoe

  • Guest
Re: Tablet patents
« Reply #7 on: July 20, 2001, 04:14:00 PM »
my experience is that 25% of people will eat foods that contain oil before they consume their pill, which can greatly inhibit the absorbsion into the body.  another 25% are either naturally sensitive to the pill or have taken MAOI's, etc. to increase the effects of the pill.  it is hard to judge the consistency of your pills based off of how people said they reacted to them, because even the same person won't get the same effects off of identical pills taken at different times due to outside influences.


If pacman influenced us, we'd glide around dark rooms eating pills and listen to repetitive music.

Grouch

  • Guest
Part 1
« Reply #8 on: July 21, 2001, 03:21:00 AM »
Ok, I couldn't resist, but a few posts are all you're getting.  I'd post the blueprints for my press which are accurate to 1/1000th of an inch, but this site is about chemistry....:)

Tablet Processing

By Dr. Cecil W. Propst

Table of Contents
·   Process Objective o   Content Uniformity o   Material Composition ·   Wet Granulation o   Advantages of Wet Granulation o   Disadvantages of Wet Granulation o   Dry Mixing o   Wet Massing o   Ingredients for Wet Granulation §   Binders §   Avicel® PH Microcrystalline Cellulose (MCC) in Wet Granulation o   Wet Milling o   Drying of Granules o   Dry Granule Milling ·   Direct Compression o   Advantages of Direct Compression §   Disadvantages of Direct Compression §   Final Blending §   Adhesive mixing-Fines §   Adhesive mixing-Coarse §   Carrier Blends §   Mixing by Dilution o   Dry Granulation §   Advantages of Dry Granulation §   Disadvantages of Dry Granulation §   Special Procedures §   Special Procedures: Extrusion-Spheronization §   Extrusion Equipment §   Liquid Carrier-Based Granulations §   Cushion-Based Blends §   Handling of Powders §   Containment

Process Objective

The objective of pharmaceutical processing in manufacturing solid dosage forms is to prepare the running powder to feed the tablet press and/or capsule-filling machine.
There are a number of required characteristics for the running powder, and many of the requirements vary, depending on the equipment used to manufacture the dosage form. Of these properties, homogeneity of the mix, material flow, controlled bulk density, and proper lubricity are the most important. For tablets and some of the capsule-filling machines, both compressibility and consolidation characteristics of the running powder are also key.
Three main manufacturing methods are used to prepare the running powder:
·  Wet granulation
·  Direct compression
·  Dry granulation or slugging
Almost all formulations require supplemental materials (excipients) to be added to the recipe in addition to the active ingredient to increase the dosage form size, and for other essential functions, such as binding and disintegration. The ingredient classification used is:
·  Fillers
·  Binders
·  Disintegrants
·  Lubricants
·  Wetting agents
·  Glidants
·  Antiadherents
·  Colors and flavors
·  Preservatives
The choice of excipients greatly depends on the properties of the drug substance, the behavior of the product as it is being processed, and the properties required for the final dosage form. In order to deliver a stable, uniform, and effective drug product, it is essential to know the properties of the active ingredient, the active ingredient in combination with the required excipients, and the requirements of the dosage form, and then to apply these requirements to the process.
To better understand these process objectives, a focus on the general requirements of the solid dosage form is required.
Content Uniformity
The content uniformity of the solid dosage form is controlled by two components: First, the variation in the weight of the dosage form, and second, the variation in the direct distribution in the running powder.
The dosage weight is controlled mainly by the bulk density of the running powder. Variation in flow of the feed material can vary the weight of fill of the dosage form only if the flow rate is insufficient to fill the cavity in the time allowed by the machine for the filling process. If the powder flow is fast enough (Figure 1), a reserve of fill time will be available so that a small change in flow rate will have little or no effect on the weight of the final dosage form. Thus, a process that creat es a freely flowing feed material with a controlled narrow range bulk density is to be considered ideal for controlling dosage weight.
Among other things, a shift in the particle size distribution can change bulk density.
As shown in Figure 2, a change in the amount of smaller particles (fines) can cause a dramatic change in the bulk density of the powder bed. Fines in the context of this section and for pharmaceutical powders are defined as passing through a 210-mm screen.
As the amount of fines increases from 0% to approximately 40%, so does the bulk density of the feed material (also Figure 2). This increase in bulk density occurs until the amount of fines in the mix reaches a critical content. After this critical amount is reached, adding more fines causes the density to decrease.
Fines fill the voids present in a powder bed of larger (coarser) particles (Figure 3). Once the voids created by the coarse particles are close to being fully occupied, the fines begin to displace particles and, in the displacement, leave behind fine particles in the space formerly occupied by the coarse particle. These fine particles have void spaces between them. As a result, the bulk density falls due to the coarse particle displacement. Note that the maximum bulk density reaches a peak (Figu re 2), which limits the change in bulk density of the bed. If the process particle size distribution is controlled at this maximum, the bulk density will be less variable.
Material Composition
The process that prepares the running powder must provide a uniform chemical composition. Good mixing is essential, and segregation during the process should be prevented.
With these objectives in mind, consider the three major processes used to prepare the running powder:
·  Wet granulation
·  Direct compression
·  Dry granulation or slugging
Figure 1: Flow versus Bulk Density
 
Figure 2: Effect of Fines on Bulk Density
 
Figure 3: Effect of Fines on Voids Created by Coarse Particles
 
Wet Granulation
Wet granulation is a process of dry mixing, wet mixing, and particle size enlargement, and is a process of particle attachment (agglomeration). In the most complex form (Figure 4), it consists of six steps:
1.   Dry mixing
2.   Wet mixing
3.   Milling of the wetted mass
4.   Drying
5.   Milling of the dried mass
6.   Final blending
Figure 4 illustrates the wet granulation process, in which a planetary mixer is used for both the dry mixing and wet mixing steps. A milling step may be required after wet granulating to reduce the particle size to achieve uniform drying. The tray drier d ries the materials in 4 to 24 hours, depending on the manner in which the drier is set up and the final liquid content specification for the dried material. After the material is dried, a milling step may be needed to reduce the clusters that form during drying. A rotating shape V-Mixer is used in this illustration for final blending.
Now the material is ready for the dosage form manufacturing unit. The wet granulation process of Figure 4 illustrates a very complex process arrangement. A simpler process (Figure 5) employs a single-step fluid bed wet granulator to do the dry mixing, wet massing, and drying steps all in one unit. Milling is not usually required when a fluid bed is used to wet granulate. A finishing mixer, such as the V-Mixer, is needed after fluid bed drying to blend the lubricant, color, and flavor, as required, into th e running powder.
The wet granulation process binds the primary particles of the dry mix together to form an enlarged particle called a granule. These granules are actually enlarged primary particle agglomerates and are usually rounded, and therefore, free flowing.
Advantages of Wet Granulation
·  Physical characteristics of the drug are usually not important.
·  The coalescing of particles locks in blend uniformity.
·  A wide variety of powder materials can be processed into a uniform mix with improved flow.
·  Optimum fill density can be achieved by adjusting the process to create the optimum final particle size distribution.
·  Compressibility and consolidation are improved via the choice of the correct binder and the moisture content of the granules.
·  Dissolution is modified through hydrophilization to improve wetting or, with the choice of more insoluble binders, to obtain a modified release pattern.
·  Dust and segregation tendencies are reduced.
Figure 4: Wet Granulation
 
Figure 5: Single-Step Fluid Bed Wet Granulator
 
Disadvantages of Wet Granulation
·  Large number of process steps; each step requires qualification, cleaning, and cleaning validation.
·  Long process time, particularly for drying.
·  High labor and manufacturing costs.
·  Some material loss during processing.
·  Problems associated with heat and solvent sensitive drugs.
·  Capital requirements for extra building space and equipment.
·  Upon aging, dissolution from granules can be slowed after tableting.
·  Assay problems may occur for low dosage drugs due to incomplete extraction if the active ingredient is complexed by the binder, or adsorbed onto one of the other excipients.
·  Still no exact way to determine granulation endpoint (torque, power consumption, etc.).

Dry Mixing
When wet granulating, the components in the mix can be milled to a fine powder, and even micronized if necessary, prior to mixing. Micronized powders can be blended for the dry mix, then the particle size enlarged by agglomeration in the wet massing step. This fine powder mixture can be blended into a homogeneous mass with a great deal of mechanical agitation (and/or pressure). Once mixed, these fine powder dispersions segregate with difficulty, and thus tend to remain mixed. Many granulators, such as ext ruders and instantizers, need to be fed with metered materials or a dry mix. Other granulators, such as conventional fluid beds, require that the active ingredient be added in the spray to obtain good content uniformity for certain low-dose formulations. Most other granulators can perform the dry mix step in the same vessel as the wet massing vessel (e.g., a high shear granulator).
Wet Massing
Water or other solvents and/or binder solutions are added slowly over an extended time period (or all at once) to the dry powder. This is done with the mixing to blend the liquid into the powder. Adequate mixing time must be provided after addition of the liquid to allow the granules to develop.
The structure of the developed granule (Figure 6) can vary depending on the process chosen. Such flexibility allows for a strategy to be developed to obtain the desired density, porosity, texture, and dissolution pattern of the granule formed. Some of the key characteristics of granule development include:
·  Liquid content-the capillary granule contains the greatest amount of liquid per unit mass.
·  Amount of surface liquid changes as the granulation process develops-usually the funicular phase and the overwet capillary phase have the greatest amount of surface liquid.
·  Porosity is highest in the dry mix followed by the pendular granule; porosity of the granule is lowest in the kneaded capillary.
·  Torque generated on the agitator will be greatest during the overwet capillary phase; also, a peak in torque often occurs at the completion of the funicular phase, just upon entering the capillary phase.
Figure 6: Granules Structure Development
 
·  Texture can be made soft (melt in the mouth) using pendular granules; the capillary and kneaded capillary forms tend to be gritty.
·  Dissolution is generally fastest with higher porosity granules; however, if a disintegrant is added to the dry mix, the problems of dense capillary granule disintegration can be minimized.
·  Consolidation is essentially developed in the granule by establishing a plane of deformation in the binder film used as the granulation binder; establishing the proper distribution of this film, along with the dispersion of the nonconsolidatable compo nents, is important.
·  Friability or dust generation during further processing is reduced as the process approaches the capillary/kneaded capillary phase.
·  In most cases, percent of fines on milling is least with the capillary/kneaded capillary granule.
The structure of the granules that are formed are dependent on the amount of added liquid, the time allowed to granulate, and the type of granulator used.
As shown in Figure 7, the fluid bed tends to produce the pendular form, and can yield a funicular arrangement. High shear tends to yield funicular granules, but also can make capillary and kneaded capillary granules. Tumbling granulators tend to make capillary granulations. Extruders are usually set up to make kneaded capillary structured granules. It is important to avoid adding too much granulating solution or running a high shear granulator beyond (or sometimes even into) the kneaded capillary pha se. Both can result in a very dense matrix. The mass can be doughlike and become very difficult, if not impossible, to process further. In such cases, screens may clog in the wet phase mill, dried granules can be too hard, compression forces necessary for ta bleting can be high, and disintegration of the granules may be prolonged.
Ingredients for Wet Granulation
Other than the drug material itself, the wet binder is the most important ingredient in the wet granulation process. The choice of the binder will influence the granule size, hardness, wetting, disintegration, and consolidation characteristics.
The surface tension of the binding solution controls the granule strength in the wet phase and, therefore, the particle size of the granule (Figure 8). As a result, changes in surface tension can be employed to control the particle size of the granulation produced.
In fluid bed processing, which uses atomization spraying (nebulization), surface tension is not as important a parameter as viscosity in controlling the particle size of the granules. Viscosity is the controlling parameter when using atomizers. Viscosity controls droplet size, and droplet size controls the granule size developed in the fluid bed.
Figure 7: Granule Form Dependent Upon Mixing / Granulation Equipment
 
Figure 8: Effect of Surface Tension on Granule Strength and Density
 
Binders
The role of the binder is paramount to the development of the structure and performance of the granulation. Linear polymers are ideal in that they can be used at low concentrations. With some residual moisture present, the polymer can perform the essential role of plastic deformation and bonding during tableting. Branched binder structures, such as high bloom strength gelatins, have a tendency to create harder granules and generally require higher concentrations to achieve the same particle size. Since Section 4 is devoted to binders, the discussion here will be limited to the processing aspects of the binder.
The hydration level of the binder must be uniform from batch to batch. This is especially critical with branched polymers, such as starch and many of the natural gums. If the extent of hydration is variable, this can contribute to changes in particle size and density between batches. Controlling the duration and temperature of heating in preparing the granulation fluid is important.
Liquid distribution is the key to the success of the wet massing step. Either atomization or slow pouring and sufficient mixing time is required to obtain proper distribution of the granulation fluid.
Avicel® PH Microcrystalline Cellulose (MCC) in Wet Granulation
Major advantages provided by Avicel® PH-101 and PH-102 in the wet granulation process of tablet making are:
·  Rapid, even wetting
Wicking action thoroughly distributes the granulating fluid throughout the powder bed.
·  Control of wet mass consistency
Large surface area and adsorptive capacity provide a wider range of liquid addition without overwetting.
·  Less screen blocking
Good wet mass consistency aids in trouble-free screening.
·  Uniform, rapid drying
Promotes rapid release and evaporation of liquid from the wet granulation.
·  Content uniformity control of water-soluble drugs
Regulates active ingredient variation in all particles of the granulation.
·  Wet binder-like activity
Auxiliary wet binder promotes harder granules with less fines.
·  Use of Avicel® MCC in postaddition step provides:
Excellent binding
High hardness at low pressures
Low friability
Good disintegration
As a wet-massing adjunct only, the total quantity of MCC is added to the initial dry blend. Preferably, one half is incorporated into the wet mass and the remainder into the final blend. This postaddition of Avicel® PH is most useful for the assurance of trouble-free tableting when compression is sensitive to variations in raw materials or processing.
Wet Milling
A wet milling step may be necessary after the wet massing step to reduce the particle size of the wet granule in preparation for drying. If milling is needed, it will result in cleavage of the pendular bonds (Figure 9) and separation of the firmer-structu red granules (called granulytes). This opens the clusters, which are fairly dry, without exposing the capillary water included in the small granulytes.
Plugging of the screen and build-up in the mill are problems for many types of equipment. The best mills place the grinding zone of the mill as close to the retention screen as possible. Two such designs are featured in the oscillating granulator (Figure 10) and cone mill (Figure 11). The variable speed of the blades of the cone mill allow for a variable impact velocity, which can be adjusted to reduce breakage of the capillary particle, therefore allowing cleavage at the pendular bridge and press particles into the screen. The mill zone is formed by the blade and the screen, and when the granule is small enough, it can be immediately screened.
Drying of Granules
Caution is needed in drying because of the potential decomposition and chemical migration that can occur during the process. The high temperature and high solvent content present at the beginning of the drying process may lead to hydrolysis. At the end of the drying process, dehydration reactions can possibly occur.
The air temperature and humidity of the oven controls the rate of drying. As a minimum, the temperature and time of drying should be controlled. Although the ambient humidity of the air is important, it has limited impact on most drying operations, as room temperature air is heated to 60° C to 80° C during the drying process. Migration of dissolved ingredients can occur during drying. Wicking agents, such as microcrystalline cellulose, can be used to reduce and even prevent migration. Migration can occur between particles or within a single particle from the core of the particle to the surface. Changes in granule consistency and surface characteristics can result in changes in porosity and binding strength. Migration can deposit drug at the surface , and affect the structure of the tablet during compression, and generate dust from the surface during handling.
End-point control of drying is important. The residual moisture in the granule aids in the plastic deformation characteristics of the particle during compression. If too dry, a granule will be created that will brittle-fracture excessively when compressed on a tablet press. If too wet, the granules will be sticky and may bind to the tooling.
The correct end point can be obtained by as simple a technique as applying a given inlet temperature to the process for a given length of time. Another approach (Figure 12) tracks the wet bulb temperature and compares it with the product temperature. For example, a temperature difference (DT) of 35° C between the wet bulb thermometer reading and that of the product can be set to stop the dryer at a specific time (e.g., 40 minutes), or it can be set to continue drying for a specific time after the product temperature begins to rise. The drying process is stopped when either a DT of 35° C is reached (primary control), or at 40 minutes beyond the point where the product temperature rise is detected (secondary control).
Figure 9: Wet Milling
 
Figure 10: Oscillating Granulator
 
Figure 11: Cone Mill
 
Figure 12: End-Point Control
 
The final moisture content of the dried granulation is an important consideration for both granulation stability and granulation compactability. For crystalline binders (sugar, corn syrup, dextrose), the moisture content generally must be below 1% to prevent sticking, yet greater than 0.4% to allow for compactability. For polymer-type binders (PVP, HPMC, gelatin), the finished moisture content is usually higher (at 0.8% or greater) to create a plastic-deforming particle.
Dry Granule Milling
Milling of the dried granulation is not always necessary. Particle sizes larger than 2000 µm (10 mesh) are usually considered too large for tableting purposes.
Direct Compression
The ideal process from a capital and operational cost basis is direct compression. This is, at most, a two-step process involving screening and/or milling and final mixing.
An effective excipient binder is needed and should have good compression and consolidation properties as a dry additive, even at low concentrations (< 30%) in the formulation.
Good adhesive properties in the dry form are a combination of a rough and porous surface combined with a van der Waal's and/or a hydrophilic bonding mechanism to attach the active ingredient(s) to the excipient. This feature is needed to assure good mixing of drug and excipients and to prevent segregation.
Advantages of Direct Compression
·  Economy in labor, time, equipment, operational energy, and space.
·  Problems due to heat and moisture eliminated.
·  Greater physical stability provided; hardness and porosity changes less with time when direct compression is broadly compared to wet granulation systems.
·  Extraction of the drug from the dosage form is not inhibited during the assay procedure (polymer binding).
·  Choice of ingredients allows the formulator to improve or retard dissolution rate.
Disadvantages of Direct Compression
·  Critical nature of the raw materials; need for greater quality control in purchasing to assure batch uniformity.
·  Difficulty obtaining dense hard tablets for high-dose drugs.
·  Nonhomogenous distribution of low-dose drugs due to segregation after blending (content uniformity).
·  Sensitivity of direct compression "running" blends to overlubrication.
·  Limitations in color variations.
·  Need for assisted feed and precompression for some high-dose drugs.
·  Need for commensurate particle size or particle size distribution between drug and excipients.
Avicel® PH MCC is one of the most useful excipients available for direct-compression tableting. Its strong bonding properties and capacity for dry binding other materials have made MCC a standard to which other direct compression excipients are often compared. MCC performs many functions in the direct compression process:
·  Strong, dry binder
·  High dilution potential
·  High tablet hardness at low punch pressures
·  Low tablet friability
·  Excellent tablet disintegration
·  Flow aid
·  Inherent lubrication
·  Antiadherent
Final Blending
Final blending is usually done in a cone or V-type blender (Figure 13). To obtain the final blend, it is necessary to consider the objectives of the mixing steps:
·  To achieve drug content uniformity
·  To obtain uniformity of flow and bulk density
·  To effect distribution of lubricant, color, and surface active agents
·  To reduce or eliminate segregation
Adhesive mixing-Fines
Particles smaller than 50 µm are candidates for mixing by aggregation (Figure 13). Particles of 10 µm or smaller have a tendency to selfadhere easily. This adhesion means that, if all the cohesive attachments between like materials are severed and converted to unlike attachments, a very effective mix can be generated that is less prone to segregation. For example, a particulate binding of the type A-A and B-B (like to like) can be broken and rejoined to form an A-B and A-B type (unlike to unlike).
Blending a formulation containing particles of Avicel® PH-101 MCC (50 µm in size) with other particles of similar size produces a product which is less prone to segregate. In addition, most modern tablet presses and encapsulating machines can use such finer particle size powders in the feed system.
Adhesive mixing-Coarse
Blending of powders when the particle size of the active ingredient is 200 µm or larger presents the problem of lack of significant surface adhesion. A mix, when achieved, can result in a blend that may separate. The adhesive surface force between particles is not strong enough to prevent separation. Therefore, coarse blends (particle ingredients generally larger than 200 µm) are usually restricted to formulations with high doses of active ingredients. To reduce segregation, the porosity of the bed should be minimized and vibration exposure reduced.
Figure 13: Final Blending
 
Carrier Blends
This type of blend is characterized by fine particles attached to larger particles called carriers. For maximum effect, the smaller particles should be less than 10 µm in size. The fines attached to coarse particles are called ordered units. The larger particles are greater than 90 µm in size, and have pores and/or indentations in the surface to aid in the attachment of the smaller particles. This attachment is another adhesive attachment mechanism similar to the fine-fine attachment.
Mechanical stability is an important property of powder mixtures. An ordered unit (in this case, fine particles adhering to larger carrier particles) can separate in two ways. First, the smaller particles can lose their attachment and separate. Second, the ordered units can be of varying size due to the varying size of the carrier particles and can therefore separate.
Mixing by Dilution
Mixing by dilution is often used to incorporate very potent low-dose active ingredients into a formulation. Equal volumes of the drug and a fine-sized particle excipient, such as microcrystalline cellulose, are mixed. This first step can include milling of the drug with the excipient to assure the removal of aggregates. This premix is combined with an additional volume of excipient, usually equal to the total volume of the premix, and the combination is mixed further. This progression of mixing by dilution with a fine particle excipient allows for an energetic dispersion of a concentrate of drug into a matrix or premix, which is then blended with the remaining materials in subsequent steps.
An example of mixing by dilution involves spraying of the solution of a drug onto an absorbing substance. The drug being sprayed is spread over a large mass of excipient, which can absorb the liquid and attach the drug. Avicel® PH MCC is an example of a good absorber. Avicel® PH will absorb the liquid and the drug, and the mixture can then be further blended into a formulation. This method is used to obtain a more uniform distribution of the drug.
Wet Milling
Dry Granulation
The third process for making the "running" powder for tableting or encapsulation is the dry granulating process (Figure 14). This process requires five steps:
·  Mixing
·  Roller compaction
·  Milling
·  Screening
·  Final blending
The process is continuous and no heat or moisture are applied, yet the particle size of the mixture is increased.
The roller compactor and tablet press perform the same functions. Material is fed to the rollers and the powder is compressed. A dwell time under pressure allows for consolidation of the feed into a sheet or flakes. The product then exits the compression zone and is released from the rolls. The roller compactor lacks an upper punch to hold the materials in the compression zone, called the nip area (Figure 15). Air moves up against the powder flow. The faster the rollers turn, the more material is compressed, and the greater the volume of air is displaced.
Figure 14: Roller Compactor
 
Figure 15: Nip Area (Region of Roller Compactor)
 
The material must be properly gripped by the roller. Accumulation of most larger particles can occur in the nip area. This can lead to excessive pressures being generated for short times and banging of the rollers as they open to allow material to flow th rough. Machining of pockets or gripping indentations in the rollers can reduce the tendency for larger particles to be retained. It is apparent that the major controls are:
·  Pressure applied

The time under pressure and the amount of pressure applied is of primary importance; it is controlled by roller speed and the height of the nip area. The nip area (Figure 15) expands as more gripping force or friction is applied by the feed screw on the roller surface. The friction between the material being fed and the roller prevents the material from slipping on the roller surface, and thus, draws the material into the high-pressure area.
·  Subsequent milling process
·  Material characteristics

Particle size distribution, compressibility, and consolidation characteristics must be considered. It is important to keep in mind that certain materials, such as lactose (which compact by a brittle-fracture mechanism), will be less compactable if too high a pressure is used during initial roller compression. With other materials, such as ibuprofen, the elasticity can be reduced by applying higher pressures in roller compression.
These surface attachments are usually weak, therefore the granules/sheets produced are fragile. Upon milling, a significant amount of dust is usually generated, which is removed by screening and is recycled back through the roller compaction system. This feature is needed to assure good mixing of drug and excipients and to prevent segregation.
Advantages of Dry Granulation
·  Permits mechanical handling without loss in mix quality.
·  Eliminates the problems due to heat and moisture.
·  Improves flow of powders by increasing particle size.
·  Decreases the elastic recovery for certain compounds, thereby increasing final compactability.
·  Facilitates extraction of drug from dosage form during analysis (shows less tendency to interfere due to polymer binding).
Disadvantages of Dry Granulation
·  High amount of recycle or reprocessing (dissolution, friability, batch control).
·  Possible loss in tablet compressibility in the material during roller compacting.
·  Particle erosion and segregation during finished mixing and handling (content uniformity).
·  Limitations in color variety.
Special Procedures
Many predosage form manufacturing processes can be considered specialized and can be employed to generate a very special product to be used for the running powder. These processes include:
1.   Extrusion-spheronization
2.   Liquid carriers-based granulation
3.   Cushion-based blends
Special Procedures: Extrusion-Spheronization
A unique way to make spherical particles is to combine an extruder with a spheronizing machine. The spheronizer, or marumerizer, (Figure 16), was the first machine used for this extrusion-spheronization application. It produces dense spherical particles from fine powders.
The formulation requires special materials which must be plastically deformable when wet, but not sticky. Microcrystalline cellulose (Avicel® PH) is the most popular ingredient for this purpose, and is used at levels of at least 20% in such formulations.
Basically, the process consists of producing roughly cylindrical pellets from the plastic mass of the mixed powders using water or other solvents, sometimes in the presence of a binder. The mass is extruded through a radial screen or axial die plate by means of a screw feeder. The larger diameter-denser pellets are made using an axial extruder. Spheres as small as 0.5 mm are made with a radial screen extruder.
The pellets, once formed, are placed into the spheronizer. The base plate of the spheronizer spins to create friction and a bumping action, which break down the pellets until the length-to-diameter ratio is approximately the same, thus forming spheres. Total spheronization process times range from 30 seconds to 5 minutes or longer.
The centrifugal force created by the base plate aggressively carries the deposited feed pellets from the center of the machine to the wall, then rolls them up the wall. This action creates an annulus ring of continually moving and rolling material. The action also forces the rounder, smaller particles toward the interior of the roll, while the larger, more elongated particles tumble near the surface, facing the friction plate as it rolls under the ring. Interparticulate frictional forces, plus those between particles and the moving base, spheronize and increase the density of the particles. The product size distribution is usually extremely uniform, and the output can be as great as 2000 kg/hour.
Extrusion Equipment
To spheronize a material, a preformed particle is needed. The extrusion method involves the application of pressure to a wet mass until it flows through a defined opening (orifice) in a metal plate. It is obvious that the technique controls two dimensions of an agglomerate. The width is determined by the size of the orifice, while the length is controlled by the characteristics of the material and the rheology imparted to the particle by the process. Because the orifice defines the cross-sectional geometry, extrudate length is usually the only dimensional variable.
Two types of screw extrusion devices are used widely:
·  Axial
·  Radial
The lower-pressure radial extruder (Figure 17) uses a transport screw to move the material along the screen. The material exits the die holes as it is spread across the screen. As a result, smaller diameter, softer extrudate particles can be produced.
An axial extruder (Figure 18) is operated at a higher pressure and forms denser particles. This design utilizes a transport section to move the material forward, and often a compression zone (having progressively closer screw flights) to increase the density of the material.
Figure 16: Spheronizer (Marumerizer)
 
Figure 17: Twin Screw Radial
 
Figure 18: Axial Extruder
 
Liquid Carrier-Based Granulations
Many granulations are made with the idea of distributing a liquid into or onto a carrier particle (see Mixing by Dilution). Adding a granulating and/or coating step can seal the particle/liquid mixture as well as modify the redissolution of the drug subst ance.
A taste-masking example might involve the granulation of the absorbed drug onto Avicel® PH MCC with a pH-activated polymer such as Aquacoat® CPD (cellulose acetate phthalate). This massing and polymer barrier would prevent the dissolution of the drug in the mouth during chewing, yet would release the drug in the stomach or duodenum upon exposure to the correct pH.
Cushion-Based Blends
Several products in the marketplace are made as coated extended-release or delayed-release beads in a tablet matrix. The compression process is used to create the dosage form. The rupture of the bead coating in compression must be avoided. Low-compression pressures must be applied during the tableting process. The formation of the tablet at low pressures, with little (if any) internal friction, is needed. Dry binders, such as Avicel® PH MCC, are used with a waxy material, such as PEG 8000, to obtain a reasonable tablet structure while applying low levels of pressure.
Handling of Powders
Segregation of the active ingredient during the handling process (Figure 19) must be controlled to assure proper product performance. It can be prevented by one of two mechanisms:
·  Containment
·  Attachment (aggregation)
Both of these mechanisms treat the particles as a group. Containment holds the group as a set volume of particles, while attachment creates a particle cluster by some sort of adhesive force. The containment mechanism is the more important of the two.
Containment
The set volume of contained particles could be the powder filled into a capsule, into a vial, in front of a blade in a ribbon blender, or in the plug grouping of a dense phase conveyor. Because the particles are not allowed very much movement with respect to each other when transferred, their tendency to segregate from each other is reduced.
The closer the process is to containing the individual particle and allowing only groups to move, the less tendency there is for segregation. Some containment trends include:
·  Low-porosity powder beds, which reduce the segregation tendency of finer particles percolating through pores in the particle bed.
·  Charging into plastic deflated bags; the force of the material moving into the open bag is more of a containment system than simply allowing the material to charge into a container. The bag weight, as it is filled, is supported to allow gradual entry. Also, once the bag is filled, it is tied very tightly to discourage bed expansion.
·  Moving mixed materials into bins, rather than pneumatically or by screw conveyor.
Figure 19: Active Ingredient Variation During Processing
 
FMC logo, Avicel, Ac-Di-Sol-trademarks of FMC Corporation.


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Part 3
« Reply #9 on: July 21, 2001, 03:42:00 AM »
Tablet IngredientsBy Dr. Zak T. Chowhan
Table of Contents
·   Excipients o   Choice of Excipients §   Direct-Compression Excipients §   Directly Compressible Fillers-Binders-Disintegrants §   Cellulose §   Avicel® PH Microcrystalline Cellulose NF, Ph. Eur., JP, BP §   Ceolus™ Microcrystalline Cellulose, NF, Ph. Eur., JP §   Microfine Cellulose §   Lactose §   Super-Tab™ Spray Dried Lactose Monohydrate NF, Ph. Eur., JP, BP §   Alpha-Lactose Monohydrate §   Anhydrous Alpha-Lactose §   Anhydrous Beta-Lactose §   Agglomerated Lactose §   Other Sugars §   Compressible Sugar NF §   Dextrose Excipient NF §   Dextrates NF §   Starch and Starch Derivatives §   Native Starches §   Pregelatinized Starch NF §   Sodium Starch Glycolat NF §   Inorganic Salts §   Dibasic Calcium Phosphate USP §   Tribasic Calcium Phosphate NF §   Calcium Sulfate NF §   Polyols §   Mannitol USP §   Sorbitol NF §   Xylitol NF §   Coprocessed Excipients §   Ludipress® §   Cellactose® §   Pharmatose® DCL 40 §   Wet-Granulation Excipients §   Binders §   Avicel® PH Microcrystalline Cellulose NF, Ph. Eur., JP, BP §   Cellulose Derivatives §   Povidone USP §   Copolyvidone §   Gelatin NF §   Natural Gums §   Starch Paste §   Pregelatinized Starch NF §   Sucrose NF §   Other Binders §   Disintegrants §   Ac-Di-Sol® Croscarmellose Sodium NF, Ph. Eur., JPE §   Sodium Starch Glycolate NF, Explotab®, Primojel® §   Crospovidone NF §   Lubricants §   Magnesium Stearate §   Calcium Stearate §   Stearic Acid §   Sodium Stearyl Fumarate §   Hydrogenated Vegetable Oils §   Mineral Oil §   Polyethylene Glycols §   Antiadherents §   Glidants §   Dry Granulation Excipients ExcipientsTablet ingredients consist of Active Pharmaceutical Ingredient(s) (API) and excipients. In order to deliver an accurate amount of a drug for its intended clinical use in a convenient unit dosage form, excipients perform very important functions, specifically as: ·  Fillers/Diluents ·  Binders ·  Disintegrants/Super Disintegrants ·  Lubricants ·  Antiadherents ·  Glidants ·  Wetting/Surface Active Agents ·  Colors/Pigments ·  Flavors ·  Sweeteners ·  Taste-Maskers Choice of ExcipientsThe choice of excipients in a tablet formulation depends on the API, the type of tablet, the desired characteristics, and the manufacturing process used. Several types of tablets are available on the market. These include prompt release, from which the drug dissolves in a very short time (sublingual or buccal tablets), and immediate release and modified release, which include most of the orally administered tablets that are swallowed. Other types include chewable, effervescent, bilayer, multiple compressed, and topical tablets, and tablets for solution. The desired characteristics of a tablet may be achieved by adding colors, pigments, sweeteners, flavors, and a sugar or film coating. The types of excipients selected for a formulation depend on the basic process used to manufacture the tablets. Compacted or compressed tablets are produced from granulations or powder mixtures made by the following general techniques: ·  Direct compression (dry mixing and blending) ·  Wet granulation (high shear, low shear) combined with tray drying or fluid-bed drying ·   Wet granulation and drying in the same equipment ·  Dry granulation by roller compaction or slugging Over the past four decades, improvements in the availability of excipients with consistent physical properties (including particle size and shape, and improved functionality such as compaction and flow), have revolutionized tablet production on a commerci al scale. In addition, the availability of a diversity of equipment for the wet granulation process (including high-shear granulators, fluid-bed granulators and dryers, extrusion granulators, continuous granulators, and granulators with wet granulation an d drying combined in the same equipment), have made tablet production more economical. However, tablet production by direct compression still remains the method of choice because it offers economic advantages by eliminating the wet granulation and drying steps. Specialized processes may be used for certain types of tablets, such as extrusion; a combination of extrusion, spheronization, and compaction; a coating for modified-release tablets; and freeze drying for prompt-release tablets. The evolution in tablet film coating technology has made it a preferred method for taste-masking and trade-dressing, as well as for modifying release and allowing site-specific delivery of drug. The sugar-coating operation has also been refined over the years as a result of improvements made in the equipment and the process, and is still in use. In order to perform the intended functions, the delivered dose of the drug is the primary consideration in selecting the excipient type, grade, and concentration (level) in a formulation. The type of tableting process employed is also important. For high- dosage drugs, the tableting process of choice is generally the wet granulation process, unless mechanical properties of the API are better suited to the direct blending and compression process. Other considerations in the selection of excipients are the physical and chemical compatibility with the API. In general, the chemical and physical stability of the API is investigated in preformulation studies by mixing the API and individual excipients or combinations, and aging them under controlled storage conditions of heat and relative humidity. The effect on the stability of the API and excipients can be determined through this method. Direct-Compression ExcipientsThe direct-compression process generally involves mixing an active pharmaceutical ingredient with excipients prior to compaction. The selected excipients must meet all of the functionality requirements to produce compacted tablets on a commercial scale. T he basic functional requirements are compaction, flowability, lubrication, disintegration, and dissolution. When selecting excipients for direct compression, several factors must be considered: high compactibility; good flowability and blending properties without a potential for segregation of API and excipients (incompleteness of mixing); low lubricant sensitivity to compaction; good stability; enhancement of tablet disintegration and dissolution; non-interference with the biological availability of the active ingredient; batch-to-batch reproducibility of the physical and physical-mechanical properties; worldwide continuous availability and compendial acceptability; and cost effectiveness. Some of these criteria are difficult to attain because they requi re universal consistency in the physical and chemical properties of the excipients to obtain reproducibility in the production of dosage forms. It is, therefore, important that the selected excipients in a formulation are manufactured by reputable manufac turers who can guarantee that the process and the in-process controls are identical in different plants around the world. Directly Compressible Fillers-Binders-DisintegrantsThe process of direct compression was revolutionized by the introduction of Avicel® PH microcrystalline cellulose (MCC), although spray-dried lactose had been introduced one year earlier. In combination, these two excipients are used in most direct-compre ssion formulations. Other directly compressible excipients, commonly referred to as fillers-binders, have appeared in the pharmaceutical market over the past three decades. To improve the functionality of native starches, partially pregelatinized starch w as introduced as a filler, binder, and disintegrant, and is successfully used in formulations to perform these functions. The inorganic excipients, such as dibasic calcium phosphate dihydrate (Emcompress®), calcium sulfate dihydrate (Compactrol®), and tri calcium phosphate (Tritab®), are directly compressible and are to be used with caution because of their potential to slow down the in vitro dissolution of the drug after the tablet has aged. The most important excipients identified below are used as directly compressible fillers. Some grades of these classes of excipients are also used as fillers in the wet-granulation process.


Cellulose
Cellulose forms the backbone of many excipients used in marketed drug products. Pharmaceutical grades of cellulose are obtained by either mechanical or chemical processing, or through a combination of both. Pure cellulose can be ground mechanically or fol lowing additional treatment by hydrochloric acid. The resulting powder is cellulose powder, or microcrystalline cellulose. Powdered cellulose has lower compressibility when compared with microcrystalline cellulose, and is generally not used in directly co mpressible formulations.
Avicel® PH Microcrystalline Cellulose NF, Ph. Eur., JP, BP
Microcrystalline cellulose is described in the National Formulary (NF) as a purified, partially depolymerized cellulose prepared by treating alpha cellulose, which is obtained as a pulp from fibrous plant material with mineral acids. Of the celluloses, Av icel® PH microcrystalline cellulose (MCC) is the substance most often used in tableting as a filler, disintegrant, flow aid, and dry binder in directly compressed tablets. It has extremely good binding properties as a dry binder. During compression, Avice l® PH MCC is believed to undergo stress relief deformation by several mecha-nisms. It produces hard tablets at low compression forces and can be used alone or in combination with other directly compressible excipients, such as lactose, starches, etc. Stro ng binding properties are caused by hydrogen bonds between the hydroxyl groups on the plastically deformed, adjacent cellulose particles.
The compressibility of Avicel® PH MCC depends on its moisture content. It has been suggested that, at its equilibrium moisture content of 5%, most of the water will be within the porous structure of microcrystalline cellulose, and a large portion of this bound moisture is expected to hydrogen-bond to small units of cellulose within the particle.
In wet granulations, Avicel® PH MCC also acts as a binder and permits rapid addition of the granulation solution because of its ability to absorb water. It is the best spheronization excipient, and up to 70% of an API can be loaded in the formulation. The spheres that are produced have low friability and a good aspect ratio.
Several grades of Avicel® PH MCC, which vary in particle size and moisture content (Table 1), are available for different applications. For APIs that are water soluble, nonhygroscopic, and difficult to agglomerate, Avicel® PH MCC functions as a wet binder and helps in forming agglomerates that do not powder on dry milling.
In direct-compression formulations, Avicel® PH-102 MCC can improve flow characteristics. The grades of larger particle size, such as PH-200, can be used in formulations having flow problems. This is attributed to the more rounded particle shape of PH-200, compared with PH-102 aggregates. The compaction properties of PH-102 and PH-200 are essentially identical. Table 2 gives typical values of particle size, bulk density, and loss on drying of commercial grades of Avicel® PH MCC. These grades are engineered for the following specific applications:
·  PH-101 is one of the most widely used materials for direct compression and wet granulation applications
·  PH-102 has a larger particle size and may be valuable in improving flow
·  PH-105 has the smallest particle size with excellent compaction properties
·  PH-103, PH-112, and PH-113 have reduced moisture content and are ideal for moisture-sensitive, active pharmaceutical ingredients
·  PH-200 has a large particle size and offers increased flowability
·  PH-301 has a higher bulk density than its particle size equivalent (PH-101) and good flowability
·  PH-302 has a bulk density similar to PH-301, a particle size similar to PH-102, and offers better flowability
Avicel® PH MCC has a high dilution potential, which is defined as "the ability of a given quantity of an excipient to bind a specified amount of an active ingredient to form an acceptable tablet." This high dilution potential is attributed to low bulk den sity (which imparts high covering power), broad particle size distribution (which allows optimum packing density), and its superior binding properties.
In addition to the compaction and binding properties, which result in the production of tablets with excellent hardness and low friability, Avicel® PH MCC has good lubrication and disintegration properties. A mixture of Avicel® PH MCC with up to 40% Super -Tab™ spray-dried lactose monohydrate NF can be compressed without the addition of a lubricant. The lubricating property is attributed to a very low coefficient of friction and very low residual die-wall pressure. The disintegrant properties of Avicel® PH MCC are attributed to penetration of water into the hydrophilic tablet matrix by means of capillary action of the pores, followed by a subsequent disruption of the hydrogen bonds, which holds the matrix together.
Ceolus™ Microcrystalline Cellulose, NF, Ph. Eur., JP
Ceolus™ is the newest highly specialized grade of microcrystalline cellulose offered by FMC. It exhibits superior compressibility and high dilution potential. Because of these properties, it is most suited for the formulation of small size tablets with a high content of active pharmaceutical ingredient.
Microfine Cellulose
Elcema® is a mechanically produced cellulose powder, which is supplied in a granular grade (G-250). It is the only grade that may be used in direct compression because of the improved flow and compaction properties. However, unlike microcrystalline cellul ose, it possesses poor dilution potential.
Table 1: Avicel® PH Microcrystalline Cellulose - Product Types
 
Table 2: Avicel® PH Microcrystalline Cellulose - Typical Average Particle Size, Bulk Density, and Loss on Drying at the Time of Shipment
 
Lactose
Lactose is the most commonly used filler in tablet formulations. It is a natural disaccharide produced from cow's milk which contains approximately 4.6% lactose, corresponding to approximately 38% of its dry solids. It exists in two isomeric forms, alpha- lactose and beta-lactose, and can be either crystalline or amorphous. Crystalline alpha-lactose occurs in the monohydrate and anhydrous forms. The pure amorphous form of lactose is not available commercially and is generally present in modified forms of l actose in varying amounts.
Super-Tab™ Spray Dried Lactose Monohydrate NF, Ph. Eur., JP, BP
Super-Tab™ is a spray dried lactose monohydrate specifically engineered for direct compression, and is particularly suitable for APIs which do not compress well. It is used up to approximately 15% concentration in the formulation. A combination with Avice l® PH MCC is sometimes preferred, depending on the physical and physicomechanical properties of the API. Due to its solubility, Super-Tab™ spray dried lactose monohydrate is less likely to cause an increase of the in vitro dissolution time of the API of t he tablet on aging. Super-Tab™ spray dried lactose monohydrate and other commercially available spray dried lactose monohydrate products contain approximately 10% to 20% of amorphous lactose, and approximately 80% to 90% of alpha-lactose monohydrate. The compressibility of s pray dried lactose is not affected by moisture. Super-Tab™ has low sensitivity to the effect of lubricants (especially alkali stearates) on compression.
Alpha-Lactose Monohydrate
Commonly referred to as lactose, hydrous lactose, or regular lactose, this filler is generally used in powdered form for tablets prepared by means of a wet granulation technique. In direct compression, coarse, regular grade, or a sieved, crystalline fract ion of alpha-lactose monohydrate may be used because of the good flowability. Alpha-lactose monohydrate contains one molecule of water, which corresponds to 5% water of crystallization. In practice, alpha-lactose monohydrate (100-mesh) is often combined w ith Avicel® PH MCC, which improves the disintegration time. However, the crushing strength increases proportionally to the percentage of Avicel® PH MCC.
Anhydrous Alpha-Lactose
The compaction property of alpha-lactose monohydrate is increased by thermal or chemical dehydration of the crystals. During dehydration, aggregates of anhydrous alpha-lactose are formed from the monohydrate single crystals. Anhydrous alpha-lactose is rar ely used alone in directly compressible formulations because of the lack of disintegrating properties. It is used in combination with Avicel® PH MCC.
Anhydrous Beta-Lactose
The commercial products consist of extremely fine agglomerated crystals, produced by the roller-drying of a solution of alpha-lactose monohydrate, followed by sieving. Beta-lactose was designed for directly compressible methods. The product is not hygrosc opic, and is an ideal excipient for moisture-sensitive drugs.
Agglomerated Lactose
Granulated forms of alpha-lactose monohydrate improve the compaction and flow properties of alpha-lactose monohydrate. In direct compression formulations, it is used in combination with Avicel® PH MCC.
Other Sugars
Compressible Sugar NF
Large crystals of sucrose flow very well through a hopper or a bin orifice, but the compaction properties are poor. To overcome this problem, sucrose is commonly modified to make it more compactible. The modified form is known as Compressible Sugar NF. Th e products that fall into this category are composed of sucrose containing starch, malto-dextrin, or invert sugar. The compactibility of compressible sugar depends on its moisture content. An equilibrated moisture content of 0.4% is considered optimum. Be cause of the high solubility of sucrose, tablets containing compressible sugar as a filler do not disintegrate, but rather the sugar dissolves, releasing the API.
Dextrose Excipient NF
Dextrose is available in the anhydrous and monohydrate forms. The compression properties of anhydrous dextrose are poor. A 50:50 mixture of anhydrous dextrose and dextrose monohydrate produces soft compacts.
Dextrates NF
The NF describes Dextrates as a purified mixture resulting from controlled enzymatic hydrolysis of starch. It contains between 93% and 99% dextrose, and may be either the hydrous or anhydrous form. Because of its sweet taste and negative heat of solution, dextrates are recommended for chewable tablets.
Starch and Starch Derivatives
Starch and starch derivatives are among the most commonly used excipients in tablet formulations. Depending on the type of starch, its function is as a disintegration agent, binder, and/or filler. The most commonly used starch is derived from corn, althou gh wheat, potato, and rice starch are also used. Starch is modified by partially or fully splitting the starch grain by mechanical or chemical methods. Starch derivatives, such as esterified and etherified starches (known as carboxymethyl starches), hydro xyethyl starches, and granulated or agglomerated starches, are also used.
Native Starches
Native starches used as excipients are obtained from corn, wheat, rice, and potatoes. Tapioca starch is no longer used in any of the drug products marketed in the United States. Of the native starches, corn starch is most commonly used. Starch is not a si ngle compound, but is a mixture of naturally occurring high molecular weight polymers. The polymers are polysaccharides, consisting of D-glucopyranose units connected by alpha 1-4 linkages. The two main polysaccharides are amylose, which is a linear poly mer comprising approximately 27% of the total, and amylopectin, which is a branched polymer, representing the balance. Native starches are used as disintegrants, but with the introduction of super disintegrants, starch is no longer the disintegrant of cho ice. Poor flow, and loss of binding and compactibility in the presence of a lubricant, make them less suitable for directly compressible tablet formulations. Native starches are also used in old formulations as a binder that comes in the form of a 5% to 1 0% paste cooked in a double boiler.
Pregelatinized Starch NF
Pregelatinized starch is obtained by a chemical or mechanical process that ruptures the starch granules in the presence of water. Partially pregelatinized starch acts as a binder, as well as a disintegrant. If starch is fully pregelatinized, it loses its disintegrant properties and acts only as a binder. The advantage of a partially pregelatinized starch over the native starches is that it combines several functions: filler, binder, and disintegrant. The flow properties are rather poor, whereas the bindin g properties of pregelatinized starch are good. On mixing with alkali stearates (used as lubricants), pregelatinized starch loses its compressibility. An acceptable solution to the lubricant sensitivity of pregelatinized starch or native starches is to us e stearic acid or hydrogenated vegetable oils in place of the metallic stearate.
Sodium Starch Glycolate NF
Sodium starch glycolate is the sodium salt of a carboxymethyl ether of starch. The addition of carboxymethyl groups to starch makes the starch grains more hydrophilic, but not completely water soluble. The degree of substitution is controlled to limit wat er solubility. These modifications make it one of the best disintegrants at a 4% to 8% level in the formulation.
Inorganic Salts
The three most commonly used inorganic salts are dicalcium phosphate, tricalcium phosphate, and calcium sulfate.
Dibasic Calcium Phosphate USP
The most common, directly compressible filler-binder in this class is dibasic calcium phosphate dihydrate. In addition, anhydrous dibasic calcium phosphate is also used as a directly compressible filler-binder. It should be used with caution with APIs tha t have limited solubility in water, as it will further impede dissolution. Dibasic calcium phosphate dihydrate is slightly alkaline and should not be used with APIs that are sensitive to a pH above 7. It is one of the most abrasive excipients and will aff ect the life of tablet tooling.
Di-Tab® is a brand of unmilled dibasic calcium phosphate dihydrate. Emcompress®, on the other hand, is a unique form of dibasic calcium phosphate dihydrate, in which the particle size distribution is controlled to ensure flowability.
Tribasic Calcium Phosphate NF
Tribasic calcium phosphate is available as a directly compressible excipient in the form of TriTab® and Tri-Cafos®. The commercially available product is hydroxyapatite, Ca5(OH)(PO4)3, also commonly (and erroneously) referred to as basic tricalcium phosph ate, Ca3 (PO4)2 Ca(OH)2, or tribasic calcium phosphate. It is a variable mixture of calcium and phosphates used as a filler-binder in directly compressible tablets, and as a filler in tablets prepared by wet granulation. A serious drawback of the tribasic calcium phosphate is its high tendency to adhere to dies and punches. To overcome this shortcoming, higher concentrations of lubricant or antiadherent may be required. Tribasic calcium phosphate loses compressibility when mixed with magnesium stearate. T he lubricant sensitivity is greater than that of dicalcium phosphate. Another drawback of tribasic calcium phosphate is its deleterious effect on dissolution, especially after aging of the tablets.
Calcium Sulfate NF
The specially processed grade of calcium sulfate dihydrate (terra alba), marketed as Compactrol®, is an inexpensive filler. It has been demonstrated that tablets prepared with Compactrol® decrease in hardness on accelerated storage conditions, however, th ere is no effect on disintegration time or dissolution time of the drug.
Polyols
Polyols include sorbitol, mannitol, and xylitol. Chemically, sorbitol is an isomer of mannitol. The most significant differences between mannitol and sorbitol are hygroscopicity and solubility. Sorbitol is hygroscopic above 65% relative humidity, whereas mannitol is nonhygroscopic. The aqueous solubility of sorbitol is higher than that of mannitol.
Mannitol USP
Four polymorphic forms of mannitol have been characterized: alpha, beta, gamma, and an unidentified form. Under compactional pressure, no polymorphic transition has been observed. Mannitol is commonly used in chewable tablets prepared by the wet granulati on process. Mannitol powder has poor flow and compaction characteristics. Granular mannitol is commercially available for direct compression and has excellent flow and compression properties.
Sorbitol NF
Chemically, sorbitol is closely related to glucose, which can be obtained from starch or sucrose. Pharmaceutical-grade sorbitol is available in several different physical forms from various suppliers. Four different crystalline, polymorphic forms of sorbi tol have been characterized, as well as an anhydrous form. Differences in shape and structure of the several sorbitol products result in different behaviors on compaction. Direct-compaction grades of sorbitol, available from several manufacturers, can be used for the production of chewable tablets, lozenges, and disintegrating tablets. The hygroscopicity of sorbitol limits its use in tableting.
Xylitol NF
Xylitol is used as a noncariogenic sweetening agent in tablets, syrups, and coatings. It is also used as an alternative to sucrose in foods and confectionary products.
Coprocessed Excipients
Coprocessed excipients have not gained popularity because of their availability only in fixed ratios. It is important to be completely flexible in the choice of the excipients and their ratios in developing formulations for new active pharmaceutical ingre dients. Another reason that the coprocessed excipients are not popular in the pharmaceutical industry is that the product must show a definite advantage over an ordinary physical mixture of the components in order to be admitted to the compendia. Coproces sed excipients can duplicate the advantages of other starting materials while overcoming their respective disadvantages. Examples include Ludipress® (BASF), Cellactose® (Meggle), and Pharmatose® DCL 40 (DMV). Although spray-crystallized dextrose-maltose ( Emdex®) and compressible sugar are coprocessed products, in reality they are commonly considered as single components and are official in the USP/NF.
Ludipress®
Ludipress® is a coprocessed product containing 93.4% alpha-lactose monohydrate as a filler, 3% povidone as a binder, and 3.4% crospovidone as a disintegrant.
Cellactose®
Cellactose® is a coprocessed product consisting of approximately 75% alpha-lactose monohydrate and 25% cellulose. The compactibility and flow properties of Cellactose® are superior to those of physical blends of agglomerated lactose (Tablettose®), with ei ther cellulose powder (Elcema® P100) or Avicel® PH-102.
Pharmatose® DCL 40
This coprocessed product contains 95% anhydrous lactose and 5% lactitol. It is claimed that the product has a better dilution potential than other commercially available lactose-based products.
Wet-Granulation Excipients
Binders
One of the important functions of excipients in a tablet formulation is to agglomerate (adhere together) the API, fillers, and other excipients, with the exception of lubricants, glidants, etc. (i.e., the "running powder"). Agglomeration of the API and ex cipients by the wet granulation process serves two purposes: 1) to improve powder flow so that the bulk powder can be accurately subdivided for delivery of the dose; and 2) to improve compactibility, which produces tablets with low friability and good cru shing strength. This is achieved by using excipients that have binding properties due to cohesive and adhesive forces. Most binders are hydrophilic and soluble in water. Natural gums and polymers function by forming a thin film on the surface of particle s. When compacted, the particles tend to agglomerate. Highly soluble materials, such as sugar, bind particles together by forming crystal bridges. Binders for the wet granulation process are usually dissolved in water or a solvent (generally alcohol), and the binder solution is used to form a wet mass or granulation. Sometimes it is more convenient to mix the binder in a dry form with the API and excipients, then granulate with water. Most binders are effective in the presence of small amounts of moisture . Van der Waals' forces and hydrogen-bonding play a major role in binding particles together. Microcrystalline cellulose is the only wet granulation binder that also works well as a dry binder in directly compressible formulations.
Avicel® PH Microcrystalline Cellulose NF, Ph. Eur., JP, BP
Avicel® PH MCC functions as an effective wet binder. It provides rapid wicking action in the wet phase, and permits faster addition of the granulation solution. Avicel® PH MCC also produces less screen blockage during particle sizing, speeds drying, limit s or eliminates case hardening, and eliminates or reduces color mottling. It works as an intragranular disintegrant, and breaks up the granules into small particles for rapid dissolution of the drug. When mixed with the dried granules, Avicel® PH MCC impr oves compressibility, and helps in the disintegration of the tablets by working as an intergranular disintegrant.
Cellulose Derivatives
Cellulose derivatives, including Methylcellulose USP, Carboxymethylcellulose Sodium USP, Hydroxypropyl Methylcellulose USP, Hydroxyethyl Cellulose NF, and Hydroxypropyl Cellulose NF, are examples of substances used as wet binders. The concentration of the binders is 2% to 5% of the formulation.
Povidone USP
Povidone is perhaps one of the most commonly used binders today. Several grades of povidone are available, which differ in molecular weight of the polymer. The most common is povidone K-29/32, which is normally used in concentrations of 2% to 5% of the fo rmulation. Higher molecular weight grades, such as K90, offer a better binding property at lower concentrations. Povidone is soluble in water and alcohol, and a 5% solution is normally used for granulation. It can also be dry-mixed with the API, and then wet granulated with water or alcohol. It may be best to use an alcoholic solution of povidone if the API is highly water soluble.
Copolyvidone
Copolyvidone is a linear copolymer of three parts: 1-vinylpyrrolidin-2-one, and two parts vinyl acetate. It is a relatively new binder in the United States. It has been used in a number of applications as a binder in 1% to 5% concentration.
Gelatin NF
Gelatin as a binder has been replaced by synthetic polymers. When used as a binder in formulations, its level is 1% to 3% in the formula. It is first hydrated in cold water, then dissolved by heating to boiling, and the heated solution used to granulate. The most effective concentration of the solution is 5% to 10%.
Natural Gums
Several natural gums, such as acacia, tragacanth, guar, and pectin, are used as binders at 1% to 5% formulation concentration. The drawback of the natural gums is the variability in quality. They have been largely replaced by the synthetic polymers. Acaci a was the most popular natural gum, and it produced hard tablets.
Starch Paste
Starch paste is prepared by suspending 5% to 10% starch in cold water and heating in a double boiler until fully gelatinized. The concentration of starch in the formula may vary between 2% to 5%. Starch paste makes soft granules, but its concentration in the formula is limited because of the viscosity of the gel, which becomes difficult to handle during granulation.
Pregelatinized Starch NF
A better alternative to starch paste is pregelatinized starch, partially pregelatinized (Starch 1500®), or fully pregelatinized starch. The concentration of pregelatinized starch in the formula will depend on the type of pregelatinized starch. Partially p regelatinized starch may be used in 10% to 25% concentration in the formula and is dry mixed with the API and excipients, which are then granulated with water. It provides good binding properties and acts as a disintegrant.
Sucrose NF
A 50% to 70% solution of sucrose is used as a wet binder. The granules formed are hard and may require excessive machine pressure to compact. Sometimes it is used in combination with starch paste or pregelatinized starch.
Other Binders
Less frequently used binders include corn syrup, polyethylene glycols, and sodium alginate. Corn syrup produces hard granules (perhaps the strongest of all the sugars), and may prolong disintegration time. High molecular weight polyethylene glycols are we ak binders and may cause filming and sticking during compaction. Sodium alginate at a low concentration of 0.5% to 3.0% produces strong granules, which have a tendency to prolong the disintegration time of tablets in which it is used as a binder.
Disintegrants
The function of a disintegrant in a tablet formulation is to break up the tablets and granules into particles of the API and excipients, which were agglomerated and compacted. Starch is the classical disintegrant, and was the first most commonly used disi ntegrant in compacted tablets. The increased demand for faster dissolution, the problem of tablet softening of aged tablets due to the high concentration of starch in the formulation, and lower compactibility of formulations containing starch resulted in the development of super disintegrants. Table 3 is a list of the most commonly used disintegrants and the recommended concentrations in tablet formulations. Although Avicel® PH microcrystalline cellulose and partially pregelatinized starch (Starch 1500®) are frequently used in formulations to perform both the functions of compaction and disintegration, the three super disintegrants briefly discussed in the following paragraphs are the disintegrants of choice today.
Ac-Di-Sol® Croscarmellose Sodium NF, Ph. Eur., JPE
Ac-Di-Sol® Croscarmellose Sodium is an internally cross-linked sodium carboxymethylcellulose. It is the super disintegrant of choice for many tablet formulations. The cross-linking serves to greatly reduce water solubility, while allowing the material to swell and absorb many times its weight of water. It does this without losing the integrity of individual fibers. Ac-Di-Sol® is normally very effective when used in wet granulation at 2% concentration. In some formulations, a 1% to 2% intragranular and 1% to 2% intergranular concentration produces tablets with excellent disintegrant properties. Besides its disintegrating properties, Ac-Di-Sol® Croscarmellose Sodium has good binding and compression properties. Unlike starch, it aids compressibility.
Sodium Starch Glycolate NF, Explotab®, Primojel®
This material is the sodium salt of a carboxymethyl ether of starch, prepared in a similar manner to carboxymethyl-cellulose. The addition of carboxymethyl groups increases hydrophilicity, but does not make the material completely water soluble. The exten t of solubility depends on the degree of substitution. The modified starch grains swell in water, but maintain their integrity. This causes tablet disintegration without releasing the soluble components inside each grain, which might increase the viscosit y, thus delaying water penetration. As a disintegrant, sodium starch glycolate appears to be most effective when added to the dry granules at concentrations ranging from 2% to 8%.
Crospovidone NF
Cross-linked polyvinylpyrrolidone is another super disintegrant, which is a homopolymer of N-vinyl-2-pyrrolidone. High molecular weight and cross-linking makes the material water insoluble but still hydrophilic. It is this insolubility in water and its swelling capacity that make it a super disintegrant. Crospovidone NF is used in 2% to 5% concentrations. It is reported as a useful binder-disintegrant in wet granulation formulations.
Table 3: Most Commonly Used Disintegrants and the Recommended Levels in a Formulation
 
Lubricants
The primary function of a lubricant in a tablet formulation is to prevent sticking of the tablet to the punch faces, and to reduce friction between the die wall and the tablet during compression and ejection of the tablet. Magnesium stearate is the most c ommonly used and effective lubricant for tablets. Calcium stearate is not as popular a lubricant as magnesium stearate. Other lubricants, such as stearic acid, hydrogenated vegetable oils, and mineral oil, are used only if there is a chemical or physical incompatibility with magnesium stearate. Hydrogenated vegetable oil and mineral oil-type lubricants form a finite film on punch and die surfaces. These are called fluid lubricants. Magnesium stearate-type lubricants attach to the metal oxide film on the p unch and die surfaces. These are called boundary lubricants. Table 4 gives a list of the most commonly used lubricants and the recommended levels in a formulation.
Magnesium Stearate
Magnesium stearate is the most effective and most commonly used lubricant. The material derived from animal sources is a variable mixture of stearate and palmitate, and has the best morphology for lubrication if manufactured by the precipitation process. Magnesium stearate derived from vegetable sources is more than 90% stearate and is not as effective a lubricant as the material prepared from animal sources. Magnesium stearate is generally effective at levels of 0.2% to 2%. It is usually blended with the powder or granulation mix for a relatively short time (not more than 5 minutes) because of its adverse effect on compaction and in vitro dissolution with most formulations.
Calcium Stearate
Although calcium stearate has somewhat similar lubricant properties to magnesium stearate, its use in tablet formulation is limited.
Stearic Acid
The lubricant properties of stearic acid powder are inferior to magnesium or calcium stearate. Stearic acid powder is used as a lubricant if magnesium stearate cannot be used because of a physical or chemical incompatibility problem. Stearic acid is often referred to as a die-wall lubricant, whereas the metal stearates are punch-face lubricants. For extremely shiny tablets, both can be used together.
Sodium Stearyl Fumarate
Sodium stearyl fumarate has good lubricant properties but is not as popular as magnesium stearate. It is less sensitive to overblending, and it does not affect compressibility.
Hydrogenated Vegetable Oils
Hydrogenated vegetable oils are waxy solids. A powder is produced by spray congealing. The particle size is relatively large, and the lubrication properties are marginal.
Mineral Oil
Light mineral oil is a good lubricant. It is not popular because uniform blending with granulations or powder mixtures is difficult.
Polyethylene Glycols
Higher molecular weight polyethylene glycols, which are solids at room temperature, can be used if solubility characteristics of the lubricant are important. These materials are not very effective lubricants.
Table 4: Most Commonly Used Lubricants and their Recommended Levels in a Formulation
 
Antiadherents
Antiadherents prevent sticking of the tablet blend to the punch face and die wall. They are used in combination with magnesium stearate when sticking becomes a problem (and is difficult to overcome at low concentration levels of the magnesium stearate). Preferably, antiadherents are blended with the dried granules before compaction. Table 5 provides a list of the most commonly used antiadherents and the recommended concentration in a tablet formulation.
Table 5: Commonly Used Antiadherents
 
Glidants
Glidants are used in tablet formulations to improve flow. They are more frequently used in direct blend, rather than wet granulated formulations. Because of the shape and size of the particles, glidants behave as ball bearings to improve flow in low conce n-trations. They are mixed into the final tablet blend in dry form. Table 6 provides a list of the most commonly used glidants and their recommended concentrations in a formulation.
Table 6: Commonly Used Glidants
 
Dry Granulation Excipients
The same excipients that are used in direct compression can also be used in dry granulation.
FMC logo, Avicel, Ac-Di-Sol-trademarks of FMC Corporation.
Aerosil, Elcema-trademarks of Degussa Aktiengesellschaft.
Cab-O-Sil-trademark of Cabot Corporation.
Cellactose, Tablettose-trademarks of Meggle GmbH.
Ceolus-trademark of Asahi Chemical Industry Co. Ltd.
Compactrol, Emcompress, Emdex, Explotab-trademarks of Edward Mendell Co., Inc.
Di-Tab-trademark of Rhone-Poulenc Basic Chemicals Co.
Ludipress-trademark of BASF Aktiengesellschaft.
Pharmatose-trademark of Campina Melkunie B.V.
Primojel-Cooperatieve Verkoop-En Productievereniging Van Aardappelmeel En Derivaten "Avebe" B.A.
Starch 1500-trademark of Fusion UV Systems, Inc.
Super-Tab-trademark of The Lactose Company of New Zealand Limited.
Syloid-trademark of W.R. Grace & Co. Connecticut.
Tri-Cafos-trademark of Chemische Fabrik Budenhein Rudolf A. Oetker.
Tritab-trademark of Therapeutic Antibodies, Inc.


Grouch

  • Guest
Part 2
« Reply #10 on: July 21, 2001, 04:05:00 AM »
I can't post the link for these because you need an account to log in etc.  Maybe Rhodium can take these pages and put them on his site.  These will answer ALL questions regarding tabbin!

...ahhh fuck, it's not working.  There are about 4 really significant parts.  Maybe I'll try again later.

Grouch

  • Guest
Part 2a
« Reply #11 on: July 21, 2001, 04:27:00 AM »
Compression/Compaction
By Dr. Keith Marshall

General Introduction

Tablets comprise the largest group of delivery systems for all prescribed and over-the-counter medications, and therefore, warrant detailed consideration of their design, development and manufacture. The main objective of this chapter is to outline contemporary approaches to the development and production of these important dosage forms. The underlying basic principles of tablet technology and their pragmatic applications will be reviewed.
Compressed tablets may be defined as drug delivery systems intended to be taken by mouth and made up of a single solid body.
Some of the most common types include:
·   Immediate release, coated or uncoated (swallowable)
·   Modified release, coated or uncoated (swallowable)
·   Effervescent (dissolved/suspended in water before drinking)
·   Chewable (chewed before swallowing)
·   Lozenge (dissolved slowly in the mouth)
The most popular of these is the immediate release tablet, intended to be swallowed whole, and release the medicament rapidly in the stomach.
The Pros and Cons of Tablets
Some of the reasons for the popularity of tablets include:
·   Ease of accurate dosage, patient takes one or more discrete units
·   Good physical/chemical stability,because of low moisture content
·   Competitive unit production costs
·   Elegant distinctive appearance, easily identifiable
·   High level of patient acceptability and compliance
Among the few disadvantages of tablets as a dosage form is the possibility for bioavailability problems, due to the fact that dissolution must precede absorption of the active ingredient. This requires that tablets for immediate release of medicament should disintegrate rapidly after ingestion to facilitate solution of the active component.
In addition, there is the chance that GI irritation could be caused by locally high concentrations of medicament. Also, from a patient standpoint, a small proportion of people do have difficulty in swallowing tablets, and so size and shape become important considerations.
The Sophisticated Tablet
It should be realized that tablets are rightly regarded as complex drug delivery systems, and that to trivialize their design, development and manufacture is certain to invite significant problems at some stage in development or during product life.
With this philosophy in mind, it is obvious that it will be important to begin by considering the important and relevant properties of the materials used to manufacture a tablet. There is no doubt that many tableting problems arise because of failure to pay attention to the properties of the raw materials, and/or appreciate how they are likely to behave when they are subjected to the tablet machine cycle.
Some Important Properties of Powders Intended for Tablets
During the manufacture of tablets, bulk powders or granules will be subjected to significant, and in some cases, massive applied mechanical loads. Their behavior under these circumstances may be the major factor controlling the success or failure of the manufacturing operation involved.
Deformation
All solid materials change in shape/volume when subjected to mechanical forces, perhaps better expressed as the force per unit area over which it acts, i.e., a pressure. These latter forces are sometimes considered at points in the system and are referred to as the stress on that particular region of the material. At least three types of stress may be distinguished, as shown in Figure 1:
 
The relative change in geometry is called strain. In the present context of particular interest are the strains caused by application of a compressive stress as shown in Figure 2.
 
There are several ideal model behaviors that facilitate understanding of what may be occurring in the tableting materials when under load. When force is first applied to the material in the die of the tablet press, there will be some degree of repacking of the particles, leading to a higher bulk density. This is usually limited to the initial low load region and is quickly superceded by other phenomena.
One possibility is that application of an increasing compressive load results in failure of the structure and the particle breaks into two or more pieces. This behavior, known as brittle fracture, is found in such excipients as dicalcium phosphate, some sugars, and in some active ingredients. Another possibility is that the material behaves like a spring, and the application of an instantaneous stress causes a matching instantaneous strain response, with immediate total recovery to the original geometry on removal of the load, as shown in Figure 3.
 
At the other extreme, the strain caused by the applied stress may continue to increase with time until the load is removed (see Figure 3). At this point, there is no tendency to recover to the original geometry. Therefore, the amount of strain is time dependent and is not spontaneously reversible. This viscous response to loading is called plastic deformation.
In practice, most solids demonstrate properties which lie between these two extremes and are described by models combining them, resulting in visco-elastic behavior. The simplest combination of these models that might equate to a real powder particle is illustrated in Figure 4. Note that in this case there will be some degree of time dependency to the deformation process, and if the solid material is not given time to deform, then the solid will have to react in some other way. This could be a major problem as the process is scale up to faster presses with less time available to make each individual tablet. Note also that there will be some time dependent recovery after the load is removed. If a sufficiently strong tablet has not been formed at the point of maximum loading, then the recovery may result in failure of the tablet structure, or at least in localized regions of it.
 
Effect of Massive External Forces
Because of ambiguities in existing literature, it is first necessary to clarify the definitions relating to the process of tableting. It may be defined as the compaction of a powdered or granular mixture in a die, between two punches, by application of a significant mechanical force.
The compaction process itself may be simply stated as the compression and consolidation of a two-phase system (particulate solid/air) due to applied forces. Compression is considered an increase in bulk density as a result of displacement of the air phase by solid. Consolidation is an increase in mechanical strength of the mass as a result of particle-particle interactions.
Compression
On application of external force, the bulk volume may be decreased by the several mechanisms referred to above. The significance of these deformation mechanisms to the tableting process is that if brittle fracture occurs during the unloading and ejection processes, then the tablet structure may fail. Similarly, since elastic behavior is spontaneously reversible, the tablet must be strong enough to accommodate this elastic recovery without failure.
Because most tablet formulations are mixtures and many contain organic compounds, the sequence of events as the applied force increases is likely to be a limited repacking of particles, giving way to some elastic deformation.
However, in many pharmaceutical systems, the applied force will exceed the elastic limit of the material. Subsequent compression will then be due to visco-elastic or plastic deformation, and/or brittle fracture, depending on whether the material is ductile (easily deformed) or brittle.
Consolidation
In tableting, consolidation is due mainly to the close approach of particle surfaces to each other, facilitating intermolecular bonding by van der Waals forces, for example. Alternatively, since the entire applied load must be transmitted via particle-particle point contacts, considerable pressures may develop at these points. This can cause frictional heating with a possibility of localized melting, especially if a low melting point solid is present. The resultant relief of the local stress at the point contact would lead to resolidification, forming a bridge between the particles.
It follows that the consolidation process will be influenced by:
·   The chemical nature of the surface
·   The extent of the available surface
·   The presence of surface contaminants
·   The intersurface distances
It is easy to see how the last three of these factors might affect the compaction process, since if large, clean surfaces can be brought into intimate contact, then bonding should occur. Brittle fracture (and plastic deformation) should generate clean surfaces, which the applied force will ensure are kept in close proximity. Of course, as compaction proceeds, some of the bonds that are formed will be broken to facilitate further compression. Nevertheless, the overall effect is usually an increasing number of bonded areas.
It is also important to appreciate that having compacted the material, the load must be removed and the tablet has to be ejected from the die. This will introduce new stresses into it. Therefore, at the point of maximum applied load, a structure which is strong enough to accommodate the new stresses must be developed. In other words, the mechanical strength of the tablet will be a reflection of the number of surviving bonds after it leaves the press.
On the other hand, plastic deformation is not spontaneously reversible, but is time-dependent, and therefore, tablet press speed may be a major factor. However, continuing plastic deformation during unloading and ejection may relieve the induced stresses during these parts of the tableting cycle, and thus avoid structural failure of the tablet.
Die Compaction (Tableting)
All tablet presses employ the same basic principle. They compact the granular or powdered mixture of ingredients in a die between two punches; the die and its associated punches being called a station of tooling. The simplest arrangement is illustrated in Figure 5.
 
Since tableting involves the two distinct processes of compression (volume reduction) and consolidation (increasing mechanical strength), any attempt to identify the dominant mechanisms in a particular case must take both into account. In addition, because time-dependent phenomena may be involved, the sensitivity to press speed must also be studied.
Simple Tablet Press Cycle
It will be convenient to study the basic process by reference to this simplest tableting cycle, i.e., that of a single station (eccentric) press. In such a system, the cycle of punch movements will be as illustrated in Figure 6, and these will generate the typical force profiles shown in Figure 7.
 
 
It is important to appreciate what forces are acting during tableting because changes in the applied forces may well swamp the effect of other variables. Therefore, formulation development must be carried out under conditions where the maximum load applied to the tablet mass is accurately known. In a simple tableting event, mechanical force is applied to the upper punch, FU, which goes through the cycle, and produces the reaction forces shown in Figure 8:
·   That transmitted axially to the lower punch, FL
·   That transmitted axially to the die-wall, FD
·   That transmitted radially to the die-wall, FR
and since there must be an axial balance of forces, then:

       FU    =    FL    +     FD
 
System Geometry
If the simple system incorporates flat faced cylindrical tooling, we can distinguish the following properties of material fed to the die:
·   True volume of its solid components, va
·   Bulk volume occupied by the material, vb, equal to the volume of the die cavity 0.25šD2H (for cylindrical geometry)
·   Voidage within the material, vv, where
   vv =   vb   -   va
The extent of the residual air spaces in tablets plays a major role in dissolution by wicking liquid into the tablet structure to disintegrate it. It will be convenient to consider these void spaces in terms of the dimensionless quantity called porosity, E, defined as follows:
   E   (in %)   =   (1-va/vb)100
Force-Time Profiles
It is important to appreciate that for a given set of pressing conditions, the force generated as a result of punch movements is a function of the true volume of the solid in the die cavity and NOT the weight. It follows that comparative testing should be carried out with compression weights adjusted from the value of true density, to give a constant true volume of solid in the die during each experiment.
One of the simplest plots which can be obtained from the most basic instrumentation on a tablet press is the compaction force versus time profile, as seen in Figure 9. The area under this curve is indicative of the resistance the material offers to the compaction process. A common term found in pharmaceutical literature refers to a dwell time under load. This is now generally accepted to mean the time for which 90% of the peak load is being applied. It is also approximately the same as the time it takes for the punch head flat to traverse its contact with the lowest part of the upper compression roll of a rotary press, or highest part of the lower roll.
 
Figure 9: Compaction force versus Time profile
More specifically, if the compaction event is carried out slowly, then the ratio of the area to peak force, over the area from peak force, gives an approximate indication of the extent of the elastic recovery. The two areas should be equal if the material is perfectly elastic, and the ratio will be larger the more brittle fracture or plastic deformation dominates the behavior of the material.
Compressibility
A finite end to the compressional process occurs when the air spaces are completely eliminated. And there is frequently an inverse relationship between the residual porosity and the strength of the compact. This changing porosity of the tablet mass during the tableting cycle is a convenient and valuable means of following the degree of compression achieved as a result of the applied force. Several workers have attempted to analyze the porosity versus force plots, and many equations have been proposed for the force region in which most tablets are produced. All of these equations include a term for the initial porosity of the mass, just before load is applied. This means that for a given applied force, the final porosity depends on the initial porosity. However, there is no universal equation that describes the behavior of a wide range of materials over the entire force profile.
Heckel Plots
Among these many equations relating porosity to applied load is that usually credited to Heckel1 which has been widely used in tableting studies, producing data similar to that shown in Figure 10. It is based upon an equation involving the assumption that the material behaves in an analogous way to a first order reaction, where the pores are the reactant, i.e.:
    Ln  E-1    =    KyP +    Ko
where Ko is related to the initial repacking stage, or function of Eo, and Ky is a material-dependent constant inversely proportional to its yield strength Py, by the following;
     Py    a   1  /  Ky
where Py is the point at which plastic or visco-elastic deformation becomes dominant.
Note that a high slope is indicative of a low yield pressure and hence plastic behavior should be expected at low applied loads, and vice-versa. It follows that materials that are brittle in nature will tend to give low values for Heckel plot slopes.
The curved region at the low end of the pressure scale on Heckel plots has received additional attention and has been related to the initial packing stage. It should be noted that the Heckel equation predicts that as the porosity approaches zero at higher pressures, the y axis values of the plot will approaches infinity, and therefore the linear region must be a limited one.
Porosity data can be obtained from in die measurements using instrumentation which follows punch movements throughout the compaction cycle. Alternatively, measurements of tablet geometry out of die can be made when the tablet has been ejected. It is important to appreciate that the data obtained from the two techniques may be significantly different, since the latter will include any tablet expansion as a result of elastic recovery on unloading. For this reason, the method of obtaining porosity data should be clearly stated.
 
Density Distributions in Compacts
An intrinsic property associated with materials compacted in a die is the development of a typical pattern of density. That shown in Figure 11, for a double-ended compaction (such as in a rotary tablet machine), is a possible result of this phenomenon and might be the cause of the typical hard core found in some tablets (seen during disintegration tests). It is most likely to be present at higher applied forces and when the thickness to-diameter ratio is large.
 
Frictional Effects
One of the most common manifestations of the strength of the forces at surfaces is the phenomenon of friction. This effect opposes the relative motion between two solid surfaces in contact, so that in the absence of a sustaining force, motion ceases. In the above example of the tableting event (see Figure 8), the simplest equation to describe friction between the tablet materials and the die wall is:
    FD   =    µwFR
where µw is the average coefficient of die-wall friction, an important additional factor which will now be considered.
Frictional effects undoubtedly play a major role in the progress of the compressional sequence of tableting, and we may distinguish two major components:
i.   Inter-particulate friction, arising at particle/particle contacts, which can be expressed in terms of a coefficient of inter-particulate friction and which will be more significant at lower applied loads. Materials that reduce this effect are referred to as glidants; colloidal silica being one widely used example.
ii.   Die-wall friction, resulting from material being pressed against the die wall and moved down it, and expressed as µw, the coefficient of die-wall friction. This effect becomes dominant at higher applied forces, once particulate rearrangement has ceased, and it is a particularly important factor in tableting. In fact, most tablets contain a small amount of an additive designed to reduce die-wall friction and which are called lubricants; magnesium stearate being the most popular choice.
A measure of this die-wall friction can be obtained by collecting FL and FU data from a single station press at different H/D ratios and then applying an equation of the form:     LnFL / FU    =    kH / D
where the constant k includes a term for the average µw.
Experimental results demonstrate that in unlubricated systems the exact relationship is widely variable, but there is a definite trend for die-wall lubrication to result in constant FL/FU ratios. Indeed the ratio has been termed the coefficient of lubricant efficiency, the so-called R value, but is dependent on the H/D ratio and is not always linearly related to FU.
Some materials also tend to adhere to punch faces, and thus a third group of additives is recognized that minimize this phenomena and are called anti-adhesives. Talc is a common example.
Load Removal and Tablet Ejection
Tableting is a dynamic cyclic operation in that a load is applied and must then be removed to facilitate ejection of the tablet from the die. The strength of the tablet so produced, is therefore, a function of those bonds made during loading which survive the unloading and ejection parts of the cycle. For this reason, it is important to study the entire compaction event and evaluate the region beyond the point of maximum loading.
Removal of Applied Load
As the top punch moves away from the tablet surface following the point of maximum penetration into the die, the tablet may expand due to elastic recovery and visco-elastic recovery. The former is a very rapid process, while the latter may even continue after the tablet is ejected from the die.
Ejection
The process of ejecting tablets (from the die) introduces a new set of stresses into them and the tablet structure must be able to withstand them. The practice of including a lubricant in tablet formulations to reduce friction at the die wall plays a major role in minimizing the potential for failure of the tablet structure during ejection.
A typical ejection force trace from an instrumented ejection cam is shown in Figure 12. Many workers have reported relationships between the applied force to produce the tablet and that needed to eject it from the die. Among the more useful seem to be those relating the ejection force per unit area of tablet/die-wall contact to the maximum applied compaction pressure P. Many materials give linear plots, and a very steep slope in these indicates an undesirable sensitivity to compaction force levels. Some workers have used the area under the ejection force versus lower punch movement plot to obtain a Work of Ejection.
 
Consolidation Potential
One of the major essential properties of a tablet is that it shall possess adequate mechanical strength. Therefore, the second major component of the compaction process (in addition to compression) is the increase in mechanical strength of the tablet mass as the load is increased. This phenomenon called consolidation and the effect of every conceivable variable on tablet strength has been widely studied.
Compaction Force Versus Tablet Strength
One of the commonest tests is to make tablets at different known compaction forces and determine their strength as exemplified by the force necessary to break them. Some typical examples of compaction force versus tablet strength data are shown in Figure 13. Excessive compaction forces usually result in little increase in tablet strength and may even lead to a loss of strength. Again, it should be noted that a very steep slope in such plots is indicative of a pronounced sensitivity to compaction force levels which might be a source of problems in a production environment.
The valuable information, which this type of data can provide during formualtion development, places compaction force vs. tensile strength profiles high on the list of essential tests. However, the data (slopes) generated from the profiles give little indication of underlying mechanisms to facilitate formulation improvement, if acceptable strength is not achieved.
 
Energy Involved in Compaction
Intuitively, one might anticipate that the energy input necessary to form a tablet should be a more important parameter to study the process than using compaction force. It has already been noted that some of the bonds formed between particles will be broken to facilitate compression. In materials which readily bond and/or form strong bonds, a greater resistance to this compression can be anticipated, than for those where bonding is poor. The ease with which the machine can compress the material may therefore, be indicative of potential tablet strength.
The amount of energy consumed in the compaction sequence is of great interest because it affects machine requirements, and that proportion stored in the tablet retains destructive capability. Work is involved in the following processes which form a part of the compaction cycle:
1.   To facilitate particle re-arrangement and overcome inter-particulate friction
2.   To overcome particle die-wall friction
3.   For elastic deformation deformation
4.   To break bonds
5.   To eject the tablets
6.   To move various press parts
The first item usually only involves a comparatively small amount of work in the earlier stages of the compaction event. Overcoming friction at the die wall should also be a minimum energy requirement if the system is adequately lubricated. Items 3, 4 and 5 account for most of the energy delivered to the compacting mass as appreciable forces are applied, and many studies have been carried out to try and estimate the contribution of each.
The work required for item 6 can be separated in time from the other components, and that required to move press parts can be eliminated from the detection system.
Work of Compaction
Plots of applied force versus punch displacement give rise to the typical curve seen in Figure 14. The area under the curve (force times distance) represents the total work involved in the compaction cycle. If the hypothesis given earlier is accepted, then a proportion of this work must have gone into breaking bonds and may provide a means of predicting strength from work data.
 
Analysis of Force-Displacement Curves
The curved downward decompression trace arises because of elastic recovery of the compact, and in data from a single station press, the differences between upper and lower punch curves are due to frictional effects at the die wall. Consequently, the enclosed area Wn represents the net work involved in the process.
Distinctive curves, related to the stress/strain properties of the material, have been demonstrated and the results are also related to the state of lubrication. Indeed, the technique has proved particularly useful for evaluating lubricants, being a more sensitive parameter than an R value (see page 10).
The Tableting Process
Having discussed the underlying mechanisms involved in the process of tableting, the basic process and contemporary tableting equipment will now be considered. Perhaps the most important point to appreciate about tablet manufacture is that although the aim is to achieve medicament content uniformity (hence weight uniformity), the material is actually metered out by volume. This necessitates a constant die-cavity volume at the point of fill and a constant bulk density of the material in the die. This, in turn, places great importance on the qualities of the material fed to the press and, in particular, certain desirable properties of the granulation, i.e.:
·   Good flow properties, i.e., optimum particle size distribution, regular shape and smooth particle surface
·   Homogeneous, i.e., low segregation tendency, uniform particle density, optimum bulk density, low porosity particles
·   Compactible, i.e., will actually form tablets
·   Ejectible, i.e., after being formed into a tablet can be removed intact from the die
The effect of changes in these characteristics should be studied as part of the development program leading to an optimized formulation under production conditions. More specifically, changes in these factors as the processing is scaled from R&D lot sizes to full production batches must be determined; their effect minimized and documented.
Introduction to Tablet Presses
All tablet presses employ the same basic principle: they compact the granular or powdered mixture of ingredients in a die between two punches, and the die and its associated punches are called a station of tooling, as shown in Figure 5. Presses can be divided into two distinct categories on this basis:
i.   Those with a single station of tooling -single station or eccentric presses
ii.   Those with several stations of tooling -multi-station or rotary presses
The former are used primarily in an R&D role and for small quantities of complex-shaped or large-sized pieces, while the latter, having higher outputs, are used in most production operations. All commercial types have essentially the same basic operating mechanism; the die is filled, the mass is compacted and then the tablet is ejected. The punch movements necessary to accomplish the three parts of this cycle are obtained by cam action.
Tablet presses, especially large, contemporary production machines are powerful mechanical devices capable of exerting massive forces, via the tooling, on the mass in the die cavity (and anything else that gets in the way!). For this, and other reasons, it is important that modern high speed tablet presses be operated by qualified trained personnel and be maintained by equally experienced engineers. Regulatory requirements and prolongation of the life of these expensive items of capital equipment, dictate thorough cleaning and inspection, with good record keeping, all at appropriate time intervals.
Because of these needs, many of the latest models of production presses also incorporate high levels of electronic monitoring and control of the press operation. These additional features become a necessity when it is no longer possible for an operator to react quickly enough to ensure that the press is operating in the validated mode, or to detect a problem early enough to avoid a major failure.
Tablet Machine Design
Single Station Presses
The simple cycle of this type of press only offers the operator a limited opportunity to make adjustments, as summarized in Figure 15.
 
It is, therefore, important that the press is not required to compensate for poor formulations. Sizes of machines in this group vary widely from small ones, capable of making tablets up to 12 mm in diameter, at rates of about 80 tablets per minute (t.p.m.). These can exert maximum forces of the order of 20 kN. At the other end of the spectrum are large machines with maximum tablet diameters around 80 mm and capable of loads up to 200 kN or greater.
In a few cases, tablets can only be made on the single station type of machine, probably because their way of operating gives the material a longer dwell time under load, and indeed, this is their main advantage. The output rate from single station presses can be increased by the use of multi-tip tooling, but the rotary machine remains the method of choice for large scale production. Therefore, although a single station press may be used in the early stages of tablet formulation development, it is imperative that as soon as sufficient material is available, the technology should then be transferred to a multi-station press with dwell times as close to those in production as possible.
Multi-Station Presses
Multi-station presses involve the same three steps in the tabletting cycle, but these take- place simultaneously in different stations of the rotating turret carrying the tooling (Figure 16 and Figure 17) and generate a punch movement pattern as seen in Figure 18. However, the operator only has a limited number of options in adjusting the running of the press (Figure 19). The number of stations was commonly around 16 in early machines, giving outputs between 500 to 1000 t.p.m. with diameters up to 15 mm, while high speed contemporary presses have closer to 80 stations and outputs in excess of 12,000 t.p.m.
 
 
 
 
The operating cycle and methods of realizing the filling, compacting and ejection operations are basically different between the two types of presses (as listed in Table I). It is vital that these differences be fully appreciated when translating information obtained on one type of press into anticipated performance on the other.
 
In fact, it may be necessary to distinguish between different models of the same group, especially when considering those with high output rates. In particular, there is a large difference in the time available for the machines to make a single tablet. This parameter is particularly critical where the dominant deformation mechanism is visco-elastic or plastic.
For this reason, it is important to appreciate that contemporary tablet manufacturing formulations are adequately tested on production speed presses, before transferring the technology from the development to the manufacturing department.
The smaller rotary presses still offer the following advantages over larger, newer models:
·   More flexibility in formulations they can handle
·   Shorter change over times
·   Less stations of tooling to buy
·   Less capital cost
Contemporary Tableting Processes
The development of tableting equipment has been largely one of continuing evolution, but there is now evidence that inherent limits to further development of some press variables on existing lines are being approached. At present, and in the immediate future, one may anticipate the continuing competition between vendors and the added possibility of some more revolutionary machine designs, but with perhaps one exception, recent history is not encouraging.
Apart, perhaps, from presses designed to produce coated or layered products, in many areas the incentives for improvement have come from the users (rather than the machine manufacturers) as a result of trends in tableting operations. These include the need for higher rates of production and more uniform products, the wish to directly compress powders, a desire to automate or at least continuously monitor the process and the need for improved hygiene during operation to satisfy regulatory agencies.
High Production Rates
Having briefly reviewed some of the more basic aspects of tableting equipment, the most popular innovative trends of this technology will now be discussed. One of the more important characteristics of a tablet machine is the rate at which the machine can produce a product.
The ways in which individual manufacturers of equipment have sought to achieve higher outputs fall into four groups:
i.   By increasing the rate of compression,i.e., turret speed
ii.   By increasing the number of stations
iii.   By increasing the number of points of compression
iv.   By increasing the effective number of punches, i.e., multi-tipped types
Each of these approaches has its own particular advantages and disadvantages, are in addition, all make demands on other aspects of press design and certain general inherent characteristics of tableting have had to be taken into account.
For example:
i.   Formulations developed for slower presses may not run satisfactorily on higher speed machines
ii.   Some granulations may not flow faster enough to fill the dies satisfactorily, so that weight variation from tablet to tablet increases
iii.   Need for a higher level of competency of the set-up personnel and machine operators
iv.   Noise created by the higher speeds can increase to a level that is uncomfortable to the operator and even above that permitted by regulatory authorities
v.   Capital costs for equipment may increase beyond the reach of smaller manufacturers, or those with limited profit margins
Other than following press operation instructions, probably the six key factors involved in producing satisfactory tablets at high speed are:
(i)Satisfactory robust and flowable granulation (ii)Optimized press operating conditions for that specific product (iii)Variable speed feeders, optimally set-up (iv)Satisfactory tail-over dies (seals the die cavities between filling and compession steps) and lower punch flight controls (prevents vertical movement of the dies) (v) Efficient dust extraction system (vi)Electronic self-adjusting controls to monitor and control uniformity of tablet weight and other key press functions
High Turret Speed
It is important to realize that in the fastest running presses, horizontal punch velocities may exceed 4 m/sec, and vertical punch velocities may exceed 2 m/sec. These conditions require the most careful attention to press design, construction and operation, if acceptable levels of wear and trouble-free production are to be achieved.
The Press designer must always bear in mind the inherent relationship between the centrifugal force, G, the pitch circle radius, r, and the speed, n, (rpm) of the revolving turret, i.e.:
    G    =  k  r  n2
where G is in multiples of the gravitational force and, in high speed presses, may be as much as 10 times that of first generation multi-station machines.
This leads to possible movement of material in the die, which can be minimized by introducing a precompression stage, unless material is actually being lost from the die cavity. In this eventuality, it may be necessary to take advantage of variable punch penetration to carry the uncompressed material lower in the die, or virtually seal off the cavities between filling and compression points with spring loaded tail over dies.
A further problem associated with the increased turret speeds is the chance of punch velocities along the camming, particularly the weight adjustment cam, exceeding some critical value leading to a phenomenon known as punch flight. The machine modification of fitting springloaded plungers, which pressed against the punch body, originally developed as anti-turning devices, is some help in this respect, but generated cams are now the design of choice.
Precompression
Most high speed presses have a two-step compaction cycle, to facilitate removal of air from the feed, minimize loss of material from the die cavity, and reduce the work of the main compression rolls. This is achieved by introducing a second set of smaller compression rolls which can apply variable but lower forces before the material reaches the main rolls.
Many of the more recent models have two identical compression stations, and have been shown to produce stronger tablets. In fact, in some cases, a higher first compression force than the second can even be beneficial. It has been suggested that one of the reasons for this observation is that higher first compressions result in higher temperatures of the material at the second point of applying load. They fill, therefore would, be more ductile with increased plastic deformation which may increase tablet strength, due to greater interparticle bonding with fewer bond ruptures.
Several press manufacturers now provide for operating their machines under these conditions. It is important to use large diameter rolls at both stages, since small rolls and high forces can lead to tableting problems due to a higher loading rate. A further refinement, which extends the time under load, is the addition of a spring-loaded section called a dwell bar between the first and second compression stages, which is said to facilitate even higher production speeds.
Cams
For high-speed machines it has been necesssary to ensure that punch heads remain in contact with cam tracks by installing so called generated cams, so as to avoid punch flutter. In these, the punches are forced to follow a specific path by being held firmly in a cam track which controls all their vertical movements precisely.
Many of the cams in newer presses are of special plastic construction to facilitate high speed operation, prolong cam and tool life, and to produce less heat and noise. It is also essential to keep the angle of the weight adjustment cam track something less than 8°. This has involved the provision of interchangeable cams which reduce the excess of material originally filled into the die. It should be noted that higher press speeds may require more die overfill because of greater density variations in the feeder.
The gradients on ejection cams also vary widely between vendors of presses, and the debate continues as to whether rapid or slow ejection is preferable. Therefore, when switching products between machines, this factor should not be ignored.
Feeders
The original method of feeding the dies was from a stationary feed frame, material falling under the influence of gravity into the die cavities, the feed frame being designed to pass material to and fro across the die surface. More sophisticated types are needed for high-speed machines which do not rely on gravity alone, but provide a mechanism which assists material flow.
Contrary to some of the literature references, in the highest speed presses there are no longer force feeders, but devices which also partially fluidize the material and facilitate its transport into the die cavities under the partial vacuum created by descent of the lower punches. For this reason, it is advantageous to control the rate of flow of material into the feeder chamber so that there is space for expansion, i.e., it is not choke fed. Also for this reason, many recent designs incorporate three paddles (Figure 20), by having an upper one which meters material from the hopper to the twin paddles of the feeder. In earlier models, the speed of these paddle feeders was linked directly to turret speed, but it is now recognized that a variable speed, independent of the turret speed, is preferable.
 
It is important to appreciate that modern feeders have a multi-functional role. In addition to feeding the dies, they also carry on their leading edge, the device which sweeps the ejected tablets from the press. The trailing edge of the feeder incorporates the blade which sweeps the ejected overfill material from the die cavities just before they emerge from underneath the feeder.
Adjustments of these two additional controls, as well as an optimum clearance between feeder and rotating die table, is critical, and so the attachment and rigid locking of the feeder onto the press is a vital factor in successful operation. Even so, modern feeder designs provide rapid release for removal and are easy to strip down for thorough cleaning and inspection.
Lubrication
In the modern tablet press, the contacting surfaces of some individual components are under load and are moving relative to one another at high speeds. It is obvious that to maintain successful operation, an appropriate amount of a lubricant must be present at these surfaces at all times. It is no longer possible to expect an operator to achieve this requirement, and so presses are now fitted with ancillary equipment that provides individually measured amounts of lubricant on an optimized schedule, directly to all critical locations requiring lubrication. In many cases, transducers on the press are constantly monitoring regions where failure of the automated lubrication system would lead to increasing frictional forces, and they can stop the press or activate some alarm system.
Increased Number of Stations
The best compromise between strength of turret and maximum number of stations which can be accommodated at a given diameter, involves three variables:
i.   The diameter of the dies
ii.   The distance between dies (known as the web; see Figure 21)
iii.   The size and geometry of the die locking mechanism
 
Turret Web
As more stations are fitted into the turret so the metal web between the dies becomes thinner, retaining sufficient strength and providing adequate locking becomes a design problem. Die-locking nuts should only be tightened when the entire die set is fitted; torques not exceeding 15 foot-pounds should be used and a torque wrench employed. As little as 8 foot-pounds may be adequate with new tooling.
Multi-Sequence Presses
Reducing the entire sequence of the compressional cycle into half the turret periphery, as a means of virtually doubling output, was realized in the first double-rotary presses just after the turn of the century. By this means, two tablets are produced by each station during each turret revolution.
One of the more critical factors in operating these presses is to ensure that both sides of the machine are producing tablets with closely similar characteristics. This requirement is not as easy to achieve as might be expected, and some of the differences encountered include:
i.   Feed to each side of the press is not the same, due to differences in level of material in the hoppers and/or segregation in them or the bulk container (ii) The feeders are behaving differently
ii.   Dust extraction not the same on both sides
iii.   Punch penetration settings and/or overfill cams are different
In some machines, the tablets produced on one side of the press are carried round to the opposite side, so that there is a single product outlet from the machine. However, for the above reasons, separate outlets are to be preferred.
This concept of multi-sequencing has now been taken a stage further in a four-sided press in which the entire compression cycle is restricted to one quarter of the cycle and repeated to give a total of four tablets from each station every revolution. This Magna Press (Vector Corp.) has a rated output of almost a million tablets per hour, achieved by using a large turret (90 stations), but a low turret speed of 45 rpm.

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Part 2b
« Reply #12 on: July 21, 2001, 04:32:00 AM »
Multi-Tipped Tooling
The ability to compress a particular product on presses with different output rates, without affecting the time for the actual compaction cycle, is especially attractive, for at least three reasons. The first is the circumvention of difficulties associated with some minimum compaction and recovery time, related to the deformation characteristics of the major components. Second is the need to allow a finite time for the displacement of the air inevitably present in the feed material, and finally, the flexibility offered by being able to run a single formulation on different machines.
In view of these factors, it is perhaps surprising that the use of multi-tip tooling has not been more popular. Typical multi-tip tools are shown in Figure 22 and up to 6 tips per stem are now offered by some manufacturers. The most likely explanation for any reticence to use this approach is the increased restrictions on tablet diameter, the need for keying of such tooling and the higher initial and maintenance costs. For the latter reason, the introduction of tooling where the individual tips on a particular punch stem are readily replaceable has immediate appeal, although matching and maintaining constant overall length of each punch and tip demands an excellent tool maintenance facility.
A further disadvantage to this approach to increased output is the difficulty in instrumenting the press to measure the compaction forces being generated at each punch tip.
 
Ancillary Equipment
The modern tableting process requires several additional pieces of ancillary equipment to the press itself. The trend towards more automation and instrumentation, and in some cases to introduce total automatic control of the process the so-called lights out operating conditions, has increased the need for such peripherals.
Among the more common are:
·   Deduster attached to press outlet
·   Metal check attached to deduster outlet
·   Weight check device which samples press output
·   Tablet strength check on samples from press output
·   Thickness and diameter check on samples from press output
Multi-purpose control units, which accomplish most of these functions and others, are available from many vendors.
In addition, lights out operation may necessitate devices which monitor the level of the feed in the hopper and automatically add more on demand. Similarly, a full product container can be detected and automatically substituted with an empty one. These trends require provision of larger cubicles for each tablet machine, and it is important to consider this when planning new, or refurbished, tableting facilities.
All the above peripherals are in addition to the now commonly installed instrumentation package available with virtually all high- speed presses. These packages facilitate continuous automatic monitoring of machine performance, and can be coupled to the various devices reviewed here.
Tablet Tooling
The punches and dies of modern tablet machines fall into the category of precision tooling and, as such, should be treated with the proper respect. They are manufactured by special techniques to very close specifications, such as those defined in the IPT2 and Euronorm (Eurotooling) standards. A brief description of the steps in this process will serve to emphasize the respect that should be given to tooling.
Punches
Upper punches typically have more clearance in the die than the lower ones, since only the former are required to move in and out of the die cavity. This greater clearance also serves to facilitate escape of entrained air. The barrels of shaped and embossed upper punches are keyed to prevent any rotation in the press guides. Sculptured tooling, i.e., three-dimensional profiles, can now be made (which are costly) or even different shapes within a single set, while retaining the same tablet volume.
The Hob
Any punch markings are usually cold compressed into the punch tip face by means of a hardened hob. The hob is, therefore, an all important aspect of modern tooling and thus worthy of brief comment. It is manufactured to very accurate limits by a skilled tool maker, who produces the hob from a large detailed template. The result is a precise hob, which can be reproduced exactly, only by the possession of the template, thus counterfeiting is very difficult, yet any vendor can be asked to make the tooling.
Matched Tooling
One of the most critical specifications for tooling in contemporary multi-station machines is uniformity of overall geometry, ard, therefore, all tooling must be matched. This is necessary because such machines are now usually equipped with transducers to monitor the forces being exerted on the material in the die, and use this information to record and even control uniformity of tablet weight. Applied force can only be correlated to tablet weight if tooling is matched (see later).
Inspection
Full inspection of all punches and dies in the set should be carried out before and immediately after use. If excessive or unusual wear is seen, the source must be identified and any problem rectified. Any such occurrence is added to an on-going history of this particular set of tooling, and means that each set of tooling, whether off or on the press in individual stations, must be identifiable. Some of the most critical points to check for wear include:
·   Upper and lower punch tips
·   Upper and lower punch head flats
·   Upper and lower punch inside head angles
·   Upper and lower punch head outside angles
·   Keyway
·   Die bores
The vendors of tablet tooling have many years of in depth experience of designing, manufacturing and advising on tablet tools. Probably, the best advice to give to a would- be purchaser of new tablet tooling is to sit down with the tool vendor, tell them your wishes, but pay very close attention to their response. This is an area where taking expert advice can really be an extremely rewarding exercise.
Tableting Problems
Perhaps the two most important points to appreciate about the properties of tablets are that, in most cases, an optimum balance in the inherent compromise between rapid dissolution and mechanical strength is sought and, superimposed on this need, is a requirement for an accurate uniform dosage between tablets in a batch and between different batches. Many of the common problems with tablets arise due to the failure of efforts to meet these criteria.
In this section, those processing factors (rather than formulation factors), which can influence these important attributes of pharmaceutical tablets, shall be reviewed briefly. The discussion is restricted to those tablets where rapid release of drug is desired. See Section 5. of this Manual for a more detailed discussion.
Release Profile
The major formulation factors found to affect the release profile of drug from immediate release pharmaceutical tablets could include changes in:
·   Disintegrant efficiency
·   Binder characteristics
·   Lubricant properties
·   Particle size distribution
·   Moisture level
Similarly, processing factors affecting the profile could include:
·   Excessive compaction force
·   Over-mixed lubricant
·   Longer dwell time (e.g., press slowed down)
·   Change in bulk density
·   Segregation of ingredients
Some of these factors affect the disintegration process, which is usually a required precursor to dissolution, and is necessary for absorption of the medicament. Thus, all steps leading to the latter process must be carefully considered.
Weight Variation
Uniformity in the content of active ingredient between tablets within a batch is a major requirement, and is affected by the actual tableting process. One obvious factor contributing to this uniformity is the variation in individual tablet weights, and the formulation-related reasons for poor weight uniformity include changes in:
·   Particle size distribution
·   Bulk density
·   Moisture level
·   Shape of a major ingredient
Processing factors which may affect weight variation are:
·   Unmatched lower punch lengths
·   Uneven die filling
·   Poor hopper and feeder settings
·   Collection of product during starting and stopping of the press
·   Faulty machine parts such as cams and dust collection components
Content Uniformity
All the above factors contribute to content uniformity, but in addition, this problem may also be caused by non-uniform distribution of active in the feed and/or segregation, and by preferential loss of active as fines during tableting. It is important to appreciate that even the most sophisticated tablet machine may not be able to compensate for an essentially bad feed material, and it is the responsibility of the formulators to ensure that machines are fed with formulations of robust character.
Mechanical Strength Problems
The mechanical strength of tablets may be described in several ways, including the force required to fracture them. The so-called breaking force is the most common measurement (crushing strength is a misnomer). Resistance to surface abrasion is also a popular test and is expressed in terms of a friability value.
Among the problems with the mechanical integrity of tablets encountered during manufacture are capping, lamination, chipping, stress cracking and sticking (picking) of material to the punch faces, as illustrated in Figure 23.
The strength of a tablet may be influenced by the following parameters:
·   Compaction force and compaction rate
·   Dominant deformation mechanism(s)
·   Formulation factors, e.g., binder and lubricant
·   Moisture
 
Capping and Lamination
Capping is the phenomenon where the upper part of the tablet horizontally separates caps from the remainder during ejection, or during subsequent handling. Some of the factors that may contribute to this defect are listed in Table II. The failure of tablets along several horizontal planes is called lamination and the same factors may contribute to this problem. In addition, relaxation of various regions of the tablet, as they emerge from the die during ejection (Figure 24), may be a factor if bonding is weak and visco-elastic recovery is pronounced. The problem can sometimes be circumvented by the use of tapered dies, i.e., the upper part of the die bore has an outward taper of 3° to 5°.
 
 
Chipping
Sometimes tablets leaving the press, or during subsequent handling and coating operations, are found to have small chips missing from their edges. This fault is described as chipping and, in addition to the obvious formulation deficiencies, may be caused by compaction conditions which make too soft or too brittle tablets. Incorrect machine settings, especially the ejection take-off plate and excessively harsh handling of bulk tablets after they leave the press, may be additional factors. Friability testing is a good indicator of an inherent tendency for a given batch of product to chip and should be a routine in-process check.
Stress Cracking
Sometimes small, fine cracks can be observed on the upper and lower surface of tablets, or more rarely on the side wall (Figure 23). These are referred to as stress cracks and in some cases it may be an incipient problem which is not detected until attempts are made to coat the tablets, during packaging, or on final visual inspection. It may be noted that the remedy for stress cracking may involve significant changes to the formulation or process, including the geometry of the tooling.
Picking
In some instances, a small amount of the tablet material may stick to the active punch faces, and this is referred to as picking. As tablets are repeatedly made in this station of tooling, the problem gets worse as more and more material gets added to that already stuck to the punch face. The problem tends to be more prevalent on upper punches. Among the remedies for this phenomenon are those listed in Table III.
One of the more useful procedures for determining the cause of this particular problem involves recovering a small amount of the material from the punches to which it is sticking. This material is then analyzed to find out whether it is rich in any component of the mixture, including the level of moisture. This procedure is now perfectly feasible with the sophisticated analytical tools available today.
 
Rate of Compaction (Press Speed)
Due to the fact that some solid deformation mechanisms are time-dependent, the duration for which appreciable load is applied and the rate at which load is applied may be highly significant. In other words, sensitivity to strain-rate may be an important property of materials subjected to compaction. In terms of tableting, these variables are often expressed in terms of the dwell time and rise time, respectively (see Figure 9).
Effects of Compaction Rate
The significance of this sensitivity to compaction rate lies in the scale-up or transfer of formulations from slower research and development tablet presses to the high-speed machines commonly used in the production environment. In the latter case, dwell times may be less than 5 msec. compared to values at least one order of magnitude greater in machines often found in research and development facilities.
Switching from one press to another may involve a change in:
·   Compression roll diameter, which in turn affects the loading profile on the material
·   Change in turret size and, more specifically, the pitch circle, may also lead to a different loading pattern
One example of a way to at least determine a rank order of loading rates is to calculate a quantity called the constant strain period or CSP. This is the time during which the punch head flat L (a fixed size in standard tooling) moves under the lowest point of the upper compression roll, or uppermost part of the lower roll, as illustrated in Figure 25. In other words, the time during which the punch tips are closest to each other.
 
From a knowledge of only the pitch circle radius, r, and rotational speed of the turret, R (in rpm), the angular velocity, v, and hence the CSP can be calculated from the following equations:
    v   =    2  p  r  R
and
    CSP  (msec)    =   60,000   L  /  v
It is worth noting that the CSP approximates to the dwell time, i.e., that time for which 90% of the peak load is being applied. Some examples of CSP for a range of presses, operating at their minimum and maximum speeds, are given in Table IV (values calculated from vendors specifications).
 
Problems of Scale Up
Some of the tablet properties most likely to be affected during scale-up include:
·   Weight and weight uniformity
·   Disintegration and dissolution
·   Breaking force and friability
·   Tablet average thickness
Attention should be paid to changes in any press parameters, since all are likely to vary between slower/smaller presses and the common high-speed presses found in production. However, three key factors must be taken into account when scaling up a tableting process.
First, because this usually means a faster running press, the quality of the feed must be optimized to provide the ideal flow into the dies. In other words, homogeneous feeding conditions to the dies must be maintained and is a parameter which is affected by both feed and press characteristics.
Second, it is important to appreciate the problems which may occur when a tableting process is scaled up to a press where the time to make each individual tablet is significantly reduced. If the change is dramatic, there may be a change in compaction mechanism, and the tablet strength could be adversely affected. Hence, it is necessary to measure the possible change in dwell time via a calculation of the change in CSP. Finally, the effectiveness of the lubrication is also influenced by material and press properties and is another common source of scale-up problems.
Table 5 lists some common ranges of values of machine forces which are routinely monitored and will form the basis of specifications which must be maintained through the various stages of development to full-scale production.
 
Tablet Press Selection
The cost of a new high-speed tablet press may exceed one million dollars and the selection process is, therefore, a major exercise. The first decisions will be based on what types of tablet production the press is to be used for, including:
·   Desired range of tablet output
·   Maximum compaction forces
·   Types of tooling, i.e., tablet sizes and shapes, keyed
·   Need for two equal main compression stations
·   Desirable type of feeder
·   Degree of automation anticipated
Decisions concerning additional press characteristics usually follow logically, including the following considerations:
·   Ease of change-over of product
·   Design and construction of critical cams
·   Type and efficiency of dust extraction system
·   Details of the lubrication system
·   Likely noise levels under normal operation
·   Capital cost of machine
There are many major decisions about the extent to which press-monitoring and automation are required. In this context, it must be remembered that, although very sophisticated systems are now available, they do add substantial amounts to capital costs. The major items include the following:
·   Desired mode of operator-press interaction
·   Method and degree of any weight control
·   Monitoring and rejection of tablets which are out of specification
·   Periodic sampling and testing of critical tablet parameters
·   Recording of batch record information
·   Storage of master product specifications
It can also be extremely valuable to conduct a thorough comparison of vendor profiles before committing to a particular make of press. Important factors (not in order of importance) include:
·   Ease of access to a machine trial facility
·   Reputation for meeting delivery agreements
·   Local availability and extent of inventory of spare parts
·   Help with the development of the validation package
·   Service capabilities from local engineers
·   Provision of comprehensive operator training
·   History of company viability and stability
Because added instrumentation may double the cost of the press alone, potential purchasers should be encouraged to insist that vendors provide them with the level of instrumentation they desire, by means of modular construction. This avoids being forced to purchase unwanted features.

Some Recent Trends
Among the more important recent innovations in tableting operations has been the introduction of a revolutionary tablet machine design in which centrifugal effects are utilized to fill the dies and so contribute to more uniform filling. However, it does require special tooling, and therefore, adds considerable initial cost in switching to this type of machine. Among the other features of this press are an efficient clean-in-place provision, which is facilitated by the unique design of the compaction area. The press is manufactured by IMA.
There is an increasing trend to at least purchase tableting equipment with the instrumentation capability to operate in a lights out environment. More specifically, tablets are being sampled and tested for their weight, thickness and strength as they exit the press. In addition, numerous transducers are constantly monitoring key press functions including compaction, ejection, pull-down cam and pull-up cam forces.
Instrumented Tablet Machines (ITM's)
The last few years have seen a significant increase in the number and variety of instrumentation/automation packages available from tablet machine manufacturers. Most are concerned with monitoring and, to some extent, controlling production presses, in particular, the minimization of tablet weight/hardness variation. Paralleling these have been some instrumentation systems designed more as an adjunct to the research and development function. Although, until recently, many of them have been built by the researchers themselves, rather than purchased from a machine vendor.
Comtemporary Practice
The common contemporary practice is to purchase the necessary transducers and their associated electronics, together with a software package either from the tablet machine vendor or a company specializing in instrumentation. In some cases, special replacement parts, such as compression roll pins, punch holders and ejection cams, can be purchased from the vendor as part of an instrumentation package.
It is common practice to take the analog data from the above transducers, digitize it, and transfer it either to a main frame computer, or more usually to a PC which is integral to most commercial packages.
ITM's in Research and Development
The basic principles of the compaction process and their importance in the technology of pharmaceutical tablets have already been reviewed. The need to establish the compaction behavior of individual components and the total tableting formulation, in order to optimize functionality, is a logical corollary. More specifically, there is a need to quantify, or at least rank-order, the intrinsic compressibility and the consolidation potential of the materials. Sensitivity to the rate of compaction and optimization of the lubrication level are two additional important factors that should be studied. Measurement of punch and die forces plus the relative displacement of the punches can provide raw data, which when suitably processed and interpreted, facilitates evaluation of many of these compaction parameters.
In spite of their historical use, it can be argued that the value of using a single-station press for development work on formulations for preparing production batches on multi-station presses is strictly limited. Where material factors, rather than process factors, are the most important, this is less true, unless the rate of loading is critical. Because of this latter factor, many workers have resorted to the use of instrumented, specially designed, small rotary presses as a preliminary step to transferring to a production type press.
More recently, sophisticated systems have been introduced (Compaction Simulators) which are capable of mimicking (in real time) the compaction cycle of any press and so have all the advantages of using a single station of tooling while still following rotary press action, to a large extent.
Another recent important general development has been an increasing interest in functionality testing and evaluating tablet ingredients for consistent quality in terms of their role in the product. Among the important parameters which are relevant to tableting materials are:
·   Degree of Compressibility
·   Consolidation Potential
·   Compaction Rate Sensitivity
·   Lubrication Effectiveness
Significance of Press Signals
Highly sophisticated instrumentation packages capable of monitoring many critical press functions are available on most contemporary high-speed tablet machines. In particular, the forces being exerted at each step of the press cycle, together with feeder torque and temperature measurements, are proving invaluable in detecting developing problems at an early stage.
Ejection Forces
It is now possible to purchase a press with a special ejection cam capable of monitoring ejection forces from individual stations. If the formulation has been adequately lubricated, these forces should remain small, i.e., a fraction of 1 kN. Such instrumentation provides a powerful tool for ensuring optimum lubrication levels during formulation development, as well as a vital monitoring function during production runs.
If the ejection force monitor indicates increasing values of these forces, then among the possibilities which may be causing this are:
·   Inadequate die-wall lubrication, usually seen at each and every station
·   Material between lower punch tip and the die-wall
·   Material between lower punch barrel and the punch guide
·   Damaged tooling
Where the presence of material between the lower punch and the die wall and/or between the lower punch and its guide is suspected, it indicates either wear on these working surfaces or an excess of fine powder. As with the other likely reasons for this problem, the remedial steps are obvious.
Lower Punch Pulldown Forces
It is now possible to monitor the forces involved in causing punches to follow certain cam paths. In particular, the force necessary to pull the lower punches down to the fill position after tablet ejection, the so-called lower punch pulldown force, LPPF, can be monitored.
Among the reasons why these normally low forces (circa 0.1 kN) might be seen to increase, are the result of fine powder migrating into the same spaces as discussed for ejection forces. When both ejection and pulldown forces are increasing, it suggests that this is the major source of the problem.
Upper Punch Pullup Forces
The force needed to pull the upper punches out of the dies after tablet compaction, the upper punch pullup force, UPPF, can also be monitored. The most likely cause of increasing pull up forces is penetration of fine material into the space between the barrel of the upper punch and the punch guide. Another major cause is damaged tooling, but in such cases, the changes in pull up forces are usually much more variable from station to station.
Sweep-Off Forces
Possibly the smallest of the measured forces at the present time is that necessary to knock the tablet off the lower punch tip and out of the press (sweep-off). Values of around 10 Newtons have been recorded. Unless the tablet size or shape is unusual, a significant increase beyond this level of force is indicative of tablet adhesion to the punch face and may even indicate filming or picking. These necessitate immediate and appropriate remedial action.
Feeder Paddle Shaft Torque
Monitoring the torque experienced by the shaft of the main chamber feeder paddles provides valuable information about conditions in the feeder. If, as surmised, partially fluidized conditions in the feeder chamber are desirable, then increasing torque values may indicate conditions moving towards choke feeding and possible greater weight variation. The situation may be controlled in those presses where the feeder has a third upper metering chamber with its own paddle.
It is extremely useful to be able to address all the above potential problems early on in their development, if significant damage to both tools and the press is to be avoided. Contemporary instrumentation has the ability to sense such problems before they become serious and facilitates the trend towards automation.
Commercial Instrumentation Packages
The most recent developments in instrumentation are the very sophisticated micro-computer controlled systems, which in addition to all the features discussed above, virtually take over setting up and in-process monitoring from the operator. All the necessary information concerning each of the company's tablets is stored in memory and is called up via a unique product code.
Dialogue between the operator and the computer-controlled press is via a terminal, using menus. All machine settings and controls are effected by the microprocessors. Additionally, these computers usually have provision for display and when requested, a hard copy of the progress of the batch being run. All in-process checks are done automatically at programmed timings and any necessary adjustments made and logged. Finished tablets are periodically removed from the immediate press vicinity to a secure storage area. All these aspects of the process, including every adjustment and important event, are noted by the computer and made available as a hardcopy manufacturing batch record at the end of the process. It is very important to involve the vendor in the complex process-validation exercise that must accompany commissioning such a plant.
Weight Monitoring in Production Presses
Currently, most production presses are provided with a means to measure compressional forces, and this information can then be interpreted in terms of changes in tablet weight. However, the translation of compressional force into an equivalent tablet weight is not a simple process. Many factors have to be taken into account, and there is a limit to the accuracy of the procedure.
Compressional force will only be a direct function of tablet weight providing:
i.   The formulation is homogeneous, i.e., of uniform density
ii.   The compressional force/tablet weight function is constant
iii.   The volume of the die cavities at the point of maximum compression is constant
The latter supposition will only be absolutely valid when:
·  The overall length of the punches and tip geometry is constant
·  The die bores are uniform
·  The pressure rolls are perfectly cylindrical and mounted centrally
Although reaction due to tablet weight variation is usually greater, the resolution of the instrumentation may well depend on these factors.
Special Tablet Types
Most of this section has been devoted to conventional tablets, but there are some more novel types such as layered tablets and those that are compression-coated. In addition, there are those which are not intended to be swallowed, such as effervescent, chewable and lozenge forms, although the latter may be prepared by alternative techniques to tableting. The properties, ingredients and processing of these special types of tablet may be quite different to those of the major group and will be briefly referred to in this section.
Layered Tablets
It is now possible to produce tablets composed of two or three distinct layers of material of different composition.
Some of the advantages associated with this type of tablet are:
·   Co-presentation of incompatible medicaments
·   Facilitates repeat or prolonged action properties
·   Renders more difficult to copy or counterfeit
·   Gives a distinctive appearance
It is probably true to say that the latter factor, if different colored layers are used, is just as frequent a reason to use the method as any other.
Among the main major manufacturing points that distinguish them from the types reviewed above is the need to pay particular attention to dust extraction to prevent cross contamination of the various layers. Compression of the first layer must be carried out at a fairly low compaction force to ensure that a good bond is obtained between it and the second layer. The same would apply to the latter if a third layer was to be introduced.
The changes needed to modify the press action to facilitate layering require removal of one ejection cam from a double rotary machine. It is usually not possible to run a press making layered tablets quite as fast as in the conventional mode. Other manufacturing points include:
·   Better to use only simple tablet shapes
·   Must use a low first compression force
·   Must ensure no cross-contamination of layers
Compression Coated Tablets
Tablet presses can also be modified to compress a coating around a so-called core tablet, also known as a tablet within a tablet. In fact, it is possible to make a tablet within a tablet, within a tablet! The advantages for this tablet form are:
·   Co-presentation of incompatible medicaments
·   Facilitates repeat or prolonged action properties
·   Permits coating without use of liquids or heat
Perhaps the most important of these advantages is the ability to coat without the use of liquids. However, the finish on compression- coated products is not as good as that obtained by conventional coating methods.
Two general modified press types are available. In one, the Manesty Drycoater, there are essentially two conventional presses mounted on a single base plate and linked via a transfer mechanism.
Cores are manufactured on one press and transferred to the dies of the second press, which already contain a proportion of the coating material. The core is centralized and the remaining coating material added just prior to the second compaction event.
The second type, the Kilian Prescoter, involves preparing the cores first on the press or on a separate machine. The bulk cores are then fed by a special mechanism into the dies of the coating press, which again contain a portion of the coating material. Similarly, the core should be as soft as possible without failure during the transfer process, and the second part of the coating material is added on top of the centralized core.
In both machines there are several important manufacturing constraints, including:
·   Better to use only simple tablet shapes
·   Must use a low core compression force
·   Must ensure no cross contamination of layers
·   Specially modified press required
·   Must ensure accurate positioning of core tablet
·   Usually operated at a slower speed than normal
The two most critical of these are the centralization of the core in the coating mass, and the need to ensure that each coated tablet has one whole core inside it. This latter requirement necessitates the use of a fail safe core detection system, with the capability to reject individual tablets not containing a whole core. The best method with contemporary presses is to use the sensitive force detection mechanisms to monitor the final compaction force. In older machines a mechanical device in the transfer arm was used.
Effervescent Tablets
Two distinct types of compressed tablets may be distinguished that possess an effervescent-base system: those intended to be dissolved and the resultant liquid taken orally, versus those intended for external use only. The effervesence-producing medium is usually a mixture of organic acids and carbonates or bicarbonates, that release carbon dioxidein the presence of moisture. Less frequently, with systems intended only for external use, peroxide mixtures are used to release oxygen.
Undoubtedly, the major difficulty with these special tablet forms is the need to strictly control the humidity to which the ingredients are exposed. It is also important to remember that the effervescent process, once initiated, generates water which serves to defeat the process of humidity control.
Among the other unique requirements of these systems is the need to eliminate or strictly minimize any water insoluble component. In tableting, this presents a problem with respect to die wall lubrication. Although there are several soluble lubricant possibilities, they all require higher concentraions than conventional ones such as magnesium stearate.
It is highly desirable that all processing and packaging of effervescent systems be carried out under carefully controlled conditions, including:
·   Manufacture and storage in a controlled temperature of 25° C
·   Manufacture and storage at a relative humidity below 25% RH
·   Package in foil or plastic as soon as possible after manufacture
Chewable Tablets
Tablets that are intended to be chewed in the mouth are quite popular. They are often formulated to provide a localized release of medicament to treat conditions in the mouth and/or throat. They are also a popular choice for the group of antacid products.
Their main distinguishing characteristics from conventional tablets are in their formulation. Since they are not required to disintegrate spontaneously, many do not contain a disintegrant. However, slow release of medicament has led the Pharmacopeia3 to require that chewable tablets pass a dissolution test; hence, some now include a disintegrating agent. In addition, they are commonly quite hard, but somewhat brittle. The other formulation aspect is the need for a good mouthfeel and a pleasant taste.
From a manufacturing standpoint, many chewable tablets contain a high dose of drug and are consequently quite large. For this reason, they are often compressed on machines using the larger D tooling and capable of exerting higher compaction forces.
Lozenges
The special type of tablet that is intended to be allowed to dissolve slowly in the mouth can be manufactured by one of two main techniques. They are often made by what is essentially a candy manufacturing procedure, while others, sometimes called troches, are made by compaction.
In many ways, this latter method resembles that of making chewable tablets, but they usually contain a significant quantity of sugars. Once again, they are usually hard and brittle, requiring high compaction forces. They often contain higher levels of lubricant than normal, and many are sensitive to moisture.
Tablet Strength
The mechanical strength of compacts can be interpreted in several ways including:
·   The force necessary to cause the structure to fail in some way
·   The resistance to surface abrasion
·   Surface hardness as measured by resistance to indentation
Tablet Failure Tests
There are a number of ways in which mechanical load can be applied to a compact to determine its strength, and there are many names given to the results; e.g., hardness, crushing strength, fracture resistance, tensile strength, etc. For this reason, it is important to define the test conditions precisely when reporting data.
Breaking Force
In the processes under review here, probably the most widely used test is what is commonly called determination of the crushing strength, but this is a misnomer. The most correct name for this test is breaking force. This parameter may be defined as the compressional force, FC, which, when applied across a specific plane of the compact, just causes it to fracture and is, therefore, a function of the compact geometry. The most popular version for pharmaceutical tablets is to cause them to fail by applying a load across the tablet diameter, or other fixed orientation, by means of a moving plunger, while the tablet rests against a fixed anvil, as shown in Figure 26.
 
Virtually all compacts are anisotropic and, therefore, the test conditions rarely provide well characterized stress patterns which would permit exact interpretation of the findings in terms of intrinsic material strength. In many instances, due to test instrument design, the compact is crushed into several pieces, and an overall demolition force!! value is all that can be quoted.
Newer models of breaking force testers, where the force is measured by means of an electronic load cell, are preferred. They are capable of detecting the initial break in the tablet and recording the force that caused it. Unlike earlier models, they do not continue to apply load that essentially demolishes the tablet structure and record that force.
Tensile Strength
When electronic-based testers are used, the compact frequently has a clean break across its diameter, and it is then possible to calculate a tensile strength ST from:
    ST    =    2  FC  /  p  H  D
where FC is the force needed to fail the compact, H and D are the height and width of the break, respectively. This property should be used whenever possible, because it is much less dependent on compact geometry than breaking force.
Several breaking force testers are available commercially. Older models used the compression of a spring or hydraulic means to apply and monitor the load, and some were manually operated. As a result, there were multiple sources of error, often caused by aged instrumentation. In contemporary models, plunger movement is motorized, and the load on the compact is automatically measured by means of an anvil or plunger electronically instrumented to measure the load directly. Such instruments are preferable for the reasons referred to above and because of their superior accuracy.
Surface Abrasion
The resistance of the surface of the compact to attrition during subsequent processing (e.g., coating), handling and transport is of general importance. There are several tests for assessing this property, but many involve weighing the compacts before and after subjecting them to a standardized period of controlled agitation.
For example, in the pharmaceutical industry a popular test is measurement of what is termed friability. This involves subjecting approximately 6 g. (wo) of dedusted tablets to a free fall of 6 inches for 100 times in a rotating drum. The tablets are then reweighed (w) and the friability, f, is calculated from:
    f  (in %)    =   100  [  1-  (w/wo)  ]
Values of f from 0.8 to 1.0 percent are usually regarded as the upper limit of acceptability. Similar procedures have been used, but less frequently, to determine the abrasion resistance of pellets and even granular powders.
References
1.   Heckel RW, Trans AIME: 221, 671,1961.
2.   Tableting Specification Manual, 3rd. Edition, APhA, Washington, DC, 1990.
3.   USP/NF, US Pharmacopeial Convention,Rockville, MD, 1995.
Bibliography
·   Solid Pharmaceutics: Mechanical Properties and Rate Phenomena, J.T. Carstensen. Academic Press 1980.
·   The Theory and Practice of Industrial Pharmacy, 3rd Edition, Lachman L., Lieberman H.A. and Kanig J.L., eds., Lea & Febiger 1986.
·   Principles of Powder Technology, Rhodes M., ed., Wiley, 1990
·   Modern Pharmaceutics, Banker G.S. & Rhodes C.T., eds.Dekker, 1990.
·   Physical Characterization of Pharmaceutical Solids in Drugs and the Pharmaceutical Sciences, v. 70, Brittain H.G., ed. Dekker 1995.
·   Pharmaceutical Powder Compaction Technology in Drugs and the Pharmaceutical Sciences, v. 71, Alderborn G. & Nystrom C., eds., Dekker, 1995.


Grouch

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Part 4a
« Reply #13 on: July 21, 2001, 04:38:00 AM »
Tablet Problems & Remedies
By George E. Reier, PhD

Part A. Specific Tableting Problems and Remedies (Process Format)
Dry Blending
Problem/Concept   Cause/Definition   Remedy/Suggested Solution
Particle agglomeration   ·  Occurs with fine cohesive powders, which cause "balling up" and poor distribution   ·  Fine-screen cohesive compound into bulk mix ·  Use a more effective mixer (one with increased shearing action) ·  Blend the cohesive powder with a portion (5% to 10%) of an excipient; screen (mill) if necessary; reblend and add to the bulk; blend normally Note: For direct compression excipient blends do not use a screen size or a mixer, which will change the excipient particle size distribution
Nonuniformity of mix   ·  Improper blender load   ·  Use recommended powder load in blender
   ·  Insufficient mixing   ·  Increase mixing time
   ·  Inefficient (improper) mixer   ·  Use alternative mixer with increased shearing action
   ·  Wide particle size distribution   ·  Select more uniform particle sizes of components
   ·  Overblending   ·  Reduce blending time ·  Establish optimum mixing conditions
   ·  Low-dosage actives   ·  Use a more effective mixer (one with increased shearing action)
Nonuniformity of mix (continued)   ·  Low-level excipients   ·  Blend the low-level component with a portion (5% to 10%) of an excipient; screen (mill) if necessary; reblend; add to an equal quantity of excipient and mix; screen or mill if necessary; blen d normally with remainder of bulk ·  Dissolve drug in a suitable solvent and add or spray onto a portion of the bulk or an excipient; blend; remove solvent Note: For direct compression excipient blends do not use a screen size or a mixer, which will change the excipient particle size distribution
Segregation after blending   ·  Particle size distribution too wide   ·  Use a narrower particle size range of components
Wet Granulation (Massing)

Problem/Concept   Cause/Definition   Remedy/Suggested Solution
Doughy mass   ·  Too much water (often seen on scale-up)    ·  Add granulating water slowly; mix well after each addition
   ·  Overmixing during granulation step   ·  Reduce water or mixing time
   ·  Wrong binder   ·  Change binder
   ·  Component of mix (e.g., active drug or excipient)    ·  If possible, use alcohol/water or alcohol as granulating fluid - select appropriate binder; use of Avicel(r) PH-101 gives 1) less sticky or doughy mass which is easier to screen; and 2) allows a wider range of solvent volume
Moisture sensitive drugs   ·  Instability with water   ·  If possible, use ethyl alcohol or isopropyl alcohol (if latter, determine acceptable residual solvent by GC or other appropriate method) as granulating fluids, ethyl cellulose and PVP as binders ·  Try slugging or roller compaction as dry granulation methods
Wet Screening
Problem/Concept   Cause/Definition   Remedy/Suggested Solution
Screen clogging   ·  Doughy or sticky wet mass   ·  Avoid oscillating granulator ·  Use extrusion-type granulator or Fitz Mill(r) without screens ·  Reduce granulation time ·  Add 5% to 20% Avicel(r) PH-101 (gives less sticky or doughy mass, easier to screen)
   ·  Too much water in mass   ·  Reduce water content; add water gradually and mix well after each addition
   ·  Mass sensitive to water content   ·  Incorporate 5% to 20% Avicel(r) PH-101 (allows a wider range of solvent volume)
   ·  Gummy binder   ·  Change binder
   ·  Component or active ingredient    ·  Use diluted or anhydrous ethyl or isopropyl alcohol (if latter, determine acceptable residual solvent level by GC or other appropriate method); change binder

Drying
Problem/Concept   Cause/Definition   Remedy/Suggested Solution
Nonuniform drying   ·  Poor air circulation (tray dryer)    ·  Have oven air circulation checked and corrected
   ·  Dryer overload   ·  Reduce number of trays ·  Reduce thickness of wet mass on the trays (tray load) ·  Try fluid bed dryer
Granule case hardening (hard crust forms with incomplete drying inside granule)    ·  Too rapid evaporation of water ·  Oven drying conditions too efficient   ·  Try recirculating oven air (damper closed) for initial 15 to 30 minutes, then open damper partially for a short period, and finally open damper fully ·  Reduce drying temperature ·  Add Avicel(r) PH-101 to formulation (gives more even water evaporation and uniform granule moisture content) ·  Use a fluid bed dryer
Color migration   ·  Colors migrate to granule surfaces (wet granulation); tablets have mottled appearance   ·  Use lakes instead of soluble dyes (will minimize but not eliminate) ·  Decrease the size of the wet granules ·  Decrease thickness of granulation bed; stir granulation bed frequently during drying to expose fresh surfaces at the top of the wet mass ·  Use Avicel(r) PH-101 - reduces or eliminates dye migration in wet granulation
Drug migration   ·  Drug migrates to granule surfaces; content uniformity problems may result as drug becomes part of "fines" after dry screening, or there is a loss of drug with subsequent low tablet assays   ·  See remedies under "Color migration"
Dry Screening (Dry Granulation)
Problem/Concept   Cause/Definition   Remedy/Suggested Solution
Excess fines   ·  Granulation over-dried   ·  Decrease drying time/temperature ·  Establish optimum moisture content
   ·  Screen size too small   ·  Use larger screen size
   ·  Rotor/screen clearance too close   ·  Adjust rotor clearance
   ·  Overloading of mill or granulator   ·  Slow feed of material to mill or granulator
   ·  Weak granules   ·  Increase granulating fluid ·  Increase binder content ·  Increase wet massing time
Difficult to screen   ·  Granules too hard   ·  Decrease drying temperature (case hardening) ·  Decrease water content (use alcohol/water) ·  Decrease binder content ·  Use weaker binder
   ·  Moisture in granulation   ·  Increase drying time ·  Establish optimum moisture content
Poor color distribution   ·  Dye migration to granule surface (nonuniformity of color throughout granule)    ·  Use lakes instead of soluble dyes (will minimize but not eliminate problem) ·  Decrease the size of the wet granules ·  Decrease thickness of granulation bed; stir granulation bed frequently during drying to expose fresh surfaces at the top of the wet mass ·  Use Avicel(r) PH-101 - reduces or eliminates dye migration in wet granulation
Feed Hopper
Problem/Concept   Cause/Definition   Remedy/Suggested Solution
Poor flow "rat-holing" "bridging"    ·  Too many fines in wet granulation   ·  Reduce fines (see "Dry screening: Excess fines")
   ·  In direct compression, particle size of drug or excipients too small and/or of shape that will not flow   ·  Select larger particle size; use Avicel(r) PH-102 or PH-200 in place of PH-101 or other excipient ·  Add glidant (0.1% to 0.5%) (e.g., Cab-O-Sil(r), Aerosil(r)) ·  Use induced or force-feed mechanism on press ·  Change particle shape of active ingredient to one that is more likely to flow
   ·  Poor inherent flow   ·  Add 0.1% to 0.5% glidant ·  Dry granulate (by slugging or roller compacting) with a mixture of Avicel(r), Cab-O-Sil(r), and magnesium stearate
   ·  Atmospheric moisture adsorption   ·  Process in low humidity atmosphere ·  Add moisture absorber (e.g., 0.1% to 0.5% calcium silicate, Cab-O-Sil(r), Syloid(r))
Flooding   ·  Excessive flow properties (fluidization) of one or more components (could be from an excess of glidant or lubricant)    ·  Identify causative component and exclude or modify particle size ·  Select narrow range of particle sizes; avoid excess fines
   ·  Flow is erratic and feed frame is flooded at times   ·  Use an induced or force-feed mechanism on press, which may control flow
Particle segregation   ·  Particle size range of mix too wide   ·  Use a narrower particle size range of ingredients ·  See "Dry screening: Excess fines"
   ·  Too wide a density difference in mix particles   ·  Control differences in density of particles
   ·  Mixer too vigorous; produces fines   ·  Use a mixer with a gentler mixing action
   ·  Use of vibrators (to promote flow from hopper)    ·  Use force-flow feed mechanisms rather than hopper vibrators
   ·  Excessive machine vibration   ·  Isolate hopper from tablet machine
Tablet Weight
Problem/Concept   Cause/Definition   Remedy/Suggested Solution
Weight variation outside limits   ·  Poor or erratic powder flow, flooding   ·  Correct powder flow problem (See "Feed hopper")
   ·  Particle size range too wide   ·  Narrow the particle size range; avoid excess fines ·  Use Avicel® PH-200 to minimize weight variation
   ·  Particle size not suitable for die diameter   ·  Adjust particle size range to recommended optimum for die diameter
   ·  Punches not within specifications   ·  Examine punch length dimensions
   ·  Particle segregation as press RPM's increase   ·  Narrow the particle size range ·  Compress at slower RPM
   ·  Lower punch "hang up" (material between lower punch and die wall or lower punch and punch guide)    ·  Clean; improve dust collection ·  Check for proper clearance between die wall and lower punch ·  Increase lubricant concentration in formulation ·  Remove below 200 mesh fines
Punches and Dies
Problem/Concept   Cause/Definition   Remedy/Suggested Solution
Punch binding (powder adheres to punch edges and dies; punches may bind in dies)    ·  Poor finish or worn punches and dies ·  Inadequate lubrication   ·  Polish, reface, or replace tooling ·  Increase or change lubricant; use microfine lubricants; screen into mix ·  Increase lubricant blending time
   ·  Too many fines or coarse particles in mix   ·  Design better particle size range; use tapered dies
   ·  Wet granulation insufficiently dried   ·  Dry granulation to satisfactory moisture limits
   ·  Hygroscopic ingredients   ·  Process under low humidity conditions ·  Use moisture scavengers (e.g., calcium silicate, Syloid(r), Cab-O-Sil(r))
   ·  Adhesive components   ·  Increase lubricant level ·  Add 0.5% Cab-O-Sil(r) or Syloid(r) ·  Add 5% to 10% low moisture grades Avicel® PH-112 and PH-113
Punch filming or sticking (picking) - (powder adhesion to punch faces, usually upper)    ·  Poor finish on punch faces ·  Embossed letters    ·  Polish punch faces; refinish ·  Avoid using certain letters (e.g., "A", "B", "P", "R") ·  Use shallow embossing with tapered edges rather than edges directly perpendicular to punch face
   ·  Punch tips burred   ·  Refinish or replace
   ·  Punch concavity too great   ·  Reduce punch concavity or use flat face punches
   ·  Poor binding between surface granules or particles   ·  Increase binder (wet or dry)
   ·  Low melting point ingredient   ·  Adsorb low melting point ingredient on Avicel(r), replace with higher melting point ingredient
   ·  Inadequate lubrication   ·  Increase or change lubricant ·  Use microfine lubricants, screen into mix ·  Increase lubricant mixing time
   ·  Insufficiently dried wet granulation   ·  Dry granulation and establish moisture limits
   ·  Hygroscopic components   ·  Process under low humidity conditions ·  Use moisture adsorbent (e.g., calcium silicate, Syloid(r))
   ·  Adhesive components   ·  Increase lubricant level ·  Add 0.5% Cab-O-Sil(r) or Syloid(r) or 5% to 10% Avicel(r) PH-101
   ·  Tablets too soft   ·  Increase compression pressure
Punch and die abrasion   ·  Abrasive components   ·  Exclude or reduce to a fine particle size ·  Increase lubricant level ·  Blend abrasive component directly with the lubricant ·  Use minimum tableting pressure possible ·  Use more wear-resistant tooling (harder metal)
Capping and laminating Capping is separation of the top or bottom from the main body of the tablet. Laminating is transverse cracking and separation of the tablet into two or more layers.    ·  Inadequate bonding of the powder particles (direct compression) or granules (wet granulation) to form cohesive tablets   ·  Use a stronger binder or additional binder ·  Avicel(r) PH-101 and PH-102 are particularly effective direct compression binders (15% to 25%) and as auxiliary binders in wet granulation (5% to 15%)
   ·  Poor finish or worn punches and dies   ·  Polish, reface, or replace ·  Chrome plate punch faces
   ·  Too many fines in granulation   ·  Modify granulation process for minimum fines
   ·  Granulation too dry   ·  Adjust moisture level and establish optimum moisture limits
   ·  Granulation too wet (usually associated with sticking or picking)    ·  Continue to dry and establish optimum moisture limit
   ·  Overlubrication of final tableting mix   ·  Decrease lubricant level ·  Blend lubricant for minimal time required; establish optimum mixing time
   ·  High level of ingredient with poor compression properties (also sometimes ascribed to air-entrapment by powder bed)    ·  Use precompression on tablet press ·  Slow the speed of the tablet machine
   ·  Punch concavity too deep   ·  Change to standard concave or flat face punches
   ·  Punch edges worn or damaged   ·  Refinish or replace
   ·  Lower punch too low at tablet take-off   ·  Adjust lower punch flush with die face
   ·  Compression too low in die cavity   ·  Compress in upper portion of die
   ·  Excessive tableting pressure   ·  Decrease pressure
   ·  Die wall binding   ·  Use sufficient lubricant ·  Use tapered dies
Chipping/splitting   ·  Poor finish or worn punches and dies   ·  Polish, reface, or replace punches and dies
   ·  Lower punch setting too low at tablet take-off   ·  Adjust lower punch flush with die face
   ·  Tablet sweep-off blade on feed frame set too high   ·  Adjust setting
Score line or tablet imprint not sharp   ·  Faulty punch debossing design   ·  Redesign using tapered sides on the punch debossing ·  Chrome-plate punch face
   ·  Granulation too coarse   ·  Reduce particle size of granulation
   ·  Binder not strong enough   ·  Use a stronger binder
Layered tablets splitting   ·  Poor bonding between layers   ·  Use a stronger binder or higher concentration
   ·  Compression pressure too high   ·  Compress at lower pressures
   ·  Overlubrication   ·  Decrease lubricant level ·  Blend lubricant for minimal time required; do not blend for long periods of time
Layers not sharply defined   ·  Granulation too coarse ·  Too many fines   ·  Reduce particle size of granulation - less than 16 mesh ·  Remove fines below 200 mesh
Low hardness   ·  Compression force (pressure) too low   ·  Increase pressure (caution: do not exceed recommended pressure for punch size used)
   ·  Overlubrication   ·  Decrease lubricant level ·  Blend lubricant for minimal time required; establish optimum mixing time ·  Replace metallic stearates with other lubricants (e.g., stearic acid)
   ·  Granulation too soft   ·  Use additional binder ·  Direct compression -- use additional Avicel(r) PH
   ·  Excipient (i.e., too much starch can give a soft tablet)    ·  Reduce level of causative excipient
   ·  Moisture content too high (granulation underdried or high humidity in compressing area)    ·  Determine optimum moisture content ·  Use moisture adsorbent (e.g., calcium silicate, Syloid(r))
   ·  Moisture content too low (granulation overdried or low humidity in compressing area)    ·  Determine optimum moisture content ·  Add additional moisture
Variable hardness   ·  Tooling   ·  Examine punch lengths
   ·  Uneven die fill   ·  See "Table Weight: Weight variation"
   ·  Overblending   ·  Optimize blending time to minimize creation of fines
High friability   ·  Inadequate bonding of the tablet mix   ·  Increase binder level or change to stronger binder ·  Add or increase Avicel(r) PH-101 or PH-102 (10% to 20%) ·  Avicel(r) PH gives low friability at lower hardness/machine pressures
   ·  Too much or too little compression pressure   ·  Adjust pressure for acceptable friability
   ·  Overlubrication   ·  Decrease lubricant level ·  Blend lubricant for minimal time required; establish optimum mixing time ·  Replace metallic stearates with other lubricants (e.g., stearic acid)
Disintegration too long   ·  Tablet hardness too high   ·  Reduce machine pressure for acceptable tablets ·  Use less binder in granulation
   ·  Overlubrication (waterproofing)    ·  Decrease lubricant level ·  Blend lubricant for minimal time required; establish optimum mixing time ·  Replace metallic stearates with other lubricants (e.g., stearic acid)
   ·  Requires additional disintegrant or a different disintegrant   ·  Consider a "super disintegrant" (e.g., Ac-Di-Sol(r), 2% to 5%) ·  Include Avicel(r) PH-101 or PH 102 (added dry), about 10% as an auxiliary disintegrant ·  Consider adding a surfactant (e.g., DOSS, 0.1%)
   ·  Tablet hardness too low   ·  Increase hardness to allow swellable disintegrant to function
Mottling   ·  Uneven distribution of the dye in colored tablets   ·  Increase mixing time or use high shear mixer
   ·  Dye migration during drying process   ·  See "Drying: Color migration" ·  See "Dry screening: Poor color distribution"
   ·  Preferential absorption of soluble dye by component of mix   ·  Replace causative component ·  Replace soluble dye with microfine lake pigment
   ·  High level of uncolored additives (e.g., fillers, lubricants, disintegrants)    ·  Reduce quantity of additives ·  Color additives with soluble dye or mix with lake pigment
   ·  In direct compression, uneven distribution of lake dye   ·  Use microfine lake dye ·  Increase blending time ·  Mill lake dye with 5% excipient, then blend with bulk ·  Reduce size of larger particles of excipient or active ·  Use lower drying temperature
Tablets contain "dirty" specks   ·  Misaligned upper cam tracks - rubbing of punches on cam actually rubs off metal which is introduced into material being compressed   ·  Check alignment of upper cam tracks
   ·  No lubrication on upper cam tracks   
   ·  Excessive or improper lubrication on upper punch shanks (no dust caps on punches) - dust mixes with excess oil or grease and falls into material being compressed   ·  Use dust caps on upper punches
Tablets uniformly discolored   ·  Feed frame rubbing on die table ·  Feed hopper rubbing on turret ·  Abrasive materials wearing screens, scooper, etc.    ·  Check clearance between feed frame and die table ·  Check clearance between feed hopper and turret ·  Check for presence of abrasive materials
Part B. General Tableting Problems and Remedies (Alphabetical Order Format)
Problem/Concept   Cause/Definition   Remedy/Suggested Solution
Active ingredients      ·  See "Sticky ingredients" ·  See "Low to medium level of active" ·  See "High percent active" ·  See "Attraction of particles" ·  See "Dosage variation" ·  See "Density" ·  See "Elastic material"
Adsorbents   ·  Materials used to overcome oiliness or stickiness of tablet ingredients   ·  Use starch, Avicel(r) PH-101, silicon (Syloid(r)) or tribasic calcium phosphate
Agglomeration of particles   ·  Occurs with fine cohesive powders causing "balling" or lump formation and poor distribution of the powder   ·  Fine-screen cohesive compound into bulk mix ·  Use a more effective mixer (one with increased shearing action) ·  Blend the cohesive powder with a portion (5% to 10%) of an excipient; screen (mill) if necessary; reblend and add to the bulk; blend normally Note: For direct compression excipient blends do not use a screen size or a mixer, which will change the excipient particle size distribution
Aging of tablets      ·  See "Loss of hardness (with time)"
Air entrapment   ·  Very low density materials with very high porosity (sometimes ascribed as cause for tablet capping, splitting, or laminating)    ·  See "Capping and laminating" ·  See "Binding"
Antiadherent   ·  Materials that aid in preventing the tablet mix from sticking to punch faces   ·  See Section 4 for a description of excipients and their uses
Attraction of particles (aggregation or agglomeration)    ·  Fine cohesive powders   ·  Modify particle size distribution
   ·  Static electricity   ·  Mechanically disperse ·  Drain off static charge
   ·  Low relative humidity   ·  Slightly increase moisture level ·  See "Blending" ·  Densify as last resort
Binder   ·  Wet granulation - substances which are added in solution (usually) or sometimes dry, followed by granulating solvent to "glue" a powder mix into granules for solid dose preparation ·  Direct compression - substances which give compressibility or cohesiveness to the powder mix   ·  See Section 4 for a description of excipients and their uses
Binding (bonding or compressibility)    ·  Relative degree of cohesiveness between particles or granules   ·  See "Blending" ·  Be careful not to overblend or overlubricate
   ·  Compressibility of active ingredients determines (to some extent) the percent that can be incorporated into a direct compression formulation ·  Particular binder and concentration influences degree of binding and tablet hardness   ·  Optimize particle size and particle size distribution of active and excipients ·  Use excipients which are compressible and designed for direct compression process ·  Determine that granulation and/or other excipients have proper moisture content
Binding in the die (punches)       ·  See "Punch binding"
Bioavailability   ·  The rate and extent to which an active ingredient is absorbed in-vivo ·  May or may not be correlated with dissolution   ·  See "Dissolution" ·  Use up to 50% soluble filler (lactose, dextrose) with insoluble drugs (direct compression)
Bisected or debossed tablets (not sharp or well-defined)    ·  Poor design on tooling   ·  Redesign tooling, consult tooling supplier ·  Increase binder in formulation
Blending   ·  Mixing of powders to obtain a homogeneous mixture (for compression) ·  Optimized blending may depend on type of mixer (low shear, high shear, etc.) ·  Overblending is probably more common than underblending ·  Overblending causes overdistribution of the lubricant which can result in poor disintegration/ dissolution, poor compressibility, demixing (segregation)    ·  Optimize blending or mixing time
Bonding      ·  See "Binding"
Bridging   ·  Lack of powder fluidity; actual stoppage of powder flow as powder compacts in hopper or feed-frame   ·  See "Die fill" ·  See "Flow problems"
Brittle fracture   ·  Bonding mechanism of some materials (e.g., lactose), in which single particles fracture under pressure to produce multiple particles having clean surfaces, which then bond with each other to form a compact   ·  See Section 2 for a discussion of compression mechanisms
Bulk density      ·  See "Density, bulk"
Capping and laminating Capping is separation of the top or bottom from the main body of the tablet. Laminating is transverse cracking and separation of the tablet into two or more layers.    ·  Inadequate bonding of the powder particles (direct compression) or granules (wet granulation) to form cohesive tablets ·  Poor finish or worn punches and dies   ·  Use a stronger binder or additional binder ·  Avicel(r) PH-101 and PH-102 are particularly effective direct compression binders (15% to 25%) and as auxiliary binders in wet granulation (5% to 15%) ·  Polish, reface, or replace ·  Chrome-plate punch faces
   ·  Too many fines in granulation   ·  Modify granulation process for minimum fines
   ·  Granulation too dry   ·  Adjust moisture level and establish optimum moisture limits
   ·  Granulation too wet (usually associated with sticking or picking)    ·  Continue to dry and establish optimum moisture limit
   ·  Overlubrication of final tableting mix   ·  Decrease lubricant level ·  Blend lubricant for minimal time required; establish optimum mixing time
   ·  High level of ingredient with poor compression properties (also sometimes ascribed to air-entrapment by powder bed)    ·  Use precompression on tablet press ·  Slow the speed of the tablet machine
   ·  Punch concavity too deep   ·  Change to standard concave or flat-face punches
   ·  Punch edges worn or damaged   ·  Refinish or replace
   ·  Lower punch too low at tablet take-off   ·  Adjust lower punch flush with die face
   ·  Compression too low in die cavity   ·  Compress in upper portion of die
   ·  Excessive tableting pressure   ·  Decrease pressure
   ·  Die wall binding   ·  Use sufficient lubricant ·  Use tapered dies
Case hardening   ·  Rapid evaporation of water, which forms hard outer crust often associated with incomplete drying inside granules ·  Oven drying conditions too efficient   ·  Try recirculating oven air (damper closed) for initial 15 to 30 minutes then open damper partially for a short period and finally open damper fully ·  Reduce drying temperature ·  Add Avicel(r) PH-101 to formulation (gives more even water evaporation and uniform granule moisture content) ·  Use a fluid bed dryer
Chipping/splitting   ·  Poor finish or worn punches and dies   ·  Polish, reface, or replace punches and dies
   ·  Lower punch setting too low at tablet take-off   ·  Adjust lower punch flush with die face
   ·  Tablet sweep-off blade on feed frame set too high   ·  Adjust setting ·  See "Capping and laminating" ·  See "Binding/bonding"
Clogging of screen (wet mass)    ·  Doughy or sticky wet mass   ·  Avoid oscillating granulator ·  Use extrusion-type granulator or Fitz Mill(r) without screens ·  Reduce granulation time ·  Add 5% to 20% Avicel(r) PH-101 (gives less sticky or doughy mass, easier to screen)
   ·  Too much water in mass   ·  Reduce water content; add water gradually and mix well after each addition
   ·  Mass sensitive to water content   ·  Incorporate 5% to 20% Avicel(r) PH-101 (allows a wider range of water volume, gives "shorter", less doughy, less sticky mass)
   ·  Gummy binder   ·  Change binder
·  Active ingredient    ·  Use diluted or anhydrous ethyl or isopropyl alcohol (if latter, determine acceptable residual solvent level by GC or other appropriate method); change binder   
Coarse particles   ·  Mottled appearance in direct compression ·  Segregation   ·  Design particle size distribution for optimum flow, color distribution, binding ·  Some fines are needed for good binding
Color distribution   ·  Dye migration leading to mottling   ·  In direct compression, preblend or mill color with portion of excipient ·  In wet granulation, use a dye soluble in the granulating solution ·  May help to use a lower temperature for tray drying; use a fluid bed dryer ·  See "Color migration"
Color migration   ·  Colors migrate to granule surface (wet granulation); will cause mottling of tablets; often associated with case hardening   ·  Use lakes instead of soluble dyes (will minimize but not eliminate) ·  Decrease the size of the wet granules ·  Decrease thickness of granulation bed; stir granulation bed frequently during drying to expose fresh surfaces at the top of the wet mass ·  Use Avicel(r) PH-101 - reduces or eliminates dye migration
Compressibility      ·  See "Binding (bonding or compressibility)"
Content uniformity      ·  See "Dosage variation"
Demixing   ·  Segregation/ separation, usually caused by overmixing rather than undermixing   ·  Optimize blending times specific to mixer (blender) employed ·  See "Overblending" ·  See "Segregation"
Density, bulk (loose density)    ·  Usually defined as the ratio of weight of a powder (or mixture of powders) to its volume on an "as-is" basis (not tapped) ·  Low bulk density often related to poor flow especially at high dosage (active)    ·  See "Flow" ·  See "Die fill" ·  See "Dry granulation" ·  Select higher density grades Avicel® PH-301 and PH-302
Density, tapped   ·  Usually defined as the ratio of weight of a powder (or mixture of powders) to its volume after being tapped or caused to consolidate ("settle") in some way ·  Too dense - can cause segregation   ·  See "Segregation"

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Part 4b
« Reply #14 on: July 21, 2001, 04:41:00 AM »
Die fill ( nonuniform)    ·  Lack of consistent powder flow into dies, causing variations in tablet weight, hardness, and disintegration/ dissolution   ·  Adjust particle size range to recommended optimum for die diameter ·  Reduce fines ·  Select larger particle size; use Avicel(r) PH-102 or PH-200 in place of PH-101 or other excipient ·  Add glidant (0.1% to 0.5%) (e.g., Cab-O-Sil(r), Aerosil(r)) ·  Use induced or force-feed mechanism on press ·  Change particle shape of active ingredient to one that is more likely to flow
      ·  Dry granulate (by slugging or roller compacting) with a mixture of Avicel(r), Cab-O-Sil(r), and magnesium stearate ·  Process in low humidity atmosphere ·  Add moisture absorber (e.g., 0.1% to 0.5% calcium silicate, Cab-O-Sil(r), Syloid(r))
Diluent   ·  Inert material(s) added to give the necessary bulk for solid dosage preparation   ·  See Section 4 for a description of excipients and their uses
Dilution potential   ·  The percent of an active (usually poorly compressible such as ascorbic acid or APAP) that can be compressed with an excipient to form a tablet having 1% or less friability   ·  Avicel(r) PH has a very high dilution potential when used as a binder
Direct compression   ·  Method of manufacturing tablets by compressing directly a dry blend of active and excipient powders; the powders are neither wet or dry granulated   ·  See Sections 2 - 4
Disintegrant   ·  Material added to tablets to aid them in breaking apart so that particles of drug can dissolve   ·  See Section 4 for a description of excipients and their uses
Disintegration too long or incomplete   ·  Tablet hardness too high   ·  Reduce machine pressure for acceptable tablets ·  Use less binder in granulation
   ·  Overlubrication (waterproofing)    ·  Decrease lubricant level ·  Blend lubricant for minimal time required; establish optimum blending time ·  Replace metallic stearates with other lubricants (e.g., stearic acid)
   ·  Requires additional disintegrant or a different disintegrant   ·  Consider a "super disintegrant" (e.g., Ac-Di-Sol(r), 2% to 5%) ·  Include Avicel(r) PH-101 or PH-102 (added dry), about 10% as an auxiliary disintegrant ·  Consider adding a surfactant (e.g., DOSS, 0.1%)
   ·  Tablet hardness too low   ·  Increase hardness to allow swellable disintegrant to function
Disintegration during coating   ·  Caused by soft cores or rapidly disintegrating tablets   ·  Increase tablet strength (increase binder, add better binder, compress harder) ·  Apply a seal coat (Aquacoat(r) ECD) ·  If possible, lower spray rate of aqueous coating
Dissolution   ·  Measure of the rate and extent to which an active component is released into solution from a drug product ·  May or may not be correlated with bioavailability   ·  Use most soluble form of drug ·  Micronize insoluble drugs - in general, use smallest particle size possible ·  Consider using a wetting agent ·  Add additional disintegrant or a different disintegrant - granules must disintegrate for good dissolution
   ·  Poor dissolution   ·  Optimize tablet hardness versus friability and disintegration/ dissolution ·  Conduct preformulation studies to be certain there is no active/excipient interaction (binding) ·  Use a soluble filler with insoluble actives ·  Use less lubricant, establish optimum blending time
      ·  See "Bioavailability" ·  See "Disintegration"
Dosage variation   ·  Improper mixing/segregation   ·  See "Blending, overblending and demixing" ·  See "Flow problem" ·  See "Segregation" ·  See "Die fill (nonuniform) ·  See "Nonuniformity of mix"
Doughy mass   ·  Too much water (often seen on scale-up)    ·  Add granulating water slowly; mix well after each addition
   ·  Overmixing during granulation step   ·  Reduce water or mixing time
   ·  Wrong binder   ·  Change binder
   ·  Component of mix (e.g., active drug or excipient)    ·  If possible, use alcohol/water or alcohol as granulating fluid - select appropriate binder, use of Avicel(r) PH-101 gives 1) less sticky or doughy mass, which is easier to screen; and 2) allows a wider range of solvent volume
Drug migration   ·  Drug migration to surface of granulation ·  May lead to content uniformity problems as drug becomes part of "fines" after dry screening, or there is a loss of drug with subsequent low tablet assays   ·  See "Color migration"
Dry blending      ·  See Section A: "Dry blending"
Dry granulation (by slugging or compaction)    ·  Method for compacting powders by slugging or roller compaction and then size reducing the compacts to the desired particle size for tableting ·  Often preferred when 1) it is difficult or impossible to directly compress; and 2) the actives are unstable when subjected to wet granulation   ·  See Section 2 ·  See "Slugging" ·  See "Roll compaction"
Dry screening   ·  Granules too hard   ·  Decrease drying temperature (case hardening) ·  Decrease water content (use alcohol/water) ·  Decrease binder content ·  Use weaker binder
   ·  Moisture in granulation   ·  Increase drying time ·  Establish optimum moisture content
Drying   ·  Overdrying can cause static flow, case hardening, drug/color migration, lamination/capping/ splitting   ·  Set in-process moisture specifications on wet granulated materials ·  See Section A: "Drying"
   ·  Underdrying can cause weak granules, filming, and sticking of punches   ·  See Section A: "Drying" ·  Control moisture in direct compression excipients for proper compressibility
Dye migration      ·  See "Color migration"
Ejection problem      ·  See "Punch binding"
Elastic material   ·  Actives or excipients that are deficient in plastic flow properties, and therefore lack bonding or binding properties ·  Often are springy or spongy and have "spring back" characteristics (i.e., return to original size/shape) ·  Results in capping, lamination, splitting, and lack of compressibility in general   ·  Use materials that have plastic flow (low in elasticity) and that, once compressed, "stay compressed" (do not "spring back"), such as Avicel(r) PH
Entrapment of air      ·  See "Air entrapment"
Excess fines (wet granulation)    ·  Low moisture in granulation   ·  Decrease drying time; establish optimum moisture content
   ·  Screen size too small (dry screening)    ·  Use larger screen size
   ·  Rotor/screen clearance too close   ·  Adjust clearance of rotor
   ·  Overloading granulator or mill   ·  Feed granulator gradually
   ·  Weak granules   ·  Increase binder content/ granulating fluid ·  Increase wet massing time ·  Use stronger binder
Expanding tablets      ·  See "Elastic material" ·  See "Capping and laminating" ·  See "Active ingredients" ·  See "Binding"
Filler   ·  Inert material(s) added to give the necessary bulk for solid dosage preparation   ·  See Section 4 for a description of excipients and their uses
Filming of punches      ·  See "Punch filming or sticking (picking)"
Fines (direct compression)    ·  Poor flow ·  Improper die fill ·  Poor binding   ·  An optimum percent of fines serves a useful purpose of dusting the actives, especially oleaginous ones or those with elastic deformation properties, and aids in bonding and filling voids within the tablet ·  Too many cause segregation
Fines (wet granulation)       ·  See "Excess fines (wet granulation" ·  See "Fines (direct compression)" above
Flooding   ·  Excessive flow properties (fluidization) of one or more components (could be from an excess of glidant or lubricant) ·  Flow is erratic and feed frame is flooded at times   ·  Identify causative component and exclude or modify particle size ·  Select narrow range of particle sizes; avoid excess fines ·  Induced or force-feed mechanism on press may control flow ·  See "Flow problem"
Flow problem   ·  Too many fines in wet granulation   ·  Reduce fines (see "Dry Screening- Excess fines")
   ·  In direct compression, particle size of drug or excipients too small and/or of shape that will not flow   ·  Select larger particle size; use Avicel(r) PH-102 or PH-200 in place of PH-101 or other excipient ·  Add glidant (0.1% to 0.5%), e.g., Cab-O-Sil(r), Aerosil(r) ·  Use induced or force-feed mechanism on press ·  Change particle shape of active ingredient to one that is more likely to flow
   ·  Poor inherent flow   ·  Add 0.1% to 0.5% glidant ·  Dry granulate (by slugging or roller compacting) with a mixture of Avicel(r), Cab-O-Sil(r), and magnesium stearate
   ·  Atmospheric moisture absorption   ·  Process in low humidity atmosphere ·  Add moisture absorber (e.g., 0.1% to 0.5% calcium silicate, Cab-O-Sil(r), Syloid(r) )
Friability (high)    ·  Inadequate bonding of the tablet matrix   ·  Increase binder level or change to stronger binder ·  Add or increase Avicel(r) PH-101 or PH-102 (10% to 20%), which give low friability at lower hardness/machine pressures
   ·  Too much or too little compression pressure   ·  Adjust pressure for acceptable friability
   ·  Overlubrication   ·  Decrease lubricant level ·  Blend lubricant for minimal time required; establish optimum blending time ·  Replace metallic stearates with other lubricants (e.g., stearic acid)
Glidant   ·  Excipient used to improve fluidity of powders   ·  See Section 4 ·  Add 0.1% to 0.5% Cab-O-Sil(r) or Aerosil(r) fumed silica to improve flow ·  Small increase in lubricant may be necessary to offset slight punch/die binding effect of glidant
Granulation, dry      ·  See "Dry granulation" ·  See Section 2
Granulation, wet      ·  See "Wet granulation" ·  See Section 2
Hard tablets      ·  Use Avicel(r) to obtain hard tablets with low machine pressure-also to reduce tablet friability ·  See "Binding (bonding or compressibility)" ·  Decrease compressing speed to increase tablet hardness
Hardness increases with time   ·  Probably more prevalent in wet granulated products, although it can happen in directly compressed tablets ·  Can be caused by water of crystal-lization/hydration interacting with ingredients or other kinds of interactions between active materials/excipients   ·  Optimize moisture content of granulations ·  Conduct preformulation studies, even though data at accelerated temperature/ humidity conditions may not always be relevant to shelf-life conditions
Hardness, variable   ·  Tooling   ·  Examine punch lengths
   ·  Uneven die fill   ·  See "Weight variation"
   ·  Overblending   ·  Optimize blending time to minimize creation of fines
High friability      ·  See "Friability (high)"
High level of active   ·  Direct compression   ·  High percentages of actives can be directly compressed depending on physical form (low density, entrapped air, etc.), flow, and compressibility properties
   ·  Dry/wet granulation   ·  If unable to compress directly, dry granulation or wet granulation are possible alternatives depending on active's physical properties
High relative humidity      ·  See "Relative humidity"
Hopper flow      ·  See "Die fill" ·  See "Flow Problem" ·  See "Segregation"
Hygroscopic ingredients   ·  Moisture pick-up   ·  Process under low humidity conditions ·  Use moisture scavengers (e.g., calcium silicate, Syloid(r), Cab-O-Sil(r) )
Hygroscopic tablets   ·  Moisture pick-up   ·  Compress and package under low humidity conditions (to maintain tablet hardness and active ingredient stability) ·  Use moisture scavengers (e.g., calcium silicate, Syloid(r), Cab-O-Sil(r) ) ·  Keep tablet containers well closed (use adequate closures especially if plastic or blister packed)
Laminating      ·  See "Capping and laminating"
Layered tablets splitting (poor bonding between layers; layers peel or split apart)    ·  Poor bonding between layers   ·  Use a stronger binder or higher concentration
   ·  Compression pressure too high   ·  Compress at lower pressures
   ·  Overlubrication   ·  Decrease lubricant level ·  Blend lubricant for minimal time required; establish optimum mixing times ·  See "Capping and laminating" ·  See "Lubricants"
Loss of hardness (with time)    ·  Tablets with Avicel(r) PH lose some hardness with time at high humidity, but most of the hardness is quickly regained at normal humidity   ·  See "Hygroscopic ingredients" ·  See "Hygroscopic tablets"
Low hardness   ·  Compression force (pressure) too low   ·  Increase pressure (caution-do not exceed recommended pressure for punch size used)
   ·  Overlubrication   ·  Decrease lubricant level ·  Blend lubricant for minimal time required; establish optimum mixing times ·  Replace metallic stearates with other lubricants (e.g., stearic acid)
   ·  Granulation too soft   ·  Use additional binder ·  Direct compression-use additional Avicel(r) PH
   ·  Excipient (i.e., too much starch can give a soft tablet)    ·  Reduce level of causative excipient
   ·  Moisture content too high   ·  Granulation underdried ·  High humidity-use moisture scavenger or moisture adsorbent (e.g., calcium silicate, Syloid(r))
   ·  Moisture content too low   ·  Granulation overdried ·  Low humidity-direct compression excipients too low in moisture content
Low to medium level of active (in direct compression)       ·  Use 10% to 20% Avicel(r) PH combined with compressible lactose and/or dicalcium phosphate ·  With higher levels of Avicel(r) PH use less magnesium stearate, since Avicel(r) PH is self-lubricating ·  At low-dosage level-blend or mill active with part (e.g., 10% of excipient) and then blend with remainder of formulation ·  At very low-dosage levels (<1%), dissolve active in solvent and spray on excipients
Lubricants   ·  Materials added to reduce friction between the die wall and the tablet mix, and hence facilitate ejection of the tablets from the die   ·  See Section 4 for a description of excipients and their uses ·  See "Punch binding" ·  Add lubricant at end of blending operation-do not overblend ·  Screen into bulk powders through a 40- to 60-mesh screen prior to final mixing
      ·  If disintegration/dissolution is a problem with magnesium stearate, use stearic acid (1% to 2%) ·  With higher levels of Avicel(r) PH use less magnesium stearate (since Avicel(r) PH is self-lubricating)
Mixing      ·  See "Blending" ·  See Section A, "Dry blending"
Modified direct compression   ·  Modification of direct compression process to assure good dispersion of low-level actives or for other reasons ·  Avoids granulation of entire formulation   ·  Dissolve actives in volatile solvents and spray onto excipients ·  Granulate a small portion of the formulation and directly compress this granulation with the remainder (major part) of the formulation ingredients
Moisture sensitive actives   ·  Unstable in the presence of water    ·  Use direct compression or dry granulation ·  Use low moisture grades Avicel® PH-112 and PH-113 ·  Use nonaqueous granulating solvent (flammability and residual solvent cautions must be observed)
Mottling      ·  See "Color distribution"
Nonuniform die fill       ·  See "Die fill (nonuniform)"
Nonuniform drying (tray drying)    ·  Poor air flow (circulation) ·  Overloaded trays   ·  Correct air circulation pattern ·  Reduce number of trays ·  Reduce tray load ·  See "Drying"
Nonuniformity of mix   ·  Improper blender load   ·  Use recommended powder load in blender
   ·  Insufficient mixing   ·  Increase mixing time
   ·  Inefficient (improper) mixer   ·  Use alternative mixer with increase shearing action
   ·  Wide particle size distribution   ·  Select more uniform particle sizes of components
   ·  Overblending   ·  Reduce blending time ·  Establish optimum mixing conditions
   ·  Low-dosage actives   ·  Use a more effective mixer (one with increased shearing action)
   ·  Low-level excipients   ·  Blend the low-level component with a portion (5% to 10%) of an excipient; screen (mill) if necessary; reblend; add to an equal quantity of excipient and mix; screen or mill if necessary; blend normally with remainder of bulk
      ·  Dissolve drug in a suitable solvent and add or spray onto a portion of the bulk or an excipient; blend; remove solvent Note: For direct compression excipient blends do not use a screen size or a mixer which will change the excipient particle size distribution
Oleaginous or sticky actives      ·  See "Punch binding" ·  See "Sticky ingredients"
Ordered mixing (adhesive blending)    ·  Small-sized (drug) particles adhesively held on the surface of larger-sized (excipient) particles ·  Segregation does not occur ·  Usually requires a high-intensity mixer    ·  See Section 2
Overblending   ·  Can cause powder separation (segregation or demixing) ·  Can cause particle size reduction leading to other problems ·  Can cause "waterproofing" of tablet by lubricant   ·  Optimize mixing times ·  See "Blending"
Oven drying      ·  See "Drying"
Overwetting of wet mass   ·  A common problem in wet granulation ·  Some actives alone and in combination with excipients are more sensitive than others (due to solubility)    ·  See "Clogging of screen"
Partial direct compression      ·  See "Modified direct compression"
Particle density variation      ·  See "Density, bulk (loose density)" ·  See "Density, tapped" ·  See "Die fill (nonuniform)" ·  See "Punch binding"
Particle size distribution      ·  See "Binding (bonding or compressibility)" ·  See "Die fill (nonuniform)" ·  See "Fines (direct compression)" ·  See "Flooding" ·  See "Flow problem" ·  See "Nonuniformity of mix" ·  See "Ordered mixing (cohesive blending)" ·  See "Segregation"
Picking   ·  Tablet surfaces "pitted" ·  Small areas of compressed powder left on punch faces (mostly upper) after compression-tablet surface is "picked" ·  Often associated with punch filming and sticking   ·  See "Punch filming or sticking"
Poor binding      ·  See "Binding (bonding or compressibility)"
Poor color distribution      ·  See "Color distribution" ·  See "Color migration"
Poor flow ("rat-holing" or "bridging")       ·  See "Flow problem"
Poor granule disintegration   ·  Wet granulation   ·  Granules must be disintegrated for prompt and full drug release (dissolution) ·  Include a portion (50%) of the disintegrant (Ac-Di-Sol(r)) for this purpose in the materials being granulated (disintegrant "inside" the granulation)
Poor layer demarcation   ·  Granulation too course ·  Too many fines   ·  Reduce particle size of granulation-less than 16 mesh ·  Remove fines below 200 mesh
Poor tablet finish/appearance   ·  Picking ·  Mottling ·  Coarse particles   ·  See "Filming of punches" ·  See "Color distribution" ·  See "Coarse particles"
Postgranulation addition   ·  Excipients added after drying the granules and screening them Examples: disintegrant, lubricant, additional binder   ·  See Sections 2 and 4
Powder separation      ·  See "Coarse particles" ·  See "Demixing" ·  See "Fines (direct compression)" ·  See "Flow problem" ·  See "Nonuniformity of mix" ·  See "Overblending" ·  See "Segregation"
Precompression   ·  Application of a relatively small amount of tableting pressure immediately prior to application of main tableting pressure ·  Aids in removing entrapped air   ·  See Section 3
   ·  Aids in preventing/minimizing capping/laminating of difficult-to-compress materials by allowing time for relaxation between compressions ·  Requires a rotary tablet machine equipped for pre-compression   
Punch and die abrasion   ·  Abrasive components   ·  Exclude or reduce to a fine particle size ·  Increase lubricant level ·  Blend abrasive component separately with the lubricant ·  Use minimum tableting pressure possible ·  Use more wear-resistant tooling (harder metal)
Punch binding (powder adheres to punch edges and dies; punches may bind in dies)    ·  Poor finish or worn punches and dies ·  Inadequate lubrication   ·  Polish, reface or replace tooling ·  Increase or change lubricant; use microfine lubricants; screen into mix ·  Increase lubricant blending time
   ·  Too many fines or coarse particles in mix   ·  Design better particle size range; use tapered dies
   ·  Wet granulation insufficiently dried   ·  Dry granulation to satisfactory moisture limits
   ·  Hygroscopic ingredients   ·  Process under low humidity conditions ·  Use moisture scavengers (e.g., calcium silicate, Syloid(r), Cab-O-Sil(r)) ·  Use low moisture grades Avicel® PH-112 and PH-113
   ·  Adhesive or oleaginous components   ·  Increase lubricant level ·  Add 0.5% Cab-O-Sil(r) or Syloid(r) ·  Add 5% to 10% Avicel(r) PH-101
Punch filming or sticking (picking)-(powder adhesion to punch faces, usually upper)    ·  Poor finish on punch faces ·  Embossed letters    ·  Polish punch faces; refinish ·  Avoid using certain letters (e.g., "A", "B", "P", "R") ·  Use shallow embossing with tapered edges rather than edges perpendicular to punch face
   ·  Punch tips burred   ·  Refinish or replace
   ·  Punch concavity too great   ·  Reduce punch concavity or use flat-face punches
   ·  Poor binding between surface granules or particles   ·  Increase binder (wet or dry)
   ·  Low melting point ingredient   ·  Adsorb low melting point ingredient on Avicel(r) PH, replace with higher melting point ingredient
   ·  Inadequate lubrication   ·  Increase or change lubricant ·  Use microfine lubricants, screen into mix ·  Increase lubricant mixing time
   ·  Insufficiently dried wet granulation   ·  Dry granulation and establish moisture limits
   ·  Hygroscopic components   ·  Process under low humidity conditions ·  Use moisture adsorbent (e.g., calcium silicate, Syloid(r))
   ·  Adhesive components   ·  Increase lubricant level ·  Add 0.5% Cab-O-Sil(r) or Syloid(r) or 5% to 10% Avicel(r) PH-101
   ·  Tablets too soft   ·  Increase compression pressure
Rat-holing   ·  Limited flow of a powder or mixture directly over the discharge of a hopper, leaving a hole in the center of the powder as flow slows or stops ·  Part of the remaining powder, which is around the hole, may fall into the hole with the net result being an uneven flow of powder and/or lumps from the hopper   ·  See "Bridging" ·  See "Die fill ( nonuniform)" ·  See "Flow problem" ·  See "Glidant"
Relative humidity (RH)    ·  Ratio of the amount of water the air is holding to the amount it could hold (at saturation) at a given temperature   ·  Keep tableting area <55% RH - higher RH can cause flow problems and sticking depending on materials present
   ·  Raising the temperature, all other things remaining constant, lowers the relative humidity but the absolute amount of water present is the same   ·  Keep tableting area >40% to 45% RH-lower humidity can cause flow because of static and drying out of material being compressed with, perhaps, some loss of compressibility ·  See "Hygroscopic ingredients" ·  See "Hygroscopic tablets"
Roll compacting   ·  Forcing powder (almost always a formulation containing filler, lubricant, and disintegrant) between two oppositely turning rolls in order to form a dense compact in the form of a relatively flat sheet as it exits the rolls ·  The sheet (which often breaks under its own weight as it exits the rolls) is milled to form granules, which can then be used for tableting after adding additional lubricant, disintegrant, etc.    ·  See Section 2 ·  Use Avicel® PH-101
Score line or tablet imprint not sharp   ·  Faulty punch embossing design   ·  Redesign using chamfered edges on the punch embossing ·  Chrome-plate punch face
   ·  Granulation too coarse   ·  Reduce particle size of granulation
   ·  Binder not strong enough   ·  Use a stronger binder
Screen clogging (wet mass)       ·  See "Clogging of screen (wet mass)"
Segregation   ·  Particle size range of mix too wide   ·  Use a narrower particle size range of ingredients ·  Limit the amount of the fines present
   ·  Too wide a density difference   ·  Control differences in the density of particles
   ·  Mixer too vigorous, produces fines   ·  Use a mixer with a gentler mixing action
   ·  Use of vibrators (to promote flow from hopper)    ·  Use force-feed mechanisms rather than hopper vibrators
Slugging   ·  Use of relatively large punches and dies to produce tablets from a poor flowing powder mix ·  Tablets usually not well-controlled with respect to weight and hardness   ·  See "Dry granulation"
   ·  Tablets milled to produce granules which can then be used (after adding additional lubricant, disintegrant, etc.) to produce uniform tablets of desired size, weight, hardness, etc.    
Soft tablets      ·  See "Binding (bonding or compressibility)" ·  See "Capping and laminating" ·  See "Coarse particles" ·  See "Die fill (nonuniform)" ·  See "Elastic material" ·  See "Excess fines (wet granulation)" ·  See "Friability (high)" ·  See "Hardness, variable" ·  See "Loss of hardness (with time)" ·  See "Low hardness"
Splitting (tablets)       ·  See "Capping and laminating" ·  See "Chipping/splitting"
Sticking to punch face      ·  See "Punch filming or sticking"
Sticky ingredients      ·  Fines in excipient mix (especially Avicel(r) PH) aid in "drying up" oleaginous actives, giving better flow and tableting ·  See "Punch filming or sticking" ·  See "Punch binding"
Tablet binding in the die      ·  See "Punch binding"
Tablets contain "dirty" specks    ·  Misaligned upper cam tracks- rubbing of punches on cam actually rubs off metal, which is introduced into material being compressed   ·  Check alignment of upper cam tracks
   ·  No lubrication on upper cam tracks   
   ·  Excessive or improper lubrication on upper punch shanks (no dust caps on punches)-dust mixes with excess oil or grease and falls into material being compressed   ·  Use dust caps on upper punches
Tablets uniformly discolored   ·  Feed frame rubbing on die table ·  Feed hopper rubbing on turret ·  Abrasive materials wearing screens, scooper, etc.    ·  Check clearance between feed frame and die table ·  Check clearance between feed hopper and turret ·  Check for presence of abrasive materials
Underblending      ·  See "Blending"
Variable hardness   ·  Tooling   ·  Examine punch lengths
   ·  Uneven die fill   ·  See "Weight variation"
   ·  Overblending   ·  Optimize blending time to minimize creation of fines
Weight variation (outside limits)    ·  Poor or erratic powder flow, flooding   ·  Correct powder flow problems (See "Feed Hopper" in Part A)
   ·  Particle size range too wide   ·  Narrow the particle size range; avoid excess fines
   ·  Particle size not suitable for die diameter   ·  Adjust particle size range to recommended optimum for die diameter
   ·  Punches not within specifications   ·  Examine punch length dimensions
   ·  Particle segregation as press RPM's increase   ·  Narrow the particle size range ·  Compress at slower RPM
   ·  Lower punch "hang up" (material between lower punch and die wall or lower punch and punch guide)    ·  Clean; improve dust collection ·  Check for proper clearance between die wall and lower punch ·  Increase lubricant concentration in formulation
      ·  Remove below 200 mesh fines
Wet granulation   ·  Process whereby active drugs and excipients are wet massed (wet with a solvent containing a binder in solution, usually), screened, dried, and screened again ·  Used for high-dose active drugs which have poor flow and either cannot be or are difficult to directly compress ·  Used for active drugs which are very fine and/or low density   ·  See Section 2


Grouch

  • Guest
tablet tips
« Reply #15 on: July 21, 2001, 04:44:00 AM »
Do you have any of these problems:
 A groove wearing on the inside head angle of the lower punch
 High tablet ejection pressure
 Powder buildup on the relief area of the lower punch
 
Such problems can be attributed to:
 Material adhering to the die cavity
 The lower punch is not clearing excess powder from the die cavity
 Sometimes the powder is just sticky and wants to adhere to the lower punch relief area and die cavity.
 
Although there may be a number of causes for this occurrence, check the sharpness of the tip straight's trailing edge .
 
Instruct your maintenance personnel to not polish or round off this edge .
Instruct your tool vendor to keep this edge sharp .
When this edge is rounded off it will not properly remove any excess powder that may accumulate on the die cavity, and allow powder to collect behind the tip straight. Lower punch inside angle head wear increases as powder accumulates in all areas.
 
Our tip is to add a bake lite relief at the end of the tip straight, this will help to maintain a sharp edge and reduce material buildup on the relief area.
 
WITH BAKELITE RELIEF

         TOPIC: Surface Pressure Problems such as: Picking, Surface Abrasion / Erosion and Excessive Compression Force may be due to inconsistant surface pressure. There are combinations of factors contributing to this problem:  Dwell Time  Press Speed  Punch Head Design  Formulation Compressibility  Punch Tip Cup  Cup Design  Cup Depth Before we explain in more depth how to solve these problems, you should first have a basic concept of how powder is formed into a solid tablet. Understanding this basic concept, we can theorize what may or may not be occurring in order to solve our problem. To compress a tablet requires a rotary or single station press and three components that constitute one station of tooling: Upper Punch, Lower Punch and Die.  During the compression cycle the die cavity is filled with powder, then the upper and lower punch move together in a vertical direction under two compression rolls to form a solid tablet. The duration of time the punches are under these rolls is called dwell time. There may be only fractions of a second of dwell time to form the solid tablet due to variables in press speeds, punch head size or punch head design. Within that fraction of a second the following must occur: The applied compression force must reach the apex or deepest point on the punch cup contour so that the tablet core and any particle in contact with any punch or die surface can achieve adequate bonding; thereby achieving uniform tablet hardness. Also any air within the powder must be displaced around the punches so as not to inhibit the material bonding process. Although there are other reasons why we may have a Picking, Surface Abrasion / Erosion, and Excessive Compression Force, for this scenario we'll consider our required production press speed is too fast and is providing too short of a dwell time duration. We determined this by evaluating the results of reducing press speed and found tablet quality improved. Reducing press speed thereby increased the dwell time duration permitting sufficient time for the force to reach the deepest point on the cup. Reducing press speed may solve the problem, but it will also slow production. In this scenario, any solution effecting production speed was not acceptable. Our course of action is then to evaluate the punch tip cup and determine if it is contributing to, or creating an inconsistent surface pressure problem. Keep in mind what is occurring on the punch tip cup as the upper and lower punch are moving together in a vertical direction to compress the powder. Compression force begins at the outer punch tip perimeter and progresses toward the deepest point on the cup as the punches move closer together. We'll evaluate why our existing cup contour is not providing a consistent surface pressure, and prove if altering the cup contour will improve the compression characteristics. .  At Elizabeth Carbide Die we have a computerized method for evaluating force displacement across a punch tip cup contour. Force displacement can be defined as the cup contour's ability to produce uniform tablet hardness within a given dwell time. It is possible to use this method to evaluate any cup form, but for ease of explanation we'll use a round punch tip with a Tableting Specification Manual single radius extra deep concave cup.  By evaluating the vertical force pattern on the existing "T.S.M." extra deep concave punch cup form, we can compare any subsequent patterns and establish a theory to the cause of our problem. Notice the progression of force on the cup form is illustrated as different colored rings and is due to the spherical cup design and depth. Because compaction force had to build from the outer perimeter in a series of rings to the deepest cup area, consequently the insufficient dwell time did not allow pressure to reach the deepest area on the cup to promote material bonding.  Due to the amount of volume our deep concave cup has, we'll need to use a cup design that will hold as much volume and provide the force displacement characteristics to solve our problem. A compound radius cup design may be the best design, because of the three radii construction. The outside two small radii provide the elevation for volume and the larger center radius may improve our force displacement at the apex of the cup. Now we'll apply the same amount of force to this design as we did to the deep concave cup design, and evaluate the results.   When comparing two-force displacement plots, we're looking for any change in color or pattern indicating an increase in force or change in the distribution of force to the powder. Evaluating the compound cup design, we first see a coloration change in the outer yellow zone indicating a slight increase in force due to the two small radii used to form our contour. We can change the effectiveness of these radii by increasing the size or rotation of the radii. As we move to the center of the cup, there is a new spiral pattern formed by the larger radius forming the contour. Increasing or decreasing this radius will change its effectiveness. Although we can not prove these are the best combination of radii to solve our problem, we have proven the cup design and patterns formed will have some effect on the cup's ability to transfer force to the powder and reduce picking, surface abrasion / erosion. Tablet volume and size restrictions will dictate design variables and any subsequent effect the cup design will have on solving the problem. By changing the cup design / force displacement our goal is to reduce the force necessary to achieve tablet hardness, thereby increasing tool life.


Formulation:
As a tooling and press supplier, we are not experts in this area, but we do understand how atmospheric conditions as well as acidic and abrasive properties can affect the entire pressing operation.
Is the formulation humidity sensitive?
 YES  NO
Powder with a high moisture content can increase compression force, and may adhere to the punch's surface.
Is the formulation temperature sensitive?
 YES  NO
If a certain temperature makes the powder sticky, there would be a need to reduce any friction around the tooling by checking lubrication, tool set-up, and ejection pressure.

Is the formulation by nature sticky?
 YES  NO
Some powders are sticky and hard to compress. If this is the case, a coating may need to be applied to the punch tip surface.
Remedy: We can apply chrome to the punch tip surface. And, although we do not ship any tooling directly to a coating vendor, we can suggest other types of coating.
*It is our policy to send all tooling directly to our customers for their inspection
Is the formulation abrasive?
 YES  NO
Remedy : To extend tool life, we can improve the punch tip edge by increasing the land, changing the contour radii, or suggesting a tool wear resistant material.
 
Press:
Many of these problems are associated with press maintenance and set-up.
Are the press's punch guides worn or out of tolerance?
 YES  NO
If the punch guides are worn, they can cause upper and lower punch misalignment. This misalignment creates non-uniform punch tip edge wear and leads to:
·   Premature tool retirement
·   Flashing
·   Increased tablet ejection pressure
·   Premature die cavity wear
Are the press's die sockets worn or out of tolerance?
 YES  NO
A worn die socket can be due to improper tool set-up. It occurs when the die periphery is not installed parallel to the die socket and perpendicular to the die table. Forcing the die into the socket removes a small amount of material and can damage the sockets. This wear causes increased tablet ejection pressure, inside lower punch head angle wear, pull down cam wear and die cavity wear.
Remedy : Use a die alignment tool or see EEE tooling .
Are there any dinks or dents on the sides of the punch tip?
 YES  NO
Care should be taken so the punch tip does not come in contact with other punches or any hard surface when; unpacking boxes of tooling, cleaning tooling, and during press set up. Dents can score the die cavity, reduce tool life and affect tablet quality.
 
Remedy : Before installing the press carefully remove damage by stoning and polishing.
Do you have just a few punches out of the set with cracked punch tips?
 YES  NO
When a press sits idle, the powder inside the die cavity under the feed shoe will settle, increasing the volume or weight of powder in the subsequent number of dies. As these punches pass under the pressure rolls, the load increases and punch tip fracture .
Remedy : Turn the press table by hand to eject the increased powder weight out of the dies that were stationary under the feed shoe.
Are there any vertical wear marks on opposing sides of the punch tip periphery?
 YES  NO
During press set up, if the upper punch is not in align with the die so a consistent punch to die clearance occurs, opposing points on the tip periphery may come in contact with the die cavity.
 
Remedy : See EEE tooling , we provide a special alignment punch to easily maintain a consistent punch to die clearance .
Do the punch heads appear to be gouged or have skid marks?
 YES  NO
In this case the pressure roll is not rotating properly, and drags the punches as they pass between the rolls.
 
Remedy : There are four things you can do in this situation:
·   Lubricate the rolls
·   Check the roll for damage
·   Polish the punch heads
·   Check the cam track for steel particles.
 
Tooling:
During inspection of the tools, can you insert the punch tip into the die cavity? But once you install them into the press, the punch tip does not want to fit properly in the die cavity?
 YES  NO
When this occurs the punch to tip concentricity is out of tolerance. This means if you found the center of the barrel and center of the punch tip periphery, both should be in-line. The upper punch, lower punch and die must align in a fixed position to move in a true vertical direction.
 
Remedy : Return the tools back to the tool vendor. Do not attempt to stone the punch tip periphery to make it fit. Tools like this can reduce valuable production time and may damage other press parts.
Are there dark vertical lines on the band section of your tablets?
 YES  NO
Tooling can cause these lines when the tablet has a small corner radius. Shapes which are prone to this are: squares, hexagons, and triangles. This problem occurs when a large amount of clearance is at the corners, compared to the straight areas. This is due to punch wear or improper grinding procedures.
 
Cause : A consistent amount of metal was not ground off the punch tip periphery. Actually, more metal was removed from the corners. This allows powder to pass between the punch and die, and then darkens due to friction.
Remedy : If a tooling vendor does not have quality computerized grinding machines, even remaking the tooling will not solve this problem.
 
Do you have powder adhering to the punch face? This can occur around any identification text embossed on the punch face?
 YES  NO
When this occurs it's known as picking or sticking and can be caused by pits on the punch face and/or improper draft angle on the embossing.
 
Remedy : If the punch face is pitted:
·   Re-polish the punch face
·   Apply some type of coating
·   Formulation Related - Add lubrication if possible
·   Increase dwell time by reducing press speed
·   Increase compression force *
·   Redesign tablet with a Finite Analysis Study
* Never exceed recommended compression force limits. If you must press at the high limit to solve a problem, a tablet redesign is necessary.
Tooling with embossed text: Does the height of the embossing on the punch taper down on the top and bottom of the text, making it less distinctive on your new tools?
 YES  NO
This can be a tablet design problem or due to over polishing.
 
Remedy : Visually inspect the punch tip face when tools are received. This is essential before, and after, sending the punch tips to a coating vendor. Using a tool in this condition can be detrimental to tablet quality, especially if the tablets will be coated. You should return tooling to the tool vendor for replacement, or advise the coating vendor that the tools have been damaged. When maintaining existing tools, be careful not to over polish.
Do you have punch tips fracturing before providing an acceptable amount of tool life?
 YES  NO
Most times the recommended compression limits have been exceeded. Before contacting the tool vendor, gather as much information as possible, such as compression force specs. and pressing duration before the fracture occurred.
 
Remedy : Check the punch heads for any signs of overload. The tool vendor should perform a Finite Element Analysis study along with Fatigue Analysis . Providing an alternative tablet contour design can also improve tool life.
 
Tablet:
When tablet quality problems arise, provide the tool vendor with sample tablets. If the tablets are coated, supply core and coated samples and tooling. A tool vendor should evaluate all samples and provide drawings indicating a course of action. If existing Hob fixtures can be utilized or new fixtures need to be produced, a copper impression or an Elizatab may be supplied for approval by the customer before new tooling is produced.
The tablet detail drawing is critical documentation that should be utilized if any problems arise at the product development stage, or at any time during tablet production. All revisions should be documented and all required sizes indicated on the drawing to reproduce any new tooling consistently for the life of the product.
Please check if any of these quality problems exist in you tableting operation.
Capping       YES  NO
  Laminating      YES  NO
  Edge chipping      YES  NO
  Picking      YES  NO
Twinning      YES  NO
  Sticking      YES  NO
  Flashing      YES  NO
  Surface abrasion      YES  NO
  Unequal partial dosage from score / bisect      YES  NO
 Tablets shingle on die table      YES  NO


Rhodium

  • Guest
Re: tablet tips
« Reply #16 on: July 21, 2001, 05:36:00 AM »
Thank you very much for this. Could you possibly email me a zip file of the texts as html documents including all the pictures to rhodium@privacyx.com so I don't have to sit up all night editing this to a readable format, and then end up with no pictures anyway? I WILL put this on my page immediately after I know what the best format available to me is.


https://www.rhodium.ws


Grouch

  • Guest
Re: tablet tips
« Reply #17 on: July 21, 2001, 06:47:00 AM »
I'll edit it nicely into five parts and send it to you this week.

Semtexium

  • Guest
Re: tablet tips
« Reply #18 on: July 21, 2001, 08:44:00 AM »
Hey Grouchy, why does this look so damn familiar...?   :P


::)  ::)

abc123

  • Guest
Re: tablet tips
« Reply #19 on: August 04, 2001, 11:59:00 PM »
While left alone with my thoughts after digesting recently obtained toxicology data pertaining to the proposed "neurological damage" that has been associated with MDMA consumption, I've come to the realization that perhaps it is the duty of those who should wish to engage in the act of preparing such a product for distrubution (albeit via gel caps or press pills not that I would ever have anything to do with such an illegal activity mind you....) should be concerned with the saftey and long term well being of their consumers.
  The current toxological standard for "neurological damage" in living subjects (all animals from rats to primates seem to be the gaumet of available research data specimens available from obtainable medical research doccuments), is the decrese in the amount of 5-hydroxyindole acetic acid measured in the urinary out put of said test subjects. Acccording to the medical folks this is ment to be indicitive as sign of either damage or impairment to the "normal" function of serotongenic nuerons. Well up to this point you may be saying "no shit so what's your point? Tell us something we don't know, so we can progesss to producing a safer product that won't have the problems that seem to be the major source of serious negative long term side effects that that could effect the consumer.
  Well after some careful research, I believe that I may have found a way for bees to have their cake and keep all of their brain cells too!!!!
  Current proposed mechanisms for the proposed damage caused from using MDMA involves the formation of free radical intermidetes formed when the normal protien structure of the enzymes envolved in the drug's normal course of metabolism, are physicaly altered via the slight pH change that occurs as hyperthermia sets in as a side effect in the user. It is belived that these "altered" enzymes either evolve "new active sites" that metabolize the drug into a primary free radical species as an intermediate during metabolism. It is hypothised that this proposed free radical serves to oxidize (either/and/or)serotongenic/catacolamine receptors, and thereby oxidize the "subject" ligand-based receptor,and disrupt the normal function of the nueron and it's homeostatic function.
  According to shitloads of data available to anyone via GratefulMed (this is a great site and is a must for any one intrested in learning about the nuts and bolts of applied nueroscience), recent data has shown that administration of either or both alpha-liprotic acid or ascorbic acid (that's Vitamen C Bubba!!!)have shown in animal test subjects to maintain normallevels of 5-hydroxyindole acetic acid in their urine......
  What I am proposing is that either or both ascorbic acid and alpha-liprotic should or possiably be used as an additive in both pressed and gel caped products.... I've heard of people having no recovery problems the day after a binge using this method. I believe this to be due to the fact that alpha-liprotic acid is a free radical inhibitor and vitamen C is a strong anti-oxident. Hence both compounds are not only Bio friendly and benifical, but serve to act as competive inhibitors that work to react with the evil MDMA free radical before it can do it's thing at a normaly encountered receptor site. This of course leaves the receptor sites and their ligands intact and  help to prevent any damage from occuring.

I'm very interested in this topic and would love to entertain any comments our fellow bees may have regarding it's practical application to this deliema.

Thanks for reading.