A tablet is a mixture of active substances and excipients, usually in powder form, pressed or compacted into a solid. The excipients include binders, glidants (flow aids) and lubricants to ensure efficient tabletting; disintegrants to ensure that the tablet breaks up in the digestive tract; sweeteners or flavours to mask the taste of bad-tasting active ingredients; and pigments to make uncoated tablets visually attractive. A coating may be applied to hide the taste of the tablet's components, to make the tablet smoother and easier to swallow, and to make it more resistant to the environment, extending its shelf life.
The compressed tablet is the most popular dosage form in use today. About two-thirds of all prescriptions are dispensed as solid dosage forms, and half of these are compressed tablets. A tablet can be formulated to deliver an accurate dosage to a specific site; it is usually taken orally, but can be administered sublingually, rectally or intravaginally. Tablet formation represents the last stage in down-stream processing within the pharmaceutical industry. It is just one of the many forms that an oral drug can take such as syrups, elixirs, suspensions, and emulsions. It consists of an active pharmaceutical ingredient (A.P.I.) with biologically inert excipients in a compressed, solid form.
Medicinal tablets were originally made in the shape of a disk of whatever color their components determined, but are now made in many shapes and colors to help users to distinguish between different medicines that they take. Tablets are often stamped with symbols, letters, and numbers, which enable them to be identified. Sizes of tablets to be swallowed range from a few millimeters to about a centimeter. Some tablets are in the shape of capsules, and are called "caplets".
Medicines to be taken orally are very often supplied in tablet form; indeed the word tablet without qualification would be taken to refer to a medicinal tablet. Medicinal tablets and capsules are often called pills. Other products are manufactured in the form of tablets which are designed to dissolve or disintegrate; e.g. cleaning and deodorizing products.

Tabletting formulations

Capping (top) and lamination (right) tablet failure modes
In the tablet-pressing process, it is important that all ingredients be fairly dry, powdered or granular, somewhat uniform in particle size, and freely flowing. Mixed particle sized powders can segregate due to operational vibrations, which can result in tablets with poor drug or active pharmaceutical ingredient (API) content uniformity. Content uniformity ensures that the same API dose is delivered with each tablet.
Some APIs may be tableted as pure substances, but this is rarely the case; most formulations include excipients. Normally, an inactive ingredient (excipient) termed a binder is added to help hold the tablet together and give it strength. A wide variety of binders may be used, some common ones including lactose powder, dibasic calcium phosphate, sucrose, corn (maize) starch, microcrystalline cellulose and modified cellulose (for example hydroxymethyl cellulose).

Often, an ingredient is also needed to act as a disintegrant that hydrates readily in water to aid tablet dispersion once swallowed, releasing the API for absorption. Some binders, such as starch and cellulose, are also excellent disintegrants.
Small amounts of lubricants are usually added, as well. The most common of these is magnesium stearate; however, other commonly used tablet lubricants include stearic acid (stearin), hydrogenated oil, and sodium stearyl fumarate. These help the tablets, once pressed, to be more easily ejected from the die.
Friability is an important factor in tablet formulation to ensure that the tablet can stay intact and withhold its form from any outside force of pressure:
where Wo is the original weight of the tablets, and Wf is the final weight of the tablets after the collection is put through the friabilator.
Friability below 0.8% is usually considered satisfactory.

Advantages and disadvantages

Variations on a common tablet design, which can be told apart by both color and shape
Tablets are easy and convenient to use. They provide an accurately measured dosage in a convenient portable package, and can be designed to protect unstable medications or disguise unpalatable ingredients. Coatings can be coloured or stamped to aid tablet recognition. Manufacturing processes and techniques can provide tablets special properties; for example enteric coatings or sustained release formulations.
Tablets cannot be used adequately in case of emergency cases. This is because the rate at which the active ingredient reaches the site to be treated is slow. Other means such intravenous and intramuscular injections are more effective. Some drugs may be unsuitable for administration by the oral route. For example protein drugs such as insulin may be denatured by stomach acids. Such drugs cannot be made into tablets. Some drugs may be deactivated by the liver (the "first pass effect") making them unsuitable for oral use. Drugs which can be taken sublingually bypass the liver and are less susceptible to the first pass effect. Bioavailability of some drugs may be low due to poor absorption from the gastric tract. Such drugs may need to be given in very high doses or by injection. For drugs that need to have rapid onset, or that have severe side effects, the oral route may not be suitable. For example Salbutamol, used to treat problems in the pulmonary system, can have effects on the heart and circulation if taken orally; these effects are greatly reduced by inhaling smaller doses direct to the required site of action.

Tablet properties
Tablets can be made in virtually any shape, although requirements of patients and tabletting machines mean that most are round, oval or capsule shaped. More unsusual shapes have been manufactured but patients find these harder to swallow, and they are more vulnerable to chipping or manufacturing problems.
Tablet diameter and shape are determined by a combination of a set of punches and a die. This is called a station of tooling. The thickness is determined by the amount of tablet material and the position of the punches in relation to each other during compression. Once this is done, we can measure the corresponding pressure applied during compression. The shorter the distance between the punches, thickness, the greater the pressure applied during compression, and sometimes the harder the tablet. Tablets need to be hard enough that they don't break up in the bottle, yet friable enough that they disintegrate in the gastric tract.
The tablet is composed of the Active Pharmaceutical Ingredient (that is the active drug) together with various excipients. These are biologically inert ingredients which either enhance the therapeutic effect or are necessary to construct the tablet. The filler or diluent (e.g. lactose or sorbitol)is a bulking agent, providing a quantity of material which can accurately be formed into a tablet. Binders (e.g. methyl cellulose or gelatin) hold the ingredients together so that they can form a tablet. Lubricants (e.g. magnesium stearate or polyethylene glycol) are added to reduce the friction between the tablet and the punches and dies so that the tablet compression and ejection processes are smooth. Disintegrants (e.g. starch or cellulose) are used to promote wetting and swelling of the tablet so that it breaks up in the gastro intestinal tract; this is necessary to ensure dissolution of the API. Superdisintegrants are sometimes used to greatly speed up the disintegration of the tablet. Additional ingredients may also be added such as coloring agents, flavoring agents, and coating agents. Formulations are designed using small quantities in a laboratory machine called a Powder Compaction Simulator. This can prove the manufacturing process and provide information for the regulatory authorities.

Manufacturing
In the tablet-pressing process, it is important that all ingredients be dry, powdered, and of uniform grain size as much as possible. The main guideline in manufacture is to ensure that the appropriate amount of active ingredient is equal in each tablet so ingredients should be well-mixed. Compressed tablets are exerted to great pressure in order to compact the material. If a sufficiently homogenous mix of the components cannot be obtained with simple mixing, the ingredients must be granulated prior to compression to assure an even distribution of the active compound in the final tablet. Two basic techniques are used to prepare powders for granulation into a tablet: wet granulation and dry granulation.
Powders that can be mixed well do not require granulation and can be compressed into tablets through Direct Compression

Direct Compression
This method is used when a group of ingredients can be blended and placed in a tablet press to make a tablet without any of the ingredients having to be changed. This is not very common because many tablets have active pharmaceutical ingredients which will not allow for direct compression due to their concentration or the excipients used in formulation are not conducive to direct compression.
Granulation is the process of collecting particles together by creating bonds between them. There are several different methods of granulation. The most popular, which is used by over 70% of formulation in tablet manufacture is wet granulation. Dry granulation is another method used to form granules.

Wet granulation
Wet granulation is a process of using a liquid binder or adhesive to the powder mixture. The amount of liquid can be properly managed, and over wetting will cause the granules to be too hard and under wetting will cause thém to be too soft and friable. Aqueous solutions have the advantage of being safer to deal with than solvents.

Procedure of Wet Granulation

Step 1:
Weighing and Blending - the active ingredient, filler, disintegration agents, are weighed and mixed.

Step 2:
The wet granulate is prepared by adding the liquid binder/adhesive. Examples of binders/adhesives include aqueous preparations of cornstarch, natural gums such as acacia, cellulose derivatives such as methyl cellulose, CMC, gelatin, and povidone. Ingredients are placed within a granulator which helps ensure correct density of the composition.

Step 3: Screening the damp mass into pellets or granules

Step 4: Drying the granulation

Step 5: Dry screening: After the granules are dried, pass through a screen of smaller size than the one used for the wet mass to select granules of uniform size to allow even fill in the die cavity

Step 6:

Lubrication- A dry lubricant, antiadherent and glidant are added to the granules either by dusting over the spread-out granules or by blending with the granules. Its reduces friction between the tablet and the walls of the die cavity. Antiadherent reduces sticking of the tablet to the die and punch.
Stepe liquid binder, but sometimes many actives are not compatible with water. Water mixed into the powder can form bonds between powder particles that are strong enough to lock them in together. However, once the water dries, the powders may fall apart and therefore might not be strong enough to create and hold a bond. Povidone also known as polyvinyl pyrrolidone (PVP) is one of the most commonly used pharmaceutical binders. PVP and a solvent are mixed with the powders to form a bond during the process, and the solvent evaporates. Once the solvent evaporates and powders have formed a densely held mass, then the granulation is milled which results in formation of granules

Dry granulation
This process is used when the product needed to be granulated may be sensitive to moisture and heat. Dry granulation can be conducted on a press using slugging tooling or on a roller compactor commonly referred to as a chilsonator. Dry granulation equipment offers a wide range of pressure and roll types to attain proper densification. However, the process may require repeated compaction steps to attain the proper granule end point.
Process times are often reduced and equipment requirements are streamlined; therefore the cost is reduced. However, dry granulation often produces a higher percentage of fines or noncompacted products, which could compromise the quality or create yield problems for the tablet. It requires drugs or excipients with cohesive properties.
Some granular chemicals are suitable for direct compression (free flowing) e.g. potassium chloride.
Tableting excipients with good flow characteristics and compressibility allow for direct compression of a variety of drugs.

Fluidized bed granulation
It is a multiple step process performed in the same vessel to pre-heat, granulate and dry the powders. It is today a commonly used method in pharmaceuticals because it allows the individual company to more fully control the powder preparation process. It requires only one piece of machinery that mixes all the powders and granules on a bed of air.

Tablet Compaction Simulator
Tablet formulations are designed and tested using a laboratory machine called a Tablet Compaction Simulator or Powder Compaction Simulator. This is a computer controlled device that can measure the punch positions, punch pressures, friction forces, die wall pressures, and sometimes the tablet internal temperature during the compaction event. Numerous experiments with small quantities of different mixtures can be performed to optimise a formulation. Mathematically corrected punch motions can be programmed to simulate any type and model of production tablet press. Small differences in production machine stiffness can change the strain rate during compaction by large amounts, affecting temperature and compaction behaviour. To simulate true production conditions in today's high speed tablet presses, modern Compaction Simulators are very powerful and strong.
Initial quantities of active pharmaceutical ingredients are very expensive to produce, and using a Compaction Simulator reduces the amount of powder required for development.
Load controlled tests are particularly useful for designing multi-layer tablets where layer interface conditions must be studied.
Test data recorded by the Simulators must meet the regulations for security, completeness and quality to support new or modified drug filings, and show that the designed manufacturing process is robust and reliable.

Tablet presses

The tablet pressing operation

An old Cadmach rotary tablet press
Tablet presses, also called tableting machines, range from small, inexpensive bench-top models that make one tablet at a time (single-station presses), no more than a few thousand an hour, and with only around a half-ton pressure, to large, computerized, industrial models (multi-station rotary or eccentric presses) that can make hundreds of thousands to millions of tablets an hour with much greater pressure. Some tablet presses can make extremely large tablets, such as some of the toilet cleaning and deodorizing products or dishwasher soap. Others can make smaller tablets, from regular aspirin to some the size of a bb gun pellet. Tablet presses may also be used to form tablets out of a wide variety of materials, from powdered metals to cookie crumbs. The tablet press is an essential piece of machinery for any pharmaceutical and nutraceutical manufacturer.

Pill-splitters
It is sometimes necessary to split tablets into halves or quarters. Tablets are easier to break accurately if scored, but there are devices called pill-splitters which cut unscored and scored tablets. Tablets with special coatings (for example enteric coatings or controlled-release coatings) should not be broken before use, as this will expose the tablet core to the digestive juices, short-circuiting the intended delayed-release effect.

Tablet coating
Many tablets today are coated after being pressed. Although sugar-coating was popular in the past, the process has many drawbacks. Modern tablet coatings are polymer and polysaccharide based, with plasticizers and pigments included. Tablet coatings must be stable and strong enough to survive the handling of the tablet, must not make tablets stick together during the coating process, and must follow the fine contours of embossed characters or logos on tablets. Coatings can also facilitate printing on tablets, if required. Coatings are necessary for tablets that have an unpleasant taste, and a smoother finish makes large tablets easier to swallow. Tablet coatings are also useful to extend the shelf-life of components that are sensitive to moisture or oxidation. Opaque materials like titanium dioxide can protect light-sensitive actives from photodegradation. Special coatings (for example with pearlescent effects) can enhance brand recognition.
If the active ingredient of a tablet is sensitive to acid, or is irritant to the stomach lining, an enteric coating can be used, which is resistant to stomach acid and dissolves in the high pH of the intestines. Enteric coatings are also used for medicines that can be negatively affected by taking a long time to reach the small intestine where they are absorbed. Coatings are often chosen to control the rate of dissolution of the drug in the gastro-intestinal tract. Some drugs will be absorbed better at different points in the digestive system. If the highest percentage of absorption of a drug takes place in the stomach, a coating that dissolves quickly and easily in acid will be selected. If the rate of absorption is best in the large intestine or colon, then a coating that is acid resistant and dissolves slowly would be used to ensure it reached that point before dispersing. The area of the gastro-intestinal tract with the best absorption for any particular drug is usually determined by clinical trials.
This is the last stage in tablet formulation and it is done to protect the tablet from temperature and humidity constraints. It is also done to mask the taste, give it special characteristics, distinction to the product, and prevent inadvertent contact with the drug substance. The most common forms of tablet coating are sugar coating and film coating.
Coating is also performed for the following reasons:
Controlling site of drug release
Providing controlled, continuous release or reduce the frequency of drug dosing
Maintaining physical or chemical drug integrity
Enhancing product acceptance and appearance
Sugar coating is done by rolling the tablets in heavy syrup, in a similar process to candy making. It is done to give tablets an attractive appearance and to make pill-taking less unpleasant. However, the process is tedious and time-consuming and it requires the expertise of highly skilled technician. It also adds a substantial amount of weight to the tablet which can create some problems in packaging and distribution.
In comparison to sugar coating, film coating is more durable, less bulky, and less time consuming. But it creates more difficulty in hiding tablet appearance. One application of film-coating is for enteric protection, termed enteric coating. The purpose of enteric coating is to prevent dissolution of the tablet in the stomach, where the stomach acid may degrade the active ingredient, or where the time of passage may compromise its effectiveness, in favor of dissolution in the small intestine, where the active principle is better absorbed.

Tablet Technology Presses On

By Matt Bundenthal

Near infrared analysis methods can be used to check in-process quality on rotary tablet presses.

Long considered to be somewhat recession-proof, the pharmaceutical industry has certainly faced its share of significant challenges in 2008. While it remains true that the use of pharmaceutical preparations tends to increase in stressful times, the manufacturers themselves are held in check by the growing domestic and global economic crisis.

Companies are subscribing more closely than ever before to the application of due diligence, and this certainly applies to their evaluation, selection, and purchase of developmental and manufacturing equipment. An ever-growing number of firms, both name brand and generic, are increasing the exploration and implementation of the concept of equipment standardization and are making more efficient use of existing assets as they make decisions to reduce the overall number of operating sites.

Many pharmaceutical equipment vendors have also felt the pinch as a result of the industry’s newfound reluctance to approve and spend capital. Tablet presses and related peripheral equipment represent one of the most critical investments that any developer of solid dose pharmaceutical products will make. Given the spending slowdown, and with users casting a more watchful eye upon equipment standardization, press vendors are engineering developmental solutions and features that greatly increase the likelihood of a successful handshake between research-specific designs and those intended to produce product in higher volumes. It is more important than ever for the press companies to demonstrate optimal flexibility with smaller units, as well as with other technologies that broaden the overall utilization capabilities of their equipment. The brief descriptions that follow will touch upon just a few of the more dynamic technologies that are being engineered and optimized by modern press manufacturers.

Software, Single-Tablet Compaction

Lower punches in raised position during the sampling cycle.

Many tablet press manufacturers now offer a variety of research-based software packages and add-ons that facilitate the collection of useful data at the developmental stage. Going beyond the typical monitoring of preliminary and main compression and ejection forces, today’s systems for data retrieval and manipulation put greater power and versatility in the hands of the user. It is not at all uncommon for press research systems to allow for the measurement of upper and lower punch tightness, as well as the force required to remove a finished tablet from the die table surface via the take-off assembly.

Most of the data collected from the available research packages can be represented on an operator interface terminal both numerically and graphically; in most cases, it can be saved and downloaded in popular formats, including .xls and .pdf. While the power of each package varies from vendor to vendor, most of the more advanced modules place emphasis on the ability to create and analyze individual force profiles for many of the aforementioned parameters. When graphical compression force curves are created, for example, it is very useful to be able to superimpose the most recent one generated over previous curves measured at the same station on a press turret. The utility of such information can come in the form of determining how well (or poorly) a formulation compresses and whether or not there are content uniformity issues.

Some research systems also make provisions for the correlation of compression force data to other properties relating to the compression process, such as variable lubrication levels and optimal dwell times or peak compression times. Such ratios can then, in turn, provide valuable insight into key measurements affecting finished tablet criteria, including hardness, thickness, and friability.

There are also programs commercially available that create graphical representations of not only the amount of force required to compress a tablet but also the forces lost due to elasticity in the product itself and in the mechanical structure of the press. Ultimately, these graphs depict the net force that goes into compressing a tablet. Developmental personnel find this tool useful because it allows them to zero in on an optimal force, one that is substantial enough to produce a tablet to desirable specifications but not so significant as to damage the granules or cause premature wear on the press being utilized.

When graphical compression force curves are created, for example, it is very useful to be able to superimpose the most recent one generated over previous curves measured at the same station on a press turret. The utility of such information can come in the form of determining how well (or poorly) a formulation compresses and whether or not there are content uniformity issues.

The ability to compress a single tablet on presses is not particularly novel. Pharmaceutical research personnel have been doing it for decades, typically on either a single-stroke machine with only one station or on a rotary press that has blank dies installed in all but one station. While both methods work in the most rudimentary sense, they fail to account for one physical phenomenon that is inescapable when developing product on a rotary press: centrifugal force.

Although its effects are largely speed-dependent, there certainly can be causality between centrifugal force and the ability to compress a product to a desired set of criteria. The key here, especially in the eye of the developer, should be how a product compresses at various turret speeds. Some press manufacturers now offer options that allow the user to make use of the single-station format on a rotary press more effectively.

Using only one station on the turret and filling the die cavity manually can tell the software the exact rotational speed at which the press should compress. The result is that in just one revolution, the turret can ramp up to the desired speed, compress and eject the tablet, and provide statistical data for analysis. This method not only increases the usefulness of collected data; it is also suitable for working with miniscule quantities of very expensive product.

Multi-Layer Technology

Whether driven by marketing-based ideas, capacity requirements, or simple physics, there are always unique factors to consider when developing a sound procedure for a repeatable manufacturing process. Certain dosage forms can drive formulators and manufacturers to distraction, and multi-layer tablets often do. The challenges associated with multi-layer tablets are myriad. Issues with how well the different layers bind to one another, concerns with cross-contamination, and a need for optional modes of layer sampling are just a few. Fortunately, modern tablet press manufacturers continue to streamline the processes and options related to this form of compression.

The most common multi-layer dosage form is the double-layer, or bi-layer, product, followed by the triple-layer form. A number of press companies now offer small multi-layer machines that allow pharmaceutical manufacturers to make much more efficient use of valuable product as they work at the developmental stage. There are many reasons for choosing a multi-layer form over a more conventional mono-layer tablet. These can include the desire to keep sustained-release formulations separate from those that offer more immediate bioavailability, aesthetic appeal for consumers, and product line extension. Whatever the reason for gravitating to the form, reliable, desirable results are more easily achievable than ever before.

Developmental equipment for multi-layer use is available in a variety of forms. There are benchtop models and free-standing presses. Some presses offer a more conventional design that makes use of separate feeder assemblies for each granulation that goes into a multi-layer tablet, and there are alternative systems that use an indexing feed system for each layer. Multi-layer compression at this scale is typically most valuable as a study of compression feasibility.

Wash-in-place (WIP) and containment presses. With WIP systems, the bulk of the cleaning will be handled by the equipment, with minimal manual cleaning.

This type of compression can provide valuable insight into whether or not different layers bind together and the finished tablet offers the desired appearance, if that is deemed important. The potential drawback is that most developmental presses use turrets with a comparatively small pitch circle diameter. If dwell time is an important factor for finished tablet quality, then output is generally compromised.

New multi-layer presses at the larger scale definitely offer some distinct advantages, especially as pharmaceutical manufacturers adhere ever more closely to heightened quality. Many new presses offer features that are designed to mitigate the risk of compressing partial or single-layer tablets that may inadvertently make their way into a receptacle designated for acceptable tablets, especially during a first-layer sampling cycle.

Some press companies do this by moving the second-layer feeder back during this interval; some do so by physically moving the lower punches into a position during the sampling cycle in which their tips are almost flush with the die table surface as they pass under the feeder. The latter method ensures a "no-cavity" condition while at the same time reducing any risk associated with moving large components from their ideal set position. The sampling process itself has also been greatly optimized by some press manufacturers.

One new method makes use of a static sampling procedure in which the braking system on the machine stops the turret abruptly when a sample is called for. The turret moves slowly through the first-layer compression cycle, temporarily increasing the hardness so that the samples can be handled and tested, and then automatically returns to production settings. This method can be particularly advantageous, guaranteeing that the samples are filled in the same exact fashion as under production conditions and leading to more representative samples, less waste, and greater efficiencies.

Dealing With Potent Products

Reflection NIR as integrated with a tablet press offers a very different approach than that offered by transmission NIR technology. Installed on a press, a reflection NIR system allows for 100% inspection of tablet product continuity and serves as an in-line tool that can essentially check and verify a product’s chemical fingerprint.

In recent years, the pharmaceutical industry has witnessed increasing numbers of potent products and compounds. The products themselves are becoming more powerful as formulators develop substances that are increasingly effective at providing desired physiological and therapeutic effects. Airborne particulate matter, more than many other substances, can represent a great risk to the equipment operator, particularly in cases in which a formulation contains a high percentage of a potent active drug substance. Historically, handling such compounds resulted in the use of positive-pressure respirators, full-body moon suits, and a variety of other types of personal protective equipment.

These issues led to a need for specifically engineered manufacturing equipment and systems that would offer far greater protection to individuals regularly working with potent compounds. Such systems would also, as a consequence of modern engineering capabilities, lead to the ability to clean the equipment more rapidly.

The marriage of these two issues has led to the creation by some press manufacturers of machines that combine high-containment features with those that fall under the banner of either wash-in-place (WIP) or clean-in-place (CIP). The generally accepted definition of WIP systems implies that the bulk of cleaning will be handled by the equipment itself, with minimal manual cleaning required to finish the process. CIP systems purportedly complete the entire cleaning process by themselves but in practice are often quite challenging to validate reliably.

Modern containment technology found on leading tablet presses will often make use of features—such as glove ports and rapid transfer ports—that allow the user to manipulate the press without breaching the integrity of containment prior to completing a batch (for example, stopping the press to examine or replace a faulty component or tool).

Press manufacturers now offer a variety of research-based software packages and add-ons that facilitate the collection of useful data to ensure quality.

Additionally, it is not uncommon to find features on a WIP/ containment machine that allow the user to gain access to the compression area via the glove ports and make use of manual spray and vacuum wands. These, too, are engineered so that containment is assured at all times during their use. The WIP or CIP systems typically utilize a system of sparging valves and balls for the delivery of various cleaning media, and all parts that come in contact with these materials are generally manufactured from stainless steel. Alternative containment systems include machines that make use of removable compression compartments.

When selecting this type of press, it is imperative to work closely with the chosen vendor to accurately identify all critical criteria, such as the expected occupational exposure limits (OELs), that the system is designed to maintain. Toxicology studies determine the levels of exposure to a given substance that can lead to adverse health-related effects. Often, specific OELs are established only by the company producing a given product and are generally created with the assumption that they apply to healthy adults over an eight-hour workday.

Some tablet press vendors are able to provide proof that they have subjected their containment technology to rigorous surrogate testing, while others are not. When evaluating contained equipment, the prospective buyer should always ask the vendor whether or not it has performed such testing and, provided the vendor has, if the buyer can have a copy of the test results. Companies that do offer this type of technology have, in most cases, applied it to machines across their capacity range, covering both developmental and production sizes.

Analysis for Solid Dose Compression

Pharmaceutical manufacturers will always clamor for faster, more accurate methods of production with a goal of assuring their customers of better overall quality. Not long ago, many manufacturers were encouraged to begin closely evaluating what is known as PAT, or process analytical technology. First proposed by the United States Food and Drug Administration (FDA), PAT is defined by the FDA as "a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality." PAT is, therefore, essentially a framework under which a company develops faster, more accurate in- or on-line methodology for analyzing process results.

A major goal for any manufacturer today is to minimize, to the greatest possible degree, any risk of producing a product that does not meet stringent predefined parameters. Historically, mitigating this risk was achieved through the employment of rigorous end-of-process analytical work, which for a solid dosage form could include the measurement of weight, thickness, and hardness, as well as friability testing. While largely effective for ensuring that a quality product moves to the store shelves, these methods are perhaps not ideal for ensuring overall efficiencies. They are, after all, most often utilized after products are made, rather than during the production process.

A major goal for any manufacturer today is to minimize, to the greatest possible degree, any risk of producing a product that does not meet stringent predefined parameters.

One emerging technology that shows the most promise when applied to in-process quality checking on a rotary tablet press makes use of near infrared (NIR) technology. NIR is a form of spectroscopy that utilizes light with a wavelength ranging from 800 to 2,500 nm. Molecular bands created by the use of NIR technology are typically very broad and therefore inherently complex, necessitating the employment of calibration techniques for multiple wavelengths. The technology is, however, very useful for different types of rapid analysis. Particular formulations will exhibit specific qualities when subjected to an NIR light source, creating a fingerprint that can later be used as a baseline for real-time quality analysis. Depending on the sample being analyzed, NIR light is generally measured in one of two ways, reflection or transmission.

Reflection NIR technology is a method in which light emitted from a source is reflected off of a sample and the resulting spectroscopy is read by an NIR sensor. Utilized on a high-speed rotary tablet press, this form of NIR measurement is suitable for 100% analysis due to its short cycle time. That very same speed, however, may limit the scope of its analytical potential to some degree.

The transmission method of NIR measurement occurs when light emitted from a source passes through a sample and is read by an appropriate sensor on the opposite side of the sample. While inherently slower than the reflection method, transmission can prove to be more accurate from a truly analytical perspective.

Following closely on the heels of the FDA’s suggestion that pharmaceutical manufacturers seriously consider the PAT initiative, some tablet press vendors soon embarked on various endeavors to create technologies embracing the opportunities presented by the use of NIR. It is important to note that some press vendors already offer potential solutions based on both forms of NIR measurement. Where the transmission method is desired, certain devices intended for the measurement of tablet weight, thickness, and hardness are fitted with an NIR measurement cell that can infer the percentage of active pharmaceutical ingredient (API) in finished tablet samples.

These devices deliver tablets chosen for NIR measurement in a rapid, highly controlled fashion, providing the user with comprehensive information about a tablet’s chemical and physical properties. Data recorded by the NIR cell is transferred to the user interface software for inclusion in summary batch reports; if necessary, the measured data can trigger in-process changes in the press for maintaining ideal product specifications.

Reflection NIR, as integrated with a tablet press, offers a very different approach than that offered by transmission NIR technology. Installed on a press, a reflection NIR system allows for 100% inspection of tablet product continuity and serves as an in-line tool that can essentially check and verify a product’s chemical fingerprint. Light information detected by the receiver can be compared to a baseline spectrum that is representative of that emitted by the product’s ideal composition when subjected to NIR radiation. The system allows for contact-free, non-destructive analysis of the content uniformity of active ingredients.

The modern tablet press market is extremely competitive, and the various manufacturers try hard to develop products that allow them to differentiate themselves from one another. Those who benefit the most from this competition are, of course, the end users. The leading press companies have made increasingly conscious efforts to engineer solutions in direct response to specific requests from their clients. Presses that allow a dizzying amount of flexibility for running a wide array of different products in highly variable quantities are now appearing on the market.

Much effort is focused on optimizing the safety and security of both the operator and the data generated by a machine, and the most reputable vendors offer more comprehensive assistance than ever before when it comes to the generation and customization of qualification documentation. Tablet presses play an integral role in modern pharmaceutical manufacturing, and their manufacturers seem poised to keep it that way.

Bundenthal is a technical writer for Fette America, Inc. Reach him at mbundenthal@embarqmail.com or (919) 567-1001.

Production of Tablets in Pharmaceutical Manufacturing

• Dispensing
• Post Hoists
• Blending
• Granulation & Drying
• Tablet Compression
• Containment Interfaces (Hicoflex®)
• Tablet Coating

A description of the work on Precision-Granulation™ by GEA Pharma Systems and the Department of Pharmacy of the National University of Singapore and p

Precision-Granulation™ as an Alternative Granulation Method

Paper by Celine Liew, Kim Walter, Anthony Wigmore, Albert Brzeczko and Paul WS Heng

Introduction
Fluid Bed Granulation and High Shear Granulation are presently the most important wet granulation techniques employed in the pharmaceutical industry. Precision-Granulation™, a new fluid bed bottom spray method, is evaluated for comparison with the conventional granulation methods.

Objectives

1. To compare Precision-Granulation™ with Top Spray Fluid Bed Granulation and High Shear Granulation for tabletting.
2. To investigate the influence of four selected process variables, atomizing air pressure, column velocity, insert diameter and air cap area/opening, in Precision-Granulation™.
3. To prepare Acetaminophen granules by Precision-Granulation™ and Top Spray Fluid Bed Granulation.

Materials

Table 1- Formulations used in the granulation studies

Study	Part 1	Part 2	Part 1	Part 1	Part 3
Material	Formulation A1 (%)	Formulation A2 (%)	Formulation B (%)	Formulation C (%)	Formulation D (%)
Lactose 200M* (Pharmatose 200M, DMV)	88	88	-	-	-
Lactose 450M* (Pharmatose 450M, DMV)	-	-	88	-	-
Powdered sugar	-	-	-	88	-
Acetaminophen (Mallinckrodt)	-	-	-	-	88
Povidone / Polyvinyl pyrrolidone (aKollidon 30, BASF; bPlasdone K29/32, ISP)	5a	5b	5a	5a	5b
Microcrystalline cellulose (Avicel PH-101, FMC)	5	5	5	5	5
Crospovidone (Polyplasdone XL10, ISP)	2	2	2	2	2

*From DMV product literature:
- Lactose 200M - average particle size 0.040 mm; % <0.045>

Schematic diagrams of components of the Precision Granulator™ and image of the MP-1™ with Precision-Granulation™ module.

REFERENCES
1. O. Worts, Wet Granulation - Fluidized Bed and High Shear Techniques Compared, Pharm. Tech. Europe, 10(11), 27-28,30 (1998).
2. K.T. Walter, A Process for Granulation of a Particulate Material. European Patent 1064990 (2001).
3. T. Kawaguchi, H. Sunada, Y. Yonezawa, K. Danjo, M. Hasegawa, T. Makino, H. Sakamoto, K. Fujita, T. Tanino and H. Kokubo,Granulation of Acetaminophen by a Rotating Fluidized-Bed Granulator, Pharm. Dev. Tech., 5(2), 141-151 (2000).