Editing Tablet (pharmacy) (section)

==Manufacturing==
{{Also|Pharmaceutical manufacturing}}

===Manufacture of the tableting blend===
In the tablet pressing process, the appropriate amount of active ingredient must be in each tablet.  Hence, all the ingredients should be well mixed. If a sufficiently homogenous mix of the components cannot be obtained with simple blending processes, 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 granulate powders for compression into tablets: wet granulation and dry granulation.  Powders that can be mixed well do not require granulation and can be compressed into tablets through direct compression ("DC"). Direct compression is desirable as it is quicker. There is less processing, equipment, labor, and energy consumption. However, DC is difficult when a formulation has a high content of poorly compressible active ingredients.

===Wet granulation===
Wet granulation is a process of using a liquid binder to lightly agglomerate the powder mixture.  The amount of liquid has to be properly controlled, as over-wetting will cause the granules to be too hard and under-wetting will cause them to be too soft and friable. Aqueous solutions have the advantage of being safer to deal with than solvent-based systems but may not be suitable for drugs which are degraded by hydrolysis.

; Procedure
# The active ingredient and excipients are weighed and mixed.
# The wet granulate is prepared by adding the liquid binder–adhesive to the powder blend and mixing thoroughly. Examples of binders/adhesives include aqueous preparations of cornstarch, natural gums such as acacia, cellulose derivatives such as methyl cellulose, [[gelatin]], and povidone.
# Screening the damp mass through a mesh to form pellets or granules.
# Drying the granulation.  A conventional tray-dryer or fluid-bed dryer are most commonly used.
# After the granules are dried, they are passed through a screen of smaller size than the one used for the wet mass to create granules of uniform size.

Low shear wet granulation processes use very simple mixing equipment, and can take a considerable time to achieve a uniformly mixed state.  High shear wet granulation processes use equipment that mixes the powder and liquid at a very fast rate, and thus speeds up the manufacturing process. Fluid bed granulation is a multiple-step wet granulation process performed in the same vessel to pre-heat, granulate, and dry the powders.  It is used because it allows close control of the granulation process.

===Dry granulation===
Dry granulation processes create granules by light compaction of the powder blend under low pressures. The compacts so-formed are broken up gently to produce granules (agglomerates). This process is often used when the product to be granulated is sensitive to moisture and heat. Dry granulation can be conducted on a tablet press using slugging tooling or on a roll press called a roller compactor. Dry granulation equipment offers a wide range of pressures to attain proper densification and granule formation. Dry granulation is simpler than wet granulation, therefore the cost is reduced. However, dry granulation often produces a higher percentage of fine granules, which can compromise the quality or create yield problems for the tablet. Dry granulation requires drugs or excipients with cohesive properties, and a 'dry binder' may need to be added to the formulation to facilitate the formation of granules.

===Hot melt extrusion===
Hot melt extrusion is utilized in pharmaceutical solid oral dose processing to enable delivery of drugs with poor solubility and [[bioavailability]]. Hot melt extrusion has been shown to molecularly disperse poorly soluble drugs in a polymer carrier increasing dissolution rates and bioavailability. The process involves the application of heat, pressure and agitation to mix materials together and 'extrude' them through a die. Twin-screw high shear extruders blend materials and simultaneously break up particles. The extruded particles can then be blended and compressed into tablets or filled into capsules.<ref>{{cite web|title=Extrusion Speheronisation|url=http://www.pharmacmc.com/extrusion-spheronisation/|website=PharmaCMC.com|access-date=26 September 2016|url-status=dead|archive-url=https://web.archive.org/web/20161001113908/http://www.pharmacmc.com/extrusion-spheronisation/|archive-date=1 October 2016}}</ref>

===Granule lubrication===
After granulation, a final lubrication step is used to ensure that the tableting blend does not stick to the equipment during the tableting process.  This usually involves low shear blending of the granules with a powdered lubricant, such as [[magnesium stearate]] or [[stearic acid]].

===Manufacture of the tablets===
[[File:Tabletfailure.jpg|thumb|right|Tablets that failed due to capping and lamination compared to a normal tablet]]

Whatever process is used to make the tableting blend, the process of making a tablet by powder compaction is very similar.  First, the powder is filled into the die from above.  The mass of powder is determined by the position of the lower punch in the die, the cross-sectional area of the die, and the powder density.  At this stage, adjustments to the tablet weight are normally made by repositioning the lower punch.  After die filling, the upper punch is lowered into the die and the powder is uniaxially compressed to a porosity of between 5 and 20%.  The compression can take place in one or two stages (main compression, and, sometimes, pre-compression or tamping) and for commercial production occurs very fast (500–50 [[millisecond|ms]] per tablet). Finally, the upper punch is pulled up and out of the die (decompression), and the tablet is ejected from the die by lifting the lower punch until its upper surface is flush with the top face of the die.  This process is repeated for each tablet.

Common problems encountered during tablet manufacturing operations include:

* Fluctuations in tablet weight, usually caused by uneven powder flow into the die due to poor powder flow properties.
* Fluctuations in dosage of the Active Pharmaceutical Ingredient, caused by uneven distribution of the API in the tableting blend (either due to poor mixing or separation in process).
* Sticking of the powder blend to the tablet tooling, due to inadequate lubrication, worn or dirty tooling, or a sticky powder formulation
* Capping, lamination or chipping.  This is caused by air being compressed with the tablet formulation and then expanding when the punch is released: if this breaks the tablet apart, it can be due to incorrect machine settings, or due to incorrect formulation: either because the tablet formulation is too brittle or not adhesive enough, or because the powder being fed to the tablet press contains too much air (has too low bulk density).
* Capping can also occur due to high moisture content.

Consequently, permanent consistency checks are required during the manufacturing process.<ref>{{cite journal|title=Rapid tablet swelling and disintegration during exposure to brightness-mode ultrasound|vauthors=Carlson CS, Anderton N, Pohl A, Smith AJ, Kudo N, Postema M|journal=Japanese Journal of Applied Physics|volume=61|issue=SG|pages=SG1030|doi=10.35848/1347-4065/ac467f|url=https://hal.science/hal-03503073v1/file/Carlson%2Bet%2Bal_2021_Jpn._J._Appl._Phys._10.35848_1347-4065_ac467f.pdf}}</ref>

===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. Initial quantities of active pharmaceutical ingredients are very expensive to produce, and using a Compaction Simulator reduces the amount of powder required for product development.

===Tablet presses===
[[Image:Tablet press animation.gif|thumb|The tablet pressing operation (click image to enlarge)]]
[[Image:Old tablet press.jpg|thumb|upright|An old Cadmach rotary tablet press]]

[[Tablet press]]es, also called tableting machines, range from small, inexpensive bench-top models that make one tablet at a time (single-station presses), with only around a half-ton pressure, to large, computerized, industrial models (multi-station rotary presses) that can make hundreds of thousands to millions of tablets an hour with much greater pressure. The tablet press is an essential piece of machinery for any pharmaceutical and nutraceutical manufacturer. Tablet presses must allow the operator to adjust the position of the lower and upper punches accurately, so that the tablet weight, thickness and density/hardness can each be controlled. This is achieved using a series of cams, rollers, or tracks that act on the tablet tooling (punches).  Mechanical systems are also incorporated for die filling, and for ejecting and removing the tablets from the press after compression.  Pharmaceutical tablet presses are required to be easy to clean and quick to reconfigure with different tooling, because they are usually used to manufacture many different products.
There are two main standards of tablet tooling used in pharmaceutical industry: American standard TSM and European standard EU. TSM and EU configurations are similar to each other but cannot be interchanged.<ref>{{cite web|url=http://apteka95.com.ua/en/directions/1861/|title=Articles :: ГК "Аптека-95"|url-status=live|archive-url=https://web.archive.org/web/20140127040853/http://apteka95.com.ua/en/directions/1861/|archive-date=2014-01-27}}</ref>

Modern tablet presses reach output volumes of up to 1,700,000 tablets per hour. These huge volumes require frequent in-process quality control for the tablet weight, thickness and hardness. Due to efforts to reduce rejects rates and machine down-time, automated tablet testing devices are used on-line with the tablet press or off-line in the IPC-labs.

===Tablet coating===
{{See also|Film 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<ref>Gendre C., Genty M., César da Silva J., Tfayli A., Boiret M., Lecoq O., Baron M., Chaminade P., Péan J-M., Comprehensive study of dynamic curing effect on tablet coating structure, Eur. J. Pharm. Biopharm., 81 (2012), 657-665</ref> are [[polymer]] and [[polysaccharide]] based, with [[plasticizer]]s and [[pigment]]s 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 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. 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 less acidic area 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 [[controlled release|control the rate of dissolution]] of the drug in the gastrointestinal tract. Some drugs are absorbed better in certain parts of the digestive system. If this part is the stomach, a coating is selected that dissolves quickly and easily in acid. If the rate of absorption is best in the large intestine or colon, a coating is used that is acid resistant and dissolves slowly to ensure that the tablet reaches that point before dispersing. To measure the disintegration time of the tablet coating and the tablet core, automatic disintegration testers are used which are able to determine the complete disintegration process of a tablet by measuring the rest height of the thickness with every upward stroke of the disintegration tester basket.

There are two types of coating machines used in the pharmaceutical industry: coating pans and automatic coaters.<ref>[http://apteka95.com.ua/en/directions/1806/ Coating machines] {{webarchive|url=https://web.archive.org/web/20120328095614/http://apteka95.com.ua/en/directions/1806/ |date=2012-03-28 }}, apteka95.com</ref> Coating pans are used mostly to sugar coat pellets. Automatic coaters are used for all kinds of coatings; they can be equipped with a remote control panel, a dehumidifier, and dust collectors. An explosion-proof design is required for applying coatings that contain alcohol.

===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 splitting|pill-splitters]] which cut unscored and scored tablets. Tablets with special coatings (for example, enteric coatings or [[controlled release|controlled-release]] coatings) should not be broken before use, as this exposes the tablet core to the digestive juices, circumventing the intended delayed-release effect.