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In the manufacture of pharmaceuticals, encapsulation refers to a range of
dosage form Dosage forms (also called unit doses) are pharmaceutical drug products in the form in which they are marketed for use, with a specific mixture of active ingredients and inactive components (excipients), in a particular configuration (such as a ca ...
s—techniques used to enclose medicines—in a relatively stable shell known as a capsule, allowing them to, for example, be taken orally or be used as suppositories. The two main types of capsules are: * Hard-shelled capsules, which contain dry, powdered ingredients or miniature pellets made by ''e.g.'' processes of
extrusion Extrusion is a process used to create objects of a fixed cross-sectional profile by pushing material through a die of the desired cross-section. Its two main advantages over other manufacturing processes are its ability to create very complex c ...
or spheronization. These are made in two halves: a smaller-diameter “body” that is filled and then sealed using a larger-diameter “cap”. * Soft-shelled capsules, primarily used for oils and for active ingredients that are dissolved or suspended in oil. Both of these classes of capsules are made from aqueous solutions of gelling agents, such as
animal Animals are multicellular, eukaryotic organisms in the biological kingdom Animalia. With few exceptions, animals consume organic material, breathe oxygen, are able to move, can reproduce sexually, and go through an ontogenetic stage ...
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
(mainly
gelatin Gelatin or gelatine (from la, gelatus meaning "stiff" or "frozen") is a translucent, colorless, flavorless food ingredient, commonly derived from collagen taken from animal body parts. It is brittle when dry and rubbery when moist. It may also ...
) or plant
polysaccharide Polysaccharides (), or polycarbohydrates, are the most abundant carbohydrates found in food. They are long chain polymeric carbohydrates composed of monosaccharide units bound together by glycosidic linkages. This carbohydrate can react with w ...
s or their derivatives (such as carrageenans and modified forms of
starch Starch or amylum is a polymeric carbohydrate consisting of numerous glucose units joined by glycosidic bonds. This polysaccharide is produced by most green plants for energy storage. Worldwide, it is the most common carbohydrate in human die ...
and
cellulose Cellulose is an organic compound with the formula , a polysaccharide consisting of a linear chain of several hundred to many thousands of β(1→4) linked D-glucose units. Cellulose is an important structural component of the primary cell wa ...
). Other ingredients can be added to the gelling agent solution including
plasticizer A plasticizer ( UK: plasticiser) is a substance that is added to a material to make it softer and more flexible, to increase its plasticity, to decrease its viscosity, and/or to decrease friction during its handling in manufacture. Plasticiz ...
s such as
glycerin Glycerol (), also called glycerine in British English and glycerin in American English, is a simple triol compound. It is a colorless, odorless, viscous liquid that is sweet-tasting and non-toxic. The glycerol backbone is found in lipids known ...
or
sorbitol Sorbitol (), less commonly known as glucitol (), is a sugar alcohol with a sweet taste which the human body metabolizes slowly. It can be obtained by reduction of glucose, which changes the converted aldehyde group (−CHO) to a primary alcoho ...
to decrease the capsule's hardness, coloring agents,
preservative A preservative is a substance or a chemical that is added to products such as food products, beverages, pharmaceutical drugs, paints, biological samples, cosmetics, wood, and many other products to prevent decomposition by microbial growth or b ...
s, disintegrants,
lubricant A lubricant (sometimes shortened to lube) is a substance that helps to reduce friction between surfaces in mutual contact, which ultimately reduces the heat generated when the surfaces move. It may also have the function of transmitting forces, t ...
s and
surface treatment Surface finishing is a broad range of industrial processes that alter the surface of a manufactured item to achieve a certain property. Finishing processes may be employed to: improve appearance, adhesion or wettability, solderability, corrosion re ...
. Since their inception, capsules have been viewed by consumers as the most efficient method of taking medication . For this reason, producers of drugs such as OTC analgesics wanting to emphasize the strength of their product developed the “caplet”, a
portmanteau A portmanteau word, or portmanteau (, ) is a blend of wordstablet Tablet may refer to: Medicine * Tablet (pharmacy), a mixture of pharmacological substances pressed into a small cake or bar, colloquially called a "pill" Computing * Tablet computer, a mobile computer that is primarily operated by touching the ...
pills, as well as being an easier-to-swallow shape than the usual disk-shaped tablet medication.


Single-piece gel encapsulation ("soft capsules")

In 1833, Mothes and Dublanc were granted a patent for a method to produce a single-piece gelatin capsule that was sealed with a drop of gelatin solution. They used individual iron molds for their process, filling the capsules individually with a medicine dropper. Later on, methods were developed that used sets of plates with pockets to form the capsules. Although some companies still use this method, the equipment is no longer produced commercially. All modern soft-gel encapsulation uses variations of a process developed by R. P. Scherer in 1933. His innovation used a rotary die to produce the capsules. They were then filled by blow molding. This method was high-yield, consistent, and reduced waste. Softgels can be an effective delivery system for oral drugs, especially poorly soluble drugs. This is because the fill can contain liquid ingredients that help increase the solubility or permeability of the drug across the membranes in the body. Liquid ingredients are difficult to include in any other solid dosage form such as a tablet. Softgels are also highly suited to potent drugs (for example, where the dose is <100 µg), where the highly reproducible filling process helps ensure each softgel has the same drug content, and because the operators are not exposed to any drug dust during the manufacturing process. In 1949, the Lederle Laboratories division of the
American Cyanamid Company American Cyanamid Company was a leading American conglomerate which became one of the nation's top 100 manufacturing companies during the 1970s and 1980s, according to the Fortune 500 listings at the time. It started in fertilizer, but added ...
developed the "Accogel" process, allowing powders to be accurately filled into soft gelatin capsules.


Two-piece gel encapsulation ("hard capsules")

James Murdoch of London patented the two-piece telescoping gelatin capsule in 1847. The capsules are made in two parts by dipping metal pins in the gelling agent solution. The capsules are supplied as closed units to the pharmaceutical manufacturer. Before use, the two halves are separated, and the capsule is filled with powder or more normally pellets made by the process of extrusion and spheronization (either by placing a compressed slug of powder into one half of the capsule or by filling one half of the capsule with loose powder) and the other half of the capsule is pressed on. With the compressed slug method, weight varies less between capsules. However, the machinery required to manufacture them is more complex. The powder or spheroids inside the capsule contains the active ingredients and any
excipient An excipient is a substance formulated alongside the active ingredient of a medication, included for the purpose of long-term stabilization, bulking up solid formulations that contain potent active ingredients in small amounts (thus often referred ...
s, such as binders, disintegrants, fillers, glidant, and preservatives.


Manufacturing materials

''Gelatin capsules'', informally called ''gel caps'' or ''gelcaps'', are composed of
gelatin Gelatin or gelatine (from la, gelatus meaning "stiff" or "frozen") is a translucent, colorless, flavorless food ingredient, commonly derived from collagen taken from animal body parts. It is brittle when dry and rubbery when moist. It may also ...
manufactured from the
collagen Collagen () is the main structural protein in the extracellular matrix found in the body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whol ...
of animal skin or bone. ''Vegetable capsules'', introduced in 1989, are made from
cellulose Cellulose is an organic compound with the formula , a polysaccharide consisting of a linear chain of several hundred to many thousands of β(1→4) linked D-glucose units. Cellulose is an important structural component of the primary cell wa ...
, a structural component in plants. The main ingredient of vegetarian capsules is hydroxypropyl methyl cellulose. In the
21st century The 21st (twenty-first) century is the current century in the ''Anno Domini'' era or Common Era, under the Gregorian calendar. It began on 1 January 2001 ( MMI) and will end on 31 December 2100 ( MMC). Marking the beginning of the 21st centur ...
, gelatin capsules are more broadly used than vegetarian capsules because the cost of production is lower.


Manufacturing equipment

The process of encapsulation of hard gelatin capsules can be done on manual, semi-automatic, and automatic capsule filling machines. Hard gelatin capsules are manufactured by the dipping method which is dipping, rotation, drying, stripping, trimming, and joining. Softgels are filled at the same time as they are produced and sealed on the rotary die of a fully automatic machine. Capsule fill weight is a critical attribute in encapsulation and various real-time fill weight monitoring techniques such as
near-infrared spectroscopy Near-infrared spectroscopy (NIRS) is a spectroscopic method that uses the near-infrared region of the electromagnetic spectrum (from 780 nm to 2500 nm). Typical applications include medical and physiological diagnostics and research inc ...
(NIR) and
vibrational spectroscopy Infrared spectroscopy (IR spectroscopy or vibrational spectroscopy) is the measurement of the interaction of infrared radiation with matter by absorption, emission, or reflection. It is used to study and identify chemical substances or function ...
are used, as well as in-line weight checks, to ensure product quality. Volume is measured to the fill line, which is customary to the top of the smaller-diameter body half. After capping, some ullage volume (air space) remains in the finished capsule.


Standard sizes of two-piece capsules


Drug-embedded empty capsule shells

A new class of capsules has been developed whereby drugs can be embedded in the capsule shell matrix. This allows different drugs to be delivered using the same capsule. The drug might be in a solubilized form, suspended form or chemically bound form in the capsule shell matrix. The drug can be in the cap of the capsule, the body of the capsule or in both body and cap of the capsule. One can embed more than one drug in the capsule shell matrix. The drug can be in the dissolved and suspended form in the capsule shell matrix. Thus, one can create various types of variations in these "drug-embedded capsules". The rate of release of drug can vary based on the way the drug is embedded in the capsule shell matrix and drug properties.Joshi, H.N., 2018. Physically dispersed, molecularly dissolved and/or chemically bound drugs in an empty, hard capsule shell composition. U.S. Patent 9,884,024.


See also

*
Capsule endoscopy Capsule endoscopy is a medical procedure used to record internal images of the gastrointestinal tract for use in disease diagnosis. Newer developments are also able to take biopsies and release medication at specific locations of the entire g ...
*
OROS The osmotic-controlled release oral delivery system (OROS) is an advanced controlled release oral drug delivery system in the form of a rigid tablet with a semi-permeable outer membrane and one or more small laser drilled holes in it. As the tab ...
*
Pharmacy Automation - The Tablet Counter Pharmacy automation involves the mechanical processes of handling and distributing medications. Any pharmacy task may be involved, including counting small objects (e.g., tablets, capsules); measuring and mixing powders and liquids for compoundi ...
*
Pharmaceutical formulation Pharmaceutical formulation, in pharmaceutics, is the process in which different chemical substances, including the active drug, are combined to produce a final medicinal product. The word ''formulation'' is often used in a way that includes dosage ...
* Pill splitting *
Tablet Tablet may refer to: Medicine * Tablet (pharmacy), a mixture of pharmacological substances pressed into a small cake or bar, colloquially called a "pill" Computing * Tablet computer, a mobile computer that is primarily operated by touching the ...
* Oblaat


References

* *Hemant N. Joshi, US Patent #8,728,521 (May 20, 2014). *Hemant N. Joshi, US Patent # 9,884,024 (February 6, 2018). *Hemant N. Joshi, US Patent # 10,357,461 (July 23, 2019). *Harshada Sant, MS, "Joshi Capsules" US Patent Numbers # 8,728,521 and # 9,884,024, American Pharmaceutical Review, Page 60, April 2018. {{Dosage forms, state=expanded Pharmaceutical industry Drug delivery devices Dosage forms Articles containing video clips