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 cap ...

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 A suppository is a dosage form used to deliver medications by insertion into a body orifice where it dissolves or melts to exert local or systemic effects. There are three types of suppositories, each to insert into a different sections: rectal su ...

. 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 Kingdom (biology), biological kingdom Animalia. With few exceptions, animals Heterotroph, consume organic material, Cellular respiration#Aerobic respiration, breathe oxygen, are Motilit ...

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, respo ...

(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 wa ...

s or their derivatives (such as

carrageenan Carrageenans or carrageenins ( ; ) are a family of natural linear sulfated polysaccharides that are extracted from red edible seaweeds. Carrageenans are widely used in the food industry, for their gelling, thickening, and stabilizing properties. T ...

s 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 diets ...

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 wall ...

). 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 ...

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 alcohol g ...

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 by ...

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 s ...

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 Blow molding (or moulding) is a manufacturing process for forming hollow plastic parts. It is also used for forming glass bottles or other hollow shapes. In general, there are three main types of blow molding: extrusion blow molding, injection ...

. 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 ingredient An active ingredient is any ingredient that provides biologically active or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the body of humans or animals. T ...

s 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 Ring binders (loose leaf binders, looseleaf binders, or sometimes called files in Britain) are large folders that contain file folders or hole punched papers. These binders come in various sizes and can accommodate an array of paper sizes. The ...

, disintegrants, fillers,

glidant A glidant is a substance that is added to a powder to improve its flowability. A glidant will only work at a certain range of concentrations. Above a certain concentration, the glidant will in fact function to inhibit flowability. In tablet manufa ...

, and preservatives.

Manufacturing materials

''Gelatin capsules'', informally called ''gel caps'' or ''gelcaps'', are composed of

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 whole ...

of animal skin or bone. ''Vegetable capsules'', introduced in 1989, are made from

, a structural component in plants. The main ingredient of vegetarian capsules is

hydroxypropyl methyl cellulose Hypromellose (INN), short for hydroxypropyl methylcellulose (HPMC), is a semisynthetic, inert, viscoelastic polymer used in eye drops, as well as an excipient and controlled-delivery component in oral medicaments, found in a variety of commercia ...

. 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 A die is a specialized machine tool used in manufacturing industries to cut and/or form material to a desired shape or profile. Stamping dies are used with a press, as opposed to drawing dies (used in the manufacture of wire) and casting dies ( ...

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 incl ...

(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 Ullage or headspace is the unfilled space in a container, particularly with a liquid. Etymology The word ''ullage'' comes from the Latin word ''oculus'', used by the Romans to refer to a barrel cork hole. This word was, in turn, taken in medieval ...

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.

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