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Capsules are solid dosage forms in which the drug is enclosed within either a hard or soft soluble container or “shell.” The shells are usually formed from gelatin; however, they also may be made from starch or other suitable substances. Hard-shell capsule sizes range from No. 5, the smallest, to No. 000, which is the largest, except for veterinary sizes. However, size No. 00 generally is the largest size acceptable to patients. Size 0 hard gelatin capsules having an elongated body (known as size OE) also are available, which provide greater fill capacity without an increase in diameter. Hard gelatin capsules consist of two, telescoping cap and body pieces. Generally, there are unique grooves or indentations molded into the cap and body portions to provide a positive closure when fully engaged, which helps prevent the accidental separation of the filled capsules during shipping and handling. Positive closure also may be affected by spot fusion (“welding”) of the cap and body pieces together through direct thermal means or by application of ultrasonic energy. Factory-filled hard gelatin capsules may be completely sealed by banding, a process in which one or more layers of gelatin are applied over the seam of the cap and body, or by a liquid fusion process wherein the filled capsules are wetted with a hydroalcoholic solution that penetrates into the space where the cap overlaps the body, and then dried. Hard-shell capsules made from starch consist of two, fitted cap and body pieces. Since the two pieces do not telescope or interlock positively, they are sealed together at the time of filling to prevent their separation. Starch capsules are sealed by the application of a hydroalcoholic solution to the recessed section of the cap immediately prior to its being placed onto the body.
The banding of hard-shell gelatin capsules or the liquid sealing of hard-shell starch capsules enhances consumer safety by making the capsules difficult to open without causing visible, obvious damage, and may improve the stability of contents by limiting O2 penetration. Industrially filled hard-shell capsules also are often of distinctive color and shape or are otherwise marked to identify them with the manufacturer. Additionally, such capsules may be printed axially or radially with strengths, product codes, etc. Pharmaceutical-grade printing inks are usually based on shellac and employ FDA-approved pigments and lake dyes.
In extemporaneous prescription practice, hard-shell capsules may be hand-filled; this permits the prescriber a latitude of choice in selecting either a single drug or a combination of drugs at the exact dosage level considered best for the individual patient. This flexibility gives hard-shell capsules an advantage over compressed tablets and soft-shell capsules as a dosage form. Hard-shell capsules are usually formed from gelatins having relatively high gel strength. Either type may be used, but blends of pork skin and bone gelatin are often used to optimize shell clarity and toughness. Hard-shell capsules also may be formed from starch or other suitable substances. Hard-shell capsules may also contain colorants, such as D&C and FD&C dyes or the various iron oxides, opaquing agents such as titanium dioxide, dispersing agents, hardening agents such as sucrose, and preservatives. They normally contain between 10% and 15% water.
Hard gelatin capsules are made by a process that involves dipping shaped pins into gelatin solutions, after which the gelatin films are dried, trimmed, and removed from the pins, and the body and cap pieces are joined. Starch capsules are made by injection molding a mixture of starch and water, after which the capsules are dried. A separate mold is used for caps and bodies, and the two parts are supplied separately. The empty capsules should be stored in tight containers until they are filled. Since gelatin is of animal origin and starch is of vegetable origin, capsules made with these materials should be protected from potential sources of microbial contamination.
Hard-shell capsules typically are filled with powder, beads, or granules. Inert sugar beads (nonpareils) may be coated with active ingredients and coating compositions that provide extended-release profiles or enteric properties. Alternatively, larger-dose active ingredients themselves may be suitably formed into pellets and then coated. Semisolids or liquids also may be filled into hard-shell capsules; however, when the latter are encapsulated, one of the sealing techniques must be employed to prevent leakage.
In hard gelatin capsule filling operations, the body and cap of the shell are separated prior to dosing. In hard starch shell filling operations, the bodies and caps are supplied separately and are fed into separate hoppers of the filling machine. Machines employing various dosing principles may be employed to fill powders into hard-shell capsules; however, most fully automatic machines form powder plugs by compression and eject them into empty capsule bodies. Accessories to these machines generally are available for the other types of fills. Powder formulations often require adding fillers, lubricants, and glidants to the active ingredients to facilitate encapsulation. The formulation, as well as the method of filling, particularly the degree of compaction, may influence the rate of drug release. The addition of wetting agents to the powder mass is common where the active ingredient is hydrophobic. Disintegrants also may be included in powder formulations to facilitate deaggregation and dispersal of capsule plugs in the gut. Powder formulations often may be produced by dry blending; however, bulky formulations may require densification by roll compaction or other suitable granulation techniques.
Powder mixtures that tend to liquefy may be dispensed in hard-shell capsules if an absorbent such as magnesium carbonate, colloidal silicon dioxide, or other suitable substance is used. Potent drugs are often mixed with an inert diluent before being filled into capsules. Where two mutually incompatible drugs are prescribed together, it is sometimes possible to place one in a small capsule and then enclose it with the second drug in a larger capsule. Incompatible drugs also can be separated by placing coated pellets or tablets, or soft-shell capsules of one drug into the capsule shell before adding the second drug.
Thixotropic semisolids may be formed by gelling liquid drugs or vehicles with colloidal silicas or powdered high molecular weight polyethylene glycols. Various waxy or fatty compounds may be used to prepare semisolid matrices by fusion.
Soft-shell capsules made from gelatin (sometimes called softgels) or other suitable material require large-scale production methods. The soft gelatin shell is somewhat thicker than that of hard-shell capsules and may be plasticized by the addition of a polyol such as sorbitol or glycerin. The ratio of dry plasticizer to dry gelatin determines the “hardness” of the shell and may be varied to accommodate environmental conditions as well as the nature of the contents. Like hard shells, the shell composition may include approved dyes and pigments, opaquing agents such as titanium dioxide, and preservatives. Flavors may be added and up to 5% sucrose may be included for its sweetness and to produce a chewable shell. Soft gelatin shells normally contain 6% to 13% water. Soft-shell capsules also may be printed with a product code, strength, etc. In most cases, soft-shell capsules are filled with liquid contents. Typically, active ingredients are dissolved or suspended in a liquid vehicle. Classically, an oleaginous vehicle such as a vegetable oil was used; however, nonaqueous, water-miscible liquid vehicles such as the lower-molecular-weight polyethylene glycols are more common today due to fewer bioavailability problems.
Available in a wide variety of sizes and shapes, soft-shell capsules are both formed, filled, and sealed in the same machine; typically, this is a rotary die process, although a plate process or reciprocating die process also may be employed. Soft-shell capsules also may be manufactured in a bubble process that forms seamless spherical capsules. With suitable equipment, powders and other dry solids also may be filled into soft-shell capsules.
Liquid-filled capsules of either type involve similar formulation technology and offer similar advantages and limitations. For instance, both may offer advantages over dry-filled capsules and tablets in content uniformity and drug dissolution. Greater homogeneity is possible in liquid systems, and liquids can be metered more accurately. Drug dissolution may benefit because the drug may already be in solution or at least suspended in a hydrophilic vehicle. However, the contact between the hard or soft shell and its liquid content is more intimate than exists with dry-filled capsules, and this may enhance the chances for undesired interactions. The liquid nature of capsule contents presents different technological problems than dry-filled capsules in regard to disintegration and dissolution testing. From formulation, technological, and biopharmaceutical points of view, liquid-filled capsules of either type have more in common than liquid-filled and dry-filled capsules having the same shell composition. Thus, for compendial purposes, standards and methods should be established based on capsule contents rather than on whether the contents are filled into hard- or soft-shell capsules.
Capsules may be coated, or, more commonly, encapsulated granules may be coated to resist releasing the drug in the gastric fluid of the stomach where a delay is important to alleviate potential problems of drug inactivation or gastric mucosal irritation. The term “delayed-release” is used for Pharmacopeial monographs on enteric coated capsules that are intended to delay the release of medicament until the capsule has passed through the stomach, and the individual monographs include tests and specifications for Drug release (see Drug Release 724) or Disintegration (see Disintegration 701).
Extended-release capsules are formulated in such manner as to make the contained medicament available over an extended period of time following ingestion. Expressions such as “prolonged-action,” “repeat-action,” and “sustained-release” have also been used to describe such dosage forms. However, the term “extended-release” is used for Pharmacopeial purposes and requirements for Drug release (see Drug Release 724) typically are specified in the individual monographs.