AEROSOLS
Pharmaceutical aerosols are products that are packaged under pressure and contain therapeutically active ingredients that are released upon activation of an appropriate valve system. They are intended for topical application to the skin as well as local application into the nose (nasal aerosols), mouth (lingual aerosols), or lungs (inhalation aerosols). These products may be fitted with valves enabling either continuous or metered-dose delivery; hence, the terms “[DRUG] Metered Topical Aerosols,” “[DRUG] Metered Nasal Aerosols,” etc.
The term “aerosol” refers to the fine mist of spray that results from most pressurized systems. However, the term has been broadly misapplied to all self-contained pressurized products, some of which deliver foams or semisolid fluids. In the case of Inhalation Aerosols, the particle size of the delivered medication must be carefully controlled, and the average size of the particles should be under 5 µm. These products are also known as metered-dose inhalers (MDIs). Other aerosol sprays may contain particles up to several hundred micrometers in diameter.
The basic components of an aerosol system are the container, the propellant, the concentrate containing the active ingredient(s), the valve, and the actuator. The nature of these components determines such characteristics as particle size distribution, uniformity of dose for metered valves, delivery rate, wetness and temperature of the spray, spray pattern and velocity or plume geometry, foam density, and fluid viscosity.
Types of Aerosols
Aerosols consist of two-phase (gas and liquid) or three-phase (gas, liquid, and solid or liquid) systems. The two-phase aerosol consists of a solution of active ingredients in liquefied propellant and the vaporized propellant. The solvent is composed of the propellant or a mixture of the propellant and cosolvents such as alcohol, propylene glycol, and polyethylene glycols, which are often used to enhance the solubility of the active ingredients.
Three-phase systems consist of a suspension or emulsion of the active ingredient(s) in addition to the vaporized propellants. A suspension consists of the active ingredient(s) that may be dispersed in the propellant system with the aid of suitable excipients such as wetting agents and/or solid carriers such as talc or colloidal silicas.
A foam aerosol is an emulsion containing one or more active ingredients, surfactants, aqueous or nonaqueous liquids, and the propellants. If the propellant is in the internal (discontinuous) phase (i.e., of the oil-in-water type), a stable foam is discharged; and if the propellant is in the external (continuous) phase (i.e., of the water-in-oil type), a spray or a quick-breaking foam is discharged.
Propellants
The propellant supplies the necessary pressure within an aerosol system to expel material from the container and, in combination with other components, to convert the material into the desired physical form. Propellants may be broadly classified as liquefied or compressed gases having vapor pressures generally exceeding atmospheric pressure. Propellants within this definition include various hydrocarbons, especially halogenated derivatives of methane, ethane, and propane, low molecular weight hydrocarbons such as the butanes and pentanes, and compressed gases such as carbon dioxide, nitrogen, and nitrous oxide. Mixtures of propellants are frequently used to obtain desirable pressure, delivery, and spray characteristics. A good propellant system should have the proper vapor pressure characteristics consistent with the other aerosol components.
Valves
The primary function of the valve is to regulate the flow of the therapeutic agent and propellant from the container. The spray characteristics of the aerosol are influenced by orifice dimension, number, and location. Most aerosol valves provide for continuous spray operation and are used on most topical products. However, pharmaceutical products for oral or nasal inhalation often utilize metered-dose valves that must deliver a uniform quantity of spray upon each valve activation. The accuracy and reproducibility of the doses delivered from metering valves are generally good, comparing favorably to the uniformity of solid dosage forms such as tablets and capsules. However, when aerosol packages are stored improperly, or when they have not been used for long periods of time, valves must be primed before use. Materials used for the manufacture of valves should be inert to the formulations used. Plastic, rubber, aluminum, and stainless steel valve components are commonly used. Metered-dose valves must deliver an accurate dose within specified tolerances.
Actuators
An actuator is the fitting attached to an aerosol valve stem, which when depressed or moved, opens the valve, and directs the spray containing the drug preparation to the desired area. The actuator usually indicates the direction in which the preparation is dispensed and protects the hand or finger from the refrigerant effects of the propellant. Actuators incorporate an orifice that may vary widely in size and shape. The size of this orifice, the expansion chamber design, and the nature of the propellant and formulation influence the delivered dose as well as the physical characteristics of the spray, foam, or stream of solid particles dispensed. For inhalation aerosols, an actuator capable of delivering the medication in the proper particle size range and with the appropriate spray pattern and plume geometry is utilized.
Containers
Aerosol containers usually are made of glass, plastic, or metal, or a combination of these materials. Glass containers must be precisely engineered to provide the maximum in pressure safety and impact resistance. Plastics may be employed to coat glass containers for improved safety characteristics, or to coat metal containers to improve corrosion resistance and enhance stability of the formulation. Suitable metals include stainless steel, aluminum, and tin-plated steel. Extractables or leachables (e.g., drawing oils, cleaning agents, etc.) and particulates on the internal surfaces of containers should be controlled.
Manufacture
Aerosols are usually prepared by one of two general processes. In the “cold-fill” process, the concentrate (generally cooled to a temperature below 0
) and the refrigerated propellant are measured into open containers (usually chilled). The valve-actuator assembly is then crimped onto the container to form a pressure-tight seal. During the interval between propellant addition and crimping, sufficient volatilization of propellant occurs to displace air from the container. In the “pressure-fill” method, the concentrate is placed in the container, and either the propellant is forced under pressure through the valve orifice after the valve is sealed, or the propellant is allowed to flow under the valve cap and then the valve assembly is sealed (“under-the-cap” filling). In both cases of the “pressure-fill” method, provision must be made for evacuation of air by means of vacuum or displacement with a small amount of propellant vapor. Manufacturing process controls usually include monitoring of proper formulation and propellant fill weight and pressure testing, leak testing, and valve function testing of the finished aerosol. Microbiological attributes should also be controlled.
Extractable Substances
Since pressurized inhalers and aerosols are normally formulated with organic solvents as the propellant or the vehicle, leaching of extractables from the elastomeric and plastic components into the formulation is a potentially serious problem. Thus, the composition and the quality of materials used in the manufacture of the valve components (e.g., stem, gaskets, housing, etc.) must be carefully selected and controlled. Their compatibility with formulation components should be well established so as to prevent distortion of the valve components and to minimize changes in the medication delivery, leak rate, and impurity profile of the drug product over time. The extractable profiles of a representative sample of each of the elastomeric and plastic components of the valve should be established under specified conditions and should be correlated to the extractable profile of the aged drug product or placebo, to ensure reproducible quality and purity of the drug product. Extractables, which may include polynuclear aromatics, nitrosamines, vulcanization accelerators, antioxidants, plasticizers, monomers, etc., should be identified and minimized wherever possible.
Labeling
Medicinal aerosols should contain at least the following warning information on the label as in accordance with appropriate regulations.
Warning—
Avoid inhaling. Avoid spraying into eyes or onto other mucous membranes.
note—The statement “Avoid inhaling” is not necessary for preparations specifically designed for use by inhalation. The phrase “or other mucous membranes” is not necessary for preparations specifically designed for use on mucous membranes.
Warning—
Contents under pressure. Do not puncture or incinerate container. Do not expose to heat or store at temperatures above 120
F (49
C). Keep out of reach of children.
In addition to the aforementioned warnings, the label of a drug packaged in an aerosol container in which the propellant consists in whole or in part of a halocarbon or hydrocarbon shall, where required under regulations of the FDA, bear either of the following warnings:
Warning—
Do not inhale directly; deliberate inhalation of contents can cause death.
Warning—
Use only as directed; intentional misuse by deliberately concentrating and inhaling the contents can be harmful or fatal.
CAPSULES
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.
delayed-release 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
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.
EMULSIONS
Emulsions are two-phase systems in which one liquid is dispersed throughout another liquid in the form of small droplets. Where oil is the dispersed phase and an aqueous solution is the continuous phase, the system is designated as an oil-in-water emulsion. Conversely, where water or an aqueous solution is the dispersed phase and oil or oleaginous material is the continuous phase, the system is designated as a water-in-oil emulsion. Emulsions are stabilized by emulsifying agents that prevent coalescence, the merging of small droplets into larger droplets and, ultimately, into a single separated phase. Emulsifying agents (surfactants) do this by concentrating in the interface between the droplet and external phase and by providing a physical barrier around the particle to coalescence. Surfactants also reduce the interfacial tension between the phases, thus increasing the ease of emulsification upon mixing.
Natural, semisynthetic, and synthetic hydrophilic polymers may be used in conjunction with surfactants in oil-in-water emulsions as they accumulate at interfaces and also increase the viscosity of the aqueous phase, thereby decreasing the rate of formation of aggregates of droplets. Aggregation is generally accompanied by a relatively rapid separation of an emulsion into a droplet-rich and droplet-poor phase. Normally the density of an oil is lower than that of water, in which case the oil droplets and droplet aggregates rise, a process referred to as creaming. The greater the rate of aggregation, the greater the droplet size and the greater the rate of creaming. The water droplets in a water-in-oil emulsion generally sediment because of their greater density.
The consistency of emulsions varies widely, ranging from easily pourable liquids to semisolid creams. Generally oil-in-water creams are prepared at high temperature, where they are fluid, and cooled to room temperature, whereupon they solidify as a result of solidification of the internal phase. When this is the case, a high internal-phase volume to external-phase volume ratio is not necessary for semisolid character, and, for example, stearic acid creams or vanishing creams are semisolid with as little as 15% internal phase. Any semisolid character with water-in-oil emulsions generally is attributable to a semisolid external phase.
All emulsions require an antimicrobial agent because the aqueous phase is favorable to the growth of microorganisms. The presence of a preservative is particularly critical in oil-in-water emulsions where contamination of the external phase occurs readily. Since fungi and yeasts are found with greater frequency than bacteria, fungistatic as well as bacteriostatic properties are desirable. Bacteria have been shown to degrade nonionic and anionic emulsifying agents, glycerin, and many natural stabilizers such as tragacanth and guar gum.
Complications arise in preserving emulsion systems, as a result of partitioning of the antimicrobial agent out of the aqueous phase where it is most needed, or of complexation with emulsion ingredients that reduce effectiveness. Therefore, the effectiveness of the preservative system should always be tested in the final product. Preservatives commonly used in emulsions include methyl-, ethyl-, propyl-, and butyl-parabens, benzoic acid, and quaternary ammonium compounds.
See also Creams and Ointments.
EXTRACTS AND FLUIDEXTRACTS
Extracts are concentrated preparations of vegetable or animal drugs obtained by removal of the active constituents of the respective drugs with suitable menstrua, by evaporation of all or nearly all of the solvent, and by adjustment of the residual masses or powders to the prescribed standards.
In the manufacture of most extracts, the drugs are extracted by percolation. The entire percolates are concentrated, generally by distillation under reduced pressure in order to subject the drug principles to as little heat as possible.
Fluidextracts are liquid preparations of vegetable drugs, containing alcohol as a solvent or as a preservative, or both, and so made that, unless otherwise specified in an individual monograph, each mL contains the therapeutic constituents of 1 g of the standard drug that it represents.
A fluidextract that tends to deposit sediment may be aged and filtered or the clear portion decanted, provided the resulting clear liquid conforms to the Pharmacopeial standards.
Fluidextracts may be prepared from suitable extracts.
GELS
Gels (sometimes called Jellies) are semisolid systems consisting of either suspensions made up of small inorganic particles or large organic molecules interpenetrated by a liquid. Where the gel mass consists of a network of small discrete particles, the gel is classified as a two-phase system (e.g., Aluminum Hydroxide Gel). In a two-phase system, if the particle size of the dispersed phase is relatively large, the gel mass is sometimes referred to as a magma (e.g., Bentonite Magma). Both gels and magmas may be thixotropic, forming semisolids on standing and becoming liquid on agitation. They should be shaken before use to ensure homogeneity and should be labeled to that effect. (See Suspensions.)
Single-phase gels consist of organic macromolecules uniformly distributed throughout a liquid in such a manner that no apparent boundaries exist between the dispersed macromolecules and the liquid. Single-phase gels may be made from synthetic macromolecules (e.g., Carbomer) or from natural gums (e.g., Tragacanth). The latter preparations are also called mucilages. Although these gels are commonly aqueous, alcohols and oils may be used as the continuous phase. For example, mineral oil can be combined with a polyethylene resin to form an oleaginous ointment base.
Gels can be used to administer drugs topically or into body cavities (e.g., Phenylephrine Hydrochloride Nasal Jelly).
INHALATIONS
Inhalations are drugs or solutions or suspensions of one or more drug substances administered by the nasal or oral respiratory route for local or systemic effect.
Solutions of drug substances in sterile water for inhalation or in sodium chloride inhalation solution may be nebulized by use of inert gases. Nebulizers are suitable for the administration of inhalation solutions only if they give droplets sufficiently fine and uniform in size so that the mist reaches the bronchioles. Nebulized solutions may be breathed directly from the nebulizer or the nebulizer may be attached to a plastic face mask, tent, or intermittent positive pressure breathing (IPPB) machine.
Another group of products, also known as metered-dose inhalers (MDIs) are propellant-driven drug suspensions or solutions in liquified gas propellant with or without a cosolvent and are intended for delivering metered doses of the drug to the respiratory tract. An MDI contains multiple doses, often exceeding several hundred. The most common single-dose volumes delivered are from 25 to 100 µL (also expressed as mg) per actuation.
Examples of MDIs containing drug solutions and suspensions in this pharmacopeia are Epinephrine Inhalation Aerosol and Isoproterenol Hydrochloride and Phenylephrine Bitartrate Inhalation Aerosol, respectively.
Powders may also be administered by mechanical devices that require manually produced pressure or a deep inhalation by the patient (e.g., Cromolyn Sodium for Inhalation).
A special class of inhalations termed inhalants consists of drugs or combination of drugs, that by virtue of their high vapor pressure, can be carried by an air current into the nasal passage where they exert their effect. The container from which the inhalant generally is administered is known as an inhaler.
OINTMENTS
Ointments are semisolid preparations intended for external application to the skin or mucous membranes.
Ointment bases recognized for use as vehicles fall into four general classes: the hydrocarbon bases, the absorption bases, the water-removable bases, and the water-soluble bases. Each therapeutic ointment possesses as its base a representative of one of these four general classes.
Hydrocarbon Bases
These bases, which are known also as “oleaginous ointment bases,” are represented by White Petrolatum and White Ointment. Only small amounts of an aqueous component can be incorporated into them. They serve to keep medicaments in prolonged contact with the skin and act as occlusive dressings. Hydrocarbon bases are used chiefly for their emollient effects, and are difficult to wash off. They do not “dry out” or change noticeably on aging.
Absorption Bases
This class of bases may be divided into two groups: the first group consisting of bases that permit the incorporation of aqueous solutions with the formation of a water-in-oil emulsion (Hydrophilic Petrolatum and Lanolin), and the second group consisting of water-in-oil emulsions that permit the incorporation of additional quantities of aqueous solutions (Lanolin). Absorption bases are useful also as emollients.
Water-Removable Bases
Such bases are oil-in-water emulsions, e.g., Hydrophilic Ointment, and are more correctly called “creams.” (See Creams.) They are also described as “water-washable,” since they may be readily washed from the skin or clothing with water, an attribute that makes them more acceptable for cosmetic reasons. Some medicaments may be more effective in these bases than in hydrocarbon bases. Other advantages of the water-removable bases are that they may be diluted with water and that they favor the absorption of serous discharges in dermatological conditions.
Water-Soluble Bases
This group of so-called “greaseless ointment bases” comprises water-soluble constituents. Polyethylene Glycol Ointment is the only Pharmacopeial preparation in this group. Bases of this type offer many of the advantages of the water-removable bases and, in addition, contain no water-insoluble substances such as petrolatum, anhydrous lanolin, or waxes. They are more correctly called “Gels.” (See Gels.)
Choice of Base—
The choice of an ointment base depends upon many factors, such as the action desired, the nature of the medicament to be incorporated and its bioavailability and stability, and the requisite shelf-life of the finished product. In some cases, it is necessary to use a base that is less than ideal in order to achieve the stability required. Drugs that hydrolyze rapidly, for example, are more stable in hydrocarbon bases than in bases containing water, even though they may be more effective in the latter.
PASTES
Pastes are semisolid dosage forms that contain one or more drug substances intended for topical application. One class is made from a single-phase aqueous gel (e.g., Carboxymethylcellulose Sodium Paste). The other class, the fatty pastes (e.g., Zinc Oxide Paste), consists of thick, stiff ointments that do not ordinarily flow at body temperature, and therefore serve as protective coatings over the areas to which they are applied.
The fatty pastes appear less greasy and more absorptive than ointments by reason of a high proportion of drug substance(s) having an affinity for water. These pastes tend to absorb serous secretions, and are less penetrating and less macerating than ointments, so that they are preferred for acute lesions that have a tendency towards crusting, vesiculation, or oozing.
A dental paste is intended for adhesion to the mucous membrane for local effect (e.g., Triamcinolone Acetonide Dental Paste). Some paste preparations intended for administration to animals are applied orally. The paste is squeezed into the mouth of the animal, generally at the back of the tongue, or is spread inside the mouth.
POWDERS
Powders are intimate mixtures of dry, finely divided drugs and/or chemicals that may be intended for internal (Oral Powders) or external (Topical Powders) use. Because of their greater specific surface area, powders disperse and dissolve more readily than compacted dosage forms. Children and those adults who experience difficulty in swallowing tablets or capsules may find powders more acceptable. Drugs that are too bulky to be formed into tablets or capsules of convenient size may be administered as powders. Immediately prior to use, oral powders are mixed in a beverage or apple sauce.
Often, stability problems encountered in liquid dosage forms are avoided in powdered dosage forms. Drugs that are unstable in aqueous suspensions or solutions may be prepared in the form of granules or powders. These are intended to be constituted by the pharmacist by the addition of a specified quantity of water just prior to dispensing. Because these constituted products have limited stability, they are required to have a specified expiration date after constitution and may require storage in a refrigerator.
Oral powders may be dispensed in doses premeasured by the pharmacist, i.e., divided powders, or in bulk. Traditionally, divided powders have been wrapped in materials such as bond paper and parchment. However, the pharmacist may provide greater protection from the environment by sealing individual doses in small cellophane or polyethylene envelopes.
Granules for veterinary use may be administered by sprinkling the dry powder on animal feed or by mixing it with animal food.
Bulk oral powders are limited to relatively nonpotent drugs such as laxatives, antacids, dietary supplements, and certain analgesics that the patient may safely measure by the teaspoonful or capful. Other bulky powders include douche powders, tooth powders, and dusting powders. Bulk powders are best dispensed in tight, wide-mouth glass containers to afford maximum protection from the atmosphere and to prevent the loss of volatile constituents.
Dusting powders are impalpable powders intended for topical application. They may be dispensed in sifter-top containers to facilitate dusting onto the skin. In general, dusting powders should be passed through at least a 100-mesh sieve to assure freedom from grit that could irritate traumatized areas (see
Powder Fineness 811).
SUPPOSITORIES
Suppositories are solid bodies of various weights and shapes, adapted for introduction into the rectal, vaginal, or urethral orifice of the human body. They usually melt, soften, or dissolve at body temperature. A suppository may act as a protectant or palliative to the local tissues at the point of introduction or as a carrier of therapeutic agents for systemic or local action. Suppository bases usually employed are cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.
The suppository base employed has a marked influence on the release of the active ingredient incorporated in it. While cocoa butter melts quickly at body temperature, it is immiscible with body fluids and this inhibits the diffusion of fat-soluble drugs to the affected sites. Polyethylene glycol is a suitable base for some antiseptics. In cases where systemic action is expected, it is preferable to incorporate the ionized rather than the nonionized form of the drug, in order to maximize bioavailability. Although nonionized drugs partition more readily out of water-miscible bases such as glycerinated gelatin and polyethylene glycol, the bases themselves tend to dissolve very slowly and thus retard release in this manner. Oleaginous vehicles such as cocoa butter are seldom used in vaginal preparations because of the nonabsorbable residue formed, while glycerinated gelatin is seldom used rectally because of its slow dissolution. Cocoa butter and its substitutes (Hard Fat) are superior for allaying irritation, as in preparations intended for treating internal hemorrhoids.
Cocoa Butter Suppositories
Suppositories having cocoa butter as the base may be made by means of incorporating the finely divided medicinal substance into the solid oil at room temperature and suitably shaping the resulting mass, or by working with the oil in the melted state and allowing the resulting suspension to cool in molds. A suitable quantity of hardening agents may be added to counteract the tendency of some medicaments such as chloral hydrate and phenol to soften the base. It is important that the finished suppository melt at body temperature.
The approximate weights of suppositories prepared with cocoa butter are given below. Suppositories prepared from other bases vary in weight and generally are heavier than the weights indicated here.
Rectal Suppositories
for adults are tapered at one or both ends and usually weigh about 2 g each.
Vaginal Suppositories
are usually globular or oviform and weigh about 5 g each. They are made from water-soluble or water-miscible vehicles such as polyethylene glycol or glycerinated gelatin.
Suppositories with cocoa butter base require storage in well-closed containers, preferably at a temperature below 30
(controlled room temperature).
Cocoa Butter Substitutes
Fat-type suppository bases can be produced from a variety of vegetable oils, such as coconut or palm kernel, which are modified by esterification, hydrogenation, and fractionation to obtain products of varying composition and melting temperatures (e.g., Hydrogenated Vegetable Oil and Hard Fat). These products can be so designed as to reduce rancidity. At the same time, desired characteristics such as narrow intervals between melting and solidification temperatures, and melting ranges to accommodate various formulation and climatic conditions, can be built in.
Glycerinated Gelatin Suppositories
Medicinal substances may be incorporated into glycerinated gelatin bases by addition of the prescribed quantities to a vehicle consisting of about 70 parts of glycerin, 20 parts of gelatin, and 10 parts of water.
Glycerinated gelatin suppositories require storage in tight containers, preferably at a temperature below 35
.
Polyethylene Glycol–Base Suppositories
Several combinations of polyethylene glycols having melting temperatures that are above body temperature have been used as suppository bases. Inasmuch as release from these bases depends on dissolution rather than on melting, there are significantly fewer problems in preparation and storage than exist with melting-type vehicles. However, high concentrations of higher-molecular-weight polyethylene glycols may lengthen dissolution time, resulting in problems with retention. Labels on polyethylene glycol suppositories should contain directions that they be moistened with water before inserting. Although they can be stored without refrigeration, they should be packaged in tightly closed containers.
Surfactant Suppository Bases
Several nonionic surface-active agents closely related chemically to the polyethylene glycols can be used as suppository vehicles. Examples of such surfactants are polyoxyethylene sorbitan fatty acid esters and the polyoxyethylene stearates. These surfactants are used alone or in combination with other suppository vehicles to yield a wide range of melting temperatures and consistencies. One of the major advantages of such vehicles is their water-dispersibility. However, care must be taken with the use of surfactants, because they may either increase the rate of drug absorption or interact with drug molecules, causing a decrease in therapeutic activity.
Tableted Suppositories or Inserts
Vaginal suppositories occasionally are prepared by the compression of powdered materials into a suitable shape. They are prepared also by encapsulation in soft gelatin.
SUSPENSIONS
Suspensions are liquid preparations that consist of solid particles dispersed throughout a liquid phase in which the particles are not soluble. Dosage forms officially categorized as “Suspensions” are designated as such if they are not included in other more specific categories of suspensions, such as Oral Suspensions, Topical Suspensions, etc. (see these other categories). Some suspensions are prepared and ready for use, while others are prepared as solid mixtures intended for constitution just before use with an appropriate vehicle. Such products are designated “for Oral Suspension”, etc. The term “Milk” is sometimes used for suspensions in aqueous vehicles intended for oral administration (e.g., Milk of Magnesia). The term “Magma” is often used to describe suspensions of inorganic solids such as clays in water, where there is a tendency for strong hydration and aggregation of the solid, giving rise to gel-like consistency and thixotropic rheological behavior (e.g., Bentonite Magma). The term “Lotion” has been used to categorize many topical suspensions and emulsions intended for application to the skin (e.g., Calamine Lotion). Some suspensions are prepared in sterile form and are used as Injectables, as well as for ophthalmic and otic administration. These may be of two types, ready to use or intended for constitution with a prescribed amount of Water for Injection or other suitable diluent before use by the designated route. Suspensions should not be injected intravenously or intrathecally.
Suspensions intended for any route of administration should contain suitable antimicrobial agents to protect against bacteria, yeast, and mold contamination (see Emulsions for some consideration of antimicrobial preservative properties that apply also to Suspensions). By its very nature, the particular matter in a suspension may settle or sediment to the bottom of the container upon standing. Such sedimentation may also lead to caking and solidification of the sediment with a resulting difficulty in redispersing the suspension upon agitation. To prevent such problems, suitable ingredients that increase viscosity and the gel state of the suspension, such as clays, surfactants, polyols, polymers, or sugars, should be added. It is important that suspensions always be shaken well before use to ensure uniform distribution of the solid in the vehicle, thereby ensuring uniform and proper dosage. Suspensions require storage in tight containers.
Oral Suspensions
Oral Suspensions are liquid preparations containing solid particles dispersed in a liquid vehicle, with suitable flavoring agents, intended for oral administration. Some suspensions labeled as “Milks” or “Magmas” fall into this category.
Topical Suspensions
Topical Suspensions are liquid preparations containing solid particles dispersed in a liquid vehicle, intended for application to the skin. Some suspensions labeled as “Lotions” fall into this category.
Otic Suspensions
Otic Suspensions are liquid preparations containing micronized particles intended for instillation in the outer ear.
Ophthalmic Suspensions
See Ophthalmic Preparations.
TABLETS
Tablets are solid dosage forms containing medicinal substances with or without suitable diluents. They may be classed, according to the method of manufacture, as compressed tablets or molded tablets.
The vast majority of all tablets manufactured are made by compression, and compressed tablets are the most widely used dosage form in this country. Compressed tablets are prepared by the application of high pressures, utilizing steel punches and dies, to powders or granulations. Tablets can be produced in a wide variety of sizes, shapes, and surface markings, depending upon the design of the punches and dies. Capsule-shaped tablets are commonly referred to as caplets. Boluses are large tablets intended for veterinary use, usually for large animals.
Molded tablets are prepared by forcing dampened powders under low pressure into die cavities. Solidification depends upon crystal bridges built up during the subsequent drying process, and not upon the compaction force.
Tablet triturates are small, usually cylindrical, molded or compressed tablets. Tablet triturates were traditionally used as dispensing tablets in order to provide a convenient, measured quantity of a potent drug for compounding purposes. Such tablets are rarely used today. Hypodermic tablets are molded tablets made from completely and readily water-soluble ingredients and formerly were intended for use in making preparations for hypodermic injection. They are employed orally, or where rapid drug availability is required such as in the case of Nitroglycerin Tablets, sublingually.
Buccal tablets are intended to be inserted in the buccal pouch, and sublingual tablets are intended to be inserted beneath the tongue, where the active ingredient is absorbed directly through the oral mucosa. Few drugs are readily absorbed in this way, but for those that are (such as nitroglycerin and certain steroid hormones), a number of advantages may result.
Soluble, effervescent tablets are prepared by compression and contain, in addition to active ingredients, mixtures of acids (citric acid, tartaric acid) and sodium bicarbonate, which release carbon dioxide when dissolved in water. They are intended to be dissolved or dispersed in water before administration. Effervescent tablets should be stored in tightly closed containers or moisture-proof packs and labeled to indicate that they are not to be swallowed directly.
Chewable Tablets
Chewable tablets are formulated and manufactured so that they may be chewed, producing a pleasant tasting residue in the oral cavity that is easily swallowed and does not leave a bitter or unpleasant aftertaste. These tablets have been used in tablet formulations for children, especially multivitamin formulations, and for the administration of antacids and selected antibiotics. Chewable tablets are prepared by compression, usually utilizing mannitol, sorbitol, or sucrose as binders and fillers, and containing colors and flavors to enhance their appearance and taste.
Preparation of Molded Tablets
Molded tablets are prepared from mixtures of medicinal substances and a diluent usually consisting of lactose and powdered sucrose in varying proportions. The powders are dampened with solutions containing high percentages of alcohol. The concentration of alcohol depends upon the solubility of the active ingredients and fillers in the solvent system and the desired degree of hardness of the finished tablets. The dampened powders are pressed into molds, removed, and allowed to dry. Molded tablets are quite friable and care must be taken in packaging and dispensing.
Formulation of Compressed Tablets
Most compressed tablets consist of the active ingredient and a diluent (filler), binder, disintegrating agent, and lubricant. Approved FD&C and D&C dyes or lakes (dyes adsorbed onto insoluble aluminum hydroxide), flavors, and sweetening agents may also be present. Diluents are added where the quantity of active ingredient is small or difficult to compress. Common tablet fillers include lactose, starch, dibasic calcium phosphate, and microcrystalline cellulose. Chewable tablets often contain sucrose, mannitol, or sorbitol as a filler. Where the amount of active ingredient is small, the overall tableting properties are in large measure determined by the filler. Because of problems encountered with bioavailability of hydrophobic drugs of low water-solubility, water-soluble diluents are used as fillers for these tablets.
Binders give adhesiveness to the powder during the preliminary granulation and to the compressed tablet. They add to the cohesive strength already available in the diluent. While binders may be added dry, they are more effective when added out of solution. Common binders include acacia, gelatin, sucrose, povidone, methylcellulose, carboxymethylcellulose, and hydrolyzed starch pastes. The most effective dry binder is microcrystalline cellulose, which is commonly used for this purpose in tablets prepared by direct compression.
A disintegrating agent serves to assist in the fragmentation of the tablet after administration. The most widely used tablet disintegrating agent is starch. Chemically modified starches and cellulose, alginic acid, microcrystalline cellulose, and cross-linked povidone, are also used for this purpose. Effervescent mixtures are used in soluble tablet systems as disintegrating agents. The concentration of the disintegrating agent, method of addition, and degree of compaction play a role in effectiveness.
Lubricants reduce friction during the compression and ejection cycle. In addition, they aid in preventing adherence of tablet material to the dies and punches. Metallic stearates, stearic acid, hydrogenated vegetable oils, and talc are used as lubricants. Because of the nature of this function, most lubricants are hydrophobic, and as such tend to reduce the rates of tablet disintegration and dissolution. Consequently, excessive concentrations of lubricant should be avoided. Polyethylene glycols and some lauryl sulfate salts have been used as soluble lubricants, but such agents generally do not possess optimal lubricating properties, and comparatively high concentrations are usually required.
Glidants are agents that improve powder fluidity, and they are commonly employed in direct compression where no granulation step is involved. The most effective glidants are the colloidal pyrogenic silicas.
Colorants are often added to tablet formulations for esthetic value or for product identification. Both D&C and FD&C dyes and lakes are used. Most dyes are photosensitive and they fade when exposed to light. The federal Food and Drug Administration regulates the colorants employed in drugs.
Manufacturing Methods
Tablets are prepared by three general methods: wet granulation, dry granulation (roll compaction or slugging), and direct compression. The purpose of both wet and dry granulation is to improve flow of the mixture and/or to enhance its compressibility.
Dry granulation (slugging) involves the compaction of powders at high pressures into large, often poorly formed tablet compacts. These compacts are then milled and screened to form a granulation of the desired particle size. The advantage of dry granulation is the elimination of both heat and moisture in the processing. Dry granulations can be produced also by extruding powders between hydraulically operated rollers to produce thin cakes which are subsequently screened or milled to give the desired granule size.
Excipients are available that allow production of tablets at high speeds without prior granulation steps. These directly compressible excipients consist of special physical forms of substances such as lactose, sucrose, dextrose, or cellulose, which possess the desirable properties of fluidity and compressibility. The most widely used direct-compaction fillers are microcrystalline cellulose, anhydrous lactose, spray-dried lactose, compressible sucrose, and some forms of modified starches. Direct compression avoids many of the problems associated with wet and dry granulations. However, the inherent physical properties of the individual filler materials are highly critical, and minor variations can alter flow and compression characteristics so as to make them unsuitable for direct compression.
weight variation and content uniformity
Tablets are required to meet a weight variation test (see
Uniformity of Dosage Units 905) where the active ingredient comprises a major portion of the tablet and where control of weight may be presumed to be an adequate control of drug content uniformity. Weight variation is not an adequate indication of content uniformity where the drug substance comprises a relatively minor portion of the tablet, or where the tablet is sugar-coated. Thus, the Pharmacopeia generally requires that coated tablets and tablets containing 50 mg or less of active ingredient, comprising less than 50% by weight of the dosage-form unit, pass a content uniformity test (see
Uniformity of Dosage Units 905), wherein individual tablets are assayed for actual drug content.
disintegration and dissolution
Disintegration is an essential attribute of tablets intended for administration by mouth, except for those intended to be chewed before being swallowed and for some types of extended-release tablets. A disintegration test is provided (see
Disintegration 701), and limits on the times in which disintegration is to take place, appropriate for the types of tablets concerned, are given in the individual monographs.
For drugs of limited water-solubility, dissolution may be a more meaningful quality attribute than disintegration. A dissolution test (see
Dissolution 711) is required in a number of monographs on tablets. In many cases, it is possible to correlate dissolution rates with biological availability of the active ingredient. However, such tests are useful mainly as a means of screening preliminary formulations and as a routine quality-control procedure.
Coatings
Tablets may be coated for a variety of reasons, including protection of the ingredients from air, moisture, or light, masking of unpleasant tastes and odors, improvement of appearance, and control of the site of drug release in the gastrointestinal tract.
plain coated tablets
Classically, tablets have been coated with sugar applied from aqueous suspensions containing insoluble powders such as starch, calcium carbonate, talc, or titanium dioxide, suspended by means of acacia or gelatin. For purposes of identification and esthetic value, the outside coatings may be colored. The finished coated tablets are polished by application of dilute solutions of wax in solvents such as chloroform or powdered mix. Water-protective coatings consisting of substances such as shellac or cellulose acetate phthalate are often applied out of nonaqueous solvents prior to application of sugar coats. Excessive quantities should be avoided. Drawbacks of sugar coating include the lengthy time necessary for application, the need for waterproofing, which also adversely affects dissolution, and the increased bulk of the finished tablet. These factors have resulted in increased acceptance of film coatings. Film coatings consist of water-soluble or dispersible materials such as hydroxypropyl methylcellulose, methylcellulose, hydroxypropylcellulose, carboxymethylcellulose sodium, and mixtures of cellulose acetate phthalate and polyethylene glycols applied out of nonaqueous or aqueous solvents. Evaporation of the solvents leaves a thin film that adheres directly to the tablet and allows it to retain the original shape, including grooves or identification codes.
delayed-release tablets
Where the drug may be destroyed or inactivated by the gastric juice or where it may irritate the gastric mucosa, the use of “enteric” coatings is indicated. Such coatings are intended to delay the release of the medication until the tablet has passed through the stomach. The term “delayed-release” is used for Pharmacopeial purposes, and the individual monographs include tests and specifications for
Drug release (see
Drug Release 724) or
Disintegration (see
Disintegration 701).
extended-release tablets
Extended-release tablets 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 typically are specified in the individual monographs.
