〈1151〉 PHARMACEUTICAL DOSAGE FORMS

854 ⟨1146⟩ Packaging Practice / General Information USP 36

not provide adequate protection against moisture perme- Materials—The repackager or dispenser shall place anation. Records must be kept of the temperature of the facil- appropriate beyond-use date on the label and package inity where the dosage forms are stored, and of the plastic appropriate materials. Materials used by the repackager shallmaterials used in packaging. not be reactive, additive, or absorptive, and must meet the

requirements described in 21 CFR 175 and 177.Storage—The dispenser shall rotate and monitor stockMINIMUM REQUIREMENTS closely to ensure that the dispensing of preparations is on a

first-in–first-out (FIFO) basis. The repackager or dispenserThe previous sections serve as a general introduction to shall store preparations under required environmental condi-repackaging by providing a basic understanding of materials tions (e.g., controlled room temperature with a mean ki-selection, the form-fill-seal process, and the importance of netic temperature not higher than 25°).performance of the sealed container. In this section, certainDrug Product—The repackager or dispenser shall ex-minimum requirements for repackaging, which must be

amine preparations for evidence of instability such asmet, are described in more detail.change in color or odor, and shall exercise professionalPersonnel—Each person with responsibility for the re- judgment as to the acceptability of a package.packaging of a preparation shall have the education, train-

Complaints—The repackager or dispenser will maintaining, and experience, or any combination thereof, to performwritten procedures describing the handling of written andassigned functions in a manner such that the safety, iden-oral complaints regarding a drug product and will ensuretity, strength, quality, purity, potency, and pharmaceuticalthat complaints are investigated and appropriately resolved.elegance of the drug dosage form are retained. Training

Returned Goods—Policies and procedures relating to re-should be documented.turned goods should be developed to ensure proper han-Personnel engaged in the repackaging of a preparationdling.shall wear clean clothing appropriate for the duties or

processes performed. Reprocessing—Reprocessing of repackaged unit-dosecontainers (i.e., removing medication from one unit-doseFacility—The repackaging facility may require areas ofcontainer and placing it into another unit-dose container)low relative humidity, and temperature conditions shouldshall not be done. However, reprocessing of the secondarymeet controlled room temperature requirements specified inpackage (e.g., removing the blister card from the cardboardthe General Notices.carrier and placing the blister card into another cardboardEquipment—Equipment used in the repackaging of acarrier) is allowed provided the original beyond-use date ispreparation shall be of appropriate design and suitably lo-maintained, and provided the integrity of the blister is en-cated to facilitate operations for its intended use. Its designsured.should allow for cleaning to preclude cross-contamination as

Special Considerations—If a product is known to be ox-well as for maintenance to be performed. Equipment shallygen sensitive or if it exhibits extreme moisture or light sen-be constructed so that those surfaces that contact compo-sitivity (e.g., cold form foil), it shall not be repackaged. If anents or a preparation are not reactive, additive, or absorp-product is refrigerated, it shall not be repackaged unlesstive.proper environmental conditions and suitable materials areAny substances required for operation, such as lubricantsavailable. Certain drug products (such as oncologic agents,or coolants, shall not come into contact with componentshormones, or penicillin derivatives) require special handlingor a preparation.because they are considered very potent or toxic, and be-Equipment and utensils shall be cleaned, maintained, andcause transfer of any portion of these products to anothersanitized at appropriate intervals to prevent malfunctions orproduct could have deleterious effects.contamination. Preventive maintenance should be per-

▲ USP36formed at appropriate intervals in accordance with theequipment manufacturer’s recommendation. Any instru-ments used to monitor critical parameters should be cali-brated on a defined schedule.

Process—Steps should be taken to determine the criticalprocess parameters (e.g., seal temperature, dwell time) inoperating the equipment. Set points for these parametersshould be documented and procedures established to en- ⟨1151⟩ PHARMACEUTICALsure that they are adhered to each time the equipment isoperated. DOSAGE FORMS

Labeling—The labeling requirements for a commercialrepackager and a pharmacist are different. For example, thecommercial repackager must comply with 21 CFR 201.1,but the pharmacist or dispenser does not have to complywith this requirement. If stability data are unavailable, the GENERAL CONSIDERATIONSdispenser shall repackage only an amount of stock sufficientfor a limited time and shall include product name and This chapter provides general descriptions of and defini-strength, lot number, manufacturer, and appropriate be- tions for drug products, or dosage forms, commonly usedyond-use date on the label. When quantities are repackaged to administer the active pharmaceutical ingredient (API). Itin advance of immediate needs, each preparation must bear discusses general principles involved in the manufacture oran identifying label, and the dispenser is required to main- compounding of these dosage forms and recommendationstain suitable repackaging records showing the name of the for proper use and storage. A glossary is provided as a re-manufacturer, lot number, expiration date, date of repack- source on nomenclature.aging, and designation of persons responsible for repack- A dosage form is a combination of API and often excipi-aging and for checking. The repackager or dispenser will ents to facilitate dosing, administration, and delivery of theuse documented controls to prevent labeling errors. medicine to the patient. The design and testing of all dos-

USP 36 General Information / ⟨1151⟩ Pharmaceutical Dosage Forms 855

Figure 1. Compendial Taxonomy for Pharmaceutical Dosage Forms.

age forms target drug product quality.1 A testing protocol evaluation of API particle or droplet size, incorporation tech-must consider not only the physical, chemical, and biologi- niques, and excipient properties.cal properties of the dosage form as appropriate, but also Stability—Drug product stability involves the evaluationthe administration route and desired dosing regimen. The of chemical stability, physical stability, and performanceinterrelationships of dosage forms and routes of administra- over time. The chemical stability of the API in the dosagetion have been summarized in the compendial taxonomy form matrix must support the expiration dating for thefor pharmaceutical dosage forms (see Figure 1).2 The organ- commercially prepared dosage forms and a beyond-use dateization of this general information chapter is by the physical for a compounded dosage form. Test procedures for po-attributes of each particular dosage form (Tier Two), gener- tency must be stability indicating (see Validation of Com-ally without specific reference to route of administration. In- pendial Procedures ⟨1225⟩). Degradation products should beformation specific to route of administration is given when quantified. In the case of dispersed or emulsified systems,needed. consideration must be given to the potential for settling or

Tests to ensure compliance with Pharmacopeial standards separation of the formulation components. Any physicalfor dosage form performance fall into one of the following changes to the dosage form must be easily reversed (e.g.,areas. by shaking) prior to dosing or administration. For the exam-

Dose Uniformity (see also Uniformity of Dosage Units ple of tablets, capsules, and oral suspensions, in vitro release⟨905⟩)—Consistency in dosing for a patient or consumer re- test procedures such as dissolution and disintegration pro-quires that the variation in the API content of each dosage vide a measure of continuing consistency in performanceunit be accurately controlled throughout the manufactured over time (see Dissolution ⟨711⟩, Disintegration ⟨701⟩, andbatch or compounded lot of drug product. Uniformity of Drug Release ⟨724⟩).dosage units typically is demonstrated by one of two proce- Bioavailability (see also In Vitro and In Vivo Evaluation ofdures: content uniformity or weight variation. The proce- Dosage Forms ⟨1088⟩ and Assessment of Drug Product Perfor-dure for content uniformity requires the assay of API content mance—Bioavailability, Bioequivalence, and Dissolutionof individual units and that for weight variation uses the ⟨1090⟩)—Bioavailability is influenced by factors such as theweight of the individual units to estimate their content. method of manufacture or compounding, particle size, crys-Weight variation may be used where the underlying distri- tal form (polymorph) of the API, the properties of the excip-bution of API in the blend is presumed to be uniform and ients used to formulate the dosage form, and physicalwell-controlled, as in solutions. In such cases the content of changes as the drug product ages. Assurance of consistencyAPI may be adequately estimated by the net weight. Con- in bioavailability over time (bioequivalence) requires closetent uniformity does not rely on the assumption of blend attention to all aspects of the production (or compounding)uniformity and can be applied in all cases. Successful devel- and testing of the dosage form. With proper justification, inopment and manufacture of dosage forms requires careful vitro release (e.g., disintegration and dissolution) testing

may sometimes be used as a surrogate to demonstrate con-1 In the United States a drug with a name recognized in USP–NF must complywith compendial identity standards or be deemed adulterated, misbranded, sistent availability of the API from the formulated dosage.or both. To avoid being deemed adulterated such drugs also must comply Manufacture—Although detailed instructions about thewith compendial standards for strength, quality, or purity, unless labeled to

manufacture of any of these dosage forms are beyond theshow all respects in which the drug differs. See the Federal Food, Drug, andCosmetic Act (FDCA), Sections 501(b) and 502(e)(3)(b), and Food and Drug scope of this general information chapter, general manufac-Administration (FDA) regulations at 21 CFR 299.5. In addition, to avoid being turing principles have been included, as well as suggesteddeemed misbranded, drugs recognized in USP–NF also must comply with testing for proper use and storage. Information relative tocompendial standards for packaging and labeling, FDCA Section 502(g).“Quality” is used herein as suitable shorthand for all such compendial require- extemporaneous compounding of dosage forms can bements. This approach also is consistent with U.S. and FDA participation in the found in Pharmaceutical Compounding—Nonsterile Prepara-International Conference on Harmonization (ICH). The ICH guideline on spec- tions ⟨795⟩ and Pharmaceutical Compounding—Sterile Prepa-ifications, Q6A, notes that “specifications are chosen to confirm the quality of

rations ⟨797⟩.the drug substance and drug product…” and defines “quality” as “The suita-bility of either a drug substance or drug product for its intended use. This Route of Administration—The primary routes of admin-term includes such attributes as identity, strength, and purity.” istration for pharmaceutical dosage forms can be defined as2 Marshall K, Foster TS, Carlin HS, Williams RL. Development of a compendialtaxonomy and glossary for pharmaceutical dosage forms. Pharm Forum. mucosal, gastrointestinal, parenteral (by injection), inhala-2003;29(5):1742–1752. tion, and topical/dermal, and each has subcategories as

needed. Many tests used to ensure quality generally are ap-

856 ⟨1151⟩ Pharmaceutical Dosage Forms / General Information USP 36

plied across all of the administration routes, but some tests uct and should discriminate between compounds of closelyare specific for individual routes. For example, products in- related structure that are likely to be present. Identificationtended for injection must be evaluated for Sterility Tests ⟨71⟩ tests should be specific for the API(s). The most conclusiveand Pyrogen Test ⟨151⟩, and the manufacturing process (and test for identity is the infrared absorption spectrum (seesterilization technique) employed for parenterals (by injec- Spectrophotometry and Light-Scattering ⟨851⟩ and Spectropho-tion) should ensure compliance with these tests. Tests for tometric Identification Tests ⟨197⟩). If no suitable infraredparticulate matter may be required for certain dosage forms spectrum can be obtained, other analytical methods can bedepending on the route of administration (e.g., by injec- used. Near-infrared (NIR) or Raman spectrophotometriction—Particulate Matter in Injections ⟨788⟩, or mucosal—Par- methods also could be acceptable as the sole identificationticulate Matter in Ophthalmic Solutions ⟨789⟩). Additionally, method of the drug product formulation (see Near-Infrareddosage forms intended for the inhalation route of adminis- Spectrophotometry ⟨1119⟩ and Raman Spectroscopy ⟨1120⟩).tration must be monitored for particle size and spray pattern Identification by a chromatographic retention time from a(for a metered-dose inhaler or dry powder inhaler) and single procedure is not regarded as specific. The use of re-droplet size (for nasal sprays). Further information regarding tention times from two chromatographic procedures foradministration routes and suggested testing can be found in which the separation is based on different principles or athe Guide to General Chapters, Charts 4–8 and 10–13. combination of tests in a single procedure can be accept-

An appropriate manufacturing process and testing regi- able (see Chromatography ⟨621⟩ and Thin-Layer Chromato-men help ensure that a dosage form can meet the appropri- graphic Identification Test ⟨201⟩).ate quality attributes for the intended route of Assay—A specific and stability-indicating test should beadministration. used to determine the strength (API content) of the drug

Excess Volume in Injections—Each container of an Injec- product. Some examples of these procedures are Antibiot-tion is filled with a volume in slight excess of the labeled ics—Microbial Assays ⟨81⟩, Chromatography ⟨621⟩, or Assay“size” or the volume that is to be withdrawn. The excess for Steroids ⟨351⟩. In cases when the use of a nonspecificvolumes recommended in the accompanying table are usu- assay is justified, e.g., Titrimetry ⟨541⟩, other supporting ana-ally sufficient to permit withdrawal and administration of the lytical procedures should be used to achieve specificity.labeled volumes. When evidence of excipient interference with a nonspecific

assay exists, a procedure with demonstrated specificityshould be used.Recommended Excess Volume

Impurities—Process impurities, synthetic by-products,For Mobile For Viscousand other inorganic and organic impurities may be presentLiquids LiquidsLabeled Sizein the API and excipients used in the manufacture of the 0.5 mL 0.10 mL 0.12 mL drug product. These impurities are evaluated by tests in API

1.0 mL 0.10 mL 0.15 mL and excipients monographs. Impurities arising from degra- 2.0 mL 0.15 mL 0.25 mL dation of the drug substance or from the drug-product 5.0 mL 0.30 mL 0.50 mL manufacturing process should be monitored. Residual Sol-

vents ⟨467⟩ is applied to all products where relevant.10.0 mL 0.50 mL 0.70 mLIn some cases, testing for heavy metal impurities is appro-20.0 mL 0.60 mL 0.90 mL

priate. Heavy Metals ⟨231⟩ provides the current procedures30.0 mL 0.80 mL 1.20 mL and criteria.50.0 mL or more 2% 3% In addition to the universal tests listed above, the follow-

ing tests may be considered on a case-by-case basis.Labeling Statements—Some dosage forms or articles Physicochemical Properties—Examples include pH

have mandatory labeling statements that are given in the ⟨791⟩, Viscosity ⟨911⟩, and Specific Gravity ⟨841⟩.Code of Federal Regulations (e.g., 21 CFR 201.320 and 21 Particle Size—For some dosage forms, particle size canCFR 369.21). The text of 21 CFR should be consulted to have a significant effect on dissolution rates, bioavailability,determine the current recommendations. therapeutic outcome, and stability. Procedures such as Aero-

sols, Nasal Sprays, Metered-Dose Inhalers, and Dry Powder In-halers ⟨601⟩ and Particle Size Distribution Estimation by Ana-PRODUCT QUALITY TESTS, GENERAL lytical Sieving ⟨786⟩ could be used.

Uniformity of Dosage Units—See discussion of DoseICH Guidance Q6A (available at www.ich.org) recom-Uniformity in the section General Considerations above.mends specifications (list of tests, references to analytical

procedures, and acceptance criteria) to ensure that commer- Water Content—A test for water content is includedcialized drug products are safe and effective at the time of when appropriate (see Water Determination ⟨921⟩).release and over their shelf life. Tests that are universally Microbial Limits—The type of microbial test(s) and ac-applied to ensure safety and efficacy (and strength, quality, ceptance criteria are based on the nature of the drug sub-and purity) include description, identification, assay, and stance, method of manufacture, and the route of adminis-impurities. tration (see Microbiological Examination of Nonsterile Products:

Description—According to the ICH guidance a qualita- Microbial Enumeration Tests ⟨61⟩ and Microbiological Examina-tive description (size, shape, color, etc.) of the dosage form tion of Nonsterile Products: Tests for Specified Microorganismsshould be provided. The acceptance criteria should include ⟨62⟩).the final acceptable appearance. If any of these characteris- Antimicrobial Preservative Content—Acceptance crite-tics change during manufacturing or storage, a quantitative ria for preservative content in multidose products should beprocedure may be appropriate. It specifies the content or established. They are based on the levels of antimicrobialthe label claim of the article. This parameter is not part of preservative necessary to maintain the product’s microbio-the USP dosage form monograph because it is product spe- logical quality at all stages throughout its proposed usagecific. USP monographs define the product by specifying the and shelf life (see Antimicrobial Effectiveness Testing ⟨51⟩).range of acceptable assayed content of the API(s) present in Antioxidant Content—If antioxidants are present in thethe dosage form, together with any additional information drug product, tests of their content should be performed toabout the presence or absence of other components, excipi- maintain the product’s quality at all stages throughout itsents, or adjuvants. proposed usage and shelf life.

Identification—Identification tests are discussed in the Sterility—Depending on the route of administration—General Notices and Requirements. Identification tests should e.g., ophthalmic preparations, implants, aqueous-basedestablish the identity of the API(s) present in the drug prod-


preparations for oral inhalation, and solutions for injection— API(s) dissolved in liquefied propellant. Co-solvents such assterility of the product is demonstrated as appropriate (see alcohol may be added to enhance the solubility of theSterility Tests ⟨71⟩). API(s). Three-phase inhalation and nasal aerosol systems

consist of suspended API(s) in propellant(s), co-solvents, andDissolution—A test to measure release of the API(s) frompotentially other suitable excipients. The suspension orthe drug product normally is included for dosage formsemulsion of the finely divided API typically is dispersed insuch as tablets, capsules, suspensions, granules for suspen-the liquid propellant with the aid of suitable biocompatiblesions, implants, transdermal delivery systems, and medi-surfactants or other excipients.cated chewing gums. Single-point measurements typically

Propellants for aerosol formulations are typically low mo-are used for immediate-release dosage forms. For modified-lecular weight hydrofluorocarbons or hydrocarbons that arerelease dosage forms, appropriate test conditions and sam-liquid when constrained in the container, exhibit a suitablepling procedures are established as needed (see Dissolutionvapor pressure at room temperature, and are biocompatible⟨711⟩ and Drug Release ⟨724⟩). In some cases, dissolutionand nonirritating. Compressed gases do not supply a con-testing may be replaced by disintegration testing (see Disin-stant pressure over use and typically are not used astegration ⟨701⟩).propellants.Breaking Force and Friability—These parameters are Metal containers can withstand the vapor pressure pro-evaluated as in-process controls. Acceptance criteria depend duced by the propellant. Excess formulation may be addedon packaging, supply chain, and intended use (see Tablet to the container to ensure that the full number of labeledFriability ⟨1216⟩ and Tablet Breaking Force ⟨1217⟩). doses can be accurately administered. The container and

Leachables—When evidence exists that leachables from closure must be able to withstand the pressures anticipatedthe container–closure systems (e.g., rubber stopper, cap under normal use conditions as well as when the system isliner, or plastic bottle) have an impact on the safety or effi- exposed to elevated temperatures.cacy of the drug product, a test is included to evaluate thepresence of leachables.

TYPES OF AEROSOL DOSAGE FORMSOther Tests—Depending on the type and compositionof the dosage form, other tests such as alcohol content,

Aerosol dosage forms can be delivered via various routes.redispersibility, particle size distribution, rheological proper-The container, actuator, and metering valve, as well as theties, reconstitution time, endotoxins/pyrogens, particulateformulation, are designed to target the site ofmatter, functionality testing of delivery systems, deliveredadministration.dose uniformity, viscosity, and osmolarity may be necessary.

Inhalation aerosols, commonly known as metered-dose in-halers (MDIs), are intended to produce fine particles or

DOSAGE FORMS droplets for inhalation through the mouth and deposition inthe pulmonary tree. The design of the delivery system isintended to release measured mass and appropriate qualityof the active substance with each actuation.Aerosols Nasal aerosols, commonly known as nasal MDIs, producefine particles or droplets for delivery through the nasal vesti-Aerosols are preparations packaged under pressure and bule and deposition in the nasal cavity. Each actuation ofcontain therapeutic agent(s) and a propellant that are re- the valve releases measured mass and appropriate quality ofleased upon actuation of an appropriate valve system. Upon the active substance.actuation of the valve system, the API is released as a plume Lingual aerosols are intended to produce fine particles orof fine particles or droplets. Only one dose is released from droplets for deposition on the surface of the tongue. Thethe preparation upon actuation of a metered valve. In the design of the delivery system releases one dose with eachcase of topical products and depending on the nature of actuation.the API and the conditions being treated, actuation of the Topical aerosols produce fine particles or droplets for appli-valve may result in a metered release of a controlled cation to the skin.amount of the formulation or the continuous release of the Topical aerosol drug products may be designed, asformulation as long as the valve is depressed. needed, to deliver a metered amount of formulation uponIn this chapter, the aerosol dosage form refers only to actuation of the designed valve or continuous release of for-those products packaged under pressure that release a fine mulation during depressed status of the valve.mist of particles or droplets when actuated (see Glossary).

Other products that produce dispersions of fine droplets orparticles will be covered in subsequent sections (e.g., Inhala- PACKAGINGtion Powders and Sprays).

The accuracy of a system’s delivered dose is demonstratedat the range of pressures likely to be encountered as a resultTYPICAL COMPONENTS of ambient temperature variations or storage in a refrigera-tor. As an alternative, the system should include clear in-Typical components of aerosols are the formulation con- structions for use to ensure the container and contents havetaining one or more API(s) and propellant, the container, been equilibrated to room temperature prior to use.the valve, and the actuator. Each component plays a role in

determining various characteristics of the emitted plume,such as droplet or particle size distribution, uniformity of LABELING FOR PROPER USEdelivery of the therapeutic agent, delivery rate, and plumevelocity and geometry. The metering valve and actuator act Refer to 21 CFR 201.320 and 21 CFR 369.21.in tandem to generate the plume of droplets or particles. Many experts recommend the addition of a statement in-The metering valve allows measure of an accurate volume of dicating that patients and/or consumers should seek advicethe liquid formulation under pressure within the container. and instruction from a health care professional about theThe actuator directs the metered volume to a small orifice proper use of the device.that is open to the atmosphere. Upon actuation, the formu-lation is forced through the opening, forming the fine mist

Capsulesof particles that are directed to the site of administration.Aerosol preparations may consist of either a two-phase

Capsules are solid dosage forms in which the API and(gas and liquid) or a three-phase (gas, liquid, and solid orexcipients are enclosed within a soluble container or shell.liquid) formulation. The two-phase formulation consists of


The shells may be composed of two pieces, a body and a ers, and preservatives. Gelatin capsule shells normally con-cap, or they may be composed of a single piece. Two-piece tain between 12% and 16% water.capsules are commonly referred to as hard-shell capsules, The shells are manufactured in one set of operations andand one-piece capsules are often referred to as soft-shell later filled in a separate manufacturing process. Two-piececapsules. This distinction, although it is imprecise, reflects shell capsules are made by a process that involves dippingdiffering levels of plasticizers in the two compositions and shaped pins into gelatin or hypromellose solutions, followedthe fact that one-piece capsules typically are more pliable by drying, cutting, and joining steps.than two-piece capsules. Powder formulations for two-piece gelatin capsules gener-

The shells of capsules usually are made from gelatin. How- ally consist of the API and at least one excipient. Both theever, they also may be made from cellulose polymers or formulation and the method of filling can affect release ofother suitable material. Most capsules are designed for oral the API. In the filling operation, the body and cap of theadministration. When no deliberate effort has been made to shell are separated before filling. Following the filling opera-modify the API release rate, capsules are referred to as im- tion, the machinery rejoins the body and cap and ensuresmediate-release. satisfactory closure of the capsule by exerting appropriate

force on the two pieces. The joined capsules can be sealedTwo-Piece or Hard-Shell Capsules—Two-piece capsulesafter filling by a band at the joint of the body and cap or byconsist of two telescoping cap and body pieces in a rangea designed locking joint between the cap and body. Inof standard sizes.compounding prescription practice, two-piece capsules mayOne-Piece or Soft-Shell Capsules—One-piece capsules be hand-filled. This permits the prescriber the choice of se-typically are used to deliver an API as a solution or suspen- lecting either a single API or a combination of APIs at thesion. Liquid formulations placed into one-piece capsules exact dose level considered best for an individual patient.may offer advantages by comparison with dry-filled capsules

One-Piece Capsules—One-piece shell capsules areand tablets in achieving content uniformity of potent APIsformed, filled, and sealed in a single process on the sameor acceptable dissolution of APIs with poor aqueous solubil-machine and are available in a wide variety of sizes, shapes,ity. Because the contact between the shell wall and its liquidand colors. The most common type of one-piece capsule iscontents is more intimate than in dry-filled capsules, unde-that produced by a rotary die process that results in a cap-sired interactions may be more likely to occur (includingsule with a seam. The soft gelatin shell is somewhat thickergelatin crosslinking and pellicle formation).than that of two-piece capsules and is plasticized by theModified-Release Capsules—The release of APIs from addition of polyols such as glycerin, sorbitol, or other suita-capsules can be modified in several ways. There are two ble material. The ratio of the plasticizer to the gelatin cancategories of modified-release capsule formulations recog- be varied to change the flexibility of the shell depending onnized by the Pharmacopeia: the nature of the fill material, its intended usage, or environ-

Delayed-Release Capsules—Capsules sometimes are formu- mental conditions.lated to include enteric-coated granules to protect acid-lab- In most cases, one-piece capsules are filled with liquids.ile APIs from the gastric environment or to prevent adverse Typically, APIs are dissolved or suspended in a liquid vehicle.events such as irritation. Enteric-coated multiparticulate cap- Classically, an oleaginous vehicle such as a vegetable oil wassule dosage forms may reduce variability in bioavailability used. However, nonaqueous, water-miscible liquid vehiclesassociated with gastric emptying times for larger particles such as the lower molecular weight polyethylene glycols(i.e., tablets) and to minimize the likelihood of a therapeutic now are more common. The physicochemical properties offailure when coating defects occur during manufacturing. the vehicle can be chosen to ensure stability of the API as

Extended-Release Capsules—Extended-release capsules are well as to influence the release profile from the capsuleformulated in such a manner as to make the contained API shell.available over an extended period of time following inges-tion. Expressions such as “prolonged-action”, “repeat-ac- Inhalation Powderstion”, “controlled-release”, and “sustained-release” have alsobeen used to describe such dosage forms. However, the

Inhalation Powders, commonly known as dry powder in-term, extended-release, is used for Pharmacopeial purposes.halers (DPIs), consist of a mixture of API(s) and typically theRequirements for dissolution (see Dissolution ⟨711⟩) typicallycarrier; and all formulation components exist in a finely di-are specified in the individual monograph.vided solid state packaged in a suitable container–closureMethods for modifying API release from capsules includesystem. The dose is released from the packaging by acoating the filled capsule shells or the contents in the casemechanism and is mobilized into a fine dispersion upon oralof dry-filled capsules.inhalation by the patient.

PREPARATIONTYPICAL COMPONENTS

Two-Piece Capsules—Two-piece gelatin capsules usually The basic components of the DPI are the formulation con-are formed from blends of gelatins that have relatively high sisting of the API(s) and typically the carrier, both in the drygel strength in order to optimize shell clarity and toughness state. The formulation may be packaged in pre-metered oror from hypromellose. They also may contain colorants such device-metered units. Pre-metered DPIs contain a previouslyas D&C and FD&C dyes3 or various pigments, opaquing measured amount of formulation in individual units (e.g.,agents such as titanium dioxide, dispersing agents, plasticiz- capsules, blisters) that are inserted into the device before3 In 1960 Congress enacted the Color Additive Amendments, requiring FDA use. Pre-metered DPIs may also contain pre-metered doseto regulate dyes, pigments, or other coloring agents in foods, drugs, and units as ordered multidose assemblies in the delivery system.cosmetics separately from food additives. Under the law, color additives are Pre-metered DPIs include a mechanism designed to piercedeemed unsafe unless they are used in compliance with FDA regulations.

the capsule or open the unit-dose container and allow mo-The law provides a framework for the listing and certification of color addi-tives. See FDCA section 721; see FDA regulations at 21 CFR Part 70. Colors bilization and aerosolization of the powder by the patientmust also be listed in pertinent FDA regulations for specific uses; the list of inhaling through the integral mouthpiece. Device-meteredcolor additives for drugs that are exempt from certification is published at 21 DPI(s) have an internal reservoir that contains a sufficientCFR Part 73, Subpart B. FDA also conducts a certification program forbatches of color additives that are required to be certified before sale; see 21 quantity of formulation for multiple doses that are meteredCFR Part 74 (Subpart B re: drugs). Regulations regarding certification proce- by the device during actuation by the patient. To facilitatedures, general specifications, and the listing of certified provisionally listed dosing compliance, device-metered DPIs incorporate a dos-colors are at 21 CFR Part 80. FDA maintains a color additives website with

ing administration information mechanism, such as a doselinks to various legal and regulatory resources at: http://www.cfsan.fda.gov/~dms/col-toc.html. counter or a dose indicator system.


reduce particle or droplet size and improve the physical sta-PACKAGINGbility of the resultant dosage form.

The API(s) can be added to the phase in which it is solu-For pre-metered DPIs packaged in blister units, the packsble at the beginning of the manufacturing process, or it canmust be designed to allow individual unit cavities to bebe added after the cream is prepared by a suitable disper-opened without compromising the seal of adjacent cavities.sion process such as levigation or milling with a roller mill.Package components must provide acceptable protectionCreams usually require the addition of a preservative(s) un-from humidity, light, and/or oxygen as appropriate. Theless they are compounded immediately prior to use and in-components of the DPI container–closure system typicallytended to be consumed in a relatively short period of time.are made of plastic.

Lotions—Lotions usually are prepared by dissolving ordispersing the API into the more appropriate phase (oil or

LABELING AND USE water), adding the appropriate emulsifying or suspendingagents, and mixing the oil and water phases to form a uni-

Many experts recommend the addition of a statement in- form fluid emulsion.dicating that patients and/or consumers should seek adviceand instruction from a health care professional about theproper use of the device. LABELING AND PACKAGING

Some products may require labeling directions indicatingEmulsions (Creams and Lotions) to shake well prior to application and to avoid freezing.Storage limits must be specifically indicated to prevent melt-

Creams—Creams are semisolid emulsion dosage forms. ing of semisolid components. Instructions to ensure properThey often contain more than 20% water and volatiles and dosing and administration must accompany the product.typically contain less than 50% hydrocarbons, waxes, or Tight containers are used for preparation and storage topolyols as the vehicle for the API. Creams generally are in- prevent loss by evaporation.tended for external application to the skin or to the mucousmembranes. Creams have a relatively soft, spreadable con-

Veterinary Drugs and Drug Products Deliveredsistency and can be formulated as either a water-in-oil emul-sion (e.g., Cold Cream or Fatty Cream as in the European in Animal FeedsPharmacopoeia) or as an oil-in-water emulsion (e.g.,Betamethasone Valerate Cream). Creams generally are de- Medicated articles/feeds are preparations used in veteri-scribed as either nonwashable or washable, reflecting the nary medicine to deliver the API(s) via the water or foodfact that an emulsion with an aqueous external continuous given to animals. The medicated article/feed may be eitherphase is more easily removed than one with a nonaqueous a solid or liquid and sometimes is called a premix. Medi-external phase (water-in-oil emulsion). Where the term cated articles/feeds are further subdivided into three types.“cream” is used without qualification, a water-washableproduct is generally inferred.

TYPE A MEDICATED ARTICLESLotions—Lotions are an emulsified liquid dosage formgenerally intended for external application to the skin. His- Type A medicated articles consist of a new animal drug(s)torically, some topical suspensions such as calamine lotion with or without a carrier (e.g., calcium carbonate, rice hull,have been called lotions but that nomenclature is not cur- corn, gluten) and with or without inactive ingredients. Theyrently preferred. Lotions share many characteristics with are sold to licensed feed mills or producers and are intendedcreams. The distinguishing factor is that they are more fluid to be further diluted by mixing into food or water prior tothan semisolid and thus pourable. Due to their fluid charac- consumption by the animals. Because these preparations areter, lotions are more easily applied to large skin surfaces not actually dosed to animals, they are not considered dos-than semisolid preparations. Lotions may contain antimicro- age forms.bial agents as preservatives.

TYPE B MEDICATED FEEDSPREPARATION

Type B medicated feeds are products that contain a typePharmaceutical Compounding—Nonsterile Preparations A medicated article, or another type B medicated feed, plus⟨795⟩ provides general information regarding the prepara- a substantial quantity of nutrients (not less than 25% of thetion of emulsions. total weight). Like type A medicated articles, type B medi-Creams—Creams may be formulated from a variety of cated feeds are intended for mixture with food or water and

oils, both mineral and vegetable, and from fatty alcohols, additional nutrients, are not to be fed directly to the ani-fatty acids, and fatty esters. The solid excipients are melted mals, and are not considered dosage forms.at the time of preparation. Emulsifying agents include noni-onic surfactants, detergents, and soaps. Soaps are usuallyformed from a fatty acid in the oil phase hydrolyzed by a TYPE C MEDICATED FEEDSbase dissolved in the aqueous phase in situ during the prep-aration of creams. Type C medicated feeds are made from type A medicated

Preparation usually involves separating the formula com- articles or type B medicated feeds and are prepared at con-ponents into two portions: lipid and aqueous. The lipid por- centrations of the API appropriate for administration to ani-tion contains all water-insoluble components and the aque- mals by mixing in food or water. Administration of type Cous portion the water-soluble components. Both phases are medicated feeds can be accomplished by blending directlyheated to a temperature above the melting point of the into the feed; top-dressing the preparation onto the ani-highest melting component. The phases then are mixed and mal’s normal daily rations; or heating, steaming, and ex-the mixture is stirred until reaching ambient temperature or truding into pellets that are mixed or top-dressed onto thethe mixture has congealed. Mixing generally is continued animal’s food. Another form of type C medicated feeds isduring the cooling process to promote uniformity. Tradition- compressed or molded blocks from which animals receiveally, the aqueous phase is added to the lipid phase, but the API or nutrients via licking the block.comparable results have been obtained with the reverseprocedure. High-shear homogenation may be employed to


pensing, a foam drug product is shaken well to ensure uni-PREPARATIONformity. The instructions for use must clearly note specialprecautions that are necessary to preserve sterility. In theType A medicated articles that are liquids are produced byabsence of a metering valve, delivered volume may bemixing the API(s) with a suitable solvent (e.g., water or pro-variable.pylene glycol). The API(s) is usually dissolved to produce a

solution, but suspension products also could be produced.Type A medicated articles that are solids are produced by Medical Gases (Inhalation Materials)

blending the API with excipients to provide a uniform dos-age form when mixed with the animal’s feed. Often the API Medical gases are products that are administered directlyis first mixed with an excipient (e.g., starch or sodium alu- as a gas. A medical gas has a direct pharmacological actionminosilicate) that has a similar particle size and can help or acts as a diluent for another medical gas. Gases used asdistribute the API uniformly throughout the final drug prod- excipients for administration of aerosol products, as an adju-uct. This pre-blend is then mixed with bulking excipients vant in packaging, or produced by other dosage forms, are(e.g., calcium carbonate or soybean hulls). Mineral oil may not included in this definition.be added to aid uniform distribution, to prevent particle Components—Medical gases may be single componentssegregation during shipping, and to minimize formation of or defined mixtures of components. Mixtures also can beairborne API particles during production of type B or C extemporaneously prepared at the point of use.medicated feeds.

Administration—Medical gases may be administered toType B or C medicated feeds are produced at licensedthe patient using several methods: nasal cannulas, facefeed mills or by farm producers. Type A medicated articlesmasks, atmospheric tents, and endotracheal tubes for theare added to the feeds (e.g., ground corn or oats) duringpulmonary route; hyperbaric chambers for the pulmonarythe milling process of making feeds. Liquid type A medi-and dermal routes of administration; jetted tubes that arecated articles often are sprayed in at set rates, and soliddirected at dental tissue to promote drying in preparationtype A medicated articles are added slowly to aid in creatingfor fillings and crowns; tubes for expanding the intestines touniform distribution in the feeds. Liquid type A medicatedfacilitate medical imaging during colonoscopy; tubes for ex-articles can also be mixed in with bulk water sources atpanding the pelvis via transuterine inflation in preparationprescribed amounts.for fallopian tubal ligation; and tubes for expanding angi-oplasty devices. The dose of medical gas typically is metered

LABELING AND PACKAGING by a volume rate of flow under ambient temperature andpressure conditions. Administration of a highly compressed

Type A medicated articles or type B medicated feeds in- gas generally requires a regulator to decrease the pressure, aclude special labeling to indicate that they should be used variable-volume flow controller, and suitable tubing to con-in the manufacture of animal feeds or added to the drinking duct the gas to the patient. For pulmonary administration,water. The labels indicate that they are not to be fed di- the gas flow will be directed to the nose or mouth by arectly to animals. Also included is a statement indicating suitable device or into the trachea through a mechanical“Not for Human Use”. Type A medicated articles or type B ventilator. When medical gases are administered chronically,medicated feeds are packaged either in paper bags, often provision for humidification is common. Care should be ex-with polyethylene liners for solids, and in plastic containers ercised to avoid microbial contamination.for liquids. Typical sizes are 50-lb bags or several-galloncontainers.

STORAGE

Foams Medical gases are stored in a compressed state in cylin-ders or other suitable containers. The containers must be

Medicated foams are emulsions containing a dispersed constructed of materials that can safely withstand the ex-phase of gas bubbles in a liquid continuous phase contain- pected pressure and must be impact resistant. In some casesing the API. Medicated foams are packaged in pressurized each container holds a single defined dose (e.g., generalcontainers or special dispensing devices and are intended anesthetics), but in other cases the container holds sufficientfor application to the skin or mucous membranes. The med- gas for extended administration.icated foam is formed at the time of application. Surfactantsare used to ensure the dispersion of the gas and the twophases. Medicated foams have a fluffy, semisolid consistency SPECIAL CONSIDERATIONSand can be formulated to break to a liquid quickly or toremain as foam to ensure prolonged contact. The container and system fittings should be appropriate

Medicated foams intended to treat severely injured skin or for the medical gas. Adaptors should not be used to con-open wounds must be sterile. nect containers to patient-use supply system piping or

equipment. Large quantities of gases such as oxygen or ni-trogen can be stored in the liquid state in a cryogenic con-

PREPARATION tainer and converted into a gas, as needed, by evaporation.Additional rules concerning the construction and use of cry-

A foam may contain one or more APIs, surfactants, aque- ogenic containers are promulgated by governmental agen-ous or nonaqueous liquids, and the propellants. If the pro- cies (e.g., U.S. Department of Commerce).pellant is in the internal (discontinuous) phase (i.e., is of the Containers, tubing, and administration masks employedoil-in-water type), a stable foam is discharged. If the propel- for gases containing oxygen are free of any compound thatlant is in the external (continuous) phase (i.e., is of the would be sensitive to oxidation or that would be irritatingwater-in-oil type), a spray or a quick-breaking foam is dis- to the respiratory tract.charged. Quick-breaking foams formulated with alcohol cre- A significant fraction of the dose of a medical gas may beate a cooling sensation when applied to the skin and may released into the general vicinity of the patient due to in-have disinfectant properties. complete absorption. Adequate ventilation may be neces-

sary to protect health care workers and others from expo-sure to the gas (e.g., nitrous oxide).LABELING AND USE

Foams formulated with flammable components should beappropriately labeled. Labeling indicates that prior to dis-


pediatric patients, geriatric patients, or animals). GranularLABELINGdosage forms may be formulated for direct oral administra-tion and may facilitate compounding of multiple APIs byIf required under the individual monograph, label to indi-allowing compounding pharmacists to blend various granu-cate the method of manufacture (such as oxygen via airlar compositions in the retail or hospital pharmacy. Moreliquefaction). When piped directly from the storage con-commonly, granules are reconstituted to a suspension bytainer to the point of use, the gas must be labeled for con-the addition of water or a supplied liquid diluent immedi-tent at each outlet.ately prior to delivery to the patient. Effervescent granulesWhen oxygen is in use, a posted warning should indicateare formulated to liberate gas (carbon dioxide) upon addi-the necessity of extinguishing smoking materials and avoid-tion of water. Common examples of effervescent granulesing the use of open flames or other potential ignitioninclude antacid and potassium supplementation prepara-sources.tions. Common therapeutic classes formulated as granuledosage forms include antibiotics, certain laxatives (such as

Gels senna extract products), electrolytes, and various cough andcold remedies that contain multiple APIs.

Gels are semisolids consisting either of suspensions of Granular dosage forms also are employed in veterinarysmall inorganic particles or of organic molecules interpene- medicine when they are often placed on top of or mixedtrated by a liquid. Jellies are a type of gel that typically have with an animal’s food. They are frequently provided with aa higher water content. Gels can be classed either as single- measuring device to allow addition to feeds. The resultantphase or two-phase systems. mix facilitates dosing.

A two-phase gel consists of a network of small discreteparticles (e.g., Aluminum Hydroxide Gel or Psyllium Hemicellu-lose). Gels may be thixotropic, forming semisolids on stand- PREPARATIONing and becoming less viscous on agitation. They should beshaken before use to ensure homogeneity and should be so Granules often are the precursors used in tablet compres-labeled. sion or capsule filling. Although this application represents a

Single-phase gels consist of organic macromolecules uni- pharmaceutical intermediate and not a final dosage form,formly distributed throughout a liquid in such a manner numerous commercial products are based on granules. Inthat no apparent boundaries exist between the dispersed the typical manufacture of granules, the API is blended withmacromolecules and the liquid. Single-phase gels may be excipients (processing aids) and wetted with an appropriatemade from natural or synthetic macromolecules (e.g., Car- pharmaceutical binding solution, solvent, or blend of sol-bomer, Hydroxypropyl Methylcellulose, or Starch) or natural vents to promote agglomeration. This composition is driedgums (e.g., Tragacanth). The latter preparations are also and sized to yield the desired material properties.called mucilages. Although these gels commonly are aque- Frequently, granules are used because the API is unstableous, alcohols and oils may be used as the continuous phase. in aqueous environments and cannot be exposed to waterFor example, mineral oil can be combined with a polyethyl- for periods sufficient to accommodate manufacture, storage,ene resin to form an oleaginous ointment base. and distribution in a suspension. Preparation of the liquid

Gels can be administered by the topical or mucosal dosage form from the granules immediately prior to dis-routes. Gels containing antibiotics administered by teat infu- pensing allows acceptable stability for the duration of use.sion can be used in veterinary medicine to treat mastitis. Granules manufactured for this purpose are packaged in

quantities sufficient for a limited time period—usually onecourse of therapy that typically does not exceed two weeks.

PREPARATION In addition to the API, other ingredients may be added toensure acceptable stability (e.g., buffers, antioxidants, or

See Pharmaceutical Compounding—Nonsterile Preparations chelating agents) or to provide color, sweetness, and flavor;⟨795⟩ for general procedures. Also see the information con- and for suspensions, to provide acceptable viscosity to en-tained under Suspensions for the formulation and manufac- sure adequate suspension of the particulate to enable uni-ture of gels containing inorganic components or APIs in the form dosing.solid phase. See Pharmaceutical Compounding—Sterile Prepa- Effervescent granules typically are formulated from sodiumrations ⟨797⟩ for general procedures for the preparation of or potassium bicarbonate and an acid such as citric or tar-sterile gels such as Lidocaine Hydrochloride Jelly. taric acid. To prevent untimely generation of carbon diox-

Gels formed with large organic molecules may be formed ide, manufacturers should take special precautions to limitby dispersing the molecule in the continuous phase (e.g., by residual water in the product due to manufacture and toheating starch), by cross-linking the dispersed molecules by select packaging that protects the product from moisture.changing the pH (as for Carbomer Copolymer), or by reduc- The manufacture of effervescent granules can require spe-ing the continuous phase (as for jellies formed with cialized facilities designed to maintain very low humiditysucrose). (approximately 10% relative humidity). Effervescent powder

Care should be taken to ensure uniformity of the APIs by mixtures are purposely formed into relatively course gran-dispersing them by vigorous mixing or milling or by shaking ules to reduce the rate of dissolution and provide a moreif the preparation is less viscous. controlled effervescence.

PACKAGING AND STORAGE PACKAGING AND STORAGE

Store in tight containers to prevent water loss. Avoid Granules for reconstitution may be packaged in unit-of-freezing. use containers or in containers with sufficient quantities to

accommodate a typical course of therapy (frequently 10days to two weeks with antibiotic products). PackagingGranulesshould provide suitable protection from moisture. This isparticularly true for effervescent granules. Granules may beGranules are solid dosage forms that are composed of ag-stored under controlled room temperature conditions unlessglomerations of smaller particles. These multicomponentother conditions are specifically noted.compositions are prepared for oral administration and are

Many granule products specify refrigerated storage follow-used to facilitate flexible dosing regimens as granules or asing reconstitution and direct the patient to discard unusedsuspensions, address stability challenges, allow taste mask-

ing, or facilitate flexibility in administration (for instance, to


contents after a specified date that is based on the stability Directly Compressed Gum—The gum base is suppliedof the API in the reconstituted preparation. in a free-flowing granular powder form. The powder gum

base is then dry blended with sweeteners, flavors, the API,and lubricant. The blend is then processed through a con-

LABELING AND USE ventional tablet press and tableted into desired shapes. Theresulting medicated gum tablets can be further coated with

Effervescent granules (and tablets) are labeled to indicate sugar or sugar-free excipients. These tablets can be pack-that they are not to be swallowed directly. aged in blisters or bottles as needed.

Reconstitution of granules must ensure complete wettingof all ingredients and sufficient time and agitation to allowthe soluble components to dissolve. Specific instructions for SPECIAL CONSIDERATIONSreconstitution provided by the manufacturer should be care-fully followed. Medicated gums are typically dispensed in unit-dose pack-

Reconstituted suspensions should be thoroughly mixed or aging. The patient instructions also may include a caution toshaken before use to re-suspend the dispersed particulates. avoid excessive heat.This is especially true of suspension preparations dosed frommultiple-dose containers. For particularly viscous suspensions Implantsprone to air entrapment, instructions may advise the userhow to shake the preparation to re-suspend settled particu- Implants are long-acting dosage forms that provide con-lates while minimizing air entrapment. tinuous release of the API often for periods of months to

years. They are administered by the parenteral route. Forsystemic delivery they may be placed subcutaneously, or forSPECIAL CONSIDERATIONSlocal delivery they can be placed in a specific region in thebody.For granules reconstituted to form suspensions for oral ad-

Several types of implants are available. Pellet implants areministration, acceptable suspension of the particulate phasesmall, sterile, solid masses composed of an API with or with-depends on the particle size of the dispersed phase as wellout excipients. They are usually administered by means of aas the viscosity of the vehicle. Temperature can influencesuitable special injector (e.g., trocar) or by surgical incision.the viscosity, which influences suspension properties and theRelease of the API from pellets typically is controlled by dif-ease of removal of the dose from the bottle. In addition,fusion and dissolution kinetics. The size of the pellets andtemperature cycling can lead to changes in the particle sizerate of erosion will influence the release rate, which typicallyof the dispersed phase via Ostwald ripening. Thus, clear in-follows first-order kinetics. API release from pellets for peri-structions should be provided regarding the appropriateods of six months or more is possible. Pellet implants havestorage temperature for the product.been used to provide extended delivery of hormones suchas testosterone or estradiol.

Medicated Gums Resorbable microparticles are a type of implants that pro-vide extended release of API over periods varying from a

Medicated gum is a semisolid confection that is designed few weeks to months. They can be administered subcutane-to be chewed rather than swallowed. Medicated gums re- ously or intramuscularly for systemic delivery, or they maylease the API(s) into the saliva. Medicated gums can deliver be deposited in a desired location in the body for site-spe-therapeutic agents for local action in the mouth (such as cific delivery. Injectable resorbable microparticles (or micro-antibiotics to control gum disease) or for systemic absorp- spheres) generally range from 20 to 100 µm in diameter.tion via the buccal or gastrointestinal routes (e.g., nicotine They are composed of an API dispersed within a biocompa-or aspirin). Most medicated gums are manufactured using tible, bioresorbable polymeric excipient (matrix). Poly(lac-the conventional melting process derived from the confec- tide-co-glycolide) polymers have been used frequently.tionary industry or alternatively may be directly compressed These excipients typically resorb by hydrolysis of ester link-from gum powder. Medicated gums are formulated from ages. The microparticles are administered by suspension ininsoluble synthetic gum bases such as polyisoprene, polyiso- an aqueous vehicle followed by injection with a conven-butylene, isobutyleneisoprene copolymer, styrene butadiene tional syringe and needle. Release of the API from therubber, polyvinyl acetate, polyethylene, ester gums, or microparticles begins after physiological fluid enters the pol-polyterpenes. Plasticizers and softeners such as propylene ymer matrix, dissolving some of the API that then is releasedglycol, glycerin, oleic acid, or processed vegetable oils are by a diffusion-controlled process. Drug release also can oc-added to keep the gum base pliable and to aid incorpora- cur as the matrix erodes.tion of the API(s), sweeteners, and flavoring agents. Sugars Polymer implants can be formed as a single-shaped massas well as artificial sweeteners and flavorings are incorpo- such as a cylinder. The polymer matrix must be biocompa-rated to improve taste, and dyes may be used to enhance tible, but it can be either biodegradable or nonbiodegrada-appearance. Some medicated gums are coated with magne- ble. Shaped polymer implants are administered by means ofsium stearate to reduce tackiness and improve handling dur- a suitable special injector. Release kinetics typically are noting packaging. A preservative may be added. zero-order, but zero-order kinetics are possible. API release

can be controlled by the diffusion of the API from the bulkpolymer matrix or by the properties of a rate-limiting poly-PREPARATION meric membrane coating. Polymer implants are used to de-liver potent small molecules like steroids (e.g., estradiol for

Melted Gum—The gum base is melted at a temperature cattle) and large molecules like peptides [e.g., luteinizingof about 115° until it has the viscosity of thick syrup and at hormone-releasing hormone (LHRH)]. Example durations ofthat point is filtered through a fine-mesh screen. This mol- API release are two and three months for biodegradable im-ten gum base is transferred to mixing tanks where the plants and one year for nonbiodegradable implants. An ad-sweeteners, plasticizers, and typically the API are added and vantage of biodegradable implants is that they do not re-mixed. Colorings, flavorings, and preservatives are added quire removal after release of all API content. Nonbiode-and mixed while the melted gum is cooling. The cooled gradable polymer implants can be removed before or aftermixture is shaped by extrusion or rolling and cutting. Dos- API release is complete or may be left in situ. An implantage units of the desired shape and potency are packaged can have a tab with a hole in it to facilitate suturing it inindividually. Additional coatings such as powder coatings to place, e.g., for an intravitreal implant for local ocular deliv-reduce tackiness or film or sugar coatings may be added toimprove taste or facilitate bulk packaging.


ery. Such implants may provide therapeutic release for peri- released. Intrauterine inserts such as Progesterone Intrauterineods as long as 2.5 years. Contraceptive System are used to deliver APIs locally to

Some implants are designed to form as a mass in situ. achieve efficacy while reducing side effects. Some intrauter-These implants are initially prepared as liquid formulations ine inserts are formulated to remain in the uterus for ex-comprising polymer, API, and solvent for the polymer. The tended periods of time. An intra-urethral insert of alprostadilpolymer solvent can be water or an organic solvent. After is available for the treatment of erectile dysfunction.administration of the liquid formulation to a patient by sub-cutaneous or intramuscular administration, it forms a gel or

PREPARATIONa solid polymeric matrix that traps the API and extends theAPI release for days or months. In situ-forming implants also

For general considerations see Pharmaceutical Compound-are used for local delivery of the API to treat periodontaling—Nonsterile Preparations ⟨795⟩. Inserts vary considerablydisease. The implant is formed within the periodontalin their preparation. Inserts may be molded (using technol-pocket.ogy similar to that used to prepare lozenges, suppositories,Another type of implant can be fabricated from a metalor plastics), compressed from powders (as in tableting), orsuch as titanium and plastic components. These implantsformulated as special applications of capsules (soft gelatinare administered by means of a suitable injector or by surgi-capsules and hard gelatin capsules have been employed forcal installation. A solution of API inside the implant, like anextemporaneously compounded preparations). Inserts mayLHRH solution, is released via an osmotically driven pumpbe formulated to melt at body temperature or disintegrateinside the implant. Duration of release may be as long asupon insertion. Design of the dosage form should take intoone year or more. Release kinetics are zero order. After theconsideration the fluid volume available at the insertion siteAPI is delivered, metal-based implants are removed.and minimize the potential to cause local irritation. MostAPI-eluting stents combine the mechanical effect of theinserts are formulated to ensure retention at the site ofstent to maintain arterial patency with the prolonged phar-administration.macologic effect of the incorporated API (to reduce

restenosis, inhibit clot formation, or combat infection). Asan example, a metal stent can be coated with a nonbiode- STORAGE AND LABELINGgradable or biodegradable polymer-containing API. The re-sultant coating is a polymeric matrix that controls the ex- Appropriate storage conditions must be clearly indicatedtended release of the API. in the labeling for all inserts, especially for those that are

designed to melt at body temperature. Instructions to en-sure proper dosing and administration must accompany thePREPARATIONproduct.

Pellet implants are made by API compression or molding.Cylindrical polymeric implants typically are made by melt Liquidsextrusion of a blend of API and polymer, resulting in a rodthat is cut into shorter lengths. Polymer implants also can As a dosage form a liquid consists of a pure chemical inbe made by injection molding. Still other implants are as- its liquid state. Examples include mineral oil, isoflurane, andsembled from metal tubes and injection-molded plastic ether. This dosage form term is not applied to solutions.components.

Sterility can be achieved by terminal sterilization or byemploying aseptic manufacturing procedures. STORAGE AND LABELING

Storage, packaging, and labeling consider the physicalPACKAGING AND STORAGE properties of the material and are designed to maintain po-

tency and purity.All implants are individually packaged (typically in their

injector or for veterinary use in cartridges that are placed inLotionsthe injector guns), are sterile (except for some animal health

products), and conform to the appropriate standards for in-(See Emulsions.)jection. Biodegradable implants are protected from moisture

so the polymer does not hydrolyze and alter drug releasekinetics before use. Lozenges

Lozenges are solid oral dosage forms that are designed toInsertsdissolve or disintegrate slowly in the mouth. They containone or more APIs that are slowly liberated from the flavoredInserts are solid dosage forms that are inserted into a nat-and sweetened base. They are frequently intended to pro-urally occurring (nonsurgical) body cavity other than thevide local action in the oral cavity or the throat but alsomouth or rectum (see Suppositories). The API is delivered ininclude those intended for systemic absorption after dissolu-inserts for local or systemic action. Inserts applied to thetion. The typical therapeutic categories of APIs delivered ineye, such as Pilocarpine Ocular System, typically are sterile.lozenges are antiseptics, analgesics, decongestants, antitus-Vaginal inserts for humans are usually globular or oviformsives, and antibiotics. Molded lozenges are called coughand weigh about 5 g each. Vaginal inserts for cattle aredrops or pastilles. Lozenges prepared by compression or byT-shaped, are formed of polymer, are removable, and canstamping or cutting from a uniform bed of paste sometimesbe used for up to eight days. One veterinary application isare known as troches. Troches are often produced in a circu-for estrus synchronization. Inserts intended to dissolve inlar shape.vaginal secretions usually are made from water-soluble or

Lozenges can be made using sugars such as sucrose andwater-miscible vehicles such as polyethylene glycol or glyc-dextrose or can provide the benefits of a sugar-free formula-erinated gelatin. Vaginal inserts such as dinoprostone vaginaltion that is usually based on sorbitol or mannitol. Polyethyl-insert (e.g., see USP monograph Dinoprostone Vaginal Sup-ene glycols and hypromellose sometimes are included topositories) are formulated to deliver medication to the cervixslow the rate of dissolution.and to be removed or recovered once the API has been


(see Emulsions). They may be readily washed from the skinMANUFACTUREor clothing with water, making them acceptable for cos-metic reasons. Other advantages of the water-removableExcipients used in molded lozenge manufacture includebases are that they can be diluted with water and that theygelatin, fused sucrose, sorbitol, or another carbohydratefavor the absorption of serous discharges in dermatologicalbase.conditions.Molded lozenges using a sucrose or sorbitol base contain-

ing APIs such as phenol, dextromethorphan, fentanyl, and Water-Soluble Bases—Also known as greaseless oint-dyclonine hydrochloride and menthol are prepared by cook- ment bases, they are formulated entirely from water-solubleing the sugar (sucrose, corn syrup, and sorbitol) and water constituents. Polyethylene Glycol Ointment is the only officialat about 150° to reduce the water content to less than 2%. preparation in this group. They offer many of the advan-The molten sugar solution is transferred to a cooling belt or tages of the water-removable bases and, in addition, con-cooling table, and medicaments, flavorings, and colorings tain no water-insoluble substances such as petrolatum, an-are added and thoroughly mixed while cooling. Individual hydrous lanolin, or waxes. They are more correctlydosage units of the desired shape are formed by filling the categorized as gels (see Gels).molten mass into molds. These lozenges are quickly cooled The choice of an ointment base depends on the actionin the molds to trap the base in the glassy state. Once desired, the characteristics of the incorporated API, and theformed, the lozenges are removed from the molds and latter’s bioavailability if systemic action is desired. The prod-packaged. Care is taken to avoid excessive moisture during uct’s stability may require the use of a base that is less thanstorage to prevent crystallization of the sugar base. ideal in meeting other quality attributes. APIs that hydrolyze

Compressed lozenges are made using excipients that may rapidly, for example, are more stable in hydrocarbon basesinclude a filler, binder, sweetening agent, flavoring agent, than in bases that contain water.and lubricant. Sugars such as sucrose, sorbitol, and mannitol Ophthalmic ointments are intended for application di-often are included because they can act as filler and binder rectly to the eye or eye-associated structures such as theas well as serve as sweetening agents. Approved FD&C and subconjunctival sac. They are manufactured from sterilizedD&C dyes or lakes (dyes adsorbed onto insoluble aluminum ingredients under aseptic conditions and meet the require-hydroxide) also may be present. ments under Sterility Tests ⟨71⟩. Ingredients meeting the re-

The manufacturing of compressed lozenges is essentially quirements described under Sterility Tests ⟨71⟩ are used ifthe same as that for conventional tableting, with the excep- they are not suitable for sterilization procedures. Ophthalmiction that a tablet press capable of making larger tablets and ointments in multiple-dose containers contain suitable anti-exerting greater force to produce harder tablets may be re- microbial agents to control microorganisms that might bequired (see Tablets). introduced during use unless otherwise directed in the indi-

The paste used to produce lozenges manufactured by vidual monograph or unless the formula itself is bacterio-stamping or cutting contains a moistening agent, sucrose, static (see Ophthalmic Ointments ⟨771⟩, Added Substances).and flavoring and sweetening agents. The homogenous The finished ointment is free from large particles and mustpaste is spread as a bed of uniform thickness, and the loz- meet the requirements for Leakage and for Metal Particlesenges are cut or stamped from the bed and are allowed to under Ophthalmic Ointments ⟨771⟩. The immediate containerdry. Some lozenges are prepared by forcing dampened for ophthalmic ointments is sterile at the time of filling andpowders under low pressure into mold cavities and then closing. The immediate containers for ophthalmic ointmentsejecting them onto suitable trays for drying at moderate are sealed and made tamper-proof so that sterility is en-temperatures. sured at time of first use.

A suitable ophthalmic ointment base is nonirritating tothe eye and permits diffusion of the API throughout the

PACKAGING AND STORAGE secretions bathing the eye. Petrolatum is most commonlyused as a base for ophthalmic APIs. Some absorption bases,

Many lozenges are sensitive to moisture, and typically a water-removable bases, and water-soluble bases may be de-monograph indicates that the package or container type is sirable for water-soluble APIs if the bases are nonirritating.well closed and/or moisture resistant. Storage instructionsmay include protection from high humidity.

MANUFACTURE

Ointments Ointments typically are prepared by either direct incorpo-ration into a previously prepared ointment base or by fusionOintments are semisolid preparations intended for exter- (heating during the preparation of the ointment). A levigat-nal application to the skin or mucous membranes. APIs de- ing agent is often added to facilitate the incorporation oflivered in ointments are intended for local action or for sys- the medicament into the ointment base by the direct incor-temic absorption. Ointments usually contain less than 20% poration procedure. In the fusion method, the ingredientswater and volatiles and more than 50% hydrocarbons, are heated, often in the range of 60° to 80°. Homogeniza-waxes, or polyols as the vehicle. Ointment bases recognized tion is often necessary. The rate of cooling is an importantfor use as vehicles fall into four general classes: hydrocarbon manufacturing detail because rapid cooling can impart in-bases, absorption bases, water-removable bases, and water- creased structure to the product of the fusion method.soluble bases.

Hydrocarbon Bases—Also known as oleaginous oint-ment bases, they allow the incorporation of only small PACKAGING AND STORAGEamounts of an aqueous component. Ointments preparedfrom hydrocarbon bases act as occlusive dressings and pro- Protect from moisture. For emulsified systems, tempera-vide prolonged contact of the API with the skin. They are ture extremes can lead to physical instability of the prepara-difficult to remove and do not change physical characteris- tion. When this is the case products should be clearly la-tics upon aging. beled to specify appropriate storage conditions. Ointments

typically are packaged either in ointment jars or ointmentAbsorption Bases—Allow the incorporation of aqueoustubes. Ointment jars are often used for more viscous oint-solutions. Such bases include only anhydrous componentsments that do not require sterility. Ointment tubes typically(e.g., Hydrophilic Petrolatum) or water-in-oil emulsions (e.g.,are used for less viscous ointments and those such asLanolin). Absorption bases are also useful as emollients.ophthalmic ointments that require the maintenance of steril-Water-Removable Bases—Oil-in-water emulsions (e.g., ity. The package sizes for ophthalmic preparations are con-Hydrophilic Ointment) are sometimes referred to as creams


trolled to minimize the likelihood of contamination and loss TDSs are applied to the body areas recommended by theof sterility. labeling. The API content of the system provides a reservoir

that, by design, maintains a constant API concentration atthe system–skin interface. The dosing interval of the systemPastes is a function of the amount of API in the reservoir and therelease rate. Some API concentration may remain in the res-Pastes are semisolid preparations of stiff consistency and ervoir at the end of the dosing interval, in particular forcontain a high percentage of finely dispersed solids. Pastes diffusion-controlled delivery mechanisms. [NOTE—Where theare intended for application to the skin, oral cavity, or mu- API is intended for local action, it may be embedded incous membranes. In veterinary practice, pastes are used for adhesive on a cloth or plastic backing. This type of productsystemic delivery of APIs. is sometimes called a plaster or tape (see Plasters andPastes ordinarily do not flow at body temperature and Tapes).]thus can serve as occlusive, protective coatings. As a conse-

quence, pastes are more often used for protective actionthan are ointments. PREPARATION

Fatty pastes that have a high proportion of hydrophilicsolids appear less greasy and more absorptive than oint- TDSs require a backing, a means of storing the API forments. They are used to absorb serous secretions and are delivery to the skin, an adhesive to attach the system to theoften preferred for acute lesions that have a tendency to- skin, and a removable release liner to protect the adhesive,ward crusting, vesiculation, or oozing. API, and excipients before application. The backing has low

Dental pastes may be applied to the teeth, or alternatively moisture- and vapor-transmission rates to support productthey may be indicated for adhesion to the mucous mem- stability. The adhesive layer may contain the API and perme-brane for a local effect (e.g., Triamcinolone Acetonide Dental ation enhancers in the case of matrix-type systems or multi-Paste). Some paste preparations intended for animals are laminate reservoir systems for which a priming dose is de-administered orally. The paste is squeezed into the mouth of sired. Adhesive may be applied to the entire patch releasethe animal, generally at the back of the tongue, or is spread surface or merely to the periphery. Liquid reservoir systemsinside the mouth. are often formed–filled–sealed between the backing and re-

lease-controlling materials. For monolithic adhesive matrixsystems, the API and excipients are applied as a solution orPREPARATION suspension either to the backing or the release liner, andthe solvent is allowed to evaporate.Pastes can be prepared by direct incorporation or by fu-

sion (the use of heat to soften the base). The solid ingredi-ents often are incorporated following comminution and PACKAGING AND STORAGEsieving. If a levigating agent is needed, a portion of theointment base is often employed rather than a liquid. Storage conditions are clearly specified because extreme

temperature excursions can influence the performance ofsome systems.LABELING AND STORAGE

Veterinary products should be labeled to ensure they are LABELINGnot administered to humans. Labeling should indicate theneed for protection from heat. The labeling should clearly indicate any performance limi-

tations of the system (e.g., influence of application site, hy-dration state, hair, or other variables).Transdermal Systems (Patches)

Transdermal API delivery systems (TDSs) are discrete dos- Pelletsage forms that are designed to deliver the API(s) throughintact skin to the systemic circulation. Typically, a TDS is Pellets are dosage forms composed of small, solid particlescomposed of an outer covering (barrier), an API reservoir of uniform shape sometimes called beads. Typically, pellets(possibly covered with a rate-controlling membrane), a con- are nearly spherical but this is not required. Pellets may betact adhesive applied to some or all parts of the system (to administered by the oral (gastrointestinal) or by the injec-attach the TDS to the skin surface), and a protective layer tion route (see also Implants). Pellet formulations may pro-that is removed before the patch is applied. The activity of a vide several advantages including physical separation forTDS is defined in terms of the release rate of the API(s) from chemically or physically incompatible materials, extended re-the system. The total duration of drug release from the sys- lease of the API, or delayed release to protect an acid-labiletem and the system surface area also may be stated. API from degradation in the stomach or to protect stomach

Most TDSs can be considered either matrix-type or reser- tissues from irritation. Extended-release pellet formulationsvoir-type systems. Matrix-type patches are often further di- may be designed with the API dispersed in a matrix, or thevided into monolithic adhesive matrix or polymer matrix pellet may be coated with an appropriate polymer coatingtypes. Reservoir-type systems include liquid reservoir systems that modifies the drug-release characteristics. Alternatively,and solid-state reservoir systems. Solid-state reservoir the pellet design may combine these two approaches. Inpatches also include multilaminate adhesive and multi- the case of delayed-release formulations, the coating poly-laminate polymer matrix systems. mer is chosen to resist dissolution at the lower pH of the

Drug delivery from some TDSs is controlled by diffusion gastric environment but to dissolve in the higher pH intesti-kinetics. The API diffuses from the drug reservoir directly or nal environment. Injected or surgically administered pelletthrough the rate-controlling membrane and/or contact ad- preparations (see Implants) are often used to provide contin-hesive and then through the skin into the general circula- uous therapy for periods of months or years.tion. Modified-release systems are generally designed to pro- Pellet dosage forms may be designed as single or multiplevide drug delivery at a constant rate so that a true steady- entities. Often implanted pellets will contain the desired APIstate blood concentration is achieved and maintained until content in one or several units. In veterinary practice, multi-the system is removed. Other TDSs work by active transport ple pellets may be implanted in the ears of cattle, depend-of the API. For example, iontophoretic transdermal delivery ing on animal size. Oral pellets typically are containeduses the electric current between two electrodes to enhance within hard gelatin capsules for administration. Althoughthe movement of ionized APIs through the skin. there are no absolute requirements for size, the useful size


range of pellets is governed by the practical constraints of placed by compressed tablets and capsules. Pills are distin-the volume of commonly used capsules and the need to guished from tablets because pills are usually prepared by ainclude sufficient numbers of pellets in each dose to ensure wet massing and molding technique, while tablets are typi-uniform dosing of the API. As a result, many pellets used for cally formed by compression.oral administration fall within a size range of 710 µm to2.36 mm. Pellet formulations sometimes are used to mini-

PREPARATIONmize variability associated with larger dosage forms causedby gastric retention upon stomach emptying.

Excipients are selected on the basis of their ability to pro-Enteric-coated (delayed-release) pellet formulations andduce a mass that is firm and plastic. The API is trituratedsome extended-release formulations are prepared by apply-with powdered excipients in serial dilutions to attain a uni-ing a coating to the formulated particles. The coating mustform mixture. Liquid excipients that act to bind and providebe applied as a continuous film over the entire surface ofplasticity to the mass are subsequently added to the dryeach particle. Because a small population of imperfectlymaterials. The mass is formed by kneading. The propertiescoated particles may be unavoidable, oral pellets are de-of firmness and plasticity are necessary to permit the masssigned to require the administration of a large number in ato be worked and retain the shape produced. Cylindrical pillsingle dose to minimize any adverse influence of imperfectlypipes are produced from portions of the mass. The pill pipecoated pellets on drug delivery.is cut into individual lengths corresponding to the intendedpill size, and the pills are rolled to form the final shape. Pill-

PREPARATION making machines can automate the preparation of themass, production of pill piping, and the cutting and rolling

The desired performance characteristics determine the of pills.manufacturing method chosen. In general, pellet dosageforms are manufactured by wet extrusion processes followed

PACKAGING AND LABELINGby spheronization, by wet or dry coating processes, or bycompression. Manufacture of pellets by wet coating usually

Labeling and use instructions for pills are similar to thoseinvolves the application of successive coatings upon nonpa-for tablets. Although many pills are resistant to breakage,reil seeds. This manufacturing process frequently is con-some pills are friable. Appropriate handling guidelinesducted in fluid-bed processing equipment. Dry powdershould be provided in such cases in order to avoidcoating or layering processes often are performed in special-breakage.ized rotor granulation equipment. The extent of particle

growth achievable in wet coating processes is generallymore limited than the growth that can be obtained with dry Plasterspowder layering techniques, but either method allows theformulator to develop and apply multiple layers of coatings A plaster is a semisolid substance for external applicationto achieve the desired release profile. The manufacture of and usually is supplied on a support material. Plasters arepellets by compression is largely restricted to the production applied for prolonged periods to provide protection, sup-of material for subcutaneous implantation. This method of port, or occlusion (maceration).manufacture provides the necessary control to ensure dose Plasters consist of an adhesive layer that may contain ac-uniformity and generally is better suited to aseptic process- tive substances. This layer is spread uniformly on an appro-ing requirements. priate support that is usually made of a rubber base or syn-

Alternatively, microencapsulation techniques can be used thetic resin. Unmedicated plasters are designed to provideto manufacture pellets. Coacervation coating techniques protection or mechanical support to the site of application.typically produce coated particles that are much smaller These plasters are neither irritating nor sensitizing to thethan those made by other techniques. skin.

Plasters are available in a range of sizes or cut to size toeffectively provide prolonged contact to the site of applica-PACKAGING AND STORAGE tion. They adhere firmly to the skin but can be peeled offthe skin without causing injury.Pellets for oral administration generally are filled into hard One example of a plaster currently in use is salicylic acidgelatin capsules and are placed in bottles or blister pack- plasters used for the removal of corns by the keratolytic ac-ages. The packaging provides suitable protection from mois- tion of salicylic acid.ture to ensure the stability of the pellet formulation as well

as to preserve desirable moisture content of the capsuleshells. Pellets for implantation are sterile and should be PACKAGING AND STORAGEpackaged in tight containers suitable for maintaining sterilecontents. Pellets may be stored under controlled room tem- Plasters are preserved in well-closed containers, preferablyperature conditions unless other conditions are specifically at controlled room temperature.noted.

PowdersLABELING AND USE

Powders are defined as a solid or a mixture of solids in aPellets for oral administration that are formulated to pro- finely divided state intended for internal or external use.

vide delayed or extended release must be swallowed intact Powders used as pharmaceutical dosage forms may containto ensure preservation of the desired release characteristics. one or more APIs and can be mixed with water for oralThese products should be labeled accordingly to ensure that administration or injection. Often pediatric antibiotics utilizethe material is not crushed or chewed during a powder dosage form for improved stability. In some areasadministration. medicated powders are used for extemporaneous com-

pounding of preparations for simultaneous administration ofmultiple APIs. Medicated powders also can be inhaled forPills pulmonary administration (see Inhalation Powders). Aerosol-ized powders for the lungs typically contain processing aidsPills are API-containing small, round solid bodies intended to improve flow and ensure uniformity (see Aerosols, Nasalfor oral administration. At one time pills were the most ex- Sprays, Metered-Dose Inhalers, and Dry Powder Inhalerstensively used oral dosage form, but they have been re-


⟨601⟩). Powders can also be used topically as a dustingpowder. Medicated Soaps and Shampoos

Externally applied powders should have a particle size of150 µm or less (typically in the 50- to 100-µm range) in Medicated soaps and shampoos are solid or liquid prepa-order to prevent a gritty feel on the skin that could further rations intended for topical application to the skin or scalpirritate traumatized skin. Powders are grouped according to followed by subsequent rinsing with water. Soaps andthe following terms: very coarse, coarse, moderately coarse, shampoos are emulsions or surface-active compositions thatfine, and very fine (see Powder Fineness ⟨811⟩). The perfor- readily form emulsions or foams upon the addition of watermance of powder dosage forms can be affected by the followed by rubbing. Incorporation of APIs in soaps andphysical characteristics of the powder. Particle size can influ- shampoos combines the cleansing/degreasing abilities of theence the dissolution rate of the particles and affect bioavai- vehicle and facilitates the topical application of the API tolability. For dispersed delivery systems, particle size can influ- affected areas, even large areas, of the body. The surface-ence the mixing and segregation behavior of the particle, active properties of the vehicle facilitate contact of the APIwhich in turn affects the uniformity of the dosage form. with the skin or scalp. Medicated soap and shampoo formu-

lations frequently contain suitable antimicrobial agents toprotect against bacteria, yeast, and mold contamination.PREPARATION

Powder dosage forms can be produced by the combina- PREPARATIONtion of multiple components into a uniform blend. This canalso involve particle size reduction, a process referred to as The preparation of medicated soaps and shampoos fol-comminution. Mills and pulverizers are used to reduce the lows techniques frequently used for the preparation ofparticle size of powders when necessary. As the particle size emulsified systems. To ensure uniformity, the API(s) must beis decreased, the number of particles and the surface area added to the vehicle prior to congealing (in the case ofincrease, which can increase the dissolution rate and soaps) followed by thorough mixing. If the medication isbioavailability of the API. present as a suspension, the particle size must be controlled

Blending techniques for powders include those used in to promote uniform distribution of the API and possibly op-compounding pharmacy such as spatulation and trituration timize performance. Because soap manufacture frequently(see Pharmaceutical Compounding—Nonsterile Preparations involves processing the ingredients at elevated temperature,⟨795⟩). Industrial processes may employ sifting or tumbling care must be exercised to avoid excessive degradation ofthe powders in a rotating container. One of the most com- the API during processing.mon tumble blenders is a V-blender, which is available in avariety of scales suitable for small-scale and large-scale com-pounding and industrial production. PACKAGING AND STORAGE

Powder flow can be influenced by both particle size andshape. Larger particles generally flow more freely than do Individual monographs specify the packaging and storagefine particles. Powder flow is an important attribute that can requirements for medicated soaps and shampoos in USP–NF.affect the packaging or dispensing of a medicated powder.

LABELING AND USEPACKAGING AND STORAGE

Medicated soaps and shampoos are clearly labeled to in-Powders for pharmaceutical use can be packaged in mul- dicate “For External Use Only”. The preparations also clearly

tiple- or single-unit containers. Bulk containers have been advise the patient to discontinue use and consult a physi-used for antacid powders and for laxative powders. In these cian/veterinarian if skin irritation or inflammation occurs orinstances the patient dissolves the directed amount in water persists following application.prior to administration. This type of multiple-unit packagingis acceptable for many APIs but should not be utilized for Solutionspowders that require exact dosing. Multiple-unit powdersfor topical application often are packaged in a container

A solution is a preparation that contains one or more dis-with a sifter top.solved chemical substances in a suitable solvent or mixturePotent APIs in a powder dosage form are dispensed inof mutually miscible solvents. Because molecules of an APIunit-of-use allocations in folded papers, cellophane enve-in solution are uniformly dispersed, the use of solutions aslopes, or packets. Powder boxes are often used by the dis-dosage forms generally provides assurance of uniform dos-pensing pharmacist to hold multiple doses of individualage upon administration and good accuracy when the solu-folded papers. Hygroscopic powders pose special challengestion is diluted or otherwise mixed.and typically are dispensed in moisture-resistant packaging.

Substances in solutions are more susceptible to chemicalinstability than they are in the solid state and dose-for-dosegenerally are heavier and more bulky than solid dosageLABELINGforms. These factors increase the cost of packaging andshipping relative to that of solid dosage forms. Solution dos-Typical warning statements include:age forms can be administered by injection; inhalation; and• External powders must indicate: “External Usethe mucosal, topical/dermal, and gastrointestinal routes. Ter- Only”.minology for solutions in veterinary practice includes spot-• Oral powders should indicate: “For Oral Use Only”.ons or pour-ons that refer to solutions that are applied to anIndividual monographs specify the labeling requirementsanimal’s skin for systemic absorption, dips that refer to solu-for powder dosage forms that are listed in USP–NF. Oraltions that are used for washing and disinfection (e.g., ud-powders for reconstitution prior to dispensing typically haveders, eggs, and whole animals), and drenches that includea limited shelf life (for example, two weeks), and the dis-solutions that are orally administered to livestock, usuallypensed product should indicate a beyond-use date based onwith a dosing device. Solutions administered by injection arethe date of the water addition. Pharmaceutical powders thatofficially titled injections (see Injections ⟨1⟩).are compounded indicate a beyond-use date. Compounded

Solutions intended for oral administration usually containpreparations typically are intended for immediate use andflavorings and colorants to make the medication more at-have short-term storage durations.tractive and palatable for the patient or consumer. When


needed, they also may contain stabilizers to maintain chemi- Many experts recommend the addition of a statementcal and physical stability and preservatives to prevent micro- that patients should seek advice and instruction from abial growth. health care professional about the proper use of the device.

Guidance should be provided about the proper care andcleaning of the device to prevent introduction of microbes

STORAGE AND USE into the pulmonary airways.

Light-resistant containers should be considered whenSuppositoriesphotolytic chemical degradation is a potential issue. To pre-

vent water or solvent loss, solutions are stored in tight con-Suppositories are dosage forms adapted for applicationtainers. Instructions to ensure proper dosing and administra-

into the rectum. They usually melt, soften, or dissolve attion must accompany the product.body temperature. A suppository may have a local pro-tectant or palliative effect or may deliver an API for systemic

Sprays or local action.Suppository bases typically include cocoa butter, glycerin-

Spray preparations may deliver either accurately metered ated gelatin, hydrogenated vegetable oils, mixtures of poly-or nonmetered amounts of formulation. ethylene glycols of various molecular weights, and fatty acid

By definition and in accordance with the USP drug prod- esters of polyethylene glycol. The suppository base can haveuct monographs, a spray dosage form drug product delivers a notable influence on the release of the API(s). Althoughan accurately metered spray through the delivery system, i. cocoa butter melts quickly at body temperature, it is immis-e., device. A spray drug product is a preparation that con- cible with body fluids and this inhibits the diffusion of fat-tains an API(s) in either solution or suspension form, typi- soluble APIs to the affected sites. Polyethylene glycol is acally in presence of excipients for nasal sprays, and that is suitable base for some antiseptics. In cases when systemicintended for administration using a predefined metered action is desired, incorporating the ionized rather than theamount of formulation as a fine mist of aqueous droplets. nonionized form of the API may help maximize bioavai-

Alternatively, nonmetered spray drug products can be lability. Although nonionized APIs partition more readily outgenerated by package designs that do not accurately con- of water-miscible bases such as glycerinated gelatin and pol-trol the volume of formulation delivered. These preparations yethylene glycol, the bases themselves tend to dissolve veryrelease the formulation as a fine mist of droplets upon phys- slowly, which slows API release. Cocoa butter and its substi-ical manipulation of the package by the patient. This gener- tutes (e.g., Hard Fat) perform better than other bases forally involves squeezing the sides of the container and expel- allaying irritation in preparations intended for treating inter-ling the formulation through the nozzle of the container. nal hemorrhoids. Suppositories for adults are tapered at one

Depending on the design of the formulation and the or both ends and usually weigh about 2 g each.valve system, the droplets generated may be intended forimmediate inhalation through the mouth and deposition inthe pulmonary tree or for inhalation into the nose and dep- PREPARATIONosition in the nasal cavity.

The mechanism for droplet generation and the intended Cocoa butter suppositories have cocoa butter as the baseuse of the preparation distinguish various classes of sprays. and can be made by incorporating the finely divided APIA spray may be composed of a pump, container, actuator, into the solid oil at room temperature and suitably shapingvalve, nozzle or mouthpiece in addition to the formulation the resulting mass or by working with the oil in the meltedcontaining the drug(s), solvent(s), and any excipient(s). The state and allowing the resulting suspension to cool in molds.design of each component plays a role for the appropriate A suitable quantity of hardening agents may be added toperformance of the drug product and in determining the counteract the tendency of some APIs (such as chloral hy-critical characteristics of the droplet size distribution. Droplet drate and phenol) to soften the base. The finished supposi-and particle size distributions, delivered dose uniformity, tory melts at body temperature.plume geometry, and droplet velocity are critical parameters A variety of vegetable oils, such as coconut or palm ker-that influence the efficiency of drug delivery. When the nel, modified by esterification, hydrogenation, or fractiona-preparation is supplied as a multidose container, the addition, are used as cocoa butter substitutes to obtain productstion of a suitable antimicrobial preservative may be neces- that display varying compositions and melting temperaturessary. Spray formulations intended for nasal or pulmonary (e.g., Hydrogenated Vegetable Oil and Hard Fat). These prod-administration have an aqueous base and are usually iso- ucts can be designed to reduce rancidity while incorporat-tonic and may contain excipients to control pH and viscos- ing desired characteristics such as narrow intervals betweenity. Pulmonary spray preparations typically are solutions. Na- melting and solidification temperatures and melting rangessal spray preparations may be solutions, or suspensions to accommodate formulation and climatic conditions.intended for local or systemic effect. Nasal delivery may be APIs can be incorporated into glycerinated gelatin basesused for APIs with high hepatic extraction ratios. by addition of the prescribed quantities to a vehicle consist-

ing of about 70 parts of glycerin, 20 parts of gelatin, and10 parts of water.

PACKAGING Several combinations of polyethylene glycols that havemelting temperatures that are above body temperature are

Containers typically are made of a plastic, but metal or used as suppository bases. Because release from these basesglass may be suitable. depends on dissolution rather than on melting, there are

The nasal spray pump is designed to allow convenient significantly fewer problems in preparation and storage thanone-handed operation. The nasal spray nozzle is designed so is the case for melting-type vehicles. However, high concen-that it fits comfortably into the vestibule of the nasal cavity trations of higher molecular weight polyethylene glycolsand allows the plume to be directed toward the appropriate may lengthen dissolution time, resulting in problems withregion of the cavity. retention.

Several nonionic surface-active agents closely relatedchemically to the polyethylene glycols can be used as sup-LABELING AND USE pository vehicles. Examples include polyoxyethylene sorbitanfatty acid esters and the polyoxyethylene stearates. TheseRefer to CDER Guidance for Industry: Nasal Spray and In- surfactants are used alone or in combination with other sup-halation Solution, Suspension, and Spray Drug Products— pository vehicles to yield a wide range of melting tempera-Chemistry, Manufacturing, and Controls Documentation.


tures and consistencies. A notable advantage of such vehi- upon standing. Such sedimentation may lead to caking andcles is their water dispersibility. However, care must be solidification of the sediment and difficulty in redispersingtaken with the use of surfactants because they may either the suspension upon agitation. To prevent such problems,increase the rate of API absorption or interact with the API manufacturers commonly add ingredients to increase viscos-to reduce therapeutic activity. ity and the gel state of the suspension or flocculation, in-

Compounding suppositories using a suppository base typ- cluding clays, surfactants, polyols, polymers, or sugars. Fre-ically involves melting the suppository base and dissolution quently, thixotropic vehicles are used to counter particle-or dispersion of the API in the molten base (see Pharmaceu- settling tendencies, but these vehicles must not interferetical Compounding—Nonsterile Preparations ⟨795⟩). When with pouring or redispersal. Additionally, the density of thecompounding suppositories, the manufacturer or com- dispersed phase and continuous phase may be modified topounding professional prepares an excess amount of total further control settling rate. For topical suspensions, rapidformulation to allow the prescribed quantity to be accu- drying upon application is desirable.rately dispensed. In compounding suppositories, avoid caus- The product is both chemically and physically stabletic or irritating ingredients, carefully select a base that will throughout its shelf life. Temperature can influence the vis-allow the API to provide the intended effect, and in order to cosity (and thus suspension properties and the ease of re-minimize abrasion of the rectal membranes, reduce solid in- moving the dose from the bottle), and temperature cyclinggredients to the smallest reasonable particle size. A repre- can lead to changes in the particle size of the dispersedsentative number of the compounded suppositories should phase via Ostwald ripening. When manufacturers conductbe weighed to confirm that none is less than 90% or more stability studies to establish product shelf life and storagethan 110% of the average weight of all units in the batch. conditions, they should cycle conditions (freeze/thaw) to in-

vestigate temperature effects.Unless studies confirm that the formulation will not sup-

STORAGE AND USE port microbial growth, suspensions should contain suitableantimicrobial agents to protect against bacterial, yeast, and

Suppositories typically are provided in unit-dose packag- mold contamination (see Antimicrobial Effectiveness Testinging with storage instructions to prevent melting of the sup- ⟨51⟩) or other appropriate measures should be taken topository base. Suppositories with cocoa butter base require avoid microbial contamination.storage in well-closed containers, preferably at a tempera- Suspensions for reconstitution are dry powder or granularture below 30° (controlled room temperature). Glycerinated mixtures that require the addition of water or a suppliedgelatin suppositories require storage in tight containers, formulated diluent before administration. This formulationpreferably at a temperature below 2°. Although polyethyl- approach is frequently used when the chemical or physicalene glycol suppositories can be stored without refrigeration, stability of the API or suspension does not allow sufficientthey should be packaged in tightly closed containers. shelf life for a preformulated suspension. Typically, these

Include instructions about insertion procedures to ensure suspensions are refrigerated after reconstitution to increaseease of use and absorption. Labels on polyethylene glycol their shelf life. For this type of suspension, the powdersuppositories should contain directions that they be moist- blend is uniform and the powder readily disperses when re-ened with water before insertion. constituted. Taste of the reconstituted suspension is also an

important attribute because many suspensions are used forpediatric populations.Suspensions

Injectable suspensions generally are intended for eithersubcutaneous or intramuscular routes of administration andA suspension is a biphasic preparation consisting of solidshould have a controlled particle size, typically in the rangeparticles dispersed throughout a liquid phase. Suspensionof 5 µm or smaller. The rationale for the development ofdosage forms may be formulated for specific routes of ad-injectable suspensions includes poor API solubility, improvedministration such as oral suspensions, topical suspensions, orchemical stability, prolonged duration of action, and avoid-suspensions for aerosols (see Aerosols). Some suspensions areance of first-pass metabolism. Care is needed in selectingprepared and ready for use, and others are prepared as solidthe sterilization technique because it may affect product sta-mixtures intended for reconstitution with an appropriate ve-bility or alter the physical properties of the material.hicle just before use. The term “milk” is sometimes used for

suspensions in aqueous vehicles intended for oral adminis-tration (e.g., Milk of Magnesia). The term “magma” is often PREPARATIONused to describe suspensions of inorganic solids, such asclays in water, that display a tendency toward strong hydra- Suspensions are prepared by adding suspending agents ortion and aggregation of the solid, giving rise to gel-like con- other excipients and purified water or oil to solid APIs andsistency and thixotropic rheological behavior (e.g., Bentonite mixing to achieve uniformity. In the preparation of a sus-Magma). The term “lotion” may refer to a suspension dos- pension, the characteristics of both the dispersed phase andage form although the liquid phase in these preparations is the dispersion medium should be considered. During devel-commonly an emulsion intended for application to the skin opment manufacturers should define an appropriate particle(e.g., Calamine Topical Suspension; see Emulsions). Some sus- size distribution for the suspended material to minimize thepensions are prepared in sterile form and are used as inject- likelihood of particle size changes during storage.ables (see Injections ⟨1⟩). Other sterile suspensions are for In some instances the dispersed phase has an affinity forophthalmic or otic administration. Suspensions generally are the vehicle and is readily wetted upon its addition. For somenot injected intravenously, epidurally, or intrathecally unless materials the displacement of air from the solid surface isthe product labeling clearly specifies these routes of admin- difficult, and the solid particles may clump together or floatistration. on top of the vehicle. In the latter case, a wetting agent isLimited aqueous solubility of the API(s) is the most com- used to facilitate displacement of air from the powder sur-mon rationale for developing a suspension. Other potential face. Surfactants, alcohol, glycerin, and other hydrophilicadvantages of a suspension include taste masking and im- liquids can be used as wetting agents when an aqueousproved patient compliance because of the more convenient vehicle will be used as the dispersion phase. These agentsdosage form. When compared to solutions, suspensions function by displacing the air in the crevices of the particleshave improved chemical stability. Ideally, a suspension and dispersing the particles. In the large-scale preparation ofshould contain small uniform particles that are readily sus- suspensions, wetting of the dispersed phase may be aidedpended and easily redispersed following settling. Unless the by the use of high-energy mixing equipment such as colloiddispersed solid is colloidal, the particulate matter in a sus- mills or other rotor–stator mixing devices.pension likely will settle to the bottom of the container


After the powder has been wetted, the dispersion me- of the API(s) or physically separate incompatible APIs. Tab-dium (containing the soluble formulation components such lets may be coated by a variety of techniques to provideas colorants, flavorings, and preservatives) is added in por- taste masking, protection of photo-labile API(s), extended ortions to the powder, and the mixture is thoroughly blended delayed release, or unique appearance (colors). When nobefore subsequent additions of the vehicle. A portion of the deliberate effort has been made to modify the API releasevehicle is used to wash the mixing equipment free of sus- rate, tablets are referred to as immediate-release.pended material, and this portion is used to bring the sus- Tablet Triturates—Small, usually cylindrical, molded orpension to final volume and ensure that the suspension con- compacted tablets. Tablet triturates traditionally were usedtains the desired concentration of solid matter. The final as dispensing tablets in order to provide a convenient,product may be passed through a colloid mill or other measured quantity of a potent API for compounding pur-blender or mixing device to ensure uniformity. When neces- poses, but they are rarely used today.sary, preservatives are included in the formulation of suspen- Hypodermic Tablets—Molded tablets made from com-sions to protect against bacterial and mold contamination. pletely and readily water-soluble ingredients; formerly in-Suspensions are shaken before the dose is dispensed. Be- tended for use in making preparations for hypodermic injec-cause of the viscosity of many suspension vehicles, air en- tion. They may be administered orally or sublingually whentrainment may occur during dosing. The formulation pro- rapid API availability is required, as in the case of Nitroglyc-cess allows evaluation of this possibility; adjustments in erin Sublingual Tablets.vehicle viscosity or the incorporation of low levels of an-

Bolus Tablets—Large, usually elongated, tablets intendedtifoaming agents are common approaches to minimize airfor administration to large animals. Conventional tabletingentrainment. Alternatively, specific instructions for shakingprocesses can be used to manufacture bolus tablets, but duethe formulation may be provided to minimize air incorpora-to their size higher compression forces may be necessary.tion and ensure accurate dosing.

Buccal Tablets—Intended to be inserted in the buccalpouch, where the API is absorbed directly through the oral

PACKAGING AND STORAGE mucosa. Few APIs are readily absorbed in this way (exam-ples are nitroglycerin and certain steroid hormones).

Individual monographs specify the packaging and storage Effervescent Tablets—Prepared by compaction and con-requirements for suspension products. Typically, the mono- tain, in addition to the API(s), mixtures of acids (e.g., citricgraph will indicate a container type such as tight, well- acid or tartaric acid) and carbonates and/or hydrogen car-closed, or light-resistant and may indicate storage condi- bonates. Upon contact with water, these formulations re-tions such as controlled room temperature. For additional lease carbon dioxide, producing the characteristic efferves-information about meeting packaging requirements listed in cent action.the individual monographs, refer to Containers—Glass ⟨660⟩, Chewable Tablets—Formulated and manufactured toContainers—Plastic ⟨661⟩, Containers—Performance Testing produce a pleasant-tasting residue in the mouth and to fa-⟨671⟩, Good Packaging Practices ⟨1177⟩, and the General No- cilitate swallowing. Hard chewable tablets are typically pre-tices for statements about preservation, packaging, storage, pared by compaction, usually utilizing mannitol, sorbitol, orand labeling. sucrose as binders and fillers, and contain colors and flavorsAcceptable suspension of the particulate phase depends to enhance their appearance and taste. Soft chewable tab-on the particle size of the dispersed phase as well as the lets are typically made by a molding or extrusion process,viscosity and density of the vehicle. Clear instruction is pro- frequently with more than 10% water to help maintain avided regarding the appropriate storage temperature for the pliable, soft product. Hard chewable tablets in veterinaryproduct because temperature can influence the viscosity and medicine often have flavor enhancers like brewer’s yeast ordensity (that affect suspension properties and the ease of meat/fish-based flavors.removal of the dose from the bottle), and temperature cy- Tablets for human use that include “Chewable” in the ti-cling can lead to changes in particle size of the dispersed tle must be chewed or crushed prior to swallowing to en-phase. Suspensions require storage in tight containers. Avoid sure reliable release of the API(s) or to facilitate swallowing.freezing. If tablets are designed so that they may be chewed (but

chewing is not required for API release or ease of swallow-ing), the title should not include a reference to “chewable”.LABELING AND USEIn that case, the product may still be described as “chew-able” in the ancillary labeling statement.Instructions to ensure proper dosing and administration

Tablets for veterinary use that are intended to be chewedmust accompany the product. When labeling a suspension,will include “Chewable” in the title. However, it is under-consider any air that might be entrained in the preparationstood that for veterinary products it is not possible to ensureas a result of shaking, and avoid such entrainment. Com-that tablets are chewed prior to ingestion. Chewable tabletspounded suspensions should indicate a beyond-use datemay be broken into pieces and fed to animals that normallythat is calculated from the time of compounding. Suspen-swallow treats whole.sions are shaken well before use to ensure uniform distribu-

tion of the solid in the vehicles. Modified-Release Tablets—There are two categories ofmodified-release tablet formulations recognized by thePharmacopeia:Tablets

Delayed-Release Tablets—Tablets sometimes are formu-lated with enteric coatings to protect acid-labile APIs fromTablets are solid dosage forms in which the API is blendedthe gastric environment or to prevent adverse events suchwith excipients and compressed into the final dosage. Tab-as irritation.lets are the most widely used dosage form in the U.S. Tablet

Extended-Release Tablets—Extended-release tablets are for-presses use steel punches and dies to prepare compactedmulated in such a manner as to make the API available overtablets by the application of high pressures to powderan extended period of time following ingestion. Expressionsblends or granulations. Tablets can be produced in a widesuch as “prolonged-release”, “repeat-action”, “controlled-re-variety of sizes, shapes, and surface markings. Capsule-lease”, and “sustained-release” have also been used to de-shaped tablets are commonly referred to as caplets. Special-scribe such dosage forms. However, the term “extended-ized tablet presses may be used to produce tablets withrelease” is used for Pharmacopeial purposes. Requirementsmultiple layers or with specially formulated core tabletsfor dissolution (see Dissolution ⟨711⟩) typically are specifiedplaced in the interior of the final dosage form. These spe-in the individual monographs.cialized tablet presentations can delay or extend the release


Orally Disintegrating Tablets—Orally disintegrating tab- stomach environment as well as to prolong the release oflets are intended to disintegrate rapidly within the mouth to the API to reduce dosing frequency (see Dissolution ⟨711⟩ orprovide a fine dispersion before the patient swallows the Disintegration ⟨701⟩).resulting suspension where the API is intended for gastroin-testinal delivery and/or absorption. Some of these dosage

PACKAGING, STORAGE, AND LABELINGforms have been formulated to facilitate rapid disintegrationand are manufactured by conventional means or by using

Individual monographs specify the packaging and storagelyophilization or molding processes. Further details may berequirements for tablet products. Typically, the monographfound in the CDER Guidance for Industry: Orally Disintegrat-will indicate the container type such as tight, well-closed, oring Tablets.light-resistant. For additional information on meeting USPSublingual Tablets—Sublingual tablets are intended to packaging requirements, see Containers—Glass ⟨660⟩, Con-be inserted beneath the tongue, where the API is absorbed tainers—Plastic ⟨661⟩, and Containers—Performance Testingdirectly through the oral mucosa. As with buccal tablets, ⟨671⟩. Effervescent tablets are stored in tightly closed con-few APIs are extensively absorbed in this way, and much of tainers or moisture-proof packs and are labeled to indicatethe API is swallowed and is available for gastrointestinal ab- that they should not be swallowed directly.sorption.

TapesPREPARATION

A tape is a dosage form suitable for delivering APIs to theMost compacted (compressed) tablets consist of the skin. It consists of an API(s) impregnated into a durable yet

API(s) and a number of excipients. These excipients may flexible woven fabric or extruded synthetic material that isinclude fillers (diluents), binders, disintegrating agents, lubri- coated with an adhesive agent. Typically the impregnatedcants, and glidants. Approved FD&C and D&C dyes or API is present in the dry state. The adhesive layer is de-lakes, flavors, and sweetening agents also may be present. signed to hold the tape securely in place without the aid of

Fillers or diluents are added when the quantity of API(s) is additional bandaging. Unlike transdermal patches, tapes aretoo small or the properties of the API do not allow satisfac- not designed to control the release rate of the API.tory compaction in the absence of other ingredients. Bind- The API content of tapes is expressed as amount per sur-ers impart adhesiveness to the powder blend and promote face area with respect to the tape surface exposed to thetablet formation and maintenance of API uniformity in the skin. The use of an occlusive dressing with the tape en-tableting mixture. Disintegrating agents facilitate reduction hances the rate and extent of delivery of the API to deeperof the tablet into small particles upon contact with water or layers of the skin and may result in greater systemic absorp-biological fluids. Lubricants reduce friction during the com- tion of the API.paction and ejection cycles. Glidants improve powder fluid-ity, powder handling properties, and tablet weight control.Colorants are often added to tablet formulations for esthetic LABELING, STORAGE, AND USEvalue or for product identification.

Tablets are prepared from formulations that have been Label to indicate “External Use Only”. Tapes are stored inprocessed by one of three general methods: wet granula- tight containers protected from light and moisture. To em-tion, dry granulation (roll compaction or slugging), and di- ploy the tape, one cuts a patch slightly larger than the arearect compression. that will be treated. The backing paper is removed from the

Wet Granulation involves the mixing of dry powders with adhesive side, and the tape is applied to the skin. To ensurea granulating liquid to form a moist granular mass that is optimal adhesion, the tape should not be applied to folds indried and sized prior to compression. It is particularly useful the skin. To minimize systemic absorption and to ensurein achieving uniform blends of low-dose APIs and facilitating good adhesion, tapes should be applied to dry skin.the wetting and dissolution of poorly soluble, hydrophobicAPIs.

GLOSSARYDry Granulations can be produced by passing powders be-tween rollers at elevated pressure (roll compaction). Alterna-

This glossary provides definitions for terms in use intively, dry granulation also can be carried out by the com-medicine and serves as a source of official names for officialpaction of powders at high pressures on tablet presses, aarticles, except when the definition specifically states thatprocess also known as slugging. In either case the compactsthe term is not to be used in article names. Examples ofare sized before compression. Dry granulation improves thegeneral nomenclature forms for the more frequently en-flow and handling properties of the powder formulationcountered categories of dosage forms appear in Nomencla-without involving moisture in the processing.ture ⟨1121⟩. In an attempt to be comprehensive, this glos-Direct Compression tablet processing involves dry blendingsary was compiled without the limits imposed by currentof the API(s) and excipients followed by compression. Thepreferred nomenclature conventions. To clearly identify/dis-simplest manufacturing technique, direct compression is ac-tinguish preferred from not preferred terms, entries indicateceptable only when the API and excipients possess accept-when a term is not preferred and direct the user to theable flow and compression properties without prior processcurrent preferred term. When a term is described as an attri-steps.bute of a dosage form, it is intended to distinguish the termTablets may be coated to protect the ingredients from air,from those used for actual dosage form titles. While attri-moisture, or light; to mask unpleasant tastes and odors; tobute terms are typically not used as the official name for theimprove tablet appearance; and to reduce dustiness. In ad-dosage form, when they are used they identify a specializeddition, coating may be used to protect the API from acidicpresentation of the dosage form. For example, the attribute,pH values associated with gastric fluids or to control the ratechewable, may be used with the dosage form term, tablets,of drug release in the gastrointestinal tract.to identify a specific type of tablet that must be chewedThe most common coating in use today is a thin filmprior to swallowing.coating composed of a polymer that is derived from cellu-

Aerosol: A dosage form consisting of a liquid or solidlose. Sugar coating is an alternative, less common approach.preparation packaged under pressure and intended forSugar-coated tablets have considerably thicker coatings thatadministration as a fine mist. The descriptive term aero-are primarily sucrose with a number of inorganic diluents. Asol also refers to the fine mist of small droplets or solidvariety of film-coating polymers are available and enable theparticles that are emitted from the product.development of specialized release profiles. These formula-

tions are used to protect acid-labile APIs from the acidic


Aromatic Water (not preferred; see Solution): A clear, Elixir (not preferred; see Solution): A preparation thatsaturated, aqueous solution of volatile oils or other aro- typically is a clear, flavored, sweetened hydroalcoholicmatic or volatile substances. solution intended for oral use. The term should not be

Aural (Auricular) (not preferred; see Otic): For adminis- used for new articles in USP–NF but is commonly en-tration into, or by way of, the ear. countered in compounding pharmacy practice.

Bead (not preferred; see Pellets): A solid dosage form in Emollient: Attribute of a cream or ointment indicatingthe shape of a small sphere. In most products a unit an increase in the moisture content of the skin follow-dose consists of multiple beads. ing application of bland, fatty, or oleaginous sub-

Blocks: A large veterinary product intended to be licked stances. This term should not be used in articleby animals and containing the API(s) and nutrients such names.as salts, vitamins, and minerals. Emulsion: A dosage form consisting of a two-phase sys-

Bolus (not preferred; see Tablet): A large tablet intended tem composed of at least two immiscible liquids, one offor administration to large animals. which is dispersed as droplets (internal or dispersed

Caplet (not preferred; see Tablet): Tablet dosage form in phase) within the other liquid (external or continuousthe shape of a capsule. phase), generally stabilized with one or more emulsify-

Capsule: A solid dosage form in which the API, with or ing agents. Emulsion is not used as a dosage form termwithout other ingredients, is filled into either a hard or if a more specific term is applicable (e.g., Cream, Lotion,soft shell. Most capsule shells are composed mainly of or Ointment).gelatin. Enteric-Coated (not preferred; see Delayed-Release): De-

Chewable: Attribute of a solid dosage form that is in- scriptive term for a solid dosage form in which a poly-tended to be chewed or crushed before swallowing. mer coating has been applied to prevent the release of

Coated: Attribute of a solid dosage form that is covered the API in the gastric environment.by deposition of an outer solid that is different in com- Excipient: An ingredient of a dosage form other than anposition from the core material. API. This term is not used in article names. The term,

Collodion (not preferred; see Solution): A preparation excipient, is synonymous with inactive ingredient.that is a solution dosage form composed of pyroxilin Extended-Release: Descriptive term for a dosage formdissolved in a solvent mixture of alcohol and ether and that is deliberately modified to protract the release rateapplied externally. of the API compared to that observed for an immedi-

Collodial Dispersion: An attribute of a preparation or ate-release dosage form. The term is synonymous withformulation in which particles of colloidal dimension prolonged- or sustained-release. Many extended-release(i.e., typically between 1 nm and 1 µm) are distributed dosage forms have a pattern of release that begins withuniformly throughout a liquid. a “burst effect” that mimics an immediate release fol-

Concentrate: A liquid or solid preparation of higher con- lowed by a slower release of the remaining API in thecentration and smaller volume than the final dosage dosage form.form; usually intended to be diluted prior to administra- Film: A term used to describe a thin, flexible sheet oftion. The term continues to be used for veterinary prep- material, usually composed of a polymer. Films are usedarations but is being phased out of USP–NF titles for in various routes of administration including as a meanshuman applications. of oral administration of material in a rapidly dissolving

Conventional-Release (not preferred; see Immediate-Re- form. The term, film, also may be used as an attributelease): Descriptive term for a dosage form in which no when applied to solid oral dosage forms for taste mask-deliberate effort has been made to modify the release ing, product identification, and aesthetic purposes.rate of the API. In the case of capsules and tablets, the Foam: An emulsion dosage form containing dispersedinclusion or exclusion of a disintegrating agent is not gas bubbles. When dispensed it has a fluffy, semisolidinterpreted as a modification. This term is not used in consistency.article names. Gas: One of the states of matter having no definite

Cream: An emulsion dosage form often containing more shape or volume and occupying the entire containerthan 20% water and volatiles and/or containing less when confined.than 50% hydrocarbons, waxes, or polyols as the vehi- Gastro-Resistant (not preferred; see Delayed-Release):cle for the API. Creams are generally intended for exter- Descriptive term for a solid dosage form in which anal application to the skin or mucous membranes. polymer coating has been applied to prevent the re-

Delayed-Release: A type of modified-release dosage lease in the gastric environment.form. A descriptive term for a dosage form deliberately Gel: A dosage form that is a semisolid dispersion of smallmodified to delay release of the API for some period of inorganic particles or a solution of large organic mole-time after initial administration. For example, release of cules containing a gelling agent to provide stiffness. Athe API is prevented in the gastric environment but pro- gel may contain suspended particles.moted in the intestinal environment; this term is synon- Granules: A dosage form composed of dry aggregates ofymous with Enteric-Coated or Gastro-Resistant. powder particles that may contain one or more APIs,

Dental: Descriptive term for a preparation that is applied with or without other ingredients. They may be swal-to the teeth for localized action. lowed as such, dispersed in food, or dissolved in water.

Dermal: A topical route of administration where the arti- Granules are frequently compacted into tablets or filledcle is intended to reach or be applied to the dermis. into capsules, with or without additional ingredients.

Dosage Form: A formulation that typically contains the Gum: A dosage form in which the base consists of aAPI(s) and excipients in quantities and physical form de- pliable material that, when chewed, releases the APIsigned to allow the accurate and efficient administration into the oral cavity.of the API to the human or animal patient. This term is Hard-Shell Capsule (not preferred; see Capsules): A typenot used in article names. of capsule in which one or more APIs, with or without

Dry Powder Inhaler: A device used to administer an in- other ingredients, are filled into a two-piece shell. Mosthalation powder in a finely divided state suitable for hard-shell capsules are composed mainly of gelatin andoral inhalation by the patient. This term is not used in are fabricated prior to the filling operation.article names. Immediate-Release: Descriptive term for a dosage form

Effervescent: Attribute of an oral dosage form, fre- in which no deliberate effort has been made to modifyquently tablets or granules, containing ingredients that, the API release rate. In the case of capsules and tablets,when in contact with water, rapidly release carbon di- the inclusion or exclusion of a disintegrating agent isoxide. The dosage form is dissolved or dispersed in not interpreted as a modification. This term is not usedwater to initiate the effervescence prior to ingestion. in article names.


Implant: A dosage form that is a solid or semisolid mate- Patch (not preferred): Frequently used to describe arial containing the API that is inserted into the body. Transdermal System.The insertion process is invasive, and the material is in- Pellet: A small solid dosage form of uniform, oftentended to reside at the site for a period consistent with spherical, shape. Spherical pellets are sometimes re-the design release kinetics or profile of the API(s). ferred to as Beads. Pellets intended as implants must be

Inhalation (by inhalation): A route of administration for sterile.aerosols characterized by dispersion of the API into the Periodontal: Descriptive term for a preparation that isairways during inspiration. applied around a tooth for localized action.

By Injection: A route of administration of a liquid or Pill (not preferred but frequently incorrectly used to de-semisolid deposited into a body cavity, fluid, or tissue scribe a Tablet): A solid spherical pharmaceutical dosageby use of a needle. form, usually prepared by a wet massing technique.

Insert: A solid dosage form that is inserted into a natu- This term is not used in article names.rally occurring (nonsurgical) body cavity other than the Plaster: A dosage form containing a semisolid composi-mouth or rectum. It should be noted that a suppository tion supplied on a support material for external applica-is intended for application into the rectum and is not tion. Plasters are applied for prolonged periods of timeclassified as an insert (see Suppository). to provide protection, support, or occlusion (for macer-

Intraocular: A route of administration to deliver a sterile ating action).preparation within the eye. Powder: A dosage form composed of a solid or mixture

Irrigation: A sterile solution or liquid intended to bathe of solids reduced to a finely divided state and intendedor flush open wounds or body cavities. for internal or external use.

Jelly (not preferred; see Gel): A semisolid dispersion of Powder, Inhalation: A powder containing an API forsmall inorganic particles or a solution of large organic oral inhalation. The powder is used with a device thatmolecules containing a gelling agent to promote aerosolizes and delivers an accurately metered amount.stiffness. Prolonged-Release (not preferred; see Extended-Release)

Liquid: A dosage form consisting of a pure chemical in Rectal: A route of administration (mucosal) characterizedits liquid state. This dosage form term should not be by deposition into the rectum to provide local or sys-applied to solutions. The term is not used in article temic effect.names. When liquid is used as a descriptive term, it Semisolid: Attribute of a material characterized by a re-indicates a material that is pourable and conforms to its duced ability to flow or conform to its container atcontainer at room temperature. room temperature. A semisolid does not flow at low

Lotion: An emulsion liquid dosage form applied to the shear stress and generally exhibits plastic flow behavior.outer surface of the body. Historically, this term has This term is not used in article names.also been applied to suspensions and solutions. Shampoo: A solution or suspension dosage form used to

Lozenge: A solid dosage form intended to disintegrate clean the hair and scalp. May contain an API intendedor dissolve slowly in the mouth. for topical application to the scalp.

Modified-Release: A descriptive term for a dosage form Soap: The alkali salt(s) of a fatty acid or mixture of fattywith an API release pattern that has been deliberately acids used to cleanse the skin. Soaps used as dosagechanged from that observed for the immediate-release forms may contain an API intended for topical applica-dosage form of the same API. This term is not used in tion to the skin. Soaps have also been used as linimentsarticle names. and enemas.

Molded Tablet: A tablet that has been formed by damp- Soft Gel Capsule (not preferred; see Capsule): A specificening the ingredients and pressing into a mold, then capsule type characterized by increased levels of plasti-removing and drying the resulting solid mass. This term cizers producing a more pliable and thicker-walled ma-is not used in article names. terial than hard gelatin capsules. Soft gel capsules are

Mouthwash (not preferred; see Solution): Term applied further distinguished because they are single-pieceto a solution preparation used to rinse the oral cavity. sealed dosages. Frequently used for delivering liquid

Nasal: Route of administration (mucosal) characterized compositions.by deposition in the nasal cavity for local or systemic Solution: A clear, homogeneous liquid dosage form thateffect. contains one or more chemical substances dissolved in

Ocular (not preferred; see Intraocular): Route of adminis- a solvent or mixture of mutually miscible solvents.tration indicating deposition of the API within the eye. Spirit (not preferred; see Solution): A liquid dosage form

Ointment: A semisolid dosage form, usually containing composed of an alcoholic or hydroalcoholic solution ofless than 20% water and volatiles and more than 50% volatile substances.hydrocarbons, waxes, or polyols as the vehicle. This Spray: Attribute that describes the generation of dropletsdosage form generally is for external application to the of a liquid or solution to facilitate application to theskin or mucous membranes. intended area.

Ophthalmic: A route of administration characterized by Stent, Drug-Eluting: A specialized form of implant usedapplication of a sterile preparation to the external parts for extended local delivery of the API to the immediateof the eye. location of stent placement.

Orally Disintegrating: A descriptive term for a solid oral Strip (not preferred; see Tape): A dosage form or devicedosage form that disintegrates rapidly in the mouth in the shape of a long, narrow, thin solid material.prior to swallowing. The API is intended for gastrointes- Sublingual: A route of administration (mucosal) charac-tinal delivery and/or absorption. See also CDER Guid- terized by placement underneath the tongue and forance for Industry, Orally Disintegrating Tablets. release of the API for absorption in that region.

Oro-Pharyngeal: A route of administration characterized Suppository: A solid dosage form in which one or moreby deposition of a preparation into the oral cavity and/ APIs are dispersed in a suitable base and molded oror pharyngeal region to exert a local or systemic effect. otherwise formed into a suitable shape for insertion into

Otic: A route of administration (mucosal) characterized the rectum to provide local or systemic effect.by deposition of a preparation into, or by way of, the Suspension: A liquid dosage form that consists of solidear. Sometimes referred to as Aural (Aural not particles dispersed throughout a liquid phase.preferred). Syrup (not preferred; see Solution): A solution containing

Paste: A semisolid dosage form containing a high per- high concentrations of sucrose or other sugars. Thiscentage (e.g., 20%–50%) of finely dispersed solids with term is commonly used in compounding pharmacy.a stiff consistency. This dosage form is intended for ap- Tablet: A solid dosage form prepared from powders orplication to the skin, oral cavity, or mucous membranes. granules by compaction.


Tape, Medicated: A dosage form or device composed of that are accurate and free of error. The pharmacist musta woven fabric or synthetic material onto which an API double-check each calculation before proceeding with theis placed, usually with an adhesive on one or both sides preparation of the article or prescription order. One way ofto facilitate topical application. double-checking is by estimation. This involves rounding off

Tincture (not preferred; see Solution): An alcoholic or the quantities involved in the calculation, and comparinghydroalcoholic solution prepared from vegetable materi- the estimated result with the calculated value.als or from chemical substances. Finally, the following steps should be taken: the dosage of

Topical: A route of administration characterized by appli- each active ingredient in the prescription should becation to the outer surface of the body. checked; all calculations should be doubly checked, prefera-

Transdermal System: Dosage forms designed to deliver bly by another pharmacist; and where instruments are usedthe API(s) through the skin into the systemic circulation. in compounding, they should be carefully checked to ascer-Transdermal systems are typically composed of an outer tain that they will function properly. See USP general chap-covering (barrier), a drug reservoir (that may incorpo- ters Aerosols, Nasal Sprays, Metered-Dose Inhalers, and Dryrate a rate-controlling membrane), a contact adhesive Powder Inhalers ⟨601⟩, Deliverable Volume ⟨698⟩, Density ofto affix the transdermal system to the administration Solids ⟨699⟩, Osmolality and Osmolarity ⟨785⟩, pH ⟨791⟩,site, and a protective layer that is removed immediately Pharmaceutical Compounding—Nonsterile Preparations ⟨795⟩,prior to application of the transdermal system. Pharmaceutical Compounding—Sterile Preparations ⟨797⟩, Vis-

Troche (not preferred; see Lozenge): A solid dosage form cosity ⟨911⟩, Specific Gravity ⟨841⟩, Cleaning Glass Apparatusintended to disintegrate or dissolve slowly in the mouth ⟨1051⟩, Medicine Dropper ⟨1101⟩, Prescription Balances andand usually prepared by compaction in a manner simi- Volumetric Apparatus ⟨1176⟩, Teaspoon ⟨1221⟩, Weighing onlar to that used for tablets. an Analytical Balance ⟨1251⟩, and Good Compounding Prac-

Urethral: A route of administration (mucosal) character- tices ⟨1075⟩ for information on specific instruments.ized by deposition into the urethra.

Vaginal: A route of administration (mucosal) character-BASIC MATHEMATICAL CONCEPTSized by deposition into the vagina.

Vehicle: A term commonly encountered in compound-ing pharmacy that refers to a component for internal orexternal use that is used as a carrier or diluent in which SIGNIFICANT FIGURESliquids, semisolids, or solids are dissolved or suspended.Examples include water, syrups, elixirs, oleaginous liq- Expressed values are considered significant to the lastuids, solid and semisolid carriers, and proprietary prod- digit shown (see Significant Figures and Tolerances in theucts (see Excipient). This term is not used in article General Notices). Significant figures are digits with practicalnames. meaning. The accuracy of the determination is implied byVeterinary: Descriptive term for dosage forms intended the number of figures used in its expression. In some calcu-for nonhuman use. lations zeros may not be significant. For example, for a

measured weight of 0.0298 g, the zeros are not significant;they are used merely to locate the decimal point. In theexample, 2980 g, the zero may also be used to indicate thedecimal point, in which case the zero is not significant. Al-ternately, however, the zero may indicate that the weight iscloser to 2981 g or 2979 g, in which case the zero is signifi-⟨1160⟩ PHARMACEUTICAL cant. In such a case, knowledge of the method of measure-ment would be required in order to indicate whether theCALCULATIONS IN zero is or is not significant. In the case of a volume meas-urement of 298 mL, all of the digits are significant. In aPRESCRIPTION COMPOUNDING given result, the last significant figure written is approximatebut all preceding figures are accurate. For example, a vol-ume of 29.8 mL implies that 8 is approximate. The true vol-ume falls between 29.75 and 29.85. Thus, 29.8 mL is accu-rate to the nearest 0.1 mL, which means that the

INTRODUCTION measurement has been made within ±0.05 mL. Likewise, avalue of 298 mL is accurate to the nearest 1 mL and implies

The purpose of this chapter is to provide general informa- a measurement falling between 297.5 and 298.5, whichtion to guide and assist pharmacists in performing the nec- means that the measurement has been made withinessary calculations when preparing or compounding any ±0.5 mL and is subject to a maximum error calculated aspharmaceutical article (see Pharmaceutical Compounding— follows:Nonsterile Preparations ⟨795⟩, Pharmaceutical Compounding—

(0.5 mL/298 mL) × 100% = 0.17%Sterile Preparations ⟨797⟩, and Good Compounding Practices⟨1075⟩) or when simply dispensing prescriptions (see Stabil-

A zero in a quantity such as 298.0 mL is a significant figureity Considerations in Dispensing Practice ⟨1191⟩).and implies that the measurement has been made withinCorrect pharmaceutical calculations can be accomplishedthe limits of 297.95 and 298.05 with a possible error calcu-by using, for example, proper conversions from one meas-lated as follows:urement system to another and properly placed decimal

points, by understanding the arithmetical concepts, and by(0.05 mL/298.0 mL) × 100% = 0.017%paying close attention to the details of the calculations.

Before proceeding with any calculation, pharmacists shouldEXAMPLES—do the following: (a) read the entire formula or prescription

1. 29.8 mL = 29.8 ± 0.05 mL (accurate to the nearestcarefully; (b) determine which materials are needed; and0.1 mL)then (c) select the appropriate methods of preparation and

2. 29.80 mL = 29.80 ± 0.005 mL (accurate to the near-the appropriate calculation.est 0.01 mL)There are often several ways to solve a given problem.

3. 29.800 mL = 29.800 ± 0.0005 mL (accurate to theLogical methods that require as few steps as possible shouldnearest 0.001 mL)be selected in order to ensure that calculations are done

correctly. The best approach is the one that yields results

〈1151〉 PHARMACEUTICAL DOSAGE FORMS

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