2000
`
`US-P 24
`NY 19
`
`THE UNITED STATES PHARMACOPEIA
`
`THE NATIONAL FORMULARY
`
`By authority of the United States Pharmacopeial
`Convention, Inc., meeting at Washington, D.C.,
`March 9-12, 1995. Prepared by the Committee of
`Revision and published by the Board of Trustees
`
`Official from January 1, 2000
`
`UNITED STATES PHARMACOPEJAL CONVENTION, INC.
`12601 Twinbrook Parkway, Rockville, MD 20852
`
`1
`
`CIP2103
`Argentum Pharmaceuticals LLC v. Cipla Ltd.
`IPR2017-00807
`
`

`

`NOTICE AND WARNING
`
`Concerning U.S. Patent or Trademark Rights
`The inclusion in the Pharmacopeia or in the National Formulary of a monograph on any drug in
`respect to which patent or trademark rights may exist shall not be deemed, and is not intended
`as, a grant of, or authority to exercise, any right or privilege protected by such patent or
`trademark. All such rights and privileges are vested in the patent or trademark owner, and no
`other person may exercise the same without express permission, authority, or license secured
`from such patent or trademark owner.
`
`Concerning Use of USP or NF Text
`Attention is called to the fact that USP and NF text is fully copyrighted. Authors and others
`wishing to use portions of the text should request permission to do so from the Secretary of the
`USPC Board of Trustees.
`
`The United States Pharmacopeial Convention, Inc.
`' 1999 (cid:9)
`12601 Twiobrook Parkway, Rockville, MD 20852.
`All rights reserved
`ISSN 0195-7996
`ISBN 1-889788-03-1
`
`Printed by National Publishing, Philadelphia, PA
`
`2
`
`

`

`24
`
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`
`USP 24 (cid:9)
`
`General Information / (1151s Pharmaceutical Dosage Forms (cid:9)
`
`2107
`
`the USAN adopted name listed in USAN and the USP Dictionary
`of Drug Names......
`It will be noted that the monographs on the biologics, which are
`produced under licenses issued by the Secretary of the U. S. De-
`partment of Health and Human Services, represent a special case.
`Although efforts continue toward achieving uniformity, there may
`be a difference between the respective title required by federal law
`and the USP title. Such differences are fewer than in past revisions
`of the Pharmacopeia. The USP title, where different from the FDA
`Bureau of Biologics title, does not constitute a synonym for labeling
`purposes; the conditions of licensing the biologic concerned require
`that each such article be designated by the name appearing in the
`product license issued to the manufacturer. Where a USP title dif-
`fers from the title in the federal regulations, the former has been
`adopted with a view to usefulness and simplicity and conformity
`with the principles governing the selection of monograph titles
`generally.
`
`(1151 PHARMACEUTICAL
`DOSAGE FORMS
`Dosage forms are provided for most of the Pharmacopeial drug
`substances, but the processes for the preparation of many of them
`are, in general, beyond the scope of the Pharmacopeia. In addition
`to defining the dosage forms, this section presents the general prin-
`ciples involved in the manufacture of some of them, particularly on
`a small scale. Other information that is given bears on the use of
`the Pharmacopeial substances in extemporaneous compounding of
`dosage forms.
`
`BIOAVAILABILITY
`Bioavailability, or the extent to which the therapeutic constituent
`of a pharmaceutical dosage form intended for oral or topical use is
`available for absorption, is influenced by a variety of factors.
`Among the inherent factors known to affect absorption are the
`method of manufacture or method of compounding; the particle size
`and crystal form or polymorph of the drug substance; and the dil-
`uents and excipients used in formulating the dosage form, including
`fillers, binders, disintegrating agents, lubricants, coatings, solvents,
`suspending agents, and dyes. Lubricants and coatings are foremost
`among these. The maintenance of a demonstrably high degree of
`bioavailability requires particular attention to all aspects of produc-
`tion and quality control that may affect the nature of the finished
`dosage form.
`
`STABILITY
`The term "stability," with respect to a drug dosage form, refers
`to the chemical and physical integrity of the dosage unit, and, when
`appropriate, the ability of the dosage unit to maintain protection
`against microbiological contamination. The shelf life of the dosage
`form is the time lapse from initial preparation to the specified ex-
`piration date. The monograph specifications of identity, strength,
`quality, and purity apply throughout the shelf life of the product.
`The stability parameters of a drug dosage form can be influenced
`by environmental conditions of storage (temperature, light, air, and
`humidity), as well as the package components. Pharmacopeial ar-
`ticles should include required storage conditions on their labeling.
`These are the conditions under which the expiration date shall ap-
`ply. The storage requirements specified in the labeling for the article
`must be observed throughout the distribution of the article (i.e.,
`beyond the time it leaves the manufacturer up to and including its
`handling by the dispenser or seller of the article to the consumer).
`Although labeling for the consumer should indicate proper storage
`conditions, it is recognized that control beyond the dispenser or
`seller is difficult.
`Beyond-use dating information must be provided by the manu-
`facturer in the labeling of all solid oral Pharmacopeial dosage forms
`intended for dispensing on prescription, unless the dosage form is
`packaged by the manufacturer in a container that is labeled for
`dispensing directly to the patient. To meet this requirement, there
`
`53 Fed. Reg. 5369 (1988) amending 21 CFR § 299.4
`
`must be a recommendation for an appropriate dispensing container
`(e.g., ’’tight," ’’well-closed," "light-resistant’’) and, for unit-dose
`packaging, a recommendation for the appropriate class of package
`(see Class A. B, C, or D under Results in Containers(cid:151)Permeation
`671)) and the length of time that is appropriate for a beyond-use
`date in that type of container or package. Such a beyond-use date
`may be based on an "open dish’ study in which the dosage forms
`are found to remain stable (i.e., conform to all monograph require-
`ments for the declared beyond-use time period). The open dish
`study is a study in which the dosage forms are exposed to 60%
`relative humidity at 25(cid:176) for 30 days without any container protec-
`tion: three samples of 30-unit doses from one lot are analyzed at 0
`and 30 days. The dosage forms may be protected from light during
`the study. Beyond-use dating information supported by such "open
`dish" studies need only indicate that, other than regarding the need
`for light resistance, any appropriate dispensing container may be
`used for repackaging the dosage form. Alternatively, studies con-
`ducted in containers that are one class below (i.e., more permeable
`to water vapor) the class being recommended for repackaging the
`dosage form may be substituted for "open dish" studies. For ex-
`ample, a study conducted in Class C unit-dose containers that dem-
`onstrates stability will support a recommendation for use of a Class
`B, or better, package. Beyond-use dating information may be ob-
`tained by any other type of stability study including, but not limited
`to, accelerated stability studies. Exempt from these requirements are
`drugs dispensed in a container to be used within a day and drugs
`in container-closure systems that are known to be equivalent in
`protection to the marketed container system.
`of manufactured dosage forms
`Stability Protocols(cid:151)Stability
`must be demonstrated by the manufacturer by the use of methods
`adequate for the purpose. Monograph assays may be used for sta-
`bility testing if they are stability-indicating (i.e., if they accurately
`differentiate between the intact drug molecules and their degrada-
`tion products). Stability considerations should include not only the
`specific compendial requirements, but also changes in physical ap-
`pearance of the product that would warn users that the product’s
`continued integrity is questionable.
`Stability studies on active substances and packaged dosage forms
`are conducted by means of "real-time," long-term tests at specific
`temperatures and relative humidities representing storage conditions
`experienced in the distribution chain of the climatic zone(s) of the
`country or region of the world concerned. Labeling of the packaged
`active substance or dosage form should reflect the effects of tem-
`perature, relative humidity, air, and light on its stability. Label tem-
`perature storage warnings will reflect both the results of the real-
`time storage tests and also allow for expected seasonal excursions
`of temperature.
`Controlled room temperature (see the Storage Temperature sec-
`tion under General Notices and Requirements(cid:151)Preservation, Pack-
`aging, Storage, and Labeling) delineates the allowable tolerance in
`storage circumstances at any location in the chain of distribution
`(e.g., pharmacies, hospitals, and warehouses). This terminology also
`allows patients or consumers to be counseled as to appropriate stor-
`age for the product. Products may be labeled either to store at
`’Controlled room temperature" or to store at temperatures up to
`25(cid:176)" where labeling is supported by long-term stability studies at
`the designated storage condition of 25(cid:176). Controlled room temper-
`ature limits the permissible excursions to those consistent with the
`maintenance of a mean kinetic temperature calculated to be not
`more than 25(cid:176). See Mean Kinetic Temperature. The common inter-
`national guideline for long-term stability studies specifies 25 – 2 (cid:176)
`at 60 – 5% relative humidity. Accelerated studies are specified at
`40 – 2(cid:176) and at 75 – 5% relative humidity. Accelerated studies
`also allow the interpretation of data and information on short-term
`spikes in storage conditions in addition to the excursions allowed
`for by controlled room temperature.
`The term "room temperature" is used in different ways in dif-
`ferent countries, and it is usually preferable for product labeling for
`products to be shipped outside the continental U.S. to refer to a
`maximum storage temperature or temperature range in degrees
`Celsius.
`kinetic temperature is defined
`Mean Kinetic Temperature(cid:151)Mean
`as a single calculated temperature at which the degradation of an
`article would be equivalent to the actual degradation that would
`result from temperature fluctuations during the storage period. It is
`not a simple arithmetic mean. The mean kinetic temperature is cal-
`
`3
`
`

`

`2108 (cid:9)
`
`(1151) Pharmaceutical Dosage Forms / General Information
`
`USP 24
`
`Table 1. International Climatic Zones.
`Calculated Data
`
`Derived Data
`
`(cid:176)CK
`
`20.0
`
`(cid:176) C MKT** (cid:9)
`20.0 (cid:9)
`
`RH
`42
`
`mbar***
`
`9.9
`
`(cid:176) C
`21
`
`RH
`
`45
`
`mbar
`11.2
`
`21.6
`
`22.0 (cid:9)
`
`52
`
`13.5
`
`25
`
`60
`
`19.0
`
`26.4
`
`27.9 (cid:9)
`
`35
`
`11.9
`
`30
`
`35
`
`15.0
`
`26.7
`
`27.4 (cid:9)
`
`76
`
`26.6
`
`30
`
`70
`
`30.0
`
`
`
`
`
`
`
`Climatic Zone
`
`1. (cid:9)
`
`Temperate
`United Kingdom
`Northern Europe
`Canada
`Russia
`II (cid:9) Mediterranean, Subtropical
`United States
`Japan
`Southern Europe
`(Portugal-Greece)
`
`III. Hot, Dry
`Iran
`Iraq
`Sudan
`IV. Hot, Humid
`Brazil
`Ghana
`Indonesia
`Nicaragua
`Philippines
`* Data recorded as <19(cid:176) calculated as 19(cid:176).
`** Calculated mean kinetic temperature.
`***parti al pressure of water vapor.
`
`culated from average storage temperatures recorded over a one-year
`period, with a minimum of twelve equally spaced average storage
`temperature observations being recorded. Average temperature may
`be determined using automated recording devices or as the arith-
`metic mean of the highest and lowest temperatures attained during
`the observation period as measured on a high-low thermometer. The
`mean kinetic temperature is calculated by the following equation
`(derived from the Arrhenius equation):
`
`T,, =
`
`ln(
`
`AH /R
`+ (cid:9)
`
`+ . . . – e
`
`Rl ,
`
`n
`
`in which Tk is the mean kinetic temperature; zXH is the heat of
`activation. 83.144kJ mole - ’ (unless more accurate information is
`available from experimental studies); R is the universal gas con-
`stant, 83144 X 10 - kJ mole - ’ (cid:149) degree - ’; T, is the average storage
`temperature during the first time period (e.g., month); T, is the
`is
`average storage temperature during the second time period; T
`the average storage temperature during the nth time period, n being
`the total number of average storage temperatures recorded (mini-
`mum of twelve) during the observation period; and all temperatures
`(T) being absolute temperatures in degrees Kelvin ((cid:176)K).
`convenience in planning for packaging and
`Climatic Zones(cid:151)For
`storage, and for stability studies, international practice identifies
`four climatic zones, which are described in Table 1. The United
`States, Europe, and Japan are characterized by zones I and 11. The
`values in Table I are based on observed temperatures and relative
`humidities, both outside and in rooms, from which mean kinetic
`temperatures and average humidity values are calculated.’ Derived
`values are based on inspection of data from individual cities and
`on allowances for a margin of safety in assignment of these spec-
`ified conditions.
`A discussion of aspects of drug product stability that are of pri-
`mary concern to the pharmacist in the dispensing of medications
`
`The source of the data and information in Table 1 is the Inter -
`national Conference on Harmonization sponsored by the Interna-
`tional Federation of Pharmaceutical Manufacturers Associations.
`
`may be found under Stability Considerations in Dispensing Practice
`(1191).
`Inasmuch as this chapter is for purposes of general information
`only, no statement herein is intended to modify or supplant any of
`the specific requirements pertinent to pharmaceutical preparations,
`which are given elsewhere in this Pharmacopeia.
`
`TERMINOLOGY
`Occasionally it is necessary to add solvent to the contents of a
`container just prior to use, usually because of instability of some
`drugs in the diluted form. Thus, a solid diluted to yield a suspension
`is called [DRUG] for Suspension; a solid dissolved and diluted to
`yield a solution is called [DRUG] for Solution; and a solution or
`suspension diluted to yield a more dilute form of the drug is called
`[DRUG] Oral Concentrate. After dilution, it is important that the
`drug be homogeneously dispersed before administration.
`
`AEROSOLS
`Pharmaceutical aerosols are products that are packaged under
`pressure and contain therapeutically active ingredients that are re-
`leased upon activation of an appropriate valve system. They are
`intended for topical application to the skin as well as local appli-
`cation into the nose (nasal aerosols), mouth (lingual aerosols), or
`lungs (inhalation aerosols). These products may be fitted with
`valves enabling either continuous or metered-dose delivery; hence.
`the terms "[DRUG] Metered Topical Aerosols," "[DRUG] Me-
`tered Nasal Aerosols,’ etc.
`The term ’’aerosol" refers to the fine mist of spray that results
`from most pressurized systems. However, the term has been broadly
`misapplied to all self-contained pressurized products, some of
`which deliver foams or semisolid fluids. In the case of Inhalation
`Aerosols, the particle size of the delivered medication must be care-
`fully controlled and the average size of the particles should be under
`5 p.m. These products are also known as metered-dose inhalers
`(MDI5). Other aerosol sprays may contain particles up to several
`hundred micrometers in diameter.
`The basic components of an aerosol system are the container, the
`propellant, the concentrate containing the active ingredient(s), the
`valve, and the actuator. The nature of these components determines
`such characteristics as particle size distribution, uniformity of dose
`
`4
`
`(cid:9)
`

`

`USP 24 (cid:9)
`
`General Information / (1151) Pharmaceutical Dosage Forms (cid:9)
`
`2109
`
`for metered valves, delivery rate, wetness and temperature of the
`spray, spray pattern and velocity or plume geometry, foam density,
`and fluid viscosity.
`
`Types of Aerosols
`Aerosols consist of two-phase (gas and liquid) or three-phase
`(gas, liquid, and solid or liquid) systems. The two-phase aerosol
`consists of a solution of active ingredients in liquefied propellant
`and the vaporized propellant. The solvent is composed of the pro-
`pellant or a mixture of the propellant and co-solvents such as al-
`cohol, propylene glycol, and polyethylene glycols, which are often
`used to enhance the solubility of the active ingredients.
`Three-phase systems consist of a suspension or emulsion of the
`active ingredient(s) in addition to the vaporized propellants. A sus-
`pension consists of the active ingredient(s) that may be dispersed
`in the propellant system with the aid of suitable excipients such as
`wetting agents and/ or solid carriers such as talc or colloidal silicas.
`A foam aerosol is an emulsion containing one or more active
`ingredients, surfactants, aqueous or nonaqueous liquids, and the
`propellants. If the propellant is in the internal (discontinuous) phase
`(i.e., of the oil-in-water type), a stable foam is discharged; and if
`the propellant is in the external (continuous) phase (i.e., of the
`water-in-oil type), a spray or a quick-breaking foam is discharged.
`
`Propellants
`The propellant supplies the necessary pressure within an aerosol
`system to expel material from the container and, in combination
`with other components, to convert the material into the desired
`physical form. Propellants may be broadly classified as liquefied or
`compressed gases having vapor pressures generally exceeding at-
`mospheric pressure. Propellants within this definition include vari-
`ous hydrocarbons, especially halogenated derivatives of methane,
`ethane, and propane, low molecular weight hydrocarbons such as
`the butanes and pentanes, and compressed gases such as carbon
`dioxide, nitrogen, and nitrous oxide. Mixtures of propellants are
`frequently used to obtain desirable pressure, delivery, and spray
`characteristics. A good propellant system should have the proper
`vapor pressure characteristics consistent with the other aerosol
`components.
`
`Valves
`The primary function of the valve is to regulate the flow of the
`therapeutic agent and propellant from the container. The spray char -
`acteristics of the aerosol are influenced by orifice dimension, num-
`ber, and location. Most aerosol valves provide for continuous spray
`operation and are used on most topical products. However, phar
`maceutical products for oral or nasal inhalation often utilize me-
`tered-dose valves that must deliver a uniform quantity of spray upon
`each valve activation. The accuracy and reproducibility of the doses
`delivered from metering valves are generally good, comparing fa-
`vorably to the uniformity of solid dosage forms such as tablets and
`capsules. However, when aerosol packages are stored improperly,
`or when they have not been used for long periods of time, valves
`must be primed before use. Materials used for the manufacture of
`valves should be inert to the formulations used. Plastic, rubber,
`aluminum, and stainless steel valve components are commonly
`used. Metered-dose valves must deliver an accurate dose within
`specified tolerances.
`
`-
`
`Actuators
`An actuator is the fitting attached to an aerosol valve stem, which
`when depressed or moved, opens the valve, and directs the spray
`containing the drug preparation to the desired area. The actuator
`usually indicates the direction in which the preparation is dispensed
`and protects the hand or finger from the refrigerant effects of the
`propellant. Actuators incorporate an orifice which may vary widely
`in size and shape. The size of this orifice, the expansion chamber
`design, and the nature of the propellant and formulation influence
`the delivered dose as well as the physical characteristics of the
`spray, foam, or stream of solid particles dispensed. For inhalation
`aerosols, an actuator capable of delivering the medication in the
`proper particle size range and with the appropriate spray pattern and
`plume geometry is utilized.
`
`Containers
`Aerosol containers usually are made of glass, plastic, or metal,
`or a combination of these materials. Glass containers must be pre-
`cisely engineered to provide the maximum in pressure safety and
`impact resistance. Plastics may be employed to coat glass containers
`for improved safety characteristics, or to coat metal containers to
`improve corrosion resistance and enhance stability of the formula-
`tion. Suitable metals include stainless steel, aluminum, and tin-
`plated steel. Extractables or leachables (e.g., drawing oils, cleaning
`agents, etc.) and particulates on the internal surfaces of Containers
`should be controlled.
`
`Manufacture
`Aerosols are usually prepared by one of two general processes.
`In the "cold-fill" process, the concentrate (generally cooled to a
`temperature below 00) and the refrigerated propellant are measured
`into open containers (usually chilled). The valve-actuator assembly
`is then crimped onto the container to form a pressure-tight seal.
`-
`During the interval between propellant addition and crimping, suf
`ficient volatilization of propellant occurs to displace air from the
`container. In the "pressure-fill" method, the concentrate is placed
`in the container, and either the propellant is forced under pressure
`through the valve orifice after the valve is sealed, or the propellant
`is allowed to flow under the valve cap and’then the valve assembly
`is sealed ("under-the-cap" filling). In both cases of the "pressure-
`fill" method, provision must be made for evacuation of air by
`means of vacuum or displacement with a small amount of propellant
`vapor. Manufacturing process controls usually include monitoring of
`proper formulation and propellant fill weight and pressure testing,
`leak testing, and valve function testing of the finished aerosol. Mi-
`crobiological attributes should also be controlled.
`
`Extractable Substances
`Since pressurized inhalers and aerosols are normally formulated
`with organic solvents as the propellant or the vehicle, leaching of
`extractables from the elastomeric and plastic components into the
`formulation is a potentially serious problem. Thus, the composition
`and the quality of materials used in the manufacture of the valve
`components (e.g., stem, gaskets, housing, etc.) must be carefully
`selected and controlled. Their compatibility with formulation com-
`ponents should be well established so as to prevent distortion of
`the valve components and to minimize changes in the medication
`delivery, leak rate, and impurity profile of the drug product over
`time. The extractable profiles of a representative sample of each of
`the elastomeric and plastic components of the valve should be es-
`tablished under specified conditions and should be correlated to the
`extractable profile of the aged drug product or placebo, to ensure
`reproducible quality and purity of the drug product. Extractables,
`which may include polynuclear aromatics, nitrosamines, vulcani-
`’ antioxidants, plasticizers, monomers, etc.,
`zation accelerators,
`should be identified and minimized wherever possible.
`Specifications and limits for individual and total extractables
`from different valve components may require the use of different
`analytical methods. In addition, the standard USP biological testing
`(see the general test chapters Biological Reactivity Tests,
`In Vitro
`(88)) as well as other
`(87) and Biological Reactivity Tests, In Vivo
`safety data may be needed.
`
`Labeling
`Medicinal aerosols should contain at least the following warning
`information on the label as in accordance with appropriate regula-
`tions.
`inhaling. Avoid spraying into eyes or onto other
`Warning(cid:151)Avoid
`mucous membranes.
`NOTE(cid:151)The statement "Avoid inhaling" is not necessary for
`preparations specifically designed for use by inhalation. The phrase
`"or other mucous membranes" is not necessary for preparations
`specifically designed for use on mucous membranes-
`Warn ing--Con tents under pressure. Do not puncture or incinerate
`container. Do not expose to heat or store at temperatures above
`1200 F (49(cid:176) Q. Keep out of reach of children.
`In addition to the aforementioned warnings, the label of a drug
`packaged in an aerosol container in which the propellant consists
`
`5
`
`

`

`i
`
`2110 (cid:9)
`
`(1151) Pharmaceutical Dosage Forms / General Information
`
`USP 24
`
`in whole or in part of a halocarbon or hydrocarbon shall, where
`required under regulations of the FDA, bear either of the following
`warnings:
`Warning(cid:151)Do
`not inhale directly; deliberate inhalation of con-
`tents can cause death.
`Warning(cid:151)Use
`only as directed; intentional misuse by deliber-
`ately concentrating and inhaling the contents can he harmful or
`fatal.
`
`BOLUSES
`Boluses are large elongated tablets intended for administration to
`animals (see Tablets).
`
`CAPSULES
`Capsules are solid dosage forms in which the drug is enclosed
`within either a hard or soft soluble container or "shell." The shells
`are usually formed from gelatin; however, they also may be made
`from starch or other suitable substances. Hard shell capsule sizes
`range from No. 5, the smallest, to No. 000, which is the largest,
`except for veterinary sizes. However, size No. 00 generally is the
`largest size acceptable to patients. Size 0 hard gelatin capsules hav -
`ing an elongated body (known as size OE) also are available, which
`provide greater fill capacity without an increase in diameter. Hard
`gelatin capsules consist of two, telescoping cap and body pieces.
`Generally, there are unique grooves or indentations molded into the
`cap and body portions to provide a positive closure when fully
`engaged, which helps prevent the accidental separation of the filled
`capsules during shipping and handling. Positive closure also may
`be affected by spot fusion ("welding") of the cap and body pieces
`together through direct thermal means or by application of ultra-
`sonic energy. Factory-filled hard gelatin capsules may be com-
`pletely sealed by banding, a process in which one or more layers
`of gelatin are applied over the seam of the cap and body, or by a
`liquid fusion process wherein the filled capsules are wetted with a
`hydroalcoholic solution that penetrates into the space where the cap
`overlaps the body, and then dried. Hard shell capsules made from
`starch consist of two, fitted cap and body pieces. Since the two
`pieces do not telescope or interlock positively, they are sealed to-
`gether at the time of filling to prevent their separation. Starch cap-
`sules are sealed by the application of a hydroalcoholic solution to
`the recessed section of the cap immediately prior to its being placed
`onto the body.
`The banding of hard shell gelatin capsules or the liquid sealing
`of hard shell starch capsules enhances consumer safety by making
`the capsules difficult to open without causing visible, obvious dam-
`age, and may improve the stability of contents by limiting 02 pen-
`etration. Industrially filled hard shell capsules also are often of dis-
`tinctive color and shape or are otherwise marked to identify them
`with the manufacturer. Additionally, such capsules may be printed
`axially or radially with strengths, product codes, etc. Pharmaceutical
`grade printing inks are usually based on shellac and employ FDA-
`approved pigments and lake dyes.
`In extemporaneous prescription practice, hard shell capsules may
`be hand-filled; this permits the prescriber a latitude of choice in
`selecting either a single drug or a combination of drugs at the exact
`dosage level considered best for the individual patient. This flexi-
`bility gives hard shell capsules an advantage over compressed tab-
`lets and soft shell capsules as a dosage form. Hard shell capsules
`are usually formed from gelatins having relatively high gel strength.
`Either type may be used, but blends of pork skin and bone gelatin
`are often used to optimize shell clarity and toughness. Hard shell
`capsules also may be formed from starch or other suitable sub-
`stances. Hard shell capsules may also contain colorants, such as
`D&C and FD&C dyes or the various iron oxides, opaquing agents
`such as titanium dioxide, dispersing agents, hardening agents such
`as sucrose, and preservatives. They normally contain between 10%
`and 15% water.
`Hard gelatin capsules are made by a process that involves dipping
`shaped pins into gelatin solutions. after which the gelatin films are
`dried, trimmed, and removed from the pins, and the body and cap
`pieces are joined. Starch capsules are made by injection molding a
`mixture of starch and water, after which the capsules are dried. A
`separate mold is used for caps and bodies, and the two parts are
`
`supplied separately. The empty capsules should be stored in tight
`containers until they are filled. Since gelatin is of animal origin and
`starch is of vegetable origin, capsules made with these materials
`should be protected from potential sources or microbial contamina-
`tion.
`Hard shell capsules typically are filled with powder, beads, or
`granules. Inert sugar beads (nonpareils) may be coated with active
`ingredients and coating compositions that provide extended-release
`profiles or enteric properties. Alternatively, larger dose active in-
`gredients themselves may be suitably formed into pellets and then
`coated. Semisolids or liquids also may be filled into hard shell cap-
`sules; however, when the latter are encapsulated, one of the sealing
`techniques must be employed to prevent leakage.
`In hard gelatin capsule filling operations, the body and cap of the
`shell are separated prior to dosing. In hard starch shell filling op-
`erations, the bodies and caps are supplied separately and are fed
`into separate hoppers of the filling machine. Machines employing
`various dosing principles may be employed to fill powders into hard
`shell capsules; however, most fully automatic machines form pow-
`der plugs by compression and eject them into empty capsule bodies.
`Accessories to these machines generally are available for the other
`types of fills. Powder formulations often require adding fillers, lu-
`bricants, and glidants to the active ingredients to facilitate encap-
`sulation. The formulation, as well as the method of filling, partic-
`ularly the degree of compaction, may influence the rate of drug
`release. The addition of wetting agents to the powder mass is com-
`mon where the active ingredient is hydrophobic. Disintegrants also
`may be included in powder formulations to facilitate deaggregation
`and dispersal of capsule plugs in the gut. Powder formulations often
`may be produced by dry blending; however, bulky formulations
`may require densification by roll compaction or other suitable gran-
`ulation techniques.
`Powder mixtures that tend to liquefy may be dispensed in hard
`shell capsules if an absorbent such as magnesium carbonate, col-
`loidal silicon dioxide, or other suitable substance is used. Potent
`drugs are often mixed with an inert diluent before being filled into
`capsules. Where two mutually incompatible drugs are prescribed
`together, it is sometimes possible to place one in a small capsule
`and then enclose it with the second drug in a larger capsule. In-
`compatible drugs also can be separated by placing coated pellets or
`tablets, or soft shell capsules of one drug into the capsule shell
`before adding the second drug.
`Thixotropic semisolids may be formed by gelling liquid drugs or
`vehicles with colloidal silicas or powdered high molecular weight
`polyethylene glycols. Various waxy or fatty compounds may be
`used to prepare semisolid matrices by fusion.
`Soft shell capsules made from gelatin (sometimes called softgels)
`or other suitable material require large-scale production methods.
`The soft gelatin shell is somewhat thicker than that of hard shell
`capsules and may be plasticized by the addition of a polyol such
`as sorbitol or glycerin. The ratio of dry plasticizer to dry gelatin
`determines the "hardness" of the shell and may be varied to ac-
`commodate environmental conditions as well as the nature