`
`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
`
`THE NATIONAL FORMULARY
`
`Official from January 1, 2000
`
`
`
`UNITED STATES PHARMACOPEIAL CONVENTION, INC.
`12601 Twinbrook Parkway, Rockville, MD 20852
`
`
`
`IPR2018-00390
`
`Page 1 of 3
`
`I-MAK1010
`
`IPR2018-00390
`
`Page 1 of 3
`
`I-MAK 1010
`
`

`

`
`
`USP 24
`
`2117
`
`Soluble, effervescent tablets are prepared by compression and
`contain, in addition to active ingredients, mixtures of acids (citric
`acid, tartaric acid) and sodium bicarbonate, which release carbon
`dioxide when dissolved in water, They are intended to be dissolved
`or dispersed in water before administration. Effervescent tablets
`should be stored in tightly closed containers or moisture-proof
`packs and labeled to indicate that
`they are not
`to be swallowed
`directly.
`
`Chewable Tablets
`Chewable tabiets are formulated and manufactured so that they
`may be chewed, producing a pleasant tasting residue in the oral
`cavity that is easily swallowed and does not leave a bitter or un-
`pleasant after-taste. These tablets have been used in tablet formu-
`lations for children, especially multivitamin formulations. and for
`the administration of antacids and selected antibiotics. Chewable
`tablets are prepared by compression, usually utilizing mannitol, sor-
`bitol, or sucrose as binders and fillers, and containing colors and
`flavors to enhance their appearanceandtaste.
`
`General Information / (1151) Pharmaceutical Dosage Forras
`applied to some orall parts of the System and the system/skin
`interface, and a protective liner that is removed before applying the
`system. The activity of these systems is defined in terms of the
`release rate of the drug(s) from the system. The total duration of
`drug release from the system and the system surface area may also
`be stated.
`Transdermal drug delivery systems work by diffusion: the drug
`diffuses from the drugreservoir, directly or through the rate con-
`trolling membrane and/or contact adhesive if present, and then
`through the skin into the general circulation. Typically, modified-
`release systems are designed to provide drug delivery at a constant
`fate, such that a true steady state blood concentration is achieved
`and maintained until
`the system is removed. At that time, bloéd
`concentration declines at a rate consistent with the pharmacokinetics
`of the drug.
`Transdermal drug delivery systems are applied to body areas con-
`sistent with the labeling for the product(s). As long as drug con-
`centration at
`the system/skin interface remains constant,
`the
`amount ofdrug in the dosage form does not influence plasma con-
`centrations. The functionallifetime of the system is defined by the
`initial amountof drug in the reservoir and the release rate from the
`reservoir,
`Preparation of Molded Tablets
`Note—Drugs for local rather than systemic effect are commonly
`applied to the skin embedded in glue onacloth or plastic backing.
`Molded tablets are prepared from mixtures of medicinal sub-
`These products are defined traditionally as plasters or tapes.
`stances and a diluent usually consisting of lactose and powdered
`sucrose in varying proportions. The powders are dampened with
`solutions containing high percentages of alcohol. The concentration
`of alcohol depends upon the solubility of the active ingredients and
`fillers in the solvent system and the desired degree of hardness of
`the finished tablets. The dampened powdersare pressed into molds,
`removed, and allowed to dry. Molded tablets are quite friable and
`Care must be taken in packaging and dispensing.
`
`Ocular System
`Another type of system is the ocular system, which is intended
`for placementin the lower conjunctival fornix from which the drug
`diffuses through a membrane at a constant rate (¢.g., Pilocarpine
`Ocular System).
`
`Intrauterine System
`An intrauterine system, based on a similar Principle but intended
`for release of drug over a much longer period of time.i.e., one year,
`is also available (e.g., Progesterone Intrauterine Contraceptive
`System).
`
`TABLETS
`Tablets are solid dosage forms containing medicinal substances
`with or without suitable diluents. They may be classed, according
`to the method of manufacture, as compressed tablets or molded
`tablets.
`The vast majority of all tablets manufactured are made by com-
`pression, and compressed tablets are the most widely used dosage
`form in this country. Compressed tablets are prepared by the ap-
`plication of high pressures,utilizing steel punches and dies. to pow-
`ders or granulations. Tablets can be produced in a wide variety of
`sizes, shapes, and surface markings, depending upon the design of
`the punchesanddies. Capsule-shapedtablets are commonly referred
`to as caplets. Boluses are large tablets intended for veterinary use,
`usually for large animals.
`Moldedtablets are prepared by forcing dampened powders under
`low pressure into die cavities. Solidification depends upon crystal
`bridges built up during the subsequent drying process. and not upon
`the compactionforce.
`Tablet triturates are small, usually cylindrical, molded or com-
`pressed tablets. Tablet triturates were traditionally used as dispens-
`ing tablets in order to provide a convenient, measured quantity of
`a potent drug for compounding purposes. Such tablets are rarely
`used today. Hypodermic tablets are molded tablets made from com-
`pletely and readily water-soluble ingredients and formerly were in-
`tended for use in making preparations for hypodermic injection.
`They are employed orally, or where rapid drug availability is re-
`quired such as in the case of Nitroglycerin Tablets, sublingually.
`Buccal
`tablets are intended to be inserted in the buccal pouch,
`and sublingual
`tablets are intended to be inserted beneath the
`tongue, where the active ingredient is absorbed directly through the
`oral mucosa. Few drugs are readily absorbed in this way. but for
`those that are (such as nitroglycerin and certain steroid hormones),
`a number of advantages may result.
`
`Formulation of Compressed Tablets
`Most compressed tablets consist of the active ingredient and a
`diluent(filler), binder, disintegrating agent, and lubricant. Approved
`FD&C and D&C dyes or lakes (dyes adsorbed onto insoluble alu-
`minum hydroxide),
`flavors, and sweetening agents may also be
`present. Diluents are added where the quantity of active ingredient
`is small or difficult to compress. Commontablet fillers include tac-
`tose, starch, dibasic calcium phosphate, and microcrystalline cel-
`lulose. Chewable tablets often contain sucrose, mannitol, or sorbitol
`as a filler. Where the amountof active ingredient is small, the over-
`all tableting properties arein large measure determined by the filler.
`Because of problems encountered with bioavailability of hydropho-
`bic drugs of low water-solubility, water-soluble diluents are used
`as fillers for these tablets.
`Binders give adhesiveness to the powder during the preliminary
`granulation and to the compressed tablet. They add to the cohesive
`Strength already available in the diluent. While binders may be
`added dry,
`they are more effective when added out of solution.
`Commonbinders include acacia, gelatin, sucrose. povidone. meth-
`ylcellulose, carboxymethyicellulose, and hydrolyzed starch pastes.
`The most effective dry binder is microcrystalline cellulose, which
`is commonly used for this purpose in tablets prepared by direct
`compression.
`A disintegrating agent serves to assist in the fragmentation ofthe
`tablet after administration. The most widely used tablet disintegrat-
`ing agent is starch. Chemically modified starches and cellulose, al-
`ginic acid, microcrystalline cellulose, and cross-linked povidone.
`are also used for this purpose. Effervescent mixtures are used in
`soluble tablet systems as disintegrating agents. The concentration
`of the disintegrating agent, methodof addition, and degree of com-
`paction play a role in effectiveness.
`.
`Lubricants reduce friction during the compression and ejection
`cycle. In addition,
`they aid in Preventing adherence oftablet ma-
`terial
`to the dies and punches. Metallic Stearates, stearic acid, hy-
`drogenated vegetable oils. and talc are used as lubricants. Because
`of the nature ofthis function, most lubricants are hydrophobic, and
`as such tend to reduce the rates oftablet disintegration and disso-
`lution. Consequently, excessive concentrations of lubricant should
`be avoided. Polyethylene glycols and some laury! sulfate salts have
`been used as soluble lubricants, but such agents generally do not
`Possess optimal lubricating properties, and comparatively high con-
`centrations arc usually required.
`°°
`
`
`et eres: PeEe
`
`
`:
`ets He
`:
`1
`vot
`ey
`aaa
`
`FTPBTree c OENEOEgRyeweymeascmepean at memateme om tes POSAan nee pi ee ee
`
`IPR2018-00390
`
`Page 2 of 3
`
`I-MAK1010
`
`IPR2018-00390
`
`Page 2 of 3
`
`I-MAK 1010
`
`

`

`2118
`
`
`(1161) Pharmacy Compounding Practices / General Information
`Glidants are agents that improve powder fluidity, and they are
`commonly employedin direct Compression where no granulation
`step is involved. The most effective glidants are the colloidal Ppy-
`Colorants are often added to tablet formulations for esthetic value
`or for product identification. Both D&C and FD&C dyes and lakes
`are used. Most dyes are photosensitive and they fade when exposed
`to light. The federal Food and Drug Administration regulates the
`colorants employed in drugs.
`
`rogenic silicas,
`
`OUuS OF aqueous solvents. Evaporation of the Solvents leaves a thin
`film that adheres directly to the tablet and allowsit to retain the
`Original shape, including grooves or identification codes.
`
`leric’’ coatings is indicated, Such Coatings are intended to delay the
`release of the Medication until
`the tablet has passed through the
`Stomach. The term ‘'delayed-release'’ is used for Pharmacopeial
`Purposes, and the individual monographs include tests and specifi-
`Cations for Drug release (see Drug Release (724)) or Disintegration
`(see Disintegration (701)),
`
`EXTENDED-RELEASE TABLETS
`Extended-release tablets are formulated in such Manner as to
`make the contained Medicament available Over an extended period
`of time following ingestion, Expressions such aS *“prolonged-ac-
`ion," “repeat-action,”’ and “sustained-release’’ have also been
`used to describe such dosage forms, However, the term “extended-
`release’’ is used for Pharmacopeial Purposes, and requirements for
`Orug release typically are Specified in the individual monographs.
`
`Physical evidence of Poortablet quality is discussed under Sia.
`bility Considerations in Dispensing Practicé {1191),
`WEIGHT VARIATION AND CONTENT UNIFORMITY
`Tablets are required to meet a weight variation test (see Unifor-
`mity ofDosage Units (905)) where the active ingredient comprises
`4 major portion of the tablet and where control of weight may be
`Presumed to be an adequate control of drug content uniformity.
`Weightvariation is not an adequate indication ofcontent uniformity
`where the drug substance comprises a Telatively minor Portion of
`the tablet, or where the tablet is Sugar-coated. Thus,
`the Pharma-
`50 mg or less of active ingredient, comprising less than 50% by
`(1161) PHARMACY
`i
`Pass a content uniformity test (see
`Uniformity of Dosage Units (905)), wherein individual tablets are
`COMPOUNDING PRACTICES
`Compounding is an integral part of pharmacypractice and is
`DISINTEGRATION AND DISSOLUTION
`essential to the provision Of health care. The Purpose ofthis chapter
`Disintegration is an essential attribute of tablets intended for ad-
`ministration by mouth. except those intended to be chewed before
`being swallowed and except some types ofextended-release tablets.
`extemporaneously compound preparations that are of acceptable
`A disintegration test
`is Provided (see Disintegration (701)), and
`Strength, quality, and Purity.
`limits on the times in which disintegration is to take place, appro-
`Ompoundingis different from manufacturing. which is guided
`-
`priate for the types oftablets Concerned.are given in the individual
`by GMPs(see GoodManufacturing Practices 1077), Someof the
`characteristics or criteria that differentiate compounding from man-
`For drugs of limited water-solubility. dissolution may be a more
`ufucturing include the existence of Specific Practilioner-patient-
`meaningful quality attribute than disintegration. A dissolution test
`pharmacist relationships: the quantity of medication Prepared in an-
`(see Dissolution (7) 1)is required ina number of Monographs on
`licipation of receiving a Prescription or a Prescription order: and
`tablets. In Many Cases,
`it is possible {0 correlate dissolution rates
`the conditions of sale. which are limited to specific prescription
`with biological availability of the active ingredient, However. such
`lests are useful mainly as a means of Screening Preliminary for.
`The pharmacist's responsibilities in compounding drug Prepara~-
`mulations and as a routine quality-control Procedure.
`lions are to dispense the finished Preparation in accordance with a
`Prescription or a Prescriber’s order or intent and to dispense those
`Preparations in compliance with Tequirements established by Boards
`Coatings
`of Pharmacy and Other rexulatory agencies. Pharmacists must be
`Tablets may be coated for a variety of reasons, including protec-
`familiar with Slatutes and regulations that g0vem compounding be-
`tion ofthe ingredients from air, moisture. or light. masking of un-
`cause these requirements vary from state to Stale.
`Pleasant tastes and odors, improvement of appearance, an.' contro}
`The pharmacist
`is responsible for compounding preparations of
`Ofthe cite of drug release in the gastrointestinal tract,
`#Cceptabl> strength, quality. anc ourity with appropriate Packaging
`und labeling in accordance with good pharmacy Praclices, official
`
`
`monographs.
`
`orders.
`
`IPR2018-00390
`
`L-MAK 1010
`
`IPR2018-00390
`
`Page 3 of 3
`
`I-MAK 1010
`
`