2005
`
`THE UNITED STATES PHARMACOPEIA
`USP 28
`
`NE 23
`THE NATIONAL FORMULARY
`
`By authority of the United States Pharmacopeial
`Convention, Inc., meeting at Washington, D.C.,
`April 12-16, 2000. Prepared by the Council ofExperts
`and published by the Board of Trustees
`Official from January 1, 2005
`
`The designation on the coverofthis publication, “USP NF
`2005,” is for ease of identification only. The publication
`contains two separate compendia: The United States
`Pharmacopeia, Twenty-Eighth Revision, and the National
`Formulary, Twenty-Third Edition.
`
`UNITED STATES PHARMACOPEIAL CONVENTION,INC.
`12601 Twinbrook Parkway, Rockville, MD 20852
`
`|9s Par Pharm.,Inc.
`
`Par Pharm., Inc.
`Exhibit 1054
`Page 001
`
`

`

`NOTICE AND WARNING
`
`Concerning U.S. Patent or Trademark Rights
`
`The inclusion in the United States Pharmacopeiaorin the National Formulary of a monographon any drug
`in respect to whichpatentor trademark rights may exist shall not be deemed, andis not intended as, a grant of,
`or authorily 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 mayexercise the same without
`express permission, authority, or license secured from such patent or trademark owner.
`
`Concerning Use of USP or NF Text
`Use of the USP-NF is subject to the terms and conditions of the USP-NF License Agreement. Attention
`is called to the fact that USP and NFtext 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.
`
`Copyright © 2004 The United States Pharmacopeial Convention,Inc.
`12601 Twinbrook Parkway, Rockville, MD 20852
`All rights reserved.
`ISSN 0195-7996
`ISBN 1-889788-25-2
`Printed in Canada by WebcomLimited, Toronto, Ontario
`
`Par Pharm., Inc.
`
`Par Pharm., Inc.
`Exhibit 1054
`Page 002
`
`

`

`Basket-rack Assembly—Thebasket-rack assembly consists of six
`open-endedtransparenttubes, each 7.75 + 0.25 cm long and having
`an inside diameter of 20.7 to 23 mm and a wall 1.0 to 2.8 mm thick;
`the tubesare held in a vertical position by twoplastic plates, each 8.8
`to 9.2 cm in diameter and 5 to 7 mm in thickness,with six holes, each
`22 to 26 mm in diameter, equidistant from the centerof the plate and
`equally spaced from one another. Attached to the undersurface of the
`lowerplate is a woven stainless steel wire cloth, which has a plain
`square weave with 1.8- to 2.2-mm mesh apertures and with a wire
`diameter of 0.63 + 0.03 mm.- The parts of the apparatus are
`assembled and rigidly held by means ofthree bolts passing through
`the two plastic plates. A suitable means is provided to suspend the
`basket-rack assembly from the raising and lowering device using a
`pointon its axis.
`The design of the basket-rack assembly may be varied somewhat
`provided the specifications for the glass tubes and the screen mesh
`size are maintained.
`
`Disks—Theuse of disks is permitted only where specified in the
`monograph. If specified in the individual monograph, each tube is
`provided with a cylindrical disk 9.5 +0.15 mm thick and
`20.7 + 0.15 mm in diameter. The disk is made of .a suitable,
`transparentplastic material having a specific gravity of between 1.18
`and 1.20. Five parallel 2-mm holes extend between the’ends of the
`cylinder. One of the holes is centered on the cylindrical axis. The
`other holes are centered 6 mm from the axis on imaginary lines
`perpendicular to the axis and parallel to each other. Four identical
`trapezoidal-shapedplanesare cut into the wall of the cylinder; nearly
`perpendicular to the ends of the cylinder. The trapezoidal: shape is
`symmetrical; its parallel sides coincide with the ends of the cylinder
`and are parallel to an imaginary line connecting the centers of two
`adjacentholes 6 mm from the cylindricalaxis. The parallel side of the
`trapezoid on the bottom ofthe cylinder has a length of 1.6 mm,andits
`center lies at a depth of 1.8 mmfrom the cylinder’s circumference.
`The parallel side of the trapezoid on the top of the cylinder has a
`length of 9.4 + 0.2 mm,andits centerlies ata depth of 2.6 + 0.1 mm
`from the cylinder’s circumference. All surfaces of the disk are
`smooth.If the use of disks is specified in the individual monograph,
`add a disk to each tube, and operate the apparatus as directed under
`Procedure.
`
`PROCEDURE
`
`Uncoated Tablets—Place 1 tablet in each of the six tubes ofthe
`basket and operate the apparatus, using water maintained at 37 + 2°
`as the immersion fluid unless otherwise specified in the individual
`monograph.Atthe end ofthe time limit specified in the monograph,
`lift the basket from the fluid, and observethetablets: all of the tablets
`have disintegrated completely. If 1 or 2 tablets fail to disintegrate
`completely, repeatthe test on 12 additionaltablets: not less than 16 of
`the total of 18 tablets tested disintegrate completely.
`Plain Coated Tablets—Apply the test for Uncoated Tablets,
`operating the apparatus for the time specified in the individual
`monograph.
`tablet in
`Delayed-Release (Enteric Coated) Tablets—Place |
`cach of the six tubes of the basket and, if the tablet has a soluble
`external coating, immersethe basket in water at room temperature for
`5 minutes. Then operate the apparatus using simulated gastric fluid
`TS maintained at 37 + 2° as the immersion fluid. After 1 hour of
`operation in simulated gastric fiuid TS,lift the basket from the fluid,
`and observethe tablets: the tablets show no evidence of disintegra-
`tion, cracking, or softening. Operate the apparatus, using simulated
`intestinal fluid TS. maintained at 37 + 2° as the immersionfluid, for
`the time specified in the monograph. Lift the basket from the fluid,
`and observethe tablets: all of the tablets disintegrate completely. If |
`or 2 tablets fail
`to disintegrate completely, repeat the test on 12
`additional tablets: not less than 16 of the total of 18 tablets tested
`disintegrate completely.
`Buccal Tablets—Apply the test for Uncoated Tablets. After 4
`hours,lift the basket from the fluid, and observethetablets: all of the
`tablets have disintegrated. If 1 or 2 tablets fail
`to disintegrate
`
`completely, repeat the test on 12 additionaltablets: not legg ha
`the total of 18 tablets tested disintegrate completely.
`Sublingual Tablets—Apply the test
`for Uncoateg
`Observethe tablets within the time limit specified in th
`monograph:all ofthe tablets have disintegrated. If 1 or2 tabl
`disintegrate completely, repeat the test on 12 additional tabja,
`less than 16 ofthe total of 18 tablets tested disintegrate coi
`Hard Gelatin Capsules—Apply the test for Uncoated
`Attach a removable wire cloth, which hasa plain square We
`1.8- to 2.2-mm mesh apertures and with a wire diameter of
`0.655 mm, as described under Basket-Rack Assembly, to th
`of the upperplate of the basket-rack assembly. Observe the
`within the time limit specified in the individual monograph:
`capsules have disintegrated except for fragments from th
`shell. If 1 or 2 capsules fail to disintegrate completely, Tepe
`on 12 additional capsules: not less than 16 ofthe total of18
`tested disintegrate completely.
`.
`Soft Gelatin Capsules—Proceed as directed under Hard Gey,
`Capsules.
`
`(711) DISSOLUTION
`
`This test is provided to determine compliance with the dissoht
`requirements wherestated in the individual monographfora ta
`capsule dosage form. Ofthe types of apparatus describedhere}
`the one specified in the individual monograph. Wherethelabel
`that an article is enteric-coated, and a dissolution or disintegration
`that does not specifically state thatit is to be appliedto enteric-
`articles is includedin the individual monograph,thetest for De
`Release Articles under Drug Release (724)
`is applied unl
`otherwise specified in the individual monograph. Forhard or
`gelatin capsules and gelatin-coated tablets that do not confo’
`Dissolution specification, repeat the test as follows. Where waler6
`medium with a pH ofless than 6.8 is specified as the Medium’
`individual monograph, the same Mediumspecified may be
`the addition of purified pepsin that results in an activity of
`Units or less per 1000 mL. For media with a pH of 6.8 o
`pancreatin can be added to produce not more than 1750 USP
`protease activity per 1000 mL.
`USP Reference Standards (11)—USP Prednisone Table
`(Dissolution Calibrator, Disintegrating). USP Salicylic Acie
`RS (Dissolution Calibrator, Nondisintegrating).
`Apparatus 1—Theassembly consists ofthe following: é
`vessel made of glass or other inert, transparent material!; a
`metallic drive shaft; and a cylindrical basket. The vessel
`immersed in a suitable water bath of any convenientsize ¢
`a heating jacket. The waterbath or heating jacket permits he
`temperature inside the vessel at 37 + 0.5° duringthetest and
`the bath fluid in constant, smooth motion. Nopart ofthe.
`including the environment
`in which the assembly 1s
`contributes significant motion, agitation, or vibration bey!
`due to the smoothly rotating stirring element. Apparatus tha’
`observation of the specimenandstirring element during
`preferable. The vesselis cylindrical, with a hemisphericalbo
`with one of the following dimensions andcapacities: for
`capacity of 1 L, the height is 160 mm to 210 mm and
`diameter is 98 mm to 106 mm; for a nominal capacity of
`height is 280 mm to 300 mm andits inside diameteris 98 m
`mm; and for a nominal capacity of 4 L, the height is 280 mm
`mm andits inside diameter is 145 mm to 155 mm.Its $
`flanged atthe top. A fitted cover maybe usedto retard evap
`The shaft is positioned so thatits axis is not more than 2 ml
`point from the vertical axis of the vessel androtates smoo
`without significant wobble. A speed-regulating device 18
`allows the shaft rotation speed to be selected and mainta “
`rate specified in the individual monograph, within +4%:
`
`
`' The materials should not sorb, react, or interfere’ with the spect
`tested.
`I
`> Ifa coveris used,it provides sufficient openingsto allow ready. f
`the thermometer and withdrawal of specimens.
`
`Par Pharm., Inc.
`
`Par Pharm., Inc.
`Exhibit 1054
`Page 003
`
`

`

`
`
`NOTES—
`
`(1) Shaft and blade material:
`
`303(or equivalent)
`stainless steel.
`
`(2) A and B dimensions are
`not to vary more than
`
`0.5 mm when part is
`rotated on ¢ axis.
`
`(3) Tolerances are 1.0mm,
`
`unlessotherwise stated.
`
`
`41.5 mm radius
`1.2mmriz
`
`Prin
`
`a\
`
`9.4 to 10.1 mm diameter
`before coating
`
`ares»
`
`
`
`A 35.8mm=Vn.
`
`
`
`‘\
`
`°
`
`19.0mm|
`40.5mm
`1
`
`cA
`
`1
`
`Screen with welded seam:
`40 X 40 mesh,0.25-mm wire
`'
`Screen
`diameterwith wire openings of
`f
`byt 42.0apts
`
`t
`0.40 + 0.04 mm; where 20-
`aa
`40410mm
`meshscreenis specified, use
`I
`th the disso uti
`
`“4PoGon 20 X 20 mesh,0.40-mm wire
`er, Si
`A
`diameterwith wireopeningsof
`eT1DE:
`0.90 + 0.09
`mm.
`[N
`
`Ke
`Nore—Maximumallowable
`After weldin: the eama
`re the abe!
`at ‘A* is £ 1.0 mm when
`ightly
`ale
`”
`Pie
`qunout
`beslightly altered.]
`at
`=}
`"
`[ 74.0 mm to 75.0mm Foto
`
`disintegra ‘the part is rotated onGaxis
`
`to enteric-co
`with baskel mounted.
`Fig, 2. Paddle Stirring Element
`
`
`
`not less
`
`and basket componentsofthestirring element are fabricated
`
`snless steel, type 316 or equivalent, to the specifications shown
`sre
`1. Unless otherwise specified in the individual monograph,
`ncoated
`
`-mesh cloth. A basket having a gold coating 0.0001 inch (2.5
`in the
`hick may be used. The dosageunit is placed in a dry basketat
`Or 2 table
`
`ginning of each test, The distance betweenthe inside bottom of
`tional tab
`el and the basketis maintained at 25 + 2 mm duringthetest.
`
`grate eo Mple
`/ncoated |
`quare w
`
`
`
`
`aly, re
`
`.
`
`e
`
`Vent hole
`2.0 + 0.5 mm diameter
`
`°
`Retention spring with
`3 tangs on 120° centers
`
`Clear opening
`20.2 £0.1 mm
`
`¢
`
`6.3 to6.5 or
`9.4 to 10.14mm
`
`54+05mm
`
`Screen O.D.
`22.2+1.0mm
`
`
`
`
`
`
`: applied unle
`For hardor
`
`750 USPL
`
`3
`
`Fig. 1. Basket Stirring Element
`
`
`pparatus 2—Use the assembly from Apparatus 1, except that a
`idle formed from a blade anda shaft is usedasthestirring element.
`shaft is positioned so that its axis is not more than 2 mm at any
`
`!
`1
`itfrom the vertical axis of the vessel and rotates smoothly without
`reriall
`icant wobble. The vertical center line of the blade passes
`
`4
`j
`igh the axis of the shaft so that the bottom ofthe blade is flush
`1 the bottom of ‘the shaft. The paddle conforms to.
`the
`
`ications shown in Figure 2. The distance of 25 +2 mm
`
`k
`’
`een the blade andthe inside bottom ofthe vessel is maintained
`
`“oftheassem
`g the test. The metallic or suitably inert, rigid blade and shaft
`‘
`;
`a single entity. A suitable two-part detachable design may
`on
`ed provided the assembly remains firmly engaged during the
`
`
`ratus that
`The paddle blade and shaft may be coated with a suitable inert
`
`during the
`ing The dosage unit is allowed to sink to the bottom ofthe vessel
`erical bottom
`otation of the blade is started. A small,
`loose piece of
`
`as: for a Dl
`live material such as not more than a few turnsof wire helix
`be attached to dosage units that would otherwise float. Other
`sinker devices may be used.
`
`
`
`4
`
`Apparatus Suitability Test—Individually test 1 tablet of the USP
`Dissolution Calibrator, Disintegraling Type and 1
`tablet of USP
`Dissolution Calibrator, Nondisintegrating Type, according to the
`operating conditions specified. The apparatusis suitable if the results
`obtained are within the acceptable rangestated in the certificate for
`that calibrator in the apparatus tested.
`Dissolution Medium—Usethe solventspecified in the individual
`monograph.If the Dissolution Mediumis a buffered solution, adjust
`the solution so that its pH is within 0.05 unit of the pHspecified in the
`individual monograph. [NOTE—Dissolved gases can cause bubbles to
`form, which may change the results of the test. In such cases,
`dissolved gases should be removedpriorto testing.*]
`Time—Wherea single time specificationis given, the test may be
`concluded in a shorter period if the requirement for minimum amount
`dissolved is met. If two or more timesare specified, specimensare to
`be withdrawn only at the stated times, within a tolerance of +2%.
`Procedure for Capsules, Uncoated Tablets, and Plain Coated
`Tablets—Placethe stated volumeofthe Dissolution Medium(+ 1%)
`in the vessel of the apparatus specified in the individual monograph,
`assemble the apparatus, equilibrate the Dissolution Mediwn to
`37 + 0.5°, and remove the thermometer. Place 1 tablet or 1 capsule
`in the apparatus, taking care to exclude air bubbles from the surface of
`the dosage-form unit, and immediately operate the apparatus at the
`rate specified in the individual monograph. Within the time interval
`specified, or at each of the times stated, withdraw a specimen from a
`zone midway betweenthe surface ofthe Dissolution Mediumand the
`top of the rotating basketor blade, not less than 1 cm from the vessel
`wall. [NOTE—Replacethe aliquots withdrawn for analysis with equal
`volumes of fresh Dissolution Medium at 37° or, where it can be
`shown that replacement of the medium is not necessary, correct for
`the volume changein the calculation. Keep the vessel covered for the
`duration ofthe test, and verify the temperature of the mixture under
`test at suitable times.] Perform the analysis as directed in the
`
`3 One methodof deaeration is as follows: Heat the medium, whilestirring
`gently, to about 41°, immediately filter under vacuum usinga filter having a
`porosity of 0.45 um orless, with vigorousstirring, and continuestirring under
`vacuum for about 5 minutes, Other validated deaeration techniques for
`removalof dissolved gases may be used.
`
`Par Pharm., Inc.
`
`Par Pharm., Inc.
`Exhibit 1054
`Page 004
`
`

`

`individual monograph*. Repeat the test with additional dosage form
`units.
`If automated equipmentis used for sampling and the apparatus is
`modified, validation of the modified apparatus is needed to show that
`there is no changein the agitation characteristics ofthetest.
`Where capsule shells interfere with the analysis, remove the
`contents of not fewer than 6 capsules as completely as possible, and
`dissolve the empty capsule shells in the specified volume of
`Dissolution Medium. Perform the analysis as directed in the
`individual monograph. Make any necessary correction. Correction
`factors greater than 25% of the labeled content are unacceptable.
`Procedure for a Pooled Sample for Capsules, Uncoated
`Tablets, and Plain Coated Tablets—Use this procedure where
`Procedure for a Pooled Sample is specified in the individual
`monograph. Proceed as directed under Procedure for Capsules,
`Uncoated Tablets, and Plain Coated Tablets. Combine equal volumes
`of the filtered solutions of the six or twelve individual specimens
`withdrawn,and use the pooled sample asthe test solution. Determine
`the average amountofthe active ingredient dissolved in the pooled
`sample.
`Interpretation—
`Unit Sample—Unless otherwise specified in the individual
`monograph,
`the requirements are met if the quantities of active
`ingredient dissolved from the units tested conform to the accompa-
`nying Acceptance Table.Continue testing through the three stages
`unless the results conform at either S, or S,. The quantity, Q, is the
`amount of dissolved active ingredient specified in the individual
`monograph, expressedas a percentageof the labeled content; the 5%,
`15%, and 25% valuesin the Acceptance Table are percentages of the
`labeled content so that these values and Q are in the same terms.
`
`
`
`
`
`To determine the range of temperatures within which
`liquid distils, or the percentage ofthe materialthatdistil b a!
`specified temperatures, use Mcthod I or MethodII ag direoy:
`individual monograph.The /owerlimit of the rangeis the ten
`indicated by the thermometer whenthefirst drop ofcondensa
`the tip of the condenser, and the upperlimit is the Dry Poin
`temperature at which the last drop of liquid evaporates
`lowest point in the distillation flask, without regard to
`remaining onthe side of the flask, or the temperature obsery,
`the proportion specified in the individual monograph
`collected.
`NOTE—Coolallliquids that distill below 80° to between 1(
`15° before measuring the sample to be distilled,
`
`METHODI
`
`Apparatus—Use apparatussimilarto that specified forMeth
`except that the distilling flask is of 50- to 60-mL capacity,
`neckofthe flask is 10 to 12 cm long and 14 to 16 mm inj
`diameter. The perforation in the upperinsulating board,ifone
`should be such that when the flask is setinto it, the portion of
`belowthe uppersurface of the insulating materialhas a capacity
`to 4 mL.
`Procedure—Proceed as directed for Method IT, but pla
`flask only 25 mL ofthe liquid to be tested.
`
`
`
`Acceptance Table
`
`METHODII
`
`S;
`
`12
`
`Pooled Sample—Unless otherwise specified in the individual
`monograph,
`the requirements are met if the quantities of active
`ingredient dissolved from the pooled sample conform to the
`accompanying Acceptance Table for a Pooled Sample. Continue
`testing through the three stages unlessthe results conform at either S,
`or S,. The quantity, QO, is the amountof dissolved active ingredient
`specified in the individual monograph, expressed as a percentage of
`the labeled content.
`
`Acceptance Table for a Pooled Sample
`Number
`
`Stage
`Tested
`Acceptance Criteria
`Ss;
`6
`Average amountdissolvedis not less than
`+ 10%,
`Average amountdissolved (S, + S,) is equal
`to or greater than O + 5%.
`12
`Average amount dissolved (S, + S, + §;) is
`
`equal to or greater than Q.
`
`S,
`
`S;
`
`Number
`Apparatus—Use an apparatus consisting ofthe followin;
`
`
`Stage_Tested Acceptance Criteria
`Distilling Flask—A round-bottomdistilling flask, of hea’
`S,
`6
`Each unit is not less than Q + 5%.
`glass, of 200-mL capacity, and havingatotal length of 17 t
`and aninside neck diameter of 20 to 22 mm. Attached abo
`S;
`6
`Average of 12 units (S, + S,) is equal to or
`greater than Q, and no unitis less than O —
`on the neck, approximately 12 cm from the bottom ofthe
`15%.
`side-arm 10 to 12 cm long and 5 mm in internal diame!
`Average of 24 units (S, + S, + §,) is equal to
`forms an angle of 70° to 75° with the lower portion ofthe neck
`or greater than Q, not more than 2 units are
`Condenser—Astraight glass condenser 55 to 60 cmin length
`less than Q— 15%,andno unit is less than 0
`a water jacket about 40 cm in length, or a condenserof o
`— 25%,
`having equivalent condensing capacity. The lower endo}
`condenser may be bent to provide a delivery tube,or it
`connected to a bent adapter that serves as a delivery tube.
`Insulating Boards—Twopieces of insulating board,
`thick and 14 to 16 cm square, suitable for confining the
`lowerpart ofthe flask. Each board has a holein its center, and
`boards differ only with respect to the diameter of the hol
`diameters are 4 and 10 cm,respectively. In use, the boards
`one uponthe other, and resting on a tripod or other suitabl
`with the board having the larger hole on top.
`Receiver—A 100-mL cylinder graduated in 1-mL subdi
`Thermometer—In order to avoid the necessity for an
`stem correction, an accurately standardized, partia
`thermometer having the smallest practical subdivisions (1
`than 0.2°) is recommended. Suitable thermometers are ava
`the ASTM E-1 series 37C through 41C, and 102C through 10
`Thermometers (21)). Whenplacedin position, the stem islo
`the centerofthe neck andthetop ofthe contraction chamber (@
`if 37C or 38Cis used)is level with the bottom ofthe outlet to the si®
`arm.
`
`Heat Source—A small Bunsen burner or an electric
`mantle capable of adjustment comparable to that possib
`Bunsen burner.
`Procedure—Assemble the apparatus, and place in the
`mL ofthe liquid to be tested,taking care not to allow any of
`to enter the side-arm.Insert the thermometer, shield the ent
`and flask assembly from external air currents, and apP!
`regulating it so that between 5 and 10 minutes elapse befor
`
`dropofdistillate falls from the condenser. Continuethe dist
`
`arate of 4 to 5 mL ofdistillate per minute, collecting the¢
`
`the receiver. Note the temperature whenthefirst dropofdist
`from the condenser, and again whenthelast drop ofliqu!
`
`
`
`6
`
`
`
`* Iftest specimensarefiltered, use an inert filter that does not cause adsorption
`ofthe active ingredient or contain extractable substances that would interfere
`with the analysis.
`
`
`
`
`
`Par Pharm., Inc.
`
`Par Pharm., Inc.
`Exhibit 1054
`Page 005
`
`

`

`Nicaragua
`
`
`
`
`
`
`al Information
`
`(1151) Pharmaceutical Dosage Forms
`
`2701
`
`‘Table 1.
`
`international Climatic
`
`7AMES
`
`
`
`
`
`_Derived Data.as,
`
`Ye
`
`Co RH
`mbar
`21
`45
`1.2
`
`
`13.5
`25
`60
`19.0
`
`(Temperate
`Japan
`Jnited Kingdom
`orthern Europe
`anada
`ussia
`United States
`
`(Mediterranean,Subtropical
`United States
`Japan
`Southern Europe
`(Portugal-Greece)
`(oiDry
`ran
`raq
`Sudan
`WW,Hot,Humid —
`Brazil
`Ghana
`ndonesia
`
`~
`
`Eg 30
`
`——
`
`35005.0
`
`
`~ 7626.6
`30
`70
`30.0
`
`
`Data recorded as < 19°
`calculated as 19°,
`
`culated mean Kinetic temperature.
`
`
`Partial pressure of water vapor.
`
`
`
`
`
`(1151) PHARMACEUTICAL
`DOSAGE FORMS —
`
`_ Dosage forms are provided tor most of the Pharmacopeial drug
`aibstances, but the processesfor the preparation of manyofthemare.
`in general, beyond the scope of the Pharmacopeia.
`In addition to
`defining the dosage forms, this section presents the general principles
`involved in the manufacture of some ofthem, particularly on a small
`cae. Other
`informauion thal
`is given bears on the use of the
`in extemporaneous compounding of
`Pharmacopeial substances
`dosage forms.
`
`BIOAVAILABILITY
`
`
`
`woavallability, or the e
`tent 1o which the therapeutic constituent of
`| Piarmacentical dosage form intended for oral or topical use is
`
`
`available for absorption, is influenced
`bya variety of factors. Among
`he inherent factors known to affec absorption are
`the method of
`paiacture or method of compounding: the particle size and crystal
`> polymorph of the drug substance; and the diluents and
`scipients used in formulating the dosage form,
`includingfillers,
`
`
`inders, disintegrating agents,
`b ibricants, coatings, solvents, sus-
`
`pending agents, and dyes. Lubricants and coatings are foremost
`
`ong these, The maintenance of a demonsttrably high degree of
`
`loavailability requires particular attention to all aspects of
`loduction and quality control
`that may affect
`the nature of the
`fhished dosage form.
`
`
`
`
`
`TERMINOLOGY
`
`
`Occasionally it is necessary to add solvent to the contents of 4
`
`‘Ontainer just prior to use, usually because ofinstability of some
`tugsin the diluted form. Thus, a solid dilutedlo yield a suspensionis
`
`alled [DRUG] jor Suspension; a solid dissolvedand diluted to yield
`Solution is called [DRUG]
`for Sofution;, and a solution or
`
` : Desnsion diluted to yield a more dilute form of the drug is called
`DRUG] Oral Concentrate. After dilution,
`it
`is important that the
`tug be homogeneously dispersed belure administration.
`
`
`
`
`
`AEROSOLS
`
`Pharmaceutical aerosols are products that are packaged under
`pressure and contain therapeutically active ingredients that” are
`released upon activation of an appropriate valve system. They are
`imtended for topical applicationto the skin as well as local application
`into the nose (nasa! aerosols), mouth (lingual aerosols), or lungs
`(inhalation aerosols). These products may be fitted with valves
`enabling either continuous or metered-dose delivery; hencé; the terms
`“IDRUG| Metered Topical Aerosols,” “[DRUG] Metered Nasal
`Aerosols,” ete.
`The term “aerosol”refers to the fine mist of spraythat results from
`
`most pressurized systems. However,
`the term has been broadly
`misayaplie2d to all self-contained pressurized products, some of which
`deliver foarns or semisolid fluids. In the case of Inhalation Aerosols,
`the particle size of the delivered medication ‘must be carefully
`controlled, andthe average size ofthe particles should be under 5 um.
`These products are also known as metered-dose inhalers (MDI).
`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 ofthese components determines
`such characteristics as particle size distribution, uniformity of dose
`for metered valves, delivery ratc, wetness and temperature of the
`spray, spray pattem and velocity or plume geometry, foam density,
`and fluid viscosity.
`
`Types of Aerosols
`
`Aerosols consist oftwo-phase (gas and liquid) or three-phase (gas,
`liquid, andsolid orliquid) systems. The two-phase aerosol consists of
`a
`solution of active ingredients in liquefied propellant and the
`vaporized|propellant, The solvent is composed ofthe’propellant or a
`mixture of the propellant and cosolvents such as alcohol, propylene
`glycol, and polyethylene glycols, whichare often used to enhance the
`solubility of the active ingredients.
`Three-phase systems consist of a suspension or emulsion of the
`active ingredient(s)
`in addition to the vaporized propellants. A
`suspension consists ofthe active ingredient(s) that maybe dispersed
`inin
`the propellant system with the aid of suitable excipients such as
`vetting agents and/orsolid carriers such as tale or colloidal silicas.
`
`
`
`
`
`Par
`
`Pharm., Inc.
`Exhibit 1054
`Page 006
`
`Par Pharm., Inc.
`Exhibit 1054
`Page 006
`
`

`

`2702
`
`(1151) Pharmaceutical Dosage Forms / General iaformution
`
`
`
`
`
`Manufacture
`
`Acrosols are usually prepared by one of two e
`the “cold-fll’ process,
`the concentrate (gen
`temperature below 0°) and the refrigerated propellant ar
`into open containers (usually chilled). The valve-actu;
`then crimped onto the containerto forma pressure-tig
`the interval between propellant addition and crimp;
`
`volatilization of propellant occurs to displace air from the eer
`
`In the “pressure-fill” method,
`the concentrate is placed |
`
`contamer, and either the propellant is forced underpr
`ropellant 4
`the valve orifice afterthe valve is sealed, or the p
`to flow under the valve cap and then the valve
`(“under-the-cap” filling). In both cases of the “pr
`provision must be made for evacuation of air by m
`displacement with a srnall amountofpropellant vapo
`process controls usually include monitoring of proper ¢
`and propellantfill weight andpressuretesting, leak testing-ang
`function testing of the finished aerosol. Microbiological aga
`shouldalso be controlled.
`
`|
`ayespot
`dvough ¢
`actory-fi
`banding, i
`
`Extractable Substances
`Since pressurized inhalers and aerosols are no
`with organic solvents as the propellant or the vehic!
`
`extractables from the elastomeric and plastic component
`formulation is a potentially serious problem. Thus,
`
`and the quality of materials used in the manufacture
`
`components should be well established so as to prev
`ofthe valve components and to minimize changes in the medic
`delivery, leak rate, and impurity profile ofthe drug product ove
`
`The extractable profiles of a representative sample of each
`elastomeric andplastic components ofthe valve should be estab
`underspecified conditions and should he correlated to the extra
`
`profile of the aged drug product or placebo, to ensure reprod
`quality and purity of the drug product. Extractab
`i
`
`include polynuclear aromatics, nitrosamines, vulcani
`
`alors, antioxidants, plasticizers, monomers, etc., should bé-i
`and minimized wherever possible.
`:
`Specifications and limits for individual and total extractable.
`
`different valve components may require the use ofdifferent and
`
`methods.
`In addition,
`the standard USP biological testing
`general test chapters Biological Reactivity Tests,
`In Vitro |
`Biological Reactivity Tesis, In Vivo (88)) as well as othersaf
`may be needed.
`:
`
`
`
`
`is an emulsion containing one or more active
`A foam aerosol
`ingredients, surfactants, aqueous or nonaqueous liquids, and -the
`propellants. Hf the propellant is in the intemal (discontinuous) phase
`(Le., of the oil-in-water typc), a stable foamis discharged; andifthe
`propellant is in the external (continuous) phase (i.e., of the water-in-
`
`oil type), a spray or a quick-breaking foamis discharged.
`
`Propellants
`
`The propellant supplies the necessary pressure within an aerosol
`system to expel malerial from the containerand, in combination with
`other components, to convert the material into the desired physical
`form. Propellants may be broadly classified as
`liquefied or
`compressed gases having vapor pressures generally exceeding
`atmospheric pressure. Propellants within this definition include
`various hydrocarbons, especially halogenated derivatives of methane,
`ethane, and propane, low molecular weight hydrocarbons suchas the
`butanes and pentanes, and compressed gases such as carbon divxide,
`nitrogen, and nitrous oxide. Mixtures of propellants are frequently
`used to obtain desirable pressure, delivery, and spray characteristics.
`A good propellant sysiem 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 ofthe
`therapeutic agent and propellant
`from the container, The spray
`characteristics of the acrosol are influenced by orifice dimension,
`number, and location. Most aerosol valves provide for continuous
`spray operation and are used on most topical products. However,
`pharmaceutical products for oral or nasa!
`inhalation often utilize
`metered-dose valves that must deliver a uniform quantity of spray
`uponeach vaive activation. The accuracy and reproducibility of the
`doses delivered from metering valves are generally good, comparing
`favorably to the uniformity of solid dosage forms suchas tablets and
`capsules. However, when aerosol packagesare stored improperly, or
`when they have not been used for long periods of time, valves must
`be primed before use. Matcrials 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
`
`Au actualoris the fitting attached to an aerasol 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 whichthe preparation is dispensed
`and protects the hand or finger from the refrigerant effects of the
`propellant. Actuators incorporate an orifice that may vary widely in
`size andshape. The size ofthis orifice, the expansion chamberdesign,
`and the nature of the propellant and formulation influence the
`delivered dose as well as the physical characteristics of the spray,
`foam, orstreamofsolid particles dispensed. For inhalation aerosols,
`an actuator capable of delivering the medication in the properparticle
`size range and with the appropriate spray pattern and plume geometry
`is utilized.
`
`Containers
`
`Aerosol containers usually are made ofglass,plastic, or metal, or a
`combination of these materials. Glass containers must be precisely
`engineered to provide the maxi