THE UNITED STATES PHARMACOPEIA
`
`THE NATIONAL FORMULARY
`
`12601 Twinbrook Parkway, Rockville, MD 20852
`
`The designation on the cover of this 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.
`
`By authority of the United States Pharmacopeial
`Convention, Ina, meeting at Washington, D. C,
`April 12—16, 2000. Prepared by the Council ofExperts
`and published by the Board of Trustees
`
`Oflicz’alfi‘om January 1, 2005
`
`UNITED STATES PHARMACOPEIAL CONVENTION, INC.
`
`Par Pharm., Inc.
`Exhibit 1054
`Page 001
`
`

`

`NOTICE AND WARNING
`
`Concerning US. Parent or Trademark Rig/its
`
`The inclusion in the United States Phannacopeia 01‘ in the National Formulaiy 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.
`
`Printed in Canada by Webcom Limited, Toronto, Ontario
`
`Concerning Use ofUSP 01' NF Text
`
`Use of the USP~NF is subject to the terms and conditions of the USPJVF License Agreement. Attention
`is called to the fact that USP and NI? 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.
`
`Copyright (Q 2004 The United States Pliarrnacopeial Convention, Inc.
`12601 Twinbrook Parkway, Rockville, MD 20852
`All rights reserved.
`ISSN 0195-7996
`ISBN 1—8897884252
`
`Par Pharm., Inc.
`Exhibit 1054
`Page 002
`
`

`

`Basket—rack Assembly—The basket-rack assembly consists of six
`open-ended transparent tubes, each 7.75 i 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 tubes are held in a vertical position by two plastic 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 center of the plate and
`equally spaced from one another. Attached to the under surface of the
`lower plate 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 i 0.03 mm. The parts of the apparatus are
`assembled and rigidly held by means of three 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
`point on 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—The use 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 i 0.15 mm thick and
`20.7 J_r 0.15 mm in diameter. The disk is made of a suitable,
`transparent plastic 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—shaped planes are 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
`adjacent holes 6 mm from the cylindrical axis. The parallel side of the
`trapezoid on the bottom of the cylinder has a length of 1.6 mm, and its
`center lies at a depth of 1.8 mm from the cylinder’s circumference.
`The parallel side of the trapezoid on the top of the cylinder has a
`length of9.4 i 0.2 mm, and its center lies at a depth of2.6 i 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 TabletsiPlace 1 tablet in each of the six tubes of the
`basket and operate the apparatus, using water maintained at 37 i 2“
`as the immersion fluid unless otherwise specified in the individual
`monograph. At the end of the time limit specified in the monograph,
`lift the basket from the fluid, and observe the tablets: all of the tablets
`have disintegrated completely. If 1 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.
`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 1
`each of the six tubes of the basket and, if the tablet has a soluble
`external coating, immerse the basket in water at room temperature for
`5 minutes. Then operate the apparatus using simulated gastric fluid
`TS maintained at 37 i 2“ as the immersion fluid. After 1 hour of
`operation in simulated gastric fluid TS, lift the basket from the fluid,
`and observe the tablets: the tablets show no evidence of disintegra-
`tion, cracking, or softening. Operate the apparatus, using simulated
`intestinal fluid TS maintained at 37 i 2° as the immersion fluid, for
`the time specified in the monograph. Lift the basket from the fluid,
`and observe the tablets: all of the tablets disintegrate completely. If 1
`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 Uncaated Tablets. Afler 4
`hours, lift the basket from the fluid, and observe the tablets: all of the
`tablets have disintegrated. If 1 or 2 tablets fail
`to disintegrate
`
`'
`
`This test is provided to determine compliance with the diss ,
`requirements where stated in the individual monograph for a ‘
`capsule dosage form. Of the types of apparatus described he ,
`the one specified in the individual monograph. Where the la
`that an article is enteric-coated, and a dissolution or disintegra In
`that does not specifically state that it is to be applied to cute
`articles is included in the individual monograph, the test forD
`Release Articles under Drug Release (724)
`is applied Hm
`otherwise specified in the individual monograph. For hard:
`gelatin capsules and gelatin-coated tablets that do not confo
`Dissolution specification, repeat the test as follows. Where W .
`medium with a pH of less than 6.8 is specified as the Mediu
`individual monograph, the same Medium specified 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 (ll)—USP Prednisoné
`(Dissolution Calibrator; Disintegraring). USP Salicylic Aci.
`RS (Dissolution Calibrator; Nondisinregrating).
`Apparatus l—The assembly consists of the following.
`vessel made of glass or other inert, transparent material‘;
`metallic drive shaft; and a cylindrical basket. The vessel
`immersed in a suitable water bath of any convenient size _
`a heating jacket. The water bath or heating jacket permits 4
`temperature inside the vessel at 37 i 05° during the test an
`the bath fluid in constant, smooth motion. No part of the.
`including the environment
`in which the assembly 15
`contributes significant motion, agitation, or vibration hey
`due to the smoothly rotating stirring element. Apparatus tha
`observation of the specimen and stirring element during
`preferable. The vessel is cylindrical, with a hemisphencal b0
`with one of the following dimensions and capacities: for
`capacity of l L, the height is 160 mm to 210 mmfifld
`diameter is 98 mm to 106 mm; for a nominal capacity 0f“
`height is 280 mm to 300 mm and its inside diameter is 98 I!
`m; and for a nominal capacity of 4 L, the height is 280 mm
`mm and its inside diameter is 145 mm to 155 mm. Its S
`flanged at the top. A fitted cover may be used to retard eVaP
`The shaft is positioned so that its axis is not more than 2 “
`point from the vertical axis of the vessel and rotates 511309
`without significant wobble. A speed-regulating devrqe 11?
`allows the shafi rotation speed to be selected and mall.)1m ‘
`rate specified in the individual monograph, within i4/“-' ‘
`
`
`completely, repeat the test on 12 additional tablets: not less I,
`the total of 18 tablets tested disintegrate completely,
`Sublingual Tablets—Apply the test
`for Uncoated
`Observe the tablets within the time limit specified in th
`monograph: all ofthe tablets have disintegrated. If 1 or 2 tab]
`disintegrate completely, repeat the test on 12 additional ta .
`less than 16 of the total of 18 tablets tested disintegrate I”:
`Hard Gelatin Capsules—Apply the test for Ultcoafed'
`Attach a removable wire cloth, which has a plain square W ”‘
`1.8- to 2.2-mm mesh apertures and with a wire diameter 0 "I
`0.655 mm, as described under BasketrRack Assembly, to
`of the upper plate of the basket-rack assembly. Observe flfe
`within the time limit specified in the individual monograph:
`capsules have disintegrated except for fragments from [h
`shell. If 1 or 2 capsules fail to disintegrate completely, mpg
`on 12 additional capsules: not less than 16 of the total on?
`tested disintegrate completely.
`-
`Soft Gelatin Capsules—Proceed as directed under Hard ,3,“
`Capsules.
`
`<711> DISSOLUTION
`
`l The materials should not sorb, react, or interfere with the Spec.
`tested.
`2 ifa cover is used, it provides sufficient openings to allow ready“
`the thermometer and withdrawal of specimens.
`
`Par Pharm., Inc.
`Exhibit 1054
`Page 003
`
`

`

`and basket components of the stirring element are fabricated
`less steel. type 316 or equivalent, to the specifications shown
`‘4 re 1, Unless otherwise specified in the individual monograph,
`r, mesh cloth. A basket having a gold coating 0.0001 inch (25
`‘ ' k may be used, The dosage unit is placed in a dry basket at
`‘ g of each test. The distance between the inside bottom of
`e1 and the basket is maintained at 25 i 2 mm during the test.
`
`.
`
`‘
`
`E
`
`a
`
`9.4 to 10.1 mm diameter
`before CDfll/Ilg
`
`Io
`
`
`
`removal of dissolved gases may be used.
`
`Apparatus Suitability Test—Individually test 1 tablet of the USP
`Dissolution Calibratol; Disintegraling B’pe and 1
`tablet of USP
`Dissolution Calibrator; Nondisinregrating Type, according to the
`operating conditions specified. The apparatus is suitable if the results
`obtained are within the acceptable range stated in the certificate for
`that calibrator in the apparatus tcstcd.
`Dissolution Medium—Use the solvent specified in the individual
`monograph. If the Dissolution Medium is a buttered solution, adjust
`the solution so that its pH is within 0.05 unit of the pH specified in the
`individual monograph. [NOTEiDissolved gases can cause bubbles to
`form, which may change the results of the test. In such cases,
`dissolved gases should be removed prior to testingfij
`Time—Where a single time specification is given, the test may be
`concluded in a shorter period if the requirement for minimum amount
`dissolved is met, If two or more times are specified, specimens are to
`be withdrawn only at the stated times, within a tolerance of :2%.
`Procedure for Capsules, Uncoated Tablets, and Plain Coated
`Tablets—Place the stated volume of the Dissolution Medium (-_|- 1%)
`in the vessel of the apparatus specified in the individual monograph,
`assemble the apparatus, equilibrate the Dissolution Medium to
`37 i 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 between the surface of the Dissolution Medium and the
`top of the rotating basket or blade, not less than 1 cm from the vessel
`wall. [NOTE—Replace the 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 change in the calculation. Keep the vessel covered for the
`duration of the test, and verify the temperature of the mixture under
`test at suitable times] Perform the analysis as directed in the
`
`
`(E
`
`6.3 to 6.5 or
`9.4 to 10.1 mm
`
`Screen OD.
`22.2 t 1.0 mm
`
`Screen with welded seam:
`40 X 40 mesh, 0.25-mm wire
`diameter with wire openings oi
`0.40 1 0.04 mm; where 20-
`mesh screen is specified, use
`20 X 20 mesh, GAO-mm wire
`diameter with wire openings of
`0.90 i 0.09 mm. [NOTE
`After welding. the screen may
`be slightly altered]
`
`Vent hole
`2.0 1 0.5 mm diameter
`
`Retention spring with
`3 iargs on 120“ centers
`
`Clear opening
`202:0.1mrn
`
`37.0 t
`3.0 mm
`
`:t 1.0 mm
`ODE"
`
`.
`
`._
`
`'
`
`'
`
`th the was:
`
`Molt—Maximum allowable
`i
`l
`at'A“ isiiflmmwhen
`-partis rotated on (Eaxis
`H i basket mounted,
`
`;
`
`Fig. 1. Basket Stirring Element
`
`i
`
`raj aratus 2~Use the assembly from Apparatus I, except that a
`ii" formed from a blade and a shaft is used as the stirring element.
`in ft is positioned so that its axis is not more than 2 mm at any
`m'n mthc vertical axis of the vessel and rotates smoothly without
`it ant wobble. The vertical center line of the blade passes
`tip the axis of the shaft so that the bottom of the blade is flush
`“7 he bottom of the shaft. The paddle conforms to the
`cations shown in Figure 2. The distance of 25 i 2 mm
`the blade and the inside bottom of the vessel is maintained
`' the test. The metallic or suitably inert, rigid blade and shalt
`e a single entity. A suitable two-part detachable design may
`*--';.I provided the assembly remains firmly engaged during the
`it- paddle blade and shafi‘ may be coated with a suitable inert
`“" ‘The dosage unit is allowed to sink to the bottom of the vessel
`otation of the blade is started. A small,
`loose piece of
`live material such as not more than a few turns of wire helix
`"‘ attached to dosage units that would otherwise float. Other
`sinker devices may be used.
`
`.
`
`(2) A and 8 dimensions are -
`not to vary more than
`0.5 mm when part is
`rotated on ‘1: axis.
`(3) Tolerances are #0 mm,
`unless otherwise stated.
`
`NOTES—
`{0 Shaft and blade material:
`303 {or equivalent)
`
`stainlesssteel.
`
`41.5 mm lad/us
`1.2 mm «1di
`,_.
`-t\
`‘\‘
`\\B
`
`4 01 1.0mm
`
`L; 74.0 mm to 75.0 mm *4
`Fig. 2. Paddle Stirring Element
`
`3 One method of deaeration is as follows: Heat the medium, while stirring
`gently, to about 41", immediately filter under vacuum using a filter having a
`porosity of 0.45 pm or less, with vigorous stirring. and continue stirring under
`vacuum for about 5 minutes. Other validated deaeration techniques for
`
`Par Pharm., Inc.
`Exhibit 1054
`Page 004
`
`

`

`(721) DISTILLING ;;
`
`To determine the range of temperatures Within which
`liquid distils, or the percentage ofthe material that distils b 'n
`specified temperatures, use Method 1 or Method [1 as d- t v.
`individual monograph. The lower limit of the range is the te
`indicated by the thermometer when the first drop ofcondens
`the tip of the condenser, and the upper limit is the Dry Pom
`temperature at which the last drop of liquid evaporates
`lowest point in the distillation flask, without regard to
`remaining on the side of the flask, or the temperature observ
`the proportion specified in the individual monograph I
`collected.
`
`NOTE~Cool all liquids that distill below 80° to between '3
`15° before measuring the sample to be distilled.
`
`METHOD I
`
`Apparatus—Use apparatus similar to that specified ft)qu ,,
`except that the distilling flask is of 50- to 60—mL capacity in
`neck of the flask is 10 to 12 cm long and 14 to 16 mm {1;
`diameter. The perforation in the upper insulating board, ifone
`should be such that when the flask is set into it, the portion of
`below the upper surface of the insulating material has a capac i
`to 4 mL.
`
`Procedure—Proceed as directed for Method II, but p ‘
`flask only 25 mL of the liquid to be tested.
`
`Acceptance Table
`
`METHOD II
`
`Number
`
`Tested
`Stage
`Acceptance Criteria
`SI
`6
`Each unit is not less than Q + 5%.
`S2
`6
`Average of 12 units (SI + $2) is equal to or
`greater than Q, and no unit is less than Q —
`15%.
`Average of 24 units (SI + S2 + 8,) is equal to
`or greater than Q, not more than 2 units are
`less than Q 7 15%, and no unit is less than Q
`
`— 25%.
`
`12
`
`individual monograph“. Repeat the test with additional dosage form
`units.
`If automated equipment is used for sampling and the apparatus is
`modified, validation of the modified apparatus is needed to show that
`there is no change in the agitation characteristics of the test.
`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 fiJr 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 as the test solution. Determine
`the average amount of the active ingredient dissolved in the pooled
`sample.
`Interpretation—
`Unit SampleiUnless 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 SI or $2. The quantity, Q, is the
`amount of dissolved active ingredient specified in the individual
`monograph, expressed as a percentage of the labeled content; the 5%,
`15%, and 25% values in the Acceptance Table are percentages of the
`labeled content so that these values and Q are in the same terms.
`
`from the condenser, and again when the last drop Ofllqwd
`
`S3
`
`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 unless the results conform at either S1
`or S2. The quantity, Q, is the amount of 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
`6
`Average amount dissolved is not less than Q
`+ 10%.
`Average amount dissolved (Sl .+ 8,) is equal
`to or greater than Q + 5%.
`12
`Average amount dissolved (SI + S, + 8,) is
`
`equal to or greater than Q.
`
`6
`
`
`
`lt'test specimens are filtered, use an inert filter that does not cause adsorption
`"l
`of the active ingredient or contain extractable substances that would interfere
`with the analysis.
`
`Apparatus—Use an apparatus consisting of the followin'
`Distilling Flask—A round-bottom distilling flask, ofhea
`glass, of 200—mL capacity, and having a total length of 17"
`and an inside neck diameter of 20 to 22 mm. Attached abo
`on the neck, approximately 12 cm from the bottom of the
`side-arm 10 to 12 cm long and 5 mm in intemal diame
`forms an angle of 70u to 75C with the lower portion of they .
`Condenser-A straight glass condenser 55 to 60 cm in lo,‘
`a water jacket about 40 cm in length, or a condenser of 0
`having equivalent condensing capacity. The lower en‘ '
`condenser may be bent to provide a delivery tube, or it
`connected to a bent adapter that serves as a delivery tube. p .
`Insulating Boards—Two pieces of insulating board,
`thick and 14 to 16 cm square, suitable for confining the
`lower part of the flask. Each board has a hole in its center, :
`boards differ only with respect to the diameter of the 1101
`diameters are 4 and 10 cm, respectively. In use, the boards
`one upon the other, and resting on a tripod or other suitabl
`with the board having the larger hole on top.
`Receivet'iA lOO-mL cylinder graduated in l-mL $1!de
`Thermometer—In order to avoid the necessity for all
`stern correction, an accurately standardized, partia
`thermometer having the smallest practical subdivisions (11
`than 0.2“) is recommended. Suitable thermometers are 2W~
`the ASTM E-l series 37C through 41C, and 102C through. ‘
`Thermometers (21)). When placed in position, the stem 15, [ii
`the center of the neck and the top of the contraction chambfl
`if 37C or 38C is used) is level with the bottom ofthe outlet
`arm.
`
`Heat Source—A small Bunsen burner or an electrit‘:
`mantle capable of adjustment comparable to that P0551b
`Bunsen burner.
`
`Procedure—Assemble the apparatus, and place in the
`mL of the liquid to be tested, taking care not to allow any or
`to enter the side-arm. Insert the thermometer, shield the 61‘
`and flask assembly from external air currents, and “PP
`regulating it so that between 5 and 10 minutes elapse 1361:” ,
`drop of distillate falls from the condenser. Continue the ‘11 '
`a rate of 4 to 5 mL of distillate per minute, collecting me,‘
`the receiver. Note the temperature when the first drop‘0f,
`
`Par Pharm., Inc.
`Exhibit 1054
`Page 005
`
`

`

`wetting agents and/or solid carriers such as talc or colloidal silicas.
`
`Pharmaceutical aerosols are products that are packaged under
`pressure and contain therapeutically active ingredients that are
`released upon activation of an appropriate valve system They are
`intended for topical application to the skin as well as local application
`into thc nosc (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
`“lDRUtij Motored Topical Aerosols,” “[DRUG] Metered Nasal
`Aerosols,” etc.
`The term “aerosol” refers to the fine mist of spray that results from
`most
`t,
`surized systems. However,
`the term has been broadly
`mist pplied to all selficontainod pressurized products, some of which
`deliver foams or semisolid fluids. in thc case of Inhalation Aerosols,
`the particle size of the delivered medication must be carefully
`controllcd, and the average size of the particles should be under 5 um.
`These products ore also known as motored—dose inhalcrs (MDls).
`Other aerosol sprays may contain particles up to several hundred
`micrometers in diameter.
`The basic components of an aerosol system are the container, the
`propcllant,
`thc concentrate containing the active ingrodiends),
`the
`valve. and thc actuator: The nature oi’thesc components determines
`such characteristics as particle size distribution, uniformity of dose
`for motored valves. delivery ratc, wctncss and temperature of the
`spray, spray pattern and vclocity or plume geometry, foam density,
`and lhiid viscosity.
`
`
`
`
`
`
`
`AEROSOLS
`
`Types of Aerosols
`
`Acrosols constst ot‘two-phasc (gas and liquid) or throophasc (gas,
`liquid. and solid or liquid) systems. The two-phase aerosol consists of
`a
`solution of active ingredients in liquefied propellant and the
`vaporized propcllant. The solvent is composed ofthe propellant or a
`mixture ol the propellant and cosolvcnts such as alcohol, propylene
`glycol. and polyethylene glycols, which are ottcn used to enhance the
`solubility of the active ingredients.
`\
`'
`Tltt‘et:~ph21.sc systems consist of a suspension or emulsion of the
`active ingrediends)
`in addition to the vaporized propellants. A
`suspension consists of the active ingrediends) that may be dispersed
`in the propellant system with the aid of suitable excipients such as
`
`7
`
`_
`
`"of Enfornzutzon
`
`it fit) itiiarinaccuticai Bosage 33mins
`
`'t'nlatt’ l. lutisritational l‘iliinutis: Zones
`
`
`
`_l_3crivcd Data
`is
`RH
`45
`
`.
`
`inbar
`l
`l .2
`
`r npnn
`lnited Kingdom
`ortltern Europe
`anada
`ussia
`Unith States
`(«firm i (air on, MEWW
`United States
`r apart
`Southern Europe
`(Portugal—(J‘reec )
`or
`ran
`raq
`Sudan
`
`N.
`
`Jr:
`Ghana
`ndoncsia
`
`culzitcd as 1‘) L
`l‘)
`Data recorde: as
`cultith mean liinctic tonpcratrrc.
`al pressure oi"
`*zncr vapor.
`
`(l l5 i PHARMAf/‘iillrl‘ltlAll
`DOSAGE litflth/lg
`
`, Dosttge i‘ornis are provided it); most ot‘ the l’lintinacopcial drug
`‘
`.tances. out the processor; for the propuaiion ot‘niuny ot’tliein arc,
`i general, beyond the scopc oi
`the Pharniacopcia,
`in addition to
`tlefm is; the dosage forms, this section presents the general principles
`in lved in the inninititctnrc ot‘sonic ot‘tlteni. particularly on a small
`lc. Other
`inlbrination that
`is given bears on thc usc ot'
`the
`
`dosage forms.
`
`BREAK/Al FLARE iti'l‘Y
`
`tent to \vtiiclithc tlicrapcutic constituent of
`. availability, or tho r
`.pliarmaccntiml rlosagc t‘ortn ir- ‘ndcd for oral or topical use is
`Wailalilc {or absorption. is intlucnc
`by it variety ot‘t‘actors. Among
`herent factors known to ttftce absorption are the method ot‘
`titanutacturc or method ol‘compounding; tho particic size and crystal
`or polymorph oi the drug substance; and tho dilucnts and
`is used in tin-mutating the dos gc form,
`including tillers,
`disintegrating ancnts,
`lubricants, coatings, solvents, Sit,—
`llending agcnts, and dyes. Lub
`ants and coatings are foremost
`‘ong thcse. The maintenance 0: a demonstrably high degrcc of
`Iozivailability requires panicultt‘ nttcnti’in to all aspects of
`I'Qduction and quality control
`that may aticct
`tl
`nature ot‘ the
`fintsiiei. dosage lorin.
`
`'
`
`TERM iNQLGGY
`
`Occasionally it is necessary to add solvent to the contents oi‘
`‘Ontaii ct just prior to use usually bi“ nsc ot’ instaliility'of some
`mils in the diluted 'toriu, Thus, a solid d1 itcd to yield a suspension is
`filled [DRllGl/m- Sn.»‘[mn'lmz; a solid dissolved (and diluted to yield
`Solution is called [URL/G]
`[627' Solution; and a solution or
`‘ dispel
`ion diluted to yield a inorc dilutc form of the drug is called
`DRUG] ()rtrl ('oiir'e'nirutc. Attcr dilution,
`is important that lhc
`111;; be homogeneously dispersed before administration.
`
`Par Pharm., Inc.
`Exhibit 1054
`Page 006
`
`

`

`2702
`
`{l 35?} iliiarmacentical lineage forms ,3 General Iii/bromine!
`
`is an emulsion containing one or more active
`‘ol
`A foam :ier
`ingredients stirritCtants, aqueous or uonaqueous liquids, and the
`propellants. If the propellant is in the internal (discontirmous) phase
`(ie, of the oibirnwatcr type), a stable foam is discharged; and if the
`propellant is in the external (continuous) phase tie, ofthe water—in-
`oil type). a spray or u quiclcbrcaking foam
`.ischargcd.
`
`Manufacture
`
`Aerosols are usually prepared by one of i\‘\{1
`the “cold-till" process.
`the concentrate (gen
`temperature below 0 ‘) and the refrigerated props
`into open containers (usually chilled). The valve-act
`then crimped onto the container to form a pressure
`
`'
`
`Propeliants
`
`The propellant supplies the necessary pressure Within an aerosol
`system to expel material from the container and, in combination with
`other components, to convert the material into the desired physical
`form. Propellants may be broadly classified as
`liquefied or
`compressed gases having vapor pressures generally exceeding
`atmospheric pressure. Propellants within this dcl‘inition include
`various hydrocarbons, especially halogenated derivatives of methane,
`ethane, and propane, low molecular weight hydrocarbons such as the
`butancs 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.
`
`p ,
`
`.
`
`the concentrate
`In the “pressuredill” method,
`container. and either the propellant is forced under
`the valve orifice after the valve is sealed. or the i
`to flow under the valve cap and then the vr
`(“under—tliewcap” filling). in both cases oftlte “pr
`provision must be made for evacuation of air by in
`displacement with a small amount of propellant wpo
`process controls usually include monitoring of pror
`and propellant fill weight and pressure testing. teal;
`l
`function testing of the finished aerosol. Micr
`should also be controlled.
`
`Extractable Substances
`
`.
`
`tent
`
`Since pressurized inhalers and aerosols are no
`with organic solvents as the propellant or the vc
`extractables from the clastomcric and plzis‘ic rompt
`formulation is a potentially serious problem. Thus.
`.'
`and the quality of materials used in the nituiulhcure
`components (cg, stem, gaskets, housing, etc.) must
`selected and controlled. Their compatibility will
`components should be well established so as to
`of the valve components and to minimize changes in the medic
`delivery, leak rate. and impurity profile ol‘thc drug product ave
`The extractable profiles of a representative sample of each
`elastomeric and plastic components of the valve should
`est
`under specified conditions and should be correlated to the extra
`profile or the aged drug product or placebo, to ensure r“
`quality and purity of the drug product. Extractnh
`include polynuclear aromatics, nitrosamincs. vulcani
`
`Valves
`
`
`
`The primary function of the valve is to regulate the flow of the
`therapeutic agent and propellant
`from the container. “he spray
`characteristics of the aerosol are influenced by orifice timcnsion,
`number. and location. Most aerosol valves provide for continuous
`spray operation and are used on most topical products However,
`pharmaceutical products for oral or nasal
`inhalation of'en utilize
`metered~dose valves that must deliver a uniform quantity of Spray
`upon each valve activation, The accuracy and reproducibility of the
`doses delivered from metering valves are generally good, comparing
`favorably to the uniformity of solid dosage forms such as tablets and
`capsules, However; when aerosol packages are stored improperly, or
`when they have not been used for long periods of time, valves must
`be primed before use. Materials used For the manufacture of valves
`should be inert to the formulations used. Plastic, rubber. aluminum,
`and stainless steel valve components are commonly used. Victor‘ch
`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 indi ‘ates the direction in which the preparation is dispensed
`and protects the hand or finger from the refrigerant effects of the
`propellant. Actuators incorporate an orifice that may vary widely in
`size and shape. The size ofthis orifice, the expansion chamber design,
`and the nature of the propellant and lbrmulation 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 ofglass, plastic, or metal. or a
`combination oi‘ these materials. Glass containers must be precisely
`engineered to provide the maximum in pressure safety and impact
`resistance. Plastics may be employed to coat glass containers for
`improved safety characteristics, or
`to coat metal containers to
`improve corrosion resistance and enhance stability of the formula-
`tion. Suitable metals include stainless steel, aluminum, and tin~plated
`steel. Extl‘actublcs or leachables (e.g..ydra\ving oils, cleaning agents,
`etc.) and particulates on the internal surfaces 0 l‘ containers should be
`controlled.
`‘
`
`dial
`
`Medicinal aerosols should contain at least the following ‘
`information on the label as
`in accordance with app
`regulations.
`I'VamingiAvoid inhaling. Avoid spraying into eyes or on ,
`mucous membranes
`.
`in
`NO'I‘E- The statement “Avoid inhaling" is not
`preparations specifically designed for use by inhalation. The I
`“or other mucous membranes" is not necessary for prepflfli
`specifically designed for use on mucous membranes.
`A,
`I'Varm'ng Contents under pressure. Do not puncun'e or in
`container. Do not expose to heat or store at temperatures above it
`(49” C). Keep out of reach of children.
`,
`.
`the label t
`i