THE UNITED STATES PHARMACOPEIA
`
`THE NATIONAL FORMULARY
`
`By authority of the United States Pharmacopeial
`Convention, Inc., meeting at Washington, D. C.,
`March 8-10, 1990. Prepared by the Committee of
`Revision and published by the Board of Trustees
`
`Official from January 1, 199 5
`
`.
`
`I
`
`•
`
`UNITED STATES PHARMACOPEIAL CONVENTION, INC.
`12601 Twinbrook Parkway, Rockville, MD 20852
`
`Nexus Ex. 1076
`Page 1 of 15
`
`

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`r•
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`... (
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`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.
`© 1994
`12601 Twinbrook Parkway, Rockville, MD 20852.
`All rights reserved
`ISSN 0195-7996
`ISBN 0-913595-76-4 (cloth)
`0-913595-81-0 (leather)
`
`Printed by Rand McNa!ly, 1133 County Str_eet, Taunton,.MA , .02780-~795
`.. . .
`..
`,, .
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`Nexus Ex. 1076
`Page 2 of 15
`
`

`

`,,
`
`. :ire the peak response m tios of warfarin to
`J.
`pro-
`,d fl:; ·ned from the Assay preparation and I
`:
`'· ' ~ ob~a• respectively.
`t le Stan-
`r,ort,
`,, 1<1
`• 1',.Jf /1
`',f,e;
`
`. sodium Tablets
`{sr•l1
`.
`,,r
`rill sodium Tablets contain not Jess than
`,
`11i' nt and not more than J 05.0 percent of the
`!ot ce ount of C19H 1sNa04•
`L'· ,;d 3Jll
`.
`.
`/.l'"
`,nd storage-Preserve m tight, light-resistant con(cid:173)
`tiJ'I
`ce standards (II )-USP Warfarin RS.
`-~'
`,.f ~tfe~ n--
`.
`.
`,. '(~tJO tention time of the maJor peak obtained from th
`
`1 fbe ::arion correspo~ds to th~t obtained from the Sta,,:
`~rpreP,arion, both relative to the internal standard, obtained
`jprtP0 in the Assa;:.
`.
`~,rt't~~urate a quantity ?f fm~ly pow~ered Tablets, equivalent
`'t fn 00 mg of warfann sodm~, ~Hh 50 mL of water, cen-
`1,iut 2 d filter the supernatant hqu1d. Extract with so mL of
`,Jif 3~sfcr the aqueou~ layer to a se~ond separator, and dis(cid:173)
`;;tr• rra ether. Adjust with ~ydrochlonc acid to a pH of less
`·~ rbe • g short-range pH indicator paper and extract with
`;,J, fs~Joroforll_l, Transfer the c~lorofor~ layer to another
`ymL ~ extract with 50 mL of sodium hydroxide solution (I
`tJl'lto' d discard the c~loroform. Transfer the aqueous layer
`,1.W), kan and adjust with hydrochloric acid to a pH of Jess
`H · d ·
`' "'8 er,
`) t
`· ·
`t
`, 1 II" using the p m 1ca or paper. ? prec1p1tate the warfarin.
`•xture and allow the prec1p1tate to coagulate Filter
`>JD J(
`; rhe ::he precipitat~ with four _5-mL portions of w~ter. If
`cJ11'85
`• •tate is not white or practically white, dissolve it in a
`Jff';[:.01ume of sodium hydroxide solution ( I in 250), dilute
`;:iim_ ter to 50 mL, and repeat the foregoing procedure, be(cid:173)
`~~ ~awith "Extract with 50 mL ~f ether." Dry the precipitate
`P"\m over phosphorus pentox1de for 4 hours: the infrared
`3C~ion spectrum of the warfarin so obtained exhibits maxima
`,_i
`iii-~ the same wavelengths as that of a similar preparation of
`• RS
`'
`til B
`-p U'arfarm
`•
`C Dissolve a quantity of finely powdered Tablets, equivalent
`rout JOO mg of warfarin sodium, in 25 mL of water, and
`f~.if necessary: a 5-mL portion of the filtrate responds to the
`
`Official Monographs / Water
`
`]635
`
`(330.32/308.34)(900C)(Ru/Rs),
`in w~ich C is the concentration, in mg per mL, of USP Warfarin
`RS in the Standard stock solution, 330.32 and 308. 34 arc the
`molecular weights of warfarin sodium and warfarin, respectively,
`and Ru and Rs arc the ratios of the peak responses of v.:arfann
`toh those of propylparaben obtained from the Test solutwn and
`t e Standard solution, respectively.
`Tolerances- Not less than 80% (Q) of the labeled amount of
`C
`19H1 5NaO4 is dissolved in 30 minutes.
`Uniformity of dosage units (905): meet the requirements.
`Assay-
`pH ~.4 buffer and Chromatocraphic system- Proceed as di(cid:173)
`rected m the Assay under WarJarin Sodium.
`Sol~ent mixture- Prepare a mixture of pH 7.4 buffer and
`accton1trile (85 : 15).
`Mobile phase- Prepare a filtered and degassed mixture of
`!]lethanol, .water, and glacial acetic acid (68: 32: I). Make ad(cid:173)
`Justments 1f necessary (sec System Suitability under Chroma(cid:173)
`tography ( 621) ).
`bbrt~rnal standard solution- Prepare a solution of propylpar(cid:173)
`a e~ m acetonitrile having a concentration of I mg per mL.
`Diluted ifllernal standard solution- Dilute a volume of Inter(cid:173)
`Ila/ standard solutio11 with Solvent mixture to obtain a solution
`having a concentration of 0. I mg of propylparaben per mL.
`~tandard preparation- Transfer about 62.5 mg of USP War-
`~rm RS? accurately weighed, to a 200-mL volumetric flask, and
`issolve m 78 mL of O. J N sodium hydroxide. Add 50 mL of
`0.2 M monobasic potassium phosphate, dilute with water to vol(cid:173)
`ume, and mix. Transfer 15.0 mL of this solution to a 50-mL
`v?lumet~ic flask. Add 5.0 mL of Internal standard solution, and
`dilute with Solvent mixture to volume.
`Assay preparation- Weigh and finely powder not less than 20
`Tab_Jets. Transfer an accurately weighed portion of the powder,
`equ1~alent to about 5 mg of warfarin sodium, to a 50-mL volu(cid:173)
`metnc flask, and add 5 mL of Internal sta11dard solution and
`about 30 mL of Solvent mixture. Sonicate for IO minutes, and
`then shake by mechanical means for 60 minutes. Dilute with
`solvent mixture to volume, and filter.
`Procedure-Separately inject equal volumes (about 20 µL) of
`the Standard preparation and the Assay preparation into the
`chromatograph, record the chromatograms, and measure the re(cid:173)
`sponses for the major peaks. Calculate the quantity, in mg, of
`C19H1sNaO4 in the portion of Tablets taken by the formula:
`
`df
`
`(330.32/308 .34)C(Ru/Rs),
`in which 330.32 and 308.34 are the molecular weights of warfarin
`sodium and warfarin, respectively, C is the concentration, in mg
`per mL, of USP Warfarin RS in the Standard preparation, and
`Ru and Rs are the ratios of the peak responses of warfarin to
`those of propylparaben obtained from the Assay preparation and
`the Standard preparation, respectively.
`
`Water for Injection
`
`» Water for Injection is water purified by distillation
`or by reverse osmosis. It contains no added substance.
`NOTE-Water for Injection is intended for use as
`a solvent for . the preparation of parenteral solutions.
`Where used for the preparation of parenteral solu(cid:173)
`tions subject to final sterilization, use suitable means
`to minimize microbial growth, or first render the
`Water for Injection sterile and thereafter protect it
`from microbial contamination. For parenteral solu(cid:173)
`tions that are prepared under aseptic conditions an.d
`are not sterilized by appropriate filtration or. in !he
`final container, first render the Water for lnJection
`sterile and, thereafter, protect it from microbial con(cid:173)
`tamination.
`
`ssoJve .
`>lutio s in lo
`n.
`the
`[) . require,
`n 24.o Usp
`
`ts A and 11
`·tals Unde;
`
`t Sterility
`
`labeling
`
`system(cid:173)
`!·u,n.
`in a sol!
`:etic acid
`1bout LO
`
`iP War-'
`ask, and
`'.5.0 m
`vater to
`'nternal
`1itb pH
`
`han 10
`nt vol·
`,Jution
`5 rnL
`7ution
`J vol·
`
`'JSOJ
`mg,
`1jec·
`
`tin
`be
`]~111
`!l.
`
`:i.l for Sodium (191) .
`~ lution (711)-
`Vtdium: water; 900 mL.
`.~paratus 2:' 50 rpm.
`Time: 30 mmutes.
`.
`.Vobile phase and Chromatographic system-Proceed as di-
`::.1ed in the Assay.
`lllfernal standard solution-Prepare a solution of propylpar-
`oo in water containing, in each mL, an amount of propylpar(cid:173)
`ttn equivalent to 0.0025 times the labeled amount, in mg, of
`riarin sodium in each Tablet. [NOTE-A small amount of
`tt'Janol may be used if necessary, to dissolve the propylpara-
`'
`~)
`S1andard stock solution-Dissolve an accurately weighed
`i.!DtityofUSP Warfarin RS in water to obtain a solution having
`!~nconcentration of about 0.001 IL mg per mL, L being the
`~tkd amount, in mg, ·of warfarin sodium in
`the_ Table~s.
`· DTE-Use a small amount of 0.1 N sodium hydroxide to aid
`1Diss-Olution.J
`Ji1@dard solution-To 3.0 mL of Standard sfock solution,
`l .O mL of Internal standard solution, and mix.
`.
`; ; solution-To a filtered 3.0-mL aliquot of the solutJ_on
`i CSI, add 1.0 mL of Internal standard solution, and mix.
`J tdure-Separately inject equal volumes (about 40 µL) of
`t- lofldard solution and the Test solution into the chromato-
`~~}COrd the chromatograms and measure the responses for
`'-'J'Jr
`ks
`'
`~·
`·•,:id~ pea • Calculate the quantity, in mg, of war,arm so-
`solved by the formula:
`
`Nexus Ex. 1076
`Page 3 of 15
`
`

`

`1636 Water / Official Monographs
`
`Packaging and storag~ Where packaged, preserve in tighta~~~;
`taincrs. Where packaged, it may be sto~ed at a temper
`below or above the range in which microbial growth occurs.
`USP Reference standards ( 11 )- USP Endotoxin RS.
`Bacterial endotoxins (85) -
`lt contains not more than 0.25 USP
`Endotoxin Unit per mL.
`
`Bacteriostatic Water for Injection
`
`» Bacteriostatic Water for Injection is Sterile Wat~r
`for Injection containing one or more suitable anti(cid:173)
`microbial agents.
`NOTE-Use Bacteriostatic Water for Injection with
`due regard for the compatibility of the antimicrobial
`agent or agents it contains with the particular me(cid:173)
`dicinal substance that is to be dissolved or diluted.
`Packaging and storage-Preserve in single-dose or in multiple(cid:173)
`dose containers, preferably of Type I or Type II glass, of not
`larger than 30-mL size.
`Labeling-Label it to indicate the name(s) and proportion(s) of
`the added antimicrobial agent(s). Label it also to include the
`statement "NOT FOR USE IN NEWBORNS" in boldface capital
`letters on the label immediately under the official name, printed
`in a contrasting color, preferably red. Alternatively, the state(cid:173)
`ment may be placed prominently elsewhere on the label if the
`statement is enclosed within a box.
`USP Reference standards ( 11 )-USP Endotoxin RS.
`Antimicrobial agent(s}-lt meets the requirements under Anti(cid:173)
`microbial Preservatives-Effectiveness ( 5 l), and meets the la(cid:173)
`beled claim for content of the antimicrobial agent(s), as deter(cid:173)
`mined by the method set forth under Antimicrobial Agents-
`Content (341).
`·
`.
`Bacterial endotoxins (85)-It contains not more than 0.5 USP
`,
`·
`·
`Endotoxin Unit per mL.
`Sterility-It meets the requirements under Sterility Tests (71).
`pH (791): between 4.5 and 7 .0, determined potentiometrically
`in a solution prepared by the addition of 0.30 mL of saturated
`potassium chloride solution to l 00 mL of test specimen.
`Particulate matter (788): meets the requirements under Small-
`.
`volume Injections.
`Other requirements-It meets the requirements of the tests for
`Sulfate, Calcium, Carbon dioxide, and Heavy metals under Ster(cid:173)
`ile Water for Injection.
`
`Sterile Water for Inhalation
`
`>~ ~teri!e Water for Inhalatio~ is water purified by
`d1stdlat1on or by reverse osmosis and rendered sterile
`~t cont~in_s _no antimicrobial agents, except.where used
`m hum1d1f1ers ?r o~her similar devices and where li(cid:173)
`able to contammatlon over a period of time or other
`added substances.
`.
`,
`'
`. . .
`'
`NOTE-Do not _u~e St~rile .Water for Inhalation
`f?r p~renteral admm1strat1on or for other sterile com(cid:173)
`pend1al dosage forms.
`Packaging and storag~Preserve in single-do~e· ~ontain
`Labeling-Label it to indicate that it is for inhalation e~s.
`therapy
`only an'd that it is not for parenteral administration -
`USP Re~erence standards ( 11 )-USP Endotoxin RS.
`Bacteria! endo_toxins (85)-It contains not more than o 5 USP
`Endotoxm Umt per mL.
`·
`
`u ion Per 1&la1ning t
`
`f.Js~
`Sterility-It meets the requirements unde
`pH (791): between 4.? and 7.5, in a sor ~terifitn
`23
`.% (
`mL of saturated potassmm chloride sol rlutton Co
`specimen.
`.
`Chloride-To 20 mL ma _color-compari
`llll rir ,~
`nitric acid and 1 ~L _of silver nitrate T~n tube add
`turbidity fo~m~d w1thm 10 mmutes is not' and genu 5 ~re;,
`duced in a s1m1larly treated co~trol consisti~reater thf II mu.:
`purity Water (s~e under Chemical Resista g of 20 llJL 1ha1 ~
`( 661) ), conta!mng 10 ~g of Cl, viewed 3i~-Glass Coor lt1i_
`surface with hght entering the tubes from hnw~rd ov ~'Qi~>--
`t e s1d
`er a ~:-'
`.
`I
`Other reqmrements- t meets the require
`cs (0.5 ~'i
`Sulfiate Calcium, Carbon dioxide and H ments of the r,~l.
`f h
`. metals u llS I·
`'
`d
`'
`eavy
`le ,
`rifted Water an o t e tests for Amm
`stances, and Total solids under Sterile W,n,a, Oxidizal,er ~
`aterJorJn ·
`_e 1~
`~tctzor..
`
`Sterile Water for Injection
`stenhzed and smtably packaged. It co t 10Jection
`
`» ~t~rile Water. for Injection is Water f
`
`.
`
`timicrobial agent or other added subst~~~ns no an.
`Packaging and storage--Preserve in single-dos
`·
`containers, of not larger than I-liter size. Gla~/ass ~r Plast!c
`preferably of Type I or Type II glass.
`containers a.1
`Labeling-Label it to indicate that no antimicrob· 1
`stance has been added, and that it is not suitable f~a _or others~~
`injection without its first having been made app; 1~travascu1zr
`oximately ~
`tonic by the addition of a suitable solute.
`USP Reference standards ( 11 )-USP Endotoxin RS
`Bacteria~ endo!oxins (85)-It contains not more than.or U
`Endotoxm Umt per mL.
`· ) SP
`Steri_lity-It meets the requirements under Sterility Tests (ii).
`Part1culat~ m~tter _ (788): meets the requirements under Sma!J.
`volume In1ectzons.
`A~monia-For Sterile Water for Injection in containers haiiq
`a fill volume of less than 50 mL, dilute 50 ml with 50 ml ci
`High-J?ur~ty !'Yater (see Reagents under Containers (661)),and
`use this dilution as the test solution; where the fill volume~ SO
`mL or m_ore, use 100 mL of Sterile Water for Injection as tbc
`test solution. To 100 mL of the test solution add 2 ml of alkaliDc
`mer~uric-p?tassium iodide TS: any yellow color produced im(cid:173)
`mediately 1s not darker than that of a control containing 30 P!
`of added NH3 in High-purity Water (see Reagents under Cc:.,,
`tainers ( 66 I)) (0.6 ppm for Sterile Water for Injection in coo(cid:173)
`tainers having a fill volume of less than 50 ml; 0.3 ppm 11·b~
`the fill volume is 50 mL or more).
`C_hl?ride:-To 20 mL in a color-comparison tube add 5 ~roP5d
`mtnc acid and I mL of silver nitrate TS and gently mu: !.nJ'
`turbidi~y formed within 1 O minutes is not' greater than that fZ
`duc~d, m a si~ilarly treated control consisting of 20 ml of H~
`.purzty Water (see under Reagents in Containers (661))_~:rf~tt
`m_g 1 O_ µg of Cl (0.5 ppm), viewed downward over a dark ) •
`, ulfcric
`with hght enJering the tubes from the sides.
`Oxidizable substances-To 100 mL add 10 ml of 2 !' s . ...
`'d
`I · uon 1n ,,
`ac.1 , and heat to boiling. For Sterile Water for nJe~ 0 4 [Ill I
`tamers having a fill volume of less than 50 mL, a~ · .. ~bt.1
`0.1 fl!· potassiu~ permanganate, and boil for 5 mi~~;isi..~~
`the ftll volume 1s 50 mL or more, add 0.2 mL of O. l. itate i~
`permanganate and boil for 5 minutes. If a precip thft"'' 1
`'
`d filter
`l ·
`,.,.._
`1
`1 disJr~31·
`C?O m an ice bath to room temperature, an
`smter~d-glass filter: the pink color does not complete y / 51,Jib
`T t I
`for Tora · •Cf
`•
`.
`.
`0 a sohds-Proceed as directed in the te5t f Sterile \H·
`under !'urijied Water. The following limits apply orf 1p5 thanlcSI
`for lnJection in containers having a fill volume 0morc. but :i.
`mL, 0.004%; where .the fill volume is 30 m\ %0 rnL or 1111
`than 100 mL 0.003%· and for a fill volume 0
`0.002%.
`'
`'
`
`.
`
`purU
`HP
`» Pu:
`ion-ex
`suitab
`with ·
`Prote 1
`conta
`Ne
`ingret
`form~
`than ;
`to me
`or fit
`after
`use F
`ente1
`for I
`Steri
`P1ck1
`tainc1
`label
`Prcpa
`p1i (
`lll a !
`l>Otas
`t\Jo1
`
`Sih,c1 ~. bidi
`
`~
`Potai
`. t ~
`\ti It
`l0.3
`c'1c!
`llltij
`
`i
`
`Nexus Ex. 1076
`Page 4 of 15
`
`

`

`05r 23
`)ltf requlremen1s- 1t n,
`Of/1 sulfate, Calcium c c;:1s the requirements of the tests for
`[ •,r;,a IVater.
`' a, on dioxide and f/eavy metals under
`'
`
`f~flJ•
`
`sterile Water for Irrigation
`Sterile Water_f or Irrigation is Water for Injection
`nd suitably packaged. It contains no an(cid:173)
`~erilize~ a
`1
`s,..,icrob1a agent or other added substance.
`1111•
`}(aging and storage-:--Preserve in single-dose glass or plastic
`I'•' ainers. Glas~ containers arc preferably of Type I or Type II
`
`c0nt The cont~mer may contain a volume of more than I liter
`!tass. y be designed to empty rapidly.
`'
`nd tllll
`1 ·
`. d'
`a rng-Labe tt tom 1cate that no antimicrobial or other sub-
`i,bt 1 has been added. The designations "For irrigation only"
`stan:~r,,1ot for injection" appear prominently on the label.
`and Reference standards ( 11 )-USP Endotoxin RS.
`lJSP
`. uircments-It meets the requirements or all or the tests
`ot11tr ~rile Water for Injection except the test for Particulate
`under (788) .
`,natter
`
`1637
`
`Official Monographs I Witch
`acid to a pH of 3.0 to 4.0 (using short-range pH '"<!;.s tor ~aft0
`. h
`
`Heuy metals- Adjust 40 mL of Purified Watei: wi~h 1 N acct:)
`.,.;
`
`.' ai:1 a
`add 10 mL of freshly prepared hydrogen sulfide
`the liquid to stand for 10 minutes: the color of the hquit w~hn
`viewed downward over a white surface, is not darker t an
`color of a mixture of 50 mL of the same Purified W ater wit
`the same amount of 1 N acetic acid as was added to the teSl
`specimen. matched color-comparison tubes being used for the
`comparison.
`O~idizable substances-To 100 mL add 10 mL of 2 N_ sulfuric
`acid, and heat to boiling. Add 0.1 mL of 0 .1 N potassium per•
`manganate, and boil for 1 0 minutes:
`the pink color does not
`completely disappear.
`Total solids-Evaporate 100 mL on a steam bath to dryness,_and
`dry l~e residue at 105° for 1 hour: not more than 1 mg of residue
`remains (0.001%).
`
`Wax, Carnauba-see Wax, Carnauba NF
`Wax, Cetyl Esters-see Cetyl Esters Wax NF
`Wax, Emulsifying-see Wax, Emulsifying NF
`Wax, Microcrystalline-see Wax, Microcrysta\\ine
`NF
`Wax, White-see Wax, White NF
`Wax, Yellow-see Wax, Yellow NF
`
`C
`
`White Lotion
`
`40 g
`40 g
`
`» Prepare White Lotion as follows:
`Zinc Sulfate .. .. . .. .. .. .. .. .. .. .. .. .. . . . ..
`Sulfurated Potash........................
`Purified Water, a sufficient quantity,
`to make ................................. 1000 mL
`Dissolve the Zinc Sulfate and the Sulfurated Potash
`separately, each in 450 mL of Purified Water, and
`filter each solution. Add the sulfurated potash so(cid:173)
`lution slowly to the zinc sulfate solution with constant
`stirring. Then add the required amount of purified
`water, and mix.
`NOTE-Prepare the Lotion fresh, and shake it
`thoroughly ~efore dispensing.
`Packaging and s~orage-;--Dispense in tight containers.
`
`C
`·c
`
`).
`lf
`).
`
`p
`
`) .
`l-
`
`g ,r
`d
`0
`e ,.
`g
`!·
`l·
`e
`
`1
`
`••
`
`Witch Hazel
`
`» Witch Hazel is a clear, colorless distillate prepared
`from recently cut and partially' dried dormant twigs
`of Harnarnelis virginiana Linne.
`.
`Prepare Witch Hazel as follows. Macerate~ weigh(cid:173)
`ed amount of the twigs for about ~4 ~ours. m about
`twice their weight of water, then distil until not less
`than 800 mL and not more than 850 mL of clear,
`colorless distillate is obtained from each l OOOh g
`the twigs taken. Add l 50 mL of Alcohol to eac
`mL of distillate, and mix thoroughly.
`.
`Packaging and storage-Preserve in tight containers, and avo1d
`exposure .to excessive heat.
`
`8 ~6
`
`purified Water
`~O
`J8.02
`..
`2 purified Water is water obtained by. distillation,
`~ xchange treatment, reverse osmosis, or other
`10~~\le process. It is prepared from water complying
`5~~: the regulations. of the federal_ E~vironmental
`; tection Agency with respect to dnnkmg water. It
`r~tains no add~d substanc.e. .
`·
`co NOTE-Purified Water_ is intended for .use as an
`in redient in the prepar.atlon of compendial dosage
`f ~s Where used for sterile dosage forms, other
`ilian i or parenteral administration, process the article
`to meet the requirements under Sterility Tests (71 ),
`or first render the Purified. Water st~rile. and there-.
`after protect it from microbial contammahon. Do not
`use Purified Water in preparations intended for par(cid:173)
`enteral administration. For such purposes use Water
`for Injection, Bacteriostatic Water for Injection, or
`Sterile Water for Injection.
`Ma~ng and storage-Where ·packaged, preserve in tight' con(cid:173)
`tainm.
`ubtling-Where 'packaged, label it to indicate the method of
`preparation.
`, , . .
`. •
`,
`·
`,
`1H (791): bet~een 5.0 and 7.0, determined potentiometrically •
`in a ~lution prepared by the addition of 0.~0 mL. of _saturated
`lll!assium chloride solution to l 00 mL of test specimen..
`.
`~~To 100 mL add 5 drops of nit~ic acid ·and l' mL of
`~ .
`d
`er nitrate TS: no opalescence is produce .
`~ te_-To 100 ml add l mL of bariurri ·chloride TS: no tur-
`• .' ty 15 produced
`.
`:rra~monia~To.'ioo mL add 2 mL of alkaline m~rcuri~(cid:173)
`ttdarkm todid~ TS: any yellow color pro.duced immediately is
`•Hi her t~an that of a control containing 30 µg of added NH3
`ruy Water (see under: Reagents in Containers ( 661))
`~m.
`.
`.
`·.·
`:di,;To 100 mL add 2 mL of ammonium oxalate TS: no
`~ _is Produced.
`.
`·
`· .
`
`~l: ·p
`·~t0rjde-To 25 mL add 25 mL of calcium hydroxide.TS:
`
`1u
`
`:
`
`re remains clear.
`
`, ' .
`
`.
`
`.
`
`.
`
`Nexus Ex. 1076
`Page 5 of 15
`
`

`

`General Chapters
`General Tests and Assays
`
`---
`
`General Requirements
`for Tests and Assays
`
`(1)
`
`INJECTIONS
`
`INTRODUCTION
`Parenteral articles are preparations intended for injection
`through the skin or other external boundary tissue, rather than
`through the alimentary canal, so that the active substances they
`contain are administered, using gravity or force, directly into a
`blood vessel, organ, tissue, or lesion. Parenteral articles are pre(cid:173)
`pared scrupulously by methods designed to ensure that they meet
`Pharmacopeial requirements for sterility, pyrogens, particulate
`matter, and other contaminants, and, where appropriate, contain
`inhibitors of the growth of microorganisms. An Injection is a
`preparation inte~de~ for parenteral ad~inist~ation and/o~ for
`constituting or diluting a parenteral article pnor to administra(cid:173)
`tion.
`
`NOMENCLATURE AND DEFINITIONS
`
`Nomenclature
`The following nomenclature I?ertains to five_ general types of
`preparations, all of which are smtable f~r, and intended for, _par(cid:173)
`enteral administration. They may contain buffers, preservatives,
`or other added substances.
`[DRUG] Injection-Liquid preparations that are drug sub-
`l.
`stances or solutions thereof.
`.
`. .
`2.
`[DRUG] for Injection-Dry solids th~t, u_pon the addition
`of suitable vehicles, yield solutions conforming in all respects to
`.
`the requirements for Injections.
`[DRUG] lnjectabl~ Emulsi£?n-Li9uid preparaJ1ons of ?rug
`3.
`substances dissolved or dispersed in~ smta~le ~mulsion m~dmm.
`[DRUG] I1:jectab_le Susren!wn-~iqmd preparations of
`4.
`solids suspended in a smtable hquid medium.
`.
`[DRUG] for lnjectabl~ Susp~nsion-Dry ~ohds that, U}?On
`5.
`the addition of suitable vehicles, yield preparations confo~ming
`in all respects to the requirements for Injectable Suspenswns.
`
`Definitions
`
`PHARMACY BULK PACKAGE
`A Pharmacy bulk package is a ~ontainer o~ a sterile prepa(cid:173)
`ration for parenteral use that contains many smgle doses. The
`
`1650
`
`C,()rltcnts arc i_ntcnded for use in a pharmacy ~dmixturc program
`and are rcstncted to the preparation of admixtures for infusion
`or, ~hrough a sterile transfer device, for the filling of empty sterile
`synnges.
`The closure shall be penetrated only one time after constitution
`with a suitable sterile transfer device or dispensing set which
`allows measured dispensing of the contents. The Pharmacy bulk
`package is to be used only in a suitable work area such as a
`laminar flow hood (or an equivalent clean air compounding area).
`Designation as a Pharmacy bulk package is limited to prep(cid:173)
`arations from Nomenclature categories 1, 2, or 3 as defined above.
`Pharmacy bulk packages, although containing more than one
`single dose, are exempt from the multiple-dose container volume
`limit of 30 mL and the requirement that they contain a substance
`or suitable mixture of substances to prevent the growth of mi(cid:173)
`croorganisms.
`-Where a container is offered as a Pharmacy bulk package, the
`label shall (a) state prominently "Pharmacy Bulk Package-Not
`for direct infusion," (b) contain or refer to information on proper
`techniques to help assure safe use of the product, and (c) bear
`a statement limiting the time frame in which the container may
`be used once it has been entered, provided it is held under the
`labeled storage conditions.
`
`LARGE- AND SMALL-VOLUME INJECTIONS
`Where used in this· Pharmacopeia, the designation Large-vol(cid:173)
`ume intravenous solution applies to a single-dose injection that
`is intended for intravenous use and is packaged in containers
`labeled as containing more than 100 mL. The designation Small(cid:173)
`volume Injection applies to an Injection that is packaged in con(cid:173)
`tainers labeled as containing 100 mL or less.
`
`BIOLOGICS
`The Pharmacopeial definitions for sterile preparations for p~r(cid:173)
`enteral use generally do not apply in the case of the b1olog1cs
`because of their special nature and licensing requirements (see
`Biologics (1041) ).
`
`INGREDIENTS
`
`Vehicles and Added Substances
`Aqueous Vehicles-The vehicles for aqueous Injections m~e}
`the requirements of the Pyrogen Test ( l 51) or the Bacte~ia
`Endotoxins Test (85), whicheve~ is specified. Wat.~r f 0\~(i;
`tion generally is used as the veh1~le, unles~ othen~ise ~~ded in
`in the individual monograph. Sodmm <:blonde i:na). be a ·c· and
`amounts sufficient to_ re~der the ~esult,mg s_ol~!1on isot?~e 'used
`Sodium Chloride huect1011, or R111ger s ~111e~t,or1, n:a) thef\\ is,
`in whole or in part instead of Water for huect,011 u~~e~s_o
`Jyin~
`specified in the individual monograph. Fo~ con_dition~t; f P • •
`to other adjuvants, see Added Substa11ces m this chap
`·
`
`Nexus Ex. 1076
`Page 6 of 15
`
`

`

`General Requirements / Injections
`
`(1)
`
`1651
`
`concentra~ion of each ingredient named in the official title is
`sta~d as if part of the official title, e.g., Dextrose Injection 5%,
`or extrose (5%) and Sodium Chloride (0.2%) Injection.
`f The la~cling includes the following information if the complete
`ormula 1s not specified in the individual monograph: (1) In the
`case _of a liquid preparation. the percentage content of each in(cid:173)
`gredient or the amount of each ingredient in a specified volume,
`except that ingredients added to adjust to a given pH or to make
`the so!ution isotonic may be declared by name and a statement
`of their ~ff ect; and (2) in the case of a dry preparation or other
`preparatton to which a diluent is intended to be added before
`use, the amount of each ingredient, the composition of recom(cid:173)
`!llended diluent(s) [the name(s) alone, if the formula is specified
`m th_e _individual monograph], the amount to be used to attain a
`spec1f1c. concentration of active ingredient and the final volume
`of solution so obtained, a brief description of the physical ap(cid:173)
`pearance of the constituted solution, directions for proper storage
`of t_he constituted solution, and an expiration date limiting the
`penod during which the constituted solution may be expected to
`h~ve the required or labeled potency if it has been stored as
`directed.
`Containers for Injections that are intended for use as dialysis,
`hemofiltration, or irrigation solutions and that contain a volume
`of more than I liter are labeled to indicate that the contents are
`not intended for use by intravenous infusion.
`Injections intended for veterinary use arc labeled to that effect.
`The container is so labeled that a sufficient area of the con(cid:173)
`tainer remains uncovered for its full length or circumference to
`permit inspection of the contents.
`
`PACKAGING
`
`Containers for Injections
`Containers, including the closures, for preparations for injec(cid:173)
`tions do not interact physically or chemically with the prepara(cid:173)
`tions in any manner to alter the strength, quality, or purity beyond
`the official requirements under the ordinary or customary con(cid:173)
`ditions of handling, shipment, storage, sale, and use. The con(cid:173)
`tainer is made of material that permits inspection of the contents.
`The type of glass preferable for each parenteral preparation is
`usually stated in the individual monograph.
`.
`For definitions of single-dose and multiple-dose containers, see
`Containers under General Notices. Containers meet the require(cid:173)
`ments under Containers ( 661}.
`Containers are closed by fusion, or by application of suitable
`closures in such manner as to prevent contamination or loss of
`content;. Closures for multiple-dose containers permi~ the with(cid:173)
`drawal of the contents without removal or destruction of the
`closure. The closure permits penetration by a need!~, and, upon
`withdrawal of the needle, at once recloses the contamer agamst
`contamination.
`.
`The use of a black closure system on a vial (e.g., a bbck fhp(cid:173)
`off button and a black ferrule to hold the elastomeric clo~ui:e),
`or the use of a black band or series of bands above the constnct1on
`on an ampul, is prohibited except for Potassium Chloride for
`\
`Jnject~on Concentrate.
`
`Containers for Sterile Solids
`Containers, including the closure~, for dry soli~s inten~ed for
`parenteral use do not interact physically or chem1c~lly with t_he
`preparation in any manner to alter the strength, quahty, or purity
`beyond the official ~equire~ents under the ordinary or customary
`conditions of handling, shipment, storage, sale,_ ~nd use.
`.
`A container for a sterile solid permits the add1t1?n of a st1:1table
`solvent and withdrawal of portions of th~. resulting solution <?r
`suspension in such manner that the stenhty of the product 15
`maintained.
`.
`d
`f r
`Where the Assay in a monograph provides a proce ure 0
`Assay preparation in which the total wit~draw~ble ~onted~~!~~
`to be withdrawn from a single-dose container \~tth a ypos com(cid:173)
`needle and syringe, the contents adre t~ be ,y1thdorafwanr!ted ca-
`'bl
`· t
`dry hypo erm1c synnge
`l
`plete Y as possi ~ m O a
`.
`t be withdrawn and
`1
`pacity not exceeding three times the vo ume ~ 5 cm ( I inch) in
`fitted with a 2_1-gauge needle tt Jes~ t~~bbl~s and discharged
`length, care bemg tak~n t? expe any au
`'
`into a container for d1lut1on and assay.
`
`f 1
`.
`. ·ctes- Fixcd 01I~ 1;1sed as vehicles for nonaqucous
`(5
`er \ e~1 of vcg~tablc or!g!n, arc odorless or nearly so, and
`01~ {I~ are u gcstmg ranc1d1ty. They meet the requirements
`1
`0 od9' ~;lid paraffin under Mineral Oil, the cooling bath
`;~1
`~; ," {11,st t0~ncd at 10°, have~ Saponi.fication value of between
`l'~' 11u1in1a1 (sec fats and Fixed Oils (401) ), have an Iodine
`tl'~g{ld 200 , en 79 and 128 (see Fats and Fixed Oils (40l))
`,~~'of bel''e equirements of the following tests.
`'
`R n
`thC r
`./1Jl
`,, {ltcc1 . ble Motter- e u_x on a steam bath IO ml of th
`,r.d,t.saPo~~f of sodi~m hydrox!de solu_tion (1 in 6) and 30 mL
`. L,iith 1, with occas1o~al shakmg until the mixture becomes
`,u! li.-ohOI, ·fer the solution ~o a shallow dish, evaporate the al(cid:173)
`~',!r. ,ra~;earn bath, and mix the residue with 1 oo ml of water:
`11,hol on_ 3
`1 tion results.
`~ty Acids-The free fatty acids in 10 g of oil_require
`~c1,3P
`free F lization not more than 2.0 ml of 0.020 N sodium hy(cid:173)
`ff 0eutra Fats and Fixed Oils ( 401) ).
`d~0,ide (~f~ mono- or diglyc~ri~es of fatty acids may be used as
`
`5ynthe ovided they are hqmd and remain clear when cooled
`i,hiclein~\ave an Iodine value of not more than 140 (see Fats
`10 tO . ed Oils (401) ).
`.
`and fix and other nonaqueous _v~h1c!es may _b~ used, provided
`wse af e in the volume of tnJect1on administered and also
`1hey_ard ~hey do not interfere with the therapeutic efficacy of
`provide ration or with its response to prescribed assays and tests
`h prepa
`.
`·
`t e ed Substances-:-~mt~ble