”We: Immiafi Compendia of Standards
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`ADAMIS EXHIBIT 1014
`Page A
`Page A
`
`Volume 2
`
`TableofContents
`
`0 GeneralChaptersTOC 0 USPGeneral Notices
`
`ADAMIS EXHIBIT 1014
`
`

`

`2009
`
`USP 32
`
`NF 27
`Volume 2
`
`THE UNITED STATES PHARMACOPEIA
`
`THE NATIONAL FORMULARY
`
`By authority of the United States Pharmacopeial
`Convention, meeting at Washington, D.C., March 9-13,
`2005. Prepared by the Council of Experts and published
`by the Board of Trustees
`
`Official from May 1, 2009
`
`The designation on the cover of this publication, "USP NF
`2009," is for ease of identification only. The publication
`contains two separate compendia: The United States
`Pharmacopeia, Thirty-Second Revision, and The National
`Formulary, Twenty-Seventh Edition.
`
`THE UNITED STATES PHARMACOPEIAL CONVENTION
`12601 Twinbrook Parkway, Rockville, MD 20852
`
`..
`
`Page B
`
`ADAMIS EXHIBIT 1014
`
`

`

`-
`
`SIX-MONTH IMPLEMENTATION GUIDELINE
`
`The United States P'1armacopeia- Nt11io11al Formu/ary and its Supple111em become official six months after being released to the public.
`The USP-NF, which is released on November I of each year. become official on May 1 of the following year.
`This change wa adopled to give users more time to bring their methods and procedures into compliance with new and revised USP-NF
`requirements.
`The table below describes the new official dates. The 2008 USP31-NF26, and the Supplements and Interim Revision Announcements
`(IRAs) to that edition, will be official until May 1, 2009, at which time the USP32-NF27 becomes official.
`
`Publication
`USP32-NF27
`
`Release Date
`Nov. 1, 2008
`
`Official Date
`May 1, 2009
`
`First Supplement
`
`Feb. 1, 2009
`
`Aug. 1, 2009
`
`Second Supplement
`
`June 1, 2009
`
`Dec. 1, 2009
`
`USP33-NF28
`
`Nov. 1, 2009
`
`May 1, 2010
`
`Official Until
`May 1, 2010 (except as superceded by Supplements, IRAs, and
`Revision Bulletins)
`May 1, 2010 (except as superceded by Second Supplement,
`IRAs, and Revision Bulletins)
`May 1, 2010 (except as superceded by lRAs and Revision But-
`letins)
`May 1, 2011 (except as superceded by Supplements, IRAs, and
`Revision Bulletins)
`
`IRAs will continue to become official on the first day of the econd month of the Pharmacopeial Forum (PF) issue in which they are
`published as final. For instance, IRAs published as tJn"al in the May-June PF (issue 3) will become official on June 1. This table gives the
`details of the IRAs that will apply to USP3J- NF'26 and USP32- NF27.
`
`[RJ\ *
`Jan. I, 2009 IRA, PF 35(1)
`Mar. l 2009 IRA, PF 35(2)
`May .I, 2009 !RA, PF 35(3)
`July I. 2009 IRA, PF 35(4)
`Sept. I, 2009 IRA, PF 35(5)
`Nov. 1, 2009 IRA, PF 35(6)
`Jan. l, 20LO IRA. PF 36(1)
`Mar. 1, 20 10 /RA, PF 36(2)
`
`Release Date
`Jan. I , 2009
`Mar. I , 2009
`May I, 2009
`July I 2009
`Sept. 1, 2009
`Nov . .I , 2009
`Jan. 1, 2010
`Mar. I, 2010
`
`Official Dare
`Feb. l, 2009
`April I. 2009
`June l, 2009
`Aug. I, 2009
`Oct. l, 2009
`Dec. I, 2009
`Feb. I, 20 10
`April I, 20 10
`
`Revises
`USP3 l- NF26 and its Supplements
`USP3!-NF26 and ii Supplements
`USP32- !VF27
`USP32-NF27 and First Supplement
`USP32- NF27 and Fir ·r Supplement
`USP32-NF27 and it Supplements
`USP32- NF27 and its Supplements
`USP32- NF27 and it S11ppleme111s
`
`*NOTE- Beginn.ing January ! , 2007, U P ceased identifying IRAs numerically (First, Second. etc.) and in tead now designate them by
`the dace on which they are publi hed.
`Revision Btdleti11s publi hed on the USP websi te will continue to become official immediately upon publication unless the Revision
`Bulletin specifies otherwise.
`Revisions that contain a pecific official date shall. continue ro become official upon such specified date, which supercede · the general
`official date for the publication.
`For more information about the change in official dates please visit the U P websit at htlp://www.usp.org.
`
`NOTICE AND WARNING
`Concerning U.S. Patent or Trademark Righrs--Tbe inclusion in The United States Pha.rmacopeia or in the National Formulary of a
`monograph on any drug in respect to which parent or trademark rights may exist shall not be deemed, and is n.ol intended as, a grant of, or
`authority to exercise any right or privilege protected by such patent or m1demark. AU such rights and privileges are vested in the patent or
`trademark owner, and no other per on 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.
`
`Copyright © 2008 The United States Pharmacopeial Convention
`12601 Twinbrook Parkway, Rockville, MD 20852
`
`All rights reserved.
`
`ISSN: 0195-7996
`ISBN: 1-889788-69-2
`
`Printed in the United States by United Book Press, Baltimore, Maryland
`
`Page C
`
`ADAMIS EXHIBIT 1014
`
`

`

`2258
`
`Ephedrine I Official Monographs
`
`USP 32
`
`Ephedrine
`
`H OH ~
`' CH,
`CH,
`
`CroHrsNO 165.23
`Benzenemethanol, a-(1-(methylamino)ethyl]-, [R-(R*,S*)]-.
`(-)-Ephedrine
`[299-42-3].
`Hemihydrate
`174.24
`[50906-05-3].
`» Ephedrine is anhydrous or contains not more than
`one-half molecule of water of hydration. It contains not
`less than 98.5 percent and not more than 100.5 percent
`of C10H1sNO, calculated on the anhydrous basis.
`
`Packaging and storage-Preserve in tight, light-resistant contain(cid:173)
`ers, in a cold place.
`Labeling-Label it to indicate whether it i hydrous or anhydrou .
`Where the quantity of Ephedrine is indkated in the labeling of any
`preparation containing Ephedrine, this shall be underst od to b
`in
`terms of anhydrous Ephedrine.
`USP Reference standards (11)-USP Ephedrine Sulfate RS.
`Identification-Accurately weigh about 100 mg, and add by buret
`the exact volume of 0.1 N sulfuric acid, determined in the Assay. to
`neutralize it. Dilute with water in a volumetric flask to 25 mL. Mix
`2 mL with lO mL of alcohol, and evaporate on a steam bath with
`the aid of a cuffent of air to dryness: the residue so obtained re(cid:173)
`sponds to Identification test A under Ephedrine Sulfate.
`Specific rotation (781S): between -40.3° and -43.3°.
`Test solution: 25 mg per mL, in 0.6 N hydrochloric acid.
`Water, Method lb (921): between 4.5% and 5.5%, for hydrated
`Ephedrine; not more than 0.5% for anhydrous Ephedrine.
`Residue on ignition (281): not more than 0.1 %.
`Chloride (221)-A solution of 500 mg shows no more chloride
`than corresponds to 0.20 mL of 0.020 N hydrochloric acid
`(0.030%).
`Sulfate-Dissolve 100 mg in 40 mL of water, and add 1mLof3 N
`hydrochloric acid and l mL of barium chloride TS: no turbidity de(cid:173)
`velops within 10 minutes.
`Ordinary impurities (466)-
`Test solution: methanol.
`Standard solution: methanol.
`a mixture of isopropyl alcohol, ammonium hydroxide,
`Eluant:
`and chloroform (80 : 15 : 5).
`1, followed by 4.
`Visualization:
`Assay-Dissolve about 500 mg of Ephedrine, accurately weighed,
`in I 0 mL of neutralized alcohol, and add 5 drops of methyl red TS
`and 40.0 mL of 0.1 N hydrochloric acid VS. Titrate the excess acid
`with 0.1 N sodium hydroxide VS. Perform a blank determination
`(see Residual Titrations under Titrimetry (541)). Each mL of 0.1 N
`hydrochloric acid is equivalent to 16.52 mg of CroH1sNO.
`
`Ephedrine Hydrochloride
`
`CroHrsNO · HCI 201.69
`Benzenemethanol, a-[ 1-(methylamino )ethyl]-, hydrochloride,
`[R-(R*,S*)]-.
`(-)-Ephedrine hydrochloride
`
`[50-98-6].
`
`» Ephedrine Hydrochloride contains not less than 98.0
`percent and not more than 100.5 percent of C10H1 5NO.
`HCl, calculated on the dried basis.
`
`Packaging and storage-Preserve in well-closed, light-resistant
`containers.
`USP Reference standards (11)-USP Ephedrine Sulfate RS.
`Identification-
`A: Dissolve 100 mg in 5 mL of water, add 1 mL of potassium
`carbonate solution (I in 5), and extract with 2 mL of chloroform:
`the IR absorption spectrum of the chloroform extract so obtained
`exhibits maxima only at the same wavelengths as that of a similar
`preparation of USP Ephedrine Sulfate RS.
`B: A solution of it responds to the tests for Chloride (191).
`Melting range, Class I (741): between 217° and 220°.
`Specific rotation (781S): between -33.0° and -35 .5°.
`Test solution: 50 mg per mL, in water.
`Acidity or alkalinity-Dissolve 1.0 g in 20 mL of water and add I
`drop of methyl red TS. If the solution i · yellow, iris changed to red
`by not more than 0.10 mL of 0.020 N sulfuric acid. lf the solution is
`pink, it is changed to yell.ow by not more than 0.20 rnL of 0.020 N
`sodium hydroxide.
`Loss on drying (731)-Dry it at l05° for 3 hours: it loses not more
`than 0.5% of its weight.
`Residue on ignition (281): not more than 0.1%.
`Sulfate-Dissolve 50 mg in 40 mL of water, and add 1 mL of 3 N
`hydrochloric acid and 1 mL of barium ch\olide TS: no turbidity de(cid:173)
`velops within 10 minutes.
`Ordinary impurities (466)-
`Test solution: alcohol.
`Standard solution: alcohol.
`Eluant: a mixture of isopropyl alcohol, ammonium hydroxide,
`and chloroform (80 : 15 : 5).
`I, followed by 4.
`Visualization:
`Assay-Dissolve about 500 mg of Ephedrin Hydrochloride, accu(cid:173)
`rately weighed, in 25 rnL of glacial acetic acid. Add I 0 mL of mer(cid:173)
`"I' crystal violet TS, and titrate with
`curic acetate TS and 2 drop ·
`0.1 N perchloric acid VS to an emerald-green en !point. Perform a
`blank determination, and make any necessary corre ·tion. Each mL
`of 0.1 N perchloric acid is equivalent to 20.17 mg of CroHr 5NO ·
`HCI.
`
`Ephedrine Sulfate
`
`(C10H1iN0)2 · H2S04 428.54
`Benzenemethanol, a-(1-(methylamino)ethyl]-, [R-(R*,S*)]-, sulfate
`(2 : 1) (salt).
`(-)-Ephedrine sulfate (2: 1) (salt)
`
`[134-72-5].
`
`» Ephedrine Sulfate contains not less than 98.0 percent
`and not more than 101.0 percent of (C10H1sN0)2 ·
`H2S04, calculated on the dried basis.
`
`Packaging and storage-Preserve in well-closed, light-resistant
`containers.
`USP Reference standards (l l)-USP Ephedrine Sulfate RS.
`Identification-
`A:
`Infrared Absorption (197K).
`B: A solution of it responds to the tests for Sulfate (191).
`Specific rotation (781S): between -30.5° and -32.5°.
`Test solution: 50 mg per mL, in water.
`Acidity or alkalinity-Dissolve l.O gin 20 mL of water, and add 1
`drop of methyl red TS. If the solution is yellow, it is changed to red
`by not more than O. l 0 mL of 0.020 N sulfuric acid. If the solution is
`
`ADAMIS EXHIBIT 1014
`
`Page 2258
`
`

`

`USP 32
`
`Official Monographs I Ephedrine 2259
`
`pink, it is changed to yellow by not more than 0.20 mL of 0.020 N
`sodium hydroxide.
`Loss on drying (731)-Dry about 500 mg, accurately weighed, at
`105° for 3 hours: it loses not more than 0.5% of its weight.
`Residue on ignition (281 ): not more than 0.1 %.
`Chloride (221)-A 200-mg portion shows no more chloride than
`corresponds to 0.40 mL of 0.020 N hydrochloric acid (0.14%).
`Ordinary impurities (466)-
`alcohol.
`Test solution:
`Standard solution: alcohol.
`a mixture of isopropyl alcohol, ammonium hydroxide,
`Eluant:
`and chloroform (80 : 15 : 5).
`Visualization: 1, followed by 4.
`Assay-Transfer about 300 mg of Ephedrine Sulfate, accurately
`weighed, to a separator, and dissolve in about 10 mL of water. Satu(cid:173)
`rate the solution with sodium chloride (about 3 g), add 5 mL of 1 N
`sodium hydroxide, and extract with four 25-mL portions of chloro(cid:173)
`form. Wash the combined chloroform extracts by shaking with
`IO mL of a saturated solution of sodium chloride, and filter through
`chloroform-saturated purified cotton into a beaker. Extract the wash
`solution with 10 rnL of chloroform, and add to the main chloroform
`extract. Add methyl red TS, and titrate with 0.1 N perchloric acid in
`dioxane VS. Perform a blank determination, and make any neces~
`sary correction. Each rnL of 0.1 N perchloric acid is equivalent to
`21.43 mg of (C10H1sN0)2 · H2S04.
`
`aid of 10 rnL of water, add methanol to volume, and mix. Dilute
`5.0 mL of this solution with water to 100.0 mL.
`Assay prepw'{//ion- W eigh accurarely th content· .of not les
`than 20 Cap. ules, and mix . Tran fer an accurately weighed portion
`of the mixture, equivalent to about 25 mg of ephedrine sulfate, to a
`glass-stoppered conical nask, and add by pipe! 50 mL of a I in 5
`mixture of water in methanol. Shake by mechanical means for 10
`, and tilt r. Dilute 5.0 mL of the filtrate with water to
`minut
`100.0 rnL.
`Procet/11re- Transfer 5-mL portion of the Assay preparation
`and the Swndard preparation (o separate glas - coppered 50-mL
`centrifug Lllb
`. Add I mL of saturated sodium carbonru.e olution
`and 2 m.L of odium metapcri dri
`solution (I in 50) to each tube,
`mix, and allow co stand for 10 rnlmHei . Pipet 20 rnL of 11-hexane
`into each tube, .hake for 30 second and allow the phase. to epa(cid:173)
`rate. Concomitantly detetmine the abs rbances of lhe 11-hexane ex(cid:173)
`tra t
`in I-cm ells at the wavelength of maximum absorbance at
`about 242 nm, wilb a suitable spectrophotometer, u ing n-hexane as
`the blank. Calculate the quantity, in mg, of (CioH1sNO)i · H2S04 in
`the p rtion of Capsule contents taken by Lhe formula:
`
`C(Aul As)
`• is lhe concentrali n, in µg per mL, of USP Ephedrine
`in which
`ulfate RS in the Standard preparation, and Au and As are the ab(cid:173)
`sorba11ces of U1e hexane extracts of the Assay preparation and the
`Sta11dard preparation , respectively.
`
`Ephedrine Sulfate Capsules
`
`Ephedrine Sulfate Injection
`
`tight,
`
`light-resistant
`
`in
`
`» Ephedrine Sulfate Capsules contain not less than 92.0
`percent and not more than 108.0 percent of the labeled
`amount of (C10H1sNOh · H2S04.
`Packaging and storage-Preserve
`containers.
`USP Reference standards (11)-USP Ephedrine Sulfate RS.
`Identification-Macerate the contents of a sufficient number of .
`Capsule , equivalent to about 200 mg of ephedrine su lfate, with
`15 mL of warm alcohol for 20 minute
`filler. and evaporate the fil(cid:173)
`tnue on a steam bath Lo dryne s: Lhe residue so obtained re. ponds to
`Lbe Identification tests under Ephedrine Sulfate.
`Dissolution (711)-
`Medium: water; 500 mL.
`Apparatus 1: 100 rpm.
`Time: 30 minutes.
`Procedure-Dilute filtered portions of the solutions under test
`wi U1 water 10 a concentration of about 25 µg per rnL. Transfer 5.0-
`mL portions to suitable tubes. Add 1 rnL of a saturated sodium car(cid:173)
`bonate solution and 2 mL of sodium metaperiodate solution (2 in
`100) to each, mix, and allow to stand for 10 minutes. Add 20.0 mL
`of hexanes, shake for 30 seconds, and allow the phases to separate.
`Measure the absorbances of the hexanes extract in 1-cm cells at the
`wavelength of maximum absorbance, at about 242 nm, with a suita(cid:173)
`ble spectrophotometer, using hexanes as the blank. Determine the
`amount of (C10B 1sN0)2 • HzSO. d.is olved by comparison with a
`simi larly treated Standard soluti n having a known concentration of
`USP Ephedrine Sulfate RS in water. Remove tbe contents of 1 Cap(cid:173)
`sule a completely as possible, with the aid of a current of air, dis(cid:173)
`solve the empty capsule hell in the M dium, determine the ab(cid:173)
`sorbance at the same dilution and in the same manner as for the
`Capsules, and make any necessary corrections.
`Tolerances-Not less than 80% (Q) of the labeled amount of
`(C10H1sN0)2 · H2S04 is dissolved in 30 minutes.
`Uniformity of dosage units (905): meet the requirements.
`Assay-
`Standard preparation-Weigh accurately about 25 mg of USP
`Ephedrine Sulfate RS, transfer to a 50-rnL volumetric flask with the
`
`terile solution of
`» Epheckine Sulfate Inje tion is a
`Ephedrine Sulfate in Water for Injection. It contains not
`than 95.0 percent and not m re than 105.0 percent
`le
`of the labeled amount of (C10H1sN0)2 · H2S04.
`Packaging and storage-Preserve in single-dose or in multiple(cid:173)
`dose, light-resistant containers, preferably of Type I glass.
`USP Reference standards (11)-USP Endotoxin RS. USP Ephe(cid:173)
`drine Sulfate RS.
`Identification-
`A: Mix I mL of Lnjection with 5 rnL of alcohol , and evaporate
`on a team bath with the aid of a current of air to dryne s: the resi(cid:173)
`due so obtained respond
`Identification tests under Ephedrine
`t
`Sulfate.
`B:
`It responds to the tests for Sulfate (191).
`Bacterial endotoxins (85)-It contains not more than 1.7 USP En(cid:173)
`dotoxin Units per mg of ephedrine sulfate.
`pH (791): between 4.5 and 7.0.
`Other requirements-It meets the requirements under Injections
`(1).
`Assay-Tran fer an accurately measured volume of lnjecifon,
`equivalent to about 250 mg of ephedri ne ulfate, 10 a eparator, add
`water, if necessary, to make about 10 mL, and proceed a directed
`in the Assay under Ephedrine uifate, beginni ng with ' Saturate the
`solulion."
`
`Ephedrine Sulfate Nasal Solution
`
`» Ephedrine Sulfate Nasal Solution contains not less
`than 93.0 percent and not more than 107.0 percent of
`the labeled amount of (C10H1sNO)z · H2S04.
`
`Packaging and storage-Preserve
`containers.
`
`in
`
`tight,
`
`light-resistant
`
`ADAMIS EXHIBIT 1014
`
`Page 2259
`
`

`

`2260 Ephedrine I Official Monographs
`
`USP 32
`
`ephedrine sulfate [(C10H1sN0)2 · H2S04] in the portion of Oral Solu(cid:173)
`tion taken by the formula:
`
`C(Au I As)
`in which C is the concentration, in µg per mL, of USP Ephedrine
`Sulfate RS in the Standard preparation; and Au and As are the ab(cid:173)
`sorbances of the soluti.ons from the Assay preparation and the Stan(cid:173)
`dard preparation, respectively.
`
`Epinephrine
`
`C9HuN03 183.20
`1,2-Benzenediol, 4-[l-hydroxy-2-(methylamino)ethyl]-, (R)-.
`(-)-3,4-Dihydroxy-a-[(methylamino )methyl]benzyl akohol
`43-4] .
`
`[51-
`
`» Epinephrine contains not less than 97 .0 percent and
`not more than 100.5 percent of C9H13N03, calculated
`on the dried basis.
`
`USP Reference standards ( l l)-USP Ephedrine Sulfate RS.
`Identification-It responds to the Identification tests under Ephe(cid:173)
`drine Sulfate Injection.
`Microbial enumeration tests (61) and Absence of specified
`microorganisms (62)-It meets the requirements of the tests for
`absence of Staphylococcus aureus and Pseudomonas aeruginosa.
`Assay-
`Standard preparation-Weigh accurately about 26 mg of USP
`Ephedrine Sulfate RS, transfer to a 50-rnL volumetric flask with the
`aid of 10 mL of water, add methanol to volume, and mix. Pipet
`5 mL of the resulting solution into a 100-mL volumetric flask, di(cid:173)
`lute with water to volume, and mix.
`Assay preparation-Transfer an accurately measured volume of
`Nasal Solution, equivalent to about 26 mg of ephedrine sulfate, to a
`50-mL volumetric flask, dilute with a 1 in 5 mixture of water in
`methanol to volume, and mix. Pipet 5 rnL of the resulting solution
`into a 100-mL volumetric flask, dilute with water to volume, and
`mix.
`Procedure-Transfer 5-mL portions of lhe Assay prnparation
`and Lhe Sumda.rd preparation to separate glass-stoppered. 50-mL
`centrifuge lubes. Add l mL of saturated sodium carbonat so.lution
`and 2 mL of sodium metaperiodate olulion (l in 50) tO each tube,
`. Pipet 20 rnL of 11-hexane
`mix, and a llow to . cand for I 0 minut
`into each Lube, hake fo r 30 seconds, and allow the phases to cpa(cid:173)
`rate. Concomitantly determine the absorbances of the 11-hexane ex(cid:173)
`tracts in 1-cm cells at the wavelength of maximum absorbance at
`about 242 nm, with a suitable spectrophotometer, using n-hexane as
`the blank. Calculate the quantity, in mg, of (C 10H1sN0)2 · H2S04 in
`each mL of the Nasal Solution taken by the formula:
`
`(CI \!)(Aul As)
`in which Vi s the volume, in mL, of Nasal Solution taken, C is the
`concentration, in µg per mL, of USP Ephedrine Sulfate RS in the
`Standard preparation, and Au and As are the absorbances of the
`hexane extracts of the Assay preparation and the Standard prepara(cid:173)
`tion, respectively.
`
`Ephedrine Sulfate Oral Solution
`
`» Ephedrine Sulfate Oral Solution contains, in each
`100 mL, not less than 360 mg and not more than
`440 mg of ephedrine sulfate [(C10H1sNOh · H2S04].
`
`Packaging and storage-Preserve in tight, light-resistant contain(cid:173)
`ers, and avoid exposure to excessive heat.
`USP Reference standards (l 1)-USP Ephedrine Sulfate RS.
`Identification, Angular rotation (781A)-Use the 0.1 N sulfuric
`acid extract of the chloroform solution obtained as directed for As(cid:173)
`say preparation: the angular rotation is levorotatory.
`Alcohol content (611): between 2.0% and 4.0% of C2H50H.
`Assay-
`Standard preparation-Dissolve an accurately weighed quantity
`of USP Ephedrine Sulfate RS in O. l N sulfuric acid to obtain a solu(cid:173)
`tion having a known concentration Qf about 20 µg per mL.
`Assay preparation-Transfer 5 fµL of Oral Solution to a
`separator, add 1 mL of 1 N sulfuric acid, and extract with 10 mL of
`chloroform. Discard the extract, and add 5 mL of potassium carbon(cid:173)
`ate solution (1 in 5). After gas evolution has ceased, extract the so(cid:173)
`lution with three IO-mL portions of chloroform, and combine the
`extracts in a second separator. Extract the chloroform solution with
`50.0 mL of 0.1 N sulfuric acid. Filter the acid layer through paper,
`and dilute 5.0 mL of it with 0.1 N sulfuric acid to 100.0 mL.
`Procedure-Proceed as directed for Procedure in the Assay
`under Ephedrine Sulfate Capsules. Calculate the quantity, in mg, of
`
`in
`
`tight,
`
`light-resistant
`
`Packaging and storage-Preserve
`containers.
`USP Reference standards (11)-USP Epinephrine Bitartrate RS.
`USP Norepinephrine Bitartrate RS.
`Identification-To 5 mL of pH 4.0 acid phthalate buffer (see
`Buffer Solutions in Lhe section Reagents, Indicators, and Solutions)
`f a slightly acid solution of Epinephrine (1 in 1000)
`add 0.5 mL
`and 1.0 mL of 0. I N iodine. Mix, and allow to stand for 5 minutes.
`Add 2 mL of sodium thiosulfate solution (I in 40): a deep red color
`is produced.
`Specific rotation (781S): between -50.0° and -53.5°.
`Test solution: 20 mg per mL, in 0.6 N hydrochloric acid.
`Loss on drying (731)-Dry it in vacuum over silica gel for 18
`hours: it loses not more than 2.0% of its own weight.
`Residue on ignition (281): negligible, from 100 mg.
`Limit of adrenalone-Its absorptivity (see Spectrophotometry and
`Light-scattering (851)) at 310 nm, determined in a solution in dilute
`hydrochloric acid (1 in 200) containing 2 mg per mL, is not more
`than 0.2.
`Limit of norepinephrine-
`Epinephrine standard solution-Dilute with methanol an accu(cid:173)
`rately measured volume of R solution of U P Epinephrine Bitartrate
`RS in formic acid containing nbout 364 mg per mL to obtain a solu(cid:173)
`tion having a concentration of ab ul 20 mg per mL.
`Norepinephrine standard solution-Dilute with methanol an ac(cid:173)
`curately measured volume of a olution of USP Norepinephrine Bi(cid:173)
`tartrate RS in fom1ic acid cootain.iag 16 mg per mL to obtain a solu(cid:173)
`tion having a known concentration of I .6 mg per mL.
`Test solution-Dissolve 200 mg of Epinephrine in 1.0 mL of for(cid:173)
`mic acid, dilute with methanol to 10.0 mL, and mix.
`Procedure-Apply 5-µL portions of Epinephrine standard solu(cid:173)
`tion, Norepinephrine standard solution, and Test solution to a suita(cid:173)
`ble chin-layer chromacographic plate ( ee Chromatography (62 1))
`coated with a 0.25-mm layer of chr matographic ·il.ica gel mixture.
`Allow the ·pots to dry, and develop the chromatogram in an unsatu(cid:173)
`rated tank u ing a olvent y rem con ·isling of a mixture of 11-buta(cid:173)
`n I, water, and form ic acid (7: 2: l) until che olvent fro nt has
`moved about three-fourths of the length of U1c plate. Remove the
`plate from the devel ping chamber, mark the olvenl front and al(cid:173)
`low the solvenl Lo evaporate in warm circulating air. Spray with
`Fo.lin-Ciocalteu Phenol TS, followed by odium carbon:ice olution
`( 1 in LO): the RF value of the principal spot obtained from the Tes/
`
`ADAMIS EXHIBIT 1014
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`USP 32
`
`Official Monographs I Epinephrine 2261
`
`to that obtained from !he l!"'pinepltrine s1a11-
`solwion. corresµond
`dard solution. Any spot obtained from tl\e Tes/ solwio11 i not larg r
`nor more inten e than the . p I' with Lhe same R~- value obtained
`from 1he Nonipinephrine standard so/111ion corresponding lo not
`more thau 4.0% of n01·epinephrine.
`
`Change to read:
`
`Assay-Dis olve about 300 mg of Epinephrine, accurately
`weighed, in 50 rnL of •glacial acetic acid • .1o.usm warming slightly if
`rystal violet TS, and titrate with
`necessary to effect soluti n. Add
`O.l N perchloric acid VS. Perform a blank determination and make
`any nece sary correction. Each mL or 0. I N perchloric acid i
`equivalent to 18.32 mg of C9H13N03.
`
`Epinephrine Inhalation Aerosol
`
`» Epinephrine Inhalation Aero. ol i a solution of Epi(cid:173)
`nephrine in propellants and Alcohol prepared with the
`aid of mineral acid in a pre urized container. lt con(cid:173)
`tains not less than 90.0 percent and not more Llum 115.0
`percent of the labeled amount of ep:inepbrine (C9H13
`N03).
`Packaging and storage-Preserve in small, nonreactive, light-re(cid:173)
`sistant aerosol containers equipped with metered-dose valves and
`provided with oral inhalation actuators.
`USP Reference standards (11)-USP Epinephrine Bitartrate RS.
`Identilication-Place JO mL of water in
`. mall beaker, and de(cid:173)
`liver 2 pray from the Inhalation Aerosol under the surface of 1he
`water, actuating the valve by pre sing the 1jp against the boll m of
`lhe beaker. To 5 mL of the solmion add I drop of dilute sulfuric
`acid (l lu 200), add 0.5 mL of 0.1 N iodine, allow to
`lflncl for 5
`minutes, and add I mL or OJ N sodium thio. ulfate: a 1:ed-br wn
`color is produced.
`Delivered dose uniformity over the entiJ·e contents: meets the
`requirement for Metered-Dose 111/zalers under Aerosols, Nasal
`Sprays, Metered-Dose Inhalers, and D1y Powder Inhalers (601).
`PROCEDURE FOR DOS · UNJFORMIJY-
`Ferro-citrate solution and Buffer solution-Prepare as directed
`under Epinephrine Assay (391).
`Sumdard prepara1io11r--Dissolve an accurately weighed quantity
`of USP Epinephrine j3itartrate RS in a freshly prepared sodium bi(cid:173)
`sulfite solution ( I in 500), and dilute quanl'itatively and stepwise
`with the same odium bisulfite solL1tion as neces ary to obrain a ~o­
`.lution baving a known concentration of abou t 18 µg per mL.
`Tesr preparation- Di. charge the minimum recommended dose
`into the sampling apparatu and detach the inhaler as direeted.
`Rinse the apparatus (filter and interior) with fottr 5.0-mL portions
`of a freshly prepared sodium bisullite solution (1 in 500), and tran -
`fer the resulting sol ution quantitatively to a 50-mL centrifuge tube.
`Add l.O mL of chloroform, insert the sropper, hake vigorously for I
`minute, and centrifuge for 5 mjnutes. Use the clear upematanr. as
`directed in the Pro edure.
`Procedure-lnto three eparate fla ks, transfer the Test prepara·
`tion , 20.0 mL of the Standard preparation, and 20.0 mL of water to
`provide the blank. To each llask add 100 µL of Ferro-citra/e sol11-
`rio11 and I .0 mL of Buffer solt11io11, and mix. Concomitantly deter(cid:173)
`mine the absorbances with a suitable pect.rophotometer, in 5-cm
`cells, of the solutions from the Test prepara1io11 and tl1e Standard
`preparation, at the wavelength of maximtuJl absorbance ac about
`530 nm, against the blank. Calculate the quantity, in µg , of
`C9H 1,NOJ contained in the minimum dose taken by the formula:
`
`(183.20 I 333.29)(20CN)(Au I As)
`in which C is the concentration, in µg per mL, of USP Epinephrine
`Bitartrate RS in the Standard preparation; N is the number of
`
`sprnys di charged 1.0 obtain the mrn1mum recommended dose;
`the molecular weight of epinephrine and
`183.20 and 333.29 ar
`epinephrine bilarlrate, re.!ipectiv ly ; and A 11 and As are the ab-
`of the elution from the Test fJfeparation and the Stan-
`orban
`dard prepara1io11, respecLivcly.
`Assny-Weigh the Inhalation Aero ol chill LO a tcmperaLUre below
`-30°, remove the valve by uitable means and allow the Inhalation
`Aerosol 10 warm slowly LO room temperature LO expel the more vol(cid:173)
`atile propellant rrn tion-. Transfer the residues in the aerosol
`container and valve to a J 25-mL eparator with the aid or ix 5-mL
`portion of dilme ulfuric a id (I in !000) and extract the solution
`with three 25-mL por1ion of chi roform. Proceed as directed in the
`Assay under Epinephrine Nasal Solu1ion, beginning v.iith "Rinse the
`stopper and mouth of the eparator, ' but u. e I 0.0 mL instead of
`5.0 mL of chloroform in the determinatjon of the specific rotation.
`Dry 1he empty aerosol container and valve, weigh them, and deter(cid:173)
`mi ne the ne1 weight of the Inhalatjon Aero ol. Calculate the quan(cid:173)
`tity, in mg, of C9H1 JNO_, in the Inhalation Aerosol raken by the
`formula:
`
`(183.20 I 309.32)(W)(0.5 + 0.5R I 93)
`in which 18 .20 and 309.32 are the molecular weight of epineph(cid:173)
`rine and triacetylepinephrine, respecLively, and Wis the weight, in
`mg, and R is the specific rotation (in degrees w.ithout regard to the
`sign), of 1h
`is lated triacetylcpinepbrine.
`
`Epinephrine Injection
`
`» Epinephrin Injection is a steJ"ile olution of Epineph(cid:173)
`rine in Water for Injection prepared with the aid of Hy(cid:173)
`drochloric Acid or other suitable buffers. It contain not
`le s than 90.0 percent and not more than 115.0 percent
`of the labeled am unt of epinephrine (G.iH13N03).
`Packaging and storage-Preserve in single-dose or multiple-dose,
`light-resistant containers, preferably of Type I glass.
`Labeling-The label indicates that the Injection is not to be used if
`its color is pinkish or darker than slightly yellow or if it contains a
`precipitate.
`USP Reference standards (11 )-USP Endo toxin RS. USP Epi·
`nephrine Bitartrate RS.
`Color and clarity-
`Standard solution- Transfer 2.0 mL of 0.100 N iodine VS to a
`500-mL volumetric flask, dilute with water to volume, and mix.
`Procedure-Yi. ually examine a portion of the fnjection (Test so(cid:173)
`'/111io11) in a suitable clear glass test wbe against. a white background:
`it is not pinkish and il contain no precipitate. If any yellow color is
`observed in the Tes/ olutio11 concomitantly dete1mine the ab(cid:173)
`sorbances of the Test solwio11 and the Sta11dard solution in I-cm
`cel ls with a suitable spectr photometer set at 460 nm: tbe ab-
`orbance of Lhe Test solution does not exceed that of the Standard
`solution.
`Identification-
`It responds to the Identification test under Epinephrine Na(cid:173)
`A:
`sal Solution.
`B: The retention time of the major peak in the chromatogram of
`the A say preparation corresponds to that in the chromatogram of
`the S1andard preparmion, as obtained in the Assay.
`Bacterial endotoxins (85)-It contains not more than 357 .0 USP
`Endotoxin Units per mg of epinephrine.
`pH (791): between 2.2 and 5.0.
`Total acidity-Transfer 5.0 mL of Injection to a flask, add 10 mL
`of water, and titrate with 0.01 N sodium hydroxide VS to a pH of
`7.40. Perform a blank determination, and make any necessary cor-
`
`ADAMIS EXHIBIT 1014
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`Page 2261
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`2262 Epinephrine I Official Monographs
`
`USP 32
`
`rection. Not more than 25.0 mL of 0.01 N sodium hydroxide is
`required.
`Other requirements-It meets the requirements under Injections
`( l).
`Assay-
`Mobile phase-To I L of 0.05 M monoba ic sodium pho phate
`add about 519 mg of odium 1-octanesulfonate and aboul 45 mg of
`edetate disodium, and mix. Adjust by the dropwise addition of
`phosphoric acid , if neces ary, co a pH of 3 .. Mix 85 volumes of
`this olution wiU1 15 volume of methanol. Make adjustments if
`nece . ary ( ee System Suitability under Chromatography (621)).
`Standard prept1ratio11-Dissolv an accurately weighed quantity
`of USP Epinephrine Bitartrate RS in Mobile phase, and dilute quan(cid:173)
`titatively, and stepwi e if nee ssary, witll Mobile phase l'O obtain a
`olution having a known concentration of about 0. l mg of epineph(cid:173)
`ri.ne per mL.
`Assay preparation-Transfer an accurately measured volume of
`Injection, equivalent to about l mg of epinephrine, to a 10-mL vol(cid:173)
`umetric flask, dilute with Mobile phase to volume, and mix.
`System suitability preparation-Dissolve 10 mg of dopamine hy(cid:173)
`drochloride in 100 mL of the Standard preparation, and mix.
`Chromatographic system (see Chromatography (621))-The liq(cid:173)
`uid chromatograph is equipped with a 280-nm detector and a 4.6-
`mm x 15-cm column that contains packing L7. The flow rate is
`about 2 mL per mh1ute. Chromatograph the Stwulard preparation
`and the System suitability preparation, and record the peak re(cid:173)
`sponses n directed for Procedure: the relative retention limes are
`about 1.0 for epinephrine and 2.0 for dopamine hydrochloride; the
`resolurion, R. b