U.S. Pharmacopeia
`
`National Formulary
`
`
`
`Volume 2
`
`Table of Contents
`
`General Chapters TOC
`General Notices
`
`USP Monographs (A-I)
`Combined Index
`
`
`
`
`
`
`
`Global l'xperlise
`Trusted Standards
`Improved Heallh
`
`U.S.Pl1armal:opeial
`Con venliun
`
`ADAMIS EXHIBIT 1015
`
`Page 1 of 18
`
`ADAMIS EXHIBIT 1015
`Page 1 of 18
`
`

`

`2014
`
`USP 37
`NF 32
`Volume 2
`
`THE UNITED STATES PHARMACOPEIA
`
`THE NATIONAL FORMULARY
`
`By authority of the United States Pharmacopeial Convention
`Prepared by the Council of Experts and its Expert Committees
`
`Official from May 11 20 7 4
`
`The designation on the cover of this publication, "USP NF 2014," is for ease of
`identification only. The publication contains two separate compendia: The United
`States Pharmacopeia, Thirty-Seventh Revision, and The National Formulary, Thirty-
`Second Edition.
`
`THE UNITED STATES PHARMACOPEIAL CONVENTION
`12601 Twinbrook Parkway, Rockville, MD 20852
`
`ADAMIS EXHIBIT 1015
`Page 2 of 18
`
`

`

`u:
`
`- '
`
`f
`
`
`
`-4
`
`SIX-MONTH IMPLEMENTATION GUIDELINE
`
`The United States Pharmacopeia-National Formulary and its supplements become official six months after being released to
`the public. The USP- NF, which is released on November 1 of each year, becomes official on May 1 of the following year. This
`six-month implementation timing gives users more time to bring their methods and procedures into compliance with new
`and revised USP- NF requirements.
`The table below describes the official dates of the USP-NF and its supplements. The 2013 USP 36-NF 31, and its supple(cid:173)
`ments, Interim Revision Announcements (IRAs) and Revision Bulletins to that edition, will be official until May 1, 2014, at which
`time the USP 37-NF 32 becomes official.
`
`Publication
`USP 37-NF 32
`
`Release Date
`November 1, 2013
`
`Official Date
`May 1, 2014
`
`First Supplement to the
`USP 37-NF 32
`Second Supplement to the
`USP 37-NF 32
`USP 38-NF 33
`
`February 1, 2014
`
`August l, 2014
`
`lune 1, 2014
`
`December 1, 2014
`
`Official Until
`May 1, 2015 (except as superseded by supplements, IRAs, and
`Revision Bulletins)
`May 1, 2015 (except as superseded by Second Supplement, IRAs,
`and Revision Bulletins)
`May 1, 2015 (except as superseded by IRAs and Revision Bulletins)
`
`November 1, 2014
`
`May 1, 2015
`
`May 1, 2016 (except as superseded by supplements, IRAs, and
`Revision Bulletins)
`
`I he table below gives the details of the IRAs that will apply to USP 31-NF 32.
`
`IRA
`40(1)
`40(2)
`40(3)
`40(4)
`40(5)
`40(6)
`
`Pf Posttna Date
`lanuarv 2 2014
`March 3 2014
`Mav l 2014
`lulv l 2014
`Seotember 2 2014
`November 3 2014
`
`Comment Due Date
`March 31 2014
`Mav 31 2014
`lulv 31 2014
`Seotember 30 2014
`November 30 2014
`lanuarv 31 2015
`
`IRA Postina Date
`Mav 30 2014
`lulv 31 2014
`Seotember 26 2014
`November 26 2014
`lanuarv 30 2015
`March 27 2015
`
`IRA Official Date
`lulv 1 2014
`Seotember 1 2014
`November 1 2014
`lanuarv 1 2015
`March 1 2015
`Mav 1 2015
`
`Revision Bulletins published on the USP website become official on the date specified in the Revision Bulletin.
`
`NOTICE AND WARNING
`
`Concerning U.S. Patent or Trademark Rights-The inclusion in The United States Pharmacopeia or in the National Formulary of a
`monograph on any drU<~ 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
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`
`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 © 2013 The United States Pharmacopeial Convention
`12601 Twinbrook Parkway, Rockville, MD 20852
`
`All rights reserved.
`
`ISSN: 0195-7996
`
`ISBN: 978-1-936424-22-1
`
`Printed in the United States by United Book Press, Inc., Baltimore, MD
`
`'
`
`.
`
`ADAMIS EXHIBIT 1015
`Page 3 of 18
`
`

`

`USP l
`
`' sodium
`md allow
`, shake for
`?asure the
`at the
`42 nm,
`; as the
`so. dis·
`ndard solu
`rine Sufi.lie
`; com·
`·, dissolve
`? the ab(cid:173)
`anner as
`ions.
`ed amoun
`
`require·
`
`25 m9 or
`umetnc
`)I to vol.
`water to
`
`1ts of not
`3tely
`)Ut 25 mg
`flask, and
`n melha(cid:173)
`md filtpr
`ll.
`preparo.
`;-stop-
`3ted SO·
`aperiodate
`stand for
`:>e, shake
`Concom1·
`extracts
`rbance .it
`. using n-
`1, of
`tents
`
`JSP Ephr
`u and A
`Assay
`ely.
`
`>lution
`1. It
`ot more
`t of
`
`or in
`of Type I
`
`Identification -
`A: Mix 1 ml of Injection with 5 ml of alcohol, and evap-
`Jfille on a steam bath with the aid of a current of air to
`.ness: the residue so obtained responds to Identification
`\U under Ephedrine Sulfate.
`B: It responds to the tests for Sulfate (191 ).
`l ade.rial endotoxlns (85}-lt contains not more than 1.7
`USP Endotoxin Units per mg of ephedrine sulfate.
`pH (791 ): between 4.5 and 7.0.
`Other requirements-It meets the requirements under ln(cid:173)
`«11ons (1 ).
`Assay-Transfer an accurately measured volume of lnjec-
`n. equivalent to about 250 mg of ephedrine sulfate, to a
`1eparator, add water, if necessary, to make about 10 ml,
`nd proceed as directed in the Assay under Ephedrine Su/(cid:173)
`ate, beginning with "Saturate the solution."
`
`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)i · HiS04.
`P1<kaging and storage-Preserve in tight, light-resistant
`:ontainers.
`USP Refer ence standards (11 }(cid:173)
`USP Ephedrine Sulfate RS
`ldtntificatlon-lt responds to the Identification tests under
`Ephedrine Sulfate Injection.
`Mlcrobial enumeration tests (61) and Tests for speci(cid:173)
`fied microor ganisms (62}-lt meets the requirements of
`he tests for absence of Staphylococcus aureus and Pseudo(cid:173)
`"OODS oeruginosa.
`Assay-
`Standord preparation-Weigh accurately about 26 m9 of
`JSP Ephedrine Sulfate RS, transfer to a 50-ml volumetric
`llask with the aid of 10 ml of water, add methanol to vol(cid:173)
`ume, and mix. Pipet 5 ml of the resulting solution into a
`100-ml volumetric flask, dilute with water to volume, and
`mix.
`Assay preparation-Transfer an accurately measured vol(cid:173)
`Jme of Nasal Solution, equivalent to about 26 mg of ephe(cid:173)
`anne 5ulfate, to a 50-ml volumetric flask, dilute with a 1 in
`) mixture of water in methanol to volume, and mix. Pipet
`5 ml of the resulting solution into a 100-ml volumetric
`llask, dilute with water to volume, and mix.
`Procedure-Transfer 5-ml portions of the Assay prepara(cid:173)
`tion and the Standard preparation to separate glass-stop(cid:173)
`pered, 50-ml centrifuge tubes. Add 1 ml of saturated so(cid:173)
`dium carbonate solution and 2 ml of sodium metaperiodate
`iolution (1 in 50) to each tube, mix, and allow to stand for
`IOminutes. Pipet 20 ml of n-hexane into each tube, shake
`IOr 30 seconds, and allow the phases to separate. Concomi(cid:173)
`•antly determine the absorbances of the n-hexane extracts
`1n 1-cm cells at the wavelength of maximum absorbance at
`about 242 nm, with a suitable spectrophotometer, using n(cid:173)
`hexane as the blank. Calculate the quantity, in mg, of
`(C1~HuNO)i · HiSO. in each ml of the Nasal Solution taken
`try the formula:
`
`(CI V)(Au I As)
`
`n which Vis the volume, in ml, of Nasal Solution taken, C
`is the concentration, in µg per ml, of USP Ephedrine Sulfate
`
`Official Monographs I Epinephrine 2805
`
`RS in the Standard preparation, and Au and As are the ab(cid:173)
`sorbances of the hexane extracts of the Assay preparation
`and the Standard preparation, 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 •
`[(C10H1sN0)2 · HiS04].
`Packaging and storage-Preserve in tight, light-resistant
`containers, and avoid exposure to excessive heat.
`USP Reference standards (11 )-
`USP Ephedrine Sulfate RS
`Identification, Angular rotation (781A)-Use the 0.1 N sul(cid:173)
`furic acid extract of the chloroform solution obtained as di(cid:173)
`rected for Assay preparation: the angular rotation is levorota(cid:173)
`tory.
`Alcohol content (611): between 2.0% and 4.0% of
`C2HsOH.
`Assay-
`Standard preparation-Dissolve an accurately wei9hed
`quantity of USP Ephedrine Sulfate RS in 0.1 N sulfuric acid
`to obtain a solution having a known concentration of about
`20 µg per ml.
`Assay preparation-Transfer 5 ml 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 carbonate solution (1 in 5). After gas evolution
`has ceased, extract the solution with three 10-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 ephedrine sulfate [(CioHrsNO)z · HiSO.] in the por(cid:173)
`tion of Oral Solution taken by the formula:
`C(Au I As)
`
`in which C is the concentration, in µg per ml, of USP Ephe(cid:173)
`drine Sulfate RS in the Standard preparation; and Au and As
`are the absorbances of the solutions from the Assay prepara(cid:173)
`tion and the Standard preparation, respectively.
`
`Epinephrine
`
`183.20
`C9H13N03
`1,2-Benzenediol, 4-[1-hydroxy-2-(methylamino)ethyl]-, (R)-;
`(-)-3,4-Dihydroxy-cx-[(methylamino)methyl]benzyl alcohol
`[51-43-4J.
`
`DE.FINmON
`Epinephrine contains NlT 97.0% and NMT 100.5% of
`C9H13N03, calculated on the dried basis.
`
`ADAMIS EXHIBIT 1015
`Page 4 of 18
`
`

`

`2806 Epinephrine I Official Monographs
`
`USP 37
`
`USP 37
`
`IDENTIFICATION
`• A. To 5 ml of pH 4.0 acid phthalate buffer (see Reagents,
`Indicators, and Solutions-Buffer Solutions) add 0.5 ml of a
`slightly acid solution of Epinephrine (1 in 1000) and
`1.0 ml of 0.1 N iodine. Mix, and allow to stand for 5
`min. Add 2 ml of sodium thiosulfate solution (1 in 40).
`Acceptance criteria: A deep red color is produced.
`
`ASSAY
`• PROCEDURE
`Sample: 300 mg
`Analysis: Dissolve the Sample in 50 ml of glacial acetic
`acid, warming slightly if needed to dissolve. Add crystal
`violet TS to tne Sample, and titrate with 0.1 N perchlo(cid:173)
`ric acid VS. Perform a blank determination, and make
`any necessary correction. Each ml of 0.1 N perchloric
`acid is equivalent to 18.32 mg of epinephrine
`(C9HnN03).
`Acceptance criteria: 97.0%-100.5% on the dried basis
`
`IMPURITIES
`• RESIDUE ON IGNITION (281): Negligible, from 100 mg
`• LIMIT OF ADRENALONE
`Sample solution: 2 mg/ml of Epinephrine in dilute hy(cid:173)
`drochloric acid (1 in 200)
`Analysis: Determine the absorptivity of the Sample so(cid:173)
`lution at 310 nm (see Spectrophotometry and Light-Scat(cid:173)
`tering (851)).
`Acceptance criteria: NMT 0.2
`• LIMIT OF NOREPINEPHRINE
`Standard stock solution A: 364 mg/ml of USP Epi(cid:173)
`nephrine Bitartrate RS in formic acid
`Standard solution A: 20 mg/ml of epinephrine in
`methanol, from Standard stock solution A
`Standard stock solution B: 16 mg/ml of USP Norepi(cid:173)
`nephrine Bitartrate RS in formic acid
`Standard solution B: 1.6 mg/ml of USP Norepineph(cid:173)
`rine Bitartrate RS in methanol from Standard stock solu(cid:173)
`tion B
`Sample solution: 20 m9/ml of Epinephrine. Dissolve
`200 mg of Epinephrine m 1.0 ml of formic acid, and
`dilute with methanol to 10.0 ml.
`Chromatographic system
`(See Chromatography (621 ), Thin-Layer Chromatogra(cid:173)
`phy.)
`Mode: TLC
`Adsorbent: 0.25-mm layer of chromatographic silica
`gel mixture
`Application volume: 5 µl
`Developing solvent system: n-Butanol, water, and
`formic acid (7:2:1)
`Spray reagent: Folin-Ciocalteu phenol TS
`Analysis
`Samples: Standard solution A, Standard solution 8, and
`Sample solution
`In an unsaturated chamber, develop the plate in the
`Developing solvent system until the solvent front has
`moved three-fourths the length of the plate. Remove
`the plate from the chamber, mark the solvent front,
`and allow the solvent to evaporate in warm circulat(cid:173)
`ing air. Spray with Spray reagent, followed by sodium
`carbonate solution (1 in 10).
`Acceptance criteria: The RF value of the principal spot
`from the Sample solution corresponds to that of Stan(cid:173)
`dard solution A. Any spot from the Sample solution is
`not larger or more intense than the spot with the same
`RF value from Standard solution 8, corresponding to
`NMT 4.0% norepinephrine.
`
`SPECIFIC TESTS
`• OPTICAL ROTATION, Specific Rotation (781 S): -50.0° to
`- 54.0°
`Sample solution: 20 mg/ml, in 0.6 N hydrochloric acid
`• Loss ON DRYING (731): Dry it in a vacuum over silica gel
`for 18 h: It loses NMT 2.0% of its weight.
`
`ADDITIONAL REQUIREMENTS
`• PACKAGING AND STORAGE: Preserve in tight, light-resistan
`containers.
`• USP REFERENCE STANDARDS (1 1)
`USP Epinephrine Bitartrate RS
`USP Norepinephrine Bitartrate RS
`
`Epinephrine Inhalation Aerosol
`
`» Epinephrine Inhalation Aerosol is a solution of
`Epinephrine in propellants and Alcohol prepared
`with the aid of mineral acid in a pressurized con·
`tainer. It contains not less than 90.0 percent and
`not more than 115.0 percent of the labeled
`amount of epinephrine (C9Hn N03).
`Packaging and storage-Preserve in small, nonreactive,
`light-resistant aerosol containers equipped with metered
`dose valves and provided with oral inhalation actuators
`USP Reference standards (11 )-
`USP Epinephrine Bitartrate RS
`Identification-Place 10 ml of water in a small beaker,
`and deliver 2 sprays from the Inhalation Aerosol under the
`surface of the water, actuating the valve by pressing the Up
`against the bottom of the beaker. To 5 ml of the solution
`add 1 drop of dilute sulfuric acid (1 in 200), add 0.5 ml ol
`0.1 N iodine, allow to stand for 5 minutes, and add 1 ml d
`0.1 N sodium thiosulfate: a red-brown color is produced
`Delivered dose uniformity over the entire contents
`meets the requirements for Metered-Dose Inhalers under
`Aerosols, Nasal Sprays, Metered-Dose Inhalers, and Dry /IQ'.'.
`Inhalers (601 }.
`PROCEDURE FOR DOSE UNIFORMITY-
`Ferro-citrate solution and Buffer solution-Prepare as d1·
`rected under Epinephrine Assay (391 ).
`Standard preparation-Dissolve an accurately weighed
`quantity of USP Epinephrine Bitartrate RS in a freshly pre
`pared sodium bisulfite solution (1 in 500), and dilute quan(cid:173)
`titatively and stepwise with the same sodium bisulrite solu
`tion as necessary to obtain a solution having a known
`concentration of about 18 µg per ml.
`Test preparation-Discharge the minimum recommended
`dose into the sampling apparatus and detach the inhaler J
`directed. Rinse the apparatus (filter and interior) with tour
`5.0-ml portions of a freshly prepared sodium bisullite solu(cid:173)
`tion (1 in 500), and transfer the resulting solutions quant
`tively to a 50-ml centrifuge tube. Add 10 ml of chloroform
`insert the stopper, shake vigorously for 1 minute, and centn
`fuge for 5 minutes. Use the clear supernatant as directed
`the Procedure.
`Procedure-4nto three separate flasks, transfer the Ttll
`preparation, 20.0 ml of the Standard preparation, and
`20.0 ml of water to provide the blank. To each flask add
`100 µl of Ferro-citrate solution and 1.0 ml of Buffer solut
`and mix. Concomitantly determine the absorbances with 1
`suitable spectrophotometer, in 5-cm cells, of the solution
`from the Test preparation and the Standard preporatton, a
`the wavelength of maximum absorbance at about 530
`against the blank. Calculate the quantity, in µg, of
`C9H13N03 contained in the minimum dose taken by the
`formula:
`
`(183.20 I 333.29)(20CN)(Au I Ai)
`
`in which C is the concentration, in µg per ml, or USP Ep
`nephrine Bitartrate RS in the Standard preparation; N 1s the
`number of sprays discharged to obtain the minimum r
`ommended dose; 183.20 and 333.29 are the rncle1.ul •r
`
`.,,
`
`19hts of
`wefy; and
`!rom the Ti
`1pect1vely.
`Auay-W1
`below -30'
`e lnhalati
`o expel th
`1dues in
`parator VI
`Cid (1 in 1
`portions of
`nder Epim
`topper anc
`lead of 5.C
`ecific rot<
`e1gh therr
`Aerosol. Ca
`1halation /.
`
`Eplneph
`
`Ep1neph1
`nephrine i
`d of Hyd
`contains
`ore than
`I epinept-
`P1ckaglng ,
`dose, lig~
`m.
`ubellng-T
`ed if its col
`contains a
`USP Referer
`P Endotoxi
`IP Ep1nephr
`Color and cl
`Standards
`a 500-ml •
`lld mix.
`Procedure(cid:173)
`/ solution)
`e backgrc
`te If an)
`omitantl)
`and the 5
`lrophotor
`solution d
`Wentlflcatlo
`A". It respor
`I Solution
`B The rete
`m of the A
`matograrr
`Assay.
`llcterlal enc
`.0 USP Enc
`
`ADAMIS EXHIBIT 1015
`Page 5 of 18
`
`

`

`JSP 37
`
`USP 37
`
`Official Monographs I Epinephrine 2807
`
`sistant
`
`1 of
`a red
`con(cid:173)
`and
`
`:tive,
`ed(cid:173)
`·s.
`
`:er,
`- the
`he tip
`ti on
`nl of
`ml of
`ed.
`mts:
`::!r
`Powder
`
`di-
`
`ed
`>re(cid:173)
`~uan­
`solu-
`
`!nded
`ler as
`'our
`solu(cid:173)
`mtita(cid:173)
`>form,
`centri(cid:173)
`ed in
`
`·st
`
`jd
`1tion,
`ith a
`ons
`• at
`nm,
`
`e
`
`Epi(cid:173)
`the
`ec-
`
`weights of epinephrine and epinephrine bitartrate, respec(cid:173)
`tivefy; and Au and As are the absorbances of the solutions
`from the Test preparation and the Standard preparation, re(cid:173)
`spectively.
`Assay-Weigh the Inhalation Aerosol, chill to a temperature
`below -30°, remove the valve by suitable means, and allow
`the Inhalation Aerosol to warm slowly to room temperature
`to expel the more volatile propellant fractions. Transfer the
`residues in the aerosol container and valve to a 125-ml
`separator with the aid of six 5-ml portions of dilute sulfuric
`acid (1 in 1000), and extract the solution with three 25-ml
`portions of chloroform. Proceed as directed in the Assay
`under Epinephrine Nasal Solution, beginning with "Rinse the
`stopper and mouth of the separator, /1 but use 10.0 ml in(cid:173)
`stead of 5.0 ml of chloroform in the determination of the
`specific rotation. Dry the empty aerosol container and valve,
`weigh them, and determine the net weight of the Inhalation
`Aerosol. Calculate the quantity, in mg, or C9HnN03 in the
`Inhalation Aerosol taken by the formula:
`(183.20 I 309.32)(VV)(0.5 + 0.5R I 93)
`
`In which 183.20 and 309.32 are the molecular weights of
`epinephrine and triacetylepinephrine, respectively, and W is
`the weight, in mg, and R 1s the specific rotation (in degrees,
`without regard to the sign), of the isolated triacetyfepineph(cid:173)
`rine.
`
`Epinephrine lniection
`• Epinephrine Injection is a sterile solution of Epi(cid:173)
`nephrine in Water for Injection prepared with the
`aid of Hydrochloric Acid or other suitable buffers.
`It contains not less than 90.0 percent and not
`more than 115.0 percent of the labeled amount
`of epinephrine (C9HnN03).
`Packagin~ and storage-Preserve In single-dose or multi(cid:173)
`ple-dose, light-resistant containers, preferaoly of Type I
`glass.
`Labeling-The label indicates that the fnj"ection is not to be
`used if its color is pinkish or darker than s ightly yellow or if
`It contains a precipitate.
`USP Reference standards (11 )(cid:173)
`USP Endotoxin RS
`USP Epinephrine Bitarlrate 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-Visually examine a portion of the Injection
`(Test solution) in a suitable clear glass test tube against a
`white background: it is not pinkish and it contains no pre(cid:173)
`cipitate. If any yellow color 1s observed in the Test solution,
`concomitantly determine the absorbances of the Test solu(cid:173)
`tion and the Standard solution in 1-cm cells with a suitable
`spectrophotometer set at 460 nm: the absorbance of the
`Te5t solution does not exceed that of the Standard solution.
`Identification-
`A: It responds to the Identification test under Epinephrine
`Nasal Solution.
`B: The retention time of the major peak in the chromato(cid:173)
`gram of the Assar preparation corresponds to that in the
`chromatogram o the Standard preparation, as obtained in
`Lhe Assay.
`Bacterlal endotoxins (85)-lt 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 correction. Not more than 25.0 ml of
`0.01 N sodium hydroxide is required.
`Other requirements-ft meets the requirements under In(cid:173)
`jections (1 } .
`Assay-
`Mobile phase-To 1 L of 0.05 M monobasic sodium phos(cid:173)
`phate add about 519 mg of sodium 1-octanesulfonate and
`about 45 mg of edetate disodium, and mix. Adjust by the
`dropwise addition of phosphoric acid, if necessary, to a pH
`of 3.8. Mix 85 volumes of this solution with 15 volumes of
`methanol. Make adjustments if necessary (see System Suita(cid:173)
`bility under Chromatography (621 )).
`Standard preparation-Dissolve an accurately weighed
`quantity of USP Epinephrine Bitartrate RS in Mobile phase,
`and dilute quantitatively, and stepwise if necessary, with
`Mobile phase to obtain a solution having a known concen(cid:173)
`tration of about 0.1 mg of epinephrine per ml.
`Assay preparation-Transfer an accurately measured vol(cid:173)
`ume of Injection, equivalent to about 1 mg of epinephrine,
`to a 10-ml volumetric flask, dilute with Mobile phase to vol(cid:173)
`ume, and mix.
`System suitability preparation-Dissolve 10 mg of dopa(cid:173)
`mine hydrochloride in 100 ml of the Standard preparation,
`and mix.
`Chromatographic system (see Chromatography (621 })-The
`liquid 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 minute. Chromatograph the
`Standard preparation and the System suitability preparation,
`and record the peak responses as directed for Procedure: the
`relative retention times are about 1.0 for epinephrine and
`2.0 for dopamine hydrochloride; the resolution, R, between
`epinephrine and dopamine hydrochloride is not less than
`3.5; and the relative standard deviation for replicate injec(cid:173)
`tions is not more than 2.0%.
`Procedure- Separately inject equal volumes (about 20 µl)
`of the Standard preparation and the Assay preparation into
`the chromatograph, record the chromatograms, and meas(cid:173)
`ure the responses for the major peaks. Calculate the quan(cid:173)
`tity, in mg, of epinephrine (C9Hu N01) in each ml of the
`Injection taken by the formula:
`(183.20/333.29)(1 O)(C/V)(ru I rs)
`
`in which 183.20 and 333.29 are the molecular weights of
`epinephrine and epinephrine bitartrate, respectively; C is the
`concentration, in mg per ml, of USP Epinephrine Bitartrate
`RS in the Standard preparation; Vis the volume, in ml , of
`Injection taken; and ru and rs are the peak responses ob(cid:173)
`tained from the Assay preparation and the Standard prepara(cid:173)
`tion, respectively.
`
`Epinephrine Inhalation Solution
`» Epinephrine Inhalation Solution is a sterile solu(cid:173)
`tion of Epinephrine in Purified Water prepared
`with the aid of Hydrochloric Acid. It contains, in
`each 100 ml, not less than 0.9 g and not more
`than 1 .1 5 g of C9HnN03.
`Packaging and storage-Preserve in small, well-filled,
`tight, light-resistant containers.
`
`I
`
`VJ
`I
`
`t I
`
`I
`l
`
`I
`
`ADAMIS EXHIBIT 1015
`Page 6 of 18
`
`

`

`2808 Epinephrine I Official Monographs
`
`USP 37
`
`USP 37
`
`Jter-washE
`IN hydrc
`'he separate
`ashed ethE
`ind elute th
`j{t n the se
`01J1acid layt
`500-ml volu
`SO-ml portic
`1queous ext1
`'ldrochloric
`Procedure·
`he Assay pn
`avelength 1
`11uitable sp•
`11 the blank.
`1ach ml oft
`
`irwhich C is
`ne in the St
`Ophthalmic ~
`rbances of
`tion, respec
`
`Labeling-The label indicates that the Inhalation Solution is
`not to be used if its color is pinkish or darker than slightly
`yellow or if it contains a precipitate.
`Color and clarity-Using the Inhalation Solution as the
`Test solution, proceed as directed for Color and clarity under
`Epinephrine Injection.
`Identification-It meets the requirements for the Identifi(cid:173)
`cation test under Epinephrine Nosal Solution.
`Sterility (71 ): meets the requirements.
`Assay-Pipet 10 ml of Inhalation Solution into a 125-ml
`separator, and extract the solution with two 10-ml portions
`of chloroform. Proceed as directed in the Assay under Epi(cid:173)
`nephrine Nosal Solution, beginning with "Rinse the stopper
`and mouth of the separator," but use for the acetylation
`1 .05 g of sodium bicarbonate and 0.50 ml of acetic anhy(cid:173)
`dride, and extract the acetylated product with six 15-ml
`portions of chloroform instead of the 25-ml portions speci(cid:173)
`fied therein, and use 15.0 ml of chloroform instead of
`5.0 ml in the determination of the specific rotation.
`
`by means of small portions of chloroform to a tared 50-ml
`beaker, and heat again to evaporate the solvent complet
`Heat further at 105° for 30 minutes, cool in a desiccator.
`and weigh the residue of triacetylepinephrine. Add 5.0 ml
`of chloroform, cover the beaker, gently swirl the contents
`until the residue has completely dissolved, and determine
`the specific rotation, R, using a 200-mm semimicro polanm(cid:173)
`eter tube.
`Calculate the quantity, in mg, of C9HnN03 in the volome
`of Nasal Solution taken by the formula:
`(183.20/309.32)(W)(0.5 + 0.5R I 93)
`
`in which 183.20 and 309.32 are the molecular weight.s of
`epinephrine and triacetylepinephrine, respectively; and W1
`the weight, in mg, and R is the specific rotation (in degrm,
`without re~ard to the sign), of the isolated
`triacetylep1nephrine.
`
`Epinephrine Nasal Solution
`» Epinephrine Nasal Solution is a solution of Epi(cid:173)
`nephrine in Purified Water prepared with the aid
`of Hydrochloric Acid. It contains, in each 100 ml,
`not less than 90 mg and not more than 115 mg
`of (9H 13N03.
`Packa9lng and storage-Preserve in small, well-filled,
`tight, light-resistant containers.
`Labeling-The label indicates that the Nasal Solution is not
`to be used if its color is pinkish or darker than slightly yel(cid:173)
`low or if it contains a precipitate.
`Color and clarity-Using the Nasal Solution as the Test
`solution, proceed as directed for Color and clarity under Epi(cid:173)
`nephrine Injection.
`Identification-To 5 ml of pH 4.0 acid phthalate buffer
`(see Buffer Solutions in the section Reagents, Indicators, and
`Solutions) add 0.5 ml of Nasal Solution and 1.0 ml of 0.1 N
`iodine. Mix, and allow to stand for 5 minutes. Add 2 ml of
`sodium thiosulfate solution (1 in 40): a deep red color is
`produced.
`Assay-Pipet 30 ml of Nasal Solution into a 125-ml
`separator, add 25 ml of chloroform, shake vigorously for
`1 minute, allow the liquids to separate, and discard the
`chloroform. Wash twice more with chloroform, separating
`and discarding the lower layer as completely as possible
`each time. Rinse the stopper and mouth of the separator
`with a few drops of water. Add 0.2 ml of starch TS, then
`while swirling the separator add iodine and potassium io(cid:173)
`dide TS 1 dropwise until the blue color formed persists, and
`immediately add just sufficient 0.1 N sodium th1osulfate to
`dischar9ic the blue color. [NOTE-Proceed with the assay
`from this point without delay.]
`Add to the liquid in the separator 2.10 g of sodium bicar(cid:173)
`bonate, preventing it from coming in contact with the
`mouth of the separator, and swirl until most of the bicarbo(cid:173)
`nate has dissolved. By means of a 1-ml syringe that is not
`fitted with a needle, rapidly inject 1.0 ml of acetic anhy(cid:173)
`dride directly into the contents of the separator. Immedi(cid:173)
`ately insert the stopper in the separator, and shake vigor(cid:173)
`ously until the evolution of carbon dioxide has ceased (7 to
`10 minutes), releasing the pressure as necessary through the
`stopcock. Allow to stand for 5 minutes, and extract the solu(cid:173)
`tion with six 25-ml portions of chloroform, filtering each
`extract through a small pledget of cotton, previously
`washed with chloroform, into a beaker.
`Evaporate the combined chloroform extracts on a steam
`bath in a current of air to about 3 ml, transfer the residue
`
`Epinephrine Ophthalmic Solution
`» Epinephrine Ophthalmic Solution is a sterile,
`aqueous solution of Epinephrine prepared with
`the aid of Hydrochloric Acid. It contains not less
`than 90.0 percent and not more than 115.0 per
`cent of the labeled amount of (9HnN03. It con
`tains a suitable antibacterial agent and may con
`tain an anti-oxidant, suitable buffers, and
`chelating and tonicity-adjusting agents.
`Packaging and storage-Preserve in tight, lighl-res1sta
`containers.
`Labeling-The label indicates that the Ophthalmic Soluti
`is not to be used if its color is pinkish or darker than shg
`yellow or if it contains a precipitate.
`USP Reference standards (11 )-
`USP Epinephrine Bitartrate RS
`Color and clarity-Using the Ophthalmic Solution as the
`Test solution, proceed as directed for Color and clarity under
`Epinephrine Injection.
`Identification-
`A: The UV absorption spectrum of the Assay preparal
`prepared as directed in the Assay exhibits maxima and m
`rma at the same wavelengths as that of a similar solution
`USP Epinephrine Bitartrate RS.
`B: A solution (1 in 2) is levorotatory.
`Sterility (71 ): meets the requirements.
`pH (791 ):
`between 2.2 and 4.5.
`Assay-
`pH 5.8 Buffer-Mix 1 volume of 1 M dibasic potassu
`phosphate with 9 volumes of 1 M monobasic potassium
`phosphate. Adjust by the addition of small volumes of
`solution to a pH of 5.80 ± 0.05.
`Standard preparation-Dissolve a suitable quantity of
`Epinephrine Bitartrate RS, accurately weighed, in 0.1 N
`drochloric acid to obtain a solution having a known c
`tration of about 40 µg of epinephrine per ml.
`Assay preparation-Transfer an accurately measured
`ume of Ophthalmic Solution, equivalent to about 20 mg
`epinephrine, to a 250-ml beaker containing 2.0 ml of
`5.8 Buffer. Add 9 g of chromatographic siliceous earth,
`mix. Carefully transfer the mixture to a 45- x 2.2-cm ch
`matographic tube containing a pledget of glass wool di
`bottom, and tap the column gently to effect packing D
`wash the beaker with about 1 g of chromatographic 111
`ceous earth, add to the column, and plug the top v·1t
`pledget of glass wool. Wash the column with 100 ml of
`
`ADAMIS EXHIBIT 1015
`Page 7 of 18
`
`

`

`USP 37
`
`USP 37
`
`Official Monographs I Epinephrine 2809
`
`I 50-ml
`npletely.
`:ator,
`5.0ml
`ntents
`rmine
`polarim-
`
`volume
`
`1hts of
`nd WIS
`degrees,
`
`·rile,
`with
`)t less
`.0 per(cid:173)
`t con(cid:173)
`y con-
`
`esistant
`
`Solution
`1 slightly
`
`as the
`y under
`
`oration
`nd min(cid:173)
`..1tion of
`
`ssium
`:ium
`of either
`
`'of USP
`N hy(cid:173)
`concen·
`
`~d vol·
`>mg of
`of pH
`:h, and
`l chro·
`11 at the
`~·Dry·
`sili-
`1ith a
`l of
`
`water-washed ether, and discard the eluant. Add 10.0 ml of
`0.1 N hydrochloric acid to a 125-ml separator, and flace
`the separator under the column. To about 100 ml o water(cid:173)
`washed ether add 1 ml of bis(2-ethylhexyl) phosphoric acid,
`and elute the column with this solution, collecting the elu(cid:173)
`ate in the separator. Extract the epinephrine into the aque(cid:173)
`ous acid layer, and carefully transfer the aqueous layer to a
`500-ml volumetric flask. Shake the ether layer with two
`50-ml portions of 0.1 N hydrochloric acid, add the acidic
`aqueous extracts to the volumetric flask, dilute with 0.1 N
`hydrochloric acid to volume, and mix.
`Procedure-Concomitantly determine the absorbances of
`the Assay preparation and the Standard preparation at the
`wavelength of maximum absorbance at about 280 nm, with
`a suitable spectrophotometer, using 0.1 N hydrochloric acid
`as the blank. Calculate the quantity, in mg, of C9H13N03 in
`each ml of the Ophthalmic Solution taken by the formula:
`0.5(C I \!)(Av I As)
`
`in which C is the concentration, in µg per ml, of epineph(cid:173)
`rine in the Standard preparation; V is the volume, in ml, of
`Ophthalmic Solution taken; and Au and As are the ab(cid:173)
`sorbances of the Assay preparation and the Standard prepa(cid:173)
`ration, respectively.
`
`Epinephrine Bitartrate
`(9HnN03 · C1H606 333.29
`1,2-Benzenediol, 4-[1-hydroxy-2-(methylamino)ethyl]-, (R)-,
`[R·(R*,R*)]-2,3-dihydroxybutanedioate (1 :1) (salt).
`(-)-3,4-Dihydroxy-a-[(methylamino)methyl]benzyl alcohol
`(+)·tartrate (1 :1) salt
`[51-42-3).
`1> Epinephrine Bitartrate con