=i ee
`
`The Official Compendia of Standards
`
`i bee oo
`NF
`
`Page A
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`SY U.S. PHARMACOPEIA
`U (@) The Standard ofQuality™
`
`ADAMIS EXHIBIT 1013
`Page A
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`ADAMIS EXHIBIT 1013
`
`

`

`2004
`
`USP 27
`
`NF 22
`
`THE UNITED STATES PHARMACOPEIA
`
`THE NATIONAL FORMULARY
`
`By authority of the United States Pharmacopeial
`Convention, Inc., meeting at Washington, D. C.,
`April 12- 16, 2000. Prepared by the Council of Experts
`and published by the Board of Trustees
`
`Official from January 1, 2004
`
`The designation on the cover of this publication, "USP NF
`2004," is for ease of identification only. The publication
`contains two separate compendia: The Pharmacopeia of the
`United States Twenty-seventh Revision, and the National
`Formulary, Twenty-second Edition.
`
`UNITED STATES PHARM.ACOPEIAL CONVENTION, INC.
`12601 Twinbrook Parkway, Rockville, MD 20852
`
`(
`
`Page B
`
`ADAMIS EXHIBIT 1013
`
`

`

`NOTICE AND WARNING
`
`Concerning U.S. Patent or Trademark Rights
`
`The inclusion i.n the Phannacopeia 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
`
`Use of the USP-NF is subject to the terms and conditions of the USP- NF License Agreement. Attention
`is called to the fact that USP and 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 ~ 2003 The United States Pharmacopeial Convention, Inc.
`1260 I Twinbrook Parkway, Rockville, MD 20852
`All rights reserved.
`ISSN 0195-7996
`ISBN 1-889788-19-8
`Printed in Canada by Webcom Limited, Toronto, Ontario
`
`'
`
`Page C
`
`ADAMIS EXHIBIT 1013
`
`

`

`710
`
`Epinephrine / Official Monographs
`
`USP27
`
`separator. Extract the chlorofonn 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 I 00.0 mL.
`Procedure-Proceed as directed for Procedure in the Assay under
`Ephedrine Sulfate Capsules. Calculate the quantity, in mg, of
`(C10HuN0)2 · H2S04 in the portion of Syrup taken by the fonnula:
`C(AulAs).
`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
`absorbances of the solutions from the Assay preparation and the
`Standard preparation, respectively.
`
`solution. Any spot obtained from the Test solution is not larger nor
`more intense than the spot with the same R1 value obtained from the
`Norepinephrine standard solution, corresponding to not more than
`4.0% of norepinephrine.
`Assay-Dissolve about 300 mg of Epinephrine, accurately weighed,
`in 50 mL of glacial acetic acid TS, wanning slightly if necessary lo
`effect solution. Add crystal violet TS, and titrate with 0.1 N percbloric
`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 C9H1>N03.
`
`Epinephrine
`
`C9H13N0 1 183.20
`1,2-Benzenediol, 4-[1-hydroxy-2-(methylamino)ethyl]-, (R)-.
`(-)-3,4-Dihydroxy-a-[(methylamino)methyl]benzyl alcohol
`[51-43-4].
`
`»Epinephrine contains not less than 97.0 percent and not
`more than 100.5 percent of C9H 13N03, calculated on the
`dried basis.
`
`Packaging and storage-Preserve in tight, I ight-resistant 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 the section Reagents, indicators, and Sollltions) add 0.5
`mL of a slightly acid solution of Epinephrine ( l in 1000) and 1.0 mL
`ofO.l 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 J 00 mg.
`Limit of adrenalone--Its absorptivity (see Spectrophotometry and
`Light-Scattering (851)) at 310 nm, determined in a solution in dilute
`hydrochloric acid {I in 200) containing2 mg per mL, is not more than
`0.2.
`Limit of norepinephrine--
`Epinephrine standard solution-Dilute with methanol an ac(cid:173)
`curately measured volume of a solution of USP Epinephrine
`Bitartrate RS in foanic acid containing about 364 mg per mL to
`obtain a solution having a concentration of about 20 mg per mL.
`Norepinephri11e standard solution-Dilute with methanol an
`accurately dleasured volume of a solution of USP Norepinepbrine
`Bitartrate RS in foonic acid containing 16 mg per mL to obtain a
`solution having a known concentration of 1.6 mg per mL.
`Test solution- Dissolve 200 mg of Epinephrine in 1.0 mL of
`formic acid, and dilute with methanol to I 0.0 mL, and mix.
`Procedure-Apply 5-µL portions of Epinephrine standard
`sol11tio11, Norepinephrine standard solution, and Test sol11tion to a
`suitable thin-layer chromatographic plate (see Chromatography
`( 621)) coated with a 0.25-mm layer of chromatographic silica gel
`mixture. Allow the spots to dry, and develop the chromatogram in an
`unsaturated tank using a solvent system consisting of a mixture of
`11-butano~ water, and formic acid (7: 2: 1) until the solvent front has
`moved about three-fourths of the length of the plate. Remove the
`plate from the developing chamber, mark the solvent front, and allow
`the solvent to evaporate in warm circulating air. Spray with
`Folin-Ciocalteu Phenol TS, followed by sodiwn carbonate solution
`(I in I 0): the R1 value of the principal spot obtained from the Test
`sol11tion corresponds to that obtained from the Epinephrine standard
`
`'
`
`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 container. It
`contains not less than 90.0 percent and not more than
`115.0 percent of the labeled amount of epinephrine
`(C~nN03).
`
`Packaging and storage- Pteserve in small, nonreactive, lig·
`ht-resistant aerosol containers equipped with metered-dose valves
`and provided with oral inhalation actuators.
`USP Reference standards (11)- USP Epinephrine Bitartrate RS.
`Identification- Place I 0 mL of water in a small beaker, and deliver2
`sprays from the Inhalation Aerosol under the surface of the water,
`actuating the valve by pressing the tip against the bottom of Llie
`beaker. To 5 mL of the solution add I drop of dilute sulfuric acid (1 in
`200), add 0.5 mL of 0.1 N iodine, allow to stand for 5 minutes, and
`add 1 mL ofO. l N sodium thiosulfate: a red-brown color is produced
`DeUvered dose uniformity over the entire contents: meets the
`requirements for Metered-Dose Inhalers under Aerosols,
`Metered-Dose Inhalers, and Dry Powder Inhalers (601 ).
`PROCEDUREFORDOSEUNIFORMITY-
`Fen·o-citrate solution and Buffer solution-Prepare as directed
`under Epinephrine Assay (391}.
`Standard preparation- Dissolve an accurately weighed quantity of
`USP Epinephrine Bitartrate RS in a freshly prepared sodium bisulfite
`solution {I in 500), and dilute quantitatively and stepwise with the
`same sodium bisulfite solution 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 as directed. Rinse
`the apparatus (filter and interior) with four 5.0-mL portions of a
`freshly prepared sodium bisulfite solution (1 in 500), and transfer tbe
`resulting solutions quantitatively to a 50-mL centrifuge tube. Add 10
`mL of chloroform, insert the stopper, shake vigorously for l minute.
`and centrifuge for 5 minutes. Use the clear supernatant as directed in
`the Procedure.
`Procedure-Into three separate flasks, transfer the Test preparation.
`20.0 mL of the Standard preparation, and 20.0 mL of water to
`
`provide the blank. To each Bask add 100 µL of Ferro-citrate solution I
`blank. Calculate the quantity, in µg, of C9HnN01 contained in the I
`
`and 1.0 mL of Buffer solution, and mix. Concomitantly determine the
`absorbances with a suitable spectrophotometer, in 5-cm cells, of the
`solutions from the Test preparation and the Standard preparation, al
`the wavelength of maximum absorbance at about 530 nm, against the
`
`minimum dose taken by the formula:
`(183.20 / 333.29)(20CN)(Aul As),
`in which C is the concentration, in µg per mL, of USP Epinepbrint
`Bitartrate RS in the Standard preparation; N is the number of spra~
`discharged to obtain the minimum recommended dose; I 83.20 and
`333.29 are the molecular weights of epinephrine and epinephrine
`bitartrate, respectively; and Au and As are the absorbances of Ilic
`solutions from the Test preparation and the Standard preparatio~
`respectively.
`Assay- Weigh the Inhalation Aerosol, chill to a temperature belo11
`- 30°, remove the valve by suitable means, and allow the Inhalatioo
`Aerosol to wann slowly to room temperature to expel the mort
`volatile propellant fractions. Transfer the residues in the aero~
`
`ADAMIS EXHIBIT 1013
`
`Page 710
`
`

`

`USP 27
`
`Official Monographs / Epinephrine
`
`711
`
`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," but use 10.0 mL instead of 5.0
`mL of chloroform in the determination of the specific rotation. Dry
`lheempty aerosol container and valve, weigh them, and determine the
`net weight of the Inhalation Aerosol. Calculate the quantity, in mg, of
`Ciff13N03 in the Inhalation Aerosol taken by the formula:
`(183.20 / 309.32)(W)(0.5 + 0.5R/93),
`in which 183.20 and 309.32 are the molecular weights of epinephrine
`and triacetylepinephrine, respectively, and Wis the weight, in mg, and
`R is lhe specific rotation (in degrees, without regard to the sign), of the
`isolated triacetylepinephrine.
`
`Epinephrine Injection
`
`» Epinephrine Injection is a sterile solution of Epineph(cid:173)
`rine 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 C9H13N03.
`Packaging and storage-Preserve in single-dose or in multi(cid:173)
`ple-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 Epinephrine Bitartrate RS.
`USP Endotoxin RS.
`Color and clarity-
`Sta11dard solution-Transfer 2.0 mL of O.lOON iodine VS to a
`500-mL volumetric fl.ask, 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 precipitate. If any
`the Test solution, concomitantly
`yellow color is observed in
`determine the absorbances of the Test solution and the Standard
`solution in I-cm cells with a suitable spectrophotometer set at 460
`nm: the absorbance of the Test solution does not exceed that of the
`Standard solution.
`It responds to the Identification test under Epineph(cid:173)
`Jdentification-
`rine Nasal Solution.
`It contains not more than 357.0 USP
`Bocterinl endotoxins (85}
`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 0.0 1 N sodium hydroxide VS to apH of7.40.
`Perform a blank determination, and make any necessary correction.
`Not more than 25.0 mL of O.Dl N sodium hydroxide is required.
`Other requirements- It meets the requirements under Injections
`{I).
`Assay-
`Mobile phase-To l liter of 0.05 M monobasic sodium phosphate
`add about 519 mg of sodium l-octanesulfonate and about 45 mg of
`edetate disodium, and mix. Adjust by the dropwise addition of
`phosphoric acid, if necessary, to a pH of3.8. Mix 85 volumes of this
`solution with 15 volumes of methanol. Make adjustments if necessary
`(see System Suitability under Chromatography (62 1)).
`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 concentration of about 0.1 mg of
`epinephrine per mL.
`Assay preparation- Transfer an accurately measured volume of
`Injection, equivalent to about l mg of epinephrine, to a 10-mL
`vollllnetric flask, dilute with Mobile phase to volume, and mix.
`System suitability preparation-Dissolve 10 mg of dopamine
`hydrochloride in 100 mL of the Standard preparation, and mix.
`
`Chromatographic system (see Chromatog~aphy (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 fl.ow rate is
`about 2 mL per minute. Chromatograph the Standard preparation
`and the System suitability preparation, and record the peak responses
`as directed under Procedure: the resolution, R, between the
`epinephrine and dopamine hydrochloride peaks is not less than 3.5,
`and the relative standard deviation for replicate injections 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 measure the
`responses for the major peaks. The relative rete9tion times are
`about 1.0 for epinephrine and 2.0 for dopamine hydrochloride.
`Calculate the quantity, in mg, ofC~13N03 in each mL of the Injection
`taken by the fonnula:
`
`'(cid:173)
`
`(183.20 /333.29)(10)(C/ V)(rul 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
`r5 are the peak responses obtained from the Assay preparation and the
`Standard preparation, respectively.
`
`Epinephrine Inhalation Solution
`
`» Epinephrine Inhalation Solution is a sterile solution 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 1.15 g of C9H 13N03.
`Packaging and storage-Preserve in small, well-filled, tight,
`light-resistant containers.
`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 Identification test
`under Epinephrine Nasal Solution.
`Sterility (71): meets the requirements.
`Assay- Pipet 10 mL of Inhalation Solution into a 125-mL separator,
`and extract the solution with two 1 O·mL portions of chloroform.
`Proceed as directed in the Assay under Epinephrine Nasal Solution,
`beginning w ith "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 anhydride, and extract the acetylated product with six 15-mL
`portions of chloroform instead of the 25-mL portions specified
`therein, and use 15.0 mL of chloroform instead of 5.0 mL in the
`determination of the specific rotation.
`
`Epinephrine Nasal Solution
`
`» Epinephrine Nasal Solution is a solution of Epineph(cid:173)
`rine 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 ofC9H13N03•
`Packaging 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 yellow or if it
`contains a precipitate.
`
`ADAMIS EXHIBIT 1013
`
`Page 711
`
`

`

`712
`
`Epinephrine / Official Monographs
`
`USP 27
`
`Color and clarity-Using the Nasal Solution as the Test so/utio11,
`proceed as directed for Color and clarity under Epinephrine
`Injection.
`Identification-To 5 mL of pH 4.0 acid phthalate buffer (see Buffer
`Solutions in the section Reagents, Indicators, and SolutiDns) add 0.5
`mL of Nasal Solution and 1.0 mL ofO.l N iodIDe. Mix, and allow to
`stand for 5 minutes. Add 2 mL of sodium thiosulfate solution (l 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 l 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 iodide TS dropwise
`until the blue color formed persists, and immediately add just
`sufficient 0.1 N sodium thiosulfate to discharge 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 bicarbonate,
`preventing it from coming in contact with the mouth of the separator,
`and swirl until most of the bicarbonate has dissolved. By means of a
`1-mL syringe that is not fitted with a needle, rapidly inject 1.0 mL of
`acetic anhydride directly into the contents of the separator.
`Immediately insert the stopper in the separator, and shake vigorously
`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 solution 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 by means of small
`portions of chloroform to a tared 50-mL beaker, and heat again to
`evaporate the solvent completely. 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-mrn semimicro polarimeter rube.
`Calculate the quantity, in mg, of C9HuN01 in the volume of Nasal
`Solution taken by the formula:
`(183.20/309.32XW)(0.5 + O.SR/93),
`in which 183.20 and 309.32 are the molecular weights of epinephrine
`and triacetylepinephrine, respectively; and Wis the weight, in mg,
`and R is the specific rotation (in degrees, without regard to the sign),
`of the isolated triacetylepinepbrine.
`
`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 percent of the labeled amount of
`C9H13N03. It contains a suitable antibacterial agent and
`, may contain an anti-oxidant, suitable buffers, and
`chelating and tonicity-adjusting agents.
`
`Packaging and storage-Preserve in tight, light-resistant containers.
`Labeling- The label indicates that the Ophthalmic Solution 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 Epinephrine Bitartrate RS.
`Color and clarity- Using the Ophthalmic Solution as the Test
`solution, proceed as directed for Color and clarity under Epinephrine
`Injection.
`ldentification-
`A: The UV absorption spectrum of the Assay preparation
`prepared as directed in the Assay exhibits maxima and minima at
`the same wavelengths as that of a similar solution of USP
`Epinephrine Bitartrate RS.
`B: A solution (I 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 potassium phosphate
`with 9 volumes of 1 M monobasic potassium phosphate. Adjust by
`the addition of small volumes of either solution to a pH of 5.80 ±
`0.05.
`Standard preparation-Dissolve a suitable quantity of USP
`Epinephrine Bitartrate RS, accurately weighed, in 0.1 N hydrochloric
`acid to obtain a solution having a known concentration of about 40 µg
`of epinephrine per mL.
`Assay preparation- Transfer an accurately measured volume of
`Ophthalmic Solution, equivalent to about 20 mg of epinephrine, toa
`250-mL beaker containing 2.0 mL of pH 5.8 buffer. Add 9g of
`chromatographic siliceous earth, and mix. Carefully transfer the
`mixture to a 45- x 2.2-cm chromatographic tube containing a pledget
`of glass wool at the bottom, and tap the column gently to effect
`packing. Dry-wash the beaker with about l g of chromatographic
`siliceous earth, add to the column, and plug the top with a pledget of
`glass wool. Wash the column with 100 mL of water-washed ether,
`and discard the eluant. Add 10.0 mL ofO.l N hydrochloric acid toa
`I 2j-mL separator, and place the separntor under lhe wlwnu. To aboul
`l 00 mL of water-washed ether add l mL of bis(2-ethylhexyl)
`phosphoric acid, and elute the colwnn with this solution1 collecting
`the eluate in the separator. Extract the epinephrine into tile aqueous
`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 !he
`volumetric flask, dilute with 0.1 N hydrochloric acid to volume, and
`mix.
`Procedure-Concomitantly determine the absorbances of lh~
`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 CJI13N01 in each mL of !ht
`Ophthalmic Solution taken by the formula:
`O.S(C I V)(Aul As),
`in which C is the concentration, in µg per mL, of epinephrine in !ht
`Standard preparation; V is the volume, in mL, of OphthaimJc
`Solution taken; and Au and As are the absorbances of the Assay
`preparation and the Standard preparation, respectively.
`
`Epinephrine Bitartrate
`C9H13NQ3 • Cl160 6 333.29
`1,2-Benzenediol, 4-[ l-hydroxy-2-(methylamino )ethyl]-, (Rh [R·
`(R*,R*))-2,3-dihydroxybutanedioate (1: l) (salt).
`(-)-3,4-Dihydroxy-a:-[(methylamino)methyl]benzyl alcohol (+)·tar·
`[51-42-3].
`trate (l: I) salt
`
`» Epinephrine Bitartrate contains not less than 97.0
`percent and not more than I 02.0 percent of C9H13N01
`C.Ji6<)6, calculated on the dried basis.
`Packaging and storage-Preserve in tight, light-resistant conlainm
`USP Reference standards ( 11 }-USP Epinephrine Bitartra1e RS
`USP Norepinephrine Bitartrate RS.
`Identification-Dissolve about 500 mg in 20 mL of water containiJi&
`about 100 mg of sodium bisulfite. Add 6N ammonium hydrom
`until the solution has a distinct odor of ammonia, and allow to stallll
`in a refrigerator for I hour. Filter the precipitate, wash it with Ihm
`2-mL portions of cold water, then with 5 mL of cold alcohol, mi
`finally with 5 mL of cold ether, and dry in vacuum over silica gel fur 1
`hours. The epinephrine so obtained responds to the Identification tr>
`under Epinephrine, and its specific rotation (see Optical Rotal10A
`(781) ), determined by dissolving 200 mg, accurately weighed, 10
`sufficient dilute hydrochloric acid (1 in 20) to make 10.0 mL, 11
`between - 50° and - 53.5°.
`Melting range (741): between 147°and152°, with decomposition
`Loss on drying (731)- Dry it in vacuum over silica gel for 3 houn
`it loses not more than 0.5% of its weight.
`
`ADAMIS EXHIBIT 1013
`
`Page 712
`
`

`

`USP 27
`
`Official Monographs / Epinephrine
`
`713
`
`Residue on ignition (281): negligible, from 100 mg.
`Limit of adreoalooe-Its absorptivity (see Spectrophotometry and
`Ught-Scattering (851 )) at 310 nm, determined in a solution in dilute
`hydrochloric acid {I in 200) containing 4 mg per mL, is not more than
`0.2.
`Limit of norepinephrine bitartrate-
`Epinephrine standard solution-Dilute with methanol an ac(cid:173)
`curately measured volume of an aqueous solution of USP
`Epinephrine Bitartrate RS containing about 200 mg per mL to
`obtain a solution having a known concentration of about 20 mg per
`mL.
`Norepinephrine standard solution-Dilute with methanol an
`accurately measured volume of an aqueous solution of USP
`Norepinepbrine Bitartrate RS containing 8.0 mg per mL to obtain a
`solution having a known concentration of 0.80 mg per mL.
`Test solution- Dissolve 200 mg of Epinephrine Bitartrate in 1.0
`mLofwater, dilute with methanol to 10.0 mL, and mix.
`Procedure-Apply 5-µL portions of Epinephrine standard
`solution, Norepinephrine standard solution, and Test solution to a
`suitable thin-layer chromatographic plate (see Chromatography
`(621)) coated with a 0.25-mm layer of chromatographic silica gel
`mixture. Allow the spots to dry, and develop the chromatogram in an
`uasaturated tank using a solvent system consisting of n-butano~
`water, and formic acid (7 : 2 : 1) until the solvent front has moved
`about three-fourths of the length of the plate. Remove the plate from
`the developing chamber, mark the solvent front, and allow the solvent
`to evaporate in warm circulating air. Spray with Folin-Ciocalteu
`Phenol TS, followed by sodium carbonate solution {l to 10): the Rf
`value of the principal spot obtained from the Test solution
`corresponds to that obtained from the Epinephrine standard solution.
`Any spot obtained from the Test solution is not larger nor more
`intense than the spot with the same ~ value obtained from
`Norepinephrine standard solution, corresponding to not more than
`4.0% of norepinephrine bitartrate.
`Assay- Dissolve about 500 mg of Epinephrine Bitartrate, accurately
`weighed, in 20 mL of glacial acetic acid, warming slightly if
`necessary to effect solution. Add crystal violet TS, and titrate with
`0.1 N perchloric acid VS. Perform a blank determination, and make
`any necessary correction. Each mL of 0.1 N perchloric acid is
`equivalent to 33.33 mg of CJ{13N03 • C,H60 6 •
`
`Epinephrine Bitartrate Inhalation
`Aerosol
`
`» Epinephrine Bitartrate Inhalation Aerosol is a
`suspension of microfine Epinephrine Bitartrate in
`propellants in a pressurized container. It contains not
`less than 90.0 percent and not more than 110.0 percent of
`the labeled amount of epinephrine bitartrate (C9H 13N03 ·
`CJI60 6)·
`Packaging and storage-Preserve in small, nonreactive, lig(cid:173)
`ht-resistant aerosol containers equipped with metered-dose valves
`and provided with oral inhalation actuators.
`USP Reference standards (11)-USP Epinephrine Bitartrate RS.
`Identification-
`A: Place 10 mL of water in a small beaker, and deliver 3 sprays
`fiom the Aerosol under the surface of the water, actuating the valve
`by pressing the tip against the bottom of the beaker. Filter, and to 5
`mL of the filtrate add I drop of dilute hydrochloric acid {l in 120).
`Add 0.5 mL of 0.1 N iodine, allow to stand for 5 minutes, and add 1
`mL of 0.1 N sodium thiosulfate: a red-brown color is produced.
`B: Actuate the valve of the Aerosol by pressing the tip against a
`station of a white porcelain spot plate. Cover the spot with 2 or 3
`drops of a mixture of 3 volumes of pyridine and I volume of acetic
`anhydride: an emerald-green color is produced.
`Delivered dose uniformity over the entire contents: meets the
`requirements for Metered-Dose Inhalers under Aerosols,
`Metered-Dose Inhalers, and Dry Powder Inhalers (601) .
`
`PROCEDURE FOR DOSE UNlfORMITY-
`Ferro-citrate solution and Buffer solutio11- Prepare as directed
`under Epi11ephrine Assay (391 ).
`Standard preparatio11- Dissolve an accurately weighed quantity of
`USP Epinephrine Bitartrate RS in a freshly prepared sodium bisulfite
`solution (1 in 500), and dilute quantitatively and stepwise with the
`same sodium bisulfite solution as necessary to obtain a solution
`having a known concentration of about 15 µg per mL.
`Test preparation-Discharge the minimum recommended dose
`into the sampling apparatus and detach the inhaler as directed. Rinse
`the apparatus (filter and interior) with four 5.0-mL portions of a
`freshly prepared sodium bisulfite solution (I in 500), and transfer the
`resulting solutions quantitatively to a 50-mL centrifu~e tube. Add 10
`mL of chloroform, insert the stopper, shake vigorously for 1 minute
`and centrifuge for 5 minutes. Use the clear supernatant as directed in
`the Procedure.
`Procedure-Into three separate flasks, transfer the Test 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 l .0 mL of Buffer solution, and mix. Concomitantly determine the
`absorbances with a suitable spectrophotometer, in 5-cm cells, of the
`solutions from the Test preparation and the Standard preparation, at
`the wavelength of maximum absorbance at about 530 nm, against the
`blank. Calculate the quantity, in µg of C9H13N03 • C.H606 contained
`in the minimum dose taken by the formula:
`
`,
`
`(20CN)(Aul 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 sprays
`discharged to obtain the minimum recommended dose; and Au and As
`are the absorbances of the solutions from the Test preparation and the
`Standard preparation, respectively.
`Particle size-Proceed with Epinephrine Bitartrate Inhalation
`Aerosol as directed in the test for Particle size under lsoproterenol
`Sulfate Inhalation Aerosol. It meets the limits of the test.
`Assay-
`Ferro-citrate solution and Buffer solution- Prepare as directed
`under Epinephrine Assay (391).
`Standard preparation-Prepare as directed under Delivered dose
`uniformity over the entire contents.
`Assay preparation-{NOTE- A suitable specimen beaker is one
`having a small indentation fonned on its inside bottom surface having
`dimensions adequate to accept the aerosol valve stem during
`actuation, thereby preventing particle entrapment and side-of-stem
`leakage during the delivery of the specimen.] Place 20 mL of
`chloroform in a suitable 100-mL beaker. Prime the valve of
`Epinephrine Bitartrate Inhalation Aerosol by alternately shaking
`and firing it JO times through its oral inhalation actuator. Accurately
`weigh the Aerosol, shake it, and immediately deliver a single spray
`under the surface of the chloroform, actuating the valve by pressing
`the tip into the indentation in the bottom of the beaker. Raise the
`Aerosol above the surface of the chloroform, and shake it gently
`preparatory to delivering another spray similarly under the surface of
`the chloroform. Deliver a total of 3 sprays in this manner. Rinse the
`valve stem and ferrule with about 2 mL of chloroform, collecting the
`rinsing with the specimen in the beaker. Allow the Aerosol to dry,
`weigh it, and determine the total weight of the 3 sprays. Transfer the
`solution to a centrifuge tube with the aid of two 3-mL portions of
`chloroform, and add I 0.0 mL of freshly prepared sodium bisulfite
`solution (1 in 500). Insert the stopper, shake vigorously for 1 minute,
`centrifuge for 5 minutes, and use the clear supernatant liquid as the
`Assay preparation.
`Procedure- Transfer 5.0 mL each oflhe Standard preparation and
`the Assay preparation to separate test tubes. To each tube add l 00 µL
`of Ferro-citrate solution and 1.0 mL of Buffer solution, and mix.
`Concomitantly determine the absorbances of the solutions in I -cm
`cells at the wavelength of maximum absorbance at about 530 nm,
`with a suitable spectrophotometer, using water as the blank. Calculate
`the quantity, in mg, of C9H,3N03 • C,H60 6 in each mL of the Aerosol
`taken by the fonnula:
`
`(0.01Cd/ W)(Aul As),
`in which C is the concentration, in µg per mL, of USP Epinephrine
`Bitartrate RS in the Standard preparation, dis the density, in g per
`mL, of the Aerosol, determined