2 O75:
`
`The Official Compendia of Standards
`
`Sl
`NEF
`
`Slayback v. Eye Therapies - IPR2022-00142
`
`ULS. PHARMACOPEIA.-
`iu The StandardofQuality™.,
`
`Slayback Exhibit 1055, Page 1 of 78
`
`Slayback Exhibit 1055, Page 1 of 78
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`2005
`
`USP 28
`
`NF 23
`
`JUL 1 6 20!0
`Gooow,1 1/PRocy,-R
`LIBRA
`i::1 LLP
`,RY
`
`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, 2005
`
`The designation on the cover of this publication, "USP NF
`2005," is for ease of identification only. The publication
`contains two separate compendia: The United States
`Pharmacopeia, Twenty-Eighth Revision, and the National
`Formulary, Twenty-Third Edition.
`
`OoocfwtnPl'OOllrUP
`u~
`The NtwVork Tlmea 8ullchg
`620'911tt1A._
`NewVortc. NY 10018-1-
`
`UNITED STATES PHARMACOPEIAL CONVENTION, INC.
`12601 Twinbrook Parkway, Rockville, MD 20852
`
`Slayback Exhibit 1055, Page 2 of 78
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`NOTICE AND WARNING
`
`Concerning U.S. Patent or Trademark Rights
`
`The inclusion in the United States Pharmacopeia or in the National F ormulary 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 © 2004 The United States Phannacopeial Convention, Inc.
`12601 Twinbrook Parkway, Rockville, MD 20852
`All rights reserved.
`ISSN 0195-7996
`ISBN 1-889788-25-2
`Printed in Canada by Webcom Limited, Toronto, Ontario
`
`USP 28
`
`USP: --Mission
`
`-people
`
`officer
`
`Board
`
`coun<
`
`coun
`
`Cotn
`
`Ex.e•
`
`Ex.I
`
`Ge
`
`E:
`
`E
`
`\ ;
`
`l
`
`Slayback Exhibit 1055, Page 3 of 78
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`USP28
`
`Contents
`
`iii
`
`Contents
`
`USP 28
`
`Mission Statement and Preface
`
`V
`
`Admissions ... . . . . . .. .. . ....... .. ... . . . xxxm
`
`People .. ..... . . . .. ... .. .. . . . .. ... .... ..... xm
`
`Officers (2000-2005)
`
`. .. ........ .. .... .. ... .. . .
`
`Board of Trustees (2000-2005)
`
`Council of Experts 2000-2005
`
`Council of Expe$ Executive Committee . . . . . . . .. . .
`
`Complex Actives Division
`
`. . . . . . . . . . . . . . . . . . . . .
`
`Executive Committee
`
`. . . .. . . .. . ... . ... .. .. . .. .
`
`Expert Committees . . . .. .... . .. ... .. . . ...... . .
`
`General Policies and Requirements
`Division . ... . ... . . .. .... . . . ..... .. .... .
`
`Executive Committee .. . .. . ... .. .... . . .. . .. . . .
`
`Expert Committees . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`Infonnation Division
`
`Executive Committee
`
`Expert Committees . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`Noncomplex Actives and Excipients
`Division . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`Executive Committee
`
`Expert Committees .... . ... . .. . . . .... . . .. .... .
`
`USP Reference Standards Committee
`
`USP-FDA Antibiotic Monograph
`Subcommittee ... . .. ..... . . . . . . .. .... . .. .
`
`Headquarters Staff ... .. .... .. . . ...... . ... . .. .
`
`xiii
`
`xiii
`
`xiii
`
`xiv
`
`xiv
`
`xiv
`
`xiv
`
`xiv
`
`xiv
`
`xiv
`
`xv
`
`xv
`
`xv
`
`xvii
`
`xvii
`
`xvii
`
`xviii
`
`xviii
`
`xviii
`
`Collaborators During 2000-2004
`
`. ... .. . ... .. .. . .
`
`xxi
`
`Members of the United States Pha-macopeial Convention
`as of June 30, 2004 .. .. .. ... .. .... . .. .. .. .
`
`xxvi
`
`Articles Admitted to USP 28 by Supplement . . . . . . . . xxxiii
`
`Change in Official Titles . . . . . . . . . . . . . . . . . . . . . . .
`
`xxiii
`
`Revisions Appearing in USP 28 That were Not Included in
`. . . . . . . . . . . . . .
`USP 27 Including Supplements
`
`xxiv
`
`Articles Included in USP 27 but Not Included in USP 28 XXXV
`
`Commentary . . ... .... .. . . .... .. .. . . .. . xxxv1
`
`Notices
`General Notices and Requirements
`
`Monographs
`General Official Monographs for USP 28
`
`13
`
`Dietary Supplements
`Official Monographs
`. . ..... . ...... . . . . ...... .
`
`2059
`
`General Chapters
`See page 2198 for detailed contents
`General Tests and Assays .. .... . . ........ . . . .. .
`
`2201
`
`General Requirements for Tests and Assays . . . . . . .. .
`
`2201
`
`Apparatus for Tests and Assays . . . . .. . . . . . ... . . . .
`
`2234
`
`Microbiological Tests
`
`. . ... . . . .... .. ...... . . .. .
`
`2242
`
`Biological Tests and Assays
`
`. .......... . .. . .... .
`
`2256
`
`Chemical Tests and Assays ... . .. . .. . .. ... . .. . . .
`
`2292
`
`Physical Tests and Detenninations
`
`.. . .... . . .. ... .
`
`2359
`
`Slayback Exhibit 1055, Page 4 of 78
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`iv
`
`Contents
`
`General Information
`
`Dietary Supplement
`
`2516
`
`2768
`
`Reagents, Indicators, and Solutions
`Reagents
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2791
`
`Indicators and Indicator Test Papers
`
`. . . • . . . . . . . . . . 2852
`
`Solutions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2854
`
`Buffer Solutions . . . . . . . . . . . . . . . . . . . . . . . . . . . 2854
`
`Colorimetric Solutions
`
`. . . . . . . . . . . . . . . . . . . . . . 2854
`
`Test Solutions
`
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . 2855
`
`Volumetric Solutions
`
`. . . . . . . . . . . . . . . . . . . . . . . 2862
`
`Reference Tables
`Containers for Dispensing Capsules and Tablets . . . . . . 2869
`
`Description and Relative Solubility of USP and NF
`Articles
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2875
`
`Approximate Solubilities of USP and NF Articles
`
`. . . . 2919
`
`Atomic Weights . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2927
`
`Alcoholometric Table . . . . . . . . . . . . . . . . . . . . . . . . . 2930
`
`USP28
`
`Excipients
`USP and NF Excipients, Listed by
`Category
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`294 I
`
`Notices
`General Notices and Requirements
`
`. . . . . . . . . . . . . . . 2945
`
`Monographs
`Official Monographs for NF 23 . . . . . . . . . . . . . . . . . . 2947
`
`General Chapters
`See page 2 I 98 for detailed contents
`General Tests and Assays See USP 28, page 2201
`General Information See USP 28, page 2516
`
`Reagents
`Reagents See USP 28, page 2791
`Indicators and Indicator Test Papers See USP 28, page
`2852
`Solutions See USP 28, page 2854
`
`Intrinsic Viscosity Table . . . . . . . . . . . . . . . . . . . . . . . 2932
`
`Thermometric Equivalents
`
`2934
`
`Reference Tables
`See USP 28, page 2869
`
`NF 23
`
`People
`See USP 28
`
`Admissions
`Articles Admitted to NF 23 by Supplement
`
`viii
`
`2940
`
`Revisions Appearing in NF 23 that were not Included in NF
`22 Including Supplements
`. . . . . . . . . . . . . . . . . . 2940
`
`Appendices
`Articles of Incorporation . . . . . . . . . . . . . . . . . . . . . . .
`
`3111
`
`Constitution and Bylaws . . . . . . . . . . . . . . . . . . . . . . . 3112
`
`Rules and Procedures . ......... . . ............ . 3123
`
`USP Communications Policy
`
`. . . . . . . . . . . . . . . . . . . 3128
`
`USP Document Disclosure Policy . . . . . . . . . . . . . . . . 3129
`
`Proceedings
`
`Index
`Combined Index to USP 28 ind NF 23
`
`3131
`
`3135
`
`)
`
`\
`
`USP2, -
`
`Pro•
`USF
`United
`"to ·
`by dis1
`by its
`relatec
`optillll
`Wo·
`world
`effecti
`where
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`the SJ
`Requ
`Hi
`the t
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`-
`
`Slayback Exhibit 1055, Page 5 of 78
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`USP28
`
`USP28
`
`Official Monographs I Arginine
`
`175
`
`and add this ether
`>lutions with 20.0
`: 5-mL portions of
`beaker, and warm
`dd methyl red TS,
`ydroxide VS (see
`:h mL of 0.02 N
`0 2 • HCI · ½H20.
`
`1zolidinylidene-,
`
`:line monohydro-
`
`; not less than
`:.0 percent of
`I basis.
`
`:sistant containers.
`me Hydrochloride
`
`in 100).
`or 3 hours: it loses
`
`ric acid to a 2000-
`r, and mix. Adjust
`of 3.0, dilute with
`
`1Ssed mixture of
`:56:40:4). Make
`,mder Chromatog-
`
`1 in Mobile phase
`:lrochloride RS per
`
`nidine Hydrochlo(cid:173)
`lSk, dissolve in and
`
`phy (621})-The
`detector and an 8-
`7. The flow rate is
`System suitability
`for Procedure: the
`e than 2.2, and the
`; is not more than
`
`solution into the
`:asure the areas for
`the elution time of
`,n.] Calculate the
`ent peak and the
`
`apraclonidine peak, in the specimen of Apraclonidine Hydrochloride
`taken by the same formula:
`
`!00r,lrh
`in whi~h r, is the response of each peak other than the principal peak,
`and r, IS the sum of the responses of all of the peaks, excluding that of
`the solvent peak: not more than 1.0% for any individual impurity and
`not more than 2.0% total impurities are found.
`Assay-Dissolve about 125 mg of Apraclonidine Hydrochloride,
`accurately weighed, in 40 mL of glacial acetic acid. Add IO mL of
`mercuric acetate TS, and titrate with 0.1 N perchloric acid VS,
`determining the endpoint potentiometrically from the second
`inflection point, using a calomel-glass electrode system (see
`Titrimet,y (541 )). Perform a blank determination, and make any
`necessary correction. Each mL of 0.1 N perchloric acid is equivalent
`to 14.08 mg of C9H10Cl2N. · HCI.
`
`Apraclonidine Ophthalmic Solution
`
`» Apraclonidine Ophthalmic Solution is a sterile,
`aqueous solution of Apraclonidine Hydrochloride. It
`contains an amount of apraclonidine hydrochloride
`(C9HioChN4 · HCl) equivalent to not less than 90.0
`percent and not more than 115.0 percent of the labeled
`amount of apraclonidine (C9H10ChN4).
`Packaging and storage-Preserve in tight, light-resistant containers.
`USP Reference standards ( 11 )-USP Apraclonidine Hydrochloride
`RS.
`Identification--
`A: The retention time of the major peak in the chromatogram of
`the Assay preparation corresponds to that of the major peak in the
`chromatogram of the Standard preparation, as obtained in the Assay.
`B: Apply 2 µL of Apraclonidine Ophthalmic Solution and 2 µL
`of a Standard solution of USP Apraclonidine Hydrochloride RS in
`methanol containing about 11.5 mg per mL to a suitable high
`performance thin-layer chromatographic plate (see Chromatography
`(6_21)) coated with a 0.2-mm layer of chromatographic silica gel
`mixture, or equivalent. Allow the applications to dry, and develop the
`chromatogram in a solvent system consisting of a mixture of
`chloroform, methanol, and ammonium hydroxide (74: 22: 4) 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. Locate the spots on
`the plate by viewing under short-wavelength UV light. [NOTE-The
`apraclonidine spot should appear as a blue spot.] Spray the plate with
`fluorescamine solution, prepared by dissolving about 25 mg of
`fluorescamine in 25 mL of acetone. [NOTE-Avoid prolonged or
`re!><:"ted breathing of the aerosol from the fluorescamine spray. Also
`avoid prolonged or repeated contact with skin. Fluorescamine
`solution should be sprayed only in a hood.] Examine the plate
`under normal light and long-wavelength UV light. [NOTE-The
`apraclonidine spot should appear as a yellow spot under normal light
`and as a white spot under long-wavelength UV light.] The RF value
`and appearance of the principal spot obtained from the test solution
`corresponds to that obtained from the Standard solution.
`Sterility (71 )-It meets the requirements when tested as directed for
`Membrane Filtration under Test for Sterility of the Product to be
`Examined.
`pH (791) : between 4.4 and 7.8.
`Assay-
`Phosphate buffer-Prepare as directed in the test for Chromato(cid:173)
`graphic purity under Apraclonidine Hydrochloride.
`Mobile phase-Prepare a filtered and degassed mixture of
`Ph_osphate ~uffer, acetonitrile, and methanol (68 : 30: 2). Make
`adjustments 1f necessary (see System Suitability under Chromatog(cid:173)
`raphy (621)).
`Standard preparation-Dissolve an accurately weighed quantity of
`1:JSP Apraclonidine Hydrochloride RS in water, and dilute quantita(cid:173)
`tively, and stepwise if necessary, with water to obtain a Stock
`standard solution having a known concentration of about 0.23 mg per
`
`mL. Transfer 2.5 mL of this solution to a 50-mL volumetric flask,
`dilute with Mobile phase to volume, and mix to obtain a Standard
`preparation having a known concentration of about 11 .5 µg of USP
`Apraclonidine Hydrochloride RS per mL (equivalent to about 10 µg
`of apraclonidine per mL ).
`Resolution solution-Transfer about I mL of propiophenone to a
`100-mL volumetric flask, dilute with methanol to volume, and mix.
`Transfer 3.0 mL of this solution to a 50-mL volumetric flask, dilute
`with methanol to volume, and mix. Transfer 1.0 mL of this solution
`and 5.0 mL of the Stock standard solution to a 100-mL volumetric
`flask, dilute with Mobile phase to volume, and mix.
`Assay preparation-Transfer an accurately measured volume of
`Ophthalmic Solution, equivalent to about 20 mg of apraclonidine, to a
`100-mL volumetric flask, dilute with water to volume, and mix.
`Transfer 2.5 mL of this solution to a 50-mL volumetric flask, dilute
`with Mobile phase to volume, and mix.
`Chromatographic system (see Chromatography (62 I ) )-The
`liquid chromatograph is equipped with a 254-nm detector and an 8-
`mm x 100-mm column that contains packing L7. The flow rate is
`about 3 mL per minute. Chromatograph the Resolution solution, and
`record the peak responses as directed for Procedure: the relative
`retention times are about 0.6 for apraclonidine and 1.0 for
`propiophenone; the column efficiency determined from the analyte
`peak is not less than 1000 theoretical plates; the tailing factor for the
`analyte peak is not more than 2.2; the resolution, R, between the
`analyte and propiophenone peaks is not less than 3.0; 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 chromat(cid:173)
`ograph, record the chromatograms, and measure the areas for the
`major peaks. Calculate the quantity, in mg, of apraclonidine
`(C9H,0Cl2N4) in each mL of the Ophthalmic Solution taken by the
`formula :
`
`(245.11 /28 l.57X2C I V)(rul rs),
`
`in which 245.11 and 281.57 are the molecular weights of
`apraclonidine and apraclonidine hydrochloride, respectively; C is
`the concentration, in µg per mL, of USP Apraclonidine Hydrochlo(cid:173)
`ride RS in the Standard preparation; V is the volume, in mL, of
`Ophthalmic Solution taken; and ru and rs are the apraclonidine peak
`responses obtained from the Assay preparation and the Standard
`preparation, respectively.
`
`Arginine
`
`C,H,.N.02 174.20
`L-Arginine.
`L-Arginine
`
`[74-79-3].
`
`» Arginine contains not less than 98.5 percent and not
`more than 101.5 percent of C6H1~ 40 2, as L-arginine,
`calculated on the dried basis.
`
`Packaging and storage-Preserve in well-closed containers.
`USP Reference standards (I !}-USP L-Arginine RS. USP L-Lysine
`Hydrochloride RS.
`Identification, Infrared Absorption ( 197K).
`Specific rotation (781S}: between +26.3° and +27.7°.
`Test solution: 80 mg per mL, in 6 N hydrochloric acid.
`Loss on drying (731)-Dry it at 105° for 3 hours: it loses not more
`than 0.5% of its weight.
`Residue on ignition (281): not more than 0.3%.
`Chloride (221 }-A 1.0-g portion shows no more chloride than
`corresponds to 0.70 mL of0.020N hydrochloric acid (0.05%).
`
`Slayback Exhibit 1055, Page 6 of 78
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`USP28
`
`USP28
`
`Official Monographs I Atropine
`
`201
`
`ities-Prepare a
`per mL, and, by
`with methanol,
`1g per lilL. Apply
`ion, 1 µL of the
`L of a methanol
`mg per mL to a
`Chromatography
`raphic silica gel.
`:ram in a solvent
`n, acetone, and
`as moved about
`1e plate from the
`ow the solvent to
`g with potassium
`ot obtained from
`1m the Reference
`the first Atropine
`the principal spot
`I.
`neets the require-
`
`ately weighed, in
`al violet TS, and
`dpoint. Perform a
`ction. Each mL of
`C 11H23NO3.
`
`1ethyl-8-azabicy(cid:173)
`!: 1) (salt), mono-
`
`lfate (2: I) (salt)
`
`n 98.5 percent
`percent of
`:he anhydrous
`
`ith exceptional
`
`ners.
`1ulfate RS.
`
`nts of the tests for
`
`lower than 187°,
`,-Since anhydrous
`1elting temperature
`e immediately after
`
`ation, in degrees,
`J, in mm, of the
`1 +o.os 0 (limit of
`
`, in water to make a
`
`drop of methyl red
`not more than 0.30
`
`'o.
`meets the require-
`
`Other alkaloids-Dissolve ISO mg in 10 mL of water. To S mL of
`the solution add a few drops of platinic chloride TS: no precipitate is
`formed. To the remaining S mL of the solution add 2 mL of 6 N
`ammonium hydroxide, and shake vigorously: a slight opalescence
`may develop but no turbidity is produced.
`Assay-Dissolve about I g of Atropine Sulfate, accurately weighed,
`in SO mL of glacial acetic acid, and titrate with 0.1 N perchloric acid
`VS, determining the endpoint potentiometrically. Perform a blank
`determination, and make any necessary correction. Each mL of 0.1 N
`perchloric acid is equivalent to 67.68 mg of (C 17H23NO3)2 · H2SO •.
`
`Atropine Sulfate Injection
`
`» Atropine Sulfate Injection is a sterile solution of
`Atropine Sulfate in Water for Injection. It contains not
`less than 93.0 percent and not more than 107.0 percent of
`the labeled amount of (C 17H23NO3)2 · H2SO4 · H2O.
`Packaging and storage-Preserve in single-dose or in multiple-dose
`containers, preferably of Type I glass.
`USP Reference standards ( 11 }-USP Atropine Sulfate RS. USP
`Endotoxin RS.
`Identification (see Thin-Layer Chromatographic Identification Test
`(201}}--
`Adsorbent: chromatographic silica gel.
`Developing solvent: mixture of chloroform and diethylamine
`(9: I).
`Test preparation-Use undiluted. Apply 15 µL.
`Detection reagent: potassium iodoplatinate TS.
`Procedure-Proceed as directed for Procedure under Thin-Layer
`Chromatographic Identification Test (201}, the spots on the plate
`located by spraying with Detection reagent.
`Bacterial endotoxins (85}-It contains not more than 55.6 USP
`Endotoxin Units per mg of atropine sulfate.
`pH (791}: between 3.0 and 6.5.
`Other requirements-It meets the requirements under Injections
`(!}.
`Assay-
`Acetate buffer-Prepare a solution in water containing in each L
`0.05 mole of sodium acetate and 2.9 mL of glacial acetic acid.
`Mobile phase-Transfer 5.1 g of tetrabutylammonium hydrogen
`sulfate to a 1-L volumetric flask, add SO mL of acetonitrile, and dilute
`with Acetate buffer to volume. Adjust with SN sodium hydroxide to a
`pH ofS.S ± 0.1.
`Standard preparation-Dissolve an accurately weighed quantity of
`USP Atropine Sulfate RS in water, and dilute quantitatively with
`water to obtain a solution having a known concentration of about 80
`µg per mL.
`Assay preparation-Transfer an accurately measured volume of
`Injection, equivalent to about 2 mg of atropine sulfate, to a 25-mL
`volumetric flask, dilute with water to volume, and mix.
`Resolution solution-Prepare a solution in water containing about
`2.5 µg of p-hydroxybenzoic acid per mL. Dilute one volume of this
`solution with four volumes of the Standard preparation.
`Chromatographic system (see Chromatography (621}}--The
`liquid chromatograph is equipped with a 254-nm detector and 30-
`cm x 3.9-mm column that contains packing LI. The flow rate is
`about 2 mL per minute. Chromatograph the Standard preparation,
`and record the peak responses as directed for Procedure: the relative
`s~_dard deviation for replicate injections is not more than 1.5%. ~ a
`s_1mtlar manner, chromatograph the Resolution solution: the reten~1on
`time of p-hydroxybenzoic acid is about 1.6 relative to that of atropine,
`and the resolution, R, between the p-hydroxybenzoic acid and
`atropine peaks is not less than 2.2.
`
`Procedure-Separately inject equal volumes (about 100 µL) of the
`Standard preparation and the Assay preparation into the chromat(cid:173)
`ograph, record the chromatograms, and measure the areas for the
`major peaks. Calculate the quantity, in mg, of (C 17H,,NO3)2 · H,
`SO4 • H2O in each mL of the Injection taken by the formula:
`(694.8S/676.83)(2SC/V)(ru/ rs),
`
`in which 694.85 and 676.83 are the molecular weights of atropine
`sulfate monohydrate and anhydrous atropine sulfate, respectively; C
`is the concentration, in mg per mL, of USP Atropine Sulfate RS in the
`Standard preparation; Vis the volume, in mL, of Injection taken; and
`ru and rs are the peak responses obtained from the Assay preparation
`and the Standard preparation, respectively.
`
`Atropine Sulfate Ophthalmic Ointment
`
`» Atropine Sulfate Ophthalmic Ointment is Atropine
`Sulfate in a suitable ophthalmic ointment base. It
`contains not less than 90.0 percent and not more than
`I I 0.0 percent of the labeled amount of (C11H23NO3)2 · H2
`SO4 · H2O. It is sterile.
`Packaging and storage-Preserve in collapsible ophthalmic oint(cid:173)
`ment tubes.
`USP Reference standards ( 11 }-USP Atropine Sulfate RS.
`Identification-
`A: Transfer a portion of Ophthalmic Ointment, equivalent to
`about SO mg of atropine sulfate, to a suitable separator, and dissolve
`in 25 mL of ether. Add 25 mL of 0.01 N hydrochloric acid, shake
`vigorously, allow the layers to separate, and discard the organic
`phase. Heat the aqueous phase gently on a steam bath while passing
`nitrogen through the solution, to expel any residual ether. Proceed as
`directed under Identification-Organic Nitrogenous Bases (181},
`beginning with "In a second separator dissolve SO mg."
`8: Transfer about S g of Ophthalmic Ointment to a separator,
`dissolve in SO mL of ether, and extract with 20 mL of water: the
`extracted solution so obtained' responds to the tests for Sulfate ( 191}.
`Sterility (7 I}:
`It meets the requirements.
`Metal particles (751}:
`It meets the requirements.
`Assay-Proceed with Ophthalmic Ointment as directed in the Assay
`under Atropine Sulfate Ophthalmic Solution, but in preparing the
`Assay preparation, weigh accurately a portion of Ophthalmic
`Ointment, equivalent to about IO mg of atropine sulfate, transfer to
`a separator containing SO mL of ether, shake to dissolve, extract with
`three 25-mL portions of 0.1 M sulfuric acid, collect the acid extracts
`in a l00-mL volumetric flask, dilute with 0.1 M sulfuric acid to
`volume, and mix. Proceed as directed for the Assay preparation in the
`Assay under Atropine Sulfate Ophthalmic Solution, beginning with
`"Pipet 10 mL of this solution into a separator." Calculate the
`quantity, in mg, of atropine sulfate [(C11H2,NO3)2 · H2SO. · H2O] in the
`portion of Ophthalmic Ointment taken by the formula given therein.
`
`Atropine Sulfate Ophthalmic Solution
`
`» Atropine Sulfate Ophthalmic Solution is a sterile,
`aqueous solution of Atropine Sulfate. It contains not less
`than 93.0 percent and not more than 107.0 percent of the
`labeled amount of atropine sulfate [(C11H23NO3)2 · H2
`SO4 • H2O]. It may contain suitable stabilizers and
`antimicrobial agents.
`
`Packaging and storage-Preserve in tight containers.
`USP Reference standards ( 11 }-USP Atropine Sulfate RS.
`Identification-After evaporation to dryness, it meets the require(cid:173)
`ments for Identification test A under Atropine and for Ide11tificatio11
`test B under Atropine Sulfate.
`
`Slayback Exhibit 1055, Page 7 of 78
`Slayback v. Eye Therapies - IPR2022-00142
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`

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`202
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`Atropine / Official Monographs
`
`USP28
`
`USP28
`
`Sterility ( 7 I ) : meets the requirements.
`pH (791 ): between 3.5 and 6.0.
`Assay-
`pH 9.0 Buffer-Dissolve 34.8 g of dibasic potassium phosphate in
`900 ml of water, and adjust to a pH of 9.0, determined
`electrometrically, by the addition of 3 M hydrochloric acid or I M
`sodium hydroxide, as necessary, with mixing.
`Internal standard solution-[NOTE-Prepare fresh daily.] Transfer
`about 25 mg of homatropine hydrobromide to a 50-ml volumetric
`flask, dissolve in and dilute with water to volume, and mix.
`Standard preparation-[NOTE-Prepare fresh daily.] Dissolve an
`accurately weighed quantity of USP Atropine Sulfate RS in water,
`and dilute quantitatively, and stepwise if necessary, with water to
`obtain a solution having a known concentration of about 0.1 mg per
`ml. Pipet IO ml of this solution into a separator, and proceed as
`directed for the Assay preparation, beginning with "Add 2.0 ml of
`Internal standard solution."
`Assay preparation-Transfer an accurately measured volume of
`Ophthalmic Solution, equivalent to about 10 mg of Atropine Sulfate,
`to a I 00-ml volumetric flask, dilute with water to volume, and mix.
`Pipet 10 ml of this solution and treat as follows. Add 2.0 ml of
`Internal standard solution and 5.0 ml of pH 9.0 Buffer, and adjust
`the solution in the separator with I M sodium hydroxide to a pH of
`9 .0. Extract with two I 0-ml portions of methylene chloride, filter the
`methylene chloride extracts through 1 g of anhydrous sodium sulfate
`supported by a small cotton plug in a funnel into a 50-ml beaker, and
`evaporate under a stream of nitrogen to near-dryness. Dissolve the
`residue in 2.0 ml of methylene chloride.
`Chromatographic system (see Chromatography (621))-The gas
`chromatograph is equipped with a flame-ionization detector and a 2-
`mm x 1.8-m glass column packed with a 3% phase G3 on support
`SI AB. The carrier gas is nitrogen, flowing at a rate of 25 ml per
`minute. The column temperature is maintained at 225°. The injection
`port and detector temperatures are maintained at 250°. Chromato(cid:173)
`graph the Standard preparation, and record the peak responses as
`directed for Procedure: the resolution, R. is not less than 4.0; the
`tailing factor is not more than 2.0; and the relative standard deviation
`for replicate injections is not more than 2.0%.
`Procedure-Separately inject equal volumes (about I µl) of the
`Assay preparation and the Standard preparation into the chromat(cid:173)
`ograph, record the chromatograms, and measure the areas for the
`major peaks. Calculate the quantity, in mg, of atropine sulfate
`[(C,,H,,NO,)2 • H2SO. · H2O] in each ml of Ophthalmic Solution
`taken by the formula:
`
`(694.85/676.83)(W/V)(Rul Rs),
`
`in which 694.85 and 676.83 are the molecular weights of atropine
`sulfate monohydrate and anhydrous atropine sulfate, respectively; W
`is the weight, in mg, of USP Atropine Sulfate RS in the Standard
`preparation: Vis the volume, in ml, of Ophthalmic Solution taken;
`and Ru and Rs are the peak area ratios of atropine sulfate to
`homatropine hydrobromide obtained from the Assay preparation and
`the Standard preparation, respectively.
`
`Atropine Sulfate Tablets
`
`» Atropine Sulfate Tablets contain not less than 90.0
`percent and not more than 110.0 percent of the labeled
`amount of atropine sulfate [(C 17H23NO3)i · H2SO4 · H2O].
`Packaging and storage-Preserve in well-closed containers.
`USP Reference standards (II )-USP Atropine Sulfate RS.
`Identification-
`A: Triturate a quantity of Tablets, equivalent to about 5 mg of
`atropine sulfate, with 10 ml of water for a few minutes, and filter into
`a small separator. Render the solution alkaline with 6 N ammonium
`hydroxide, and extract with 50 ml of chloroform. Filter the
`chloroform layer, and evaporate to dryness. The residue so obtained
`meets the requirements under Identification-Organic Nitrogenous
`Bases (!RI }.
`8: A filtered solution of Tablets responds to the tests for Sulfate
`( 191 ).
`.
`
`Disintegration (70 I ):
`I 5 minutes.
`Uniformity of dosage units (905): meet the requirements.
`Assay-
`pH 9.0 Buffer. Internal standard solution, Standard preparation,
`and Chromatographic system-Proceed as directed in the Assay
`under Atropine Sulfate Ophthalmic Solution.
`Assay preparation-Weigh and finely powder not fewer than 20
`Tablets. Transfer an accurately weighed portion of the powder,
`equivalent to about I mg of atropine sulfate, to a separator, and
`proceed as directed for the Assay preparation in the Assay under
`Atropine Sulfate Ophthalmic Solution, beginning with "Add 2.0 ml
`of Internal standard solution.·•
`Procedure-Proceed as directed in the Assay under Atropine
`Sulfate Ophthalmic Solution. Calculate the quantity, in mg, of
`atropine sulfate [(C 11H,,N0,)2 · H2SO. · H2O] in the portion of Tablets
`taken by the formula:
`(694.85 I 676.83XWI I0)(R11 / Rs),
`in which 694.85 and 676.83 are the molecular weights of atropine
`sulfate monohydrate and anhydrous atropine sulfate. respectively; W
`is the weight, in mg, of USP Atropine Sulfate RS in the Standard
`preparation; and Ru and Rs are as defined therein.
`
`Activated Attapulgite
`
`» Activated Attapulgite is a highly heat-treated,
`processed, native magnesium aluminum silicate.
`
`Packaging and storage-Preserve in well-closed containers.
`Identification-Activated Attapulgite responds to the ldent(ficatio11
`test for Colloidal Activated Attapulgite, the characteristic peak,
`however, being much less intense.
`Loss on drying (731 }-Dry it at I 05° to constant weight: it loses not
`more than 4.0% of its weight.
`Loss on ignition (733}-When ignited at 1000° for I hour, it loses
`between 4.0% and I 2.0% of its weight.
`Volatile matter-When ignited at 600° for I hour, it loses between
`3.0% and 7.5% of its weight on the dried basis.
`Powder fineness-Proceed as directed in the test for Powder fineness
`under Colloidal Activated Attapulgite. The dry weight of the residue
`is not more than 0.10% of the weight of the specimen taken.
`Acid-soluble matter-Boil 2.0 g with I 00 ml of0.2 N hydrochloric
`acid for 5 minutes, and cool. Add water to adjust the volume to I 00
`ml, and filter. Evaporate 50 ml of the filtrate so obtained to dryness,
`and ignite the residue at 600'': not more than 0.25 g is found (25%).
`Organic volatile impurities, Method IV (467) : meets the require(cid:173)
`ments.
`Other requirements-It meets the requirements of the tests for
`Microbial limits, pH, Carbonate. Arsenic and l,ead, and Adsorptive
`capacity under Colloidal Activated Attapulgite.
`
`observed; the cha
`10.3 and 10.7 An.
`Microbial limits
`absence of Esche,
`pH (791 }-Dispei
`mix:
`the pH oftl
`9.5.
`Loss on drying (
`between 5.0% and
`Loss on ignition ,
`between I 7.0% an
`Volatile matter-
`7.5% and 12.5% o
`Powder fineness(cid:173)
`sodium pyrophosp
`dispersion slowly t
`Distribution Estim
`wash the residue ,
`weight: the dry wt
`0.30% of the weigl
`Acid-soluble matt,
`acid for 5 minutes,
`ml, and filter. Eva1
`and ignite the resid
`Carbonate-Mix
`effervescence occm
`Arsenic and Lead(cid:173)
`for 30 minutes, addi
`Filter into a I 00-mI
`dilute the combiner
`Arsenic-Detem
`absorption spectron
`ing (85 I}), using :
`directed by the man
`the absorbance at 18
`found.
`Lead-Determine
`spectrometry ( see ~
`using a graphite fu
`manufacturer of the 1
`283.3 nm against a :
`Adsorptive capacit
`specimen in water ac
`and shake. Add I 0
`shake. Allow to st
`supernatant to a 50-1
`the clear supernatant
`solution so obtained
`1.5 µg of methylene
`Organic volatile im
`ments.
`
`Colloidal Activated Attapulgite
`
`Aurothioglm
`
`» Colloidal Activated Attapulgite is a purified native
`magnesium aluminum silicate.
`
`Packaging and storage-Preserve in well-closed containers.
`Identification-Add 2 g in small portions to I 00 ml of water, with
`vigorous agitation. Allow to stand for at least 12 hours to ensure
`complete hydration. Place 2 ml of the resulting mixture on a suitable
`glass slide, and allow to air-dry at room temperature to produce a
`uniform film. Place the slide in a vacuum desiccator over a free
`surface of ethylene glycol. Evacuate the desiccator, and close the
`stopcock so that the ethylene glycol saturates the desiccator chamber.
`Allow to stand for 12 hours. Record the X-ray diffraction pattern (see
`X-ray D(ffraction (941 ) ). and calculate the d values: several peaks are
`
`Coi:l 11 AuO,S 392.18
`Gold, ( 1-thio-D-gluco
`( 1-Thio-D-glucopyran
`
`Slayback Exhibit 1055, Page 8 of 78
`Slayback v. Eye Therapies - IPR2022-00142
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`226
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`Bendroflumethiazide / Official Monographs
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`USP28
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`USP28
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`Bendroflumethiaz