Accessed from 10.6.1.1 by apman3 on Fri Feb 05 18:39:49 EST 2016
`
`2468 Brinzolamide / Official Monographs
`
`USP 38
`
`Sample: Sample solution
`Allow the elution to continue for 20 min, and measure
`the areas for all the peaks, excluding the peaks of Mo-
`bile phase A.
`Calculate the percentage of each impurity in the por-
`tion of Brinzolamide taken:
`Result = (rU/rT) · 100
`= peak response for each impurity
`rU
`= sum of all the peak responses
`rT
`Acceptance criteria 1: NMT 0.3% for any individual
`impurity
`Analysis 2
`Use Mobile phase B.
`Sample: Sample solution
`Allow the elution to continue for 20 min, and measure
`the areas for brinzolamide and all the peaks having a
`relative retention greater than 6.
`Calculate the percentage of each impurity in the por-
`tion of Brinzolamide taken:
`Result = (rU/rT) · 100
`= peak response for each impurity
`rU
`= sum of all the peak responses
`rT
`Acceptance criteria 2: NMT 0.3% for any individual
`impurity; NMT 1.0% for total impurities from Analysis 1
`and Analysis 2
`SPECIFIC TESTS
`• LOSS ON DRYING Æ731æ
`Analysis: Dry under vacuum at 100(cid:176)–105(cid:176) for 3 h.
`Acceptance criteria: NMT 0.5%
`ADDITIONAL REQUIREMENTS
`• PACKAGING AND STORAGE: Preserve in well-closed
`containers.
`• USP REFERENCE STANDARDS Æ11æ
`USP Brinzolamide RS
`USP Brinzolamide Related Compound A RS
`Brinzolamide (S)-isomer.
`C12H21N3O5S3
`383.52
`USP Brinzolamide Related Compound B RS
`(R-4-Amino)-2,3-dihydro-2-(3-methoxypropyl)-4H-thieno
`[3,2,-e]-thiazine-6-sulfonamide-1,1-dioxide ethandioate
`1:1.
`C10H17N3O5S3 · C2H2O4
`
`445.49
`
`.
`
`Brinzolamide Ophthalmic Suspension
`
`DEFINITION
`Brinzolamide Ophthalmic Suspension is a sterile, aqueous
`suspension of Brinzolamide containing a suitable antimi-
`crobial preservative. It contains NLT 90.0% and NMT
`110.0% of the labeled amount of brinzolamide
`(C12H21N3O5S3).
`IDENTIFICATION
`• A. The retention time of the major peak of the Sample
`solution corresponds to that of Standard solution A, as ob-
`tained in the Assay.
`ASSAY
`
`Change to read:
`• PROCEDURE
`Buffer: 11.75 g/L of ammonium acetate in water. Ad-
`just with acetic acid to a pH of 5.2.
`
`USP Monographs
`
`Change to read:
`• LIMIT OF BRINZOLAMIDE RELATED COMPOUND A
`Mobile phase: Dehydrated alcohol, s
`.chromatographic
`hexane,sUSP38 methanol, and diethylamine
`(55: 40: 5: 0.2)
`System suitability solution: 0.4 mg/mL of USP Brinzol-
`amide RS and 0.02 mg/mL of USP Brinzolamide Related
`Compound A RS in dehydrated alcohol
`Sample solution: Transfer a volume of Ophthalmic Sus-
`pension, equivalent to 10 mg of brinzolamide, to a
`25-mL volumetric flask. Dilute with alcohol to volume.
`Chromatographic system
`(See Chromatography Æ621æ, System Suitability.)
`Mode: LC
`Detector: UV 254 nm
`Column: 4.6-mm · 25-cm; packing L51
`Flow rate: 0.75 mL/min
`Injection volume: 5 mL
`System suitability
`Sample: System suitability solution
`[NOTE—The relative retention times for brinzolamide
`and brinzolamide related compound A are 1.0 and
`1.2, respectively.]
`
`Official from December 1, 2015
`Copyright (c) 2016 The United States Pharmacopeial Convention. All rights reserved.
`
`Mobile phase: Methanol and Buffer (35:65)
`Standard solution A: 0.2 mg/mL of USP Brinzolamide
`RS in Mobile phase
`System suitability solution: 0.06 mg/mL of USP Brin-
`zolamide Related Compound B RS in Standard solution
`A
`Sample solution: Nominally 0.2 mg/mL of brinzol-
`amide in Mobile phase prepared as follows. Transfer a
`volume of Ophthalmic Suspension, equivalent to 10 mg
`of brinzolamide, into a 50-mL volumetric flask, and di-
`lute with Mobile phase to volume.
`Chromatographic system
`(See Chromatography Æ621æ, System Suitability.)
`Mode: LC
`Detector: UV 254 nm
`Column: 4.6-mm · 15-cm; 5-mm packing L1
`Flow rate: 1.0 mL/min
`Injection volume: 20 mL
`System suitability
`Samples: Standard solution A and System suitability
`solution
`[NOTE—The relative retention times for brinzolamide re-
`lated compound B are between 0.48 and 0.61, and
`the relative retention time for brinzolamide is 1.0.]
`Suitability requirements
`Resolution: NLT 4.5 between the brinzolamide and
`brinzolamide related compound B peaks, System suit-
`ability solution
`.sUSP38
`Tailing factor: NMT 2.0, System suitability solution
`Relative standard deviation: NMT 2.0%, Standard
`solution A
`Analysis
`Samples: Standard solution A and Sample solution
`Calculate the percentage of the labeled amount of brin-
`zolamide (C12H21N3O5S3) in the portion of Ophthalmic
`Suspension taken:
`Result = (rU/rS) · (C S/CU) · 100
`= peak response from the Sample solution
`= peak response from Standard solution A
`= concentration of USP Brinzolamide RS in
`Standard solution A (mg/mL)
`= nominal concentration of brinzolamide in the
`Sample solution (mg/mL)
`Acceptance criteria: 90.0%–110.0%
`IMPURITIES
`
`rU
`rS
`CS
`
`CU
`
`s
`
`SENJU EXHIBIT 2281
`LUPIN v. SENJU
`IPR2015-01105
`
`Page 1 of 2
`
`

`
`Accessed from 10.6.1.1 by apman3 on Fri Feb 05 18:39:49 EST 2016
`
`USP 38
`
`Official Monographs / Bromocriptine 2469
`
`USP Monographs
`
`.
`
`Bromocriptine Mesylate
`
`
`
`750.70
`
`C32H40BrN5O5 · CH4SO3
`Ergotaman-3¢,6¢,18-trione, 2-bromo-12¢-hydroxy-2¢-
`(1-methylethyl)-5¢-(2-methylpropyl)-,
`monomethanesulfonate (salt), (5¢a)-;
`2-Bromoergocryptine monomethanesulfonate (salt)
`[22260-51-1].
`DEFINITION
`Bromocriptine Mesylate contains NLT 98.0% and NMT
`102.0% of C32H40BrN5O5 · CH4SO3, calculated on the dried
`basis.
`IDENTIFICATION
`• A. INFRARED ABSORPTION Æ197Mæ:
` Undried
`• B. ULTRAVIOLET ABSORPTION Æ197Uæ
`Sample solution: 50 mg/mL in 0.1 M methanolic meth-
`anesulfonic acid
`Acceptance criteria: Meets the requirements
`ASSAY
`• PROCEDURE
`Sample solution: 600 mg of Bromocriptine Mesylate
`Analysis: Dissolve with 80 mL of a mixture of acetic an-
`hydride and glacial acetic acid (7:1). Titrate with 0.1 N
`perchloric acid VS. Perform a blank determination, and
`make any necessary correction (see Titrimetry Æ541æ).
`Each mL of 0.1 N perchloric acid is equivalent to
`75.07 mg of C32H40BrN5O5 · CH4SO3.
`Acceptance criteria: 98.0%–102.0% on the dried basis
`IMPURITIES
`Inorganic Impurities
`• RESIDUE ON IGNITION Æ281æ:
`
` NMT 0.1%
`
` NMT 20 ppm• (Official 1-
`
`Delete the following:
`•.• HEAVY METALS, Method II Æ231æ:
`Dec-2015)
`Organic Impurities
`• PROCEDURE 1: LIMIT OF METHANESULFONIC ACID CONTENT
`Sample solution: 400 mg of Bromocriptine Mesylate
`Analysis: Dissolve with 70 mL of methanol. Titrate
`under nitrogen with 0.1 N methanolic potassium hy-
`droxide VS. Perform a blank determination, and make
`any necessary correction (see Titrimetry Æ541æ). Each mL
`of 0.1 N methanolic potassium hydroxide is equivalent
`to 9.61 mg of CH3SO3H.
`Acceptance criteria: NLT 12.5% and NMT 13.4% of
`CH3SO3H on the dried basis
`• PROCEDURE 2
`Solution A: 0.1 N citric acid solution. Adjust with hy-
`drochloric acid to a pH of 2.0.
`Diluent: Methanol and Solution A (1:1)
`Solution B: Acetonitrile and 0.01 M phosphate buffer,
`pH 7.0 (2:3)
`Solution C: Acetonitrile and 0.01 M phosphate buffer,
`pH 7.0 (3:2)
`Mobile phase: See the gradient table below.
`
`Suitability requirements
`Resolution: NLT 1.8 between the brinzolamide and
`brinzolamide related compound A peaks
`Column efficiency: NLT 2000 theoretical plates for
`the brinzolamide peak
`Tailing factor: NMT 1.8 for the brinzolamide peak
`Analysis
`Sample: Sample solution
`Calculate the percentage of brinzolamide related com-
`pound A in the portion of Ophthalmic Suspension
`taken:
`
`rU
`
`rT
`
`rU
`
`rS
`
`CS
`
`Result = (rU/rT) · 100
`= peak response for brinzolamide related
`compound A
`= sum of the peak responses for brinzolamide
`and brinzolamide related compound A
`Acceptance criteria: NMT 1.5%
`• ORGANIC IMPURITIES
`Buffer, Mobile phase, Standard solution A, System
`suitability solution, Sample solution, Chromato-
`graphic system, and System suitability: Proceed as
`directed in the Assay.
`Standard solution B: 2.5 mg/mL of USP Brinzolamide
`Related Compound B RS in Mobile phase
`Analysis
`Samples: Sample solution and Standard solution B
`Calculate the percentage of each impurity in the por-
`tion of Ophthalmic Suspension taken:
`Result = (rU/rS) · (C S/CU) · (M r1/Mr2) · 100
`= peak response for each impurity from the
`Sample solution
`= peak response for brinzolamide related
`compound B from Standard solution B
`= concentration of USP Brinzolamide Related
`Compound B RS in Standard solution B
`(mg/mL)
`= nominal concentration of brinzolamide in the
`Sample solution (mg/mL)
`= molecular weight of des-ethyl brinzolamide,
`356.46
`= molecular weight of des-ethyl brinzolamide
`oxalate, 445.49
`Acceptance criteria
`Any individual impurity: NMT 0.5%
`Total impurities: NMT 2.0%
`
`CU
`
`Mr1
`
`Mr2
`
`SPECIFIC TESTS
`• STERILITY TESTS Æ71æ:
` It meets the requirements when
`tested as directed for Test for Sterility of the Product to Be
`Examined, Membrane Filtration.
`• PH Æ791æ:
` 6.5–8.5
`ADDITIONAL REQUIREMENTS
`• PACKAGING AND STORAGE: Preserve in tight containers.
`Store at a temperature between 4(cid:176) and 30(cid:176).
`• USP REFERENCE STANDARDS Æ11æ
`USP Brinzolamide RS
`USP Brinzolamide Related Compound A RS
`Brinzolamide (S)-isomer.
`C12H21N3O5S3
`383.52
`USP Brinzolamide Related Compound B RS
`(R-4-Amino)-2,3-dihydro-2-(3-methoxypropyl)-4H-thieno
`[3,2,-e]-thiazine-6-sulfonamide-1,1-dioxide ethandioate
`1:1.
`C10H17N3O5S3 · C2H2O4
`
`445.49
`
`Official from December 1, 2015
`Copyright (c) 2016 The United States Pharmacopeial Convention. All rights reserved.
`
`Page 2 of 2