THE NATIONAL FORMULARY
`
`Official from January 1, 1995
`
`By authority of the United States Pharmacopeial
`Convention, Ina, meeting at Washington, D. C,
`March 840, 1990. Prepared by the Committee of
`Revision and published by the Board of Trustees
`
` THE UNITED STATES PHARMACOPEIA
`
`SINCE 1820
`
`Mylan V. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2015 - 1/5
`
`UNITED STATES PHARMACOPEIAL CONVENTION, INC.
`12601 Twinbrook Parkway, Rockville, MD 20852
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2015 - 1/5
`
`

`

`NOTI CE AND WARNING
`
`Concerning U.S. Patent or Trademark Rights
`
`The inclu sion in the Pharmacopeia or in the Na tional Formu la ry of a monograp h on a ny
`drug in respect to whic h patent or tradema rk rig hts may ex ist shall not be dee med, a nd is
`not intended as, a g ra nt of, or aut hority to exe rcise, a ny right or privilege protected by such
`patent or trade mark . A ll such rig hts and privileges a re vested in the patent or tradema rk
`ow ner, a nd no other person may exerci se the sa me without express permission, a uthority , or
`license secured from such patent or trademark owne r.
`
`Concerning Use of USP or N F Text
`Atte ntion is ca lled to the fact tha t US P a nd NF text is full y copyrighted . Authors and
`others wishing to use port ions of the text should request permission to do so from the
`Secreta ry of the US PC Board of Trustees.
`
`The United S ta tes Pha rmacopeia] Convention, Inc.
`1994
`©
`1260 I Twin brook Parkway, Rockv ill e, MD 20852.
`All righ1s reserved
`ISSN 0 195-7996
`IS BN 0-9 13595-76-4 (cloth)
`0-913595-81-0 (leather)
`
`Printed by Rand McNa lly, 11 33 Coun ty S treet, Taunton, MA 0278 0-3 795
`
`Mylan v. Qualicaps, IPR2017-00203
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`

`

`Hydmxypropyl / Official Monographs
`
`USP 23
`
`percent and not more than 110.0 percent of the la-
`beled amount of C27H4oO4.
`
`Hydroxypropyl Cellulose Ocular System
`
`nd stora e—Presei've in single-dose or in multiple-
`tllgscekgghllgtiifiers, prefegrably of Type I or Type III glass.
`USP Reference standards (l1)—USP Hydroxyprogesterone
`Caproate RS.
`dentification~
`_
`,
`_
`I A: Transfer a volume of Injection, equivalent to 125 mg. of
`hydroxyprogesterone Caproate, to a 60-mL separator containing
`10 mL of solvent hexane, 8 mL of methanol, and 2 mL of water.
`Insert the stopper, shake for 2 minutes, and allow the phasesto
`separate. To 3 mL of the lower layer add sulfuric acid dropwise
`until a color develops, then add 3 m_L of methanol: a purple color
`develops, and the solution, when viewed under long-wavelength
`ultraviolet light, exhibits a pale yellow fluorescence.
`_
`B: Evaporate 4 mL of the Assay preparation, obtained as
`directed in the Assay, on a water bath to dryness, and dissolve
`the residue in 0.5 mL of chloroform. Apply 10 pL of this solution
`and 10 pL of a solution of USP Hydroxyprogesterone Caproate
`RS in chloroform, containing 400 pg per mL,
`to a thin-layer
`chromatographic plate (see Chromatography (621)) coated with
`a 0.25-mm layer of chromatographic silica gel mixture, on a line
`about 2.5 cm from the bottom edge and about 2 cm apart. Place
`the plate in a developing chamber that contains and that has been
`equilibrated with a mixture of 3 volumes of chloroform and 1
`volume of ethyl acetate. Develop the plate until the solvent front
`has moved to about 10 cm above the points of application. Re-
`move the plate, mark the solvent front, and dry. Spray the plate
`with a mixture of 1 volume of sulfuric acid and 3 volumes of
`alcohol and heat in an oven at 105° for 5 minutes:
`the Rf value
`of the principal yellowish green spot obtained from the solution
`under test corresponds to that obtained from the Standard so-
`
`Water, Method I (921): not more than 0.2%.
`Other requirements—It meets the requirements under Injections
`
`Aslsfdtdazid reagent—Dissolve 375 mg of isoniazid and 0.47 mL
`of hydrochloric acid in 500 mL of methanol.
`Standard preparat1'on—Dissolve a suitable quantity of USP
`Hydroxyprogesterone Caproate RS, accurately weighed, in meth-
`anol, and dilute quantitatively and stepwise with methanol
`to
`obtain a solution having a known concentration of about 50 pg
`peifsliay preparation—Transfer to a 250-mL volumetric flask an
`accurately measured volume of Injection, equivalent to about 250
`mg of hydroxyprogesterone Caproate, add methanol to volume,
`and mix. Pipet 5 mL of this solution into a 100-mL volumetric
`flask, add methanol to volume, and mix.
`_
`Procedure——Pipet 5 mL of Assay preparation into a glass-
`stoppered, 50-mL conical flask. Pipet 5 mL of Standard prep-
`aration into a similar flask. To each flask, add 10.0 mL of Iso-
`niazid reagent, mix, and allow to stand in a water bath at 30°
`for about 45 minutes. Concomitantly determine the absorbances
`of both solutions at the wavelength of maximum absorbance at
`about 380 nm, with a suitable spectrophotometer, using as a blank
`a mixture of 5 mL of methanol and 10 mL of lsoniazia’ reagent.
`Calculate the quantity, in mg, of C27H40O4 in each mL of the
`Injection taken by the formula:
`
`5(C/V)(«4u/As),
`
`in which C is the concentration, in pg per mL, of USP Hydroxy-
`progesterone Caproate RS in the Standard preparation, V is the
`volume, in mL, of Injection taken, and AU and A5 are the ab-
`sorbances of the solutions from the Assay preparation and the
`Standard preparation, respectively.
`
`Hydroxypropyl Cellulose——see Hydroxypropyl
`Cellulose NF
`
`» Hydroxypropyl Cellulose Ocular System contains
`not less than 85.0 percent and not more than 115_()
`percent of the labeled amount of Hydroxypropyl C51.
`lulose. It contains no other substance. It is sterile_
`Packaging and st0rage—Preserve in single-dose containers, at a
`temperature not exceeding 30°.
`USP Reference standards (1 l)—USP Hydroxypropyl Cellulose
`RS.
`
`in 100 solution in methanol, based
`Identi1'ication—Prepare a I
`on the labeled amount of Hydroxypropyl Cellulose. Evaporatez
`drops of the solution on a silver chloride plate so that it forms a
`thin film:
`the infrared absorption spectrum of the film so ob.
`tained exhibits maxima only at the same wavelengths as that of
`a similar preparation of USP Hydroxypropyl Cellulose RS.
`Sterility—It meets the requirements under Sterility Tests (71),
`Weight variation—Determine the weight of each of a sufficient
`number of Systems. Not more than 1 out of 20 varies more than
`25% from the average or, failing that, not more than 6 out of 60
`(including the original 20) vary more than 25% (but none more
`than 35%) from the average weight.
`Assay—
`Standard preparation—Dissolve with agitation an accurately
`weighed quantity of USP Hydroxypropyl Cellulose RS in water
`to obtain a solution having a known concentration of about 0.05
`mg per mL.
`Assay preparation——Transfer a sufficient number of Ocular
`Systems, to provide about 25 mg of hydroxypropyl cellulose, to
`a 500-mL volumetric flask, add about 250 mL of water, and
`dissolve with agitation on a mechanical shaker. Dilute with water
`to volume, and mix.
`Procedure—Separately pipet 2 mL of the Standard prepa-
`ration, the Assay preparation, and water, to provide a blank, into
`individual 50-mL centrifuge tubes. Add to each tube 6.0 mL of
`a 1
`in 2000 solution of anthrone in sulfuric acid, and mix on a
`vortex mixer. After 40 minutes, again mix, and concomitantly
`determine the absorbances of the solutions obtained from the
`Standard preparation and the Assay preparation at 620 nm, with
`a suitable spectrophotometer, against the solution from the blank.
`Calculate the quantity, in mg, of hydroxypropyl cellulose in each
`Ocular System taken by the formula:
`
`(500)(C/N)(Au/As),
`
`in which C is the concentration, in mg per mL, of USP Hydroxy-
`propyl Cellulose RS in the Standard preparation, N is the num-
`ber of Ocular Systems taken for the Assay, and AU and A5 are
`the absorbances of the solutions from the Assay preparation and
`the Standard preparation, respectively.
`
`Hydroxypropyl Methylcellulose
`
`Cellulose, 2-hydroxypropyl methyl ether.
`Cellulose hydroxypropyl methyl ether
`
`[9004-65-3].
`
`» Hydroxypropyl Methylcellulose is a propylene g1Y'
`col ether of methylcellulose. When dried at 105° f0T
`2 hours, it contains methoxy (—OCH3) and hydroxy-
`propoxy (—OCH2CHOHCH3) groups conforming to
`the limits for the types of Hydroxypropyl Methyl-
`cellulose set forth in the accompanying table.
`~
`Packaging and storage—Preserve in well-closed containers.
`Labeling—Label it
`to indicate its substitution type and its Vi5‘
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2015 - 3/5
`
`

`

`1
`
`the giixlhdle l°ll1la]l‘;lSh5l(;lb ehlvlhll alldeguddgodume Ol
`plet_e:
`sodium lly loxl C or
`.y. we Ollcllcl
`l.S a
`e '.
`’
`,
`_ Add 1 g to 100 mL of boiling water, and stir the mixture.
`.
`f med but the powdered mammal does not dlssolve
`B.
`ufry ‘S or
`’
`'
`lllllirhllihiilbhlaéiltoiigIblblsliiidalhihiiiliiili-glng llquld ls a Q1831 or
`.
`C
`‘OP’. Pour a few mL of the mixture prepared for [de,,r,f,’Car,'0n
`ws(t:'B onto 3 glass plate, and allow the water to evaporate; a
`win self-sustaining film results.
`rent viscosity—Place a quantity, accurately weighed and
`APlll‘l,alent t0 2 g of Solids on the dried basis in a laledy Wide-
`“garb 250-mL centrifuge bottle, and add 98 g of water previ-
`glusly lieated to 80° to 90°. Stir with a propeller-type stirr_er'for
`[0 minutes, PiaCe,tii§‘« bnttit? in an 106 bath. C_0ntin1i6 the stirring.
`arrd allow to remainin the ice bath for 40 minutes to ensure that
`hydration and solution are c0mpi6t°- Adlhst the Weight 0i the
`solUii°ii
`lo loo 3’ ll necessary’ and Cellllllllge the Sollllloll lo
`.
`cm of the. Ubbelohde type as ‘directed for Procedure for Cel-
`lulose Derivatives under Viscosity (911). Its viscosity 1S not less
`than _80'0% and llol mole lllall l20:0% of llllll Sllllell Oh the label
`i0r Vlscoslly lypes of #00 lcfggléolsgs Ifltletsst’ iljlld lltlfil
`llesg lllfall
`7.50%-anil H: fiolliiill 3,2,, 10'0 Cocgtitoie: a 6
`on
`6 a e
`or
`Vlscoslly yp
`g
`p
`'
`lIn4")l::‘:ll1all1ly5ll(l)h,/;)((Zf3iltlQ’Tv3;l1']tlt at 1050 for 2 hours:
`ll loses not
`Residue on ignition (281): not more than 1.5% for Hydroxypro-
`pyl Methylcellulose having a labeled viscosity of greater than 50
`centiP0iS95» n°t in°_r€
`than 3% for H)’£ir0?iYPr0PYi M°thYiC°ihii05¢
`having a labeled viscosity of 50 centipoises or less, and not more
`lhllll
`lol Hydloxyplopyl Methylcellulose l828 of all labeled
`viscosities.
`.
`Arsenic: Method [1 (211)? 3 PPih-
`Heavy m0t8i5aM€lh0d 11 (231)I 0-001%,1rni-Oiiiydroxyiarriina
`hydrochloride solution (1 in 5) being added to the solution of the
`i'°5id“°-
`Assay—[Cauti'on—Hydriodic acid and its reaction byproducts
`are highly toxic. Perform all steps of the Assay preparation
`and the Standard preparation in a properly functioning hood.
`Specific safety practices to be followed are to be identified to
`l
`e analyst performing this test.]
`H}’dri0diC afidml-lse a reagent iiaVin8 a 5PeCiiiC 8raVit)l 0i at
`hast i-59» e‘liiiVai"«rit t0 55% Hi-
`llllewlal “ll‘l."da"‘l S0l”ll°”_TlllllSl°l aholll 2'5 3 °l.l°.lllellet
`ll°f'"l?l°lyl1V°lgh§lll* l0 ‘l .lg0'lhl‘l Vollllllellllc llasll Céllllilllllllg lo
`in
`o o-xy ene,
`1 ute wit o-xy ene to vo time, an iniX-
`Standard p
`at '0n—I to a suitable serum vial weigh about
`135 mg of adrigliigracld andn4_0 mL of Hydn-Dd,-C acid, pipet 4
`mLofInt
`l
`t
`d d
`l
`t’ n’ t
`th
`'al, and close the vial
`securely
`as saiiitailbleséiegtiiin lsliooppelhvlweigh the vial and
`contents accurately, add 30 /.LL of isopropyl iodide through the
`septum with a Syringe again weigh, and Calculate the weight of
`lsopm 1
`- d-d
`dd d, b
`d-ff
`_ Add 90 L f
`th 1
`iodidepslimiloarllytf aagairii weigyh, andrggllbliilate the weilghtlbf $gth;1
`iodide added, by difference. Shake, and allow the layers to sep-
`arate.
`Assay preparation—Transfer about 0.065 g of dried Hydroxy-
`Pr0pylMethylcel1ulose, accurately weighed, to a 5-mL thick-walled
`reaction vial equipped with a pressure-tight septum-type closure,
`add _an amount of adipic acid equal to the weight of the test
`Sliecimen, and pipet 2 mL of Internal standard solution into the
`L:
`
`Methoxy
`Hydroxypropoxy
`j__(P9i°°“t) _____tP°‘°‘=“t)
`Substitution
`
`Type Max. Min. Max. ‘ .
`
`
`
`
`2%?
`lgjrs,
`$28
`_
`38
`2906
`27.0
`30.0
`.
`7.5
`29i0
`28-0
`30-0
`-
`110
`
`loss is greater than 10 mg, discard the
`If the weight
`weigh.
`mixture, and prepare another Assay preparation.
`.
`_*
`Chromatographic system Usea gas chromatograph equippe
`with a thermal conductivity detector. Under typical conditions,
`the instrument contains a 1.8-m X 4-mm glass column packed
`with 20 percent liquid phase G28 on 100- to 120-mesh support
`SIC that is I10i silanized, the column is maintained at 130°, and
`helium is used as the carrier gas.
`In a suitable system,.the res-
`0ii1ti0niR (556 Cli’0”ial08”0Pl1)’ (621)). b6tW<‘-en tiia t0i1iCn° and
`isopropyl iodide peaks is not less than 2.0.
`Calibration-—Inject about 2 aL of the upper layer of the Stan-
`dard preparation into the gas chromatograph, and record the
`chromatogram. Under the conditions described above, the rel-
`ative retention times of methyl iodide, isopropyl iodide, toluene,
`and o—xylene are approximately 1.0, 2.2, 3.6, and 8.0, respectively.
`Calculate the relative response factor, F,,,,-, of equal weights of
`by
`Qrmi/Asmi:
`
`in which Q,,,,,- is the quantity ratio of methyl iodide to toluene in
`the Standard Preparation, and Ami
`is the Peak area ratio Oi
`methyl iodide to toluene obtained from the Standardpreparation.
`Similarly, calculate the relative response factor, F,-,-, of equal
`weights of toluene and isopropyl iodide taken by the formula:
`Q5“./Am.’
`
`in which Q,,-,- is the quantity ratio of isopropyl iodide to toluene
`in the S,a,,da,d p,.epa,at,-0,,’ and Am, is the peak area ratio of
`isopropyl iodide to toluene obtained from the Standard prepa-
`mt,-On.
`Procedure—Inject about 2 iiL of the upper layer of the Assay
`preparation into the gas chromatograph, and record the chro-
`matogram Calculate the percentage of methoxy in the Hydroxy_
`propyl Methylcellulose taken by the formula:
`
`2(31/142)F,,,,-A,,,,,r(W',/ Wu),
`
`_
`_
`in which 31/ 142 is the ratio of the formula weights of methoxy
`and methyl iodide, F,,,,- is defined under Calibration, A,,,,,,~ is the
`ratio of the area of the methyl iodide peak to that of the toluene
`peak obtained from the Assay preparation, W, is the weight, in
`g, of toluene in the Internal standard solution, and W,, is the
`weight,
`in g, of Hydroxypropyl Methylcellulose taken for the
`Assay. Similarly, calculate the percentage of hydroxypropoxy in
`the Hydroxypropyl Methylcellulose taken by the formula.
`205/ l70)F""A““(W‘/ W")’
`in which 75/170 is the ratio of the formula weights of hydroxy-
`propoxy and isopropyl iodide, F,«,~ is defined _under Calibration,
`Auii l5 the “lilo of the area of the l5°Pl°Pyl lodllle Peal‘ l° lllat
`0i the toiiiene Peak Obtained ironi tin? Assay P’9Parali0'i» W: is
`the weight, in g, of toluene in the Internal standard solution, and
`W,, is the weight, in g, of Hydroxypropyl Methylcellulose taken
`for the Assay.
`
`Hydroxypropyl Methylcellulose 2208
`
`Where this monograph is specified or referred to
`in this Pharmacopeia, see the monograph Hydroxy-
`propyl Methylcellulose.
`
`Mylan v. Qualicaps, |PR2017—OO203
`QUALICAPS EX. 2015 — 4/5
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2015 - 4/5
`
`

`

`Hydroxypropyl / Official Monographs
`
`Hydroxypropyl Methylcellulose 2906
`
`Where this monograph is specified or referred to
`in this Pharmacopeia, see the monograph Hydroxy-
`propyl Methylcellulose.
`
`the dilution fold of Vused to obtain the Assay preparation, 1/is
`the volume, in mL, of Ophthalmic Solution taken, and AU and
`A5 are the absorbances of the solutions from the Assay prepa_
`ration and the Standard preparation, respectively.
`
`USP 23
`
`Hydroxypropyl Methylcellulose 2910
`
`Where this monograph is specified or referred to
`in this Pharmacopeia, see the monograph Hydroxy-
`propyl Methylcellulose.
`
`Hydroxypropyl Methylcellulose Phthalate—see
`Hydroxypropyl Methylcellulose Phthalate NF
`Hydroxypropyl Methylcellulose Phthalate 200731‘
`see Hydroxypropyl Methylcellulose Phthalate
`200731 NF
`
`Hydroxypropyl Methylcellulose Phthalate 220824‘
`see Hydroxypropyl Methylcellulose Phthalate
`220824 NF
`
`Hydroxypropyl Methylcellulose
`Ophthalmic Solution
`
`Hydroxyurea
`
`» Hydroxypropyl Methylcellulose Ophthalmic So-
`lution is a sterile solution of Hydroxypropyl Meth-
`ylcellulose. It contains not less than 85.0 percent and
`not more than 115.0 percent of the labeled amount
`of Hydroxypropyl Methylcellulose.
`It may contain
`suitable antimicrobial, buffering, and stabilizing
`
`Packaging and storage—Preserve in tight containers.
`USP Reference standards (ll)—USP Hydroxypropyl Methyl-
`cellulose RS.
`Identification—
`
`It responds to Identification test C under Hydroxypropyl
`Methylcellulose.
`B: Heat 5 mL of Ophthalmic Solution in a test tube over a
`the warm solution turns cloudy but clears upon chill-
`
`Sterility—It meets the requirements under Sterility Tests (71).
`pH (791): between 6.0 and 7.8.
`
`Standard preparation—Dissolve a suitable quantity of USP
`Hydroxypropyl Methylcellulose RS, accurately weighed, in water,
`and dilute quantitatively with water to obtain a solution having
`a known concentration of about 100 pg per mL.
`Assay preparation—Dilute quantitatively an accurately mea-
`sured volume of Ophthalmic Solution with water to obtain a
`solution having an equivalent concentration of approximately 100
`pg of hydroxypropyl methylcellulose per mL.
`Procedure—Pipet 2 mL each of the Standard preparation, the
`Assay preparation, and water to provide a blank, into separate,
`glass-stoppered test tubes. To each tube add 5.0 mL of diphe-
`nylamine solution (prepared by dissolving 3.75 g of colorless di-
`phenylamine crystals in 150 mL of glacial acetic acid and diluting
`the solution with 90 mL of hydrochloric acid), mix, and imme-
`diately insert the tubes into an oil bath at 105° to 110° for 30
`minutes, the temperature being kept uniform within 0.1° during
`heating. Remove the tubes, and place them in an ice-water bath
`for 10 minutes or until thoroughly cool. Concomitantly deter-
`mine, at room temperature, the absorbances of the solutions from
`the Standard preparation and the Assay preparation at 635 nm,
`with a suitable spectrophotometer, using the water solution as
`the blank. Calculate the quantity, in mg, of hydroxypropyl meth-
`ylcellulose in each mL of the Ophthalmic Solution taken by the
`
`76.06
`CH4N2O;,_
`Urea, hydroxy-.
`Hydroxyurea
`
`[127-07-1].
`
`» Hydroxyurea contains not less than 97.0 percent
`and not more than 103.0 percent of CH4N2O2, cal-
`culated on the dried basis.
`
`it
`
`in a dry
`
`Packaging and storageePreserve in tight containers,
`atmosphere.
`USP Reference standards (ll)—USP Hydroxyurea RS.
`Identification, Infrared Absorption (197K).
`Loss on drying (731)—Dry it in vacuum at 60° for 3 hours:
`loses not more than 1.0% of its weight.
`Residue on ignition (281): not more than 0.50%.
`Heavy metals (231): not more than 0.003%.
`Urea and related compounds—
`Developing solvent—Shake equal volumes of isobutyl alcohol
`and water'in a separator and allow the layers to separate. US¢
`the upper layer as the Mobile phase and the lower layer as the
`Stationary phase.
`p-Dimethylaminobenzaldehyde solution, 1 %—Dissolve 1.0 E
`of p-dimethylaminobenzaldehyde in 50 mL of alcohol, add 2 mL
`of hydrochloric acid, and dilute with alcohol to 100.0 mL.
`_
`pH 6.5 buffer solution—Mix 700 mL of 0.2 M dibasic sodium
`phosphate and 300 mL of 0.1 M citric acid.
`Standard preparati0n—Prepare a solution of urea in water.
`containing 0.1 mg per mL.
`_
`Test preparation—Dissolve 10.0 mg of Hydroxyurea In 1-0
`mL of water.
`,
`Procedure—Treat a suitable chromatographic paper 51“?
`(Whatman No.
`1 or equivalent) by dipping it in pH 6.5 buff”
`solution. Dry the paper strip, and apply 100 uL of the T55‘
`preparation and 50 uL of the Standard preparation. Place 311‘
`strip in a chromatographic chamber for descending chroma10S'
`raphy containing the Stationary phase in the bottom of the chain‘
`ber and the Mobile phase in the trough. Develop for 24 h0“r,5'
`remove the strip from the chamber, air-dry, and develop 833"“
`for 24 hours. Remove the strip, air-dry, spray with p-Dintelhyli
`aminobenzaldehyde solution, 1%,.and heat at 90° for 1
`to I
`minutes. Not more than two spots, other than the major 9°,”
`
`Mylan v. Qualicaps, IPR2017-00203
`QUALICAPS EX. 2015 - 5/5
`
`