2005
`
`The Official Compendia of Standards
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1085 - Page 1
`
`

`

`2005
`
`USP 28
`
`NF 23
`
`THE UNITED STATES PHAR1\1ACOPEIA
`
`THE NATIONAL FORMULARY
`
`By a11tltority qf the United States Pharmacopeial
`Co11ve11tion, Inc., meeting at JVashi11gto11, D.C,
`April 12- 16, 2000. Prepared by the Council of Experts
`and published by the Board qf Trustees
`
`Official fiwn Ja1111a,y / , 2005
`
`The designation on the cover of this publication, "USP NF.
`2005," is for case of identification only. The publication
`contains two separate compendia: The V11itcd States
`Plwrmacopeia, Twenty-Eighth Revision, and the National
`Formulary, Twenty-Third Edition.
`
`UNITED STATES PHARMACOPEIAL CONVENTION, INC.
`12601 Twinbrook Parkway, Rockville, MD 20852
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1085 - Page 2
`
`

`

`NOTICE AND WARNING
`
`Co11ccmi11g US. Patl!Tlt or Trademark Rights
`
`The inclusion in the U11i1ed States Pltan11acopl!ia or in the Natio11a/ FormrtlmJ' 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 nrc 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.
`
`Co11ccmi11g Use of USP or NF Text
`
`Use or the USP- NF is subject to the terms and conditions or the USP- NF License Agreement. Attention
`is called to the fnct 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 fi 2004 The United States Phannacopeial Convention, Inc.
`12601 Twinbrook Parkway, Rockville, MD 20852
`All righlr reserved.
`ISSN 0195-7996
`ISBN 1-889788-25-2
`Printed in Canada by Webcom Limited, Toronto, Ontario
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1085 - Page 3
`
`

`

`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 Experts Executive Committee . .. • . • . . . ..
`
`Complex Actives Division
`
`. . . . . . . . . • . . • . . • . . . . .
`
`Executive Committee ..•.. . .•.. ..... . .• .• . •.. .
`
`Expert Committees . . . . . . .. .. . . .. .. ...• . . . . . . .
`
`Genera.I f<?licies and Requirements
`D1v1s1on . . . . . . . . . . . • . . . . . . . • . . . . . . . . . . .
`
`Executive Committee . . ... . .• . .... ... .. . . ... . .
`
`Expert Committees . . . .... . . . . ......• . •. • .... .
`
`Information Division
`
`Executive Committee
`
`Expert Committees . . . . . . . . . . . • • . . . . . . . • . • . • • .
`
`xiii
`
`xiii
`
`xiii
`
`xiv
`
`xiv
`
`xiv
`
`xiv
`
`xiv
`
`xiv
`
`xiv
`
`xv
`
`xv
`
`xv
`
`Noncomplex Actives and Excipients
`Division • • . . . . . . . . . • . . . • . . . . . . . . . . • • . . .
`
`xvii
`
`Executive Committee . . . . . . . . . . . . . . . . • . • . . . . . .
`
`xvii
`
`Expert Committees . . . . . . . . . . . . . . . . . . . • . . . . . . .
`
`xvii
`
`USP Reference Standards Committee
`
`USP- FDA Antibiotic Monograph
`Subcommittee . . . . . • . . . . . . . . . . • . . . . . . . . . .
`
`xviii
`
`xviii
`
`Headquancrs Staff . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`x, iii
`
`Collabora1ors During 2000 200-1
`
`. . . . . . . . . . . . . . . .
`
`. ·xi
`
`Members of the United S1ates Phannacopei31 Convention
`as of Jun<! 30, 2004 . . . . . . . . . . . . . . . . . . . . . . .
`
`xxvi
`
`Articles Admitted to USP 28 by Supplement . . . . . . . . xxxiii
`
`Change in Official Titles . . . . . . . . . • . • . . . . . . .. . . .
`
`xx.iii
`
`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 .. . .... . .... . ... . .. . .. . .. . xxxvi
`
`Notices
`General Notices nnd Requirements
`
`Monographs
`General Official Monographs for USP 28
`
`13
`
`Dietary Supplements
`Official Monographs
`. . . . . . . . • . . . . . . • . . . . . . . . . 2059
`
`General Chapters
`See page 2198/or detailed co11te11ts
`General Tests and Assays . . . . . . . • . . . . . . . . . . . . . . 2201
`
`General Requirements for Tests and Assays ... ... . . . 2201
`
`Apparatus for TcsL~ and Assays . . . . . . . . . . . . . . . . . . 2234
`
`Microbiological Tests . . . . . . . . . . . . . . . . . . . . . . . . . 2242
`
`Biological Tests and Ass:iys . . . . . . . . . . . . . . . . . . . . 2256
`
`Chemical Tests and Assays . . . . . . . . . . . . . . . . . . . . . 2292
`
`Physical Tests and Dct<!nninations
`
`. . . . . . . . . . . . . . . 2359
`
`-
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1085 - Page 4
`
`

`

`iv
`
`Co11te11rs
`
`General Infonnation
`
`Dietary Supplement
`
`2516
`
`2768
`
`Reagents, Indicators, and Solutions
`Reagents
`. . • . . . . . . . . . . . . . • . . . . . . . . . . . • • . . .
`
`2791
`
`Indicators and lndica1or Tcs1 Paper;
`
`. . . . . . . . • • . . . . 2852
`
`Solutions . . . . • • . .
`
`. . . . . • . . • . . . . . . . . . . . . . .
`
`2854
`
`Buffer Solutions . . . . . . . . • . . . . . . . . . . . . . . . • . . 2854
`
`Colorimetric Solutions
`
`. . . . . . . . • . . . . . . . . • • . . . 2854
`
`Test Solutions
`
`. . . . . . . . . . . . . . . . . . . . . . . . . • . . 2855
`
`Volumetric Solutions
`
`. . . . . . . . . . . . . . . . . . . . • . . 2862
`
`Reference Tables
`Conllliners for Dispensing Ca11sules 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
`
`Intrinsic Viscosity Table . . . . . . . . . . . . . . . . . . . . . . . 2932
`
`Thcnnometric Equivalents
`
`2934
`
`NF 23
`
`People
`Sl!e USP 28
`
`viii
`
`Admissions
`Articles Admiltcd to NF 23 by S11pplt!m1!11I • . . • • • . . . 2940
`
`Revisions Appearing in NF 23 that were not Included in NF
`22 Including S11pp/c111e111.r • • • • • • • . • • . . • • • • • . 2940
`
`USP 28
`
`Excipients
`USP and NF Excipicnts, Listed by
`Category
`. . . . . . . .
`. ... . ....•... .. . . .
`
`Notices
`General Notices and Requirements
`
`. . • . . . . . . . . . . . .
`
`:?9-45
`
`Monographs
`Official Monographs for NF 23 . . . . . . . . . . . . . . . . . . 2947
`
`General Chapters
`See pagl! 2198 for detailed ,·0111c111.r
`General Tests and Assays See USP 28, page 2201
`General Information Sec USP 28, page 2516
`
`Reagents
`Reagents Sec USP 28, page 2791
`Indicators and Indicator Test Papers See USP 28, page
`2852
`Solutions &•c USP 28, page 2854
`
`Reference Tables
`See USP 28, page 2869
`
`Appendices
`Articles of Incorporation ..... . ........... ..• . , .
`
`31 I I
`
`Constitution and Bylaws . . . . . . . . . . . . . . . . . . . . . . . 3112
`
`Rules and Procedures .... .... . • .... . ....... . . . 3123
`
`USP Communications Policy
`
`. . . . . . . . . . . . . . . . . . . 3128
`
`USP Document Disclosure Policy . . . . . . . . . . . . . . . . 3129
`
`Proceedings • . . . . . . . . . . . • . . . . • . . . . . . . . . . . . . . 3131
`
`Index
`Combined Index to USP 28 and NF 23 . .... .. ·;·· ·. 3135
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1085 - Page 5
`
`

`

`non (!eteetor and contains a suitable column, 1.8 m x 2.0 mm,
`cd with 5% liquid phase G2 on support SIA. The column and
`lion port are maintained isothennally at 170° and 180•,
`·vely. Using a suitable carrier gas, adjust the flow rate so
`the derivatized pantolactone elutes in al!out 4 minutes.
`ograJ>!l five injections of the Standard solution 2, and
`the peak responses as directed under Procedure: the relative
`deviation of the peak response ratios (Rs) of the five
`·ons is not more than 2.0%. The retention time of the derivatized
`Jactone is about 0'.75 relative to that ofilie derivatized internal
`In a suitable chromatogram, the resolution factor between
`ewo peaks is not less than 2.0.
`ure--lnject about 0.5 µL of Standard solution 2 into the gas
`tograph, record the chromatogram to obtain not less than 40%
`maximum recorder response, and measure the peak responses of
`derivatized pantolactone and the derivatized internal standard.
`·1ar1y inject about 0.5 µL of the Test solution, record the
`o'gram, and measure the peak responses of the corresponding
`ents. Calculate the quantity, in mg, of pantolactone in the
`n of Preparation taken by the fonnula:
`0.4CI..RulRs),
`· h Cs is the concentration, in mg per mL, of USP Pantolactone
`in Standard solution I, and Ru and Rs are the ratios of the peak
`due to the pantolactone to that due to the internal standard
`from the Test solution and the Standard solution 2,
`·vely.
`requirements-It meets the requirements for Refractive
`, Water; Residue on ignition, Limit of aminopropanol, and Assay
`Dexpanthenol.
`
`Dextran 1 is a low molecular weight fraction of
`tran, consisting of a mixture of isomaltooligosac(cid:173)
`·des. It is obtained by controlled hydrolysis and
`·onation of dextrans produced by fermentation of
`conostoc mesenteroides (strain NRRL B-512; CIP
`S9, or its sub-strains, for example L. mesenteroides B-
`2F; NCTC, 10817), in the presence of sucrose. It is a
`se polymer in which the linkages between glucose
`'ts are almost exclusively a.-1,6. Its' weight-average
`;IIOlecular weight is about 1000.
`:facu2ing and storage-Store in well-closed containers at a
`~ r e between 4° and 30°.
`LllleUag-Wherc it is int~ded for use in preparing injectable
`: : : forms, the label states that it is sterile or must be subjected to
`processing during the preparation of injectable dosage forms.
`~! Reference standards {I J}-USP Dextran I RS. USP
`-0/oxinRS.
`Wntlllcation-
`~ Infrared Absorption ( I 97K}-To I to 2 mg each of USP
`-..iran 1 RS and the sample add one to two drops of water, grind in
`;.;:ie mortar for I to 2 minutes, add about 30Q mg of potassium
`de, and mix to a slurry. [NOT&-Do not grind.} Dry under
`~ at 40" for 15 minutes, and if it is not dry, continue drying for
`==.,~_! 5 i_ninutes. Crush the residue, prepare a disk, and run the IR
`-.-uwn with a blank potassium bromide disk in the reference beam.
`~ I~ meets the requirements of the test for Molecular weight
`--ibution•and average molecular weight.
`~rb~nce {851}-The absorbance of a 15% solution in water at
`nm 1s not more than 0.12, water being used as the blank.
`~ c ~tadon (78IS}: between +148° and +164° at 20•, for a
`~ 10 water, on the dried basis (dry at 70° under vacuum to
`"!'IIIUlllt weight), and corrected for the content of sodium chloride.
`~blal llmlts (61)-The total aerobic microbial count does not
`I01 cfu per g, detennined by plate-count; and the total
`b"
`ltled molds and yeasts count does not exceed IO cfu per g.
`
`Official Monographs I Dextran
`
`601
`
`I
`
`Bacterial eodotoxios (85) (where it is labeled as intended for use in
`not more than 25.0 USP Endotoxin
`the preparation of injcctables):
`Units per g.
`pH {791 }: between 4.5 and 7.0, in a 15% solution in water,
`Loss on drying {731 }-Dry it at I 00" to I 05° for 5 hours: it loses not
`more than 5.0% of its weight.
`Heavy metals, Method II (231 ): not more than 5 µg per g.
`Limit of alcohol and related impurities--
`Test solution- Proceed as directed for Test solution in the test for
`Limit of alcohol and related impurities under Dextran 40, except to
`use S.Og ofDextran I.
`Standard solution, Chromatographic system, and Procedure-(cid:173)
`Proceed as directed in the test for Limit of alcohol and related
`impurities under Dextran 40, The total area of peaks from impurities
`in the Test solution docs not exceed the area of the n-propyl alcohol
`solution peak.
`Limit of sodium chloride-Dissolve 5 g of Dextran I, accurately
`weighed, in I 00 mL of water. Add 0.2 ml of potassium chromate TS,
`and titrate with 0.1 N silver nitrate VS (see Titrimetry (541 ) ). Each
`mL of 0.1 N silver nitrate is equivalent to S.844 mg of sodium
`chloride: not more than 1.5% of sodium chloride is found.
`Limit of nitrogenous Impurities (461 ) (where it is labeled as
`intended for use in the preparation of injectables)-
`Sulfate solution- To I 000 ml sulfuric acid add 5 g of anhydrous
`cupric sulfate and 500 g of potassium sulfate. Dissolve by heating,
`and store at 60°. [NOTE-If storage at 60'· is not possible, prepare a
`smaller quantity of Sulfate solution on the day of use, adjusting
`proportions accordingly.]
`/ndicatc>r-,-Dilute a mixture of 20 mL of, a 0.1 % solution of
`bromocresol green in alcohol l!Jld 4 mL of methyl red TS with water
`to 100 mL.
`Procedure-Transfer 0.2g Dextran I, accurately weighed, to a
`micro-Kjeldahl flask, Add 4 mL of Sulfate solution. Heat until the
`solution exhibits a clear green color and the sides of the flask are free
`from carbonaceous material. Cool, cautiously add 30 mL of water,
`mix, and transfer the solution to a steam distillation unit. Rinse the
`Kjeldahl flask with three 5-mL portions of water, adding the washings
`to the solution. Add IS mL of 45% sodium hydroxide solution,
`immediately close the distillation apparatus, and start steam
`distillation immediately. Receive the distillate in I mL of Indicator
`and sufficient water to cover the end of the condensing tube. Upon
`completion of the distillation, remove the receiving flask, and rinse
`the end of the condensing tube with a small quantity of water, adding
`the rinse to the distillate. Titrate the distillate with O.OION
`hydrochloric acid until the color changes from blue to reddish
`violet. Perform a blank .detennination1 and make any necessary
`correction. The corrected volume of O.OION hydrochloric acid
`required to change the color does not exceed 0.1 S mL ( 110 ppm of
`nitrogen).
`Molecular weight distribution and average molecular weight(cid:173)
`Mobile phase-Prepare a filtered and degassed solution of sodium
`chloride containing 2.9 g per liter.
`Calibration sc>lution-Prepare a solution containing about 0.45 mg
`of isomaltotriose (3 glucose units) and 0.60 mg of sodium chloride
`I
`per mL.
`Reference solution-Prepare a solution of USP Dextran I RS in
`Mobile phase containing 6.0 to 6.5 mg per mL.
`Test solution-Prepare a solution of Dextran I in Mobile phase
`containing 6.0 to 6.5 mg per mL.
`· Chromatographic system (see Chromatography (621}}--The
`liquid chromatograph is equipped with a differential refractive
`index detector and two I 0-mm x 30-cm columns in series that
`contain packing L54 and are maintained at 20-25•. The flow rate is
`0.07 to 0.08 mL per minute, maintained constant to ± I¾.
`Procedure-Inject about 100 µL of the Ca/ibratic>n solution,
`record the chromatogram, and note the retention times of the peaks.
`Separately inject equal volumes (about 100 µL) of the Reference
`solution and Test solution, and record the chromatograms. Using the
`retention times in the chromatogram of Calibration solution, identify
`the peaks due to isomaltotriose and sodium chloride in the
`chromatograms of Reference sc>lutic>n and Test sc>lution. Disregard
`the peak due to sodium chloride in Reference solution and Test
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1085 - Page 6
`
`

`

`602
`
`Dextran
`
`OJJ1cial Monogmpl,s
`
`USP 28
`
`so/11ticm. Calculate the weight-a\cragc mokcular weight, M-,. by the
`fonnula:
`
`kll ;M.,
`in whid 1 11: is the weight )'lmponion of oligosaccharidc i. and .\/, is
`the molecular weight of ohgosacclmride i. Use the following
`molec.'lllar \ I eight values for calcul,llion:
`11!0
`Glucose
`342
`lsomaltosc
`504
`lsomahotriose
`666
`lsomaltotctraose
`828
`lsomaltopcntaosc
`990
`lsomultohcxaosc
`1152
`lsomahohcptaosl!
`1314
`I somaltooctaosc
`1476
`lsomaltononaose
`1638
`lsomaltodL'Caosc
`1800
`lsomalloundecaosc
`1962
`lsomaltododecaose
`2124
`lsomaltotridecaosc
`2286
`lsomallotetradccaose
`2-148
`lsomollopentadecaose
`2610
`lsomaltohexadecaosc
`2772
`lsomaltohcptadccaose
`2934
`lsomaltooctadecaose
`3096
`lsomaltononadccaose
`Calculate the amounts of the fractions with fewer tl1un 3 and with
`more than 9 glucose units for the Refen:11u solutio11 and the Test
`.wl11ticm: the M. and amounts of the fractions obtained for the
`Refere11ce .m/11Jio11 are within the values stated in the data sheet that
`ac,;ompanies USP Dextran I RS. TheM •. ofDextran I is between 850
`and 11 SO. The fraction with fewer than 3 units of glucose is less than
`15%, and the fraction with more than 9 units of glucose is less than
`20%.
`
`Dextran 40
`
`Dcxtrans.
`Dextrans
`
`(900-1-54-0].
`
`» Dextran 40 is derived by controtle~ hydrolysis and
`fractionation of polysaccharides elaborated by the
`fermentative action of certain strains of le11co11ostoc
`mese11teroides {NRRL, 8.512 F; NCTC, l 0817) on a
`sucrose substrate. It is a glucose polymer in which the
`linkages between glucose units are almost entirely of the
`cc-l: 6 type. Its weight average molecular weight is in the
`35,000 to 45,000 range.
`Packaging and storage-Preserve in well-closed containers. Store at
`25' , excursions permitted between 15 and 30' .
`-
`Labeling-Where it is intended for use in preparing injectable
`dosage forms, the label states that it is sterile or must be subjected to
`furtller processing during the preparation of injectable dosage fonns.
`USP Rdercnce standards { 11 }-USP Dextran 40 RS. USP De.ttrat1
`4 Calihratio11 RS. USP Dettrat1 JO Ca/ibratio11 RS. USP Dcxtra11 40
`Calibration RS. USP De."Ctrall 70 Calibratio11 RS. USP De.'Clra11 150
`Calibratio11 RS. USP De:r:tra11 V. Marker RS. USP Dextra11 40 System
`Suitability RS. USP E11doto."Ci11 RS.
`Color or soludon-The nbsorb:mce ofa solulionin water (I in 10),
`measured in u 4-cm cell detennined nt 375 nm against a water blank,
`is not greater than 0.20.
`ldcntlficallo-
`!,!{rared Absorption ( 197K).
`A:
`B: Prepare four Test solutions of Dextrun 40 in water, in such a
`manner that the concentrutions ore accurately known and npproxi(cid:173)
`motely evenly distributed in the range or 2% to 0.5%. Using a
`cupillo.ry tube viscosimeter having dimensions such that the flow time
`or water is not less ~an 100 seconds, measure the flow times ofwnter
`
`iscosity numbci;
`
`and or the Test so/11tio11 at 20 . Calculate thi:
`c-Jch of the Test solutil/11.1· by the fonnula:
`lln[(R11 )(l • t )]) I C.
`in which R, is the rntio of the densny of the individual Test ml11ti,111 1c •
`that of\\ater; rand I arc the fiO\\ tunt:, for tht! r.m solutimr and water
`respectively; and C is the concentration, in g per ml , ofDcxtran 40 j~
`r~ of each of the IL"
`the T.:H so/111io11. PlOI th<.? ,·i,cosit} num
`.m/11tim1s against their rc~pcUi\ <.? concentrations, and clra1\
`rhc
`straight line of best fit through the points and extrapolat<.? tn 2c
`concentration: tho: rnlue of the nitcr.:cpt is bct11ccn 18 and :n mlr,cr
`g.
`SpeciHc rotation (78 IS 1:
`bt!l11 ct:n T 195 and .,.. 203 .
`T1:w .w/11tit111: 20 mg per ml, hcJh:d, if necessary, on a watcrb.uJi
`to dissolve.
`Bactcriul cndotoxins (851 /11-/wc 11 is lc1hel1!tl us i11te11cl.·dJ11rrL1"e ui
`the prc:parcuim1 of i11jc:c 111/Jh•~)- \Vhcn tested in Sodium Chloride
`Injection { I in I 0), it contains not more than 1.0 USP Endotoxin Unit 1
`per ml.
`Inject intravenously 1.0 ml of a sterile I in 10 solution or1
`Surety-
`10% Dcxtran 40 in saline TS into each oflive mice weighing 18 ~ !
`20 g. The injection period is not less than IO seconds and not greaia
`than 15 seconds, If there arc no deaths within 72 hours, it meet~ the
`requirements of the test. If I or more animals die, continue the !Cit
`using 10 mice weighing 20 ± 0.5 g. If all animals sur\'ive for 7l
`hours, the requirements of the test arc met.
`·
`pH (791}: between 4.5 and 7.0, in a solu1ion (! in 10).
`Loss on drying (731 )-Dry it at l05 for 5 hours: it loses not
`than 7.0% of its weight.
`Sulfute (211 )-A 1.5-g ponion shows no more sulfate
`corresponds to 0.45 mL of 0.020 N sulfuric acid (0.03%).
`Hcuvy metals, Met/rod fl (231 ): 5 11g per g.
`Limit or nitrogenous Impurities (ll'hc:re it i1· lubell!d as i11te11dec/
`•
`use i11 tire pn:puratio11 of i11jcctab/c•s)-
`f.
`S11{futc: .m/11tio11- To IOOO ml of sulfuric acid add 5 g ofanhy
`cupric sulfate and 500 g of potassium sulfate. Dissolve by hea ·
`and store at 60 • [NOTE- If storage at 60 is not possible, pre
`.
`smaller quantity of S11lji11e sol111io11 on the dny of use, adjusting1
`proportions accordingly.]
`.,.
`h1dicu1<1r Dilute 11 mixture of 20 ml of a 0.1% solutio11l
`bromoci:c5ol green in o\coliol and 4 mL of methyl red TS will] '
`to 100 ml.
`Procedure Transfer 0.2 g, accurately weighed, to a m!
`Kjcldahl flask. Add 4 mL of S11(fat1! solution. Heat until the sol
`c;xhibits n clear green color und the sides of t11e Ollffek nre free (cid:173)
`carbonaceous material. Cool, ond trJnsfer the solution to a s
`distillation unit. Rinse the Kjcldahl flask thn.-c times with 5 mt
`water, adding the washings to the solution. Add 15 mL of"4
`sodium hydroxide solution, immediately close .the distill ·
`apparatus, and commence steam distillation without delay. Rec ·
`the distillate in I mL of /mlit·ator in a I 00-mL tlask, keeping the
`of the condensing tube below the liquid surface for 5 minutes •
`above the liquid surface for I minute. Upon completion of ·
`distillation, remove the receiving flask. and rinse the end of
`condensing tube with a small quantity of water, addi~g the ri~c'!J
`distillate. Titrate the distillate with 0.0 ION hydrochlorii,: ac.id uµlll
`color changes from blue to reddish violet. Pcrfonn n b
`determination, and make any necessary correction.:. The co(cid:173)
`volume of 0.0 ION hydrochloric acid titrated docs not exceed .D.l
`ml (0.01 %, as N).
`.
`Limit of alcohol and related Impurities--
`Test so/111io11- Dissolve without heating 5.0 g in 100 m~ of..
`and distill the solution, collecting the first 45 mL or the d. ·"· ·
`Dill!te the distillate 1\ith water to 50.0 ml, and mix.
`Sta11clarcl so/mjo11- To 25.0 mL of the Test so/111io11 add~-~
`a 1.5% (wlv) solution of 11-propyl alcohol.
`Chromatographic system- The gas chroJ11atograP,h is c;g
`with II flame-ionization detector and contains a 2-mm x
`•
`column packed with . su[!port S3. The column tenipe '
`mnintaincd at about 160°, lhc injection porl temperature is mui' .
`at about 240 , and the detector is maintained at iibout 2 I 2J
`carrier gas is nitrogen, flowing [!t ·a rote of about 25 mL per
`[Nore;...fnjector seals may dcteri·orate nflcr multiple· injections
`Standard ond Test so/11tio11s. Inspect the seals before ·making a
`of injections.]
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1085 - Page 7
`
`

`

`Official Monographs I Dextran
`
`603
`
`give values or weight average molecular weight, M~ within 5% of the
`labeled values for each of the Calibrotio11 solutions and 180 ± 2 for
`dextrose. Chromatograph the System suitability sofutio11, and record
`the peak responses as directed for Procedure. Calculate 'Xiw of the
`total molecular weight distribution using the same method as directed
`for the Calibratio11 solutio/lS, but inserting the now known values of
`bi, b:, b,, b,, and bs. It is between 39,000 and 46,000.
`Similnrly, calculate M~ of the high-fraction dextr.ln eluted through
`section II by the formula:
`
`in which II is defined by the relations:
`
`L )', > 0.1 LY, .
`••I
`•
`(
`)
`I •
`i • 1
`
`I
`
`It is between 111,000 nnd 135,000.
`Similarly, calculate 'Xt of the low-frJction dcxtran eluted in nnd
`ofter section III by the formula:
`
`in which III is defined by:
`
`f _\', > 0.1( t .r,) .
`
`•
`
`I
`
`, • "' -
`
`I
`
`It is between 6000 and 9000.
`Pmccd11rr.• Chromatograph a 50-11L I olumc of lhe Test so/111icm,
`and record the pcak_!!!sponses. Calculate ,alttcs of the weight average
`molecular weight, ,If., of the Iota I molecular 1\eight distribution of
`the high-fr.iction dcxtran, and oftl11: 101\-fntcuon de~tran as directed
`for Srftcm S11itabili(1• under C/m,mawgraplzy (621) the values arc
`bcmccn 35,000 and 45,000, nol more than 120,000, nnd not less than
`5,000, rcspccth ely. With 1hc I alu.:s of /1 , b,. /,1 , b., and b,, obtained
`11 ith the Calilw11tio11 sol11tim1s under C/11nmmog[aphk J):W !III,
`calculate the number avcmge molecular weight, M., of the total
`molecular weight distribution of the Test solwio11 by substituting the
`
`F
`
`OMiJIIIIJ'l!'--1,,cparatcly inject equal volwnes (about l µL) of the
`·• n; the Standard sol11tio11, nnd n 0.05% (w/v) solution of n,
`.. bol and wnter, nnd mcnsure the peak R!Sponses. After
`,!for any impurities in the 11-propyl alcohol solution nnd
`·ta1 area of peaks from impurities in the Test so/111io11 does
`tlic area of the 11-propyl nlcohol solution peak.
`· · c'lmpurlties (ll'herc it is labeled.as i11tCt(ded for '!S! i11 tlzc
`II of injectables)- Prepnre n stenle solution contammg I 00
`iit. Sodium Chloride Injection. At intervals or about 48
`,
`· ~ect three 0.5-mL doses into the peritonenl cavities of each of
`-~igs. At 14 day~ ofter the first intr.1pcrito!1cal i~jection, inject
`'mll. intiavi:nously mto each of 3 of the guinea pigs, nnd at 21
`1Rl1 the other 3 b'llinea pigs similarly. Observe the nnimals for
`•
`after each intrJvcnous injection and ngain 24 hou~ later.
`exhibit no evidence of nnaphylactoid reactions, such as
`' g; bristling of hair, or respiratory distress.
`Jar w~lght distribution and weight and number nerage
`lir welghts-
`·
`"1fohi/e j,has Prepare a suitable degnsscd and filtered solution
`tfifllllining 7.1 g of nnhydrous sodium sulfate per L in water.
`£4/ibrrztion sollltio11s- Separately dissolve USP Dextr.ln 4 Cali•
`·on RS, USP Dextran IO Calibration RS, USP Dcxtran 40
`·on RS, USP Dcxtran 70 Calibration RS, and USP Dc:xtran
`· €alibration RS in Mobile phase to obtnin solutions each
`· ing 20 mg per ml.
`'arker sol111io1 Prepare n solution in Mobile phase containing 3
`fdexttose and 3 mg of USP Dextran v. Mnrker RS per ml.
`suitability so/u1io11~ Prepare a solution of USP Dextr.ln 40
`Suitability RS in Mobile phase containing 20 mg per ml.
`solutio1 Prepare a solution of Dextr.ln 40 in Mobile p/zuse
`· ing 20 mg per ml.
`matograp/ric system (sec Cl1rvli1atograp/,y {621 ) )- The
`• chromatograph is equipped with o refractive index detector
`llliee 7.5-mm x 31km columns containing packing L38, and
`'ncd at n constant temperature. Chromatograph the Marker
`'011. and record the peak responses as directed for Procedure: the
`profile shows two peaks, the first due to the 1: marker, the
`-d'due to dextrose. Determine the void volume, V.,, or the system
`le inflection point or the ascending port of the first peak.
`· e the total volume, V,, of the system as the mwdmum or the
`· ,Peak; the tailing factor, t, of the dextrose pe.ik is not more than
`• 1111d the relative stnndnrd deviation or the ratio 1:1 v, is not more
`1%. Chromatograph eoch or the Calibration sol11tio11s
`ly, and record the peak responses as directed for Procedure.
`each profile into at least 60 vertical sections or equal volume
`ts. (The actual number o r sections is represented by the
`le a in the equations below.) Record y., the heig~t abOV\: the
`, com:sponding to each value or,,,, tlte vo Jume eluted at that
`.
`~on.For each value of,,,. calculate the distribution coefficient, K,,
`•1-the fonnula:
`
`(1', - V.,) /( l'r - V,).
`Fmd i!j>propriate values of b,. b,. b,, b., and b,, using a suitable
`. lllelhod, that, when substituted in the equation:
`
`~ the resulting , alucs of ,If, substitu1ed, along \\ i1h their
`iponiJing ,alucs ofy, in tht: equation:
`
`M.
`
`I
`
`_i l'. M,)/ i .\,,
`
`, • J
`
`I
`
`-~ Gauss-Newlon mc1hml. mo,hticJ by Hanley {sec 0 . llanlcy
`G.k:ii"'elrits. 3 (1961 )], and the G Nilsson and K. Nilsson method fscc
`. .!~_'•in and K. Nilsson ] C hmmat, 101, 137 (197-l))arc suitable methods.
`•
`' C-fl1ting pmgrJm cap~blc of nonlinear regression may be used.
`
`,L ofYiallf
`1c distillal'-
`dO;mL'-"
`
`PGR2020-00009
`Pharmacosmos A/S v. American Regent, Inc.
`Petitioner Ex. 1085 - Page 8
`
`

`

`604
`
`Dextran O//u ial Mo11ograph1·
`
`<.:orrcsponding \ alu,:.~ of .M , alony: with their corresponding values of
`_, • in the ~-quarion:
`
`The numhcr a\ er.ti!.: molecular \\cighl 17_, i, hct\\ ccn 16,000 :md
`30,000. \\11cn: Deman 40 i~ labeled as mrcndcd for use in the
`preparation of injccrahks, the rJtio M, I . is 111 1hc I .4 10 I 9 rJngc.
`
`Dextran 40 in Dextrose Injection
`
`» Dextmn 40 in Dextrose Injection is a sterile solution of
`Dextran 40 and Dextrose in Water for Injection. It
`contains in each I 00 ml not less than 9,0 g and not more
`than I I .0 g of Dextran 40 and not less than 4.1 g and not
`more than 5.0 g of dextrose (C6H1206)- lt contains no
`bnctcriostatic agents,
`
`Puckuging 11nd storage-Preserve in single-dose glass or plastic
`containers.
`Lubeling- The label states the total osmolnr concentration in
`mOsmol per liter. Where the contents arc less than I 00 mL, the
`label uhematively may state the total osmollll' concentration in
`mOsmol per mL.
`USP Reforence st11nd11rds ( 11 )-USP Dcxtro.w! RS. USP E11do1rui11
`RS-
`Color or solution-Its absorbancc, detennined at 375 nm against a
`water blonk, is not greater than 0.06.
`ldentilicathm-Dilutc a portion quantitatively with dextrose solu(cid:173)
`tion (4.5 in I 00) to n concentration of about IO mg of Dextran 40 per
`mL. Using a capillary tube viscosimctcr having dimensions such that
`the now time of water is not less than I 00 seconds, measure the flow
`times of the diluted Injection and that of a dextrose solution (4.5 in
`I 00) at 20=. Calculate the intrinsic viscosity by the formula:
`lln[(R11)(1/ 10)]J / C,
`in which R,, is the ratio of the density of the diluted Injection to that of
`the i.lextrosc solution; t ani.1 10 arc the flow times for the ililuted
`Injection and the dextrose solution, respectively; and C is the
`conccntmtion, in g per mL, of Dc1ctran 40 in the diluted Injection: the
`intrinsic viscosity is between 18 lltld 23 mL per g.
`Bacteriul cndotoxins (85)-11 contains not more than 1.0 USP
`Endotoxin Unit per mL.
`Sterility (71 )-It meeL,; the requircmcnL,; when tested as directed for
`Mcmbrmw Filtmrio11 under Te.rt for Sterility ,f the Pmd11ct to he
`fa:amil/l:d.
`pH (791): henvccn 3.0 ond 7.0.
`Hcin-y metals, Mer/wt/ II (231): 5 µg per mL.
`Limit of 5-hydroxymcthylfurfurnl nnd related substances(cid:173)
`Dilute an accurately measured volume of Injection, equivalent to
`1.0 g of C6H120• · H20, v..ith water 10 500.0 mL. Determine the
`absorbancc of this solution in 11 I-cm cell at 284 nm, using water as
`the blank: the nbsorbance is not more than 0.25.
`Otbt,?r requirements-It meets the requirements for /11.fecrions {I)
`and for Partie11larc Matter i11 bifccti011s (788).
`Assay for dextrose--
`Mobile p/iar,--Use filtered and degassed 0.01 N sulfuric acid.
`System .rnilahility prcparatio11- Preparc a solution in water
`containing 5 mg each or dextrose and xylitol per mL.
`Sta11danl prcparatio11- Dissolve no accurately weighed quantity of
`USP Dextrose RS in water to obtain a solution having o known
`concentration of about 5 mg of dextrose monohydratc per mL.
`
`.
`,11-.my preparation Transfer an accur.itely measured volume
`Injection, equivalent to about 250 mg of dextrose monohydr-Jlc, 101 •
`50-mL volumetric llask, dilute \\ith water to volume, and mix.
`Chromatographic system (sec Chromatograplir (621 ))-TII,
`liquid chromato1m.1ph is equipped with a rcfracthe index dct~
`and a 7.8-mm x -30-cm column cont:uning packing LI 7. ThccollllllQ
`und, 1f necessary, the detector arc maintained at u i:on51a111 ,
`temperature of about 40 , and !he flow rate 1, ahout O 6 ml 11'!
`minute. Chromatograph the 5_rtlc111 s11iwhili11 p rcparmim1, ar~
`measure the peak rc<;ponscs as direc_tcd for Pm ccd11n
`the rcsolut~
`R, between rhc dextrose and x:yhrol pcaJ.,., 1<; nm lc,s than 2 5
`Chromatogr,1ph the: Sta1Ult1nl pn·/1Cm1tio11 as dircct.::d for f'mcc,/11r, .
`the relative standard deviation for replicate in1cc11011, 1, not more tbai,
`1.5% for de:ittrose.
`Pmcc:drll'c - Inject c11ual volumes (about 50 11L) or the S11111dart
`pn'Paration and the .-lsm_r prq,aratimr into the chromarn~
`record the chromatograms, and measure the rc, ponsc, for lhc.
`dextrose peak