Search USP29
`
`Paclitaxel
`
`C47H51 NO14
`
`85391
`
`Benzenepropanoic acid 13benzoylaminoahydroxy 612bbisacetyloxy12benzoyloxy2a344a56910111212a12bdodecahydro411dihydroxy
`ester 2aRRaci 413 4ai3 60 9aaR P
`a 12a 12aa 12ba
`4a81313tetramethy15oxo711methano1Hcyclodeca34benz12boxet9y1
`2aR4S4aS6R9S11S12S12aR12bS12a344a6910111212a12bDodecahydro469111212bhexahydroxy4a81313tetramethy1711methano5H
`33069624
`cyclodeca34benz12boxet5one
`12 benzoate 9 ester with 2R3SNbenzoy13phenylisoserine
`
`612bdiacetate
`
`Paclitaxel contains not less than 970 percent and not more than 1020 percent of C47H51N014 calculated on the anhydrous solvent
`free basis
`
`Abraxis EX2051
`Actavis LLC v Abraxis Bioscience LLC
`1PR201701101 1PR201701103 1PR201701104
`Page 1 of 7
`
`

`

`CautionPaclitaxel is cytotoxic Great care should be taken to prevent
`
`inhaling particles of Paclitaxel and exposing the skin to it
`
`Packaging and storage Preserve in tight
`
`light resistant containers
`
`and store at controlled room temperature
`
`Labeling The labeling indicates the type of process used to produce the material and the Related compounds test with which the material complies
`
`USP Reference standards c 11
`
`USP Endotoxin RS USP Paclitaxel RS USP Paclitaxel Related Compound A RS USP Paclitaxel Related Compound 8 RS
`
`Identification
`
`A Infrared Absorption
`
`197K
`
`B The retention time of the major peak in the chromatogram of the Assay preparation corresponds to that in the chromatogram of the Standard preparation as
`obtained in the Assay
`
`Specific rotation
`
`781S
`
`between 4900 and 5500 at 200 calculated on the anhydrous solvent free basis
`
`Test solution 10 mg per mL in methanol
`
`The total aerobic microbial count does not exceed 100 cfu per g It meets the requirements of the tests for the absence of
`Microbial
`limits C 61
`Staphylococcus aureus Pseudomonas aeruginosa Salmonella species and Escherichia coli
`
`Bacterial endotoxins
`
`85
`
`Water Method lc
`
`921
`
`Residue on ignition
`
`281
`
`It contains not more than 04 USP Endotoxin Unit per mg of paclitaxel
`not more than 40
`not more than 02
`
`Heavy metals Method II
`
`231
`
`0002
`
`Related compounds
`
`TEST 1 for material
`
`labeled as isolated from natural sources If the material complies with this test the labeling indicates that it meets USP Related compounds
`
`Test 1
`
`Diluent Prepare as directed in the Assay
`
`Solution A Prepare filtered and degassed acetonitrile
`Solution 8 Prepare filtered and degassed water
`
`Mobile phase Use variable mixtures of Solution A and Solution 8 as directed for Chromatographic system Make adjustments if necessary see System Suitability
`
`under Chromatography c 621
`
`Abraxis EX2051
`Actavis LLC v Abraxis Bioscience LLC
`1PR201701101 1PR201701103 1PR201701104
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`

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`System suitability solution Dissolve accurately weighed quantities of USP Paclitaxel Related Compound A RS and USP Paclitaxel Related Compound B RS in
`to obtain a solution having known concentrations of about 10 pg of each per mL Transfer 50 mL of this solution to a 50mL volumetric flask dilute with
`methanol
`Diluent to volume and mix
`
`Standard solution Dissolve with the aid of sonication an accurately weighed quantity of USP Paclitaxel RS in Diluent and dilute quantitatively
`necessary with Diluent to obtain a solution having a known concentration of about 5 pg per mL
`
`and stepwise if
`
`Test solution Use the Assay preparation
`
`The liquid chromatograph is equipped with a 227nm detector and a 46mm x 25cm column that contains
`Chromatographic system see Chromatography
`5pm packing L43 The flow rate is about 26 mL per minute The column temperature is maintained at 300 The chromatograph is programmed as follows
`Solution A
`Solution B
`Time
``0
`minutes
`035
`35
`3580
`3560
`8035
`35
`
`621
`
`j
`
`6070
`7080
`
`Elution
`
`isocratic
`
`linear gradient
`
`linear gradient
`
`65
`6520
`2065
`65
`
`lisocratic
`Chromatograph the System suitability solution and record the peak responses as directed for Procedure the relative retention times are about 078 for paclitaxel
`related compound B relative to the retention time for paclitaxel obtained from the Test solution and the resolution R
`related compound A and 086 for paclitaxel
`less than 10 Chromatograph the Standard solution and record the peak responses
`between paclitaxel related compound A and paclitaxel
`related compound B is not
`as directed for Procedure the relative standard deviation for replicate injections is not more than 20
`
`Procedure Inject a volume about 15 pL of the Test solution into the chromatograph
`taken by the formula
`Calculate the percentage of each impurity in the portion of Paclitaxel
`
`record the chromatogram and measure the areas for the major peaks
`
`100Fr
`
`ru
`
`in which F is the relative response factor for each impurity peak see Table 1 for values r is the peak area for each individual
`
`impurity and ru is the peak area for
`
`paclitaxel
`
`Relative
`Retention
`Time
`
`024
`
`053
`
`057
`
`078
`
`Relative
`Response
`
`Factor F
`129
`
`100
`
`100
`
`126
`
`Baccatin III
`
`10Deacetylpaclitaxel
`
`7Xylosylpaclitaxel
`
`Table 1
`
`Name
`
`Cephalomannine paclitaxel related compoundAalI
`
`Limit `0
`02
`05
`02
`
`Abraxis EX2051
`Actavis LLC v Abraxis Bioscience LLC
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`

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`Relative
`Retention
`Time
`
`078
`
`086
`
`110
`
`110
`
`140
`
`185
`
`Relative
`Response
`
`Factor F
`126
`
`100
`
`100
`
`100
`
`100
`
`100
`
`Name
`
`Limit `0
`
`23Dihydrocephalomannine
`10Deacety17epipaclitaxel paclitaxel related compound B
`Benzyl analog 2
`
`34Dehydropaclitaxel C
`
`7Epicephalomannine
`
`7Epipaclitaxel
`
`a21
`05
`
`b12
`
`b22
`03
`05
`
`1
`
`the sum of al and a2 is not more than
`
`2
`
`1 Resolution may be incomplete for these peaks depending upon the relative amounts present
`05
`Resolution may be incomplete for these peaks depending upon the relative amounts present the sum of b1 and b2 is not more than
`05
`3 The following chemical name is assigned to the related compound benzyl analog Baccatin III 13ester with 2R3S2hydroxy3
`acid
`pheny132phenylacetylaminopropanoic
`related impurities in Table 1 not more than 01 of any other single impurity is found and not more than 20 of
`
`In addition to not exceeding the limits for paclitaxel
`
`total
`
`impurities is found
`
`TEST 2 for material
`compounds Test 2
`
`labeled as produced by a semisynthetic process If the material complies with this test the labeling indicates that it meets USP Related
`
`Diluent Use acetonitrile
`
`Solution A Use a filtered and degassed mixture of water and acetonitrile 32
`Solution 8 Use filtered and degassed acetonitrile
`
`Mobile phase Use variable mixtures of Solution A and Solution 8 as directed for Chromatographic system Make adjustments if necessary see System Suitability
`
`under Chromatography
`
`621
`
`System suitability solution Dissolve accurately weighed quantities of USP Paclitaxel RS and USP Paclitaxel Related Compound 8 RS in Diluent using shaking
`and sonication if necessary to obtain a solution having known concentrations of about 096 mg and 0008 mg per mL respectively
`
`Test solution Transfer about 10 mg of Paclitaxel accurately weighed to a 10mL volumetric flask dissolve in and dilute with Diluent to volume using shaking and
`sonication if necessary and mix
`
`Abraxis EX2051
`Actavis LLC v Abraxis Bioscience LLC
`1PR201701101 1PR201701103 1PR201701104
`Page 4 of 7
`
`

`

`The liquid chromatograph is equipped with a 227nm detector and a 46mm x 15cm column that contains
`Chromatographic system see Chromatography k 621
`3pm packing L1 The flow rate is about 12 mL per minute The column temperature is maintained at 35
`Solution A
`Solution B
`Time
``0
`oA
`minutes
`020
`100
`0
`090
`2060 10010
`900
`10100
`6062
`6270
`100
`0
`
`0
`
`The chromatograph is programmed as follows
`
`Elution
`
`isocratic
`
`linear gradient
`
`linear gradient
`
`isocratic
`
`I
`
`Chromatograph the System suitability solution and record the peak responses as directed for Procedure the relative retention times are about 094 for paclitaxel
`related compound B and 10 for paclitaxel the resolution R between paclitaxel
`less than 12 and the relative standard
`related compound B and paclitaxel
`is not
`deviation for replicate injections is not more than 20
`
`Procedure Separately inject equal volumes about 15 pL of the Diluent and the Test solution into the chromatograph
`the peaks Disregard any peaks due to the Diluent Calculate the percentage of each impurity in the portion of Paclitaxel
`
`areas for all
`
`record the chromatograms
`
`and measure the
`
`taken by the formula
`
`in which F is the relative response factor for each impurity see Table 2 for values r is the peak area for each impurity obtained from the Test solution and rs is the
`
`sum of the areas of all the peaks obtained from the Test solution
`
`100Fr
`
`re
`
`Relative
`Retention
`Time
`
`011
`
`020
`
`042
`
`047
`
`080
`
`0921
`
`0921
`
`0941
`
`137
`
`145
`
`154
`
`Relative
`Response
`
`factor F
`124
`
`129
`
`139
`
`100
`
`100
`
`100
`
`100
`
`100
`
`100
`
`100
`
`100
`
`Table 2
`
`Name
`
`10Deacetylbaccatin
`
`III
`
`Baccatin III
`
`Photodegradant2
`
`10Deacetylpaclitaxel
`
`2Debenzoylpaclitaxel2pentenoate
`Oxetane ring opened acetyl and benzoy12
`
`10Acetoacetylpaclitaxel
`10Deacety17epipaclitaxel paclitaxel related compound B
`
`7Epipaclitaxel
`
`1013Bissidechainpaclitaxelz
`
`7Acetylpaclitaxel
`
`Limit `0
`01
`02
`01
`05
`07
`
`X1
`
`x2
`
`X3
`04
`05
`06
`
`Abraxis EX2051
`Actavis LLC v Abraxis Bioscience LLC
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`Relative
`Retention
`Time
`
`180
`
`214
`
`Relative
`Response
`
`factor F
`175
`
`100
`
`13Tesbaccatin III
`
`7Tespaclitaxel
`
`Name
`
`Limit `0
`01
`03
`
`1 Resolution may be incomplete for these peaks depending upon the relative amounts present the sum of xl x2 and x3 is not more
`than 04
`2 The following chemical names are assigned to the related compounds Photodegradant Oxetane ring opened acetyl and benzoyl
`and 1013Bissidechainpaclitaxel
`
`Photodegradant
`
`1R2R4S5S7R10S11R12S13S15S16S210diacetyloxy513dihydroxy4161717tetramethy18oxa3oxo12
`phenylcarbonyloxypentacyclo113101110411710u
`jheptadec15y1
`
`2R352hydroxy3pheny13phenylcarbonylaminopropanoate
`
`Oxetane ring opened acetyl and benzoyl migrated
`1S253R45557585 10R1355 10d iacetyloxy1247tetrahydroxy8121515tetramethy19oxo4
`phenylcarbonyloxym ethyltricyclo931038pentadec11en13y1
`
`2R352hydroxy3pheny13phenylcarbonylaminopropanoate
`
`1013Bissidechainpaclitaxel
`
`III 13ester with 2R352hydroxy3phenyl3phenylcarbonylaminopropanoic
`Baccatin
`pheny13phenylcarbonylaminopropanoic
`acid
`
`acid 10ester with 25352hydroxy3
`
`In addition to not exceeding the limits for paclitaxel
`
`total
`
`impurities is found
`
`related impurities in Table 2 not more than 01 of any other single impurity is found and not more than 20 of
`
`Organic volatile impurities Method IV 467
`
`meets the requirements
`
`467
`Residual solvents
`Official January 1 2007
`
`meets the requirements
`
`Assay
`
`Diluent Prepare a mixture of methanol and acetic acid 2001
`
`Abraxis EX2051
`Actavis LLC v Abraxis Bioscience LLC
`1PR201701101 1PR201701103 1PR201701104
`Page 6 of 7
`
`

`

`Mobile phase Prepare a filtered and degassed mixture of water and acetonitrile 119 Make adjustments if necessary see System Suitability under
`
`Chromatography
`
`621
`
`Standard preparation Dissolve using sonication if necessary an accurately weighed quantity of USP Paclitaxel RS in Diluent and dilute quantitatively
`1 mg per mL
`stepwise if necessary with Diluent to obtain a solution having a known concentration of about
`
`and
`
`Assay preparation Transfer about 10 mg of Paclitaxel accurately weighed to a 10mL volumetric flask Dissolve in Diluent using sonication if necessary dilute
`with Diluent to volume and mix
`
`The liquid chromatograph is equipped with a 227nm detector and a 46mm x 25cm column that contains
`621
`Chromatographic system see Chromatography
`5pm packing L43 The flow rate is about 15 mL per minute Chromatograph the Standard preparation and record the peak responses as directed for Procedure the
`is between 07 and 13 and the relative standard deviation for replicate injections is not more than 15
`tailing factor
`Procedure Separately inject equal volumes about 10 pL of the Standard preparation and the Assay preparation into the chromatograph
`and measure the areas for the major peaks Calculate the quantity in mg of C47H51N014
`taken by the formula
`
`chromatograms
`
`in the portion of Paclitaxel
`
`record the
`
`in which C is the concentration
`
`in mg per mL of USP Paclitaxel RS in the Standard preparation and ru and rs are the peak responses for paclitaxel obtained from
`
`10Cru rs
`
`the Assay preparation and the Standard preparation respectively
`
`Auxiliary Information Staff Liaison Feiwen Mao MS Senior Scientific Associate
`Expert Committee MDOOD05 Monograph DevelopmentOphthalmics Oncologics and Dermatologicals
`U5P29NF24 Page 1624
`Pharmacopeial Forum Volume No 304 Page 1279
`Phone Number 13018168320
`
`Abraxis EX2051
`Actavis LLC v Abraxis Bioscience LLC
`1PR201701101 1PR201701103 1PR201701104
`Page 7 of 7
`
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