throbber
EUROPEAN PHARMACOPOEIA - 8th EDITION
`published 15 July 2013
`replaces the 7th Edition on 1 January 2014
`Volumes 1 and 2 of this publication 8.0 constitute the 8th Edition of the European Pharmacopoeia. They will be
`complemented by non-cumulative supplements that are to be kept for the duration of the 8th Edition. 2 supplements
`will be published in 2013 and 3 supplements in each of the years 2014 and 2015. A cumulative list of reagents will be
`published in supplements 8.4 and 8.7.
`For legal reasons, the official publication date of a European Pharmacopoeia edition is 6 months ahead of its application
`date. However, in practice, an edition may be made available before its official publication date. Note that the early
`availability of an edition does not modify its official publication and application dates.
`If you are using the 8th Edition at any time later than 1 April 2014, make sure that you have all the published supplements
`and consult the index of the most recent supplement to ensure that you use the latest versions of the monographs and
`general chapters.
`The European Pharmacopoeia Archives contain the 1st Edition to 7th Edition in PDF format. They are available to all
`European Pharmacopoeia subscribers with an up-to-date subscription (paper, online or USB stick) and a registered EPID
`code. To gain access, please register the EPID code found on the inside-front cover.
`The registration page is accessible through the EDQM website (visit www.edqm.eu/register).
`
`EUROPEAN PHARMACOPOEIA - ELECTRONIC VERSION
`The 8th Edition is also available in an electronic format (online and USB stick) containing all of the monographs and
`general chapters found in the printed version. With the publication of each supplement the electronic version is replaced
`by a new, fully updated, cumulative version.
`PHARMEUROPA ONLINE
`European Pharmacopoeia’s free online forum (http://pharmeuropa.edqm.eu)
`Pharmeuropa Online contains preliminary drafts of all new and revised monographs proposed for inclusion in the
`European Pharmacopoeia and gives an opportunity for all interested parties to comment on the specifications before they
`are finalised. Pharmeuropa Online also contains information on the work programme or of general interest and articles
`published in Pharmeuropa Bio & Scientific Notes (containing scientific articles on pharmacopoeial matters). Archives of
`Pharmeuropa and Pharmeuropa Bio & Scientific Notes can be accessed via this website.
`
`PHARMACOPOEIAL HARMONISATION
`See the information given in general chapter 5.8. Pharmacopoeial harmonisation.
`
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`https://www.edqm.eu/store (for prices and orders)
`
`HELPDESK
`To send a question or to contact the EDQM, use the HelpDesk, accessible through the EDQM website
`(visit www.edqm.eu/hd).
`
`KNOWLEDGE
`Consult Knowledge, the free database, at www.edqm.eu to obtain information on the work programme of the European
`Pharmacopoeia, the volume of Pharmeuropa and of the European Pharmacopoeia in which a text has been published,
`trade names of the reagents (for example, chromatography columns) that were used at the time of the elaboration of the
`monographs, the history of the revisions of a text since its publication in the 5th Edition, representative chromatograms,
`the list of reference standards used, and the list of certificates granted.
`
`COMBISTATS
`CombiStats is a computer program for the statistical analysis of data from biological assays in agreement with chapter 5.3
`of the 8th Edition of the European Pharmacopoeia. For more information, visit the website (www.edqm.eu/combistats).
`
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`

`

`KEY TO MONOGRAPHS
`
`Carbimazole
`
`EUROPEAN PHARMACOPOEIA 8.0
`
`
`Version date of the text
`
`Text reference
`number
`Modification to be
`taken into account from
`the publication date of
`volume 8.0
`
`01/2008:0884
`corrected 8.0
`
`CARBIMAZOLE
`Carbimazolum
`
`N
`
`E
`
`of this solution to 10.0 mL with a mixture of 20 volumes
`of acetonitrile R and 80 volumes of water R.
`Reference solution (b). Dissolve 5.0 mg of thiamazole R in
`a mixture of 20 volumes of acetonitrile R and 80 volumes
`of water R and dilute to 10.0 mL with the same mixture of
`solvents. Dilute 1.0 mL of this solution to 100.0 mL with
`a mixture of 20 volumes of acetonitrile R and 80 volumes
`of water R.
`Column:
`– size: l = 0.15 m, Ø = 3.9 mm,
`– stationary phase: octadecylsilyl silica gel for
`chromatography R (5 µm).
`Mobile phase: acetonitrile R, water R (10:90 V/V).
`Flow rate: 1 mL/min.
`Detection: spectrophotometer at 254 nm.
`Injection: 10 µL.
`Run time: 1.5 times the retention time of carbimazole.
`Retention time: carbimazole = about 6 min.
`System suitability: reference solution (a):
`– resolution: minimum 5.0 between the peaks due to
`impurity A and carbimazole.
`Limits:
`– impurity A: not more than 0.5 times the area of the
`principal peak in the chromatogram obtained with
`reference solution (b) (0.5 per cent),
`– unspecified impurities: for each impurity, not more
`than 0.1 times the area of the principal peak in the
`chromatogram obtained with reference solution (b)
`(0.10 per cent).
`Loss on drying (2.2.32): maximum 0.5 per cent,
`determined on 1.000 g by drying in a desiccator over
`diphosphorus pentoxide R at a pressure not exceeding
`0.7 kPa for 24 h.
`Sulfated ash (2.4.14): maximum 0.1 per cent, determined
`on 1.0 g.
`ASSAY
`Dissolve 50.0 mg in water R and dilute to 500.0 mL
`with the same solvent. To 10.0 mL add 10 mL of dilute
`hydrochloric acid R and dilute to 100.0 mL with water R.
`Measure the absorbance (2.2.25) at the absorption
`maximum at 291 nm.
`Calculate the content of C7H10N2O2S taking the specific
`absorbance to be 557.
`IMPURITIES
`Specified impurities: A.
`Other detectable impurities (the following substances
`would, if present at a sufficient level, be detected by one
`or other of the tests in the monograph. They are limited
`by the general acceptance criterion for other/unspecified
`impurities and/or by the general monograph Substances
`for pharmaceutical use (2034). It is therefore not
`necessary to identify these impurities for demonstration
`of compliance. See also 5.10. Control of impurities in
`substances for pharmaceutical use): B.
`
`A. 1-methyl-1H-imidazole-2-thiol (thiamazole),
`
`C I M
`
`CAS number
`
`Chemical name
`in accordance
`with IUPAC
`nomenclature rules
`
`Application of the
`first and second
`identification is
`defined in the
`General Notices
`(chapter 1)
`
`Reference standard
`available from
`the Secretariat
`(see www.edqm.eu)
`
`Reagent described
`in chapter 4
`
`Further information
`available on
`www.edqm.eu
`(Knowledge)
`
`Reference to a
`general chapter
`
`Line in the
`margin
`indicating
`where part of
`the text has
`been modified
`(technical
`modification)
`
`Mr 186.2
`
`S P E
`
`C7H10N2O2S
`[22232-54-8]
`DEFINITION
`Ethyl 3-methyl-2-thioxo-2,3-dihydro-1H-imidazole-1-
`carboxylate.
`Content: 98.0 per cent to 102.0 per cent (dried substance).
`CHARACTERS
`Appearance: white or yellowish-white, crystalline powder.
`Solubility: slightly soluble in water, soluble in acetone and in
`ethanol (96 per cent).
`IDENTIFICATION
`First identification: B.
`Second identification: A, C.
`A. Melting point (2.2.14): 122 °C to 125 °C.
`B. Infrared absorption spectrophotometry (2.2.24).
`Preparation: discs.
`Comparison: carbimazole CRS.
`C. Thin-layer chromatography (2.2.27).
`Test solution. Dissolve 10 mg of the substance to be
`examined in methylene chloride R and dilute to 10 mL
`with the same solvent.
`Reference solution. Dissolve 10 mg of carbimazole CRS in
`methylene chloride R and dilute to 10 mL with the same
`solvent.
`Plate: TLC silica gel GF254 plate R.
`Mobile phase: acetone R, methylene chloride R
`(20:80 V/V).
`Application: 10 µL.
`Development: over a path of 15 cm.
`Drying: in air for 30 min.
`Detection: examine in ultraviolet light at 254 nm.
`Results: the principal spot in the chromatogram obtained
`with the test solution is similar in position and size to
`the principal spot in the chromatogram obtained with
`the reference solution.
`TESTS
`Related substances. Liquid chromatography (2.2.29).
`Test solution. Dissolve 5.0 mg of the substance to be
`examined in 10.0 mL of a mixture of 20 volumes of
`acetonitrile R and 80 volumes of water R. Use this solution
`within 5 min of preparation.
`Reference solution (a). Dissolve 5 mg of thiamazole R and
`0.10 g of carbimazole CRS in a mixture of 20 volumes of
`acetonitrile R and 80 volumes of water R and dilute to
`100.0 mL with the same mixture of solvents. Dilute 1.0 mL
`
`General Notices (1) apply to all monographs and other texts
`
`See the information section on general monographs (cover pages)
`
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`

`

`IMPORTANT NOTICE
`GENERAL MONOGRAPHS
`
`The European Pharmacopoeia contains a number of general monographs covering classes of products. These general
`monographs give requirements that are applicable to all products in the given class or, in some cases, to any product in the
`given class for which there is a specific monograph in the Pharmacopoeia (see 1. General Notices, General monographs).
`Where no restriction on scope of a general monograph is given in a preamble, it is applicable to all products in the class
`defined, irrespective of whether there is an individual monograph for the product in the Pharmacopoeia.
`Whenever a monograph is used, it is essential to ascertain whether there is a general monograph applicable to the product in
`question. The general monographs listed below are published in the General Monographs section (unless otherwise stated).
`This list is updated where necessary and republished in each supplement.
`
`Allergen products (1063)
`Dosage Forms monographs
`(published in the Dosage Forms section or the Homoeopathic Preparations section, as appropriate)
`Essential oils (2098)
`Extracts (0765)
`Herbal drug preparations (1434)
`Herbal drugs (1433)
`Herbal drugs for homoeopathic preparations (2045)
`(published in the Homoeopathic Preparations section)
`Herbal teas (1435)
`Herbal teas, instant (2620)
`Homoeopathic preparations (1038)
`(published in the Homoeopathic Preparations section)
`Immunosera for human use, animal (0084)
`Immunosera for veterinary use (0030)
`Methods of preparation of homoeopathic stocks and potentisation (2371)
`(published in the Homoeopathic Preparations section)
`Monoclonal antibodies for human use (2031)
`Mother tinctures for homoeopathic preparations (2029)
`(published in the Homoeopathic Preparations section)
`Pharmaceutical preparations (2619)
`Products of fermentation (1468)
`Products with risk of transmitting agents of animal spongiform encephalopathies (1483)
`Radiopharmaceutical preparations (0125)
`Recombinant DNA technology, products of (0784)
`Substances for pharmaceutical use (2034)
`Vaccines for human use (0153)
`Vaccines for veterinary use (0062)
`Vegetable fatty oils (1579)
`
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`

`Members of the European Pharmacopoeia Commission: Austria, Belgium,
`Bosnia and Herzegovina, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark,
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`Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, ‘the former
`Yugoslav Republic of Macedonia’, Turkey, Ukraine, United Kingdom and the European
`Union.
`Observers to the European Pharmacopoeia Commission: Albania, Algeria, Argentina,
`Armenia, Australia, Brazil, Canada, China, Georgia, Israel, Madagascar, Malaysia,
`Moldova, Morocco, Republic of Belarus, Republic of Guinea, Republic of Kazakhstan,
`Republic of Singapore, Russian Federation, Senegal, Syria, Tunisia, United States of
`America and WHO (World Health Organization).
`
`How to contact us
` Internet: www.edqm.eu
` Information and orders
`European Directorate for the Quality of Medicines & HealthCare (EDQM)
`Council of Europe - 7 allée Kastner
`CS 30026, F-67081 STRASBOURG, FRANCE
`Tel: +33 (0)3 88 41 30 30
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`
`Correspondence ...................................................................................................................................Via the online HelpDesk (www.edqm.eu/hd)
`How to place an order
`Publications ............................................................................................................................................................................. https://www.edqm.eu/store
`Reference standards ....................................................................................................www.edqm.eu/site/EDQM_Reference_standards-649.html
`Reference standards online order form ................................................................................www.edqm/eu/site/CRS-order-form-697.html
`Further information, including answers to the most frequently asked questions regarding ordering, is available via the HelpDesk.
`Submission of scientific articles . .................................................................................................................................. publications.info@edqm.eu
`All reference standards required for application of the monographs are available from the EDQM.
`An updated catalogue of reference standards and a list of newly released reference standards (new reference standards and new batches)
`are available on the website http://crs.edqm.eu.
`
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`

`

`EUROPEAN PHARMACOPOEIA
`EIGHTH EDITION
`Volume 1
`
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`

`EUROPEAN
`PHARMACOPOEIA
`
`EIGHTH EDITION
`Volume 1
`
`
`
`Published in accordance with the
`Convention on the Elaboration of a European Pharmacopoeia
`(European Treaty Series No. 50)
`
`Council of Europe
`Strasbourg
`
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`

`
`
`The European Pharmacopoeia is published by the Directorate for the Quality of Medicines & HealthCare
`of the Council of Europe (EDQM).
`
`© Council of Europe, 67075 Strasbourg Cedex, France - 2013
`All rights reserved. Apart from any fair dealing for the purposes of research or private study, this
`publication may not be reproduced, stored or transmitted in any form or by any means without the prior
`permission in writing of the publisher.
`
`ISBN: 978-92-871-7525-0
`
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`

`CONTENTS
`
`VOLUME 1
`
`
`
`I.
`PREFACE
`II.
`INTRODUCTION
`III. EUROPEAN PHARMACOPOEIA COMMISSION
`IV. CONTENTS OF THE EIGHTH EDITION
`GENERAL CHAPTERS
`1. General notices
`2. Methods of analysis
`2.1. Apparatus
`2.2. Physical and physicochemical methods
`2.3.
`Identification
`2.4. Limit tests
`2.5. Assays
`2.6. Biological tests
`2.7. Biological assays
`2.8. Methods in pharmacognosy
`2.9. Pharmaceutical technical procedures
`3. Materials for containers and containers
`3.1. Materials used for the manufacture of containers
`3.2. Containers
`4. Reagents
`5. General texts
`GENERAL MONOGRAPHS
`MONOGRAPHS ON DOSAGE FORMS
`MONOGRAPHS ON VACCINES FOR HUMAN USE
`MONOGRAPHS ON VACCINES FOR VETERINARY USE
`MONOGRAPHS ON IMMUNOSERA FOR HUMAN USE
`MONOGRAPHS ON IMMUNOSERA FOR VETERINARY USE
`MONOGRAPHS ON RADIOPHARMACEUTICAL PREPARATIONS AND STARTING MATERIALS FOR
`RADIOPHARMACEUTICAL PREPARATIONS
`MONOGRAPHS ON SUTURES FOR HUMAN USE
`MONOGRAPHS ON SUTURES FOR VETERINARY USE
`MONOGRAPHS ON HERBAL DRUGS AND HERBAL DRUG PREPARATIONS
`MONOGRAPHS ON HOMOEOPATHIC PREPARATIONS
`
`VOLUME 2
`
`MONOGRAPHS
`INDEX
`
`Note : on the first page of each chapter/section there is a list of contents.
`
`i
`v
`ix
`xxi
`
`1
`11
`13
`19
`117
`125
`153
`173
`227
`269
`283
`371
`373
`407
`423
`551
`739
`777
`815
`919
`1027
`1035
`
`1043
`1115
`1125
`1133
`1427
`
`1457
`3603
`
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`

`

`Naloxone hydrochloride dihydrate
`
`EUROPEAN PHARMACOPOEIA 8.0
`
`TESTS
`Absorbance. Dissolve 1.50 g in methylene chloride R and
`dilute to 50.0 mL with the same solvent. The absorbance
`(2.2.25) measured at 420 nm is not greater than 0.10.
`Related substances. Examine by thin-layer chromatography
`(2.2.27), using a TLC silica gel F254 plate R.
`
`Test solution (a). Dissolve 0.20 g of the substance to be
`examined in methylene chloride R and dilute to 10 mL with
`the same solvent.
`
`Test solution (b). Dilute 1 mL of test solution (a) to 20 mL
`with methylene chloride R.
`
`Reference solution (a). Dissolve 20 mg of nalidixic acid CRS
`in methylene chloride R and dilute to 20 mL with the same
`solvent.
`
`Reference solution (b). Dilute 2 mL of test solution (b) to
`10 mL with methylene chloride R.
`
`Reference solution (c). Dilute 1 mL of reference solution (b) to
`10 mL with methylene chloride R.
`
`Reference solution (d). Dilute 1 mL of reference solution (b) to
`25 mL with methylene chloride R.
`
`Apply to the plate 10 μL of each solution. Develop over a path
`of 15 cm using a mixture of 10 volumes of dilute ammonia R1,
`20 volumes of methylene chloride R and 70 volumes of
`alcohol R. Allow the plate to dry in air and examine in
`ultraviolet light at 254 nm. Any spot in the chromatogram
`obtained with the test solution (a), apart from the principal
`spot, is not more intense than the spot in the chromatogram
`obtained with reference solution (c) (0.1 per cent) and not
`more than one such spot is more intense than the spot in the
`chromatogram obtained with reference solution (d).
`Heavy metals (2.4.8). 1.0 g complies with test D for heavy
`metals (20 ppm). Prepare the reference solution using 2 mL
`of lead standard solution (10 ppm Pb) R.
`Loss on drying (2.2.32). Not more than 0.5 per cent,
`determined on 1.000 g by drying in an oven at 105 °C.
`Sulfated ash (2.4.14). Not more than 0.1 per cent, determined
`on 1.0 g.
`
`ASSAY
`
`Dissolve 0.150 g in 10 mL of methylene chloride R and add
`30 mL of 2-propanol R and 10 mL of carbon dioxide-free
`water R. Keep the titration vessel covered and pass nitrogen R
`through the solution throughout the titration. Keep the
`temperature of the solution between 15 °C and 20 °C. Titrate
`with 0.1 M ethanolic sodium hydroxide, determining the
`end-point potentiometrically (2.2.20) using a silver-silver
`chloride comparison electrode with a sleeve diaphragm or
`a capillary tip, filled with a saturated solution of lithium
`chloride R in ethanol R, and a glass electrode as indicator
`electrode.
`
`1 mL of 0.1 M ethanolic sodium hydroxide is equivalent to
`23.22 mg of C12H12N2O3.
`
`STORAGE
`
`Store in an airtight container, protected from light.
`
`04/2013:0729
`NALOXONE HYDROCHLORIDE
`DIHYDRATE
`Naloxoni hydrochloridum dihydricum
`
`Mr 399.9
`
`C19H22ClNO4,2H2O
`[51481-60-8]
`DEFINITION
`4,5α-Epoxy-3,14-dihydroxy-17-(prop-2-enyl)morphinan-6-
`one hydrochloride dihydrate.
`Content: 98.0 per cent to 102.0 per cent (anhydrous substance).
`CHARACTERS
`Appearance: white or almost white, hygroscopic, crystalline
`powder.
`Solubility: freely soluble in water, soluble in ethanol (96 per
`cent), practically insoluble in toluene.
`IDENTIFICATION
`First identification: A, C.
`Second identification: B, C.
`A. Infrared absorption spectrophotometry (2.2.24).
`Comparison: naloxone hydrochloride dihydrate CRS.
`B. Thin-layer chromatography (2.2.27).
`Test solution. Dissolve 8 mg of the substance to be
`examined in 0.5 mL of water R and dilute to 1 mL with
`methanol R.
`Reference solution. Dissolve 8 mg of naloxone hydrochloride
`dihydrate CRS in 0.5 mL of water R and dilute to 1 mL with
`methanol R.
`Plate: TLC silica gel G plate R.
`Mobile phase: mix 5 volumes of methanol R and 95 volumes
`of the upper layer from a mixture of 60 mL ofdilute
`ammonia R2 and 100 mL of butanol R.
`Application: 5 μL.
`Development: over 2/3 of the plate.
`Drying: in air.
`Detection: spray with a freshly prepared 5 g/L solution of
`potassium ferricyanide R in ferric chloride solution R1;
`examine in daylight.
`Results: the principal spot in the chromatogram obtained
`with the test solution is similar in position, colour and size
`to the principal spot in the chromatogram obtained with
`the reference solution.
`C. It gives reaction (a) of chlorides (2.3.1).
`TESTS
`Solution S. Dissolve 0.50 g in carbon dioxide-free water R and
`dilute to 25.0 mL with the same solvent.
`Appearance of solution. Solution S is clear (2.2.1) and
`colourless (2.2.2, Method II).
`Acidity or alkalinity. To 10.0 mL of solution S add 0.05 mL
`of methyl red solution R. Not more than 0.2 mL of0.02 M
`sodium hydroxide or 0.02 M hydrochloric acid is required to
`change the colour of the indicator.
`Specific optical rotation (2.2.7): − 181 to − 170 (anhydrous
`substance), determined on solution S.
`
`2820
`
`See the information section on general monographs (cover pages)
`
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`

`

`EUROPEAN PHARMACOPOEIA 8.0
`
`Naloxone hydrochloride dihydrate
`
`Impurity D. Liquid chromatography (2.2.29).
`Solution A. Dissolve 1.58 g of ammonium hydrogen carbonate R
`in 950 mL of water R1, adjust to pH 9.0 with concentrated
`ammonia R and dilute to 1000 mL with water R1.
`Test solution. Dissolve 0.500 g of the substance to be examined
`in a 10.3 g/L solution of hydrochloric acid R and dilute to
`20.0 mL with the same solution.
`Reference solution (a). Dissolve 10.0 mg of naloxone
`impurity D CRS in a 10.3 g/L solution of hydrochloric acid R
`and dilute to 20.0 mL with the same solution. Dilute 5.0 mL
`of this solution to 100.0 mL with a 10.3 g/L solution of
`hydrochloric acid R.
`Reference solution (b). Dilute 5.0 mL of reference solution (a)
`to 100.0 mL with a 10.3 g/L solution of hydrochloric acid R.
`Reference solution (c). To 4.0 mL of the test solution add
`2.0 mL of reference solution (a) and dilute to 20.0 mL with a
`10.3 g/L solution of hydrochloric acid R.
`Column:
`– size: l = 0.25 m, Ø = 4.6 mm;
`– stationary phase: end-capped octadecylsilyl silica gel for
`chromatography R (5 μm);
`– temperature: 40 °C.
`Mobile phase:
`– mobile phase A: acetonitrile R1, solution A (20:80 V/V);
`– mobile phase B: acetonitrile R1, solution A (40:60 V/V);
`Time
`Mobile phase A
`Mobile phase B
`(min)
`(per cent V/V)
`(per cent V/V)
`0 - 50
`100
`0
`50 - 51
`100 → 0
`0 → 100
`51 - 60
`0
`100
`
`Flow rate: 2.0 mL/min.
`Detection: spectrophotometer at 210 nm.
`Injection: 10 μL of the test solution and reference solutions (b)
`and (c).
`Relative retention with reference to naloxone (retention
`time = about 50 min): impurity D = about 0.8.
`System suitability: reference solution (c):
`– symmetry factor: maximum 1.8 for the peak due to
`impurity D.
`Limit:
`– impurity D: not more than 1.5 times the area of the
`principal peak in the chromatogram obtained with
`reference solution (b) (75 ppm).
`Related substances. Liquid chromatography (2.2.29).
`Solution A. Dissolve 1.10 g of sodium octanesulfonate R in
`950 mL of water R, adjust to pH 2.0 with a 50 per cent V/V
`solution of phosphoric acid R, filter and dilute to 1000 mL
`with water R.
`Test solution. Dissolve 0.125 g of the substance to be examined
`in a 10.3 g/L solution of hydrochloric acid R and dilute to
`25.0 mL with the same solution.
`Reference solution (a). Dissolve 5 mg of naloxone for peak
`identification CRS (containing impurities A, B, C, D, E and F)
`in 1 mL of a 10.3 g/L solution ofhydrochloric acid R .
`Reference solution (b). Dilute 1.0 mL of the test solution to
`20.0 mL with a 10.3 g/L solution of hydrochloric acid R. Dilute
`1.0 mL of this solution to 25.0 mL with a 10.3 g/L solution
`of hydrochloric acid R.
`Column:
`– size: l = 0.125 m, Ø = 4.0 mm;
`– stationary phase: end-capped octylsilyl silica gel for
`chromatography R (5 μm);
`– temperature: 40 °C.
`
`Mobile phase B
`(per cent V/V)
`0 → 100
`100
`
`Mobile phase A
`(per cent V/V)
`100 → 0
`0
`
`Mobile phase:
`– mobile phase A: acetonitrile R, tetrahydrofuran R, solution A
`(2:4:94 V/V/V);
`– mobile phase B: tetrahydrofuran R, acetonitrile R, solution A
`(4:17:79 V/V/V);
`Time
`(min)
`0 - 40
`40 - 50
`Flow rate: 1.5 mL/min.
`Detection: spectrophotometer at 230 nm.
`Injection: 20 μL.
`Relative retention with reference to naloxone (retention
`time = about 11 min): impurity C = about 0.6;
`impurity A = about 0.8; impurity F = about 0.9;
`impurity D = about 1.1; impurity E = about 3.0;
`impurity B = about 3.2.
`Identification of impurities: use the chomatogram supplied
`with naloxone for peak identification CRS and the
`chromatogram obtained with reference solution (a) to identify
`the peaks due to impurities A, B, C, D, E and F.
`System suitability: reference solution (a):
`– peak-to-valley ratio: minimum 2.0, whereH p = height
`above the baseline of the peak due to impurity D and
`Hv = height above the baseline of the lowest point of the
`curve separating this peak from the peak due to naloxone.
`Limits:
`– correction factor: for the calculation of content, multiply
`the peak area of impurity E by 0.5;
`– impurities A, B, C, E, F: for each impurity, not more
`than the area of the principal peak in the chromatogram
`obtained with reference solution (b) (0.2 per cent);
`– unspecified impurities: for each impurity, not more than
`0.5 times the area of the principal peak in the chromatogram
`obtained with reference solution (b) (0.10 per cent);
`– total: not more than 4 times the area of the principal peak
`in the chromatogram obtained with reference solution (b)
`(0.8 per cent);
`– disregard limit: 0.25 times the area of the principal peak
`in the chromatogram obtained with reference solution (b)
`(0.05 per cent).
`Water (2.5.12): 7.5 per cent to 11.0 per cent, determined on
`0.200 g.
`Sulfated ash (2.4.14): maximum 0.2 per cent, determined on
`0.50 g.
`ASSAY
`Dissolve 0.300 g in 50 mL of ethanol (96 per cent) R and add
`5.0 mL of 0.01 M hydrochloric acid. Carry out a potentiometric
`titration (2.2.20), using 0.1 M ethanolic sodium hydroxide.
`Read the volume added between the 2 points of inflexion.
`1 mL of 0.1 M ethanolic sodium hydroxide is equivalent to
`36.38 mg of C19H22ClNO4.
`STORAGE
`In an airtight container, protected from light.
`IMPURITIES
`Specified impurities: A, B, C, D, E, F.
`Other detectable impurities (the following substances would,
`if present at a sufficient level, be detected by one or other of
`the tests in the monograph. They are limited by the general
`acceptance criterion for other/unspecified impurities and/or
`by the general monograph Substances for pharmaceutical
`use (2034). It is therefore not necessary to identify these
`impurities for demonstration of compliance. See also 5.10.
`Control of impurities in substances for pharmaceutical use): G.
`
`General Notices (1) apply to all monographs and other texts
`
`2821
`
`Opiant Exhibit 2079
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00688
`Page 10
`
`

`

`Naltrexone hydrochloride
`
`EUROPEAN PHARMACOPOEIA 8.0
`
`A. 4,5α-epoxy-3,14-dihydroxymorphinan-6-one
`(noroxymorphone),
`
`B. 4,5α-epoxy-14-hydroxy-17-(prop-2-enyl)-3-(prop-2-
`enyloxy)morphinan-6-one (3-O-allylnaloxone),
`
`C. 4,5α-epoxy-3,10α,14-trihydroxy-17-(prop-2-
`enyl)morphinan-6-one (10α-hydroxynaloxone),
`
`D. 7,8-didehydro-4,5α-epoxy-3,14-dihydroxy-17-(prop-2-
`enyl)morphinan-6-one (7,8-didehydronaloxone),
`
`E. 4,5α:4′,5′α-diepoxy-3,3′,14,14′-tetrahydroxy-17,17′-
`bis(prop-2-enyl)-2,2′-bimorphinanyl-6,6′-dione
`(2,2′-binaloxone),
`
`F. 4,5α-epoxy-3,10β,14-trihydroxy-17-(prop-2-
`enyl)morphinan-6-one (10β-hydroxynaloxone),
`
`G. 4,5α-epoxy-14-hydroxy-3-methoxy-17-(prop-2-
`enyl)morphinan-6-one (3-O-methylnaloxone).
`
`01/2008:1790
`NALTREXONE HYDROCHLORIDE
`Naltrexoni hydrochloridum
`
`Mr 377.9
`
`C20H24ClNO4
`DEFINITION
`17-(Cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxy-
`morphinan-6-one hydrochloride. It may be anhydrous, a
`monohydrate or a dihydrate, a mixture or a solvate.
`Content: 98.0 per cent to 102.0 per cent (anhydrous substance).
`CHARACTERS
`Appearance: white or almost white powder, very hygroscopic.
`Solubility: freely soluble in water, slightly soluble in ethanol
`(96 per cent), practically insoluble in methylene chloride.
`IDENTIFICATION
`A. Infrared absorption spectrophotometry (2.2.24).
`Dissolve 20 mg in water R and dilute to 5 mL with the same
`solvent. Make alkaline with dilute ammonia R1. Shake
`with 10 mL of methylene chloride R, separate the organic
`layer and evaporate the solvent. Dry the residue obtained
`in vacuo.
`Comparison: naltrexone hydrochloride CRS.
`B. It gives reaction (a) of chlorides (2.3.1).
`TESTS
`Solution S. Dissolve 0.40 g in carbon dioxide-free water R and
`dilute to 20.0 mL with the same solvent.
`Appearance of solution. Solution S is clear (2.2.1) and not
`more intensely coloured than reference solution Y6 or B6
`(2.2.2, Method II).
`Acidity and alkalinity. To 10 mL of solution S, add 0.05 mL
`of methyl red solution R. Not more than 0.2 mL of0.02 M
`sodium hydroxide or 0.02 M hydrochloric acid is required to
`change the colour of the indicator.
`Specific optical rotation (2.2.7): − 187 to − 195 (anhydrous
`substance).
`Dissolve 0.40 g in water R and dilute to 20.0 mL with the same
`solvent.
`Related substances. Liquid chromatography (2.2.29).
`Test solution. Dissolve 20.0 mg of the substance to be
`examined in 0.1 M hydrochloric acid and dilute to 10.0 mL
`with the same solvent.
`Reference solution (a). Dissolve 5.0 mg of naltrexone
`impurity C CRS in 0.1 M hydrochloric acid and dilute to
`2.5 mL with the same solvent.
`Reference solution (b). Dilute 1.0 mL of the test solution
`and 1.0 mL of reference solution (a) to 100.0 mL with 0.1 M
`hydrochloric acid. Dilute 1.0 mL of this solution to 10.0 mL
`with 0.1 M hydrochloric acid.
`Column:
`– size: l = 0.15 m, Ø = 4.6 mm;
`– stationary phase: octadecylsilyl silica gel for
`chromatography R1 (5 μm);
`– temperature: 40 °C.
`Mobile phase:
`– mobile phase A: 1.1 g/L solution of sodium octanesulfonate R
`adjusted to pH 2.3 with phosphoric acid R;
`
`2822
`
`See the information section on general monographs (cover pages)
`
`Opiant Exhibit 2079
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00688
`Page 11
`
`

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