EUROPEAN PHARMACOPOEIA

1380 Pages·2015·59.33 MB·English

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Printed on acid-free paper by Druckerei C. H. Beck, Nördlingen (Germany)
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.
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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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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).
KEY TO MONOGRAPHS
Carbimazole EUROPEAN PHARMACOPOEIA 8.0

Version date of the text 01/2008:0884 of this solution to 10.0 mL with a mixture of 20 volumes
corrected 8.0 of acetonitrile R and 80 volumes of water R.
Text reference CARBIMAZOLE Reference solution (b). Dissolve 5.0 mg of thiamazole R in
a mixture of 20 volumes of acetonitrile R and 80 volumes
number Carbimazolum 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
Modification to be a mixture of 20 volumes of acetonitrile R and 80 volumes
taken into account from of water R.
the publication date of Column:
volume 8.0
– size: l = 0.15 m, Ø = 3.9 mm,
CH NOS – stationary phase: octadecylsilyl silica gel for
7 10 2 2
CAS number [22232-54-8] M 186.2 chromatography R (5 µm).
r
Mobile phase: acetonitrile R, water R (10:90 V/V).
DEFINITION
Flow rate: 1 mL/min.
Chemical name Ethyl 3-methyl-2-thioxo-2,3-dihydro-1H-imidazole-1-
in accordance carboxylate. Detection: spectrophotometer at 254 nm.
with IUPAC Content: 98.0 per cent to 102.0 per cent (dried substance). Injection: 10 µL.
nomenclature rules CHARACTERS Run time: 1.5 times the retention time of carbimazole.
Appearance: white or yellowish-white, crystalline powder. Retention time: carbimazole = about 6 min.
Solubility: slightly soluble in water, soluble in acetone and in System suitability: reference solution (a):
ethanol (96 per cent). – resolution: minimum 5.0 between the peaks due to
Application of the
impurity A and carbimazole.
first and second IDENTIFICATION
Limits:
identification is First identification: B.
defined in the Second identification: A, C. – impurity A: noN t more than 0.5 times the area of the
General Notices principal peak in the chromatogram obtained with
(chapter 1) A. Melting point (2.2.14): 122 °C to 125 °C. referencEe solution (b) (0.5 per cent),
M
B. Infrared absorption spectrophotometry (2.2.24). – unspecified impurities: for each impurity, not more
Preparation: discs. Ithan 0.1 times the area of the principal peak in the
C chromatogram obtained with reference solution (b)
Reference standard Comparison: carbimazole CRS. E (0.10 per cent).
available from C. Thin-layer chromatography (2.2.27). P Loss on drying (2.2.32): maximum 0.5 per cent,
the Secretariat Test solution. Dissolve 10 mg of the substanSce to be determined on 1.000 g by drying in a desiccator over
(see www.edqm.eu) examined in methylene chloride R and dilute to 10 mL diphosphorus pentoxide R at a pressure not exceeding
with the same solvent. 0.7 kPa for 24 h.
Reference solution. Dissolve 10 mg of carbimazole CRS in Sulfated ash (2.4.14): maximum 0.1 per cent, determined
methylene chloride R and dilute to 10 mL with the same on 1.0 g.
solvent. ASSAY
Plate: TLC silica gel GF plate R. Dissolve 50.0 mg in water R and dilute to 500.0 mL
254
Reagent described Mobile phase: acetone R, methylene chloride R with the same solvent. To 10.0 mL add 10 mL of dilute
in chapter 4 (20:80 V/V). hydrochloric acid R and dilute to 100.0 mL with water R.
Measure the absorbance (2.2.25) at the absorption
Application: 10 µL. maximum at 291 nm.
Development: over a path of 15 cm. Calculate the content of CH NOS taking the specific
Further information Drying: in air for 30 min. absorbance to be 557. 7 10 2 2
available on
Detection: examine in ultraviolet light at 254 nm. IMPURITIES
www.edqm.eu
(Knowledge) Results: the principal spot in the chromatogram obtained Specified impurities: A.
with the test solution is similar in position and size to Other detectable impurities (the following substances
the principal spot in the chromatogram obtained with would, if present at a sufficient level, be detected by one
the reference solution. or other of the tests in the monograph. They are limited
by the general acceptance criterion for other/unspecified
Reference to a TESTS impurities and/or by the general monograph Substances
general chapter Related substances. Liquid chromatography (2.2.29). for pharmaceutical use (2034). It is therefore not
necessary to identify these impurities for demonstration
Test solution. Dissolve 5.0 mg of the substance to be of compliance. See also 5.10. Control of impurities in
Line in the examined in 10.0 mL of a mixture of 20 volumes of substances for pharmaceutical use): B.
margin acetonitrile R and 80 volumes of water R. Use this solution
indicating within 5 min of preparation.
where part of Reference solution (a). Dissolve 5 mg of thiamazole R and
the text has 0.10 g of carbimazole CRS in a mixture of 20 volumes of
been modified acetonitrile R and 80 volumes of water R and dilute to
(technical 100.0 mL with the same mixture of solvents. Dilute 1.0 mL A. 1-methyl-1H-imidazole-2-thiol (thiamazole),
modification)
See the information section on general monographs (cover pages)
General Notices (1) apply to all monographs and other texts
IMPORTANT NOTICE
GENERAL MONOGRAPHS
TheEuropeanPharmacopoeiacontainsanumberofgeneralmonographscoveringclassesofproducts. Thesegeneral
monographsgiverequirementsthatareapplicabletoallproductsinthegivenclassor,insomecases,toanyproductinthe
givenclassforwhichthereisaspecificmonographinthePharmacopoeia(see1. GeneralNotices,Generalmonographs).
Wherenorestrictiononscopeofageneralmonographisgiveninapreamble,itisapplicabletoallproductsintheclass
defined,irrespectiveofwhetherthereisanindividualmonographfortheproductinthePharmacopoeia.
Wheneveramonographisused,itisessentialtoascertainwhetherthereisageneralmonographapplicabletotheproductin
question. ThegeneralmonographslistedbelowarepublishedintheGeneralMonographssection(unlessotherwisestated).
Thislistisupdatedwherenecessaryandrepublishedineachsupplement.
Allergenproducts(1063)
DosageFormsmonographs
(publishedintheDosageFormssectionortheHomoeopathicPreparationssection,asappropriate)
Essentialoils(2098)
Extracts(0765)
Herbaldrugpreparations(1434)
Herbaldrugs(1433)
Herbaldrugsforhomoeopathicpreparations(2045)
(publishedintheHomoeopathicPreparationssection)
Herbalteas(1435)
Herbalteas,instant(2620)
Homoeopathicpreparations(1038)
(publishedintheHomoeopathicPreparationssection)
Immunoseraforhumanuse,animal(0084)
Immunoseraforveterinaryuse(0030)
Methodsofpreparationofhomoeopathicstocksandpotentisation(2371)
(publishedintheHomoeopathicPreparationssection)
Monoclonalantibodiesforhumanuse(2031)
Mothertincturesforhomoeopathicpreparations(2029)
(publishedintheHomoeopathicPreparationssection)
Pharmaceuticalpreparations(2619)
Productsoffermentation(1468)
Productswithriskoftransmittingagentsofanimalspongiformencephalopathies(1483)
Radiopharmaceuticalpreparations(0125)
RecombinantDNAtechnology,productsof(0784)
Substancesforpharmaceuticaluse(2034)
Vaccinesforhumanuse(0153)
Vaccinesforveterinaryuse(0062)
Vegetablefattyoils(1579)
Members of the European Pharmacopoeia Commission: Austria, Belgium,
Bosnia and Herzegovina, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark,
Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia,
Lithuania, Luxembourg, Malta, Montenegro, Netherlands, Norway, Poland, Portugal,
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).
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EUROPEAN PHARMACOPOEIA
EIGHTH EDITION
Volume 1
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
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
CONTENTS
VOLUME 1
I. PREFACE i
II. INTRODUCTION v
III. EUROPEANPHARMACOPOEIACOMMISSION ix
IV. CONTENTSOFTHEEIGHTHEDITION xxi
GENERALCHAPTERS
1. Generalnotices 1
2. Methodsofanalysis 11
2.1. Apparatus 13
2.2. Physicalandphysicochemicalmethods 19
2.3. Identification 117
2.4. Limittests 125
2.5. Assays 153
2.6. Biologicaltests 173
2.7. Biologicalassays 227
2.8. Methodsinpharmacognosy 269
2.9. Pharmaceuticaltechnicalprocedures 283
3. Materialsforcontainersandcontainers 371
3.1. Materialsusedforthemanufactureofcontainers 373
3.2. Containers 407
4. Reagents 423
5. Generaltexts 551
GENERALMONOGRAPHS 739
MONOGRAPHSONDOSAGEFORMS 777
MONOGRAPHSONVACCINESFORHUMANUSE 815
MONOGRAPHSONVACCINESFORVETERINARYUSE 919
MONOGRAPHSONIMMUNOSERAFORHUMANUSE 1027
MONOGRAPHSONIMMUNOSERAFORVETERINARYUSE 1035
MONOGRAPHSONRADIOPHARMACEUTICALPREPARATIONSANDSTARTINGMATERIALSFOR
RADIOPHARMACEUTICALPREPARATIONS 1043
MONOGRAPHSONSUTURESFORHUMANUSE 1115
MONOGRAPHSONSUTURESFORVETERINARYUSE 1125
MONOGRAPHSONHERBALDRUGSANDHERBALDRUGPREPARATIONS 1133
MONOGRAPHSONHOMOEOPATHICPREPARATIONS 1427
VOLUME 2
MONOGRAPHS 1457
INDEX 3603
Note:onthefirstpageofeachchapter/sectionthereisalistofcontents.
EUROPEANPHARMACOPOEIA8.0 Preface
I. PREFACE
TheEuropeanPharmacopoeiawasinauguratedin1964 willnowworkonharmonisingtheirpoliciesandapproaches
throughtheConventionontheElaborationofaEuropean towardsmonographdevelopmentbydraftingwhathavebeen
PharmacopoeiaundertheauspicesoftheCouncilof termedasaworkingtitle“GoodPharmacopoeialPractices”.
Europe. The8thEditionwillbepublishedjustbeforethe Convergenceinpolicies,e.g. withregardtocontrolof
50thAnniversaryoftheEuropeanPharmacopoeia. The impuritiesbyapplyingICHQ3principles,willfacilitatefuture
workoftheEuropeanPharmacopoeiahasgonethrougha collaborationandharmonisation.
remarkabledevelopmentsincethefirstdifficultyearstoits Theimplementationdateforthe8thEditionis1January2014
currentstrongposition. The3-yearcycleofpublicationwith andthiseditionwill,overthenext3years,beaugmentedwith
thrice-yearlysupplementshasproventobeanefficientwayto 8supplementscontainingthetextsadoptedatthesessions
publishandupdatetheresultsoftheworkoftheEuropean oftheEuropeanPharmacopoeiaCommission. Asever,it
PharmacopoeiaCommissionanditsExpertGroupsand ispublishedinthe2officiallanguagesoftheCouncilof
WorkingPartiesalmostinreal-time. Europe,i.e. EnglishandFrench,bothasaprintedversionand
electronically(onlineandonaUSBkey). Itisnoteworthy
ThemonographsofthePharmacopoeia,bothspecificand
thatcertainmemberstatesundertakenationalorregional
general,togetherwithothertextsmademandatorybyvirtueof
translations,whichtheyincorporateintotheirownnational
referencetotheminmonographs,areapplicablethroughout
pharmacopoeias.
the37memberstates,andtheEuropeanUnion,whichis
alsoasignatorypartytotheEuropeanPharmacopoeia TheworkprogrammeoftheEuropeanPharmacopoeiais
Convention. Thismeansthatinadditiontoapplicability decidedbytheEuropeanPharmacopoeiaCommission,the
inallitsmemberstates,theEuropeanPharmacopoeiahas governingbodyofthePharmacopoeia. Elaborationand
aspecialroleinregulatoryprocesseswithintheEuropean approvalofmonographsandothertextsproceedthroughan
Union. Inadditiontothe38signatoriesoftheEuropean efficientandtransparentprocess,whichisbasedonscientific
PharmacopoeiaConvention,therearealsoalargenumberof co-operationbetweenthemembersofthevariousGroups
observers,comprisingtheWorldHealthOrganizationand ofExpertsandWorkingPartiessetupbytheEuropean
23countries,ofwhich16arenon-European. Thequality PharmacopoeiaCommission. Theseexpertsgivetheirtime,
standardsdevelopedthroughtheEuropeanPharmacopoeia expertiseandexperiencetoproducepublicstandardsofthe
thereforehaveanimpactonthequalityofmedicinalproducts highestquality-standardsthatarecontinuallyrevisedinline
andsubstancesfarbeyondtheEuropeanregion. Sincethe withscientificdevelopments. Themembersofthesegroups
entryintoforceofthe7thedition,Ukrainehasbecomea comefromregulatoryauthorities,officialmedicinescontrol
newmemberoftheEuropeanPharmacopoeiaConvention laboratories,pharmaceuticalandchemicalmanufacturers,
(in2013),whiletheRepublicofGuineaandSingaporehave universitiesandresearchinstitutions. Allmonographsare
becomenewobservers(in2012). experimentallyverifiedandsubmittedforpublicconsultation
byonlinepublicationinPharmeuropa,theforumofthe
The8foundercountriesoftheConventionrealisedin1964
EuropeanPharmacopoeia,beforeadoptionandpublication.
thatmanufacturingandqualitycontrolstandardsformedicinal
Thegrowingnumberofmonographsandtheneedtokeep
productsontheEuropeanMarkethadtobeharmonisedfor
themupdatedrepresentsanincreasedworkloadandan
reasonsofpublichealthandtofacilitatefreemovementof
increasedneedforexpertswithaccesstoexperimental
theseproducts. Sincethen,thepharmaceuticalworldhas
facilities. Theworkingproceduresfortheelaborationof
becomeglobalisedandinternationalharmonisationamongthe
monographsare:
3majorpharmacopoeias(EuropeanPharmacopoeia,Japanese
PharmacopoeiaandUnitedStatesPharmacopeia)becamea – Procedure1: traditionalelaborationbyGroupsofExperts
logicaldevelopment. Harmonisationactivitiesamongthese andWorkingParties.
3pharmacopoeiasstartedin1989whenthePharmacopoeial – Procedure2: adaptationofnationalmonographs. (This
DiscussionGroup(PDG)wassetup. ThePDGhasbeen procedureisnolongerusedsincetheworkhasbeen
workingonmonographsonwidely-usedexcipientsand62are completed.)
includedinitsworkprogramme. SoonafterthePDGbegan – Procedure3: elaborationofmonographsonchemical
work,itwasrecognisedthattheabsenceofharmonised substancesproducedonlybyonemanufacturerand
generalmethodsrepresentedasignificantobstacle. Awide typicallyclosetopatentexpiry. Themanufacturerand
rangeofgeneralmethods(35)havesincebeenaddedtothe nationalpharmacopoeiaauthorityinthecountrywhere
workprogramme,includingthosefromtheworkofthe thesubstanceisproducedelaboratepreliminarydrafts
InternationalConferenceonHarmonisation(ICH)and,in andchecktherequirementsexperimentally. Thisresults
particular,itsguidelineonsettingspecifications(Q6A).To inadraftthatisthenreviewedbyaGroupofExperts
date,28ofthe35generalmethodsand43of62excipient orWorkingPartyandprocessedintheusualwayby
monographshavebeenharmonised. Detailedinformationon publicenquiry. (Thisprocedurehasbeenintegratedinto
theworkprogrammeofthePDGispublishedregularlyin Procedure4.)
PharmeuropaandinGeneralChapter5.8.Pharmacopoeial
– Procedure4(P4): amodifiedversionofProcedure3
harmonisation.
forsubstancesstillunderpatent,whichwasintroduced
However,itisevidentthatharmonisationbetweenthe bytheEuropeanPharmacopoeiaCommissionin2002.
3ICHregionsisnotenoughintoday’sworld,wherea TheP4procedureinvolvescollaborationbetweenthe
highpercentageofActivePharmaceuticalIngredients manufacturerofthesubstanceandaWorkingParty
(APIs)comefromoutsideEurope,JapanandtheUSA.In solelycomposedofrepresentativesofauthoritiesand
early2012,theWHOtooktheinitiativeandconvenedthe theEDQM.Togethertheyprepareadraftmonograph
pharmacopoeiasoftheworldfortheirfirstinternational withexperimentalverificationbytheEDQMlaboratory
meetinginGeneva. Thediscussionsatthislevelclearly and/orbynationalpharmacopoeiaauthoritiesorOfficial
identifiedtheneedtostrengthencollaborationamong MedicinesControlLaboratoriesbeforepublicationfor
pharmacopoeiasworldwide. Basedontheexperienceand publicenquiry.
challengeswithexistingharmonisationinitiativessuchas – Procedure5: appliestomonographsonrawmaterialsand
PDGthatfocusonretrospectiveharmonisation,itwas stocksforhomoeopathicpreparationsauthorisedforuse
decidedtotakeadifferentapproach. Worldpharmacopoeias inthememberstates. Theworkisco-ordinatedbythe
i