British Pharmacopoeia 2001

Volume I

British Pharmacopoeia 2001

Volume I

London: The Stationery Office

Published on the recommendation of theMedicines Commission pursuant to theMedicines Act 1968 and notified in draft to theEuropean Commission in accordance withDirective 98/34/EEC

The monographs of the Third Edition of theEuropean Pharmacopoeia (1997), as amendedby the Supplement 2001 published by theCouncil of Europe in September 2000, arereproduced either in this edition of the BritishPharmacopoeia or in the associated edition ofthe British Pharmacopoeia (Veterinary)see General Notices, page 3

Effective date: 1 December 2001see Notices

In respect of Great Britain:

THE DEPARTMENT OF HEALTH

In respect of Northern Ireland:THE DEPARTMENT OF HEALTH AND SOCIAL SERVICES AND PUBLIC SAFETY

Crown Copyright 2001

Published by the Stationery Office under licence from the Controller of Her Majesty’sStationery Office for the Department of Health on behalf of the Health Ministers

Printed in the United Kingdom by the Stationery Office Limited under the authorityand superintendence of the Controller of Her Majesty’s Stationery Office and Queen’sPrinter of Acts of Parliament

This publication is a 'value added' product and falls outside the scope of the Classlicensing terms offered by HMSO. Applications to reproduce this material should bemade to the Licensing Division HMSO, St Clements House, 2–16 Colegate, NorwichNR3 1BQ or by e-mailing: anne.battley@cabinet-office.x.gsi.gov.uk.

First Published 2001

British Pharmacopoeia Commission

Office:

Market Towers1 Nine Elms LaneLondon SW8 5NQ

Telephone: +44 (0)20 7273 0561Fax: +44 (0)20 7273 0566E-mail: bpcom@mca.gov.ukWeb site: www.pharmacopoeia.org.uk

Laboratory:

Government BuildingsBlock 2, Honeypot LaneStanmoreMiddlesex HA7 1AY

Telephone: +44 (0)20 7972 1040Fax: +44 (0)20 8951 3069E-mail: queries@bpclab.co.ukWeb site: www.bpclab.co.uk

Dd........

ISBN 0 11 322446 X

Notices

Monographs of the European Pharmacopoeia are distinguished by achaplet of stars against the title. The term European Pharmacopoeia,used without qualification, means the third edition of the EuropeanPharmacopoeia comprising, unless otherwise stated, the main volume,published in 1996 as amended by any subsequent supplements andrevisions.

Patents

In this Pharmacopoeia certain drugs and preparations have beenincluded notwithstanding the existence of actual or potential patentrights. In so far as such substances are protected by Letters Patent theirinclusion in this Pharmacopoeia neither conveys, nor implies, licence tomanufacture.

Effective dates

Much of the material in this edition enters into force on 1 December2001 but certain material that has been published earlier by GazetteNotices became effective on the date stated in the relevant entry.

Preface

The British Pharmacopoeia 2001 is published for the Health Ministerson the recommendation of the Medicines Commission in accordancewith section 99(6) of the Medicines Act 1968.

The Medicines Commission believes that the British Pharmacopoeiacontributes significantly to the overall control of the quality of medicinalproducts by providing an authoritative statement of the quality that aproduct is expected to meet at any time during its period of use. Thepublicly available and legally enforceable Pharmacopoeial standards aredesigned to complement and assist the licensing and inspectionprocesses and are part of the system for safeguarding purchasers andusers of medicinal products.

The Medicines Commission wishes to record its appreciation for theservices of all who have contributed to this important work.

British PharmacopoeiaCommission

The British Pharmacopoeia Commission is appointed by the Secretaryof State concerned with health in Great Britain, the Secretaries of Staterespectively concerned with agriculture in Wales and in Scotland, theMinister of Agriculture, Fisheries and Food, the Department of Healthand Social Services for Northern Ireland and the Department ofAgriculture for Northern Ireland, acting jointly, in exercise of theirpowers under section 4 of the Medicines Act 1968.

The duties of the British Pharmacopoeia Commission are as follows:

(a) the preparation under section 99(1) of the Act of any new editionof the British Pharmacopoeia;

(b) the preparation under section 99(1) of the Act, as given effect bysection 102(1) thereof, of any amendments of the edition of theBritish Pharmacopoeia published in 1968 or any new edition of it;

(c) the preparation under section 100 of the Act (which provides forthe preparation and publication of lists of names to be used asheadings to monographs in the British Pharmacopoeia) of any listof names and the preparation under that section as given effect bysection 102(3) of the Act of any amendments of any published list;

(d) the preparation under section 99(3)(b) of the Act of anycompendium or any new edition thereof;

(e) the preparation under section 99(3)(b) of the Act, as given effect bysection 102(1) thereof, of any amendments to any suchcompendium.

Members of the British Pharmacopoeia Commission are appointedby Ministers, having regard to recommendations made by theMedicines Commission. Appointments are usually for a (renewable)term of 4 years.

Membership of the BritishPharmacopoeia Commission

Chairman: D H Calam1 OBE MA DPhil HonMRPharmS CChem FRSCHonMBIRAEuropean Co-ordinator, National Institute for BiologicalStandards and Control; Visiting Professor, University of Strathclyde

Vice-Chairman: J A Goldsmith1 BSc PhD CChem FRSC FIQAVisiting Professor, University of Strathclyde; formerly a Director ofTechnical Operations in the Pharmaceutical Industry;

A H Andrews1 BVetMed PhD MRCVSVeterinary Consultant

D I R Begg2 FRPharmS FIQA MCPPConsultant in Pharmaceutical Quality Assurance; Visiting Professor,University of Strathclyde

A F Fell1 BPharm PhD FRPharmS CChem FRSC FIQAProfessor of Pharmaceutical Chemistry, University of Bradford

V Fenton-May1 BPharm MI PharmM FRPharmSSpecialist Quality Controller to the Welsh Hospitals

A M T Lee1 BVMS PhD MRCVSA member of the Veterinary Medicines Directorate

J M Midgley1 OBE BSc MSc PhD FRPharmS CChem FRSCProfessor of Pharmaceutical and Medicinal Chemistry,University ofStrathclyde

A C Moffat1 BPharm PhD DSc CChem FRSC FRPharmS FCPPChief Scientist, Royal Pharmaceutical Society of Great Britain

N Randall1 PhD CChem FRSC FIQAA Director of Quality Assurance in the Pharmaceutical Industry

G D Rees1 BPharm PhD MRPharmS CChem MRSC FIQAA Director of Quality Assurance in the Pharmaceutical Industry

A D Woolfson1 BSc PhD CChem FRSC MPSNIProfessor of Pharmaceutics, Queens University of Belfast

Secretary andScientific Director: R C Hutton BSc PhD CChem FRSC

1Term of office ends 31 December 20012 Resigned March 2000

Membership of Committees andConsultative Groups

The Commission appointed the following Committees andCorresponding Consultative Groups to advise it in carrying out itsduties. Membership has changed from time to time; the lists belowinclude all who have served during the period 2000 to 2001.

COMMITTEESA: Medicinal Chemicals: N Randall (Chairman), G D Rees (Vice-Chairman), L Anderson, A L Barber,

T G Beaumont, J C Berridge, A C Caws, A G Davidson, W J Lough, A J Woolfe

B: Medicinal Chemicals: A F Fell (Chairman), J M Midgley (Vice-Chairman), F Breslin, H B Davis, T Duffy,B M Everett, A Holbrook1, A Hutt, M A Lee, B Midcalf, S A Norton, M Turgoose

C: General Chemicals: J M Midgley (Chairman), J A Goldsmith (Vice-Chairman), S K Branch,A C Cartwright, B M Everett, C T Goddard, P Henrys, D J Malpas, C Mroz,I D Newton, A R Rixon, J Seaton, M J Tait

D: Medicinal Chemicals: J A Goldsmith (Chairman), J F Chissell (Vice-Chairman), G P R Carr1,A Holbrook1, W J Mossop, R A Packer, G F Phillips, W J Poling, W K L Pugh,G Skellern, A A Wagland, I R Williams

E: Antibiotics: G D Rees (Chairman), D H Calam (Vice-Chairman), D Adams1, J F Chissell,J Dolman, A M French, K J Leiper, W Mann, W F H McLean, C G Taylor,I R Williams

G: Crude Drugs and Galenicals: A C Moffat (Chairman), L A Anderson (Vice-Chairman ), G Blunden1,A G Davidson, K Helliwell, P J Houghton, B P Jackson, P Linley, W F H McLean,J D Phillipson, A R Rixon, E Williamson

H: Biological Materials: D H Calam (Chairman), N Randall (Vice-Chairman), K J Ayling, T W Barrowcliffe,A F Bristow, B Cuthbertson, T Forsey, B P Hughes, D Hughes1, P Sheppard,T J Snape, W J Tarbit, L Tsang(Corresponding members K R Butterworth1, S Poole, L W Whitehouse)

J: Immunological Products: A M T Lee (Chairman), A H Andrews, M J Corbel, M A Dow, I G S Furminger,A M Pickett, A H Thomas, P W Wells, D Wood(Corresponding members E Griffiths, M L Kavanagh)

M: Microbiology : R J Pinney (Chairman), V Fenton-May (Vice-Chairman), B Alexander, R Baird,A L Davison, D P Hargreaves, W L Hooper, R Johnson, M G Lee1, B R Matthews,W F H McLean, M P Summers

N: Nomenclature: M A Simmonds (Chairman), D H Calam (Vice-Chairman), J K Aronson,D Cousins, E W Godly, P W Golightly, H McNulty, D K Mehta, G P Moss,G F Phillips, R Thorpe, A Wade1

(Corresponding members E M Cortés Montejano, S Kopp-Kubel)

P: Pharmacy D I R Begg2 (Chairman until March), A D Woolfson (Vice-Chairman until March;Chairman from April), M C Allwood1, G Davison, G Eccleston, R L Horder,M C R Johnson, M G Lee, B R Matthews, S C Nichols, G Smith, M P Summers,J D Tovey, R Withington, P Wood(Corresponding member I J McGilveray)

CONSULTATIVE GROUPSL: Surgical Materials: J M Midgley (Chairman), A Austin, J Chaston1, G J Collyer, D J Harris, D Metcalfe,

P Newlands, M Parkin, S Thomas

R: Radioactive Materials: A F Fell (Chairman), S R Hesslewood, D Lui, A M Millar, R D Pickett,A E Theobald, S Waters

Members of staff of the Commission who have taken part in theproduction of this edition include:

Secretariat: M L Rabouhans, R B Trigg, H J Judd, M Vallender, P Holland,F J Swanson, R Middleton

Laboratory: A Islam, D C Brougham, R L Turner, P K Dhanjal, T Morarji, C M Shah,R Mannan, V Pathak, M Barrett, W Jeffries

Administrative: B F Delahunty, T Garrett, J Peters, S Canciglia, A Chapman

1Term of office ended 31 April 20002Resigned March 2000

Introduction

This edition of the British Pharmacopoeia supersedes the British Pharmaco-poeia 2000 as amended by Amendments No. 1. It has been prepared by theBritish Pharmacopoeia Commission with the collaboration and support of itsadvisory Committees and experts, and contains 2,760 monographs forsubstances and articles used in the practice of medicine. Of these 1,305monographs are of national origin and 1,455 have been reproduced from the3rd edition of the European Pharmacopoeia. This new edition, together withits companion edition, the British Pharmacopoeia (Veterinary) 2001, thuscontains all monographs of the 3rd edition of the European Pharmacopoeia asamended by the Supplement 2001. The user of the British Pharmacopoeiathereby benefits by finding within this one, comprehensively indexed,compendium all current United Kingdom pharmacopoeial standards formedicines for human use.

Effective Date The effective date for this edition is 1st December 2001 unlessotherwise stated for an entry by an italicised statement showing the monthand year of its implementation. Such italicised statements are given for certainmonographs reproduced from the European Pharmacopoeia and are locatedbelow the chaplet of stars that appears alongside the monograph title, forexample ‘1/01’.

Where a monograph which appeared previously in an earlier edition of theBritish Pharmacopoeia has not been included in this new edition it remainseffective in accordance with Section 65(4) of the Medicines Act 1968.

Additions A list of monographs included within the Pharmacopoeia for thefirst time is given at the end of this introduction. It includes 43 new mono-graphs of national origin and 78 new monographs reproduced from the 2001supplement to the European Pharmacopoeia.

Revisions Monographs which have been amended technically by means ofthis edition are also listed at the end of this introduction. For the benefit ofthe reader this list indicates the section, or sections, of each monograph whichhas/have been revised.

The number of monographs for formulated preparations in which the invivo test for pyrogens is still specified has been significantly reduced. This hasbeen achieved by replacing the test for pyrogens by an in vitro test for bacterialendotoxins in monographs such as that for Ampicillin Injection, AprotininInjection and Potassium Chloride and Glucose Intravenous Infusion.

Wherever possible within the national monographs in this edition of theBritish Pharmacopoeia, tests that required the analyst to detect the presence orabsence of a particular odour [that is, that required a deliberate act ofsmelling] have been removed or modified.

European Pharmacopoeia In accordance with previous practice, all mono-graphs and requirements of the European Pharmacopoeia are reproduced inthis edition of the British Pharmacopoeia or where appropriate within itscompanion edition, the British Pharmacopoeia (Veterinary). Those texts ofthe European Pharmacopoeia not included in the 2001 Supplement butbrought into effect by rapid implementation on 1st January 2001 or other suchdate as indicated are listed in Supplementary Chapter IV B.

Where a monograph has been reproduced from the European Pharmaco-poeia this is signified by the presence of a European chaplet of stars alongsideits title. Additionally, an explicit reference to the European Pharmacopoeia iscontained within an italicised introductory statement. The entire European

Pharmacopoeia text is then bounded by two horizontal lines bearing thesymbol ‘Ph Eur’.

The European Pharmacopoeia texts have been reproduced in their entiretywithout editorial modification but, where deemed appropriate, additionalstatements of relevance to UK usage have been added (e.g. a list of BP prepar-ations). It should be noted, however, that in the event of doubt ofinterpretation in any text of the European Pharmacopoeia, the text publishedin English under the direction of the Council of Europe should be consulted.

Correspondence between the general methods of the European Pharmaco-poeia and the appendices of the British Pharmacopoeia 2001 is indicated ineach appendix and by inclusion of a check list at the beginning of the appen-dices section.

The revised general monograph of the European Pharmacopoeia for Paren-teral Preparations requires all solutions for infusion and solutions forinjection supplied in containers with a nominal content of more than 100 mlto comply with the relevant test for particulate contamination, sub-visibleparticles. The statements previously included in certain individualmonographs of the British Pharmacopoeia for Intravenous Infusions havetherefore been deleted [see Supplementary Chapter I N].

Pharmacopoeial Requirements It should be noted that any articleintended for medicinal use which is described by a name at the head of amonograph in the current edition of the Pharmacopoeia must comply withthat monograph ‘whether or not it is referred to as BP’.

It is also important to note that no requirement of the Pharmacopoeia canbe taken in isolation. A valid interpretation of any particular requirementdepends upon it being read in the context of (i) the monograph as a whole,(ii) the specified method of analysis, (iii) the relevant General Notices and (iv)where appropriate, the relevant general monograph. Familiarity with theGeneral Notices of the Pharmacopoeia will facilitate the correct application ofthe requirements. Additional guidance and information on the basis ofpharmacopoeial requirements is provided in Supplementary Chapter I. Thisnon-mandatory text describes the general underlying philosophy and currentapproaches to particular aspects of pharmacopoeial control.

General Monographs The General Monographs for dosage forms aregrouped together at the beginning of Volume II. They are followed by themonographs for the individual formulated preparations arranged inalphabetical order. The General Monographs of the European Pharmacopoeiaapply to all individual dosage forms of the type defined rather than to onlythose preparations for which a specific monograph is included (see theGeneral Notices).

Infrared Reference Spectra To enable the user to locate a particular refer-ence spectrum without difficulty, all have been assigned specific serialnumbers within this edition. These are then cited within the text whereverreference to that spectrum is made.

Nine new spectra have been added sequentially to the previous collection.

Acknowledgements The British Pharmacopoeia Commission is greatlyindebted to the members of its advisory Committees and Consultative Groupswithout whose dedicated enthusiasm and assistance this edition could nothave been prepared.

Close co-operation has continued with many organisations at home andoverseas. These include the Medicines Control Agency (of which the Pharma-copoeia secretariat and laboratory staff are a part), the National Institute forBiological Standards and Control, the Veterinary Medicines Directorate, the

Royal Pharmaceutical Society of Great Britain, the Association of the BritishPharmaceutical Industry, the European Pharmacopoeia Commission and theEuropean Directorate for the Quality of Medicines, the Therapeutic GoodsAdministration (Australia), the Health Protection Branch of the CanadianDepartment of Health and Welfare, the Committee of Revision of the UnitedStates Pharmacopeia, the Essential Drugs and Other Medicines Departmentof the World Health Organization (WHO) and the WHO CollaboratingCentre for Chemical Reference Substances.

Additions The following monographs of the British Pharmacopoeia 2001were not included in the British Pharmacopoeia 2000.

Medicinal and Pharmaceutical SubstancesAcetylcholine Chloride*Adenosine*Alendronate Sodium*Alfadex*Aprostadil*Ambroxol Hydrochloride*Amisulpride*Amlodipine Besilate*Bismuth Subgallate*Bismuth Subnitrate, Heavy*Bismuth Subsalicylate*Cassia Oil*Castor Oil, Hydrogenated*Centella*Cilazapril*Cimetidine Hydrochloride*Cisapride Tartrate*Cola*Dextran 1 for Injection*Diclofenac Potassium*Dog Rose*Enoxolone*Estrogens, Conjugated*Etofenamate*Etomidate*Ferric Chloride Hexahydrate*Feverfew*Flumequine*Ginseng*Glucose, Spray-dried Liquid*Ifosfamide*Isomalt*Juniper*Lavender Flower*Levocabastine Hydrochloride*Levodropropizine*Lofepramine HydrochlorideLoosestrife*Lovastatin*Magnesium Peroxide*Mallow Flower*Maltodextrin*Matricaria Liquid Extract*Methenamine*Neohesperidine-dihydrochalcone*Nimesulide*Nitric Oxide*Nomegestrol Acetate*Octoxinol 10*Pergolide Mesilate*Piretanide*Potassium Carbonate*

1Monograph transferred from the BP(Vet)

*denotes a monograph of the European PharmacopoeiaPropofol*Risperidone*Rosemary Leaf*Sage Leaf, Three-lobed*Silica, Dental Type*Simvastatin*Sodium Molybdate Dihydrate*Sodium Propionate1

Sodium Starch Glycollate (Type C)*Sodium Stearyl Fumarate*Sufentanil*Sugar, CompressibleSugar Spheres*Sumatriptan Succinate*Suxibuzone*Tiapride Hydrochloride*Trapidil*Ubidecarenone*Vegetable Fatty Oil*Willow Bark*

Formulated Preparations: Specific MonographsAminoglutethimide TabletsArginine Hydrochloride Intravenous InfusionAspirin Tablets, Gastro-resistantBetaxolol Eye Drops, SolutionBetaxolol Eye Drops, SuspensionCalcium Carbonate Chewable TabletsCarboplatin InjectionCo-beneldopa CapsulesCo-beneldopa Tablets, DispersibleCyproterone TabletsEtoposide CapsulesEtoposide Intravenous InfusionFerrous Sulphate Tablets, Prolonged-releaseFlecainide TabletsFluoxetine Oral SolutionFosfestrol TabletsInsulin Injection, Protamine ZincIpecacuanha Tincture, Standardised*Isosorbide Mononitrate TabletsIsotretinoin CaspulesLactulose Oral PowderLiquorice Ethanolic Liquid Extract, Standardised*Lisinopril TabletsLithium Citrate Oral SolutionLofepramine TabletsMagnesium Chloride InjectionMorphine Sulphate Tablets, Prolonged-releaseOxybuprocaine Eye DropsOxybutynin TabletsParacetamol SuppositoriesPhenol Injection, AqueousPiperacillin Intravenous InfusionPropranolol Capsules, Prolonged-releaseSalbutamol Nebuliser SolutionSalbutamol Oral SolutionSelegiline Oral SolutionSelegiline TabletsTenoxicam InjectionTenoxicam TabletsTitanium OintmentUrsodeoxycholic Acid CapsulesUrsodeoxycholic Acid TabletsVerapamil Tablets, Prolonged-release

Blood ProductsAnti-D Immunoglobulin for Intravenous Use*Varicella Immunoglobulin for Intravenous Use*

Immunological ProductsHepatitis A (Inactivated) and Hepatitis B (rDNA) Vaccine, Adsorbed*

Radiopharmaceutical PreparationsAmmonia[13N] Injection*Cyanocobalamin[58Co] Capsules*Krypton[81mKr] Inhalation Gas*Water[15O] Injection*

Omissions The following monographs of the British Pharmacopoeia 2000 arenot included in the British Pharmacopoeia 2001.

Medicinal and Pharmaceutical SubstancesAzlocillin SodiumClindamycin Palmitate Hydrochloride

Formulated Preparations: Specific MonographsAmitriptyline Oral SuspensionAzlocillin InjectionBenzaldehyde SpiritChloral Elixir, PaediatricChloral MixtureChlorothiazide TabletsClindamycin Oral Suspension, PaediatricColecalciferol Oral SolutionDebrisoquine TabletsDextan 110 Intravenous InfusionDextromoramide InjectionErgocalciferol Oral SolutionErgotamine InjectionEtacrynic Acid TabletsKanamycin InjectionMethohexital InjectionPentaerythritol Tetranitrate TabletsPhenindamine TabletsPrednisone TabletsSulfadimidine Injection2

Sulfadimidine Oral Suspenion, PaediatricSulfadimidine Tablets2

Water for Irrigation

Surgical MaterialsSterile Absorbet Cotton3

Sterile Absorbent Viscose Wadding3

2Monograph transferred to the British Pharmacopoeia (Veterinary)3Monograph suppressed by the European Pharmacopoeia on 1 January 2001

Technical Changes The following monographs in the BP 2001 have beentechnically amended since the publication of the BP 2000. This list does notinclude revised monographs of the European Pharmacopoeia. An indicationof the nature of the change or the section of the monograph that has beenchanged is given in italic type in the right hand column.

Medicinal and Pharmaceutical SubstancesAzelastine Hydrochloride 1-Methyl-4-(2-benzoylhydrazino)-

azepan; Related substancesBenzaldehyde AssayBenzatropine Mesilate Related substancesBenzydamine Hydrochloride Production; 3-Chloropropyl-

(dimethyl)amine hydrochlorideCholine Salicylate Solution IdentificationCinnamic Acid IdentificationCinnamon Oil Replaced by Ph Eur monographDextrin Replaced by Ph Eur monographDiamorphine Hydrochloride Definition; Related substances;

Assay

Diethylamine Salicylate IdentificationDisodium Hydrogen Phosphate, Anhydrous Replaced by Ph Eur monographDisodium Pamidronate Phosphate and phosphiteEthanols, Dilute Aldehydes; Volatile impuritiesFerrous Sulphate, Dried ManganeseFlurbiprofen Replaced by Ph Eur monographFoscarnet Sodium Hexahydrate Replaced by Ph Eur monographGinger Replaced by Ph Eur monographGliclazide Replaced by Ph Eur monographHalibut-liver Oil AssayMagaldrate Replaced by Ph Eur monographManganese Sulphate AssayManganese Sulphate Monohydrate Replaced by Ph Eur monographNaftidrofuryl Oxalate IdentificationNitric Acid Replaced by Ph Eur monographNutmeg Oil Replaced by Ph Eur monographParaffin, Yellow Soft Replaced by Ph Eur monographPhenindione IdentificationPhenolphthalein Replaced by Ph Eur monographPodophyllum Resin IdentificationProguanil Hydrochloride Related substancesSodium Stibogluconate IdentificationStanozolol Replaced by Ph Eur monographSulphuric Acid Replaced by Ph Eur monographTioconazole Related substancesTriethanolamine Replaced by Ph Eur monographVitamin A Ester Concentrate, Natural Assay

Formulated Preparations: Specific MonographsAmoxicillin Capsules Identification; AssayAmoxicillin Injection Identification; Pyrogens →→→→→→→→→→→→→→→→→→→→→Bacterial

endotoxins; AssayAmoxicillin Oral Suspension Identification; AssayAmpicillin Capsules Identification; AssayAmpicillin Injection Identification; AssayAmpicillin Oral Suspension Identification; AssayAprotinin Injection Pyrogens →→→→→→→→→→→→→→→→→→→→→Bacterial endotoxinsAspirin Tablets IdentificationCalcium and Colecalciferol Tablets Identification; Uniformity of contentCalcium and Ergocalciferol Tablets Identification; Uniformity of contentCalcitonin Salmon Injection Related peptidesCapreomycin Injection Pyrogens →→→→→→→→→→→→→→→→→→→→→Bacterial endotoxinsCefaclor Capsules Related substancesCefaclor Oral Suspension Related substancesCefaclor Tablets, Slow Related substancesCefazolin Injection Related substancesCefoxitin Injection Content statementCholine Salicylate Ear Drops IdentificationChorionic Gonadotrophin Injection Pyrogens →→→→→→→→→→→→→→→→→→→→→Bacterial endotoxinsCiprofloxacin Intravenous Infusion 5-HydroxymethylfurfuralCloxacillin Capsules AssayCloxacillin Injection AssayCloxacillin Oral Solution Identification; AssayCo-dergocrine Tablets Dissolution; Uniformity of contentColistimethate Injection Identification; Acidity or alkalinity;

Free colistin; Pyrogens →→→→→→→→→→→→→→→→→→→→→Bacterialendotoxins

Cortisone Tablets AssayCo-trimoxazole Intravenous Infusion Pyrogens →→→→→→→→→→→→→→→→→→→→→Bacterial endotoxinsCyclopentolate Eye Drops IdentificationDextran 70 Intravenous Infusion all testsDextran 70 Intravenous Infusion all testsDicycloverine Oral Solution/Dicyclomine Oral Related substances

Diethylamine Salicylate Cream IdentificationDocusate Enema, Compound Acidity or alkalinityDopamine Intravenous Infusion Related substances (ready-to-use

infusion); Bacterial endotoxins(all formulations)

Erythromycin Lactobionate Intravenous Infusion Pyrogens →→→→→→→→→→→→→→→→→→→→→Bacterial endotoxinsEthambutol Tablets AssayFlavoxate Tablets 3-Methylflavone-8-carboxylic acidFlucloxacillin Capsules AssayFlucloxacillin Injection Water; AssayFlucloxacillin Oral Solution Identification; AssayFlucloxacillin Oral Suspension Identification; AssayFluorouracil Injection Related substancesFluoxetine Capsules DissolutionGlyceryl Trinitrate Tablets IdentificationHalibut-liver Oil Capsules AssayHydrocortisone Acetate Injection AssayHyoscine Eye Drops AssayHyoscine Injection AssayHyoscine Tablets AssayIsoprenaline Injection Content statement (ready-to-use

injection)Isotretinoin Gel AssayKetamine Injection Foreign amines; Related substancesLidocaine and Chlorhexidine Gel/Lignocaine and

Chlorhexidine GelAromatic amines

Loperamide Capsules Uniformity of contentMannitol Intravenous Infusion Pyrogens →→→→→→→→→→→→→→→→→→→→→Bacterial endotoxinsMeglumine Amidotrizoate Injection IdentificationMetronidazole Intravenous Infusion Bacterial endotoxinsMethyl Salicylate Liniment Characteristics; IdentificationMethyl Salicylate Ointment Characteristics; IdentificationMetyrapone Capsules AssayParaffin Eye Drops, Light Liquid Polycyclic Aromatic Hydrocarbons;

Readily carbonisable substancesPentazocine Capsules IdentificationPethidine Injection AssayPhenindione Tablets IdentificationPhenoxybenzamine Capsules AssayPhenytoin Injection IdentificationPilocarpine Hydrochloride Eye Drops Acidity; Pilocarpic AcidPiperazine Citrate Elixir Weight per mlPotassium Chloride and Glucose Intravenous

InfusionPyrogens →→→→→→→→→→→→→→→→→→→→→Bacterial endotoxins

Potassium Chloride and Sodium ChlorideIntravenous Infusion

Pyrogens →→→→→→→→→→→→→→→→→→→→→Bacterial endotoxins

Potassium Chloride, Sodium Chloride andGlucose Intravenous Infusion

Pyrogens →→→→→→→→→→→→→→→→→→→→→Bacterial endotoxins

Prednisolone Tablets Dissolution; Related substancesProguanil Tablets Related substances; AssayPyridostigmine Tablets Related substancesSalbutamol Injection Related substancesSalbutamol Pressurised Inhalation IdentificationSodium Chloride Irrigation Solution DefinitionSulfadimidine Injection AssaySulindac Tablets Related substancesSpectinomycin Injection AssayTestosterone Propionate Injection AssayTioconazole Cream Related substancesTioconazole Nail Solution Identification; Related substancesUrofollitropin Injection Pyrogens →→→→→→→→→→→→→→→→→→→→→Bacterial endotoxinsVerapamil Tablets Content statementVitamins B and C Injection IdentificationZuclopenthixol Tablets Related substances; trans-Isomer;

2-Chlorothioxanthone

Changes in Title The following list gives the alterations in the titles of mono-graphs of the British Pharmacopoeia 2000 that have been retained in theBritish Pharmacopoeia 2001.

BRITISH PHARMACOPOEIA 2000 BRITISH PHARMACOPOEIA 2001

Medicinal and Pharmaceutical SubstancesAlmond Oil Virgin Almond OilCastor Oil Virgin Castor OilCinnamon Oil Ceylon Cinnamon Bark OilSorbitol 70 per cent, Crystallising Liquid Sorbitol CrystallisingSorbitol 70 per cent Non-crystallising Liquid Sorbitol Non-crystallisingSoya Oil Refined Soya OilSynthetic Retinol Concentrate Water-

dispersible FormSynthetic Retinol Concentrate

Solubilisate.Emulsion

Formulated Preparations: Specific MonographsRibavirin Solution for Nebulisation Ribavirin Nebuliser Solution

General Notices

Contents of the General Notices

Part IIIItalic introductionGeneral Notices of the European

Pharmacopoeia

1.1 General StatementsConventional terms

1.2 Other Provisions Applying to GeneralChapters and Monographs

QuantitiesApparatus and proceduresWater-bathDrying and ignition to constant massReagentsSolventsExpression of contentTemperature

1.3 General ChaptersContainers

1.4 MonographsTitlesRelative atomic and molecular massesDefinition

Limits of contentVegetable drugs

ProductionCharacters

SolubilityIdentificationTests and assays

ScopeCalculationLimitsIndication of permitted limits of impuritiesVegetable drugsEquivalents

StorageLabellingWarningsImpuritiesCritical physical propertiesReference substances, reference

preparations and reference spectraChemical reference substancesBiological reference preparationsReference spectra

1.5 Abbreviations and Symbols

1.6 Units of the International System (SI)Used in the Pharmacopoeia andEquivalence with Other Units

Part IItalic introductionEuropean Pharmacopoeia

Part IIItalic introductionOfficial StandardsExpression of StandardsTemperatureWeights and MeasuresAtomic WeightsConstant WeightExpression of ConcentrationsWater BathReagentsIndicatorsCaution StatementsTitlesChemical FormulaeDefinitionProductionManufacture of Formulated

PreparationsFreshly and Recently PreparedMethods of SterilisationWaterExcipientsColouring AgentsAntimicrobial PreservativesCharacteristicsSolubilityIdentificationAssays and TestsBiological Assays and TestsStorageLabellingAction and UseCrude Drugs

General Notices

Part I The British Pharmacopoeia comprises the entire text within this publication.The word ‘official’ is used in the Pharmacopoeia to signify ‘of the Pharmaco-poeia’. It applies to any title, substance, preparation, method or statementincluded in the general notices, monographs and appendices of the Pharmaco-poeia. The abbreviation for British Pharmacopoeia is BP.

European Pharmacopoeia

Monographs of the European Pharmacopoeia are reproduced in thisedition of the British Pharmacopoeia by incorporation of the textpublished under the direction of the Council of Europe (Partial Agree-ment) in accordance with the Convention on the Elaboration of a Euro-pean Pharmacopoeia (Treaty Series No. 32 (1974) CMND 5763) asamended by the Protocol to the Convention (Treaty Series No MISC16(1990) CMND 1133). They are included for the convenience of users

of the British Pharmacopoeia. In cases of doubt or disputereference should be made to the Council of Europe text.

Monographs of the European Pharmacopoeia are distinguishedby a chaplet of stars against the title and by an italicised statementpreceding the Definition. The beginnning and end of text from the

European Pharmacopoeia are denoted by means of horizontallines with the symbol ‘Ph Eur’ ranged left and right, respectively.

Inclusion of a triangle within the chaplet of stars denotes mono-graphs that have been adopted by the European PharmacopoeiaCommission following their preparation according to a procedure ofharmonisation agreed between the bodies responsible for the EuropeanPharmacopoeia and those of Japan and the United States of America.

The general provisions of the European Pharmacopoeia relating todifferent types of dosage form are included in the appropriate generalmonograph in that section of the British Pharmacopoeia entitled Mono-graphs: Formulated Preparations. These general provisions apply to alldosage forms of the type defined, whether an individual monograph isincluded in the British Pharmacopoeia or not.

Texts of the European Pharmacopoeia are governed by the GeneralNotices of the European Pharmacopoeia. These are reproduced as PartIII of these notices.

Part II The following general notices apply to the statements made in the monographsof the British Pharmacopoeia other than those reproduced from the EuropeanPharmacopoeia and to the statements made in the Appendices of the BritishPharmacopoeia other than when a method, test or other matter described inan appendix is invoked in a monograph reproduced from the EuropeanPharmacopoeia.

Official Standards The requirements stated in the monographs of the Pharmacopoeiaapply to articles that are intended for medicinal use but not necessarilyto articles that may be sold under the same name for other purposes. Anarticle intended for medicinal use that is described by means of anofficial title must comply with the requirements of the relevant mono-graph. A formulated preparation must comply throughout its assignedshelf-life (period of validity). The subject of any other monograph mustcomply throughout its period of use.

A monograph is to be construed in accordance with any generalmonograph or notice or any appendix, note or other explanatorymaterial that is contained in this edition and that is applicable to thatmonograph. All statements contained in the monographs, except wherea specific general notice indicates otherwise and with the exceptionsgiven below, constitute standards for the official articles. An article isnot of Pharmacopoeial quality unless it complies with all of the require-ments stated. This does not imply that a manufacturer is obliged toperform all the tests in a monograph in order to assess compliance withthe Pharmacopoeia before release of a product. The manufacturer mayassure himself that a product is of Pharmacopoeial quality by othermeans, for example, from data derived from validation studies of themanufacturing process, from in-process controls or from a combinationof the two. Parametric release in appropriate circumstances is thus notprecluded by the need to comply with the Pharmacopoeia. The generalnotice on Assays and Tests indicates that analytical methods other thanthose described in the Pharmacopoeia may be employed for routinepurposes.

Requirements in monographs have been framed to provide appropri-ate limitation of potential impurities rather than to provide against allpossible impurities. Material found to contain an impurity not detect-able by means of the prescribed tests is not of Pharmacopoeial quality ifthe nature or amount of the impurity found is incompatible with goodpharmaceutical practice.

The status of any statement given under the side-headings Definition,Production, Characteristics, Storage, Labelling or Action and use isdefined within the general notice relating to the relevant side-heading.In addition to any exceptions indicated by one of the general noticesreferred to above, the following parts of a monograph do not constitutestandards: (a) a graphic or molecular formula given at the beginning ofa monograph; (b) a molecular weight; (c) a Chemical Abstracts ServiceRegistry Number; (d) any information given at the end of a monographconcerning impurities known to be limited by that monograph; (e)information in any annex to a monograph. Any statement containingthe word ‘should’ constitutes non-mandatory advice orrecommendation.

The expression ‘unless otherwise justified and authorised’ means thatthe requirement in question has to be met, unless a competent authorityauthorises a modification or exemption where justified in a particularcase. The term ‘competent authority’ means the national, supranationalor international body or organisation vested with the authority formaking decisions concerning the issue in question. It may, for example,be a licensing authority or an official control laboratory. For a formula-ted preparation that is the subject of monograph in the British

Pharmacopoeia any justified and authorised modification to, orexemption from, the requirements of the relevant general monograph ofthe European Pharmacopoeia is stated in the individual monograph.For example, the general monograph for Tablets requires that UncoatedTablets, except for chewable tablets, disintegrate within 15 minutes; forCalcium Lactate Tablets a time of 30 minutes is permitted.

Many of the general monographs for formulated preparations includestatements and requirements additional to those of the EuropeanPharmacopoeia that are applicable to the individual monographs of theBritish Pharmacopoeia. Such statements and requirements apply to allmonographs for that dosage form included in the Pharmacopoeia unlessotherwise indicated in the individual monograph.

Where a monograph on a biological substance or preparation refers toa strain, a test, a method, a substance, etc., using the qualifications‘suitable’ or ‘appropriate’ without further definition in the text, thechoice of such strain, test, method, substance, etc., is made in accord-ance with any international agreements or national regulations affectingthe subject concerned.

Expression of Standards

Where the standard for the content of a substance described in amonograph is expressed in terms of the chemical formula for thatsubstance an upper limit exceeding 100% may be stated. Such an upperlimit applies to the result of the assay calculated in terms of theequivalent content of the specified chemical formula. For example, thestatement ‘contains not less than 99.0% and not more than 101.0% ofC20H24N2O2,HCl’ implies that the result of the assay is not less than99.0% and not more than 101.0%, calculated in terms of the equivalentcontent of C20H24N2O2,HCl.

Where the result of an assay or test is required to be calculated withreference to the dried, anhydrous or ignited substance, the substancefree from a specified solvent or to the peptide content, the determin-ation of loss on drying, water content, loss on ignition, content of thespecified solvent or peptide content is carried out by the methodprescribed in the relevant test in the monograph.

Temperature The Celsius thermometric scale is used in expressing temperatures.

Weights and Measures The metric system of weights and measures is employed; SI Units havegenerally been adopted. Metric measures are required to have beengraduated at 20° and all measurements involved in the analyticaloperations of the Pharmacopoeia are intended, unless otherwise stated,to be made at that temperature. Graduated glass apparatus used inanalytical operations should comply with Class A requirements of theappropriate specification issued by the British Standards Institution.

Atomic Weights The atomic weights adopted are the values given in the Table of Relat-ive Atomic Weights 1989 published by the International Union of Pureand Applied Chemistry. The values are based on the carbon-12 scale(Appendix XXII).

1092Constant Weight The term ‘constant weight’, used in relation to the process of drying orthe process of ignition, means that two consecutive weighings do notdiffer by more than 0.5 milligram, the second weighing being madeafter an additional period of drying or ignition under the specified

conditions appropriate to the nature and quantity of the residue (1 houris usually suitable).

Expression of Concentrations

The term ‘per cent’ or more usually the symbol ‘%’ is used with one offour different meanings in the expression of concentrations according tocircumstances. In order that the meaning to be attached to theexpression in each instance is clear, the following notation is used.

Per cent w/w (% w/w) (percentage weight in weight) expresses thenumber of grams of solute in 100 g of product.

Per cent w/v (% w/v) (percentage weight in volume) expresses thenumber of grams of solute in 100 ml of product.

Per cent v/v (% v/v) (percentage volume in volume) expresses thenumber of millilitres of solute in 100 ml of product.

Per cent v/w (% v/w) (percentage volume in weight) expresses thenumber of millilitres of solute in 100 g of product.

Usually the strength of solutions of solids in liquids is expressed aspercentage weight in volume, of liquids in liquids as percentage volumein volume and of gases in liquids as percentage weight in weight.

When the concentration of a solution is expressed as parts per million(ppm), it means weight in weight, unless otherwise specified.

When the concentration of a solution is expressed as parts of dissolvedsubstance in parts of the solution, it means parts by weight (g) of a solidin parts by volume (ml) of the final solution; or parts by volume (ml) ofa liquid in parts by volume (ml) of the final solution; or parts by weight(g) of a gas in parts by weight (g) of the final solution.

When the concentration of a solution is expressed in molarity designa-ted by the symbol M preceded by a number, it denotes the number ofmoles of the stated solute contained in sufficient Purified Water (unlessotherwise stated) to produce 1 litre of solution.

1091Water Bath The term ‘water bath’ means a bath of boiling water, unless water atsome other temperature is indicated in the text. An alternative form ofheating may be employed providing that the required temperature isapproximately maintained but not exceeded.

Reagents The reagents required for the assays and tests of the Pharmacopoeia aredefined in appendices. The descriptions set out in the appendices donot imply that the materials are suitable for use in medicine.

Indicators Indicators, the colours of which change over approximately the samerange of pH, may be substituted for one another but in the event ofdoubt or dispute as to the equivalence of indicators for a particularpurpose, the indicator specified in the text is alone authoritative.

The quantity of an indicator solution appropriate for use in acid—basetitrations described in assays or tests is 0.1 ml unless otherwise stated inthe text.

Any solvent required in an assay or test in which an indicator is speci-fied is previously neutralised to the indicator, unless a blank test isprescribed.

Caution Statements A number of materials described in the monographs and some of thereagents specified for use in the assays and tests of the Pharmacopoeiamay be injurious to health unless adequate precautions are taken. Theprinciples of good laboratory practice and the provisions of any appro-

priate regulations such as those issued in the United Kingdom inaccordance with the Health and Safety at Work etc. Act (1974) shouldbe observed at all times in carrying out the assays and tests of thePharmacopoeia.

Attention is drawn to particular hazards in certain monographs bymeans of an italicised statement; the absence of such a statement shouldnot however be taken to mean that no hazard exists.

Titles Subsidiary titles, where included, have the same significance as the maintitles. An abbreviated title constructed in accordance with the directionsgiven in Appendix XXI A has the same significance as the main title.

Titles that are derived by the suitable inversion of words of a main orsubsidiary title, with the addition of a preposition if appropriate, are alsoofficial titles. Thus, the following are all official titles: Aspirin Tablets,Tablets of Aspirin; Ginger Tincture, Tincture of Ginger; AtropineInjection, Injection of Atropine.

A title of a formulated preparation that includes the full nonpro-prietary name of the active ingredient or ingredients, where this is notincluded in the title of the monograph, is also an official title. Forexample, the title Promethazine Hydrochloride Oral Solution has thesame significance as Promethazine Oral Solution and the title Brom-pheniramine Maleate Tablets has the same significance as Bromphenir-amine Tablets.

Where the English title at the head of a monograph in the EuropeanPharmacopoeia is different from that at the head of the text incorpora-ted into the British Pharmacopoeia, the European Pharmacopoeia titleis given in an italicised statement at the head of the incorporated text.The titles and subsidiary titles (if any) of such incorporated texts havebeen declared Approved Synonyms in accordance with section 65(8) ofthe Medicines Act 1968 and are thus official titles. A cumulative list ofsuch Approved Synonyms is provided in Appendix XXI B.

Where the names of Pharmacopoeial substances, preparations andother materials occur in the text they are printed with capital initialletters and this indicates that materials of Pharmacopoeial quality mustbe used. Words in the text that name a reagent or other material, aphysical characteristic or a process that is described or defined in anappendix are printed in italic type, for example, methanol, absorbance,gas chromatography, and these imply compliance with the requirementsspecified in the appropriate appendix.

Chemical Formulae When the chemical composition of an official substance is known orgenerally accepted, the graphic and molecular formulae, the molecularweight and the Chemical Abstracts Service Registry Number are norm-ally given at the beginning of the monograph for information. Thisinformation refers to the chemically pure substance and is not to beregarded as an indication of the purity of the official material. Else-where, in statements of standards of purity and strength and in descrip-tions of processes of assay, it is evident from the context that the formu-lae denote the chemically pure substances.

Where the absolute stereochemical configuration is specified, theInternational Union of Pure and Applied Chemistry (IUPAC) R/S andE/Z systems of designation have been used. If the substance is an enan-tiomer of unknown absolute stereochemistry the sign of the optical

rotation, as determined in the solvent and under the conditions speci-fied in the monograph, has been attached to the systematic name. Anindication of sign of rotation has also been given where this is incorpor-ated in a trivial name that appears on an IUPAC preferred list.All amino acids, except glycine, have the L-configuration unless other-wise indicated. The three-letter and one-letter symbols used for aminoacids in peptide and protein sequences are those recommended by theJoint Commission on Biochemical Nomenclature of the InternationalUnion of Pure and Applied Chemistry and the International Union ofBiochemistry.

In the graphic formulae the following abbreviations are used:

Me i –CH3 i Bus –CH(CH3)CH2CH3 i

Et i –CH2CH3 i Bun –CH2CH2CH2CH3 i

Pri –CH(CH3)2 i But –C(CH3)3 i

Prn –CH2CH2CH3 i Ph i –C6H5 i

Bui –CH2CH(CH3)2 i Ac i –COCH3 i

Definition Statements given under the side-heading Definition constitute an officialdefinition of the substance, preparation or other article that is thesubject of the monograph. They constitute instructions or requirementsand are mandatory in nature.

Certain medicinal or pharmaceutical substances and other articles aredefined by reference to a particular method of manufacture. A state-ment that a substance or article is prepared or obtained by a certainmethod constitutes part of the official definition and implies that othermethods are not permitted. A statement that a substance may beprepared or obtained by a certain method, however, indicates that this isone possible method and does not imply that other methods areproscribed.

Additional statements concerning the definition of formulated prepar-ations are given in the general notice on Manufacture of FormulatedPreparations.

Production Statements given under the side-heading Production draw attention toparticular aspects of the manufacturing process but are not necessarilycomprehensive. They constitute mandatory instructions to manu-facturers. They may relate, for example, to source materials, to themanufacturing process itself and its validation and control, to in-processtesting or to testing that is to be carried out by the manufacturer on thefinal product (bulk material or dosage form) either on selected batchesor on each batch prior to release. These statements cannot necessarilybe verified on a sample of the final product by an independent analyst.The competent authority may establish that the instructions have beenfollowed, for example, by examination of data received from the manu-facturer, by inspection or by testing appropriate samples.

The absence of a section on Production does not imply that attentionto features such as those referred to above is not required. A substance,preparation or article described in a monograph of the Pharmacopoeia isto be manufactured in accordance with the principles of good manu-facturing practice and in accordance with relevant international agree-ments and supranational and national regulations governing medicinalproducts.

Where in the section under the side-heading Production a monographon a vaccine defines the characteristics of the vaccine strain to be used,any test methods given for confirming these characteristics are providedas examples of suitable methods. The use of these methods is notmandatory.

Additional statements concerning the production of formulatedpreparations are given in the general notice on Manufacture ofFormulated Preparations.

Manufacture of Formulated Preparations

Attention is drawn to the need to observe adequate hygienic precautionsin the preparation and dispensing of pharmaceutical formulations. Theprinciples of good pharmaceutical manufacturing practice should beobserved.

The Definition in certain monographs for pharmaceutical prepara-tions is given in terms of the principal ingredients only. Any ingredient,other than those included in the Definition, must comply with thegeneral notice on Excipients and the product must conform with thePharmacopoeial requirements.

The Definition in other monographs for pharmaceutical preparationsis presented as a full formula. No deviation from the stated formula ispermitted except those allowed by the general notices on ColouringAgents and Antimicrobial Preservatives. Where additionally directionsare given under the side-heading Extemporaneous Preparation these areintended for the extemporaneous preparation of relatively small quanti-ties for short-term supply and use. When so prepared, no deviationfrom the stated directions is permitted. If, however, such apharmaceutical preparation is manufactured on a larger scale with theintention that it may be stored, deviations from the stated directions arepermitted provided that the final product meets the following criteria:

(1) compliance with all of the requirements stated in the monograph;

(2) retention of the essential characteristics of the preparation madestrictly in accordance with the directions of the Pharmacopoeia.

Monographs for yet other pharmaceutical preparations include both aDefinition in terms of the principal ingredients and, under the side-heading Extemporaneous Preparation, a full formula together with, insome cases, directions for their preparation. Such full formulae anddirections are intended for the extemporaneous preparation of relativelysmall quantities for short-term supply and use. When so prepared, nodeviation from the stated formula and directions is permitted. If, how-ever, such a pharmaceutical preparation is manufactured on a largerscale with the intention that it may be stored, deviations from the form-ula and directions stated under the side-heading ExtemporaneousPreparation are permitted provided that any ingredient, other thanthose included in the Definition, complies with the general notice onExcipients and that the final product meets the following criteria:

(1) accordance with the Definition stated in the monograph;

(2) compliance with all of the requirements stated in the monograph;

(3) retention of the essential characteristics of the preparation madestrictly in accordance with the formula and directions of thePharmacopoeia.

In the manufacture of any official preparation on a large scale with theintention that it should be stored, in addition to following any instruc-tion under the side-heading Production, it is necessary to ascertain thatthe product is satisfactory with respect to its physical and chemicalstability and its state of preservation over the claimed shelf-life. Thisapplies irrespective of whether the formula of the Pharmacopoeia andany instructions given under the side-heading Extemporaneous Prepara-tion are followed precisely or modified. Provided that the preparationhas been shown to be stable in other respects, deterioration due tomicrobial contamination may be inhibited by the incorporation of asuitable antimicrobial preservative. In such circumstances the labelstates appropriate storage conditions, the date after which the productshould not be used and the identity and concentration of the antimicro-bial preservative.

Freshly and Recently Prepared

The direction, given under the side-heading ExtemporaneousPreparation, that a preparation must be freshly prepared indicates that itmust be made not more than 24 hours before it is issued for use. Thedirection that a preparation should be recently prepared indicates thatdeterioration is likely if the preparation is stored for longer than about 4weeks at 15° to 25°.

Methods of Sterilisation

The methods of sterilisation used in preparing the sterile materialsdescribed in the Pharmacopoeia are given in Appendix XVIII. Foraqueous preparations, steam sterilisation (heating in an autoclave) is themethod of choice wherever it is known to be suitable. Any method ofsterilisation must be validated with respect to both the assurance ofsterility and the integrity of the product and to ensure that the finalproduct complies with the requirements of the monograph.

Water The term Water used without qualification in formulae for formulatedpreparations means either potable water freshly drawn direct from thepublic supply and suitable for drinking or freshly boiled and cooledPurified Water. The latter should be used if the public supply is from alocal storage tank or if the potable water is unsuitable for a particularpreparation.

Excipients Where an excipient for which there is a Pharmacopoeial monograph isused in preparing an official preparation it shall comply with that mono-graph. Any substance added in preparing an official preparation shall beinnocuous, shall have no adverse influence on the therapeutic efficacy ofthe active ingredients and shall not interfere with the assays and tests ofthe Pharmacopoeia. Particular care should be taken to ensure that suchsubstances are free from harmful organisms.

Colouring Agents If in a monograph for a formulated preparation defined by means of afull formula a specific colouring agent or agents is prescribed, suitablealternatives approved in the country concerned may be substituted.

Antimicrobial Preservatives

When the term ‘suitable antimicrobial preservative’ is used it is impliedthat the preparation concerned will be effectively preserved according to

the appropriate criteria applied and interpreted as described in the testfor efficacy of antimicrobial preservation (Appendix XVI C). In certainmonographs for formulated preparations defined by means of a fullformula, a specific antimicrobial agent or agents may be prescribed;suitable alternatives may be substituted provided that their identity andconcentration are stated on the label.

Characteristics Statements given under the side-heading Characteristics are not to beinterpreted in a strict sense and are not to be regarded as officialrequirements. Statements on taste are provided only in cases where thisproperty is a guide to the acceptability of the material (for example, amaterial used primarily for flavouring). The status of statements onsolubility is given in the general notice on Solubility.

Solubility Statements on solubility given under the side-headingCharacteristics are intended as information on the approximatesolubility at a temperature between 15° and 25°, unless otherwisestated, and are not to be considered as official requirements.

Statements given under side-headings such as Solubility in ethanolexpress exact requirements and constitute part of the standards for thesubstances under which they occur.

The following table indicates the meanings of the terms used in state-ments of approximate solubilities.

Descriptive term Approximate volume ofsolvent in millilitres pergram of solute

very soluble less than 1freely soluble from 1 to 10soluble from 10 to 30sparingly soluble from 30 to 100slightly soluble from 100 to 1000very slightly soluble from 1000 to 10,000practically insoluble more than 10,000

The term ‘partly soluble’ is used to describe a mixture of which onlysome of the components dissolve.

Identification The tests described or referred to under the side-heading Identificationare not necessarily sufficient to establish absolute proof of identity. Theyprovide a means of verifying that the identity of the material beingexamined is in accordance with the label on the container.

Unless otherwise prescribed, identification tests are carried out at atemperature between 15° and 25°.

When tests for infrared absorption are applied to material extractedfrom formulated preparations, strict concordance with the specifiedreference spectrum may not always be possible, but nevertheless a closeresemblance between the spectrum of the extracted material and thespecified reference spectrum should be achieved.

Assays and Tests The assays and tests described are the official methods upon which thestandards of the Pharmacopoeia depend. The analyst is not precludedfrom employing alternative methods, including methods of micro-

analysis, in any assay or test if it is known that the method used will givea result of equivalent accuracy. Local reference materials may be usedfor routine analysis, provided that these are calibrated against theofficial reference materials. In the event of doubt or dispute, themethods of analysis, the reference materials and the reference spectra ofthe Pharmacopoeia are alone authoritative.

Where the solvent used for a solution is not named, the solvent isPurified Water.

Unless otherwise prescribed, the assays and tests are carried out at atemperature between 15° and 25°.

A temperature in a test for Loss on drying, where no temperaturerange is given, implies a range of ± 2° about the stated value.

Visual comparative tests, unless otherwise prescribed, are carried outusing identical tubes of colourless, transparent, neutral glass with a flatbase. The volumes of liquid prescribed are for use with tubes 16 mm ininternal diameter; tubes with a larger internal diameter may be used butthe volume of liquid examined must be increased so that the depth ofliquid in the tubes is not less than that obtained when the prescribedvolume of liquid and tubes 16 mm in internal diameter are used. Equalvolumes of the liquids to be compared are examined down the verticalaxis of the tubes against a white background or, if necessary, against ablack background. The examination is carried out in diffuse light.

Where a direction is given that an analytical operation is to be carriedout ‘in subdued light’, precautions should be taken to avoid exposure todirect sunlight or other strong light. Where a direction is given that ananalytical operation is to be carried out ‘protected from light’, precau-tions should be taken to exclude actinic light by the use of low-actinicglassware, working in a dark room or similar procedures.

For preparations other than those of fixed strength, the quantity to betaken for an assay or test is usually expressed in terms of the activeingredient. This means that the quantity of the active ingredientexpected to be present and the quantity of the preparation to be takenare calculated from the strength stated on the label.

In assays the approximate quantity to be taken for examination isindicated but the quantity actually used must not deviate by more than10% from that stated. The quantity taken is accurately weighed ormeasured and the result of the assay is calculated from this exactquantity. Reagents are measured and the procedures are carried outwith an accuracy commensurate with the degree of precision implied bythe standard stated for the assay.

In tests the stated quantity to be taken for examination must be usedunless any divergence can be taken into account in conducting the testand calculating the result. The quantity taken is accurately weighed ormeasured with the degree of precision implied by the standard or, wherethe standard is not stated numerically (for example, in tests for Clarityand colour of solution), with the degree of precision implied by thenumber of significant figures stated. Reagents are measured and theprocedures are carried out with an accuracy commensurate with thisdegree of precision.

The limits stated in monographs are based on data obtained in normalanalytical practice; they take account of normal analytical errors, ofacceptable variations in manufacture and of deterioration to an extent

considered acceptable. No further tolerances are to be applied to thelimits prescribed to determine whether the article being examinedcomplies with the requirements of the monograph.

In determining compliance with a numerical limit, the calculatedresult of a test or assay is first rounded to the number of significantfigures stated, unless otherwise prescribed. The last figure is increasedby one when the part rejected is equal to or exceeds one half-unit,whereas it is not modified when the part rejected is less than a half-unit.

In certain tests, the concentration of impurity is given in parentheseseither as a percentage or in parts per million by weight (ppm). Inchromatographic tests such concentrations are stated as a percentageirrespective of the limit. In other tests they are usually stated in ppmunless the limit exceeds 500 ppm. In those chromatographic tests inwhich a secondary spot or peak in a chromatogram obtained with asolution of the substance being examined is described as correspondingto a named impurity and is compared with a spot or peak in a chroma-togram obtained with a reference solution of the same impurity, thepercentage given in parentheses indicates the limit for that impurity. Inthose chromatographic tests in which a spot or peak in a chromatogramobtained with a solution of the substance being examined is described interms other than as corresponding to a named impurity (commonly, forexample, as any (other) secondary spot or peak) but is compared with aspot or peak in a chromatogram obtained with a reference solution of anamed impurity, the percentage given in parentheses indicates animpurity limit expressed in terms of a nominal concentration of thenamed impurity. In chromatographic tests in which a comparison ismade between spots or peaks in chromatograms obtained with solutionsof different concentrations of the substance being examined, the per-centage given in parentheses indicates an impurity limit expressed interms of a nominal concentration of the medicinal substance itself. Insome monographs, in particular those for certain formulated prepara-tions, the impurity limit is expressed in terms of a nominal concentra-tion of the active moiety rather than of the medicinal substance itself.Where necessary for clarification the terms in which the limit isexpressed are stated within the monograph.

In all cases where an impurity limit is given in parentheses, the figuresgiven are approximations for information only; conformity with therequirements is determined on the basis of compliance or otherwisewith the stated test.

The use of a proprietary designation to identify a material used in anassay or test does not imply that another equally suitable material maynot be used.

Biological Assays and Tests

Methods of assay described as Suggested methods are not obligatory,but when another method is used its precision must be not less thanthat required for the Suggested method.

For those antibiotics for which the monograph specifies a micro-biological assay the potency requirement is expressed in the monographin International Units (IU) per milligram. The material is not ofpharmacopoeial quality if the upper fiducial limit of error is less than thestated potency. For such antibiotics the required precision of the assay

is stated in the monograph in terms of the fiducial limits of error aboutthe estimated potency.

For other substances and preparations for which the monographspecifies a biological assay, unless otherwise stated, the precision of theassay is such that the fiducial limits of error, expressed as a percentageof the estimated potency, are within a range not wider than thatobtained by multiplying by a factor of ten the square roots of the limitsgiven in the monograph for the fiducial limits of error about the statedpotency.

In all cases fiducial limits of error are based on a probability of 95%(P = 0.95).

Where the biological assay is being used to ascertain the purity of thematerial, the stated potency means the potency stated on the label interms of International Units (IU) or other Units per gram, per milligramor per millilitre. When no such statement appears on the label, thestated potency means the fixed or minimum potency required in themonograph. This interpretation of stated potency applies in all casesexcept where the monograph specifically directs otherwise.

Where the biological assay is being used to determine the total activityin the container, the stated potency means the total number of Interna-tional Units (IU) or other Units stated on the label or, if no such state-ment appears, the total activity calculated in accordance with theinstructions in the monograph.

Wherever possible the primary standard used in an assay or test is therespective International Standard or Reference Preparation establishedby the World Health Organization for international use and the biologi-cal activity is expressed in International Units (IU).

In other cases, where Units are referred to in an assay or test, the Unitfor a particular substance or preparation is, for the United Kingdom,the specific biological activity contained in such an amount of therespective primary standard as the appropriate international or nationalorganisation indicates. The necessary information is provided with theprimary standard.

Unless otherwise directed, animals used in an assay or a test arehealthy animals, drawn from a uniform stock, that have not previouslybeen treated with any material that will interfere with the assay or test.Unless otherwise stated, guinea-pigs weigh not less than 250 g or, whenused in systemic toxicity tests, not less than 350 g. When used in skintests they are white or light coloured. Unless otherwise stated, miceweigh not less than 17 g and not more than 22 g.

Certain of the biological assays and tests of the Pharmacopoeia aresuch that in the United Kingdom they may be carried out only inaccordance with the Animals (Scientific Procedures) Act 1986.Instructions included in such assays and tests in the Pharmacopoeia,with respect to the handling of animals, are therefore confined to thoseconcerned with the accuracy and reproducibility of the assay or test.

Storage Statements under the side-heading Storage constitute non-mandatoryadvice. The substances and preparations described in the Pharmaco-poeia are to be stored under conditions that prevent contamination and,as far as possible, deterioration. Precautions that should be taken inrelation to the effects of the atmosphere, moisture, heat and light areindicated, where appropriate, in the monographs. Further precautions

may be necessary when some materials are stored in tropical climates orunder other severe conditions. The expression ‘protected from moist-ure’ means that the product is to be stored in an airtight container.Care is to be taken when the container is opened in a dampatmosphere. A low moisture content may be maintained, if necessary,by the use of a desiccant in the container provided that direct contactwith the product is avoided. The expression ‘protected from light’means that the product is to be stored either in a container made of amaterial that absorbs actinic light sufficiently to protect the contentsfrom change induced by such light or in a container enclosed in anouter cover that provides such protection or stored in a place fromwhich all such light is excluded. The expression ‘tamper-evidentcontainer’ means a closed container fitted with a device that revealsirreversibly whether the container has been opened.

Labelling The labelling requirements of the Pharmacopoeia are not compre-hensive and laws governing the statements to be declared on labels ofofficial articles should also be met. In the United Kingdom the provis-ions of regulations issued in accordance with the Medicines Act 1968,together with those of regulations for the labelling of hazardousmaterials, should be met.

Only those statements in monographs given under the side-headingLabelling that are necessary to demonstrate compliance or otherwisewith the monograph are mandatory. Any other statements are includedas recommendations.

Such matters as the exact form of wording to be used and whether aparticular item of information should appear on the primary label andadditionally, or alternatively, on the package or exceptionally in a leafletare, in general, outside the scope of the Pharmacopoeia. When the term‘label’ is used in Labelling statements of the Pharmacopoeia, decisionsas to where the particular statement should appear should therefore bemade in accordance with relevant legislation.

The label of every official article states (i) the name at the head of themonograph and (ii) a reference consisting of either figures or letters, ora combination of figures and letters, by which the history of the articlemay be traced.

The label of every official formulated preparation other than those offixed strength also states the content of the active ingredient or ingredi-ents expressed in the terms required by the monograph. Where thecontent of active ingredient is required to be expressed in terms otherthan the weight of the official medicinal substance used in making theformulation, this is specifically stated under the side-heading Labelling.Thus, where no specific requirement is included under the side-headingLabelling, it is implied that the content of active ingredient is expressedin terms of the weight of the official medicinal substance used inmaking the formulation. For example, for Ampicillin Injection, whichcontains Ampicillin Sodium but for which the content is expressed interms of the equivalent amount of ampicillin, a specific requirement tothis effect is included under the side-heading Labelling. ForAmitriptyline Tablets which contain Amitriptyline Hydrochloride andfor which the result of the assay is expressed in terms of amitriptylinehydrochloride no specific statement is included under the side-heading

Labelling; these Tablets are thus labelled with the nominal weight ofAmitriptyline Hydrochloride.

These requirements do not necessarily apply to the labelling of articlessupplied in compliance with a prescription.

Action and Use The statements given under this side-heading in monographs areintended only as information on the principal pharmacological actionsor the uses of the materials in medicine or pharmacy. It should not beassumed that the substance has no other action or use. The statementsare not intended to be binding on prescribers or to limit their discretion.

Crude Drugs The macroscopical characteristics of a crude drug includes those feat-ures that can be seen by the unaided eye or by the use of a hand lens.

Vegetable drugs are required to be free from insects and other animalmatter, and from animal excreta. Not more than traces of foreignorganic matter may be present in powdered vegetable drugs. Microbialcontamination should be minimal.

In determining the content of active principle, Acid-insoluble ash,Ash, Extractive soluble in ethanol, Loss on drying, Sulphated ash,Water, Water-soluble ash and Water-soluble extractive of vegetabledrugs, the calculations are made with reference to the drug that has notbeen specially dried unless otherwise prescribed in the monograph.

In the assays for alkaloids in crude drugs and their preparations,definite quantities of solvents are specified. The quantities are given asbeing suitable for typical cases; they may, however, be varied wherenecessary to overcome the difficulties that may be encountered inspecial instances, provided that the effect of the prescribed directions isensured.

When it is found necessary to dry a crude drug before it can bereduced to powder for the purpose of assay, a correction is made for theloss on drying and the alkaloidal content is calculated with reference tothe undried drug.

Part III Monographs and other texts of the European Pharmacopoeia that areincorporated in this edition of the British Pharmacopoeia are governed by thegeneral notices of the European Pharmacopoeia; these are reproduced below.

GENERAL NOTICES OF THE EUROPEANPHARMACOPOEIA

Text in [ ] does not form part of the General Notices of the EuropeanPharmacopoeia but has been added for the convenience of the user of theBritish Pharmacopoeia.

1.1. GENERAL STATEMENTS

The General Notices apply to all monographs and other texts of theEuropean Pharmacopoeia.

In the texts of the European Pharmacopoeia, the word ‘Pharmaco-poeia’ without qualification means the European Pharmacopoeia. Theofficial abbreviation Ph. Eur. may be used to indicate the EuropeanPharmacopoeia.

The use of the title or the subtitle of a monograph implies that thearticle complies with the requirements of the relevant monograph. Such

references to monographs in the texts of the Pharmacopoeia are shownusing the monograph title and serial number in italics.

A pharmaceutical preparation must comply throughout its period ofvalidity. The subject of any other monograph must comply throughoutits period of use. The period of validity that is assigned to any givenarticle and the time from which that period is to be calculated aredecided by the competent authority in the light of experimental resultsof stability studies.

Unless otherwise indicated in the General Notices or in the mono-graphs, statements in monographs constitute mandatory requirements.General chapters [Appendices] become mandatory when referred to in amonograph, unless such reference is made in a way that indicates that itis not the intention to make the text referred to mandatory but rather tocite it for information or guidance.

The active ingredients (medicinal substances), excipients (auxiliarysubstances), pharmaceutical preparations and other articles described inthe monographs are intended for human and veterinary use (unlessexplicitly restricted to one of these uses). An article is not of Pharma-copoeia quality unless it complies with all the requirements stated in themonograph. This does not imply that performance of all the tests in amonograph is necessarily a prerequisite for a manufacturer in assessingcompliance with the Pharmacopoeia before release of a product. Themanufacturer may obtain assurance that a product is of Pharmacopoeiaquality from data derived, for example, from validation studies of themanufacturing process and from in-process controls. Parametric releasein circumstances deemed appropriate by the competent authority is thusnot precluded by the need to comply with the Pharmacopoeia.

The tests and assays described are the official methods upon which thestandards of the Pharmacopoeia are based. With the agreement of thecompetent authority, alternative methods of analysis may be used forcontrol purposes, provided that the methods used enable an unequivocaldecision to be made as to whether compliance with the standards of themonographs would be achieved if the official methods were used. In theevent of doubt or dispute, the methods of analysis of the Pharmacopoeiaare alone authoritative.

Certain materials that are the subject of a pharmacopoeial monographmay exist in different grades suitable for different purposes. Unlessotherwise indicated in the monograph, the requirements apply to allgrades of the material. In some monographs, particularly those onexcipients, a list of critical properties that are important for the use ofthe substance may be appended to the monograph for information andguidance. Test methods for determination of one or more of thesecritical properties may be given, also for information and guidance.

The general monographs on dosage forms apply to all preparations ofthe type defined. The requirements are not necessarily comprehensivefor a given specific preparation and requirements additional to thoseprescribed in the general monograph may be imposed by the competentauthority.

Conventional terms The term ‘competent authority’means the national, supranational orinternational body or organisation vested with the authority for makingdecisions concerning the issue in question. It may, for example, be a

national pharmacopoeia authority, a licensing authority or an officialcontrol laboratory.

The expression ‘unless otherwise justified and authorised’ means thatthe requirements have to be met, unless the competent authorityauthorises a modification or an exemption where justified in a particularcase.

Statements containing the word ‘should’ are informative or advisory.In certain monographs or other texts, the terms ‘suitable’ and ‘appro-

priate’ are used to describe a reagent, micro-organism, test method etc.;if criteria for suitability are not described in the monograph, suitabilityis demonstrated to the satisfaction of the competent authority.

1.2. OTHER PROVISIONS APPLYING TO GENERALCHAPTERS [APPENDICES] AND MONOGRAPHS

Quantities In tests with numerical limits and assays, the quantity stated to be takenfor examination is approximate. The amount actually used, which maydeviate by not more than 10 per cent from that stated, is accuratelyweighed or measured and the result is calculated from this exactquantity. In tests where the limit is not numerical, but usually dependsupon comparison with the behaviour of a reference in the same condi-tions, the stated quantity is taken for examination. Reagents are used inthe prescribed amounts.

Quantities are weighed or measured with an accuracy commensuratewith the indicated degree of precision. For weighings, the precisioncorresponds to plus or minus 5 units after the last figure stated (forexample, 0.25 g is to be interpreted as 0.245 g to 0.255 g). For themeasurement of volumes, if the figure after the decimal point is a zeroor ends in a zero (for example, 10.0 ml or 0.50 ml), the volume ismeasured using a pipette, a volumetric flask or a burette, as appropriate;otherwise, a graduated measuring cylinder or a graduated pipette maybe used. Volumes stated in microlitres are measured using a micro-pipette or microsyringe. It is recognised, however, that in certain casesthe precision with which quantities are stated does not correspond tothe number of significant figures stated in a specified numerical limit.The weighings and measurements are then carried out with a suffi-ciently improved accuracy.

Apparatus and procedures

Volumetric glassware complies with Class A requirements of theappropriate International Standard issued by the InternationalOrganisation for Standardisation.

Unless otherwise prescribed, analytical procedures are carried out at atemperature between 15°C and 25°C.

Unless otherwise prescribed, comparative tests are carried out usingidentical tubes of colourless, transparent, neutral glass with a flat baseand an internal diameter of 16 mm. Equal volumes of the liquids to becompared are examined down the vertical axis of the tubes against awhite background, or if necessary against a black background. Theexamination is carried out in diffuse light.

Any solvent required in a test or assay in which an indicator is to beused is previously neutralised to the indicator, unless a blank test isprescribed.

1090Water-bath The term ‘water-bath’ means a bath of boiling water unless water atanother temperature is indicated. Other methods of heating may besubstituted provided the temperature is near to but not higher than100°C or the indicated temperature.

1093Drying and ignition to constant mass

The terms ‘dried to constant mass’ and ‘ignited to constant mass’ meanthat two consecutive weighings do not differ by more than 0.5 mg, thesecond weighing following an additional period of drying or of ignitionrespectively appropriate to the nature and quantity of the residue.

Where drying is prescribed using one of the expressions ‘in a desic-cator’ or ‘in vacuo’, it is carried out using the conditions describedunder 2.2.32. Loss on drying [Appendix IX D].

Reagents The proper conduct of the analytical procedures described in thePharmacopoeia and the reliability of the results depend, in part, uponthe quality of the reagents used. The reagents are described in generalchapter 4 [Appendix I]. It is assumed that reagents of analytical gradeare used; for some reagents, tests to determine suitability are included inthe specifications.

Solvents Where the name of the solvent is not stated, the term ‘solution’ impliesa solution in water. Where the use of water is specified or implied in theanalytical procedures described in the Pharmacopoeia or for the prepar-ation of reagents, water complying with the requirements of the mono-graph on Purified water (8) is used. The term ‘distilled water’ indicatespurified water prepared by distillation.

The term ‘ethanol’ without qualification means absolute alcohol. Theterm ‘alcohol’ without qualification means alcohol containing about 96per cent V/V of ethanol (C2H6O). Other dilutions of ethanol are indi-cated by the term ‘alcohol’ followed by a statement of the percentage byvolume of ethanol (C2H6O) required.

Expression of content In defining content, the expression ‘per cent’ is used according tocircumstances with one of two meanings:

— per cent m/m (percentage, mass in mass) expresses the number ofgrams of substance in 100 grams of final product.

— per cent V/V (percentage, volume in volume) expresses the numberof millilitres of substance in 100 millilitres of final product.

The expression ‘parts per million (ppm)’ refers to mass in mass,unless otherwise specified.

Temperature Where an analytical procedure describes temperature without a figure,the general terms used have the following meaning:

In a deep-freeze below –15°C

In a refrigerator 2°C to 8°C

Cold or cool 8°C to 15°C

Room temperature 15°C to 25°C

1.3. GENERAL CHAPTERS [incorporated in the Appendices ofthe British Pharmacopoeia]

Containers Materials used for containers are described in general chapter 3[Appendix XX]. General names used for materials, particularly plasticsmaterials, each cover a range of products varying not only in theproperties of the principal constituent but also in the additives used.The test methods and limits for materials depend on the formulationand are therefore applicable only for materials whose formulation iscovered by the preamble to the specification. The use of materials withdifferent formulations and the test methods and limits applied to themare subject to agreement by the competent authority.

The specifications for containers in general chapter 3 [AppendixXIX], have been developed for general application to containers of thestated category but in view of the wide variety of containers availableand possible new developments, the publication of a specification doesnot exclude the use, in justified circumstances, of containers thatcomply with other specifications, subject to agreement by the competentauthority.

Reference may be made within the monographs of the Pharmacopoeiato the definitions and specifications for containers provided in thissection. The general monographs for pharmaceutical dosage forms may,under the heading Definition/Production, require the use of certaintypes of container; certain other monographs may, under the headingStorage, indicate the type of container that is recommended for use.

1.4. MONOGRAPHS

Titles Monograph titles are in English and French in the respective versions[published by the Council of Europe] and there is a Latin subtitle whichmay be used in place of the English or French title as may any synonymsdeclared equivalent by the competent authority [see ApprovedSynonyms, Appendix XXI B].

Relative atomic and The relative atomic mass (Ar) or the relative molecular mass (Mr) ismolecular masses shown, as and where appropriate, at the beginning of each monograph.

The relative atomic and molecular masses and the molecular andgraphic formulae do not constitute analytical standards for thesubstances described.

Definition Statements under the heading Definition constitute an official definitionof the substance, preparation or other article that is the subject of themonograph.

Limits of content Where limits of content are prescribed, they arethose determined by the method described under Assay.

Vegetable drugs In monographs on vegetable drugs, the definitionindicates whether the subject of the monograph is, for example, thewhole drug or the drug in powdered form. Where a monograph appliesto the drug in several states, for example both to the whole drug and thedrug in powdered form, the definition states this.

Production Statements under the heading Production draw attention to particularaspects of the manufacturing process but are not necessarily compre-hensive. They constitute instructions to manufacturers. They mayrelate, for example, to source materials, to the manufacturing process

itself and its validation and control, to in-process testing or to testingthat is to be carried out by the manufacturer on the final article eitheron selected batches or on each batch prior to release. These statementscannot necessarily be verified on a sample of the final article by anindependent analyst. The competent authority may establish that theinstructions have been followed, for example, by examination of datareceived from the manufacturer, by inspection of manufacture or bytesting appropriate samples.

The absence of a section on Production does not imply that attentionto features such as those referred to above is not required. A productdescribed in a monograph of the Pharmacopoeia is manufactured inaccordance with the principles of good manufacturing practice and inaccordance with relevant international agreements and supranationaland national regulations governing products for human or veterinaryuse.

Where in the section under the heading Production a monograph on avaccine defines the characteristics of the vaccine strain to be used, anytest methods given for confirming these characteristics are provided forinformation as examples of suitable methods.

Characters The statements under the heading Characters are not to be interpretedin a strict sense and are not requirements.

Solubility In statements of solubility in the section headed Characters,the terms used have the following significance referred to a temperaturebetween 15°C and 25°C.

Descriptive term Approximate volume ofsolvent in millilitres pergram of solute

very soluble less than 1freely soluble from 1 to 10soluble from 10 to 30sparingly soluble from 30 to 100slightly soluble from 100 to 1000very slightly soluble from 1000 to 10,000practically insoluble more than 10,000

The term ‘partly soluble’ is used to describe a mixture where onlysome of the components dissolve. The term ‘miscible’ is used todescribe a liquid that is miscible in all proportions with the statedsolvent.

Identification The tests given in the identification section are not designed to give afull confirmation of the chemical structure or composition of theproduct; they are intended to give confirmation, with an acceptabledegree of assurance, that the article conforms to the description on thelabel.

Certain monographs have subdivisions entitled ‘First identification’and ‘Second identification’. The test or tests that constitute the ‘Secondidentification’ may be used instead of the test or tests of the ‘Firstidentification’ provided it can be demonstrated that the substance orpreparation is fully traceable to a batch certified to comply with all therequirements of the monograph.

Tests and assays Scope The requirements are not framed to take account of all possibleimpurities. It is not to be presumed, for example, that an impurity thatis not detectable by means of the prescribed tests is tolerated if commonsense and good pharmaceutical practice require that it be absent. Seealso below under Impurities.

Calculation Where the result of a test or assay is required to becalculated with reference to the dried or anhydrous substance or onsome other specified basis, the determination of loss on drying, watercontent or other property is carried out by the method prescribed in therelevant test in the monograph.

Limits The limits prescribed are based on data obtained in normalanalytical practice; they take account of normal analytical errors, ofacceptable variations in manufacture and compounding and of deterio-ration to an extent considered acceptable. No further tolerances are tobe applied to the limits prescribed to determine whether the articlebeing examined complies with the requirements of the monograph.

In determining compliance with a numerical limit, the calculatedresult of a test or assay is first rounded to the number of significantfigures stated, unless otherwise prescribed. The last figure is increasedby one when the part rejected is equal to or exceeds one half-unit,whereas it is not modified when the part rejected is less than a half-unit.

Indication of permitted limit of impurities The approximatecontent of impurity tolerated, or the sum of impurities, may be indica-ted in parentheses for information only. If the use of a referencesubstance for the named impurity is not prescribed, this content may beexpressed as a nominal concentration of the substance used to preparethe reference solution specified in the monograph, unless otherwisedescribed. Acceptance or rejection is determined on the basis of compli-ance or non-compliance with the stated test.

Vegetable drugs For vegetable drugs, the sulphated ash, total ash,water-soluble matter, alcohol-soluble matter, water content, content ofessential oil and content of active principle are calculated with referenceto the drug that has not been specially dried, unless otherwise prescri-bed in the monograph.

Equivalents Where an equivalent is given, for the purposes of thePharmacopoeia only the figures shown are to be used in applying therequirements of the monograph.

Storage The information and recommendations given under the heading Storagedo not constitute a pharmacopoeial requirement but the competentauthority may specify particular storage conditions that must be met.

The articles described in the Pharmacopoeia are stored in such a wayas to prevent contamination and, as far as possible, deterioration. Wherespecial conditions of storage are recommended, including the type ofcontainer (see General Notice on Containers above) and limits oftemperature, they are stated in the monograph.

The following expressions are used in monographs under Storage withthe meaning shown.

Protected from moisture means that the product is stored in an airtightcontainer. Care is to be taken when the container is opened in a dampatmosphere. A low moisture content may be maintained, if necessary,

by the use of a desiccant in the container provided that direct contactwith the product is avoided.

Protected from light means that the product is stored either in acontainer made of a material that absorbs actinic light sufficiently toprotect the contents from change induced by such light or in a containerenclosed in an outer cover that provides such protection or stored in aplace from which all such light is excluded.

Labelling In general, labelling is subject to supranational and national regulationand to international agreements. The statements under the headingLabelling therefore are not comprehensive and, moreover, for thepurposes of the Pharmacopoeia only those statements that are necessaryto demonstrate compliance or non-compliance with the monograph aremandatory. Any other labelling statements are included as recommend-ations. When the term ‘label’ is used in the Pharmacopoeia, the label-ling statements may appear on the container, the package or a leafletaccompanying the package, as decided by the competent authority.

Warnings Materials described in monographs and reagents specified for use in thePharmacopoeia may be injurious to health unless adequate precautionsare taken. The principles of good quality control laboratory practice andthe provisions of any appropriate regulations are to be observed at alltimes. Attention is drawn to particular hazards in certain monographsby means of a warning statement; absence of such a statement is not tobe taken to mean that no hazard exists.

Impurities A list of all known and potential impurities that have been shown to becontrolled by the tests in a monograph may be given for information.The list may be divided into two sublists entitled ‘Qualified impuri-ties’and ‘Other detectable impurities’. Qualified impurities are thosepreviously accepted by the competent authority as being qualified;impurities deemed qualified by other means (for example, impuritieswhich occur as natural metabolites) may also be included. Otherdetectable impurities are those potential impurities that have not beendetected in any samples of the substance during elaboration of themonograph or that occur in amounts below 0.1 per cent, but that havebeen shown to be limited by the tests.

Critical physical properties

A list of critical physical properties that are not the subject of officialrequirements but which are nevertheless important for the use of asubstance may be appended to a monograph, for information andguidance (see also above 1.1. General statement).

Reference substances, reference preparations and reference spectra

Certain monographs require the use of a reference substance, areference preparation or a reference spectrum. These are chosen withregard to their intended use as prescribed in the monographs of thePharmacopoeia and are not necessarily suitable in other circumstances.The European Pharmacopoeia Commission does not acceptresponsibility for any errors arising from use other than as prescribed.

The reference substances, the reference preparations and the referencespectra are established by the European Pharmacopoeia Commissionand may be obtained from the Technical Secretariat. They are the

official reference materials to be used in cases of arbitration. A list ofreference substances, reference preparations and reference spectra maybe obtained from the Technical Secretariat.

Local reference materials may be used for routine analysis, providedthey are calibrated against the materials established by the EuropeanPharmacopoeia Commission.

Any information necessary for proper use of the reference substanceor reference preparation is given on the label or in the accompanyingleaflet or brochure. Where no drying conditions are stated in the leafletor on the label, the substance is to be used as received. No certificate ofanalysis or other data not relevant to the prescribed use of the productare provided. No expiry date is indicated: the products are guaranteedto be suitable for use when despatched and can normally be used for notless than 6 months after receipt if the containers are stored unopened asdescribed in the accompanying leaflet; beyond this period, it is neces-sary to seek advice from the Technical Secretariat. The stability of thecontents of opened containers cannot be guaranteed.

Chemical Reference Substances The abbreviation CRS indicates aChemical Reference Substance established by the European Pharmaco-poeia Commission. Some Chemical Reference Substances are used forthe microbiological assay of antibiotics and their activity is stated, inInternational Units, on the label or on the accompanying leaflet anddefined in the same manner as for Biological Reference Preparations.

Biological Reference Preparations The majority of the primarybiological reference preparations referred to in the European Pharmaco-poeia are the appropriate International Standards and Reference Prepar-ations established by the World Health Organisation. Because thesereference materials are usually available only in limited quantities, theCommission has established Biological Reference Preparations (indica-ted by the abbreviation BRP) where appropriate. Where applicable, thepotency of the Biological Reference Preparations is expressed in Inter-national Units. For some Biological Reference Preparations, where aninternational standard or reference preparation does not exist, thepotency is expressed in European Pharmacopoeia Units.

Reference spectra The reference spectrum is accompanied byinformation concerning the conditions used for sample preparation andrecording the spectrum.

1.5 ABBREVIATIONS AND SYMBOLS

A Absorbancecentper 1

mc 1A Specific absorbance

A1 Relative atomic mass

[ ]α D20 Specific optical rotation

bp Boiling point

BRP Biological Reference Preparation

CRS Chemical Reference Substance2020d Relative density

I.U. International Unit

λ Wavelength

M Molarity

Mr Relative molecular mass

mp Melting point20Dn Refractive index

Ph. Eur. U. European Pharmacopoeia Unit

ppm Parts per million

R Substance or solution defined under“Reagents”

Rf Used in chromatography to indicate the ratioof the distance travelled by a substance tothe distance travelled by the solvent front

Rst Used in chromatography to indicate the ratioof the distance travelled by a substance tothe distance travelled by a referencesubstance

PD50 The statistically determined dose of avaccine that, in the conditions of the tests,may be expected to protect 50 per cent ofthe animals against a challenge dose ofthe micro-organisms or toxins against whichit is active.

ED50 The statistically determined dose of avaccine that, in the conditions of the tests,may be expected to induce specificantibodies in 50 per cent of the animals forthe relevant vaccine antigens.

PFU Pock-forming units or plaque-forming units.

SPF Specified-pathogen-free.

COLLECTIONS OF MICRO-ORGANISMS

ATTC American Type Culture Collection10810 University BouldevardManassas, Virginia 20110-2209, USA

C.I.P. Collection de l’Institut Pasteur (strains ofbacteria)

B.P. 52, 25 rue de Docteur Roux75724 Paris Cedex 15, France

IMI International Mycological InstituteBakeham LaneSurrey TW20 9TY, Great Britain

I.P. Institut Pasteur (strains of other micro-organisms)

Service de la Collection Nationale deCulture de Micro-organismes (C.N.C.M.)25, rue du Docteur-RouxF-75015 Paris, France

NCIMB National Collection of Industrial and MarineBacteria Ltd23 St Machar DriveAberdeen AB24 3RY, Great Britain

NCPF National Collection of Pathogenic FungiLondon School of Hygiene & TropicalMedicineKeppel StreetLondon WC1E 7HT, Great Britain

NCTC National Collection of Type CulturesCentral Public Health LaboratoryColindale AvenueLondon NW9 5HT, Great Britain

NCYC National Collection of Yeast CulturesAFRC Food Reserach InstituteColney LaneNorwich NR4 7UA, Great Britain

S.S.I. Statens Serum Institut80 Amager Boulevard, Copenhagen,Denmark

[See also Appendix XXIV]

RV Substance used as a primary standard involumetric analysis

ABBREVIATIONS USED IN THEMONOGRAPHS ON IMMUNOGLOBINS,IMMUNOSERA AND VACCINES

LD50 The statistically determined quantity of asubstance that, when administered by thespecific route, may be expected to causethe death of 50 per cent of the test animalswithin a given period.

MLD Minimum lethal dose

L+/10 dose The smallest quantity of a toxin that, in thecondition of the test, when mixed with0.1 I.U. of antitoxin and administered bythe specific route, causes the death of thetest animals within a given period.

L+ dose The smallest quantity of a toxin that, in thecondition of the test, when mixed with 1I.U. of antitoxin and administered by thespecific route, causes the death of thetest animals within a given period.

Lr/100 dose The smallest quantity of a toxin that, in thecondition of the test, when mixed with0.01 I.U. of antitoxin and injectedintracutaneously causes a characteristicreaction at the site of injection within agiven period.

Lp/10 dose The smallest quantity of a toxin that, in thecondition of the test, when mixed with0.1 I.U. of antitoxin and administered bythe specific route, causes paralysis in thetest animals within a given period.

Lo/10 dose The largest quantity of a toxin that, in thecondition of the test, when mixed with0.1 I.U. of antitoxin and administered bythe specific route, does not causesymptoms of toxicity in the test animalswithin a given period.

Lf dose The quantity of toxin or toxoid thatflocculates in the shortest time with 1 I.U.of antitoxin.

CCID50 The statistically determined quantity ofvirus that may be expected to infect 50 percent of the cell cultures to which it isadded.

EID50 The statistically determined quantity ofvirus that may be expected to infect 50 percent of fertilised eggs into which it isinoculated.

ID50 The statistically determined quantity ofvirus that may be expected to infect 50 percent of the animals into which it isinoculated.

1.6. UNITS OF THE INTERNATIONAL SYSTEM (SI) USEDIN THE PHARMACOPOEIA AND EQUIVALENCE WITHOTHER UNITS

International System of Units (SI)

The International System of Units comprises three classes of units,namely base units, derived units and supplementary units.1 The baseunits and their definitions are set out in Table 1.6-1.

The derived units may be formed by combining the base unitsaccording to the algebraic relationships linking the correspondingquantities. Some of these derived units have special names andsymbols. The SI units used in the European Pharmacopoeia are shownin Table 1.6-2.

Some important and widely used units outside the InternationalSystem are shown in Table 1.6-3.

The prefixes shown in Table 1.6-4 are used to form the names andsymbols of the decimal multiples and submultiples of SI units.

Table 1.6–1 SI Base Units

Quantity Unit Definition

Name Symbol Name Symbol

Length L metre m The metre is the length of the path travelled by light in a vacuumduring a time interval of 1/299,792,458 of a second.

Mass M kilogram kg The kilogram is equal to the mass of the international prototype ofthe kilogram

Time T second s The second is the duration of 9,192,631,770 periods of theradiation corresponding to the transition between the two hyperfinelevels of the ground state of the caesium-133 atom.

Electric current I ampere A The ampere is that constant current which, maintained in twostraight parallel conductors of infinite length, of negligible circularcross section and placed 1 metre apart in vacuum would producebetween these conductors a force equal to 2 × 10–7newton permetre of length.

Thermodynamictemperature

T kelvin K The kelvin is the fraction 1/273.16 of the thermodynamictemperature of the triple point of water.

Amount of substance N mole mol The mole is the amount of substance of a system containing asmany elementary entities as there are atoms in 0.012 kilogram ofcarbon-12*

Luminous intensity Iv candela cd The candela is the luminous intensity in a given direction of asource emitting monochromatic radiation with a frequency of540 × 1012 hertz and whose energy intensity in that direction is1/683 watt per steradian.

* When the mole is used, the elementary entities must be specified and may be atoms, molecules, ions, electrons, other particles orspecified groups of such particles.

1The definitions of the units used in the International System aregiven in the booklet Le Système International d’Unités (SI)published by the Bureau International des Poids et Mesures,Pavillon de Breteuil, F-92310 Sevres, France

Table 1.6–2 SI Units used in the European Pharmacopoeia and Equivalence with Other Units

Quantity Unit Conversion of other unitsinto SI units

Name Symbol Name Symbol Expression inSI base units

Expression inother SI units

Wave number ν one per metre 1/m m–1

Wavelength λ micrometre µm 10–6 m

nanometre nm 10–9 m

Area A, S square metre m2 m2

Volume V cubic metre m3 m3 1 ml = 1 cm3 = 10–6 m3

Frequency ν hertz Hz s–1

Density ρρρρρρρρρρρρρρρρρρρρρρρρρ kilogram percubic metre

kg/m3 Kg·m–3 1 g/ml = 1 g/cm3 =103 kg·m–3

Velocity ν metre per second m/s m·s–1

Force F newton N m·kg·s–2 1 dyne = 1g·cm·s–2 =10–5 N1 kp = 9.806 65 N

Pressure ρ pascal Pa m–1·kg·s–2 N·m–2 1 dyne/cm2 = 10–1 Pa =10–1 N·m–2

1 atm = 101 325 Pa =101.325 kPa1 bar = 105 Pa = 0.1 MPa1 mm Hg = 133.322 387 Pa1 Torr = 133.322 368 Pa1 psi = 6.894 757 kPa

Dynamic viscosity η pascal second Pa·s m–1·kg·s–1 N·s·m–2 1 P = 10–1 Pa·s =10–1 N·s·m–2

1 cP = 1 mPa·s

Kinematicviscocity

ν square metreper second

m2 /s m2·s–1 Pa·s·m2·kg–1

N·m·s·kg–11 St = 1 cm2·s–1 = 10–4 m2·s–1

Energy W joule J m2·kg·s–2 N·m 1 erg = 1 cm2·g·s–2 =1 dyne·cm = 10–1 J

1 cal = 4.1868 J

PowerRadiant flux

P watt W m2·kg·s–3 N·m·s–1

J·s–11 erg/s = 1 dyne·cm·s–1 =10–7 W = 10–7 N·m·s–1 =10–7 J·s–1

Absorbed dose(of radiant energy)

D gray Gy m2?s–2 J·kg–1 1 rad = 10–2 Gy

Electric potential,electromotive force

U volt V m2·kg·s–3·A–1 W·A–1

Electric resistance R ohm Ω m2·kg·s–3·A–2 V·A–1

Quantity of electricity Q coulomb C A·s

Activity of aradionuclide

A becquerel Bq s–1 1 Ci = 37 ×× 109 Bq =37 ×× 109 s–1

Concentration(of amount ofsubstance)

Molar concentration c mole per cubicmetre

mol/m3 mol·m–3 1 mol/l = 1M = 1 mol/dm3 =103 mol·m–1

Mass concentration ρρρρρρρρρρρρρρρρρρρρρρρρρ kilogram per cubicmetre

kg/m3 kg·m–3 1 g/l = 1 g/dm3 = 1 kg·m–3

Table 1.6–3 Units used with the International System

Quantity Unit Value in SI units

Time Symbol

Time minute min 1 min = 60 s

hour h 1 h = 60 mins = 3600 s

day d 1 d = 24 h = 86 4000 s

Plane angle degree ° 1° = (π ⁄ 180) rad

Volume litre l 1 l = 1 dm3 = 10−3 m3

Mass tonne t 1 t = 103 kg

Rotationalfrequency

revolutionper minute

r ⁄⁄ min 1 r ⁄ min = (1 ⁄ 60) s−1

Table 1.6–4 Decimal Multiples and Sub-multiples of Units

Factor Prefix Symbol Factor Prefix Symbol

1018 exa E 10−1 deci d

1015 peta P 10−2 centi c

1012 tera T 10−3 milli m

109 giga G 10−6 micro µ106 mega M 10−9 nano n

103 kilo k 10−12 pico p

102 hecto h 10−15 femto f

101 deca da 10−18 atto a

NOTES

1. In the Pharmacopoeia the Celsius temperature is used (symbol t). This is defined by the equation

t = T - To

where To = 273.15 K by definition. The Celsius or centigrade temperature is expressed in degree Celsius (symbol°C). The unit “degree Celsius” is equal to the unit “kelvin”.

2. The practical expressions of concentrations used in the Pharmacopoeia are defined in the General Notices.

3. The radian is the plane angle between two radii of a circle which cut off on the circumference an arc equal in lengthto the radius.

4. In the Pharmacopoeia conditions of centrifugation are defined by reference to the acceleration due to gravity (g):g = 9.806 65 mvs–2

5. Certain quantities without dimensions are used in the Pharmacopoeia: relative density (2.2.5), absorbance (2.2.25),specific absorbance (2.2.25) and refractive index (2.2.6) as well as quantities expressed in other units such as thespecific optical rotation (2.2.7).

6. The microkatal is defined as the enzymic activity which, under defined conditions, produces the transformation(e.g. hydrolysis) of 1 micromole of the substrate per second.