Essentials of Pharmaceutical Chemistry

321 Pages·2012·7.83 MB·English

Essentials of Pharmaceutical Chemistry

Essentials of
Pharmaceutical
Chemistry
FOURTH EDITION
Edited by
Donald Cairns
BSc,PhD,MRPharmS,CSci,CChem,FRSC
Acting Head of School of Pharmacy and Life Sciences,
The Robert Gordon University,
Aberdeen, UK
London • Chicago
Dedication
For Elaine, Andrew and Mairi
PublishedbyPharmaceuticalPress
1LambethHighStreet,LondonSE17JN,UK
(cid:13)c RoyalPharmaceuticalSocietyofGreatBritain2012
isatrademarkofPharmaceuticalPress
PharmaceuticalPressisthepublishingdivisionofthe
RoyalPharmaceuticalSociety
Firsteditionpublished2000
Secondeditionpublished2003
Thirdeditionpublished2008
Fourtheditionpublished2012
TypesetbyRiverValleyTechnologies,India
PrintedinGreatBritainbyTJInternational,Padstow,UK
ISBN9780853699798
Allrightsreserved.Nopartofthispublicationmaybereproduced,
storedinaretrievalsystem,ortransmittedinanyformorbyanymeans,
withoutthepriorwrittenpermissionofthecopyrightholder.
Thepublishermakesnorepresentation,expressorimplied,
withregardtotheaccuracyoftheinformationcontainedinthisbook
andcannotacceptanylegalresponsibilityorliabilityforanyerrorsor
omissionsthatmaybemade.
TherightofDonaldCairnstobeidentifiedastheauthorofthis
workhasbeenassertedbyhiminaccordancewiththeCopyright,
DesignsandPatentsAct,1988.
AcataloguerecordforthisbookisavailablefromtheBritishLibrary.
Contents
ix
Prefacetothefourthedition
x
Acknowledgements
xi
Abouttheauthor
1 Chemistryofacidsandbases 1
Dissociationofweakacidsandbases 3
Hydrolysisofsalts 9
Amphiproticsalts 10
Buffersolutions 11
Buffercapacity 13
Biologicalbuffers 15
Ionisationofdrugs 18
pK valuesofdrugmolecules 19
a
pHindicators 19
Tutorialexamples 22
Problems 26
2 Partitioncoefficientandbiopharmacy 29
Experimentalmeasurementofthepartitioncoefficient 32
Drugabsorption,distributionandbioavailability 35
Passivediffusion 38
ThepHpartitionhypothesis 40
Activetransportmechanisms 43
Theactionoflocalanaesthetics 44
Excretionandreabsorptionofdrugs 47
Foodanddrink 48
Tutorialexamples 50
Problems 55
vi Contents
3 Physicochemicalpropertiesofdrugs 57
Carboxylicacids 57
Phenols 61
Warfarin 62
Phenylbutazone 65
Indometacin 65
Barbiturates 65
Phenytoin 67
Sulfonamides 67
Basicdrugs 69
Basicityofheterocycliccompounds 71
Separationofmixtures 71
Tutorialexamples 73
Problems 77
4 Stereochemistry 81
Polarimetry 82
Biologicalsystems 86
Fischerprojections 87
Stereochemistrycasestudy:thalidomide 94
Geometricalisomerism 97
Tutorialexamples 99
Problems 101
5 Drugmetabolism 103
Metabolicpathways 104
CytochromesP450 105
Enzymeinductionandinhibition 109
Drugconjugationreactions(Phase2) 110
Stereochemistry 116
Metabolicpathwaysforcommondrugs 117
Tutorialexample 125
Problems 126
6 Volumetricanalysisofdrugs 129
Volumetricflask 130
Pipette 130
Burettes 131
Unitsofconcentration 131
Workedexample 133
Concentrationofactiveingredients 134
Contents vii
Designofanassay 134
Practicalpoints 137
Backandblanktitrations 140
Assayofunit-dosemedicines 143
Non-aqueoustitrations 144
REDOXtitrations 145
Compleximetrictitrations 148
Argentimetrictitrations 149
Limittests 150
Problems 151
7 Analyticalspectroscopy 155
EffectofpHonspectra 159
Instrumentation 163
Experimentalmeasurementofabsorbance 166
Dilutions 167
Quantitativeaspectsofspectroscopy 168
Beer’sandLambert’slaws 168
Methodsofdrugassay 170
Derivativespectroscopy 172
Infraredspectroscopy 174
Fluorimetry 177
Structureelucidation 178
Tutorialexamples 188
Problems 196
8 Chromatographicmethodsofanalysis 199
Definitionsusedinchromatography 199
Typesofchromatography 200
Termsusedinchromatography 211
Tutorialexamples 214
Problems 216
9 Stabilityofdrugsandmedicines 217
Oxidation 217
Hydrolysis 228
Othermechanismsofdegradation 233
Prodrugs 233
Tutorialexamples 235
Problems 237
viii Contents
10 Kineticsofdrugstability 239
Rate,orderandmolecularity 239
Rateequationsandfirst-orderreactions 240
Half-life 243
Shelf-life 243
Second-orderreactions 243
Zero-orderreactions 245
Reactionratesandtemperature 245
Tutorialexample 247
Problems 248
11 LicensingofdrugsandtheBritishPharmacopoeia 249
Europeanlicensingprocedures 250
Applicationsformarketingauthorisations 252
BritishPharmacopoeiaCommission 253
TheBritishPharmacopoeia 254
12 Medicinalchemistry:thescienceofrationaldrugdesign 259
Howdodrugswork? 259
Wheredodrugscomefrom? 266
Whydoweneednewdrugs? 271
13 Answerstoproblems 277
Selectedbibliography 293
Index 295
Preface to the fourth edition
In 2007 I wrote in the Preface to the third edition that the science and
practice of pharmacy were undergoing a period of change. Now, as I write
thePrefacetothefourtheditionofEssentialsofPharmaceuticalChemistry,
it seems that the profession is still changing. The General Pharmaceutical
Council has replaced the Royal Pharmaceutical Society as the regulator for
pharmacy, the number of schools of pharmacy in the UK continues to rise
andthereareplanstointegratethecurrentfouryearMPharmdegreeintoa
fiveyearintegratedmodelincorporatingtwosixmonthperiodsinpractice.
This new edition of EPC (as one of my students calls the book) has been
preparedagainstthischangingbackground.Ihavetriedtoincorporatesug-
gestions from users and reviewers and have updated every chapter for this
edition and included new chapters, Chromatographic methods of analysis
andMedicinal Chemistry: the Science of Rational Drug Design.
Aswithpreviouseditions,Iamverygratefulforthehelp,advice,comments
and encouragement from colleagues, reviewers and the many students of
pharmacy and pharmaceutical science who are forced to use this book as
part of their studies. I hope they find this new edition useful and, perhaps,
experiencesomeofthewonderandenjoymentIfeltwhenIwasintroduced
to the chemistry of drugs and medicines more than 30 years ago. If I was
being honest with myself, that’s still the way I feel about the subject today.
Donald Cairns
Aberdeen
June 2011