Essentials of
`Pharmaceutical Chemistry
`Fourth edition
`
`Nexus Ex. 1021
`1 of 33
`
`

`

`
`
`5 of Pharmaceutical Chemistry
`
`Nexus Ex. 1021
`Nexus Ex. 1021
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`2 of 33
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`

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`Essentials of
`Pharmaceutical
`Chemistry
`
`'·
`:'' · FOURTH EDITION
`
`Edited by
`Donald Cairns BSc, PhD, MRPharmS, CSci, CChem, FRSC
`Act ing Head of School of Pharmacy and Life Sciences,
`
`The Robert Gordon University,
`
`Aberdeen, UK
`
`(RP)
`
`London • Chicago Pharmaceutical Press
`
`Nexus Ex. 1021
`3 of 33
`
`

`

`For Elaine, Andrew and Mairi
`
`Published by Pharmaceutical Press
`
`1 Lambeth High Street, London SEl 7JN, UK
`© Royal Pharmaceutical Society of Great Britain 2012
`(P.P) is a trade mark of Pharmaceutical Press
`Pharmaceutical Press is the publishing division of the
`Royal Pharmaceutical Society
`
`First edition published 2000
`Second edition published 2003
`Third edition published 2008
`Fourth edition published 2012
`
`Typeset by River Valley Technologies, India
`Printed in Great Britain by TJ International, Padstow, UK
`
`ISBN 978 0 85369 979 8
`
`All rights reserved. No part of this publication may be reproduced,
`stored in a retrieval system, or transmitted in any form or by any means,
`without the prior written permission of the copyright holder.
`The publisher makes no representation, express or implied,
`with regard to the accuracy of the information contained in this book
`and cannot accept any legal responsibility o r liability for any errors or
`omissions that may be made.
`The right of Donald Cairns to be identified as the author of this
`work has been asserted by him in accordance with the Copyright,
`Designs and Patents Act, 1988.
`
`A catalogue record for this book is available from the British Library.
`
`MIX p-(cid:173)
`
`tMpMtlbl•tOUfCN
`FSC- C013058
`
`Jj
`FSC _...,
`
`Nexus Ex. 1021
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`

`Contents
`
`Preface to the fourth edition
`Acknowledgements
`About the author
`
`1 Chemistry of acids and bases
`
`Dissociation of weak acids and bases
`Hydrolysis of salts
`Amphiprotic salts
`Buffer solutions
`Buffer capacity
`Biological buffers
`Ionisation of drugs
`pK a values of drug molecules
`pH indicators
`Tutorial examples
`Problems
`
`2 Partition coefficient and biopharmacy
`
`Experimental measurement of the partition coefficient
`Drug absorption, distribution and bioavailability
`
`Passive diffusion
`The pH partition hypothesis
`Active transport mechanisms
`The action of local anaesthetics
`Excretion and reabsorption of drugs
`Food and drink
`Tutorial examples
`Problems
`
`ix
`
`X
`
`xi
`
`1
`
`3
`9
`10
`11
`13
`15
`18
`19
`19
`22
`26
`
`29
`
`32
`35
`38
`40
`43
`44
`47
`48
`50
`55
`
`Nexus Ex. 1021
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`

`

`vi
`
`3
`
`contents
`
`erties of drugs
`;cal prop
`•,ocherTl
`phys•
`.
`Y/ic acids
`carbOX
`Phenols
`warfarin
`Phenylbutazone
`lndometacin
`Barbiturates
`pl,enytoin
`Sulfonamides
`
`/'c compounds
`Basic drugs
`. •ry of heterocyc 1
`Bas1c1
`Separation of mixtures
`Tutorial examples
`Problems
`
`4 Stereochemistry
`Polarimetry
`Biological systems
`Fischer projections
`Stereochemistry case study: thalidom ide
`Geometrical isomerism
`Tutorial examples
`Problems
`
`5 Drug metabolism
`Metabolic pathways
`Cytochromes P450
`Enzyme induction and inhibition
`Drug conjugation reactions (Phase 2)
`Stereochemistry
`
`Metabolic pathways for common drugs ·
`Tutorial example
`Problems
`
`6
`
`Volumetric analysis of drugs
`Volumetric fiask
`Pipette
`Burettes
`
`Units of concentration
`Worked example
`.
`f
`Concentratio
`no active ingredients
`
`81
`82
`86
`87
`95
`97
`99
`101
`
`103
`104
`105
`109
`110
`116
`117
`125
`126
`
`129
`130
`130
`131
`131
`133
`134
`
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`

`Design of an assay
`Practical points
`Back and blank titrations
`Assay of unit-dose medicines
`Non-aqueous titrations
`REDOX titrations
`Cornplexirnetric titrations
`Argentimetric titrations
`Limit tests
`Problems
`
`7 Analytical spectroscopy
`
`Effect of pH on spectra
`Instrumentation
`Experimental measurement of absorbance
`Dilutions
`Quantitative aspects of spectroscopy
`Beer's and Lambert's laws
`Methods of drug assay
`Derivative spectroscopy
`Infrared spectroscopy
`Fluorimetry
`Structure elucidation
`Tutorial examples
`Problems
`
`8 Chromatographic methods of analysis
`
`Definitions used in chromatography
`Types of chromatography
`Terms used in chromatography
`Tutorial examples
`Problems
`
`9 Stability of drugs and medicines
`
`Oxidation
`Hydrolysis
`Other mechanisms of degradation
`Prodrugs
`Tutorial examples
`Problems
`
`Contents I vii
`
`134
`137
`140
`143
`144
`145
`148
`149
`150
`151
`
`155
`
`159
`163
`166
`167
`168
`168
`170
`172
`174
`177
`178
`188
`196
`
`199
`
`199
`200
`211
`214
`216
`
`217
`
`217
`228
`233
`233
`235
`237
`
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`viii I Contents
`
`I
`
`10 Kinetics of drug stability
`Rate, order and molecu lari ty
`Rate equations and first-order reactions
`Half-life
`Shelf-life
`Second-order reactions
`Zero-order reactions
`Reaction rates and temperature
`Tutorial example
`Problems
`
`11 Licensing of drugs and the British Pharmacopoeia
`European licensing procedures
`Applications for marketing authorisations
`British Pharmacopoeia Commission
`The British Pharmacopoeia
`
`12 Medicinal chemistry: the science of rational drug design
`How do drugs work?
`Where do drugs come from?
`Why do we need new drugs?
`
`13 Answers to problems
`
`Selected bibliography
`Index
`
`239
`239
`2~
`243
`243
`243
`245
`245
`247
`248
`
`249
`2so
`252
`253
`254
`
`259
`259
`266
`271
`
`277
`
`293
`295
`
`Nexus Ex. 1021
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`

`

`B;eface tcf~the~,fourth'. ,edition' _·, . . ',
`
`1
`
`I
`
`-
`
`-
`
`0
`
`-
`
`~
`.
`
`O
`
`:~V-... ~
`,. :I
`
`~ ...
`•
`
`.
`
`r
`
`- .
`
`.
`
`.
`
`-
`
`,
`
`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
`the Preface to the fourth edition of Essentials of Pharmaceutical Chemistry,
`it seems that the profession is still changing. The General Pharmaceutical
`Council has replaced the Royal Pharmaceutical Sociery as the regulator for
`pharmacy, the number of schools of pharmacy in the UK continues to rise
`and there are plans to integrate the current four yea r MPharm degree into a
`five year integrated model incorporating two six month periods in practice.
`This new edition of EPC (as one of my students calls the book} has been
`prepared against this changing background. I have tried to incorporate sug(cid:173)
`gestions from users and reviewers and have updated every chapter for this
`edition and included new chapters, Chromatographic methods of analysis
`and Medicinal Chemistry: the Science of Rational Drug Design.
`As with previous editions, I am very grateful for the help, 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,
`experience some of the wonder and enjoyment I felt when I was introduced
`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
`
`·----
`
`Nexus Ex. 1021
`9 of 33
`
`

`

`Id not have been completed without the help of a gr
`k
`.
`eat man
`This boo cou
`very grateful co my colleagues, past and present f
`h .Y
`I
`I
`ll
`.
`. 1 l
`peop e.
`am
`or t e1r
`f
`d encouragement and part1cu ar y, or a owmg me to ass.
`d .
`.1
`a vice an
`. k
`lIUt ate
`.
`.
`h .
`d practice (with or without the1r nowledge). This book
`t eir goo
`Would
`.
`.
`be poorer without rhetr efforts. Special thanks must go to PauJ Hambleton
`who read and commented on my first drafts and who not only allowed
`to use a great many of his examination questions but also provided m::
`of the answers!
`I am grateful to Louise Mcindoe Christina de Bono and all the sraff at
`the Pharmaceutical Press for keeping me on track when diversions threat(cid:173)
`ened and giving helpful advice about indexes content pages, etc.
`Finally, I must thank my wife Elaine who looked after the weans while
`I bashed the keyboard upstairs.
`
`Nexus Ex. 1021
`10 of 33
`
`

`

`' ,-
`-'About the author
`
`-
`
`v:· -
`
`·
`
`Donald Cairns obtained a Bachelor of Science degree in pharmacy from
`the University of Strathclyde in 1980 and after a pre-registration year spent
`in hospital pharmacy, he returned to Strathclyde to undertake a PhD on
`the synthesis and properties of benzylimidazolines. Following a year as a
`post-doctoral research fellow in the department of pharmacy at Sunder(cid:173)
`land Polytechnic (now the University of Sunderland), Dr Cairns moved
`to Leicester Polytechnic (now De Montfort University} where he held a
`five-year lectureship in pharmacy. In 1992 Dr Cairns was appointed senior
`lecturer in medicinal chemistry in Sunderland School of Pharmacy and in
`2003 moved to a post of Associate Head of the School of Pharmacy at
`The Robert Gordon University in Aberdeen. In 2006, he was promoted to
`Professor of Pharmaceutical and Medicinal Chemistry at RGU and in 2010
`was appointed Acting H ead of the School of Pharmacy and Life Sciences.
`Professor Cairns has served as external examiner at Strathclyde, Liver(cid:173)
`pool, Aberdeen and Belfast Schools of Pharmacy and has authored over 70
`peer reviewed research papers.
`His research interests include the design and synthesis of selective anti(cid:173)
`cancer agents, the molecular modelling of drug-DNA interactions and the
`design of prodrugs for the treatment of nephropathic cystinosis.
`Donald Cairns is a member of the General Pharmaceutical Council, the
`Royal Pharmaceutical Society, the Association of Pharmaceutical Scientists
`and in 2008 was made a Fellow of the Royal Society of Chemistry. In 2006
`he was appointed to the British Pharmacopoeia Commission and serves on
`an Expert Advisory Group of the Commission on Human Medicines.
`
`To travel hopefully is a better thing than to arrive, and the true success is
`to labour.
`
`Robert Louis Stevenson, 1850-1894
`
`Nexus Ex. 1021
`11 of 33
`
`

`

`•
`
`. !f • •
`
`' . . . . . . . . .
`·.· : .. ·::: ;z: .· .... .. .
`.. . . . . . .
`
`stability of drugs and
`·--~ . .
`r11e~ c1nes
`
`..,_
`
`ti.mes have quite complicated chemical structures and are by
`Drugs some
`.
`'
`biologically active compounds. It should not, therefore come
`. .
`I
`.
`,
`defin1uon,
`.
`rise that these reactive molecu es undergo chemical reactions that
`as a surp
`.
`d h
`. .
`d d
`.
`lt in their decomposmon an
`etenoratlon, an
`t at these processes
`rbesu as soon as the drug is synthesised or the medicine is formulated .
`eg1n
`.
`.
`.
`.
`Decomposition reacuons of this type lead to, at best, drugs and medicines
`ihat are less active than intended (i.e. of low efficacy); in the worst-case
`scenario, decomposition can lead to drugs that are actually toxic to the
`patient. This is clearly bad news to all except lawyers, so the processes of
`decomposition and deterioration must be understood in order to minimise
`the risk to patients.
`There are almost as many ways in which drugs can decompose as
`there are drugs in the British Pharmacopoeia, but most instability can be
`accounted for by the processes of oxidation and hydrolysis.
`
`Oxidation
`
`Oxidation is the process whereby an atom increases the number of bonds it
`h;s to oxygen, decreases the number of bonds it has to hydrogen, or loses
`e ectrons. The deterioration of drugs by oxidation requires the presence of
`molecular oxygen and proceeds under mild conditions. Elemental molecular
`~:g~n, or 02, possesses a diradical (unpaired triplet) electronic configura(cid:173)
`i/ e110 the ground state and is said to be paramagnetic (a species with all
`ectrons p · d .
`is called diagmagnetic). The structure of oxygen can be
`repres
`d aire
`ente as ·o o·
`or valen b = or 0=0 depending on whether the molecular orbital
`ce ond th
`·
`• ·
`-
`that the r d'
`eory is employed. The important fact for drug stability 1s
`chain rea:t_ical species possesses two unpaired electrons which can initiate
`·r
`ions res 1 .
`.
`1 the reacti
`u tmg m the breakdown of drug molecules, particularly
`m
`0 n occur
`·
`h
`eta! ions
`s in t e presence of catalysts such as light, heat, some
`d
`Phenols (suc:n peroxides. The types of drug that are affected include
`as morphine ), catecholamines ( e.g. adrenaline (epinephrine)
`
`Nexus Ex. 1021
`12 of 33
`
`

`

`21s I Essentials or Pha1maceu1ical Chemistry
`
`:ind noradrenaline (norepinephrine)) as well as polyunsatur d
`a~ co
`·
`·
`•
`.
`
`such as oils. fats and fa r-soluble v1tamtns (e.g. vitamins A and £/1Pounds
`
`Autoxidatlon
`
`.
`Radical chain reactions of this type are called autoxidat,on .
`reaction
`II h
`can be quite complicated. A , ~wever, proceed via a number of d's and
`16cre1c
`steps, namel}' initiation. propagation and termination.
`
`Initiation
`Initiation involves homolytic fi ssion of a covalent bond in the drug
`1
`to produce free radicals (Fig. 9.1) . The energy source for this procrno ecule
`f tt·
`· h
`I
`· I
`· 'bl
`ess 0 fren
`comes from light, e1t er u trav1O et or v1s1 e, a mg Onto the sam I L'
`P e. 1gbr
`I
`·
`ffi ·
`b ·
`h ·
`of these wavelengt s 1s su c1ent y energenc to
`ring about cleavag
`f
`.
`.
`.
`e o the
`pair of electrons m a covalent bond to yield two radicals.
`Stage 1 Chain initiation: involves homolytic fission to produce free r d'
`a 1ca s
`1
`(Fig. 9.1).
`
`r\
`Drug : H
`v
`
`-
`
`Drug· + H 0
`
`Figure 9. 1. The mechanism of Initiation.
`
`Propagation
`Propagation is the main part of the chemical reaction, in which free radicals
`react together to produce more and more reacting species (Fig. 9.2). [n the
`case of oxidation, this involves the production of peroxides and hydroper(cid:173)
`oxides. l11ese hydroperoxides may then undergo further decomposition 10
`give a range of low-molecular-weight aldehydes and kerones. Carbonyl
`compounds of this type usually bave characteristically unpleasant smells,
`which allows their presence to be detected, literally by following one's nose.
`They can arise not only from the decomposition of drugs bur also from che
`aut0xidation of fats, oils and foodstuffs as well as the perishing of rubber
`and tbe hardening of pamts.
`Stage 2 Chain propagation: free radicals are consumed and generated
`(Fig. 9.2).
`
`Termination
`Reactive free radicals join together to form covalent bonds. This effect(cid:173)
`ively ends the chain reaction process and produces stable compounds
`(Fig. 9.3).
`Stage 3 Chain termination: reactive free radicals are consumed but not
`generated.
`
`Nexus Ex. 1021
`13 of 33
`
`

`

`, , , , , , , , . (cid:157) -
`
`Stability of drugs and medicines I 219
`
`.nf'.o-o·
`DflJ9
`molecular
`oxygen
`
`-
`
`Drug-o-o·
`peroxide free radical
`
`0 • Drug-H
`orug-O-
`
`. - Drug-0-0- H + Drug·
`hydroperoxide
`(oxidised drug)
`
`hanlsm of propagation.
`Themec
`
`(igure 9.2.
`
`Drug-o-o·
`
`Drug·
`
`Drug·
`
`Drug'
`
`-
`
`-
`
`Drug-0-0-Drug
`
`Drug-Drug
`
`The mechanism of termination.
`
`figUrf 9,3,
`
`b·i·ty of free rad icals
`Sta 11
`. useful to be a ble to look at the structure o f a drug molecule and be able
`1115
`'f
`· h
`1 1
`'d
`.
`.bl
`diet which sites, 1 any, m t e mo ecu e are susceptt e to ox1 atJve
`ro pre
`deterioration. To do this we must have an understa nding of the ease of
`formation and the stability of free radical species.
`The most common bond in a drug molecule to be broken during an
`auroxidarion process is a covale nt bond between hydrogen a nd another
`amm, usually carbon. It follows, therefore, that the more easily this bond
`undergoes homolysis, the more susceptible the drug will be to autoxidation
`(Fig. 9.4).
`
`(',
`Drug : H ~ Drug· + H •
`V
`
`figure 9.4. Autoxldatlon of carbon-hydrogen bonds.
`
`The breaking of a bond in this way gene ra tes rwo radicals, each with an
`unpaired electron. (Note the curved half-arrows in the reaction mechanism.
`'fy
`Tues
`·
`the movement of one electron, as o pposed ro the full arrow
`l e ~•gm
`ound tn most reaction schemes, which implies the movement of two elec-
`trons l Al h
`h
`t oug almost all free radicals a re unstable and react to gain a n
`·
`,
`ll:tra elect
`ron to complete a full octet of electrons in their outer electron
`shell
`
`mor~ ;~mt radicals are relatively more stable than others, a nd hence will be
`
`iS(with elr to form and persist. In general, the more substituted a radical
`be to ta: yl gr?ups) the more stable it will be, and the more likely it will
`lists the elp~rr •n chemical reactions. A rank order can be drawn up that
`re anve st bT .
`a I ltles of free rad icals; a highly substituted tertiary (3°)
`
`Nexus Ex. 1021
`14 of 33
`
`

`

`220 I Essentials o Pharmaceutical Chemistry
`
`radi • I i on id ra bly m re
`ta ble than a secondary (2 o)
`11 TI1 I a ·t ·t ble a lk I ra dica l is the methyl radical who~ a Prirnan, (
`.
`.
`,
`1ch h
`-, 1°)
`ut riru 11t und therefore no mec hanism whereby the un
`. as no alk
`• 11 b
`tabi li d:
`Paired eleqr:~
`o > o > Io > Hj
`
`R di al in w hich the lo ne electro n can be distributed aro d
`•
`un
`the
`by r ona n e effect are pa rticula rly sta ble and occur •
`tnolecut
`in a nu b
`e
`.
`.
`b rn er of
`0 jdat ive reaction mecha111sm s. Examples of comparatively
`l d f
`d.
`d'
`sta le
`f
`of this type are che benzyl ree ra 1ca an
`ree r adicals com . .
`ra icals
`b
`a1ning th
`.
`b' .
`(or propenyl} group. These p ec1es can e sta 1hsed, as show
`.
`. e all}']
`n in Fig. 9.5
`.
`
`(._CH 2
`
`~~ -
`U
`
`CH2
`
`c:~
`cU u
`
`6·
`
`Figure 9.5. The stability of allyl and benzyl radicals.
`
`Drugs that are susceptible to oxidation of carbon-hydrogen bonds in(cid:173)
`clude ethers (which oxidise to form highly explosive peroxides), aliphatic
`amines (which oxidise at the a-hydrogen atom) and aldehydes (which are
`easily oxidised to carboxylic acids and peroxy acids). Examples of these
`reactions are shown in Fig. 9.6.
`Other bonds that oxidise easily are the oxygen-hydrogen bond found
`in phenols and the nitrogen-hydrogen bonds found in aromatic amines
`(Fig. 9.7).
`In the case of oxidation of phenols, the reaction can very quickly give:
`complex mixture of products. This is because the phenoxy radical forme
`on abstraction of the hydrogen radical, H• can give rise to carbon-carbon,
`carbon-oxygen and oxygen-oxygen coupling reactions.
`
`Nexus Ex. 1021
`15 of 33
`
`

`

`•'.-• .. •. . . . . . .
`•t .'::. : : : : : ... : : J: ...
`~/:;-:. ;::: . . .
`. .
`
`fJ'~· ••• • •
`t • •
`
`• i\t • • •
`
`Stability of drugs and med icines I 22 1
`
`H
`I ocH2cH3
`cH
`C~3
`her
`I et
`DiethY
`
`_:rt'.-.
`initiation
`
`cHi:HOCH2CH3
`
`1
`
`o-d
`I
`
`·o-o·
`
`- CH 3CHOCH2CH 3
`
`Hl'i CH3CHOCH2c H3
`
`cHi:HOCH2CH3
`
`+
`
`0 -0 -H
`I
`CH3CHOCH 2CH3
`
`i
`
`Chain reaction
`
`Further decomposition
`
`H
`/
`I
`-CH -N ".
`
`H
`o~c/
`
`o~
`--.::::c;;
`
`/
`
`.
`-CH - N "
`0
`II
`C
`
`·o-o·
`~ etc.
`
`0
`II
`C
`
`-H' -
`6 - H CJ~~o~
`~ 6 ~ etc.
`
`i~
`Fe1+, Co3+
`
`Benzaldehyde
`
`~__)
`l)
`Resonance stabilised acyl radical
`
`·o-o·
`
`+
`
`Perbenzoic acid
`
`Figure 9.6.
`Carbon-hydr
`1h
`ogen bond cleavage in ethers, amines and aldehydes.
`'d
`.
`.
`.
`I .
`h
`ion fe Pl-I at Which th
`e P eno 1s stored 1s also importan t smce a p henox1 e
`h.
`( ' orrned
`•gh PH, can easily be oxidised to the phenoxy radical
`Pig. 9,8).
`
`at
`
`Nexus Ex. 1021
`16 of 33
`
`

`

`phenoxy radical
`
`- - etc.
`
`H
`
`H....._ N/
`
`o~
`
`Range of coupling reactions
`
`g e.
`Figure 9.7. oxygen-hydrogen and nitrogen- hydrogen bond cleava
`
`o: -
`
`Phenol
`
`Phenoxide ion
`
`o·
`
`6
`
`Phenoxy radical
`
`OH 6 6
`
`OH-
`
`-e
`Easily oxidised
`
`of\__~~_F\_
`~ - ~ o ~
`
`0
`
`0
`
`HO
`
`Aq·
`(coloured
`. u1none
`oxidation product)
`
`Figure 9.8.
`
`Oxidat· ion of th e Phenoxid
`. e ion.
`
`! T'"tome,1,m
`
`0
`
`OH
`
`Nexus Ex. 1021
`17 of 33
`
`

`

`Slability of drugs and med,cinf!~ I 223
`
`h olic groups include the nnalgesics morphine (::incl
`.
`C011cain1r1g p encetamol as well as the bronchodilaror salbuLamol
`gs
`d para
`.
`,
`iaresl 311
`ment of acute asthma (Fig. 9.9).
`pro
`1,ce<l oP d in rhe rreat
`r'.Jel)' 0sc
`,1•10
`
`OH
`
`Paracetamol
`
`Morphine
`
`HO
`
`Salbutamol
`
`figure 9.9. The structures of morphine, paracetamol and salbutamol.
`
`Drugs that contain rwo phenolic groups, such as adrenaline (epineph(cid:173)
`rme) and other catecholamines such as noradrenaline (norepinephrine)
`and isoprenaline are particularly susceptible to oxidation and have to be
`formulated at acidic pH. All of these compounds are white crystall ine
`solids, which darken on exposure to air. Adrenaline forms the red coloured
`compound adrenochrome on oxidation (Fig. 9 .10), which can further poly(cid:173)
`merise co give black compounds similar in structure to melanin, the natural
`skin pigment. Injections of adrenaline that develop a pink colour, or thar
`contain crystals of black compound, should not be used for th is reason.
`Ad~enaline for injection is formulated as the acid ramate (Fig. 9.10),
`w~ich, in aqueous solution, gives a pH of approximately 3. It is called the
`ac,~ canrate since only one carboxylic acid group of tartaric acid is used
`up in salt formation with adrenaline. This leaves the remaining carboxylic
`&roup co function as an acid.
`.
`Cleavage of h
`asirn•l
`t e n1 trogen-hydrogen bond in aromatic amines occurs in
`I ar manner to h d
`.
`.
`.
`of prod
`t at . escnbed for phenols, to give a complex nuxrure
`d
`1·
`Ucts ue to
`coup mg reactions of the type shown in Fig. 9.11.
`
`Nexus Ex. 1021
`18 of 33
`
`

`

`224 I E s ntlal of Pharrnaceu1lcol Ch mlstry
`
`H OH
`
`HO
`
`HO
`
`Adrenali ne (epinephrine)
`
`Oxlda tlo
`several
`SI ps
`
`H OH H H
`\ I
`N'-.....
`(+) CH 3
`
`HO
`
`HO
`
`H
`
`0
`
`OH
`
`0
`
`H
`
`OH
`
`Adrenaline acid tartrate
`
`Figure 9.1 o. Oxidation of adrenaline (epinephrine).
`
`H 0
`
`~ etc.
`
`Range of coupling react ions
`
`Figure 9.11. Nitrogen-hydrogen bond cleavage in amines.
`
`Prevention of oxidative deterioration
`
`A number of steps can be taken to minimise oxidative decomposition in
`drugs and medicines. These can be summarised as follows.
`
`Exclusion of oxygen
`This is pretty obvious: if oxygen in the air is causing the oxidation, t~en
`exclusion of oxygen from the formulation will minimise oxidative detenor·
`ation. lhis is usually achieved by replacing the oxygen with an inert gads
`.
`.
`I b
`ell fille
`.
`atmosphere (e.g. mtrogen or argon). The contamer should a so e w
`f
`·r getting to
`. h
`d
`d
`•b 'li
`wit pro uct an closed tightly to minimise the poss1 1 ty o ai
`the medicine.
`
`Nexus Ex. 1021
`19 of 33
`
`

`

`Stability of drugs and medicines I 225
`
`d glass containers
`cofoure
`beror
`1. ht of wavelengths <470 nm and so affords some
`f of1'1
`I des ,g
`d S
`. I f
`I ·
`U5eo
`e"c u
`.. e compoun s. pec1a ormu at1ons, such as mc-
`.sens1t1V
`.
`1ass
`.
`d in the treatment of asthma, also offer protection
`J11ber _g
`ro )lght
`A 0rect1°fl inhalers use . ce the drug is dissolved or suspended in propellant
`pr dose
`en sin
`.
`•
`ered . It and o-"Yg d luminium contamer.
`r/ of11 hg ,d ·o a seale a
`re 1
`r
`d sco
`. agents
`gn
`of chefattn9_
`can be catalysed by the presence of tiny amounts of
`use
`f f
`actions
`d
`· ·
`2+
`·
`· ·
`·d rio0 re
`· 05 pm Cu
`can 1mt1ate ecompos1t1on o ats) aod so
`0
`· 1 sp apparatus should be used wherever possible during
`Ot' laions (e.g.
`I or g as
`iera
`eptible compounds. If the presence of metal ions cannot
`n ·nless sree
`sra1
`e of susc
`h
`d' d'
`nufactur
`helating agents, sue as 1so mm edetate, are used to
`. d then c
`.
`.
`.
`.
`n1a
`be 3voide '
`ve metal ions. D1sodmm edetate 1s the d1sodium salt of
`,helate a~d r~;~etraacetic acid (EDTA) and is shown in Fig. 9.12.
`th lened1a01
`e Y
`O
`
`h
`
`riH
`
`N ~ \
`p - Na+
`HO
`~o
`Na+·0)----1
`
`0
`
`Figure 9_ 12, The structure of disodium edetate.
`
`Use of antioxidants
`Antioxidants are compounds that undergo oxidation easily to form free
`radicals but which are then not sufficiently reactive to carry on the decom(cid:173)
`position chain reaction. They selflessly sacrifice themselves to preserve the
`drug or medicine. Most antioxidants are phenols and a few of the most
`commonly used are shown in Fig. 9 .13. Ascorbic acid ( vitamin C) also
`functions as an antioxidant and is added to medicines and foodstuffs for this
`~eason. :ood manufacturers enthusiastically label their products as having
`ad
`d vitamin C'. What they are not so keen to tell you is that the vitamin
`f
`is not the
`h
`th .
`re or t e consumers' benefit but rather as an antioxidant to stop
`eir product decomposing oxidatively (see Fig. 9 .14 ).
`Autoxid t'
`a ion of fats and oils
`p·
`. .
`lXed oils and fat
`that are u d
`s are naturally occurring products, usually of plant ongm,
`se exten . I .
`. stve Y In pharmaceutical formulation. They are very sus-
`ceptible to O
`.
`Precaution Xtdattve decomposition (a process called rancidity) and special
`s must be t k
`· d
`Po · ·
`SitJon. C
`a en to control their stability and prevent their ecom-
`f h'
`ompound
`Jl
`s O t 1s type exist as complex mixtures of structura Y
`
`de
`
`Nexus Ex. 1021
`20 of 33
`
`

`

`oH
`_ ; y c(CH3h
`
`1cH,J,C y
`
`CH3
`
`d hydroxytofuene
`aucylate
`
`Butylated hydroxyanisofe
`
`1 ted hydroxytoluene (BHT) and butylated hyd
`fhe strllctures of buty a
`roxyan1s01e
`
`Figure 9, 13,
`(BHA).
`
`(OJ (cid:141)
`
`CH20H
`I
`H - C - OH
`
`0
`
`0
`
`0
`
`0
`
`tructure of ascorbic acid, showing oxidation to diketone.
`.
`Th
`e 5
`Figure 9.14,
`simjlar oils, the composition of which can vary from year to year depending
`on factors such as climate, time of harvest, and so on . Chemically, fixed oils
`and fats are esters of the alcohol glycerol (propan - 1,2,3-triol) with th
`molecules of Jong-chain carboxylic acids, called fatty acids, which ma r:e
`the same or different depending on the oil (Fig. 9 . 15).
`y e
`
`0
`II
`CH2 - 0 - C - Rl
`
`I
`11
`CH - O - C - R2
`
`I
`CH2 -
`
`11
`0 - C-R3
`
`Figure 9. 15. Th
`e structure of triglycerides.
`Compounds of h.
`t is type are call d t · l
`·
`.
`within th
`e molecule wh
`e
`rig ycertdes and contain several sites
`f h
`d
`o t e mo!
`ere autoxidat.
`I
`ecu e. This i
`ion can occur to cause break own
`('
`.
`d
`'f h
`i.e. contain
`s especially t
`l
`at east one c b
`t e fatty acids are unsaturate
`cont ·
`rue 1
`I
`ains sev
`ar on-c b
`.
`era double bo d
`ar on dou ble bond· if the carbon chain
`n s, the oil .
`.
`'
`is said to be polyunsaturated).
`Nexus Ex. 1021
`21 of 33
`
`

`

`. . . .
`. . . . .
`. . . . . .
`. . . . . .
`. . . . .
`
`Stability of drugs and medicines
`
`I 227
`
`. . of oils is very important in pharmaceuticals since non-pola r
`..-1, srab1htY
`rive steroids and neuroleptic tranquillisers) are often
`. I
`I
`we
`oncracep
`f
`.
`.1 . i·ection veluc es or mtramuscu ar or depot ini·ection.
`(e.g- c
`· 01 Y 10
`d ug5
`.
`1 ulated 111
`pe can be given, for example, once a rnonth, and the
`•
`f this cy
`· 1 h
`f
`· ·
`·
`·
`ff
`forJll
`. tions o_
`h rmacolog1cal e ect as 1t eac es out o the Injection site
`!JlleC eJ'erts its P a m Oils used as injection vehicles include arachis oil
`dfllg
`[oodstrea
`.
`.
`.
`,
`. 0 rhe b
`!ant, o live 011, castor oil and ethyl oleate, the ethyl ester
`f JI) me p
`eanut p
`.
`'d (F' 9 16)
`u1r
`fatty acid ole1c aCJ
`1g.
`.
`,
`1 s-carbon
`rO
`of the
`
`-r-0
`H= c (CH2)6C"--
`
`I
`
`OC2H5
`
`H
`
`(CH2)6CH3
`
`figure 9.16,
`
`The structure of ethyl oleate.
`
`'Jhese oils, if they are to be used parenterally, need to be chemically
`e and free from microbial contamination. As stated above, plant oils are
`p~:n complex mixtures of chemically similar compounds and so require
`;pecial fo.cms of pharmaceutical assay (e.~. determination of their acid
`and saponification values) as well as physical methods of assay such as
`determination of density (i.e. weight per millilitre) and measurement of their
`refractive index. Increasingly, modern instrumental methods of analysis,
`such as gas chromatography are being used to identify component oils and
`ensure purity (e.g. the BP assay of Arachis Oil).
`
`Ageing
`
`The effects of oxygen are not limited to the oxidation of small molecules
`found in drugs and medicines. It is now thought that most of the chemical
`effects of human ageing are the result of sustained a nd cumulative oxidative
`~mage on important macromolecules present in our cells (particularly
`NA). The old joke co the effect that air is poisonous - everyone who
`b
`ff d ·
`reathes th
`.
`.
`e stu
`bo.
`1es - does have some truth m 1t. As soon as we are
`th
`sp r~
`e cells in our bodies begin to suffer damage from reactive oxygen
`ec1es (such h d
`Th
`as Y roxyl and superoxide radicals).
`ese reactiv
`·
`in all
`e species are formed by the breakdown of oxygen present
`our ceUs and
`f
`such as h
`, once ormed, can react with essential cell components
`Darn! ospholipid membranes, cellular proteins and DNA.
`to subseqge to DNA results in genetic mutations, which can be passed on
`c II
`I
`uent gene
`.
`rations of cells. If the oxidative damage is severe, t 1e
`e in que
`.
`stion will
`d
`e£i
`enter a programme o f cell death , called apoptosis, an
`ectivefy c
`.
`ommit suicide .
`
`Nexus Ex. 1021
`22 of 33
`
`

`

`,
`
`228 I b)entlals of Phiirrnaceulical Chemistr y
`
`To counteract rhcse onslaughts by renctivc forms o f oxyg
`.
`en, the b
`d f
`I
`,,,olved n number of elegant c ence mec rnn1sms. Rcp.., 1·r
`Ody
`.
`.
`enzyn,
`1a e
`,
`.
`I
`u
`· t .•,.mngcd DNA bases nnd repa ir them 111 situ without d.
`es can
`etc1.: u..
`1srupti
`J
`,
`.
`fum:rion of rhe ONA. Similnrly, damaged membrane is repaired
`ng th~
`.
`. II
`to rest
`cell integrity. TI,esc repa ir enzymes arc essenr,a y catalysing an intr . ore
`l:ir R'EOOX process and require a number of essential nutrie
`acellt,.
`11·
`·
`nts suet
`·
`"d
`vimmins c and E to act as anttox1 ants.
`. 1 as
`1e ageing effects £
`o ox1da .
`d
`dnmt,ge cannot be reversed (yet!) an no amou nt of expensiv
`ttvc
`. f
`.
`b
`e cosme .
`h
`reparations will stop skin rom ageing, ut t e amount of dama
`tic
`P
`f ·
`·
`k
`ge to cell
`·
`may be reduced by an adequate inta e o vitamins and anrioxid
`s
`.
`.
`ants in th
`.
`.
`diet. 11,e most recent nutrittona I adv ice 1s to consume at least five hel .
`c
`.
`.
`d
`pings of
`d
`fresh fru it and vegetables every ay to matntatn an a equate dietary .
`.
`fl
`.
`d
`.
`intake
`of essential antioxidants. It 1s a sa re ect1on on o ur society that much
`more
`. .
`•
`.
`time, money and advertistng are spent on expensive cosmetic 'remedie , f
`ageing than are spent ensuring a healthy diet for all in the populations. or
`
`Hydrolysis
`
`Hydrolysis, in its widest se~se, is the br~aking of ~ chemi_cal bond through
`the reaction with water. This contrasts with hydration, which is the addition
`of the elements of water to a multiple bond, but with no associated fragmen(cid:173)
`tation of the molecule. A large number of functional groups found in drugs
`are prone to hydrolysis on storage (Fig. 9 .17), but the most commonly
`encountered are esters and amides.
`The hydrolysis of esters and amides occurs as a result of nucleophilic
`attack on the carbon of the carbonyl group and subsequent cleavage of the
`carbon-oxygen or carbon-nitrogen single bond. The carbon of the carbonyl
`group is more positive than expected as a result of the high electronegativity
`of the adjacent oxygen. The unequal sharing of the bond electrons causes a
`polarisation of the bond so that the carbon bears a partial positive charge
`( 6 + ) , while the oxygen has a partial negative charge ( 6-).
`Hydrolysis reactions occur quite slowly, but, in the presence of acid or
`alkali, the rate of the reaction increases and significant decomposition can
`occur. It should be remembered that many drugs are amines, which can
`be rendered water soluble by formation of their hydrochloride salt. Salts
`of weak bases and strong mineral acids are acidic by partial hydrolysis (see
`Chapter 1 if this is not familiar) and the hydrogen ion formed by hydrolysis
`of the salt can catalyse hydrolysis reactions on the drug itself. Similarly,
`drugs that are salts of weak acids with strong bases are alkaline in solution
`and the hydroxyl ion produced by partial hydrolysis of the salt can act as
`a catalyst and bring about decomposition. The mechanisms of acid- aocl
`base-catalysed hydrolysis of esters are shown in Figs. 9.18 and 9.l9; che
`mechanisms for hydrolysis of amides are similar.
`
`Nexus Ex. 1021
`23 of 33
`
`

`

`I
`
`Stabil" of d
`
`, am eo
`
`_ I 229
`
`Name
`
`ester
`
`cyclic ester
`
`Examples
`
`ethyl ole.ate, aspirin. prOQin
`
`warfarin. nyst.atin, digo n,
`digitoxin
`
`thioester
`
`spironolactone
`
`amide
`
`imide
`
`nicotinamide, paracetamol,
`procainamide
`
`phenytoin, barbiturates,
`riboflavin
`
`cyclic amide (lactam)
`
`penicillins, cephalosporins
`
`carbamate (urethane)
`
`carbachol, neostigmine,
`carbimazole
`
`imine (azomethine
`or Schiff base)
`
`diazepam, pralidoxime
`
`acetal
`
`digoxin, aldosterone
`
`6fO"p
`0
`J..0 ....--R
`,