Organic chemistry of drug degradation

307 Pages·2012·22.287 MB·English

by  Min Li

RSC Drug Discovery
Min Li
Organic Chemistry of
Drug Degradation
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Organic Chemistry of Drug Degradation
RSC Drug Discovery Series
Editor-in-Chief:
Professor David Thurston, London School of Pharmacy, UK
Series Editors:
Dr David Fox, Pfizer Global Research and Development, Sandwich, UK
Professor Salvatore Guccione, University of Catania, Italy
Professor Ana Martinez, Instituto de Quimica Medica-CSIC, Spain
Professor David Rotella, Montclair State University, USA
Advisor to the Board:
Professor Robin Ganellin, University College London, UK
Titles in the Series:
1: Metabolism, Pharmacokinetics 16: Pharmaceutical Salts and
and Toxicity of Functional Cocrystals
Groups 17: Polyamine Drug Discovery
2: Emerging Drugs and Targets for 18: Proteinases as Drug Targets
Alzheimer’s Disease; Volume 1 19: Kinase Drug Discovery
3: Emerging Drugs and Targets for 20: Drug Design Strategies:
Alzheimer’s Disease; Volume 2 Computational Techniques
4: Accounts inDrug Discovery and Applications
5: New Frontiers in Chemical 21: Designing Multi-Target Drugs
Biology 22: Nanostructured Biomaterials
6: Animal Models for for Overcoming Biological
Neurodegenerative Disease Barriers
7: Neurodegeneration 23: Physico-Chemical and
8: G Protein-Coupled Receptors ComputationalApproachesto
9: Pharmaceutical Process DrugDiscovery
Development 24: Biomarkers for Traumatic Brain
10: Extracellular and Intracellular Injury
Signaling 25: Drug Discovery from Natural
11: New SyntheticTechnologies in Products
Medicinal Chemistry 26: Anti-Inflammatory Drug
12: New Horizons inPredictive Discovery
Toxicology 27: New Therapeutic Strategies for
13: Drug Design Strategies: Type2Diabetes:SmallMolecules
Quantitative Approaches 28: Drug Discovery for Psychiatric
14: Neglected Diseases and Drug Disorders
Discovery 29: Organic Chemistry of Drug
15: Biomedical Imaging Degradation
How to obtain future titles on publication:
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delivery of each new volume immediately on publication.
For further information please contact:
BookSalesDepartment,RoyalSocietyofChemistry,ThomasGrahamHouse,
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Telephone: [phone],Fax:[phone],
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Visit our website at http://www.rsc.org/Shop/Books/
Organic Chemistry of Drug
Degradation
Min Li
Ringoes, New Jersey
Email: [email protected]
RSCDrugDiscoverySeriesNo.29
ISBN: 978-1-84973-421-9
ISSN: 2041-3203
AcataloguerecordforthisbookisavailablefromtheBritishLibrary
rMinLi2012
Allrightsreserved
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This book is dedicated to the memory of my parents,
Shaohua Li and Ruiying Yang,
for their love and inspiration.

Preface
For some time, I have had the desire to write a book on the area of drug
degradation chemistry, partly because of the need for a book with in-depth
coverage of the mechanisms and pathways of ‘‘real’’ drug degradation, which
is defined (in this book) as drug degradation that tends to occur under long
term storage and stability conditions. During the 2010 Pittcon in Orlando,
while visiting the exhibition booth of RSC Publishing, I met Ms. Roohana
Khan, then Regional Business Manager of RSC Publishing for the US, and
expressed my idea for the book. She was very interested in the idea and
promptly forwarded my initial proposal to the editors of RSC Drug Dis-
covery Series, particularly Dr. David Rotella and Mrs. Gwen Jones, which
eventually led to the book publishing contract.
Thevastmajorityofdrugsareorganicandincreasinglybiologicalmolecular
entities. Control or minimization of drug degradation requires a clear under-
standingoftheunderlyingorganicchemistryofdrugdegradation,whichisnot
only critically important for developing a drug candidate but also for main-
taining the quality, safety, and efficacy of an approved drug product over its
product life cycle. Specifically, the knowledge of drug degradation is not only
vital for developing adequate dosage forms that display favorable stability
behavior over the registered product shelf life, but also critical in assessing
which impurities would be most likely to be significant or meaningful degra-
dants so that they should be properly controlled and monitored. This book
discusses various degradation pathways with an emphasis on the underlying
mechanismsofthedegradationthattendstooccurunderthereallifescenarios,
that is, the long term storage conditions as represented by the stability condi-
tions recommended by the International Conference on Harmonisation of
Technical Requirements for Registration of Pharmaceuticals for Human Use
(ICH) and the World Health Organization (WHO). The utility and limitation
of using stress studies or forced degradation in ‘‘predicting’’ real life drug
degradationchemistryisclearlydiscussedinthebookandthereaderisalerted
RSCDrugDiscoverySeriesNo.29
OrganicChemistryofDrugDegradation
ByMinLi
rMinLi2012
PublishedbytheRoyalSocietyofChemistry,www.rsc.org
vii
viii Preface
tothestressingconditionsthattendtoproduceartificialdegradationproducts.
Organic reactions that are significant in drug degradation are discussed and
illustrated with examples of drug degradation from commercialized drug
products as well as drug candidates in various stages of pharmaceutical
and manufacturing development. This book consists of nine chapters, with
Chapters 2 and 3 devoted to hydrolytic and oxidative degradations, the two
most commonly observed types of drug degradation, the latter being perhaps
the most complex of all. In Chapter 3, the Udenfriend reaction is discussed in
detail with regard to its significant, but little yet known role in the auto-
oxidative degradation of drugs. Chapters 4 and 5 cover the remaining vast
majorityof drug degradation reactions except for photochemicaldegradation,
which isdiscussed inChapter6.Chapter7covers thechemicaldegradationof
biological drugs. The book finishes with two chapters, respectively, on strate-
gies for rapid elucidation of drug degradants and control of drug degradation
according to current regulatory requirements and guidelines. With the
increasingregulatoryrequirementsonthequalityandsafetyofpharmaceutical
products, I hope this book will be a handy resource for pharmaceutical and
analytical scientists as well as medicinal chemists. A good understanding of
drugdegradationchemistryshouldalsofacilitateleadoptimizationandhelpto
avoidthedegradationpathwaysthatmayleadtopotentiallytoxicdegradants.
Completing this book has been a laborious but fulfilling experience. As one
reviewer of the book proposal put it, ‘‘it is potentially a Herculean task’’.
Fortunately,Ihavebeenabletocompletethebooklargelyonschedule,partly
due to the encouraging and constructive comments by the two reviewers. The
subject of drug degradation chemistry involves multidisciplines. It requires
knowledge and experience in organic chemistry, medicinal chemistry, separa-
tion sciences, mass spectrometry, and NMR spectroscopy. Throughout my
professional life, I have been fortunate to have gained knowledge and experi-
ence in the above disciplines. I am forever indebted to my mentors during the
early phasesof my career for their advice, passion for science, and example of
hard work and integrity. My undergraduate major was polymer chemistry at
Fudan University, followed by two years of a master program in the same
subject.Duringthatperiod,Ihadtheopportunitytostudythephotochemistry
and photophysics of polymers under Professor Shanjun Li. This experience
triggeredmyinterestinphotochemistry,whichhasenabledmetowriteChapter6,
Photochemical Degradation. During my PhD study in the laboratory of
ProfessorEmilH.WhiteatJohnsHopkinsUniversity,Ilearnedtheprinciples
oforganicchemistry,andproteinandpeptidechemistrywithextensivehands-
on experience. In this period, I also started to learn the basics of mass spec-
trometry,particularlyfastatombombardment(FAB)ionization,thetechnique
of choice for mass spectrometric analysis of biological molecules at the time.
Use of FAB-MS turned out to be crucial in identifying the exact location of a
chemicalprobeattachedtoanactive-sitepeptideofaprotease,whichwasone
ofmymainresearchprojectsatthattime.Duringmypostdoctoralresearchin
ProfessorMichaelE.Johnson’slaboratoryatUniversityofIllinoisatChicago,
Center for Pharmaceutical Biotechnology, I had the opportunity to learn the
Preface ix
basic principles of medicinal chemistry, particularly in the field of structure-
based drug design. I am also deeply indebted to many of my colleagues in
various biotechnical and pharmaceutical companies, particularly Merck and
formerly Schering-Plough where I have spent the majority of my career, for
theirencouragementandsupport.IwouldliketothankespeciallyDr.Zi-Qiang
Gu,Dr.AbuM.Rustum,andthemembersofmyresearchgroupsatdifferent
times. Overaspanofmorethantenyears,myresearchgroupshaveperformed
hundredsofinvestigationsrelatedtovariousdrugdegradationmechanismsand
pathways; a minority of these investigation results were published, many of
which are cited in this book. The successful resolution of these challenging
investigationswouldhavenotbeenpossiblewithoutthecontributionfromthe
members of my research groups, most notably Dr. Bin Chen, Dr. Xin Wang,
Dr. Xin (Jack) Yu, Dr. Mingxiang Lin, and Dr. Russell Maus.
Special thanks go to Dr. Russell Maus who reviewed the manuscript of
Chapter 2, Dr. Gary Martin for a constructive discussion on the topic of
two-dimensional NMR spectroscopy, and to the editors of RSC Publishing
whohavedoneasuperbjobintheproductionofthebook.Finally,mygrateful
thanks go to my family, particularly my wife Beihong, for her love, support,
and unwavering confidence in me over the past 20 years.
Min Li
Ringoes, New Jersey
27 May 2012
[email protected]