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1 Drug Impurities, Degradants and the Importanceof Understanding Drug Degradation Chemistry

1 Drug Impurities, Degradants and the Importanceof Understanding Drug Degradation Chemistry

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Chapter 1
















30% H2O2




Pentoxifylline gem-dihydroperoxide

degradant (Artificial degradant)

Scheme 1.1

mixture when developing and validating stability-indicating analytical

methodologies. A common problem in the development of stability-indicating

HPLC methods using stress studies (or forced degradation) is a lack of proper

evaluation if the stress-generated degradants would be real degradants or not.

From a practical point of view, the real degradants are those that can form

under long term storage conditions such as the International Conference on

Harmonisation (ICH) stability conditions.2 On the other hand, various artificial degradants can be generated during stress studies, in particular when

excessive degradation is rendered or the stress conditions are not consistent

with the degradation pathways of the drug molecule under the usual stability

conditions. For example, forced degradation of a ketone-containing drug,

pentoxifylline, using 30% hydrogen peroxide at room temperature for eight

days produced a geminal dihydroperoxide degradation product (Scheme 1.1).4

This compound is highly unlikely to be a real degradant of the drug product.

This book is devoted to increasing our understanding and knowledge of the

organic chemistry of drug degradation. The knowledge derived from this

endeavor should also be beneficial for the elucidation of drug metabolite

structures and bioactivation mechanisms. Most drugs undergo at least certain

level of metabolism,5 that is, chemical transformation catalyzed by various

enzymes. Except in the case of pro-drugs, drug metabolites can be considered as

drug degradants formed in vivo. Chemical degradation and drug metabolism

can produce the same degradants, even though they may go through different

reaction intermediates or mechanisms. In vitro chemical reactions have been

used to mimic enzyme-catalyzed drug metabolism processes, in order to help

elucidate the enzymatic mechanisms for the catalysis.6 On the other hand,

understanding the mechanisms of drug metabolism may also facilitate the

elucidation of drug degradation pathways in vitro.

Regardless of their origins, certain drug degradants can be toxic, which is

one of the main contributors to undesirable side effects or adverse drug reactions (ADR) of drugs.7 In the early stage of drug development, the degradants

(including metabolites) and degradation pathways (or bioactivation pathways

in the case of reactive metabolites) of a drug candidate need to be elucidated,

followed by toxicological evaluation of these degradants. Dependent upon the

outcome of the evaluation, the structure of the drug candidate may have to be

modified to avoid the formation of a particular toxicophore based on the

understanding of the degradation chemistry (or bioactivation pathways)



elucidated. Failure to uncover toxic degradants, usually the low level ones, in

the early development stage can lead to hugely costly failure in later stage

clinical studies or even withdrawal of an approved drug product from the


1.2 Characteristics of Drug Degradation Chemistry

and the Scope of this Book

The vast majority of therapeutic drugs are either organic compounds or

biological entities. The latter drugs include protein and nucleic acid (RNA and

DNA)-based drugs which are biopolymers comprising small molecule building

blocks. This book focuses on the organic chemistry aspect of drug degradation,

in particular, the mechanisms and pathways of the chemical degradation of

both small and large molecule drugs under real life degradation scenarios, as

represented by the usual long term stability conditions. Stress studies or forced

degradation can help elucidate the structures of real degradants and the

degradation pathways of drugs. Nevertheless, caution needs to be taken in

differentiating the real and artificial degradants. This subject will be discussed

in detail in Chapter 8, Strategies for Elucidation of Degradant Structures and

Degradation Pathways.

Drug degradation chemistry differs from typical organic chemistry in several

ways. First, the yield of a drug degradation reaction is usually very low, from

approximately 0.05% to a few percentage points at the most. Dependent upon

the potencies and maximum daily dosages of the drugs, ICH guidelines require

that the impurities and/or degradants of a drug be structurally elucidated, once

they exceed certain thresholds, which are typically between 0.05% and 0.5%,

relative to the drug substances.8,9 For potential genotoxic impurities, they need

to be characterized and controlled at a daily maximum amount of 1.5 mg for

drugs intended for long term usage.10 Such low yields would be meaningless

from the perspective of the regular organic chemistry. Second, due to the low

yields and limited availability of samples, particularly stability samples of

formulated drugs, the quantity of a drug degradant is usually extremely low,

posing a serious challenge for its isolation and/or characterization. Despite

the advent of sensitive and powerful analytical methodologies such as

high resolution tandem liquid chromatography-mass spectrometry (LC-MS/

MS), liquid chromatography-nuclear magnetic resonance (LC-NMR), and

cryogenic micro NMR probes, the identification of drug degradants remains

one of the most challenging activities in pharmaceutical development.11 Third,

the typical conditions and ‘‘reagents’’ of drug degradation reactions are limited

in scope. For example, the ICH long term stability conditions for different

climatic zones specify the requirements for heat and moisture (relative

humidity, RH), for example, 25 1C/60% RH and 30 1C/65% RH, while the

ICH accelerated stability condition requires heating at 40 1C under 75% RH.

In addition to moisture, the other most important ‘‘reagent’’ in drug degradation reactions is molecular oxygen. Since molecular oxygen is ubiquitous


Chapter 1

and difficult to remove from drug products, oxidative degradation of drugs

is one of the most common degradation pathways. Often, the impact of

molecular oxygen can be indirect. For example, a number of polymeric

drug excipients such as polyethylene glycol (PEG), polysorbate, and povidone, are readily susceptible to autooxidation, resulting in the formation of

various peroxides including hydrogen peroxide.12–14 These peroxides can

cause significant drug degradation once formulated with drug substances

containing oxidizable moieties. In contrast, reductive degradation is rarely

seen in drug degradation reactions owing to the lack of a reducing agent in

common drug excipients that is strong enough to cause meaningful reductive

degradation. Other possible ‘‘reagents’’ in drug degradation reactions are

usually limited to drug excipients and their impurities. For example, excipients consisting of oligosaccharides and polysaccharides with reducing ends,

such as lactose and starch, are frequently used in drug formulation. The

aldehyde functionality of these excipients can react with the primary and

secondary amine groups of drugs to undergo degradation via the Maillard

reaction. This topic will be covered in Chapter 5, Drug–Excipient Interaction

and Adduct Formation.

As indicated above, this book focuses on the organic chemistry of

drug degradation, in particular, the mechanisms and pathways of the

chemical degradation of both small and large molecule drugs under real life

degradation scenarios. Owing to the variety of dosage forms of formulated

drugs, degradation of drugs can occur in various states including solid (tablets,

capsules, and powders), semi-solid (creams, ointments, patches, and suppositories), solution (oral, ophthalmic, and optic solutions, nasal sprays, lotions,

injectables), suspension (suspension injectables), and gas phase (aerosols).

Obviously, a drug molecule can exhibit different degradation pathways and

kinetics in different dosage forms. Nevertheless, as the emphasis of this book is

on drug degradation chemistry with regard to mechanisms and pathways in

general, we will not discuss in too much detail in which state a particular

degradation pathway occurs. For readers who are interested specifically in drug

degradation in the solid state, the book Solid-state Chemistry of Drugs by Byrn,

Pfeiffer, and Stowell is a good resource, in which an in-depth treatment of a

drug’s degradation behavior versus its polymorphism is presented.15

Additionally, the topic of drug degradation kinetics is outside the main

scope of this book, although kinetic parameters such as activation energy, Ea,

reactant half-life, and reaction rate constant, are used extensively in Chapter 2,

Hydrolytic Degradation, for the purpose of comparing the hydrolytic lability

of various functional groups on a semi-quantitative basis. Those who are

interested in drug degradation kinetics are referred to the book by Yoshioka

and Stella, Stability of Drugs and Dosage Forms,16 in which various kinetics

models of drug degradation are described. Note that the topic of process

impurities of drugs is also out of the scope of this book. There are a number

of publications on process chemistry development and control of process

impurities.17–19 Last, this book tries to focus mainly on the major degradation

pathways and mechanisms of drugs, rather than to be all-inclusive.



1.3 Brief Discussion of Topics that are Outside the

Main Scope of this Book

Although there will not be a detailed discussion of topics that are outside the

main scope of this book, such as those mentioned above, a brief overview of

some of these topics is beneficial for a better overall understanding of drug

degradation chemistry and this is given here.

1.3.1 Thermodynamics and Kinetics of Chemical Reactions

A change in Gibbs free energy, DG, of a chemical reaction governs the propensity of the reaction to proceed. DG is dened as follows:



where DH is the change in the reaction enthalpy, T is the reaction temperature

(in Kelvin), and DS is the change in the reaction entropy.

For a thermodynamically favored reaction, that is, a reaction that occurs

spontaneously, if allowed by the reaction kinetics, the DG of the reaction is

negative. In other words, the free energy of the products is lower than that of

the reactants in such a case. A schematic diagram of a thermodynamically

favored reaction is presented in Figure 1.1. In contrast, a thermodynamically

unfavorable reaction has a positive DG.

Kinetic energy, E

or Gibbs free energy, G

Minimum energy for reaction to proceed

or Transition state (*)


or ΔG*







Figure 1.1

Schematic diagram of a thermodynamically favored reaction, where the

Gibbs free energy of the reaction, DG, is negative. Ea is the activation

energy per the collision theory, while DG* is Gibbs free energy of activation according to transition theory.


Chapter 1

DG determines if the reaction of A ỵ B-C ỵ D is favored or not, but it does

not determine how fast the reaction, whether thermodynamically favored or

not, would take place. The rate of the reaction or its kinetics is governed by the

energy that is necessary to activate the reactants to a certain state so that they

can convert to their products. There are two theories describing this process:

collision theory and transition state theory. Collision theory is embodied in the

well-known Arrhenius equation (equation (1.2)), which was first proposed by

van’t Hoff in 1884 and later justified and interpreted by Arrhenius in 1889:20

k ẳ Ae Ea=RT


where k is the reaction rate constant, A is the pre-exponential (or frequency)

factor which can generally be approximated as a temperature-independent

constant, Ea is the activation energy which is defined as the minimum energy

the reactants must acquire through collision in order for the reaction to occur,

R is the gas constant, and T is the reaction temperature (in Kelvin).

According to the Arrhenius equation, the rate constant of a reaction is

temperature dependent and by taking the natural logarithm of equation (1.2),

the Arrhenius equation takes the following format (equation (1.3)):

ln k ẳ

Ea 1

ỵ ln A



This expression shows that the higher the temperature, the faster the reaction

rate. Additionally, if one measures the reaction rate constants (k) at different

temperatures (T), one should get a linear relationship by plotting ln k versus

1/T. Hence, the activation energy, Ea, can be obtained from the slope (–Ea/R)

of the linear plot and ln A from the y-intercept.

Despite its widespread use, the Arrhenius equation and its underlying

collision theory have been challenged over time. The major competing theory

appears to be transition state theory which was developed independently by

Eyring, and Evans and Polanyi in 1935.21 The equation derived according to

transition state theory is the Eyring equation, also called the EyringPolanyi

equation (1.4):






where DG* is Gibbs free energy of activation, kB is the Boltzmann constant, and

h is Planck’s constant.

This equation bears some resemblance to the Arrhenius equation in that the

kBT/h item corresponds to the pre-exponential factor, A, and DG* corresponds

to the activation energy, Ea. Nevertheless, in the Eyring equation, DG*, in

addition to kBT/h, is temperature dependent, as DG* ¼ DH* – TDS*. Hence, the

Erying equation can be written as equation (1.5) after taking natural logarithm



and rearrangement:

ln k=T ẳ DH =Rị 1=T ị ỵ ln kB =h ỵ DS Ã=R


where DH* is enthalpy of activation and DS* is entropy of activation.

Hence, DH* can be obtained from the slope (–DH*/R) of a linear plot of

ln k/T versus 1/T, while DS* can be obtained from the y-intercept (ln kB/h ỵ

DS*/R). Therefore, one can obtain both Ea (from equation (1.3)) and DH* and

DS* (from equation (1.5)) from a single dataset of reaction rate constant, k,

versus reaction temperature, T. Although application of the Eyring equation

enables one to obtain both DH* and DS* values and the DS* value should help

elucidate the reaction mechanism,22 it appears that the use of Arrhenius

equation exceeds the use of Eyring equation, at least in the hydrolytic stability

studies of drugs. With respect to the numeric difference between the values of

Ea and DH*, we can again rearrange the Eyring equation (1.5) into the following format (equation (1.6)):

ln k ¼ ðÀDH =Rị 1=T ị ỵ DS=R ỵ ln kB =h ỵ ln T


Among the last three items of the equation, only ln T is a variable of reaction

temperature, while the other two are constants. However, for reactions that are

studied within a relatively narrow window of temperature, say no greater than

100 K above room temperature (298 K), a temperature change of 100 K with

regard to ln T does not appear to have too much impact on the overall value of

the summation for the last three items. Hence, the Arrhenius equation may be

considered a simplified version of the Eyring equation when reactions are

studied within a relatively narrow range of temperature; the vast majority of the

degradation reactions of drugs fall into this category. Therefore, numerically

the value of Ea would not be too much different from that of DH*. Indeed, in a

hydrolysis study of a group of sulfamides, the difference between the two values

is no more than 1 kcal molÀ1.23

1.3.2 Reaction Orders, Half-lives and Prediction of Drug

Product Shelf-lives

If a reaction only involves a single reactant, A, and the rate of this reaction is

proportional to its concentration, the reaction order of this unimolecular

reaction is said to be 1 with regard to A and the reaction is a first order reaction.

This relationship can be expressed by equation (1.7):

K ẳ kẵA


where K is the reaction rate, k is the reaction rate constant, and [A] is the

concentration of A.


Chapter 1

For a first order reaction as illustrated above, K can be expressed as:

K ẳ dẵA=dt


where t is the reaction time. As a result, the first order reaction equation can be

rewritten as:

dẵA=dt ẳ kẵA or

dẵA=ẵA ẳ kdt


Integration of the equation results in the following:

ẵA ẳ ẵA0 ekt


ẵA ẵA0 ẳ ekt


where [A]0 is the initial concentration of A. The reaction time when half of A is

consumed, that is, [A]/[A]0 ¼ 1/2, is the half-life of A, t1/2. The equation now


ekt1=2 ẳ 1=2


By taking the natural logarithm and rearranging the resulting equation, t1/2

can be calculated by equation (1.12):

t1=2 ẳ ln 2=k ẳ 0:693=k


Thus, for a first order reaction, the half-life of the reactant can be readily

calculated from the reaction rate constant, k. While a true unimolecular reaction is not very common, a great number of reactions are bimolecular reactions

such as the one illustrated in Scheme 1.1. The rate of the latter reaction can be

expressed by equation (1.13), if the reaction order for either A or B is 1:

K ẳ kẵAẵB


where K is the reaction rate, k is the reaction rate constant, and [A] and [B] are

the concentrations of reactants A and B, respectively.

For a dimerization reaction of reactant A, K ¼ k[A]2, and the reaction order

for A is 2. Frequently during studies of the kinetics of bimolecular reactions,

the concentration of one reactant, for example [B], can either be kept constant

experimentally or at a large excess with respect to the other reactant. The latter

category includes the hydrolysis of drug molecules in aqueous solutions, where

water is reagent B in large excess. Consequently, [B] becomes or can be

approximated as a constant and the bimolecular rate expression can be written

as K ¼ k 0 [A], where k 0 ¼ k[B]. In such a case, the bimolecular reaction becomes

a pseudo first order reaction and the half-life of A can be calculated using the

formula for first order reaction shown in equation (1.12) above.



In order to ‘‘calculate’’ the shelf-lives of drug products, more meaningful

reaction times would usually be when 5% or 10% of the drug substances are

degraded.24 Frequently, it is desirable to perform an accelerated stability study

at a higher temperature, T1, from which the degradation rate constant of the

accelerated stability study, k1, is obtained, to ‘‘predict’’ the shelf-life of the drug

product at a regular stability temperature (e.g. 298 K), T2. In principle, this can

be readily done for drug products that follow first or pseudo first order

degradation kinetics, since the degradation rate constant at the regular stability

temperature, k2, can be calculated according to the following formula, equation

(1.14), based on the Arrhenius equation (equation (1.2)):

k2 eÀEa =RT1


k1 eÀEa =RT2



k2 ¼ k1 e R




À T11



Hence, the shelf-life, t, can be calculated or ‘‘predicted’’ based on a calculation

using equation (1.14). Nevertheless, in many cases, such predication produces

tremendous errors, rendering this approach of no or little practical value. This

is due to a number of factors. For example, the degradation mechanism may

not be the same at different temperatures. Thus, the dependence of k on T

would deviate from the Arrhenius equation. In addition, the exponential

relationship between k and T means that a small error in the k1 value at T1,

could propagate into a huge variation in the k2 value at T2.25

Because of the limitation of the above approach, various non-linear statistical models for ‘‘predicting’’ drug product shelf-lives have been developed with

varying degrees of success.26–29 Some of these models take into consideration

the degradation types of reaction orders at or greater than two using a polynomial degradation model.28 Last, it needs to be pointed out that in the past

decade or so, shelf-lives of drug products have been increasingly constrained by

the occurrence of degradants rather than by the loss of active ingredient

potency due to the advancement of analytical methodologies and tightening of

regulatory requirements.29

1.3.3 Key Elements in Solid State Degradation

Solid exists in different forms called polymorphs, which can be generally

divided into crystal and non-crystal (or amorphous) forms. Among the crystal

forms are anhydrates, solvates, and co-crystals. The most important solvates

are hydrates; anhydrates and hydrates can interconvert. For example, high

temperature and low moisture should promote the loss of crystal water from

hydrates, while the opposite combination should promote the hydration of

anhydrates. Acidic and basic drug molecules can be presented in final drug

dosage forms in their native forms or in various salt forms. Both the native and

salt forms may be capable of producing different polymorphs, that is, an

amorphous state, different crystal forms, and/or different hydration states

including anhydrates. Depending upon which form is chosen as the physical


Chapter 1

form of a drug substance in its solid, semi-solid, or other dosage form, where

the physical form of the drug molecule matters, the conversion of the selected

physical form to other forms is physical degradation, which may result in

changes in the solubility and chemical stability of the drug molecule. Such

changes are very likely to have an impact on the bioavailability and toxicity

profiles of the drug product. Therefore, selection of an appropriate physical

form is essential for maintaining drug product quality, safety, and efficacy.30–32

Different polymorphs usually have different stabilities or different rates of

degradation. In general, crystalline materials are more stable than amorphous

ones owing to more restrictive molecular mobility of the former. Likewise,

molecules tend to be more stable in solid dosage forms than in liquid ones in

most cases, albeit it may not always be the case, since molecules in solid state

are more restricted in their mobility. For example, the activation energy of the

cyclization of aspartame in the solid state forming its diketopiperazine (DKP)

degradant is 268 kJ molÀ1 (64.1 kcal molÀ1),33 which is comparable to other

solid state reactions.34 On the other hand, the activation energy for the same

degradation in solution is only 70 kJ molÀ1.35 In certain cases, a particular

degradation pathway may only occur in the solid state or associated with

particular crystal forms; such a degradation is categorized as a true solid state

degradation. A classic example is the solid state photooxidation of 21-cortisol

tert-butylacetate to the corresponding 21-cortisone ester.36,37 Among the five

crystal forms obtained, only forms I and IV are reactive. The crystal structure

of form I was resolved and its susceptibility to photooxidation was attributed to

the ease of penetration by oxygen into a channel along the axis of the helix of

the crystal.

1.3.4 Role of Moisture in Solid State Degradation and pH in

the Microenvironment of the Solid State

Moisture present in solids is generally categorized as bound (crystal water) and/

or unbound or surface absorbed water. Nevertheless, the bound water molecules can also be mobile and migrate within the crystal lattice or along the solid

surface over a long time scale.38,39 Hence, with regard to the role of moisture in

solid state degradation, Ahlneck and Zografi concluded that it is preferable to

think of it as a plasticizer rather than causing surface dissolution of the solid.40

Furthermore, moisture tends to be absorbed more favorably in minor amorphous defects or disordered regions present in crystalline materials. This causes

a further increase in molecular mobility in these already ‘‘activated’’ or ‘‘hot’’

spots, which then triggers drug degradation in these hot spots. A large number

of studies have confirmed the correlation between increased molecular mobility

caused by the plasticizing effect of water and drug degradation.37,41,42 In most

solid state degradation reactions such as hydrolysis and oxidation, water can

act as both a plasticizer and a reactant.40

The concept of pH is usually associated with aqueous solutions. With drug

products formulated in solid dosage forms, the concept of pH may be used in



two ways: first, lyophilized solid dosage forms, such as most protein-based

drugs, are typically made from pH buffered solutions. Hence, the pH of the

buffered solutions are used as the ‘‘pH’’ of the corresponding lyophilized solids

or lyophiles.43 A solid state stability study of lyophilized insulin displayed a

profile of degradation rate versus ‘‘pH’’ that is very similar to insulin degradation in solutions in the same pH range.44 Second, for other solid dosage

forms, the concept of microenvironment pH has been used, which is defined as

the pH value of the slurry resulting from the disintegration of the solid forms by

water.45 The impact of pH in such solid dosage formulations also depends on

the manufacturing process: a buffer in a formulation resulting from a wet

granulation tends to be more effective in stabilizing the drug substance than

that from a direct compression.46 It appears that wet granulation enables a

more uniform distribution of the buffer and perhaps also renders closer contact

between the buffer and the drug substance than does the direct compression.

1.4 Organization of the Book

This book is divided into nine chapters. The previous sections of this chapter

stipulate the objective and scope of the book. In addition, this chapter also

covers briefly a number of topics that are useful for the discussion in later

chapters but are outside the main scope of this book. These topics include

thermodynamics and kinetics of chemical reactions and several key concepts in

solid state chemistry.

Chapters 2 and 3 discuss hydrolytic and oxidative degradations, respectively,

which are the two most commonly observed types of drug degradation, owing

to the universal presence of moisture and oxygen. In Chapter 2, Hydrolytic

Degradation, several hydrolytic mechanisms are discussed first along with

electrical and steric effects that impact hydrolysis, followed by more than 30

examples of drugs containing functional groups susceptible to hydrolytic

degradation. The susceptibilities of these drugs are compared, whenever

possible, by their hydrolysis activation energies, on a semi-quantitative basis

in most cases. In cases where activation energies were not reported in the

literature, enthalpy of activation and/or reaction rate constants are used for the


In Chapter 3, Oxidative Degradation, several major types of autooxidation

mechanisms are discussed first, followed by discussion of specific oxidation

pathways of drugs with various functional groups and structures in relation

to each type of major autooxidation mechanism. Among the latter, the

ubiquitously known Fenton reaction and the little known, but more relevant

Udenfriend reaction, are discussed. The discussion focuses on their roles in

free radical-mediated autooxidation by activating molecular oxygen into

several reactive oxygen species (ROS), that is, O2Àd/HO2d, H2O2, and HOd.

The radicals ROS then trigger radical chain reactions, in which process

organic peroxyl radicals and hydroperoxides are predominant intermediates.

Hydroperoxides can undergo homolytic cleavage, owing to their relatively


Chapter 1

low O–O bond dissociation energies, as well as metal ion-catalyzed heterolytic cleavage. Homolytic cleavage generates alkoxyl and hydroxyl radicals,

while heterolytic cleavage reproduces peroxyl radicals. Non-radical reactions

of peroxides are also discussed, in particular those responsible for the

formation of N-oxide, sulfoxide, and epoxide degradants. Lastly, the general

mechanism for a non-radical autooxidation pathway, carbanion/enolatemediated autooxidation (base-catalyzed autooxidation), is also discussed.

This mechanism is well known in synthetic organic chemistry but much less

known for its role in degradation chemistry. Examples are used to demonstrate that this pathway can be significant for those drug molecules

containing somewhat ‘‘acidic’’ carbonated CHn moieties, particularly when

the drugs are formulated in liquid dosage forms. Overall, more than 60

examples of oxidative drug degradation in real life scenarios are presented.

These examples cover the functional groups, moieties, and structures that

are commonly seen in drug molecules.

Chapter 4, Various Types and Mechanisms of Degradation Reactions,

covers most of the commonly occurred drug degradation reactions, except for

hydrolysis, oxidation, degradation caused by interaction with excipients, and

photochemical degradation. The latter two categories of drug degradation are

discussed in Chapters 5 and 6, respectively. The degradation reactions covered

in Chapter 4 include elimination, decarboxylation, nucleophilic conjugate

addition and its reverse process, aldol condensation and the retro-aldol process,

rearrangement and isomerization, cyclization, dimerization and oligomerization, and a few examples of degradation via miscellaneous mechanisms and

pathways. While some of the above classifications are relatively specific in

scope, for example, decarboxylation, nucleophilic conjugate addition, and aldol

condensation, others are more complicated as they can involve many sub-types

or different types of degradation pathways and mechanisms. For example,

cyclization and dimerization can involve many different types of degradation

mechanisms. More than 50 examples of drug degradation are discussed in this


Chapter 5, Drug–Excipient Interaction and Adduct Formation, is organized

according to the types of interaction between a drug substance and excipients:

direct interaction between the drug substance and excipients, interaction of the

drug substance with impurities of excipients, interaction of the drug substance

with degradants of excipients, and interaction of the drug substance with

impurities from packaging materials. In the first category, the various pathways

of the well-known Maillard reaction are reviewed first, followed by discussion

of the interaction between carboxyl-containing drug substances and excipients

possessing hydroxyl and amino groups through the formation of ester and

amide linkages, respectively. Drug–excipient interaction due to transesterification is also covered. In the second part of the chapter, drug degradation

caused by reaction with impurities and degradants originating from excipients

and packaging materials is described.

Chapter 6, Photochemical Degradation, starts with a concise overview

of photophysical and photochemical events upon irradiation of a molecule with

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