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4 Carbanion/enolate-mediated Autooxidation (Base-catalyzed Autooxidation)

4 Carbanion/enolate-mediated Autooxidation (Base-catalyzed Autooxidation)

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62



Chapter 3

O



O



O



Base

R1



R2



R1



R2



R1



R2



R2 is usually an

electron-withdrawing

group

O2



O

O



O

+



R1



O



O2



R2



Carbon radical/Superoxide

anion radical complex



R1



R2



Organic peroxide



Scheme 3.15

the caged process exists, the overall rate of the carbanion/enolate-mediated

autooxidation appears much faster than a usual free radical-mediated process

and apparently displays no characteristics typical of a free radical-mediated

reaction.7,82,83



3.5 Oxidation Pathways of Drugs with Various

Structures

The origins and mechanisms of oxidative degradation of drugs of several major

types of autooxidation mechanisms have been described in Sections 3.2 to 3.4.

In this section, specific oxidation pathways of drugs with various functional

groups and functional structures will be discussed in relation to each type of the

oxidation mechanism. Note that the same type of functional group may

undergo different pathways under different conditions including different

dosages. For example, the carbon–carbon double bonds can undergo allylic

oxidation as well as epoxidation. On the other hand, formation of the same

degradant may derive from multiple degradation pathways. Epoxide, for

example, can be formed from both radical and non-radical pathways.



3.5.1 Allylic- and Benzylic-type Positions Susceptible

to Hydrogen Abstraction by Free Radicals

Drugs containing allylic- and benzylic-type moieties are susceptible to free

radical attack, because the resulting carbon-centered radicals are stabilized

by conjugation with the nearby double bond or aromatic ring. The carboncentered radicals usually react with O2 at an extremely fast rate (approaching

the diffusion controlled rate). Nonetheless, carbon-centered radicals that are



63



Oxidative Degradation

R



O

O



Figure 3.2



Scheme 3.16



Structure of the benzylic radicals derived from 2-coumaranone

derivatives.



Reproduction from Reference 85 with permission.



stabilized by extensive resonance, such as triphenylmethyl and 9-phenylfluorenyl, have greatly reduced reactivity with O2. Other factors can also have

an impact on the reactivity with O2. For example, Bejan et al. reported that the

benzylic radical derived from 2-coumaranone, which has a lactone functionality next to the radical, completely lacks any reactivity with O2 (Figure 3.2).84

During pharmaceutical development of a novel drug candidate, TCH346, for

neurodegenerative disorders, a degradant devoid of the original amine moiety

was found during long term and accelerated stability studies of a tablet formulation.85 The authors proposed the degradation mechanism shown in

Scheme 3.16.

In this drug substance, the allylic position is quite susceptible to H

abstraction by a free radical generated in autooxidation, since the radical

formed can be stabilized by an extended conjugated system. The allylic radical

should readily react with O2 to give a peroxide which would in turn produce the

alcohol intermediate. It is possible that the peroxide could directly decompose

to give the final aldehyde degradant, while producing a hydroxylamine as the



64



Chapter 3

OH

N



O



N



N



1) O2



Radical



2) H abstraction



Pathway a

O

TCH346



O



O

N



Pathway b



HO

N

O



H



HO



N



O

Aminium cation radical

O

H+



O



Aldehyde degradant



H2 O

N

HN



O



Scheme 3.17

leaving group. Hence, an alternate degradation mechanism (Scheme 3.17,

pathway a) can be proposed.

In this particular case, the benzylic position is also a to the tertiary amine

moiety. This type of structural moiety can also form an aminium radical cation

intermediate through a one electron transfer oxidation of the nitrogen atom,

which will give the same aldehyde degradant while producing an amine as the

leaving group (Scheme 3.17, pathway b). The degradant distribution in the

latter case is the same as that proposed by the original researchers. Since

the structure of the leaving group was not determined in the original study, it is

not possible to tell which degradation pathway is more likely. There will be a

more detailed discussion of the autooxidation mechanism via the aminium

radical cation intermediate in Section 3.5.3.3.

Clopidogrel bisulfate, the active pharmaceutical ingredient (API) of the

second best selling drug Plavix, contains a moiety that is similar to that in

TCH346 above: a benzylic-type 3-thiothenylmethyl position that is also a to a

tertiary amine functionality. Recently, a significant new oxidative degradant

was observed in the clopidogrel bisulfate drug substance and drug product.86

This new degradant elutes close to the void volume in the clopidogrel bisulfate

USP method87 due to the polar iminium cation moiety. Despite the thorough

structure characterization carried out by the original workers, no formation

mechanism was proposed for this new degradant. Based on the similarity of the

key functionalities between clopidogrel bisulfate and that of TCH346, formation of the new oxidative degradant can proceed through either of the two

radical pathways (Scheme 3.18) via intermediates that are analogous to those in

Scheme 3.17.



65



Oxidative Degradation

O



O



O



RH



N



O



O



P



athw



ay a



Rad



N



S



N



R



Cl



ical



O



O



HO

O2



S



Cl

HOO



S



Cl



Pa

thw

Ra

ay

tra d i c a

b

ns l o

itio r

nm

eta

lio

n



Clopidogrel



O



O



O



O

H



N



N

S



S



Cl



Cl



Major oxidative degradant



Scheme 3.18



O

N



HOO



N



N



HO



O

OH

10-Oxomorphine



H2 O



1) Radicals



[O]



2) O2

HO



O

Morphine



OH



HO



O



HO



OH



N



Peroxide intermediate



HO



O



OH



10α-Hydroxymorphine



Scheme 3.19

The molecule of morphine contains both a benzylic (C10) and an allylic

(C14) position. Two degradants resulting from C10 oxidation were observed

in morphine sulfate drug substance as well as in several pharmaceutical

preparations.88–90 The formation of these two degradants, 10a-hydroxy and

10-oxomorphine, is probably via the pathway shown in Scheme 3.19.

The stability results showed that 10-oxomorphine continuously increased

over time, while 10a-hydroxymorphine remained relatively unchanged. This

phenomenon is consistent with the above mechanism where 10a-hydroxymorphine is an intermediary degradant leading to the terminal degradant,

10-oxomorphine. Under chemical transformation conditions, no oxidation was

seen on C14 position,90 indicating the C14 allylic position is less reactive than

the benzylic C10 position towards what is presumed to be radical-mediated

autooxidation. On the other hand, the phenolic moiety of morphine (and



66



Chapter 3



related drugs, e.g., naloxone, nalbuphine, and oxymorphone) can undergo

oxidative 2,2 0 -dimerization in solutions to yield primarily 2,2 0 -morphine dimer

(pseudomorphine). Refer to Section 3.5.9 for a more detailed discussion on the

oxidation mechanism of drugs containing a phenolic moiety.

Ezlopitant, a non-peptide substance P receptor antagonist, possesses a

4-methoxybenzylic moiety as well as a diphenylmethyl moiety (Figure 3.3).

Although it is quite stable in solution, ezlopitant was found to autooxidize

relatively quickly at the 4-methoxybenzylic position to give the benzylic peroxide as the major degradant when stored in solid.91 Based on consideration of

the electronic factor, the diphenylmethyl position may be more susceptible

to the radical-mediated autooxidation. Nevertheless, steric hindrance may

inhibit the autooxidation at this position.

Avermectins and related compounds are macrolides with broad anti-parasite

activities. Their core structures contain a number of allylic and allylic-like sites,

among which the 8a-site is the most reactive one owing to its linkage to the

neighboring butadiene and ether functionalities. The resulting autooxidative

degradant is 8a-oxoavermectin (Scheme 3.20).92,93



O



NH



N



Ezlopitant



Figure 3.3



The structure of ezlopitant. The arrow indicates where peroxidation occurs.



O



O

OH 2



8



O



O

Autooxidation







8

HOO



O



5



H

HO



The moiety of ivermection and

related compounds that is susceptible

to autooxidation



Scheme 3.20



H



5

HO



OH 2



8

H2O



O



O



O



OH 2

O



O

H



5

HO



67



Oxidative Degradation

O



HO

O

O



R3



R2



R1



H



R3



R2



H



R3



R2



R3



R2



H



Radical



H



H



O2

OO



1a, Lovastatin, R1 = H;



R2



1b, Simvastatin, R1 = CH3.



R2



R3



RH



R3

H



H



1



– H2 O

OOH



O

R2



R2



R3



R3

H



H



RH



1



R3

H



O2

OO



O



O



R2



R3

H



H



H



OOH

O



R3



R2



R3



R2



R2



O



O



O



Peroxide cleavage



H



H



H



R3



R2



R3



R2



R3



R2



Oligomerization

OO

O



O



O



Various epoxides and further degradants such as

R2

R3

R

R

2



3



H



H



OO



O



O



Scheme 3.21

Other examples of autooxidation involving a diene functionality include

lovastatin and simvastatin, which are the first and second generation HMGCoA reductase inhibitors used for the treatment of hypercholesterolemia. Both

drug substances have a diene functionality embedded in their ten-membered

fused ring core structures. This diene functionality is particularly reactive

towards free radical-mediated autooxidation in both solid and solution

states.94,95 Owing to the presence of various resonance forms of the initial

radical generated and their reactions with molecular oxygen and/or

among themselves, a great number of oxidative degradants can be produced

(Scheme 3.21).

Structural variations of the benzylic and allylic moieties, such as the CH

positions that are a to a carbon–heteroatom double bond or a to a heterocyclic

aromatic ring, are also susceptible to the same free radical-mediated autooxidation. For example, the anti-psychotic drug risperidone (Figure 3.4) contains a fused pyrimidin-4-one ring (ring A). The a-position (9-position) next to

the heterocyclic pyrimidin-4-one ring was found to undergo autooxidation in

bulk drug as well as in a tablet formulation, resulting in the formation of

9-hydroxyrisperidone as the main degradant.96 This degradant is also a metabolite of the drug.97 On the other hand, N-oxidation on the middle piperidine

ring also occurred; the N-oxide was the second most significant degradant.



68



Chapter 3



N

N



O

N



Ring A



F



The arrow indicates

the hydroxylation site

N



Figure 3.4



O



Structure of risperidone.



X



?



Y



O



Z

X



X



X

Y



Via N-Oxide?



Y



X



Y



O



Y

O



O

Z

Flupenthixol, X = S, Y = –CF3;

OH

Z=



N



Epoxide intermediate

from flupenthixol,

X = S, Y = –CF3;



N



Amitriptyline, X = –CH2CH2-, Y = H,

CH3



Z=



Diene intermediates



Trifluoromethylthioxanthone,

X = S, Y = –CF3;

Dibenzosuberone,

X = –CH2CH2-, Y = H.



No epoxide intermediate

from amitriptyline could

be isolated



N

CH3



Scheme 3.22



3.5.2 Double Bonds Susceptible to Addition by Hydroperoxides

During stress testing under autoclaving conditions (B115 1C for up to 6 hours),

the aqueous solutions of two tricyclic drugs, flupenthixol (dihydrochloride salt)

and amitriptyline (hydrochloride salt) in neutral buffers displayed similar

degradation patterns.98,99 Analogous tricyclic ketones, namely trifluoromethylthioxanthone and dibenzosuberone, were formed respectively

(Scheme 3.22). It would be intuitive to postulate that the formation of the

tricyclic ketones may be mediated through an epoxide intermediate of the

parent drugs via the electrophilic oxygen transfer process as shown in the upper

pathway of Scheme 3.22, the mechanism of which has been discussed above

in Section 3.3.2. Nevertheless, such an intermediate could not be isolated in

either case, although an epoxide formed from an intermediary degradant of

flupenthixol was isolated. The latter epoxide quickly decomposed to the



69



Oxidative Degradation



corresponding tricyclic ketone, trifluoromethylthioxanthone upon exposure to

air. This observation, along with the fact that a few other intermediary

degradants were also seen during the stress test, led the authors to propose a

stepwise degradation pathway leading to the final formation of the tricyclic

ketones (Scheme 3.22).

In the course of a liquid and tablet formulation study of tiagabine, a potent

inhibitor of gamma-aminobutyric acid (GABA) uptake for the treatment of

epilepsy, two major degradants, dihydroxytiagabine and ketotiagabine, were

observed.100 The formation of dihydroxytiagabine is most likely to take place

via a transient epoxide intermediate, while ketotiagabine appears to be a further

dehydration degradant of dihydroxytiagabine (Scheme 3.23).

The indole ring is an important functional moiety that is present in the amino

acid, tryptophan; its UV absorption property is mostly responsible for the

absorbance of proteins at 280 nm, a wavelength widely used for protein

detection and assays. The indole ring also exists in many natural products,

fragrances, as well as drugs. Part of the fused pyrrole ring in indole can be

considered to be an embedded enamine moiety. As such, the double bond in the

fused pyrrole ring is quite electron-rich and hence susceptible to oxidation by

hydroperoxides. The oxidation proceeds via nucleophilic attack of the double

bond with hydroperoxide (or electrophilic oxygen transfer from the perspective

of hydroperoxide). The resulting epoxide usually further degrades into various

final degradants depending upon the structures connecting to the indole ring.

For example, epoxides of simple alkyl-substituted indoles decompose to

2-oxindoles101 (Scheme 3.24).

Nevertheless, during a hydrogen peroxide stress study of indomethacin, a

non-steroidal anti-inflammatory drug containing a 5-methoxyindole ring, two

major degradants were produced, which can be rationalized as being formed



S



S



S



S



S

S

HO



S

H 2O



O



S

O



HO

N



Tiagabine



N

CO2H



H2O



N



N

CO2H



CO2H



CO2H



Scheme 3.23



R



R



R

R'O-OH

O



N

H

3-Alkylated indoles,

R = Alkyl groups



Scheme 3.24



N

H



H



H 2,3-shift

N

H



O



70



Chapter 3

H3CO



O



N

a

ift

ay -sh

thw 2,3

Pa thyl

Me



OH



O



O



X



Cl



c

H3CO



O



N



OH



H3CO



O

O



HO-OH



N



O



c



b



O



b



c



HO



H3CO



O



Pathway b



O



N



H



O



O



Cl



Cl



Indomethacin



Pa

De thwa

ca y c

rbo

xyl

a



Cl

tio



n H3CO



O

NH

O

Cl



Scheme 3.25



O



O



N



Cl



O



N

N

HO-OH



Cl



N



NH



Cl



OH

O



H2 O



N

O



Scheme 3.26

from the epoxide intermediate through pathways that differ from Scheme

3.24.102 The expected methyl 2,3-shift (pathway a, Scheme 3.25) did not occur.

As mentioned above, drugs containing electron-deficient double bonds can

undergo epoxidation through nucleophilic oxygen transfer from hydroperoxides. One example can probably be found in the hydrogen peroxide stress of

tetrazepam, a benzodiazepine used clinically as a myorelaxant. When the stress

was conducted at 40 1C in dark, the epoxide was formed as the only degradant.103 Owing to the presence of the conjugated imine moiety, the nucleophilic

oxygen transfer in Scheme 3.26 can be proposed.

In the degradation of a tablet formulation of tetrazepam, however, the

epoxide was observed only as a minor degradant, while the main degradation

that occurred was oxidation at the 3 0 -allylic position. This suggests that the

degradation pathway to the epoxide degradant in a tablet formulation may



71



Oxidative Degradation



proceed through a radical-mediated process. Indeed, stress on a tetrazepam

solution with a radical initiator, azobisisobutyronitrile (AIBN), generated a

degradation profile that is quite similar to that of the tablet formulation in an

accelerated stability study.103



3.5.3 Tertiary Amines

3.5.3.1



Formation of N-oxides via Nucleophilic Attack

on Hydrogen Peroxide



In the case of amine oxidation by hydrogen peroxide (or hydroperoxides in

general) via a nucleophilic pathway (Scheme 3.27), tertiary alkyl amines are

most prone to producing N-oxides by oxidation, as discussed above in Section

3.3.1. The N-oxide of a tertiary alkyl amine is reasonably stable and in most

cases, can be isolated.

A great number of drugs have alkyl tertiary amine functionality and

hence are susceptible to autooxidation via the nucleophilic pathway shown in

Scheme 3.27 and subsequent degradation pathways. Tertiary amine drugs are

also susceptible to free radical-mediated autooxidation via the aminium cation

intermediate, which will be discussed in Section 3.5.3.3. A good class example

of the nucleophilic oxidative degradation can be found in phenothiazinederived drugs; there are more than two dozen such drugs according to a search

on the web site, http://drugbank.wishartlab.com.104 These drugs all contain a

tricylic phenothiazine ring with different substituents on the N atom of the ring.

The majority of the N-substituents contain either N,N-disubstituted piperazine

ring or acyclic tertiary amine moieties, most of which can be illustrated in

Figure 3.5 where the sites for N-oxide formation are indicated by arrows.

In this class of drugs, the sulfur in the tricyclic ring can compete with the side

chain tertiary amines for oxidation during the early stage of autooxidation.

Recently, Wang et al. reported a stress study of perphenazine solution in

methanol with hydrogen peroxide, which showed the formation of all the three

mono-oxidized degradants, that is, perphenazine 17N-oxide, perphenazine

14N-oxide, and perphenazine sulfoxide (Figure 3.6), in addition to lower levels

of dioxidized degradants.105

Among these degradants, 17N-oxide is most abundant in the early stage of

the stress; interestingly, 17N-oxide is also the most abundant oxidative

R1



R1

N



+



HO



OH



N



R2



R2

R3



Alkyl tertiary amine

R1, R2, R3 are

alkyl groups



Scheme 3.27



H2O

R3

N-Oxide



O



72



Chapter 3

R1

N

N



N



R1

R2



N



N



S



R2



S



Perphenazine, R1 = 2-hydroxyethyl, R2 = chloro;

Prochlorperazine, R1 = methyl, R2 = chloro;

Fluphenazine, R1 = 2-hydroxyethyl, R2 = trifluoromethyl;

Triethylperazine, R1 = methyl, R2 = ethylmercapto;

Carphenazine, R1 = 2-hydroxyethyl, R2 = propionyl;

Trifluoperazine, R1 = methyl, R2 = trifluoromethyl;

Thioproperazine, R1 = methyl, R2 = dimethylsulfamyl.



Chlorpromazine, R1 = hydrogen, R2 = chloro;

Trimeprazine, R1 = methyl, R2 = hydrogen;

Promazine, R1 = hydrogen, R2 = hydrogen;

Methotrimeparzine, R1 = (S)-methyl, R2 = methoxyl;

Triflupromazine, R1 = hydrogen, R2 = trifluoromethyl;

Acepromazine, R1 = hydrogen, R2 = acetyl;



The arrows indicate the N-oxidation sites.



Figure 3.5



Structures of phenothiazine-derived drugs.



N

N



Cl



S



OH

N



N



OH



N



N



O

N



Cl



S



Perphenazine 17N-oxide



Figure 3.6



O



OH



N



Perphenazine 14N-oxide



N



Cl



S

O



Perphenazine sulfoxide



Structures of three mono-oxidized degradants of perphenazine.



degradant in a solid formulation containing perphenazine. No oxidation

occurred on the aromatic nitrogen, as expected. This result is not in a complete

agreement with the stress study of perphenazine reported by Li et al.106

According to this study, perphenazine sulfoxide was observed as the only

mono-oxidized degradant.106 The discrepancy may be caused by one of the

following two factors: (1) the stress solution used by Li et al. is mostly aqueous,

which is quite different from the mostly methanolic solution employed by Wang

et al. (2) The two N-oxides might be formed in the stress by Li et al. but not

separated by the method they used.106

In a formulation study assessing pH effect on the control of N-oxidative

degradants, Freed et al. found that oxidation of alkyl tertiary amines by

hydroperoxides (including hydrogen peroxide in a few stress studies) can be

inhibited by lowering the pH of stress solutions or by acidifying solid dosage

formulations with citric acid.67 In one of their solution stress studies, it is

apparent that the pH of the solution needs to be controlled well below the pKa

of the tertiary amines in order to suppress the N-oxidation effectively.



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