Major degradation pathways include hydrolysis, oxidation, and photolysis.
Drug degradation
pathways
Major
degradation pathways include hydrolysis, oxidation, and photolysis.
Hydrolysis
is the common degradation pathway of carboxylic acid derivatives, such as
esters, amides, lactams, lactones, imides, and oximes (Figure
7.7).
Figure 7.7 Chemical groups susceptible to hydrolysis.
An
ester hydrolysis pathway may involve, for example, nucleophilic attack of
hydroxyl oxygen on the electropositive carbon, followed by breakage of the
labile bond in the parent compound.
Hydrolysis
is generally acid- and/or base-catalyzed, which becomes evi-dent when pH–rate
profile is constructed. Drugs that contain ester linkages include
acetylsalicylic acid (aspirin), physostigmine, methyldopa, tetracy-cline, and
procaine. Hydrolysis of the ester linkage in atropine and aspirin are shown in Figures 7.8 and 7.9,
respectively, with their typical pH–rate profiles. In case of atropine, below
pH 3, the main reaction is hydrogen-ion-catalyzed hydrolysis of the protonated
form of atropine. Above pH 5, the main reaction is hydroxide-ion-catalyzed
hydrolysis of the same species. The pH of maximum stability of atropine is 3.7.
Figure 7.8 Hydrolysis of atropine. (a) Hydrolytic reaction scheme and (b)
hydrolysis rate of atropine as a function of pH.
Figure 7.9 Hydrolysis of aspirin. (a) Hydrolytic reaction scheme and (b)
hydrolysis rate of aspirin as a function of pH.
Another
chemical structure commonly found in pharmaceuticals is the amide group. It is
considerably more stable than the ester group to hydro-lysis under normal
physiological conditions but can be broken down at extreme pH. The greater
stability of the amide group, compared with the ester group, is due to the
lower positive-charge density on the electroposi-tive carbon. Hydrolysis of the
amide group can be represented as:
Chloramphenicol
decomposition below pH 7 proceeds primarily through hydrolytic cleavage of the
amide function. Antibiotics possessing the β-lactam structure, which is a
cyclic amide, are hydrolyzed rapidly by ring
opening of the β-lactam
group. Penicillins and cephalosporins belong to this category. The
decomposition of these compounds in aqueous solution is catalyzed by hydrogen
ion, solvent, hydroxide ion, and sugars. Deamidation and isomerization of
asparaginyl residues are the major hydrolytic degrada-tion reactions in
proteins.
Hydrolysis
is frequently catalyzed by hydrogen ions (specific-acid catalysis) or hydroxyl
ions (specific-base catalysis) or both (specific-acid–base catalysis).
Hydrolysis can be minimized by determining the pH of maximal stability and then
formulating the drug product at this pH.
For
solid formulations, minimizing the exposure of the drug product to moisture
during manufacture and shelf life storage can minimize hydrolytic drug
degradation. Moisture content should be as minimal as possible in solid dosage
forms containing drugs susceptible to hydrolysis. In addition, desiccants may be used in drug product
packages, such as bottles, for stor-age over the product shelf life.
For
liquid formulations, reduction of the dielectric constant of the vehicle by the
addition of nonaqueous cosolvents
such as alcohol, glyc-erin, and propylene glycol may reduce hydrolysis. Another
strategy to suppress hydrolysis is to make the drug less soluble. For example, the stability of penicillin in
procaine–penicillin suspensions was signifi-cantly increased by reducing its
solubility by using additives such as citrates, dextrose, sorbitol, and
gluconate. Complexation of drugs with
excipients, such as cyclodextrins, may also reduce hydrolysis. For exam-ple,
the addition of caffeine to the aqueous solutions of benzocaine, procaine, and
tetracaine was shown to decrease their base-catalyzed hydrolysis.
After
hydrolysis, oxidation is the next most common pathway for drug deg-radation.
Oxidation usually involves a reaction with oxygen. As illustrated below and in Figure 7.10, oxygen exists in two states: the ground
or the triplet state, which contains two unpaired electrons in the outer
molecular orbitals, and the singlet state, which contains all paired electrons.
The * in the following molecular
orbital notation and Figure 7.10 indicates
anti-bonding molecular orbitals.
Oxygen
atom: O (total electrons = 16) 1s2, 2s2, 2px2, 2py1, 2pz1
Oxygen
molecule: O2 (total
electrons = 16)
Triplet/ground
state: 1s2, 1s*2, 2s2, 2s*2, 2px2, 2py2, 2pz2, 2px*1, 2py*1, 2pz*0
Singlet/excited
state: 1s2, 1s*2, 2s2, 2s*2, 2px2, 2py2, 2pz2, 2px*2,2py*0, 2pz*0
Figure 7.10 Molecular orbital illustration of the triplet and singlet states of
oxygen molecule.
Most
organic compounds are in the singlet state (with paired electrons). Most
organic molecules are in the paired singlet state, which is their ground state.
According to the molecular orbital theory of conservation of spin angular
momentum of electrons, reactions between two molecules in the singlet state are
favored, but not of a molecule in the singlet state with another molecule in
the triplet state. Therefore, the atmospheric oxygen (triplet state) is
unreactive. However, oxygen can be excited to singlet state both chemically and
photochemically, leading to its higher reactivity, lead-ing to oxidation reactions.
Oxidation
in small-molecule drugs often involves free radical-mediated autocatalytic
reaction initiated by the abstraction of hydrogen from the carbon next to a
heteroatom, followed by reaction with oxygen to form a peroxide free radical.
In addition, direct nucleophilic attack of the lone pair of electrons on the
nitrogen can lead to N-oxide formation. Steroids and sterols represent an
important class of drugs that are subject to oxida-tive degradation through the
carbon–carbon double bonds, to which per-oxyl radicals can readily add.
Similarly, polyunsaturated fatty acids are susceptible to oxidation. Polyene
antibiotics, such as amphotericin B, which contains seven conjugated double
bonds, are subject to attack by peroxyl radicals, leading to aggregation and
loss of activity. In proteins, several electron-rich functional groups are
susceptible to oxidation, such as sulfhy-dryl in cysteine, imidazole in
histidine, thioether in methionine, phenol in tyrosine, and indole in
tryptophan.
Oxidation
can involve coordination of the lone pair of electron on the nitrogen to oxygen
to form N-oxide or free-radical autoxidation mecha-nism. The electron transfer
or nucleophilic reactions are exemplified by peroxide anion reactions under
basic conditions. Free radical-mediated oxi-dation reactions tend to be
self-propagating until the substrate is depleted. These reactions could be
initiated by the presence of an initiator, such as heavy metal, peroxides, and
oxygen, along with environmental stresses such as heat and light. Termination
of free radical-mediated oxidative reac-tions involves bimolecular reactions of
radicals with another species, such as another free radical or a stabilizing
conjugated system, to produce non-reactive products. Free radical reactions are
characterized by a delay or lag time in
their detection, which corresponds to the time required for the gradual build-up of free radicals in
the system.
Oxidation
is frequently catalyzed by transition metal contaminants (e.g., Fe2+/Fe3+
and Cu+/Cu2+). The reacting metal species is regenerated
in these reaction systems, commonly known as Fenton’s systems.
The
free radical formed can react with oxygen to produce a peroxide radi-cal, and
the reaction propagates as:
Peroxides
(ROOR’) and hydroperoxides (ROOH) are photolabile, breaking down into hydroxyl
(HO•) and/or alkoxyl (RO•) radicals, which are them-selves highly oxidizing
species. The free radical reaction continues until all the free radicals are
consumed or destroyed by inhibitors or by side reactions, which eventually
break the chain. Reaction termination involves reactions of two free radicals
to form nonfree radical end products.
Oxidation
reaction proceeds until the substrate is consumed and/or the free radicals are
destroyed by inhibitors or by side reactions, which eventually break the chain.
The stabilization strategies for free radical-mediated oxi-dative degradation
involve either or both:
·
Inhibiting the initiation and/or propagation phases
·
Promoting chain termination
Antioxidants
are commonly used in formulations of susceptible compounds to stabilize drug
products. Antioxidants can be categorized into three gen-eral categories based
on their mechanism of action:
1. Inhibitors of
initiation:
Compounds that prevent the initiation phase
of the free radical-mediated chain reaction and/or remove catalytic
initiators. These are exemplified by the chelating agents, such as
eth-ylenediaminetetraacetic acid (EDTA).
2. Free radical
terminators:
Compounds that react with free radicals and
inhibit the propagation phase of the free radical chain reaction. These are
exemplified by butylated hydroxyanisole (BHA) and butyl-ated hydroxytoluene
(BHT).
3. Reducing agents: Compounds that
possess lower redox potential than the
oxidation substrate in the formulation, thereby acting as a reduc-ing agent by
getting preferentially oxidized. These are exemplified by ascorbic acid, thiols
(such as thioglycerol and thioglycolic acid), and polyphenols (such as propyl
gallate).
In
addition to the use of antioxidants, replacement of headspace oxygen in
pharmaceutical containers with an inert gas, such as nitrogen, can mini-mize
oxidation. The use of chelating agents, such as EDTA, and minimized content of
heavy metal ions, such as iron, cobalt, and nickel, can prevent metal-catalyzed
oxidation. Other approaches to minimize oxidation include the use of opaque or
amber containers when light-induced photooxidation is involved.
Many
pharmaceutical compounds, including phenothiazine tranquiliz-ers,
hydrocortisone, prednisolone, riboflavin, ascorbic acid, and folic acid,
degrade on exposure to light. Some light-sensitive functional groups such as
indole in tryptophan can adsorb energy from light illumination and form
electronically excited species with high reactivity. The most common
pho-todegradation of proteins is photo-induced autoxidation. The amino acids
susceptible to photooxidation are His, Trp, Met, and Cys.
Light
is a form of electromagnetic radiation, with energy given by:
E = hν = hc
/ λ (7.68)
where:
E is the energy
h is the Plank’s
constant
c is the speed of
light (3 × 108 m/sec)
λ is the frequency of light λ is the wavelength of light
Lower
the wavelength, higher the frequency and more the energy in the radiation.
Absorption of electromagnetic radiation by a molecule causes excitation of
electrons and thus higher reactivity of the molecule. As this molecule loses
energy to come back to the ground state, it can transfer that energy to another
molecule in its vicinity. This process is called photosen-sitization. Thus, a molecule that does not directly absorb
light (but acts as an acceptor of
energy quanta) can be excited in the presence of a light-absorbing molecule
(which acts as a donor of energy quanta). The acceptor molecule, thus, is
frequently termed a quencher, since
it relaxes the excited state of the donor molecule.
Colored
compounds absorb light of lower wavelength and emit it at higher wavelength.
Thus, colored compounds are usually susceptible to photolytic degradation. In
addition, photolysis of a drug substance frequently leads to discoloration, in
addition to chemical degradation.
Light
also causes electronic transition of the low-reactive triplet state of oxygen
to the higher-reactive singlet state. In addition, the excited triplet state of
organic molecules can react with the ground triplet state of oxygen. Thus,
oxidation very often accompanies photooxidation in the presence of oxygen and
light.
Photooxidation
processes can be of two types. Type I
photooxidation, also called an electron transfer or free radical process,
involves transfer of an electron or a proton by the light-absorbing donor to
the acceptor, thus converting the acceptor to a reactive anion or neutral
radical. The reactive acceptor then reacts with triplet-state oxygen. In Type II photooxidation, ground-state
triplet molecular oxygen acts as a quencher of the excited singlet or triplet
states of organic molecules, thus absorbing energy to convert itself to the
excited-state singlet molecular oxygen. The singlet molecular oxygen is more
reactive, since it has similar spin state as ground-state organic molecules.
Control
strategies to prevent photodegradation of drugs can include the use of
amber-colored glass containers and storage in the dark. Amber glass excludes
light of wavelength less than 470 nm and protects drugs sensitive to
ultraviolet light. In addition, application of primary barrier on the dos-age
form, such as film coating of tablets, can prevent drug degradation. For
example, film coating of tablets with vinyl acetate containing oxybenzone
prevents discoloration and photolytic degradation of sulfasomidine tablets.
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