Drug degradation pathways

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Chapter: Pharmaceutical Drugs and Dosage: Chemical kinetics and stability

Major degradation pathways include hydrolysis, oxidation, and photolysis.


Drug degradation pathways

Major degradation pathways include hydrolysis, oxidation, and photolysis.


Hydrolysis

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.

Ester 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.

Amide hydrolysis

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.

Control of drug hydrolysis

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.


Oxidation

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.

Control of drug oxidation

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.


Photolysis

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 of photodegradation of drugs

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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