Polyunsaturated fatty acids, commonly used in drug formulations, are particularly susceptible to oxidation, and care must be exercised to minimize degradation in formulations containing high concentrations of, for example, vegetable oils (31).
The oxidation of phenothiazines to the sulfoxide involves two single-electron transfer reactions involving a radical cation intermediate; the sulfoxide is subsequently formed by reaction of the cation with water (32).
The ether group in drugs such as econazole nitrate and miconazole nitrate is susceptible to oxidation. The process involves removal of hydrogen from the C-H bonds in the a-position to the oxygen to produce a radical, which further degrades to a-hydroperoxides and eventually to aldehydes, ketones, alcohols, and carboxylic acids (33).
An obvious precaution to minimize oxidation is to avoid contact of the drug with ions such as iron, cobalt, or nickel that are initiators of the oxidation process. Similarly, the oxygen above the formulation should be replaced with nitrogen or carbon dioxide. Even traces of oxygen are, however, sufficient to initiate oxidation, and because it is difficult to remove all of the oxygen from a container, it is common practice to add low concentrations of antioxidants and chelating agents to protect drugs against autoxidation. Mechanistically, some antioxidants, such as ascorbic acid, ascorbyl palmitate, sodium bisulfite, sodium metabisulfite, sodium sulfite, acetone sodium bisulfite, sodium formaldehyde sulfoxylate, thioglycerol, and thioglycolic acid, act as reducing agents. They are easily oxidized, preferentially undergo autoxidation, thereby consuming oxygen and protecting the drug or excipient. They are often called oxygen scavengers because their autoxidation reaction consumes oxygen. They are particularly useful in closed systems in which the oxygen cannot be replaced once it is consumed. Primary or true antioxidants act by providing electrons or labile H, which will be accepted by any free radical to terminate the chain reaction. In pharmaceuticals, the most commonly used primary antioxidants are butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), the tocopherols (vitamin E), and propyl gallate. Chelating agents act by forming complexes with the heavy metal ions that are often required to initiate oxidation reactions. The chelating agents used most often are ethylenediaminetetraacetic acid (EDTA) derivatives and salts, citric acid, and tartaric acid.
Normal sunlight or room light may cause substantial degradation of drug molecules. The energy from light radiation must be absorbed by the molecules to cause a photolytic reaction, and if that energy is sufficient to achieve activation, degradation of the molecule is possible. Saturated molecules do not interact with visible or near-ultraviolet light, but molecules that contain p-electrons usually do absorb light throughout this wavelength range.
T0nnesen (34) has reviewed the mechanisms of photodecomposition of drugs, and an extensive list of common photoreactions of drug substances has been compiled by Greenhill and McLelland (35). Certain chemical functions are known to introduce photoreactivity, including carbonyl, nitroaromatic and N-oxide functions, aryl halides, alkenes, polyenes, and sulfides. Nevertheless, it is difficult to predict which drugs are likely to be susceptible to photodegradation. Examples of drugs that are known to degrade when exposed to light include the phenothiazine tranquillizers, hydrocortisone, prednisolone, riboflavine, ascorbic acid, and folic acid. Not only is there a loss of potency of the drug when photodegradation occurs, but there is often discoloration of the product or onset of precipitation. Because sunlight is able to penetrate the skin to a sufficient depth to cause photodegradation of drugs circulating in the surface capillaries or in the eyes of patients receiving the photolabile drug, photodecomposition might occur not only during storage, but also during usage of the product. An additional problem is that excipients in the formulation (so-called photosensitizers) may absorb radiation and transfer this absorbed energy to the drug causing its degradation. Consequently, when assessing photosensitivity of a pharmaceutical product, it is necessary to consider the formulation as a whole and not just the drug itself (36).
Photolysis reactions are often associated with oxidation because the latter category of reactions can frequently be initiated by light. But photolysis reactions are not restricted to oxidation. The mechanisms of photodegradation are of such complexity as to have been fully elucidated in only a few cases. For example, the photodegradation of ketoprofen (36) (Scheme 1) can involve decarboxylation to form an intermediate (reaction 1), which then undergoes reduction (reaction 2), or dimerization of the ketoprofen itself (reaction 3).
The photodegradation of sodium nitroprusside, Na2Fe(CN)5NO2H2O, in aqueous solution is believed to result from loss of the nitro-ligand from the molecule, followed by electronic rearrangement and hydration. Sodium nitroprusside is administered by IV infusion for the management of acute hypertension. On being exposed to normal room
light, a sodium nitroprusside solution has a shelf life of only four hours (37), but when protected from light by wrapping in an aluminum foil, sodium nitroprusside 50 or 100 mg/mL was found to be stable in 5% glucose, lactated Ringer's, and normal saline solutions for 48 hours (38).
Pharmaceutical products can be adequately protected from photo-induced decomposition by the use of colored glass containers and storage in the dark. Amber glass excludes light of wavelength <470 nm and so affords considerable protection of compounds sensitive to ultraviolet light. In the clinical administration of solutions of sodium nitroprusside, for example, the infusion container should be opaque or protected with foil, but an amber-giving set may be used, to allow visual monitoring (39). Coating tablets with a polymer film containing ultraviolet absorbers has been suggested as an additional method for protection from light. In this respect, a film coating of vinyl acetate containing oxybenzone as an ultraviolet absorber has been shown (40) to be effective in minimizing the discoloration and photolytic degradation of sulfasomidine tablets.
The racemization of pharmacologically active agents is of interest because enantiomers often have significantly different absorption, distribution, metabolism, and excretion, in addition to differing pharmacological actions (41). The best-known racemization reactions of drugs are those that involve epinephrine, pilocarpine, ergotamine, and tetracycline. In these drugs, the reaction mechanism appears to involve an intermediate carbonium ion or carbanion that is stabilized electronically by the neighboring substituent group. For example, in the racemization of pilocarpine (42), a carbanion is produced and stabilized by delocalization to the enolate. In addition to the racemization reaction, pilocarpine is also degraded through hydrolysis of the lactone ring.
Most racemization reactions are catalyzed by an acid or a base. For example, the isomerization of cephalosporin esters, which are widely used as intermediates in cephalosporin synthesis and as prodrugs for oral administration of parenteral cephalosporins, is base-catalyzed according to the following mechanism (43) (Scheme 2). A proton in the 2-position is abstracted by a base (B), and the resulting carbanion can be reprotonated in the 4-postion, giving a A2-ester. On hydrolysis, A2-cephalosporin esters yield A2-cephalosporins, which are biologically inactive.
A notable exception to the generality of acid-base-catalyzed reaction is the "spontaneous" racemization of the diuretic and antihypertensive agent, chlorthalidone, which undergoes facile SN1 solvolysis of its tertiary hydroxyl group to form a planar carbonium ion. Chiral configuration is then restored by nucleophilic attack (Sn2) of a molecule of water on the carbonium ion, with subsequent elimination of a proton (44).
Was this article helpful?
Do You Suffer From High Blood Pressure? Do You Feel Like This Silent Killer Might Be Stalking You? Have you been diagnosed or pre-hypertension and hypertension? Then JOIN THE CROWD Nearly 1 in 3 adults in the United States suffer from High Blood Pressure and only 1 in 3 adults are actually aware that they have it.