Stability, drugs free radicals

It is useful to be able to look at the structure of a drug molecule and be able to predict which sites, if any, in the molecule are susceptible to oxidative deterioration. To do this we must have an understanding of the ease of formation and the stability of free radical species. 

Chloroquine and hydroxychloroquine are used mainly in malaria (see Chapter 52) and in the rheumatic diseases. The mechanism of the antiinflammatory action of these drugs in rheumatic diseases is unclear. The following mechanisms have been proposed suppression of T-lymphocyte responses to mitogens, decreased leukocyte chemotaxis, stabilization of lysosomal enzymes, inhibition of DNA and RNA synthesis, and the trapping of free radicals. 

Peroxidation and free-radical formation should be considered as important aspects of pharmaceutical stability and quality of parenteral nutriton and intravenous drugs. Peroxidation and free-radical formation depend on environmental factors, such as storage conditions and container material, but are also influenced by formulation components or additives such as tocopherols and metabisulfite. Since the generation of these harmful species occurs generally at the time of use, manufacturing quality controls fail in demonstrating their existence. 

Antioxidants are very effective in stabilizing products undergoing a free-radical mediated chain reaction. These products possess lower oxidation potentials than the active drug. Ideally, antioxidants are stable over a wide pH range and remain soluble in the oxidized form, colorless, and nontoxic. A listing of commonly used antioxidants can be found in Table 3. 

Vitamin E has been shown, in a wide range of studies, to be capable of affording considerable protection to cells exposed to free radical attack, either from pathological or drug-induced sources. In injured nervous tissue, vitamin E probably exerts its protective effect by scavenging free radicals, stabilizing cellular membranes and quenching the cascade of biochemical events that... 

Oxidative stress or imbalance between formation and deactivation of free radicals is considered to be one of the main causes of many known human diseases.1,2 Vitamins E and C are among the most attractive objects for prophylactic drug development.2,3 Aside from being natural antioxidants of direct action, their combination results in a synergistic effect.4 However, obtaining stable formulations remains a challenge since these vitamins are readily oxidized in a liquid medium. Immobilization of such biomolecules on solid surfaces may result in enhanced stabilization. 

The pharmacology of these drugs, which are also used in the treatment of malaria, is presented on p. 351. The mechanism of their anti-inflammatory activity is uncertain. Besides inhibiting nucleic acid synthesis, they are known to stabilize lysosomal membranes and trap free radicals. In treating inflammatory disorders, they are reserved for rheumatoid arthritis that has been unresponsive to the NSAIDs or else they are used in conjunction with an NSAID, which allows a lower dose of chloroquine or hydroxychloroquine to be administered. These drugs have been shown to slow progression of erosive bone lesions and may induce remission. They do cause serious adverse effects (see p. 351). 

These reactive species will likely attack and decompose the drug or excipients in the formulation. This was demonstrated for primaquine (Kristensen et al., 1998), which can be photochemically stabilized by an inert atmosphere. Photo-oxidation reactions of type I (free radical) or type II (singlet oxygen) mechanisms can take place simultaneously in a competitive fashion. Oxygen concentration and the properties of the vehicle are factors influencing the distribution between the two processes. Free radical reactions are favored by polar vehicles such as water. 

In practical terms, terminal sterilization of liquid parenteral products means sterilizaticMi by saturated steam. Production of free radicals in water prohibits the application of radiation sterilization to aqueous products, but radiation sterilization may be suitable for some solid dosage forms. Dry heat and ethylene oxide are unlikely to be of any value. In the first instance, therefore, saturated steam should be the process of first choice for sterilization of thermally stable drug substances dosage forms should not be formulated in ways that compromise thermal stability. 

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