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Modification of chemical structure of drug

The control of drug stability by modifying chemical structure using appropriate sub-stituents has been suggested for drugs for which such a modification does not reduce therapeutic efficacy. The Hammett linear free energy relationship for the effect of substituents on the rates of aromatic side-chain reactions, such as the hydrolysis of esters, is given by log k = log k0 + op (4.1)

Oxidation processes

Oxidation involves the removal of an electropositive atom, radical or electron, or the addition of an electronegative atom or radical. Oxidative degradation can occur by autoxidation, in which reaction is uncatalysed and proceeds quite slowly under the influence of molecular oxygen, or may involve chain processes consisting of three concurrent reactions - initiation, propagation and termination. Initiation can be via free radicals formed from organic compounds by the action of light, heat or transition metals such as copper and iron which are present in trace amounts in almost every buffer. The propagation stage of the reaction involves the combination of molecular oxygen with the free radical R' to form a peroxy radical ROO', which then removes H from a molecule of the organic compound to form a hydroperoxide, ROOH, and in so doing creates a new free radical (Scheme 4.4).

The reaction proceeds until the free radicals are destroyed by inhibitors or by side-reactions which eventually break the chain. The rancid odour which is a characteristic of oxidised fats and oils is due to aldehydes, ketones and short-chain fatty acids which are the breakdown products of the hydroperoxides. Peroxides (ROOR') and hydroperoxides (ROOH) are photolabile, breaking down to hydroxyl (HO') and/or alkoxyl (RO') radicals, which are themselves highly oxidising species. The presence of residual peroxides in polyoxyethylene glycols (PEGs) is a cause for concern when these excipients are used in formulation, as for example in the case of fenprostalene. 4

Drugs susceptible to oxidation

We will consider some examples of drugs and excipients that are subject to oxidative degradation owing to the possession of functional groups that are particularly sensitive to oxidation.

Termination: ROO' + ROO' —stable product ROO' + R' —»- stable product R' + R' —stable product

Scheme 4.4 Simplified oxidation scheme involving a chain process.

Steroids and sterols represent an important class of drugs that are subject to oxidative degradation through the possession of carboncarbon double bonds (alkene moieties) to which peroxyl radicals can readily add. Similarly, polyunsaturated fatty acids, commonly used in drug formulations, are particularly susceptible to oxidation and care must be exercised to minimise degradation in formulations containing high concentrations of, for example, vegetable oils.5 For drugs, such as the cholesterol-lowering agent simvastatin (I), that contain conjugated double bonds, addition of peroxyl radicals may lead to the formation of polymeric peroxides (simvastatin polymerises up to a pentamer6), cleavage of which produces epoxides which may further degrade into aldehydes or ketones.

Polyene antibiotics, such as amphotericin B (II) which contains seven conjugated double bonds (heptaene moiety), are subject to attack by peroxyl radicals, leading to aggregation and loss of activity.7

The oxidation of phenothiazines to the sulfoxide involves two single-electron transfer reactions involving a radical cation intermediate as shown in Scheme 4.5. The sulfoxide is subsequently formed by reaction of the cation with water.

The ether group in drugs such as econazole nitrate (III) and miconazole nitrate (IV) is susceptible to oxidation. The process involves removal of hydrogen from the C-H bonds in the a-position to the oxygen to produce radicals, which further degrade to a-hydroperox-ides and eventually to aldehydes, ketones, alcohols and carboxylic acids.

Structure I Simvastatin

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