An overview of the photoreactivity of pharmaceutical^ active compounds has been presented in Sec. 2. It is certainly desirable that the photoreactivity of every molecule used as a drug is investigated, in particular since this should alert about the possibility that the drug is phototoxic. However, this does not imply that every compound found to be reactive under some condition must be considered photolabile during normal storage or use conditions.

First of all, many drug substances do not significantly absorb ambient light (solar or artificial) and are sensitive only to irradiation at a shorter wavelength. In such a case it should at any rate be checked that no other component of the drug preparation, such as an associated drug or an eccipient, sensitises a reaction of an otherwise photostable substrate. As an example, an added ketone may abstract a hydrogen from such a substrate and initiate radicalic decomposition or another additive may sensitise oxygen and thus promote a photo-oxidation (many dyes are good oxygen sensitisers).283 On the other hand, an additive present in the formulation may also affect positively the photostability of the active principle (see Sec. 4).

Even when the drug is not transparent to ambient light, absorption (and consequently photoreaction) may not involve a significant fraction of the substrate. In a dilute solution, absorption takes place across the bulk of the solution, as it is apparent by inspection of Beer-Lambert's equation (see p. 82). This is, as it has been mentioned, the best condition for studying the photochemical reaction occurring. However, this does not apply to concentrated solutions, where absorption occurs only at the thin layer at the interface, for suspensions,

where part of the light is lost by reflection, or for solids, where again light is completely absorbed by the first thin layers of molecules.

Therefore, the photochemical study of a new drug should proceed along two lines. On one hand an investigation should be carried out under the best conditions for characterising the photochemical reactions, viz in dilute solutions (see e.g. the protocol proposed by Beijersbergen, p. 85) with the main aim of recognising the photoproducts and of evidencing a possible phototoxicity in an early stage of the development. On the other hand, in order to establish the stability of the dosage form the investigation must be extended to the actual pharmaceutical form and be carried out under conditions representative of those under which the drug is used and the illumination conditions to which it will be exposed. This demands that one takes care of photostability, as a part of stability studies in general, at the preformulation and formulation stage.284

In the present section two key points concerning the dependence of photochemical reaction on the conditions under which drugs are prepared or used are briefly addressed. These are solid state vs solution and anaerobic vs aerobic conditions.

3.1.1 Photoreactions in the Solid State. The different chemistry occurring by irradiating a drug in the solid state vs the solution for most drugs (and in general most molecules) has been often mentioned in Sec. 1 (see e.g. Schemes 13, 15, 28, 42). According to the different light penetration in the crystal, two different situations may arise.

1. The first case is characterised by the fact that penetration does not increase with reaction. This may be either because the photoproducts absorb themselves, thus screening the bulk of the solid from light or because loss or change of the crystalline form with reaction leads to reflection of all the light. In this case the photoreaction is limited to the first molecular layers at the surface. This may lead to a change in the appearance of the preparation, e. g. a conspicuous coloration or discoloration (usually evaluated by tristimulus colorimetry),285' 286 but may involve no serious loss of the active principle as evidenced by the appropriate assay (of course the change of colour may be unacceptable per se and force to suitably protect the preparation). Indeed, several drugs are quite sensitive in dilute solution but rather stable in the solid [e.g. indomethacin (13),19> 32 some steroids, e.g. (146),162 dilthiazem (122),132 minoxidil (123)].133 In some of these reactions the conversion proceeds up to some percent conversion and new product(s) are formed in a detectable concentration, although the reaction stops when only a fraction of the substrate is consumed. As an example, photoinduced hydrogen abstraction followed by oxygen addition to give a hydroperoxide proceeds up to ca 10% conversion by irradiating the crystalline penem derivative (197) as shown in Scheme 56. Likewise, in most reactions of steroids in the solid state (see e. g. Schemes 20 and 21) the product is formed only in a few percent yield.

2. In the latter case the photoproduct is transparent at some wavelength absorbed by the substrate. Thus, light penetrates through successive layers while the reaction proceeds and a significant part of the crystal, or the whole of it, may be transformed. This is the case for it cycloaddition processes, as in the cases of cynnamic acid287 and of thymine,288 where the adducts absorb at a much shorter wavelength than the reagents, but applies to every reaction satisfying the above criterion. Menadione offers another case of photodimerisation, where the stereoisomers obtained in the solid state differ from those obtained in solution (Scheme 77).

Schemes 20, 21 and 56 quoted above show that reactions in the solid state and in solution often involve a different moiety in the molecule, since restrictions imposed by the crystal lattice to molecular motions preclude some otherwise viable paths and vice versa introduce new paths involving interaction between functions that are close one to another in the solid state (topochemical control).289 There are several other examples, such as those of estrogens (Scheme 42) and of some benzodiazepines (Scheme 28). In several cases intra- or intermolecular (between two closely stacked molecules) hydrogen abstraction predominates in the crystals, whereas different reactions are observed in solution (e.g. aminopyrine, Scheme 13, as well as the penem in Scheme 56 above). Azapropazone (Scheme 15) shows sigmatropic shift occurring only in the solid state.

However, even when the photochemical process remains the same, the lattice constraint may still change the end result. A typical example is that of metyrapone (309), a diagnostic aid for pituitary function determination. As one may expect from the structure this ketone undergoes a very fast (xT 12 ns) a cleavage from the mt* triplet state to give a pair of radicals. In solution, the two fragments migrate and give different reactions, the main one being recombination in the para position to give conjugated alkene (310) and a polymer from it. This reaction is little affected by the nature of the solvent and the presence of oxygen.290

Polymer n n




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