Introduction

Although many pharmaceutical compounds are know to be unstable to light,1 few studies have detailed the precise chemical and physical properties that determine the susceptibilities and the resulting degradation products and their levels.2»3 Although oral pharmaceutical products may be stored in amber bottles and topical products in opaque tubes, topical products are spread onto skin where they may become exposed to sunlight and hence protection for such products by the packaging is not the only consideration and factors around the stability of the product in use should be considered.

It is important that modern analytical assay and impurity profile methods for drug substances and products be stability indicating in that they should be selective for all known degradation products. In this way, a detailed and rational study of the susceptibility of the products to photodegradation may be made in order to provide important information to help design a stable dosage form.

Compounds (1), (2) and (3) shown in Figure 1, are Leukotriene B4 antagonists which have been in development for use as potential topical drugs for the treatment of psoriasis. Since psoriatic patients often expose their skin to sunlight to improve their condition, the light stability of any topical drug indicated for Psoriasis is very important. The guideline for testing the light-stability of drugs in the solid state is exposure for 1.2 million lux hours.4 This is usually carried out by exposing a sample of the drug to high intensity light sources such as a xenon discharge lamp for up to 24 hours. The conditions are designed to simulate sunlight through a glass window by using a suitable glass filter giving significant radiation at wavelengths longer than 320.5 nm. '6

Compounds (1), (2) and (3), were exposed for varying periods in solution in acetonitrile and in the solid state to both xenon light and south light. The latter exposure was carried out by placing the samples of a south facing window ledge. After irradiation the samples were analysed using a number of methods. A relative assay and impurity profile for related compounds was carried out using high performance liquid chromatography (HPLC) and backed up by capillary electrophoresis (CE). Gel permeation chromatography (GPC) and thin layer chromatography(TLC) were also used to search for potential high molecular weight and non-ultraviolet radiation absorbing degradation products. These separation techniques were used in conjunction with a variety of detection systems such as ultraviolet (UV), fluorescence and refractive index (RI). Extensive use of coupled liquid chromatography/mass spectrometry (LC/MS) was also made. Other spectroscopic techniques such as infrared spectroscopy (IR) and nuclear magnetic resonance spectroscopy (NMR) were used to look for any physical and chemical changes.

Figure 1 Structure of (1), (2), and (3).

The aim of this work was to assess the light stability of the test compounds in solution and in the solid state and to identify and account for all the degradation products. This information was used to try and explain the chemical and physical properties that affect the light stability. A wide range of techniques were used since, even with structurally related compounds, a varying range of degradation products may be formed.

Table 1 compares the loss of HPLC area of (1), (2) and (3) after irradiation in solution in acetonitrile. In all three cases the loss of assay is accounted for by other peaks in the chromatogram as can be seen from Figure 2. In the cases of (1) and (2) the major dégradant is the formation of the ¿'-isomer of the pyridine acrylate moiety. In the case of compound (3) there is no pyridine acrylate system and a large number of minor dégradants occur which account for the observed loss in main peak area. The pyridine acrylate moiety is clearly a major factor in the stability of the compounds as its presence gives rise to a UV absorption band with significant absorption at wavelengths greater than 320nm. Light degradation will only follow absorption of light from an electronic transition within the molecule of interest. This strong absorption followed by subsequent isomerisation in the presence of light explains why (1) and (2) are less stable to light in solution than (3). The reverse phase HPLC method is able to account for the all the products of degradation.

Table 1 The loss in peak area of (1), (2) and (3) in solution in acetonitrile (0.01% w/v)

% HPLC main peak area loss after 3 hours in natural light 25% 38% 3% % HPLC main peak area loss after 5 minutes in xenon light 42% 67%_12%

3 LIGHT STRESSING OF (I), (2) AND (3) IN THE SOLID STATE

Relative stability in the solid state is much more difficult to measure, control and explain than equivalent measurements in solution. It is difficult to measure because any comparative study must ensure identical or near identical exposure for each sample. For this to be controlled the particle size and shape for each compound must be the same, as must be the bulk densities and the area of each sample exposed. Since it is almost impossible to achieve such similarities, any direct comparisons must be interpreted with care and only broad differences and trends taken into account. Table 2 presents data following the exposure of solid samples of (1), (2) and (3) to xenon light. The samples were spread thinly between two glass plates in order to provide a consistent surface for exposure between samples. Only gross differences in stability were compared and therefore no accurate comparisons of particle size and morphology were made. In the case of compound (2), two polymorphic forms of this compound are known and both were exposed to xenon light. The results in terms of loss of HPLC area are summarized in Table 2.

Given the dramatic loss of HPLC peak area for (2) form I using xenon light, the sample was exposed to diffuse light for a period of 24 hours. In this experiment a sample was placed beneath a bank of fluorescent light tubes with a plastic diffuser between light source and sample. Such conditions simulate light stability under normal handling conditions albeit for an extended period. Under these conditions (2) form I degraded by approximately 4% to the same dégradant as was formed under xenon light (see discussion in 3 .1).

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