Photolabile product

An elegant publication from Aman and Thoma [84] outlined the various options open to the stabilisation of photolabile oral products. The addition of lightabsorbing agents is a well-established approach to stabilising photolabile products [85]. Aman and Thoma [84] reported that the incorporation of light-absorbers and pigments considerably improved the photostability of the very light sensitive... 

In Figure 7 we see the attenuating effect of clothing, both black and white, on the photostability of a photolabile product. This is important to note because clothing is not a 100% protector against solar radiation. 

As described in the previous sections, plastic and glass containers used for the production of parenterals offer little or no protection against optical irradiation (Figure 14.1). It is therefore important to protect photolabile products from sunlight and artificial light sources by using an outer, nontransparent container or a colored outer bag, or wrapping with aluminum foil. 

Dehydrotestosterone acetate (174) in nonprotic solvents (dioxane, benzene) undergoes a rearrangement to the isomer (175). This product is photolabile and isomerizes readily to new cross-conjugated dienones. Thus, ultraviolet irradiation of (174), its 1-, 2- and 4-methyl homologs, and its lOa-stereoisomer (188) in dioxane solution causes, in each case, a series of rearrangements as summarized on page 331 for (174) and (188). ... 

Photolabile linkers play an important role in solid-phase organic synthesis (SPOS) due to their stability under both acidic and basic conditions. The ONb photolabile linker was modified to improve cleavage rates and yields Fmoc-Tos-OFI was released in 87% yield after 23 h (Scheme 4) [24]. Specifically, the primary alcohol was changed to a secondary benzylic alcohol and the attachment to the resin was through an alkyl chain as opposed to an amide function. Linker 20 was used for the production of carboxylic acids or carbohydrates. A second example... 

Carbene lv is photolabile, and 400 nm irradiation produces a mixture of products.108 By comparison with calculated IR spectra the major product was identified as cyclopropene 3v. The formation of 3v is irreversible, and it cannot be thermally (by annealing the matrix) nor photochemically converted back to carbene lv. The lv -> 3v rearrangement is calculated (B3LYP/6-31G(d) + ZPE) to be endothermic by only 5.4 kcal/mol with an activation barrier of 18.2 kcal/mol. Due to the two Si-C bonds in the five-membered ring of 3v this cyclopropene is less strained than 3s, which is reflected by the smaller destabilization relative to carbene lv. The thermal energy available at temperatures below 40 K is much too low to overcome the calculated barrier of 12.8 kcal/mol for the rearrangement of 3v back to lv, and consequently 3v is stable under the conditions of matrix isolation. 

There appear to be no reports of photodegradation of the hypnotic, methaqua-lone (323), but two of its metabolites are photolabile. The main metabolite, the A1-oxide (324), was photolysed at 366 nm or in sunlight to the oxaziridine (325) which could be isolated with care [184], Further degradation, either thermal or photochemical, gave the more readily isolated products (326) to (329). A mechanistic explanation for these observations was offered [185]. A solid second metabolite (330) rapidly turned maroon on exposure to laboratory light and an alcoholic solution became intensely coloured under a medium-pressure... 

Dichlorobenzidine was found to be extremely photolabile in water (Sikka et al. 1978 Banerjee et al. 1978). 3,3 -Dichlorobenzidine photolyzed yielding monoehlorobenzidine, benzidine, and a number of eolored, water-insoluble products. In natural sunlight, the half-life of 3,3 -dichlorobenzidine in water was determined to be approximately 90 seeonds. While 3,3 -diehlorobenzidine is very rapidly photolyzed rmder environmental conditions, the process may yield benzidine, a relatively photostable carcinogen (Banerjee et al. 1978). 

Benorylate (315) [4 -(acetamido)phenyl-2-acetoxybenzoate] is another example. It is the ester between two well-known antiinflamatory drugs, aspirin and paracetamol, and is employed in rheumatoid arthritis therapy. In view of the chemical structure with three photolabile groups (two esters and one amide), its possible phototoxicity has been investigated. From the preparative irradiations, it has been concluded that the PFR takes place with breaking of the central C—O bond to yield 5-acetamido-2 -acetoxy-2-hydroxybenzophenone (316). This product undergoes transacetylation to 5 -acetamido-2 -acetoxy-2-hydroxy-benzophenone (318) (Scheme 80) [300]. 

Several of the phenylene-linked carbenes and nitrenes exhibit photochemical or thermal reactivity in the matrix. The photolabile p- and m-phenylene-linked species give products of rather unexpected structures via mechanisms that are not understood yet. The o-phenylene-linked species isomerize rather easily either via ring opening of the phenylene linker or by an apparent direct reaction of the two proximal diradical centers to give ring-closure products. The available data... 

Sunlight (both in the UV and visible regions) may degrade dmg products and excipients, and, consequently, photolabile APIs can raise many formulation issues [72]. 

The 1,4-dUiydropyridines, for example, nifedipine, nicardipine and amlodip-ine, are a well-established class of anti-hypertensive drugs. They are photolabile, some markedly so, for example, nifedipine. In all cases, the major light degradation product is the resonance-stabilised, fuUy aromatic, pyridine analogue [38]. 

Schreiber and co-workers (436) prepared a library calculated to contain 2.18 million polycyclic compounds through the 1,3-dipolar cycloaddition of a number of nitrones with alkenes supported on TentaGel S NH2 resin (Scheme 1.83). (—)-Shikimic acid was converted into the polymer bound epoxycyclohexenol carboxylic acid 376 (or its enantiomer), coupled to the resin via a photolabile linker developed by Geysen and co-workers (437) to allow release of the products from the resin in the presence of live cells by ultraviolet (UV)-irradiation. A range of iodoaromatic nitrones (377) was then reacted with the ot,p-unsaturation of the polymer-bound amide in the presence of an organotin catalyst, using the tandem esterification/ dipolar cycloaddition methodology developed by Tamura et al. (84,85) Simultaneous cyclization by PyBrop-mediated condensation of the acid with the alcohol... 

Styrene, leads to [4 + 2]-adducts exclusively (251-258) 242 is also isolated in varying amounts, With methyl sorbate both [4 + 2]- and [4 + 4]-adducts (259-262) are obtained. 1,4-Dicarbomethoxybutadiene does not add to 138 242 is obtained in 90% yield. All photoadducts (251-262) are photolabile on irradiation (z — 253.7 nm) they are reconverted to 138 and the alkene. Significantly for preparative purposes, the product distributions (stereo-, regio-, and peri-selectivity) differ considerably from those obtained in the thermal Diels-Alder reactions (Section IV,B) mechanistic details are given in the original papers. 

This chemistry was repeated with a traceless photolabile linker.60 The desired biphenyl was formed, but the couplings gave side products, and all yields of the desired biphenyl were lower than 30%. 

Scheme 7 shows how trisaccharides were prepared on a radiation-grafted polymer surface.20 The photolabile 4-hydroxymethyl-3-nitrobenzamido handle21 and jV-iodosuccinimide-triethylsilyltriflate coupling chemistry were used. Product purities were similar to those obtained using Tentagel macrobeads. 

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