Photochemical and Oxidative Degradation of the Solid-State Tretinoin Tocoferil.

Abstract

Tretinoin tocoferil ((Ϯ)-3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyl-tridecyl)-2H-1-benzopyran-6-yl (2E,4E,6E, 8E )-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenoate) is an a-tocopherol ester of all-trans retinoic acid (RA) and has been safely used in the treatment of decubitus and skin ulcer to stimulate the proliferation of human skin fibroblasts.1) Toxicity tests in animal models have shown that tretinoin tocoferil is at least 150 times less toxic than all-trans RA and does not induce teratogenesis. 13-cis RA and all-trans RA are known to undergo Z-E isomerization (due to the existence of four unsaturated double bonds) and oxidation when exposed to light and air.2) RA underwent autooxidation in 90% ethanol at 25-85.5°C to give epoxides, dioxetanes, an endoperoxide and double-bond cleavage products.3) Therefore tretinoin tocoferil is also likely to be susceptible to photodegradation and oxidation.The information obtained from the stability test of the drug is useful for development and stabilization of the dosage forms, but there are no reports concerning the photostability and the oxidation of tretinoin tocoferil.The purpose of the present investigation was to evaluate photostability and oxidation profiles of tretinoin tocoferil under various environmental conditions to establish a reasonable stabilization design against light and oxygen. Elucidation of the degradation mechanism was therefore beyond the aim of this study. ExperimentalMaterials Bulk tretinoin tocoferil was obtained from Nisshin Flour Milling Co., Japan. The commercial solvents for HPLC analysis and Sudan II as an internal standard were used without further purification.Methods Tretinoin tocoferil (50 mg) was dissolved in 50 ml of dichloromethane. An aliquot of the solution (50 ml) was placed in a glass tube and evaporated to dryness at room temperature. The sample was further dried under vacuum at room temperature.Irradiation Tests Two irradiation apparatuses were employed: To study the effect of specific wavelength of light on the photostability of tretinoin tocoferil, the same grating monochromator (model CRM-FA, Japan Spectroscopic Co., Tokyo, Japan) as described in our previous paper, 4) equipped with a 5-kW xenon lamp, was used. Samples were exposed until the intensity level of the irradiation reached a definite energy(1.8ϫ10 5 J/m 2 ). To study the effect of photon sources on the photostability, a cool white fluorescent lamp (type FL20SW/M), a D65 fluorescent lamp (FLR20S · D-EDL-D65/M), or a UV-A fluorescent lamp (FLR20S · BL/M, all three lamps from Nagano Science Equipment MFG. Co., Japan) were equipped in a light-irradiation tester (LIGHTTRON LT-120(D3CJ), Nagano Science Equipment MFG. Co., Japan). The spectral irradiation intensity curves of these lamps were measured with a portable spectroradiometer (model LI-1800, LI-COR Inc., Neb., U.S.A.). Figure 1 shows the relative spectral power distribution of the lamps as measured on the surface of a sample under an irradiation condition.Unless otherwise spec...

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“…In fact, atRA is degraded upon exposure to light‐forming isomers, mainly 13‐cis retinoic acid and 9‐cis retinoic acid . Photodegradation of atRA appears to correlate with specific light conditions and can be influenced by the vehicle technology used to formulate the product . Thus, the stability of atRA in dermatological formulations is critical, prompting to the development of more or less sophisticated strategies to protect the drug from light‐induced degradation …”

“…21 Photodegradation of atRA appears to correlate with specific light conditions and can be influenced by the vehicle technology used to formulate the product. [22][23][24] Thus, the stability of atRA in dermatological formulations is critical, prompting to the development of more or less sophisticated strategies to protect the drug from lightinduced degradation. [25][26][27][28] From the data reported in Figure 5, it is clear that atRA conversion to 13-cis derivative was very fast in ethanol solution and significantly slowed down in $NS-PYRO-CB gel.…”

Effect of X-ray exposure on the pharmaceutical quality of drug tablets using X-ray inspection equipment

“…Co., Ltd., Osaka, Japan) equipped with a D65 lamp that approximates natural sun light including ultraviolet (UV) light. This apparatus is commonly used in photostability testing, as previously described 27 . At appropriate time points, tablets were removed from the exposure apparatus, and the change in color was assessed using a color-difference meter (Konica Minolta).…”

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