Thermoanalytical and spectroscopic characterisation of solid-state retinoic acid

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Abstract

Thermoanalytical (differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), thermogravimetric analysis coupled with Fourier transform infrared spectroscopy (TG/FTIR)) and spectroscopic (X-ray diffraction (XRD), ultraviolet–visible (UV–Vis), mass spectrometry (MS) and Fourier transform infrared diffuse reflectance (DRIFT) measurements have been used to characterise solid-state retinoic acid (RA) from a chemico-physical point of view. Between 130 and 160°C, a phase transition takes place that does not correspond to the transition between the known monoclinic and triclinic phases (DSC and XRD evidence). By annealing in air (in the 130–160°C temperature range and for different times), an exothermic oxidative degradation occurs that, depending on the thermal treatment, competes with the mentioned phase transition (TGA evidence). Spectroscopic techniques (UV–Vis, MS and DRIFT) allow one to conclude that the new solid phase is still constituted by retinoic acid with a different orientation of the side chain. Finally, RA does not undergo stable melting: the fragmentation patterns, both in air and in nitrogen, have been examined by TG/FTIR.

Introduction

Retinoic acid (3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenoic acid) (RA in the following), is the vitamin A acid. Two configurational isomers exist, the 13-cis-retinoic acid and all-trans retinoic acid, both of them very important for their natural function (Vaezi et al., 1994, Alam et al., 1995).

Since RA plays an important role in controlling gene expression, it has found applications in the prevention and treatment of cancer, the major therapeutic successes having up to now been obtained in certain leukaemias (Muccio et al., 1996, Muccio et al., 1998). RA is also employed in dermatology (Levin et al., 1994), namely in the treatment of skin diseases such as acne, psoriasis and skin cancer. On the other hand, the ability of some cationic polyelectrolytes to immobilize RA has spurred the engineering of new materials with interesting structural and optical properties (Thunemann, 1997, Thunemann et al., 2000).

A great deal of information exists on the pharmaceutical applications of RA, while the study of its solid-state physico-chemical properties has been only seldom undertaken. Namely, a structural study has been performed and two different crystallographic forms of RA have been brought into evidence. According to Stam and McGillavry (1963), a triclinic form of RA can be obtained by heating, at 120°C, the monoclinic form (Stam, 1972). It has to be noted that the monoclinic form would be less stable (by about 2.5 kcal/mol) and, this notwithstanding, it is the form obtained at room temperature (RT). Another paper (Tan et al., 1992) examines (by microcalorimetry and high-performance liquid chromatography) the thermal stability of all-trans RA and 13-cis-RA. This work reports differential scanning calorimetry (DSC) measurements showing that the 13-cis isomer melts at 180°C, while the all-trans RA, before melting, displays an endothermic peak at 150°C that would be due to the monoclinic–triclinic transition.

The present work will report the results obtained in a physico-chemical characterisation of solid-state all-trans RA. To this aim, use has been made of both thermoanalytical (DSC, thermogravimetric analysis (TGA) both alone and coupled with Fourier transform infrared spectroscopy (TG/FTIR) of the evolved gases) and spectroscopic (FTIR diffuse reflectance, UV–Vis spectroscopy, mass spectrometry and X-ray powder diffractometry) techniques.

Section snippets

Sample

All the measurements have been carried out on commercial all-trans RA (Sigma Aldrich, Italy). Starting from this precursor, other samples have been prepared by various thermal treatments (which will be described in due course).

Experimental techniques

Heat-flux DSC measurements were performed by a TA2920 cell connected with a TA5000 thermal analysis system (both by TA Instruments, USA). Experiments were carried out (under a dry nitrogen flux of 2 l/h) on samples of 4–5 mg that have been heated, in open or sealed Al

DSC measurements

Fig. 1 reports a typical DSC trace of a RA sample. Two peaks are showing: the peak at 183°C is due to the melting process while that at ∼150°C will be tentatively ascribed, according to Tan et al. (1992), to the monoclinic–triclinic phase transition.

Fig. 2 reports a simultaneous TGA/DSC trace. The DSC part shows the same two peaks of Fig. 1 while the TGA signal indicates that a mass loss process takes place under the melting peak. This means that RA is not stable over melting. This point is

Conclusion

The DSC peak at about 150°C corresponds to a solid-state transformation of RA. This peak no longer shows up by prolonged annealing at temperatures as low as 125–130°C. The UV–Vis and MS measurements (both in solution) do not show any difference in the molecular structure of the annealed samples. The solid-state IR spectra show evidence, mainly in the fingerprint region, of a different orientation of the side chain in thermally treated RA. The XRD patterns of the annealed samples are different

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