AAPS PharmSciTech 2011-06-01

Complexation and full characterization of the tretinoin and dimethyl-β-cyclodextrin complex.

Andreia Ascenso, Rita Guedes, Raul Bernardino, Herminio Diogo, Filomena A Carvalho, Nuno C Santos, Aida M Silva, Helena Cabral Marques

Index: AAPS PharmSciTech 12(2) , 553-63, (2011)

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Abstract

The aim of this work is to prepare tretinoin/dimethyl-beta-cyclodextrin complexes and fully characterize them through various analytical techniques. According to the phase solubility studies performed, the equilibrium for maximum complexation is reached in about 8 days presenting an A(L)-type diagram (soluble complexes) corresponding mainly to 1:1 stoichiometry (K(s) = 13,600 M(-1)), although the possibility of the presence of 1:2 complexes was mathematically proven. Differential scanning calorimetry, X-ray diffraction and all the other analytical techniques have proven the presence of true complex formation in all the preparation methods tested. H-NMR and FTIR spectra allowed the selection of the best complexation method. The comparison between Raman spectra revealed that the more relevant feature is the band at 1,573 cm(-1), which corresponds to the entire delocalization of the superconjugated system, and after inclusion is observed as a positive frequency shift. Based on these results and the data obtained by molecular modelling calculations, it is proposed that the structure of the drug included into the cyclodextrin corresponds to the side chain including the functional group COOH. The complex was also analysed by atomic force microscopy to determine its size distribution which was heterogeneous and polymodal. However, it could be observed that they all have the same phase constitution.