Obtenção e caracterização de pseu-polimorfos de doxiciclina

Abstract

The active pharmaceutical ingredient (API) doxycycline (DOX), C22H24N2O8, 2-naphthacenecarboxamide, IUPAC name 4(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-, [4S-(4α, 4aα, 5α, 5aα, 6α,12aα)], is a broad-spectrum antibiotic mainly used in the treatment of respiratory and urinary tract infections and, like many drugs, its efficacy may be affected by the polymorphism phenomenon. Up to now, only the crystal structure of doxycycline hyclate (DOX•HIC), C22H24N2O8, HCl, ½ C2H6O (ethanol), ½ H2O, 512,9 g/mol, which is the generic name of a DOX pseudo-polymorphic form used as API in brand names such as DORYX®, PERIOSTAT®, ATRIDOX®, and VIBRAMYCIN®, has been reported. Part of this study presents the monocrystal X-ray diffractometry (MXRD) structural characterization of another DOX commercial pseudo-polymorphic form, namely, doxycycline monohydrate (DOX•H2O), C22H24N2O8, H2O, 462,45 g/mol, which is the generic name of brand names such as MONODOX® and ORACEA®. Beyond to report for the first time the crystal structure of DOX•H2O, others two news pseudo-polymorphic forms of the DOX were synthetized and crystallized in the present study: 1) doxycycline dihydrate co-crystallized/solvated with acetic acid (DOX•HAc), C22H24N2O8, 2H2O, C2H4O2 (acetic acid), 512,93 g/mol; and 2) doxycycline nitrate hemihydrate (DOX•NIT), C22H24N2O8, HNO3, ½H2O, 516,46 g/mol. The crystal structure of DOX•HAc and DOX•NIT were also unambiguously determined by MXRD methods. The three new pseudo-polymorphic forms of DOX were compared with the known one, DOX•HIC, and analyzed in terms of intra and intermolecular geometries. All forms crystallize as zwitterions in which the dimethylamine group is protonated and one hydroxyl group is disprotonated. Two conformers were observed in the DOX•NIT as previously reported for DOX•HIC, i.e., the amine group is next to the enolate in one of them (T1) and beside the carbonyl in the other one (T2). In other words, occurs a rotation around the C–C bond of the amide group, directing the oxygen toward the amine group in one (T1) of the two conformers present in these solid state phases, while in the other crystallographically independent molecule (T2), the amide nitrogen atom is at the same side of the amine. Another important similarity of DOX•HIC and DOX•NIT is that in both structure the DOX appears as a cation, differently of DOX•H2O and DOX•HAc for which the DOX is neutral. In spite of being both neutral and present just one DOX molecule in the asymmetric unit, DOX•H2O and DOX•HAc differ themselves. While DOX•HIC and DOX•NIT present two tautomers, T1 and T2, the conformer T1 and tautomerism observed for T2 was found in DOX•HAc and either conformer or tautomer of T2 was found in DOX•H2O. In general, since doxycycline is a conformationally robust molecule, its framework adopts only small distortions due to variable intermolecular hydrogen bonding patterns. Nevertheless, the presence of crystallization solvent, water and/or ions in the lattice affects the rotation around the C–C bond of the amide group, directing the NH2 portion toward the amine in one (T2) of the two crystallographically independent molecules, while in the another one (T1), the amide oxygen atom is next to amine.. The crystal packing of DOX forms studied here are stabilized by several intermolecular hydrogen bonds (classical and non-classical), involving interactions DOX-DOX, DOX-water, DOX-solvent, DOX-ion water-water, solvent-solvent, ion-ion, water-solvent, ion-solvent, ion-water. The differences of these supramolecular interactions when the pseudo-polymorphic forms are compared result in significant differences in the solubility and in the dissolution profile of the DOX•HIC, DOX•H2O, DOX•HAc, and DOX•NIT also performed in this work. However, all forms do not show significant differences in the bioavailability of the API DOX. The four DOX pseudo-polymorphic forms were also characterized by powder X-ray diffraction and infrared spectroscopy.