Thermal properties of iopamidol: Crystalline anhydrous, hydrated and amorphous forms

Three crystal forms of iopamidol, an iodinated contrast media used in radiology, have been so far elucidated: an anhydrous, a monohydrate and a pentahydrate form (labeled hereafter as W0, W1 and W5, respectively), which showed the occurrence of different conformations, atropisomeric in nature. Specifically, the anhydrous and monohydrate forms contain iopamidol with a \ue2\u80\u9csyn\ue2\u80\u9d conformation of the two symmetric sidearms, while an \ue2\u80\u9canti\ue2\u80\u9d conformation was found in the pentahydrate, making it a conformational (pseudo)-polymorph of the first two. The three crystal forms have been here investigated by means of DSC, variable temperature X-ray powder diffraction and Raman spectroscopy. This study enabled us to highlight the thermal-induced transformations, leading to the discovery of new crystal forms, for a total of four hydrated and four distinct anhydrous phases. In particular, the DSC curve of W0 revealed only a reversible solid\ue2\u80\u93solid transition at around 180 \uc2\ub0C before melting, with subsequent degradation above 300 \uc2\ub0C. W1, after the loss of lattice water around 100 \uc2\ub0C, shows a characteristic split peak at about 250 \uc2\ub0C, which is attributed to melting. Below 150 \uc2\ub0C, powder diffraction of W1 suffers of minor changes, with a smooth variation of the lattice parameters, in agreement with a progressive loss of water in a reversible event, monitored also by DSC. At variance, W5 evidenced an irreversible loss of water in three distinct steps, for three, one and one H2O molecules each, respectively; subsequent transitions occur at 140 and 180 \uc2\ub0C, before melting at 240 \uc2\ub0C. Three clearly visible transformations were also detected by variable temperature powder diffraction measurements, where the loss of three molecules of water in a single step, generating a bis-hydrated species (W2), is followed by a second dehydration process leading, above 75 \uc2\ub0C, to a new monohydrate phase W1\ue2\u80\ub2, different from the known W1 form. The Raman spectra of the three crystal forms, measured upon heating up to 160 \uc2\ub0C, evidenced changes in spectral regions of amides that, according to our simulations of the vibrational properties, can be attributed to changes of the hydration properties and, more significantly, in terms of the \ue2\u80\u9csyn\ue2\u80\u9d and \ue2\u80\u9canti\ue2\u80\u9d conformations