Study of retinoic acid polymorphism

Some authors recently hypothesized the existence of a new retinoic acid (RA) phase in addition to the two already known polymorphs. We investigated RA polymorphism and our results exclude the presence of new modifications and refine the properties of the known forms. By comparison of simulated and acquired X‐Ray Powder Diffraction (XRPD) it was possible to identify only the known monoclinic (I) and the triclinic (II) modifications; the same were also characterized by DSC, IR, and Raman spectroscopy. A solubility study associated to DSC allowed establishing an enantiotropic relationship between the two forms, with form II being less stable (ΔGII/I = 0.71 kJ/mol at 37°C) below the transition temperature (136.6°C; ΔH = 3.2 kJ/mol). The intrinsic dissolution rate (IDR) (I = 61 µg/cm2 × min−1; II = 125 µg/cm2 × min−1) confirmed this energetic relationship. The kinetics of solid transition I → II was examined and its activation energy estimated (356 kJ/mol). The attempts to produce new phases allowed the development of methods to obtain the two polymorphs with high chemical and polymorphic purity. A validated DSC method is presented that enables detection of the presence of form I at a level of 1% (w/w) when in mixture with form II.