Polymorphism and Crystallization of Indomethacin

Indomethacin (IMC) was purchased from Sigma Aldrich (purity ≥ 99%). It is a model drug which presents a rich and very original through polymorphism through the α–γ monotropic system. Indeed, the commercial and more stable phase, namely the γ form [8 (link)], is not the denser phase. The long-range order is induced by the formation of dimers via H-bonding of the carboxylic acid group. The metastable α phase is denser than the γ form because it is composed of more compact trimers [9 (link)]. It was shown that devitrification of IMC occurs in the γ or α phase depending on whether the temperature of recrystallization is below or above the T_g, respectively [10 (link)]. The recrystallized α phase remains stable by cooling down to room temperature. The α phase can also be prepared by dissolution in methanol and precipitation in water at room temperature [11 (link)]. The molecular structure of IMC and the molecular packing distinctive of the α and γ phases are plotted in Figure S2.
Amino acids (AAs), i.e., L-leucine (LEU, C₆H₁₃NO₂, purity ≥ 98%), L-norleucine (NLE, C₆H₁₃NO₂, purity ≥ 98%), L-tert-leucine (TLE, C₆H₁₃NO₂, purity ≥ 99%) and L-arginine (ARG, C₆H₁₃NO₂, purity ≥ 98%) were purchased from Sigma Aldrich (St. Louis, MO, USA) and used as received without any further purification.