Reactivity Differences of Indomethacin Solid Forms with Ammonia Gas

Abstract

The present study deals with the acid−base reaction of three solid-state forms of the nonsteroidal antiinflammatory drug indomethacin with ammonia gas. X-ray powder diffraction, optical microscopy, gravimetry, and spectroscopic methods were employed to establish the extent of the reaction as well as the lattice changes of the crystal forms. The glassy amorphous form readily reacts with ammonia gas to yield a corresponding amorphous ammonium salt. In addition, the metastable crystal form of indomethacin (the α-form) also reacts with ammonia gas, but produces the corresponding microcrystalline ammonium salt. This reaction is anisotropic and propagates along the a-axis of the crystals. The stable crystal form (the γ-form), however, is inert to ammonia gas. Amorphous indomethacin can react with ammonia gas because it has more molecular mobility and free volume. The reactivity differences between the α- and γ-forms are dictated by the arrangement of the molecules within the respective crystal lattices. The recently determined crystal structure of the metastable α-form of indomethacin (monoclinic P2₁ with Z = 6, V = 2501.8 ų, D_c = 1.42 g·cm^-3) has three molecules of indomethacin in the asymmetric unit. Two molecules form a mutually hydrogen-bonded carboxylic acid dimer, while the carboxylic acid of the third molecule is hydrogen bonded to one of the amide carbonyls of the dimer. The carboxylic acid groups of the α-form are exposed on the {100} faces and are accessible to attack by ammonia gas. After one layer of molecules reacts, the reactive groups in the subsequent layer are accessible to the ammonia gas. This process proceeds along the a-axis until the ammonia gas has penetrated the entire crystal. In contrast to the α-form, the γ-form has a centrosymmetric crystal structure in which the hydrogen-bonded carboxylic acid dimers are not accessible to ammonia gas because they are caged inside a hydrophobic shield comprising the remainder of the indomethacin molecule. In view of the significantly lower density of the stable γ-form as compared to the metastable α-form (1.37 and 1.42 g cm^-3, respectively), it became apparent that the reactivity of the crystal forms depends exclusively on the molecular arrangement and not on the packing density of the indomethacin crystals.