Avibactam Tomilopil Form 1: A Rare Pharmaceutical Mesophase

Avibactam tomilopil (AVT) is an orally available prodrug of the β-lactamase inhibitor avibactam that is in development for the treatment of antibiotic-resistant urinary tract infections. Initial solid-state characterization suggested a mixture of the crystalline and amorphous phases. However, subsequent attempts to obtain fully crystalline material were unsuccessful and resulted in comparable powder X-ray diffraction patterns containing both sharp peaks and broad areas consistent with diffuse scattering. Extensive solid form screening identified no additional forms of AVT, crystalline or otherwise. Likewise, cocrystal screening found no commercially viable hits, leaving Form 1 as the only viable solid form of AVT for clinical and commercial development. It therefore became imperative to fully understand the molecular level structure of the solid. Through extensive experimental and computational analysis, it was discovered that AVT Form 1 is a thermotropic mesophase─a state of matter infrequently encountered in pharmaceuticals.