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This study investigated the solid-state physical stabilities of azithromycin dihydrate (AZM-DH), thermally prepared anhydrate and hemihydrate modifications. Programmed thermal treatment of AZM-DH in DSC yielded the formation of anhydrate amorphs (I, II), crystalline AZM anhydrate and hemihydrate phases. The formation of the anhydrate amorphs, I and II, respectively, involved different transformation pathways of solid–liquid–solid (melting and supercooling) and solid–solid (378 K for 24 h.). Both amorph phases exhibit hygroscopic behaviour, producing non-stoichiometric hydrates, with extent of moisture absorption increasing with increased storage humidity (0–96% RH/313 K). TG analysis after controlled storage (4 days at 96% RH/313 K) detected absorbed waters of hydration up to 5.9 and 5.3% for amorphs I and II, respectively. The crystal anhydrate and hemihydrate phases were hygroscopic and readily converted to the stoichiometric dihydrate form, which was compositionally stable in RH ranges from 11 to 96% at 313 K. Solubility studies, performed in distilled water at 310 K, showed an at least 1.5 fold solubility improvement for both amorph forms relative to crystalline AZM-DH, but with some evidence of solvent-mediated phase transformation after 20 min. Structural characterization by single-crystal XRD concluded that thermally stimulated amorphization required energy to disrupt intermolecular hydrogen bond interactions by bridging water molecules in addition to hydrogen bond interactions between neighbouring AZM molecules in unit cell

The relative accuracies of approximation-based integral versus differential isoconversional approaches for ‘actual’ E determination were investigated on experimental dehydration data of roxithromycin monohydrate from thermogravimetric (TG) analysis. The dehydration kinetic parameters and the relationship to the structural characteristics of the monohydrate and anhydrate forms from differential scanning calorimetry (DSC) and single-crystal X-ray diffractometry (SC-XRD) are also reported. Integral methods versus the differential Friedman isoconversional method evaluated E correspondences in both iso- and nonisothermal TG methods. The reliability in E from Friedman approached that of estimates from current most accepted integral isoconversional methods and was even superior to methods (for non-isothermal studies) that employ an approximation to the temperature integral (modified Kissinger– Akahira–Sunose, Senum–Yang fourth degree). Structural characterization (DSC, SC-XRD) and kinetic analysis from generalized kinetic master plots concluded that coordinated water occupied interlinked voids in crystal structure which may have facilitated the multidimensional diffusional loss of water upon heating without disruption of the crystal structure