Water and the relationship to the crystal structure stability of azithromycin

Abstract

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.

Preparation of Azithromycin Amorphous Solid Dispersion by Hot-Melt Extrusion: An Advantageous Technology with Taste Masking and Solubilization Effects

“…Figure 14 shows the transition of AZI from crystalline to amorphous form. In the HME process, the hydrogen bonds between AZI and the water of the crystallization is broken and the “loosely attached” water is released outside the AZI lattice, which promotes the formation of hydrogen bonds between Eudragit ® RL PO and AZI, while AZI changes from crystalline to amorphous state [ 27 , 33 ].…”

An investigation of the predominant structure of antibiotic azithromycin in chloroform solution through NMR and thermodynamic analysis

“…Stereochemistry has been shown to play an important role in the metabolism of drugs and pharmacokinetics 18,19 because proteins, which are chiral by nature, are fundamental species in these biological processes. AZM (Scheme 1) has been reported to crystallize in two stereoisomeric forms named here A 20 and B, 21 with all chiral centers inverted. The carbon atoms C3 and C5 highlighted in Scheme 1 connect the sugar rings to the macrocycle, with desosamina and cladinose sugar units' conformation being important for biological activity, and have different configurations in the two stereoisomers: C3R-C5S (A) and C3S-C5R (B) with all remaining chiral carbons from the A and B forms of AZM having inverted configurations.…”

Enhancing Dissolution Rate and Antibacterial Efficiency of Azithromycin through Drug-Drug Cocrystals with Paracetamol

“…Azithromycin (AZT, shown in Figure 1 ) is a semisynthetic macrolide derivative of erythromycin A found as monohydrate (MH), dihydrate (DH), semi-hydrate solvates [ 10 , 11 , 12 ] and pseudopolymorphic forms [ 13 ]. However, the MH and DH crystalline forms are more stable compared to other forms [ 13 , 14 ].…”