ChemInform Abstract: Solid-State Chemistry of a Novel Carbapenem with a Releasable Sidechain.

Abstract

Abstract The solid-state chemistry of amorphous and crystalline forms of a novel cationic 1-β-methyl carbapenem antibiotic 2 is described. The lyophilized chloride salt of 2 ( 2 ·Cl) is amorphous and exhibits moisture-dependent β-lactam hydrolysis rates. Hydrolysis is concomitant with ejection of the sidechain naphthosultam moiety 4 . In the lyophilized solid (with 1.8% w/w water or less), a significant contribution from a Hofmann-like elimination reaction within the sidechain structure to give products 6 and 7 is observed. Another less significant elimination pathway involving loss of acetamide from the sidechain to form 8 is also operating at low residual moisture contents. Co-lyophilization of 2 ·Cl with sucrose decreases the rate of the reactions within the sidechain as well as β-lactam hydrolysis, concomitant with a slight increase in the strength of the glassy lyophilized product based on modulated differential scanning calorimetry (MDSC). Kinetics of degradation of 2 ·Cl lyophilized in the presence of 1% trisodium citrate and 50% weight of sucrose showed a 30–40% increase in overall initial rate of degradation at 25 and 40°C with increasing moisture from 0.3 to 1.1% residual water. Moisture enhances the stability of the N , N ′-dialkyl 1,4-diaza[2.2.2]bicyclooctane (DABCO) sidechain structure in 2 ·Cl, and this protective effect slightly offsets the increase in hydrolysis rate observed with increasing moisture. The crystalline benzenesulfonate trihydrate ( 2 ·PhSO 3 ) was characterized and found to have improved thermal stability in the solid state relative to the amorphous 2 ·Cl, particularly in terms of the elimination pathway.