Solid-State Chemistry of a Novel Carbapenem with a Releasable Sidechain

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·PhSO3) 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.