Solid-state chemistry of a novel carbapenem with a releasable sidechain

The solid-state chemistry of amorphous and crystalline forms of a novel cat ionic l-beta-methyl carbapenem antibiotic 2 is described. The lyophilized c hloride salt of 2 (2.Cl) is amorphous and exhibits moisture-dependent p-lac tam hydrolysis rates. Hydrolysis is concomitant with ejection of the sidech ain naphthosultam moiety 4. In the lyophilized solid (with 1.8% w/w water o r less), a significant contribution from a Hofmann-like elimination reactio n within the sidechain structure to give products 6 and 7 is observed. Anot her less significant elimination pathway involving loss of acetamide from t he 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 beta-lactam hydrolysis, concomitant with a slight increase in the strength of the glassy lyophilized product based on modulated differential scanning calorimetry (MDSC). Kinetics of degradatio n of 2.Cl lyophilized in the presence of 1% trisodium citrate and 50% weigh t of sucrose showed a 30-40% increase in overall initial rate of degradatio n at 25 and 40 degrees 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 eff ect slightly offsets the increase in hydrolysis rate observed with increasi ng moisture. The crystalline benzenesulfonate trihydrate (2.PhSO3) was char acterized and found to have improved thermal stability in the solid state r elative to the amorphous 2.Cl, particularly in terms of the elimination pat hway. (C) 2000 Elsevier Science Ltd. All rights reserved.