Effects of compression and grinding on chemical stability of a benzodiazepine receptor agonist

SX-3228, 6-benzyl-3-(5-methoxy-1,3,4-oxadiazol-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2(1H)-one, is a newly synthesized benzodiazepine receptor agonist intended to be developed as a tablet preparation. However, it was found that the drug substance was remarkably chemically unstable in tablet form compared to the powder mixture for tableting. Chemical destabilization due to compression also occurred in the drug substance alone. After investigating the cause of the destabilization, powder X-ray diffraction analysis showed that the crystallinity of the drug substance decreased depending on the extent of mechanical treatments such as compression and grinding. In thermal analysis it became evident that the exothermic peaks due to degradation clearly broadened and shifted toward lower temperatures by these mechanical treatments. It was then revealed that the degradation temperature decreased and the amount of degradation products after storage increased with decreasing crystallinity, even though there was little change in the amount of degradation products shortly after mechanical treatments. These results demonstrated that the drug substance became chemically unstable with decreasing crystallinity. It was proved that chemical instability of the drug substance in the tablet preparation was due to decreasing crystallinity caused by compression. It would therefore be difficult to produce chemically stable tablets containing this compound using a conventional manufacturing process. Tablets for this compound should be prepared without mechanical treatments such as compression and grinding.