Fujita Megumi, Himi Satoshi, Handa Tetsurou
Formulation Research and Development Laboratories, Dainippon Sumitomo Pharma Co., Ltd., Osaka, Japan.
Chem Pharm Bull (Tokyo). 2010 Jan;58(1):51-5. doi: 10.1248/cpb.58.51.
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.
SX - 3228，即6 - 苄基 - 3 -（5 - 甲氧基 - 1,3,4 - 恶二唑 - 2 - 基）- 5,6,7,8 - 四氢 - 1,6 - 萘啶 - 2(1H) - 酮，是一种新合成的苯二氮䓬受体激动剂，拟开发为片剂制剂。然而，发现与压片用的粉末混合物相比，该原料药制成片剂后化学性质非常不稳定。仅原料药本身也会因压缩而发生化学不稳定。在研究不稳定的原因后，粉末X射线衍射分析表明，原料药的结晶度会根据压缩和研磨等机械处理的程度而降低。在热分析中可以明显看出，由于降解产生的放热峰通过这些机械处理明显变宽并向低温移动。随后发现，随着结晶度降低，降解温度下降，储存后的降解产物量增加，尽管在机械处理后不久降解产物量变化不大。这些结果表明，原料药随着结晶度降低而变得化学不稳定。已证明该片剂制剂中原料药的化学不稳定性是由于压缩导致结晶度降低所致。因此，使用传统制造工艺生产含有该化合物的化学稳定片剂将很困难。该化合物的片剂应在不进行压缩和研磨等机械处理的情况下制备。
