Fujita Megumi, Himi Satoshi, Iwata Motokazu
Formulation Research and Development Laboratories, Dainippon Sumitomo Pharma Co., Ltd, Osaka 553-0001, Japan.
Chem Pharm Bull (Tokyo). 2010 Mar;58(3):359-62. doi: 10.1248/cpb.58.359.
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. This compound, however, becomes chemically unstable due to decreased crystallinity when it undergoes mechanical treatments such as grinding and compression. A wet-granule tableting method, where wet granules are compressed before being dried, was therefore investigated as it has the advantage of producing tablets of sufficient hardness at quite low compression pressures. The results of the stability testing showed that the drug substance was chemically considerably more stable in wet-granule compression tablets compared to conventional tablets. Furthermore, the drug substance was found to be relatively chemically stable in wet-granule compression tablets even when high compression pressure was used and the effect of this pressure was small. After investigating the reason for this excellent stability, it became evident that near-isotropic pressure was exerted on the crystals of the drug substance because almost all the empty spaces in the tablets were occupied with water during the wet-granule compression process. Decreases in crystallinity of the drug substance were thus small, making the drug substance chemically stable in the wet-granule compression tablets. We believe that this novel approach could be useful for many other compounds that are destabilized by mechanical treatments.
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，拟开发成片剂制剂。然而，该化合物在经历研磨和压缩等机械处理时，由于结晶度降低而变得化学不稳定。因此，研究了一种湿法制粒压片方法，即在湿颗粒干燥前进行压缩，因为它具有在相当低的压缩压力下就能生产出硬度足够的片剂的优点。稳定性测试结果表明，与传统片剂相比，原料药在湿法制粒压片中的化学稳定性要高得多。此外，即使使用高压缩压力，发现原料药在湿法制粒压片中相对化学稳定，且该压力的影响较小。在研究了这种优异稳定性的原因后，很明显在湿法制粒压片过程中，由于片剂中几乎所有的空隙都被水占据，原料药晶体受到了近各向同性的压力。因此，原料药的结晶度降低很小，使得原料药在湿法制粒压片中化学稳定。我们认为这种新方法可能对许多因机械处理而不稳定的其他化合物有用。
