title: Stabilization study on a wet-granule tableting method for a compression-sensitive benzodiazepine receptor agonist.
abstract: 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.
authors.affiliation: Formulation Research and Development Laboratories, Dainippon Sumitomo Pharma Co., Ltd, Osaka 553-0001, Japan. megumi-fujita@ds-pharma.co.jp
authors.forename: Megumi
authors.initials: M
authors.lastname: Fujita
authors.forename: Satoshi
authors.initials: S
authors.lastname: Himi
authors.forename: Motokazu
authors.initials: M
authors.lastname: Iwata
mesh_terms: D004339:Drug Compounding; D004355:Drug Stability; D058785:GABA-A Receptor Agonists; D009287:Naphthyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D016062:Porosity; D011312:Pressure; D013499:Surface Properties; D013607:Tablets; D013696:Temperature; D017155:Wettability
chemical_list: D058785:GABA-A Receptor Agonists; D009287:Naphthyridines; D013607:Tablets; C103895:SX 3228