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, 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.
1999-09-01·Behavioural Pharmacology4区 · 心理学
Comparison of the pharmacological properties of classical and novel BZ-ω receptor ligands
4区 · 心理学
作者: Griebel, G. ; Perrault, G. ; Tan, S. ; Schoemaker, H. ; Sanger, D. J.
The experiments in this study compared the pharmacological properties of several BZ-omega receptor ligands, including the imidazobenzodiazepine imidazenil, the beta-carboline abecarnil, the pyridazinone Y-23684, the pyrido [1,2-a]benzimidazole RWJ 46771 and the 1,6-naphthyridin-2(1H)-one derivative SX-3228, with the prototypical BZs diazepam, clobazam and bretazenil. In in vitro experiments diazepam, bretazenil, imidazenil and Y-23684 displaced [3H]flumazenil binding non-selectively in membranes from rat cerebellum and spinal cord, two brain areas enriched in the BZ-omega 1 and BZ-omega 2 receptor subtypes, respectively. In contrast, abecarnil, RWJ 46771 and SX-3228 were more potent in displacing [3H]flumazenil binding to membranes from rat cerebellum than from spinal cord or hippocampus, indicating selectivity for the BZ-omega 1 receptor subtype. The in vivo experiments showed that all compounds increased the latency to clonic seizures produced by isoniazid. However, the maximal increase in latency induced by diazepam, clobazam, abecarnil, RWJ 46771 and SX-3228 was greater than that of bretazenil, imidazenil and Y-23684, thereby indicating that these latter compounds have low intrinsic efficacy. In the punished drinking, the punished lever pressing and the elevated plus-maze tests in rats, three models of anxiety, diazepam, clobazam and imidazenil elicited clear anxiolytic-like effects but at doses which were close to those producing hypolocomotion, ataxia and myorelaxation as measured in activity cages, the rotarod and the loaded grid tests, respectively. In contrast, bretazenil and Y-23684 induced anxiolytic-like activity at much lower doses than those which impaired motor performances. The magnitude of the positive effects of Y-23684 was similar to that of the reference BZs, suggesting that it may become a valuable alternative to currently used agents for the treatment of anxiety disorders. Abecarnil, RWJ 46771 and SX-3228 produced weaker or non-specific anxiolytic-like effects as they decreased anxiety-related behaviours at doses similar or close to those impairing motor performance. However, unlike the other compounds they induced myorelaxation at doses which were 3-10 times higher than those needed to produce decrease in exploratory activity. It is suggested that the behavioural profiles of abecarnil, RWJ 46771 and SX-3228 may be attributed to their selectivity for the BZ-omega 1 receptor subtype which may account for their sedative activity, thereby masking other effects including anxiolytic-like activity. This suggests that BZ receptor modulation of anxiety may involve BZ receptor subtypes other than BZ-omega 1.