Salts of benzamidopyridine derivatives and their application in medicine
A drug and pharmacy technology, applied in the field of salicylic acid crystal form and salicylate pharmaceutical composition, can solve the problems of undisclosed compound crystal structure and non-disclosure, etc.
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Embodiment 1
[0082] Example 1 Salicylate Crystal Form I
[0083] 1. Preparation of Salicylate Form I
[0084] Compound 5-(4-cyclopropyl-1H-imidazol-1-yl)-N-(6-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2 ,4] Triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide (50.4mg, 0.114mmol) was added to acetone (1.0mL), beaten for 1 hour, then added A solution of salicylic acid (20.6 mg, 0.148 mmol) in acetone (1.0 mL) was reacted for 6 hours; suction filtered, and the filter cake was vacuum-dried at room temperature overnight to obtain a white solid (65.7 mg, 99.4%).
[0085] 2. Identification of salicylate crystal form I
[0086] (1) Analysis and identification by Empyrean X-ray powder diffraction (XRPD): using Cu-Kα radiation, it has the following characteristic peaks expressed in angle 2θ: 6.99°, 7.86°, 8.12°, 8.64°, 9.92°, 11.45°, 12.18 °,12.93°,13.48°,13.93°,14.09°,14.65°,15.64°,16.28°,16.66°,17.27°,17.56°,17.73°,18.57°,18.91°,19.10°,19.96°,20.39°, 20.62°, 21.14°, 21.56°, 21.91°, 22.56°, 23.07°,...
Embodiment 2
[0088] Embodiment 2 Pharmacokinetic experiment of the present invention
[0089] Get 8-12kg male Beagle dogs and divide them into 2 groups, 3 in each group, orally administer the capsules that test samples are housed, the dose is 5mg / kg, according to the time point 0.25,0.5,1.0,2.0,4.0,6.0,9.0 and 24h blood collection. A standard curve with an appropriate range was established according to the concentration of the sample, and the concentration of the test sample in the plasma sample was determined in the MRM mode using AB SCIEX API4000 LC-MS / MS, and quantitative analysis was performed. According to the drug concentration-time curve, the pharmacokinetic parameters were calculated by WinNonLin 6.3 software non-compartmental model method. See Table 1 for details.
[0090] Table 1 PK parameters of salicylate crystal form
[0091] Test sample Dose (mg / kg) AUClast(h*ng / ml) Cmax(ng / ml) Tmax(h) Salicylate Form I 5 13400 1790 8.67
[0092] Experimenta...
Embodiment 3
[0094] Embodiment 3 Stability experiment of the salt of the present invention
[0095] (1) High temperature experiment : Take an appropriate amount of the test sample and put it into a flat weighing bottle, spread it into a thin layer with a thickness of ≤5mm, place it at a temperature of 60°C for 10 days, take a sample on the 5th and 10th day, observe the color change of the sample, and test the purity of the sample by HPLC.
[0096] (2) High humidity experiment : Take an appropriate amount of a batch of test products and put them into a flat weighing bottle, spread them into a thin layer with a thickness of ≤5mm, place them for 10 days at 25°C and RH 90%±5%, take samples on the 5th and 10th days, and observe the samples The color changes, and the purity of the sample is tested by HPLC.
[0097] Experimental results:
[0098] Under the conditions of high temperature (60°C) and high humidity (25°C, RH 90%±5%), the appearance and purity of the salt of the present invention...
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