Sulfuric Acid → HCID 71724478, compound

Participants

Reaction Conditions

Reaction Steps

100.0 g (245.5 mmoles) of sitagliptin base were dissolved at 20-22° C. in a mixture of 750 ml of absolute ethanol and 120 ml of water. A previously prepared solution of 98.1% H2SO4 (24.9 g, 240.9 mmoles) in ethanol (760 ml) was slowly added to said solution, maintaining the temperature between 20-25° C. When approximately ⅔ of the total volume of the acid solution had been added, the addition was stopped and 1.0 g (1.978 mmoles) of crystalline form M of sitagliptin sulfate obtained by means of any of the processes described in Examples 1 and 3-5 was added to the reaction mixture. The presence of a white precipitate that remains undissolved was immediately noticed. The addition of the acid solution was continued and once this ended, the mixture obtained was maintained at a temperature of 20-25° C. for 4 hours. The solid obtained was filtered and washed in the filter with absolute ethanol (2×100 ml). The wet product was dried in a vacuum oven at 40° C. for 22 hours to yield 97.1 g (192.1 mmoles) of a white crystalline solid (77.6%). XRPDs both of the wet product (FIG. 3) and of the dry product (FIG. 2) which correspond with form M of sitagliptin sulfate were performed. The DSC of the wet product (FIG. 9) shows an endothermic signal at 216.7° C. whereas the dry product showed an endothermic signal at 215.5° C. (FIG. 8). The water content determined by TGA (FIG. 13) is 0.02%. The product thus obtained had a particle size distribution (PSD) corresponding to D90: 254.21 μm, D50: 141.64 μm, D10: 5.32 μm. By adjusting the grinding conditions a product with a particle size distribution (PSD) corresponding to D90 120.84 μm, D50: 6.01 μm, D10: 1.50 μm could be obtained and it was found that the ground product is still the crystalline form of sitagliptin sulfate object of the present invention.

Provenance & Evidence