Study of the Polymorphic\nTransformation Mechanism\nand Crystal Habits Control of Peramivir from Dihydrate to Trihydrate

Peramivir is an effective antiviral drug for treating\ninfluenza\nA and B with the trihydrate form as the solid serving. However, a\nsmall amount of dihydrate still exists during the manufacturing process\nin a few production batches. Focusing on the problem, this study successfully\nobtained a new dihydrate single crystal structure, a higher-quality\ntrihydrate single crystal structure surpassing previously reported\nfindings, and a novel anhydrous form designated as form A. A comprehensive\ncomparison of the crystal structure, crystal habits, thermal analysis,\ndesolvation behavior, solubility, Hirshfeld Surfaces analysis, and\nenergy frameworks was studied between peramivir dihydrate and trihydrate\nto understand the processes of water molecules binding on and off.\nThe transformation process among the three crystal forms and the amorphous\nform revealed that the trihydrate form exhibits the most stability.\nThe study of the polymorphic transformation mechanism revealed that\ndihydrate crystals precipitate initially, dissolve thereafter, and\nthen transform into trihydrate crystals during crystallization. The\nconversion rate was related strongly to the stirring speed, and increasing\nthe stirring speed accelerated both dissolution and crystal transformation,\nresulting in a reduction in the duration of crystallization. The crystallization\ntime from dihydrate to trihydrate was shortened from 10 to 5.5 h when\nthe stirring speed was increased from 50 to 300 rpm. The contrasting\ncrystal habits of peramivir dihydrate (long rod-shaped) and trihydrate\n(tetragonal-shaped) also provide a quick estimate of mixed crystals.\nThese studies made the crystal process stable and controlled, and\npure trihydrate was obtained in a shorter time in industrial production.