Study of the Polymorphic Transformation Mechanism and Crystal Habits Control of Peramivir from Dihydrate to Trihydrate

Abstract

Peramivir is an effective antiviral drug for treating influenza A and B with the trihydrate form as the solid serving. However, a small amount of dihydrate still exists during the manufacturing process in a few production batches. Focusing on the problem, this study successfully obtained a new dihydrate single crystal structure, a higher-quality trihydrate single crystal structure surpassing previously reported findings, and a novel anhydrous form designated as form A. A comprehensive comparison of the crystal structure, crystal habits, thermal analysis, desolvation behavior, solubility, Hirshfeld Surfaces analysis, and energy frameworks was studied between peramivir dihydrate and trihydrate to understand the processes of water molecules binding on and off. The transformation process among the three crystal forms and the amorphous form revealed that the trihydrate form exhibits the most stability. The study of the polymorphic transformation mechanism revealed that dihydrate crystals precipitate initially, dissolve thereafter, and then transform into trihydrate crystals during crystallization. The conversion rate was related strongly to the stirring speed, and increasing the stirring speed accelerated both dissolution and crystal transformation, resulting in a reduction in the duration of crystallization. The crystallization time from dihydrate to trihydrate was shortened from 10 to 5.5 h when the stirring speed was increased from 50 to 300 rpm. The contrasting crystal habits of peramivir dihydrate (long rod-shaped) and trihydrate (tetragonal-shaped) also provide a quick estimate of mixed crystals. These studies made the crystal process stable and controlled, and pure trihydrate was obtained in a shorter time in industrial production.