Existence of a mannitol hydrate during freeze-drying and practical implications

We report thermal and crystallographic evidence for a previously unknown ma nnitol hydrate that is formed in the process of freeze-drying. The mannitol hydrate was produced by freeze-drying pure mannitol solutions (1-4% w/v) u sing the following cycle: (1) equilibration at -5 degrees C for 1 h; (2) fr eezing at -40 degrees C; (3) primary drying at -10 degrees C for 15 h; and (4) secondary drying at 10 degrees C for 2 h and then 25 degrees C for 5 h. This crystal form was also observed upon freeze-drying in the presence of sorbitol (1% w/v). The mannitol hydrate showed a distinct X-ray powder diff raction pattern, low melting point, and steplike desolvation behavior that is characteristic of crystalline hydrates. The mannitol hydrate was found t o be metastable, converting to anhydrous polymorphs of mannitol upon heatin g and exposure to moisture. The amount of the mannitol hydrate varied signi ficantly from vial to vial, even within the same batch. The formation of ma nnitol hydrate has several potential consequences: (1) reduced drying rate; (2) redistribution of the residual hydrate water during accelerated storag e to the amorphous drug; and (3) vial-to-vial variation of the moisture lev el.