We report thermal and crystallographic evidence for a previously unknown mannitol 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) using the following cycle: (1) equilibration at -5 degreesC for 1 h; (2) freezing at -40 degreesC; (3) primary drying at -10 degreesC for 15 h; and (4) secondary drying at 10 degreesC for 2 h and then 25 degreesC 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 diffraction pattern, low melting point, and steplike desolvation behavior that is characteristic of crystalline hydrates. The mannitol hydrate was found to be metastable, converting to anhydrous polymorphs of mannitol upon heating and exposure to moisture. The amount of the mannitol hydrate varied significantly from vial to vial, even within the same batch. The formation of mannitol hydrate has several potential consequences: (1) reduced drying rate; (2) redistribution of the residual hydrate water during accelerated storage to the amorphous drug; and (3) vial-to-vial variation of the moisture level.

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The results underscore the importance of recognizing that seemingly minor changes in formulation conditions can have profound effects on the physical chemistry of freezing and freeze drying.

The rate of hydrolysis of methylprednisolone sodium succinate in the freeze dried solid state at 40 degrees C was determined in the presence of two common bulking agents--mannitol and lactose--at two different ratios of drug to excipient. Residual moisture levels were less than 1% in all samples tested, with no significant difference in residual moisture among different formulations. Rate of hydrolysis was significantly higher in mannitol-containing formulations versus lactose-containing formulations, and the rate of hydrolysis increases with increasing ratio of mannitol to drug. Thermal analysis and x-ray diffraction data are consistent with a composition-dependent rate of crystallization of mannitol in the formulation and its subsequent effect on distribution of water in the freeze-dried matrix. Increased water in the microenvironment of the drug decreases the glass transition temperature of the amorphous phase, resulting in an increased rate of reaction. The physical state of lactose remained constant throughout the duration of the study, and the rate of hydrolysis was not significantly different from the control formulation containing no excipient. Thermal analysis and x-ray diffraction data are consistent with formation of a liquid crystal phase in freeze-concentrated solutions of methylprednisolone sodium succinate containing no excipient.