Characterization of Phase Transitions During Freeze-Drying by In Situ X-ray Powder Diffractometry

Abstract

The purpose of this research was to develop the technique of in situ freeze-drying in the sample chamber of an X-ray powder diffractometer (XRD) and to monitor the phase transitions during the freeze-drying of aqueous solutions of sodium nafcillin (I) and mannitol (II). Aqueous solutions of I and II were frozen under controlled conditions in the sample chamber of an XRD. This variable temperature XRD was modified so that the sample chamber could be evacuated and the samples dried under reduced pressures. Thus the entire freeze-drying cycle was carried out in the XRD holder and the solid-state was monitored during the various stages of the process. Frozen solutions of I when annealed at -4 degrees C, resulted in crystallization of the solute as 'sodium nafcillin hydrate' (unknown stoichiometry). Primary drying at -10 degrees C, resulted in partial dehydration to a poorly crystalline sodium nafcillin hemihydrate. There was no crystallization of mannitol when solutions of II were cooled and subjected to primary drying at -50 degrees C. During the drying, the intensities of the characteristic X-ray lines of ice (d-spacings of 3.94, 3.70 and 3.48 A) were quantified. This enabled real time monitoring of the complete sublimation of crystalline ice. When the secondary drying was carried out at -25 degrees C, mannitol crystallized as an anhydrous mixture of the delta- and beta-polymorphs. In a second set of experiments, the frozen solutions were warmed to -25 degrees C and subjected to primary drying. Mannitol crystallized and its XRD pattern matched that of mannitol hydrate reported recently (Yu et al., Pharm. Res., 14S (1997) S-445). When the secondary drying was carried out at -10 degrees C, there was no change in the XRD pattern suggesting the formation of a dehydrated hydrate. This in situ XRD technique enabled us to characterize the phase transitions during freeze-drying. It would be useful in developing a mechanistic understanding of the alterations in the solid-state during freeze-drying of complex, multi-component, pharmaceutical systems.

Phase Transitions in Frozen Systems and During Freeze–Drying: Quantification Using Synchrotron X-Ray Diffractometry

“…Although solute (e.g., buffer salt) crystallization is possible, in many cases, it is retained amorphous. Solute as well as ice crystallization from the freeze-concentrate can often be induced by annealing the frozen solutions (3,(8)(9)(10)(11)(12)(13). Pikal-Cleland et al demonstrated a decrease in crystallization of disodium hydrogen phosphate buffer (initial concentration 10 mM) in the presence of amorphous glycine (initial concentration 50 mM).…”

Investigation of PEG Crystallization in Frozen PEG–Sucrose–Water Solutions: II. Characterization of the Equilibrium Behavior During Freeze-Thawing

“…[7][8][9][10][11][12] While mannitol and glycine are examples of solutes which crystallize during freeze-drying, other solutes such as sucrose, trehalose, and PVP remain Additional Supporting Information may be found in the online version of this article. amorphous.…”

Energy/Temperature Diagram and Compression Behavior of the Polymorphs of d-Mannitol

“…It is not the intention of this work to expand these investigations to pseudo-polymorphic forms (e.g., a monohydrate), which was recently described in the literature. [17][18][19] This hydrate can be formed in the process of freeze drying. It converts to anhydrous crystal forms (mod.…”