Characterization of phase transitions during freeze-drying by in situ X- ray powder diffractometry

Raghu K. Cavatur, Raj Suryanarayanan

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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 mannitoI (II). Aqueous solutions of I and H 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°C, resulted in crystallization of the solute as 'sodium nafcillin hydrate' (unknown stoichiometry). Primary drying at -10°C, resulted in partial dehydration to a poorly crystalline sodium nafcillin hemihydrate. There was no crystallization of mannitol when solutions of H were cooled and subjected to primary drying at -50°C. During the drying, the intensities of the characteristic X-ray lines of ice (d- spacings of 3.94, 3.70 and 3.48 Å) were quantified. This enabled real time monitoring of the complete sublimation of crystalline ice. When the secondary drying was carried out at -25°C, mannitol crystallized as an anhydrous mixture of the δ- and β-polymorphs. In a second set of experiments, the frozen solutions were warmed to -25°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°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.

Original languageEnglish (US)
Pages (from-to)579-586
Number of pages8
JournalPharmaceutical Development and Technology
Issue number4
StatePublished - 1998

Bibliographical note

Funding Information:
RKC was partially supported by the International Student Work Opportunity Program of the University of Minnesota. We thank Dr. Lian Yu (Eli Lilly) for providing us some of his unpublished data on mannitol hydrate (L. Yu et al., Existence of a mannitol hydrate during freeze-drying and practical implications, manuscript under review) and for his insightful comments. We also thank Drs. Sarma Duddu (Inhale Therapeutic Systems) and Murti Vemuri (Rhone-Poulenc Rorer) for the stimulating and helpful discussions.


  • Freeze-drying
  • Mannitol
  • Phase transitions
  • Sodium nafcillin
  • X-ray powder diffractometry


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