Cavatur R K, Suryanarayanan R
College of Pharmacy, University of Minnesota, Minneapolis, USA.
Pharm Dev Technol. 1998 Nov;3(4):579-86. doi: 10.3109/10837459809028642.
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.
本研究的目的是开发在X射线粉末衍射仪（XRD）样品室中进行原位冷冻干燥的技术，并监测萘夫西林钠（I）和甘露醇（II）水溶液冷冻干燥过程中的相变。将I和II的水溶液在XRD样品室中在受控条件下冷冻。对该可变温度XRD进行了改进，以便可以抽空样品室并在减压下干燥样品。因此，整个冷冻干燥循环在XRD支架中进行，并在该过程的各个阶段监测固态情况。I的冷冻溶液在-4℃退火时，溶质结晶为“萘夫西林钠水合物”（化学计量未知）。在-10℃进行一次干燥，导致部分脱水形成结晶性较差的萘夫西林钠半水合物。当II的溶液冷却并在-50℃进行一次干燥时，甘露醇没有结晶。在干燥过程中，对冰的特征X射线线强度（d间距为3.94、3.70和3.48 Å）进行了定量。这使得能够实时监测结晶冰的完全升华。当在-25℃进行二次干燥时，甘露醇结晶为δ-和β-多晶型物的无水混合物。在第二组实验中，将冷冻溶液加热至-25℃并进行一次干燥。甘露醇结晶，其XRD图谱与最近报道的甘露醇水合物的图谱匹配（Yu等人，《药物研究》，14S（1997年）S-445）。当在-10℃进行二次干燥时，XRD图谱没有变化，表明形成了脱水水合物。这种原位XRD技术使我们能够表征冷冻干燥过程中的相变。它将有助于对复杂的多组分药物系统冷冻干燥过程中固态变化形成机理理解。
