在叔丁醇 - 水共溶剂体系冻干过程中头孢噻吩钠的结晶

Crystallization of cephalothin sodium during lyophilization from tert-butyl alcohol-water cosolvent system.

作者信息

Telang Chitra, Suryanarayanan Raj

机构信息

Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455, USA.

出版信息

Pharm Res. 2005 Jan;22(1):153-60. doi: 10.1007/s11095-004-9021-3.

DOI:10.1007/s11095-004-9021-3

PMID:15771242

Abstract

PURPOSE

Because cephalothin sodium (I) does not crystallize readily when freeze-dried from aqueous solutions, organic cosolvents were used to increase the crystallinity of lyophilized I.

METHODS

Compound I was lyophilized from water-organic cosolvent (5% w/w) systems of each ethanol, ispropanol, and tert-butyl alcohol (TBA).

RESULTS

When frozen solutions of I (10% w/w) in each of these cosolvent systems was characterized by DSC, the presence of cosolvent in the freeze-concentrate was evident. Moreover, the presence of the cosolvent accelerated the solute crystallization. This observation was based on the XRD of these systems during the various stages of freeze-drying. High initial solute concentration and annealing of frozen solutions facilitated the formation of a highly crystalline lyophile. The accelerated crystallization is attributed to supersaturation in cosolvent systems, facilitating nucleation during freezing with subsequent growth during annealing. Lyophiles obtained from water-isopropanol and water-ethanol systems collapsed, while the use of TBA as a cosolvent yielded a friable and pharmaceutically elegant cake, containing fine needle-shaped crystals of I. Gas chromatography revealed a residual TBA concentration of approximately 0.001% w/w in the crystalline lyophiles. In general, residual cosolvent levels were higher in lyophiles with lower crystallinity.

CONCLUSIONS

TBA-water was found to be a suitable freeze-drying medium to promote crystallization of I and yielded a lyophile with desirable product characteristics.

摘要

目的

由于头孢噻吩钠（I）从水溶液中冻干时不易结晶，因此使用有机共溶剂来提高冻干产物I的结晶度。

方法

将化合物I从乙醇、异丙醇和叔丁醇（TBA）各自的水-有机共溶剂（5% w/w）体系中冻干。

结果

当通过差示扫描量热法（DSC）对I（10% w/w）在这些共溶剂体系中的冷冻溶液进行表征时，冷冻浓缩物中共溶剂的存在很明显。此外，共溶剂的存在加速了溶质结晶。这一观察结果基于冻干各个阶段这些体系的X射线衍射（XRD）。高初始溶质浓度和冷冻溶液的退火促进了高度结晶冻干物的形成。加速结晶归因于共溶剂体系中的过饱和，在冷冻过程中促进成核，随后在退火过程中生长。从水-异丙醇和水-乙醇体系获得的冻干物塌陷，而使用TBA作为共溶剂得到了一种易碎且在药学上外观良好的块状物，含有I的细针状晶体。气相色谱显示结晶冻干物中TBA的残留浓度约为0.001% w/w。一般来说，结晶度较低的冻干物中残留共溶剂水平较高。