一般药品从生产出厂到药房库藏出售，要求保持至少2年的稳定不变期，这期间如果储存的条件比如湿度，温度过高，可能会导致药品的晶型改变。这其中研究最多的亚稳态晶型之一就是水分子进入药物晶型的内部结构，与原晶型分子形成氢键链接，从而形成新的晶型：水合物。关于水合物的研究，最典型的案例有1993年的卡马西平 (carbamazepine) 事件。因为储存时受潮，卡马西平药片中的无水化合物变为水合物 (如上图所示)，从而导致卡马西平的药效大幅降低。最终该药不得不全部从市场撤出。
相关阅读：Tian F, Zeitler JA, Strachan CJ, Savllle D, Gordon KC, Rades T, Journal of Pharmaceutical and Biomedical Analysis 2006, 40:271-280。
水合物的分类： Isolated-site hydrats
定义: water molecules are isolated, in another word, not in contact with one another.
特性: Removal of water from isolated site hydrates typically requires a certain higher energy than those channel hydrates. But once the dehydration starts, the majority of water will be escaped promptly。
分析测量: when analyzed by thermal methods, the dehydration of isolated site hydrates exhibits sharp dehydration endotherms (indicated by sharp endothermic peaks in differential scanning calorimetry (DSC)), and narrow weight loss ranges (observed with thermogravimetric analysis (TGA)). Also, in infrared spectroscopy, these crystalline water molecules show sharp OH bands。
Channel hydrates
定义: the crystalline water form channel-like chains along a given crystal axis.
特性: The water molecules in this class form hydrogen bonds with the adjacent water molecules. The existence of water channel facilitates the water elimination from the hydrate crystals. Once the surface crystalline water is removed, the inside water will start escaping one by one through the water channel, which results in a relatively low thermal stability of the channel hydrates.
分析测量: These hydrates usually have lower onset dehydration temperature than the isolated site hydrates. Also, the dehydration peaks in DSC is rather broad, and TGA weight loss range is rather wide too. Although they also have sharp OH bands in infrared spectra, these bands are orientated at a relatively low frequency indicating a lower bonding energy.
Ion-associated hydrates
定义: contain ion-coordinated water
特性和分析: high dehydration temperatures are characteristic for this class because of the strong bond strength of this class.
c. 多晶型水合物
定义: two or more hydrates having the same chemical composition and same molar ratio of water in the crystalline lattice, differing only in their crystal packing arrangements.
如下图，两种NF的一水化合物，同样的化学组成 (上图)，但不同的结构（下图）。
然同样为NF一水合物，其物理化学性质并不一样，比如NF一水合物在水中（23 oC）的溶解度分别为： 131 ± 12 μg/ml 和 110 ± 4 μg/ml.
不仅仅是溶解度，类似于水合物和无水合物，同一水合物不同晶型之间的其他物化性质也通常会有差异。正是这些性质的不同，水合物多晶型的结晶和筛选也是不容忽视的。
相关阅读： Tian F and Rantanen J, Food Biophysics 2011, 6, 250–258
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