Zhu H, Padden B E, Munson E J, Grant D J
Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis 55455-0343, USA.
J Pharm Sci. 1997 Apr;86(4):418-29. doi: 10.1021/js9604422.
Salts are usually considered as alternatives for drug delivery when the physicochemical characteristics of the acidic or basic parent drug are unsuitable or inadequate for a satisfactory formulation. The physical, chemical, and biological characteristics of nedocromil sodium, which is used in the treatment of reversible obstructive airways diseases such as asthma, can be altered by its conversion to other salt forms. Nedocromil zinc (NZ), a bivalent metal salt, was found to exist in several hydration states, an octahydrate, a heptahydrate, and a pentahydrate, which itself exists in two modifications, designated as A and B. The relationships between these, NZ hydrates and the nature of the water interactions in the solid phases were studied through characterization by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Karl Fischer titrimetry (KFT), hot-stage microscopy (HSM), ambient- or variable-temperature powder X-ray diffraction (PXRD), Fourier-transform infrared (FTIR) spectroscopy, solid-state nuclear magnetic resonance (SSNMR) spectroscopy, environmental scanning electron microscopy (ESEM), water uptake at various relative humidities (RH), intrinsic dissolution rate (IDR), and solubility measurements. The integral water stoichiometries of the NZ hydrates were deduced from KFT and TGA and were confirmed by elemental analysis. For the heptahydrate, the loss of 1 mol of water at a higher temperature than for the others is attribute to an identifiable water molecule that is linked directly to the zinc and to two carboxylate oxygen atoms but not to the other water molecules, as deduced from the crystal structure previously determined. Similarly, for both pentahydrate modifications, 1 mol of water was also lost at a higher temperature than the others. Results from studies using DSC, TGA, HSM, PXRD, SSNMR, and FTIR suggested that the octahydrate contains loosely bound water in its structure and is partially amorphous. The course of the dehydration processes depended on the water vapor pressure and temperature. The octahydrate and heptahydrate underwent an apparently irreversible phase transformation to the pentahydrate at an elevated temperature and water vapor pressure. Pentahydrate modifications A and B differ in their long-range order (deduced from differences in their PXRD pattern and their thermal analytical behavior), but their short-range order (i.e., molecular environments) are identical (deduced by identical SSNMR spectra). The rank order of both IDR and solubility in water at 25 degrees C was octahydrate > heptahydrate > pentahydrate modification A approximately pentahydrate modification B, corresponding to the rank order of free energy with respect to the aqueous solution and the order of preparation according to Ostwald's rule of stages.
当酸性或碱性母体药物的物理化学特性不适合或不足以形成令人满意的制剂时，盐通常被视为药物递送的替代物。用于治疗可逆性阻塞性气道疾病（如哮喘）的奈多罗米钠，其物理、化学和生物学特性可通过转化为其他盐形式而改变。奈多罗米锌（NZ）是一种二价金属盐，被发现以几种水合状态存在，即八水合物、七水合物和五水合物，而五水合物本身又存在两种变体，分别指定为A和B。通过差示扫描量热法（DSC）、热重分析（TGA）、卡尔费休滴定法（KFT）、热台显微镜（HSM）、常温或变温粉末X射线衍射（PXRD）、傅里叶变换红外（FTIR）光谱、固态核磁共振（SSNMR）光谱、环境扫描电子显微镜（ESEM）、在各种相对湿度（RH）下的吸水量、固有溶解速率（IDR）和溶解度测量等表征方法，研究了这些水合物之间的关系以及NZ水合物在固相中水相互作用的性质。NZ水合物的积分水化学计量由KFT和TGA推导得出，并通过元素分析得到证实。对于七水合物，在比其他水合物更高的温度下失去1摩尔水归因于一个可识别的水分子，该水分子直接与锌和两个羧酸根氧原子相连，但不与其他水分子相连，这是根据先前确定的晶体结构推导出来的。同样，对于两种五水合物变体，也在比其他变体更高的温度下失去了1摩尔水。使用DSC、TGA、HSM、PXRD、SSNMR和FTIR进行的研究结果表明，八水合物在其结构中含有松散结合的水，并且部分为无定形。脱水过程的进程取决于水蒸气压和温度。八水合物和七水合物在升高的温度和水蒸气压下经历了向五水合物的明显不可逆相变。五水合物变体A和B在其长程有序性（由其PXRD图谱和热分析行为的差异推导得出）上有所不同，但它们的短程有序性（即分子环境）是相同的（由相同的SSNMR光谱推导得出）。在25℃时，IDR和在水中的溶解度的排序为八水合物>七水合物>五水合物变体A≈五水合物变体B，这与相对于水溶液的自由能排序以及根据奥斯特瓦尔德阶段规则的制备顺序相对应。
