Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow, G4 0RE, United Kingdom.
Acta Crystallogr B Struct Sci Cryst Eng Mater. 2023 Apr 1;79(Pt 2):164-175. doi: 10.1107/S2052520623001282. Epub 2023 Mar 9.
Understanding the solvation and desolvation of pharmaceutical materials is an important part of materials discovery and development. In situ structural data are vital to understand the changes to crystal form that may occur in the system. In this study, the isolation and characterization of seven solvates of the L-type calcium channel antagonist, nifedipine, is described using variable-temperature powder X-ray diffraction so that the structural evolution as a function of temperature can be followed. The solvates reported herein can be split into those that are structurally similar to the previously reported dimethyl sulfoxide (DMSO) and dioxane solvates and those that have a novel packing arrangement. Of particular note is the solvate with tetrahydrofuran (THF) which has a hydrogen-bonding motif between the nifedipine molecules very similar to that of metastable β-nifedipine. In addition to variable-temperature X-ray diffraction, the stability of the solid forms was assessed using differential scanning calorimetry and thermogravimetric analysis and indicates that in all cases desolvation results in the thermodynamically stable α-polymorph of nifedipine even with the THF solvate. From the diffraction data the pathway of desolvation during heating of the DMF solvate showed conversion to another likely 1:1 polymorph before desolvation to α-nifedipine. The desolvation of this material indicated a two-stage process; first the initial loss of 90% of the solvent before the last 10% is lost on melting. The methanol solvate shows interesting negative thermal expansion on heating, which is rarely reported in organic materials, but this behaviour can be linked back to the winerack-type hydrogen-bonding pattern of the nifedipine molecules.
理解药物材料的溶剂化和去溶剂化作用是材料发现和开发的重要组成部分。原位结构数据对于理解系统中可能发生的晶体形态变化至关重要。在这项研究中，通过变温粉末 X 射线衍射描述了 L 型钙通道拮抗剂硝苯地平的七种溶剂化物的分离和表征，以便可以跟踪随温度变化的结构演变。本文报道的溶剂化物可以分为与先前报道的二甲基亚砜（DMSO）和二氧六环溶剂化物结构相似的溶剂化物和具有新颖包装排列的溶剂化物。特别值得注意的是与四氢呋喃（THF）形成的溶剂化物，其硝苯地平分子之间的氢键模式非常类似于亚稳β-硝苯地平。除了变温 X 射线衍射外，还使用差示扫描量热法和热重分析评估了固体形式的稳定性，这表明在所有情况下，去溶剂化都会导致硝苯地平的热力学稳定α-多晶型物，即使是与 THF 形成的溶剂化物也是如此。从衍射数据可以看出，在加热 DMF 溶剂化物时的去溶剂化途径表明在去溶剂化为α-硝苯地平之前，首先会转化为另一种可能的 1:1 多晶型物。该材料的去溶剂化表明是一个两阶段过程；首先是初始失去 90％的溶剂，然后在熔化时最后失去 10％。甲醇溶剂化物在加热时表现出有趣的负热膨胀，这在有机材料中很少见，但这种行为可以追溯到硝苯地平分子的Winerack 型氢键模式。
