The Complex Solid‐State Landscape of Sodium Diatrizoate Hydrates

The propensity of molecular organic compounds to form stoichiometric or nonstoichiometric crystalline hydrates remains a challenging aspect of crystal engineering and is of practical relevance to fields such as pharmaceutical science. In this work, we address the propensity for hydrate formation of a library of eight compounds comprised of 5-and 6-membered Nheterocyclic aromatics classified into three subgroups: linear dipyridyls, substituted Schiff bases, and tripodal molecules. Each molecular compound studied possesses strong hydrogen bond acceptors and is devoid of strong hydrogen bond donors. Four methods were used to screen for hydrate propensity using the anhydrate forms of the molecular compounds in our library: water slurry under ambient conditions, exposure to humidity, aqueous solvent drop grinding (SDG), and dynamic water vapor sorption (DVS). In addition, crystallization from mixed solvents was studied. Water slurry, aqueous SDG, and exposure to humidity were found to be the most effective methods for hydrate screening. Our study also involved a structural analysis using the Cambridge Structural Database, electrostatic potential (ESP) maps, full interaction maps (FIMs), and crystal packing motifs. The hydrate propensity of each compound studied was compared to a compound of the same type known to form a hydrate through a previous study of ours. Out of the eight newly studied compounds (herein numbered 4−11), three Schiff bases were observed to form hydrates. Three crystal structures (two hydrates and one anhydrate) were determined. Compound 6 crystallized as an isolated site hydrate in the monoclinic space group P2 1 /a, while 7 and 10 crystallized in the monoclinic space group P2 1 /c as a channel tetrahydrate and an anhydrate, respectively. Whereas we did not find any direct correlation between the number of H−bond acceptors and either hydrate propensity or the stoichiometry of the resulting hydrates, analysis of FIMs suggested that hydrates tend to form when the corresponding anhydrate structure does not facilitate intermolecular interactions.

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Toward an Understanding of the Propensity for Crystalline Hydrate Formation by Molecular Compounds. Part 2

Sanii

Patyk‐Kaźmierczak

Hua

et al. 2021

“…Numerous methods for the determination of stability relationships between anhydrous forms and hydrates or lower and higher hydrates have been reported, including the investigation of water (de)sorption isotherms, ,,, isothermal dehydration, − water activity in binary aqueous solutions, − solubility as a function of temperature, and intrinsic dissolution rates . Furthermore, computational techniques have been employed to calculate the enthalpy difference between hydrates (or solvates in general) and water-free forms. − …”

Section: Introductionmentioning

confidence: 99%

The Eight Hydrates of Strychnine Sulfate

Braun

Gelbrich

Kahlenberg

et al. 2020

Commercial samples of strychnine sulfate were used as the starting material in crystallization experiments accompanied by stability studies. Eight hydrate forms ( HyA – HyG ), including five novel hydrates, were verified. The crystal structures of HyA (“pentahydrate”) and HyF (“hexahydrate”) were determined from single-crystal X-ray diffraction data. HyF was identified as the most stable hydrate at high water activities at room temperature (RT), and HyA and HyC were also found to be stable at ambient conditions. Long-time storage experiments over nearly two decades confirm that these three hydrates are stable at ambient conditions (20–60% relative humidity). The other five hydrates, HyB (“dihydrate”), HyD , HyE , HyG , and HyH , are only observable at the low(est) relative humidity (RH) levels at RT. Some of these latter forms can only exist within a very narrow RH range and are therefore intermediate phases. By applying a range of complementary experimental techniques such as gravimetric moisture sorption analysis, thermal analysis, moisture controlled PXRD measurements, and variable temperature IR spectroscopy in combination with principal component analysis, it was possible to identify the distinct hydrate phases and elucidate their stability and dehydration pathways. The observed (de)hydration routes, HyA ↔ HyB , HyC ↔ HyD ↔ HyE , HyF ↔ HyG ↔ HyH and HyF → HyA ↔ HyB , depended on the initial hydrate form, particle size, and atmospheric conditions. In addition, a transformation from HyC / HyA to HyF occurs at high RH values at RT. The specific moisture and temperature conditions of none of the applied drying regimes yielded a crystalline water-free form, which highlights the essential role of water molecules for the formation and stability of the crystalline strychnine sulfate phases.

Section: Introductionmentioning

confidence: 99%

“…We could recently show this behavior for the X-ray contrast agent diatrizoic acid and its sodium salt, which both show multiple hydrates (up to the octahydrate for the sodium salt) and interconversion depending on RH. 27,28 It is also not quite clear yet what the role of the water molecules is in the crystal structure, i.e., whether it is fulfilling a purely space-filling role or if it is structure-forming. We investigated this problem by using X-ray and neutron single-crystal diffraction and used empirical crystal lattice energy calculations to deconvolute the strong molecular interactions within the hydrated crystal structure.…”

Section: ■ Introductionmentioning

confidence: 99%

Extensive Sequential Polymorphic Interconversion in the Solid State: Two Hydrates and Ten Anhydrous Phases of Hexamidine Diisethionate

Edkins

McIntyre

Wilkinson

et al. 2019

Self Cite

Crystal polymorphism and solvent inclusion is a dominant research area in the pharmaceutical industry and continues to unveil complex systems. Here, we present the solid-state system of hexamidine diisethionate (HDI), an antiseptic drug compound forming a dimorphic dihydrate as well as ten anhydrous polymorphs. The X-ray and neutron crystal structures of the hydrated crystal forms and related interaction energies show no direct interaction between the 2 cation and water but very strong interactions between cation and anion, and anion and water. This is observed macroscopically as high stability of the hydrate against dehydration by temperature and humidity. The anhydrous polymorphs reveal a rare case of sequential and reversible polymorphic transformations, which are characterized by thermal analysis and variabletemperature powder X-ray diffraction (PXRD). While most transitions are accompanied by significant structural changes, the low-energy transitions can only be detected as slight changes in the reflection positions with temperature. HDI thus represents a model compound to investigate polymorphic transitions with small structural changes.