Physicochemical Characterization of Nedocromil Bivalent Metal Salt Hydrates. 1. Nedocromil Magnesium

Abstract

Nedocromil sodium is used in the treatment of reversible obstructive airways diseases, such as asthma. The physicochemical, mechanical, and biological characteristics of nedocromil sodium can be altered by its conversion to other salt forms. In this study, three crystalline hydrates, the pentahydrate, heptahydrate, and decahydrate, of a bivalent metal salt, nedocromil magnesium (NM), were prepared. The relationships between these hydrates were studied through their 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, scanning electron microscopy (SEM), water uptake at various relative humidities (RH), intrinsic dissolution rate (IDR), and solubility measurements. The pentahydrate showed two dehydration steps, corresponding to two binding states of water, a more temperature-sensitive tetramer and a more stable monomer, deduced from the crystal structure previously determined. The heptahydrate and decahydrate each showed a dehydration step with a minor change in slope at about 50 degrees C, which was analyzed by derivative TGA and confirmed by DSC. HSM and variable temperature PXRD also confirmed the thermal dehydration behavior of the NM hydrates. The decahydrate underwent an apparently irreversible phase transformation to the pentahydrate at 75 degrees C at an elevated water vapor pressure. The PXRD, FTIR, and SSNMR of the decahydrate were similar to those of the heptahydrate, suggesting that the three extra water molecules in the decahydrate are loosely bound, but were significantly different from those of the pentahydrate. The rank order of both IDR and solubility in water at 25 degrees C was heptahydrate approximately decahydrate > pentahydrate, corresponding to the rank order of free energy with respect to the aqueous solution.

Solid-state NMR studies of pharmaceutical solids in polymer matrices

“…Bupivacaine-fb (free base) and bupivacaine-HCl have very different solid-state NMR spectra, indicating that the molecules of these compounds pack in unique crystal forms. These results are consistent with different crystalline forms of pharmaceutical compounds having unique solid-state NMR spectra [15,16,17,18,19,20,21,22,23,24,25,26]. The solid-state forms of bupivacaine in a tristearin matrix and in a matrix made of lipid, water, and protein were also investigated.…”

Identification of Phase Boundaries in Anhydrate/Hydrate Systems

“…9,46 As shown in Figures 5-7, the rate of transformation of the metastable form of caffeine to the stable form is dependent on temperature and the water activity in the vapor relative to the equilibrium water activity of the solid-state system. The phase boundary can simply be estimated by bracketing the relative humidities in which minimum conversion is detected.…”

A Thermodynamic-Based Approach to Analyzing a Highly Solvating Polymorphic System: The Desolvation Window Method

“…SW 8. 10. The experiments started at ambient temperature and heated the sample at 58C/min to 3008C under a nitrogen gas purge (flow rate was 60 mL/min).…”

“…Still other solvates are stable only below room temperature or have so far been found only to be metastable over the range studied. [3][4][5][6][7][8][9][10][11][12] These show that a solvate does not necessarily have to be the most stable form in its solvent at any temperature. The general trend is that hydrate stability is a function of temperature; this relationship has been alluded to in various works [13][14][15][16] and stated more clearly by Black et al 17 Based on these works, the following rule is emphasized:…”