Brian E. Padden

Physicochemical characterization of nedocromil bivalent metal salt hydrates. 3. Nedocromil calcium

A crystalline pentahydrate and a crystalline 8/3 hydrate of nedocromil calcium (NC) were prepared. The relationships between these solid phases and the nature of the water interactions in their structures 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, water uptake at various relative humidities (RH), intrinsic dissolution rate (IDR) and solubility measurements. The solubility and intrinsic dissolution rate of the pentahydrate in water at 25 degrees C are approximately 17% greater than the corresponding values for the 8/3 hydrate, corresponding to a greater Gibbs free energy of only 380 J.mol-1 (91 cal.mol-1) for the pentahydrate. The results of DSC, TGA, and FTIR and SSNMR spectroscopy indicate that the water of hydration is more loosely bound in the pentahydrate than in the 8/3 hydrate. On increasing the temperature in open-pan DSC and TGA, the water in the pentahydrate is released in four steps (three steps in crimped pans), whereas the water in the 8/3 hydrate is released in three steps (three steps also in crimped pans). These three stepwise dehydrations are fundamentally explained by their different water environments in the crystal structure of the 8/3 hydrate, which was determined by single-crystal XRD [crystal data: triclinic, space group P1, a = 13.2381(3) A, b = 13.3650(2) A, c = 17.8224(2) A, alpha = 68.202(1) degrees, beta = 86.894(1) degrees, gamma = 82.969(1) degrees, Z = 6]. The asymmetric unit contains three nedocromil anions and three calcium cations associated with eight water molecules. The nedocromil anions act as polyfunctional ligands to the Ca2+ ions, coordinating through both the carbonyl oxygen and the carboxylate oxygen atoms. The molecular conformations of the three nedocromil anions in the asymmetric unit are almost identical. However, the crystal structure contains two different calcium environments, one of which has the Ca2+ ion hydrated by four water molecules in the equatorial plane and by two carbonyl oxygens in its axial coordination sites. In the second environment, the Ca2+ ion has four carboxylate oxygen atoms in its equatorial plane and two water molecules in its axial coordination sites. Two of the carboxylate ligands are twisted out of the tricyclic ring, and the other two carboxylate ligands are nearly coplanar with the tricyclic ring. All of the eight water molecules in the 8/3 hydrate are linked to calcium and carboxylate ions and none are linked to other water molecules.

Neotame Anhydrate Polymorphs I: Preparation and Characterization

AbstractPurpose: To prepare, characterize, and compare polymorphs of neotame anhydrate. Methods: Neotame anhydrate polymorphs were prepared from amorphous or crystalline anhydrate by crystallization or suspension in various organic solvents, or by dehydration of neotame monohydrate. The following techniques were used for characterization: differential scanning calorimetry, thermogravimetry, hot-stage microscopy, powder X-ray diffractometry (PXRD), 13C solid-state nuclear magnetic resonance (SSNMR) spectroscopy, Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy, dynamic water vapor sorption/desorption, and density measurements. Results: Seven polymorphs (Forms A-G) of neotame anhydrate were prepared and show different thermal properties and PXRD patterns. Two enantiotropically related pairs were identified: B and C; E and A. 13C SSNMR and FTIR spectroscopy clearly distinguish between Forms A, D, F, and G, which show similar needle-shaped morphology but distinct differences in dynamic water vapor sorption/desorption and density. The 13C SSNMR chemical shifts suggest conformational polymorphism. The stability in the presence of water vapor follows the rank order, G > A > D ∼ F, which resembles the rank orders of the molar volume and of the polarity of the solvents from which they crystallized. Conclusions: The neotame anhydrate polymorphs appear to show different molecular conformations. The less dense polymorphic structures crystallize from solvents of greater polarity and sorb water vapor less rapidly and less completely. Two enantiotropic pairs were discerned.

Nuclear Magnetic Resonance and Infrared Spectroscopic Analysis of Nedocromil Hydrates

AbstractPurpose. Nedocromil sodium (NS), which is used in the treatment ofreversible obstructive airway diseases, such as asthma, has been foundto exist in the following solid phases: the heptahemihydrate, thetrihydrate, a monohydrate, an amorphous phase, which contains variableamounts of water, and a recently discovered methanol + water (MW)solvate. Our aim was to apply 13C solid-state nuclear magneticresonance (NMR) spectroscopy and solid-state Fourier transform infrared(FTIR) spectroscopy to the study of specific interactions in the varioussolid forms of NS. Methods. The 13 solid-state NMR and FTIR spectra of the varioussolid forms of NS were obtained and were related to the crystalstructures of NS, the conformations of the nedocromil anion, and theinteractions of the water molecules in these crystals. Results. The 13C solid-state NMR spectrum is sensitive to theconformation of the nedocromil anion, while the solid-state FTIR spectrumis sensitive to interactions of water molecules in the solid state. In NSmonohydrate, for which the crystal structure has not yet been solved,and in the amorphous phase, the information about the conformationsof the nedocromil anion and the interactions of the water moleculesare deduced from the 13C solid-state NMR spectra and solid-state FTIRspectra, respectively. Conclusions. 13C solid-state NMR spectroscopy and solid-state FTIRspectroscopy are shown to be powerful complementary tools forprobing the chemical environment of molecules in the solid state,specifically the conformation of the nedocromil anion and the interactions ofwater-molecules, respectively.

Crystal structure and physical characterization of neotame methanol solvate

The crystal structure of the methanol solvate (empirical formula: 2C20H30N2O5·3CH3OH) of a new dipeptide sweetener, neotame (N-(3,3-dimethylbutyl)-L-α-aspartyl-L-phenylalanine 1-methyl ester), has been determined. Crystal data: a = 9.8989(1), b = 18.1331(1), c = 27.5725(1) Å, orthorhombic, space group P212121, with Z = 4. Each unit cell includes 8 neotame and 12 methanol molecules. Disorder exists in one neotame molecule and one methanol molecule. The crystals were characterized by the following techniques: hot-stage microscopy (HSM), Karl-Fischer titrimetry (KFT), powder X-ray diffractometry (PXRD), differential scanning calorimetry (DSC), thermogravimetry (TGA), 13C solid-state nuclear magnetic resonance (SSNMR) spectroscopy. Under HSM at a heating rate of 10°C/min in silicone oil, the sample melts at 64–84°C and liberates bubbles at 71–86°C. DSC in open pans shows two overlapping endotherms at 56 and 71°C, probably due to melting and desolvation, respectively. TGA in open pans shows 5.9% weight loss due to desolvation below 70°C. Under house vacuum (23 mm Hg) over phosphorus pentoxide at 23°C, the methanol solvate produces pure amorphous anhydrate, which converts to crystalline neotame monohydrate in the presence of moisture.

An alternative interpretation of the HETCOR NMR spectra of poly(lactide)

An alternative to the assignments proposed recently by Chisholm et al. for the 1H and 13C NMR resonances of poly(lactide) based on their HETCOR spectra is presented; we find that the HETCOR spectra are consistent with older assignments of the tetrad and hexad stereosequence resonances in the 1H and 13C NMR spectra and we believe that the influence of adjacent chiral units on the NMR chemical shift extends asymmetrically and is opposite in the case of 1H and 13C nuclei; this is in contrast to the assumption that the observed chiral repeat unit for any particular stereosequence resonance is the same for 1H and 13C NMR spectra as used by Chisholm et al. in their analysis.