Energetics and Structure of Nicotinic Acid (Niacin)

Abstract

The standard molar enthalpies of formation and sublimation of crystalline (monoclinic, space group P2(1)/c) nicotinic acid (NA), at 298.15 K, were determined as Delta(f)H(m)(o)(NA, cr) = -344.7 +/- 1.2 kJ x mol(-1) and Delta(sub)H(m)(o)(NA) = 112.1 +/- 0.5 kJ x mol(-1) by using combustion calorimetry, drop-sublimation Calvet microcalorimetry, and the Knudsen effusion method. The experimental determinations were all based on a sample of NIST Standard Reference Material 2151, which was characterized in terms of chemical purity, phase purity, and morphology. From the above results, Delta(f)H(m)(o)(NA, g) = -232.6 +/- 1.3 kJ x mol(-1) could be derived. On the basis of this value and on published experimental data, the enthalpy of the isodesmic reaction nicotinic acid(g) + benzene(g) --> benzoic acid(g) + pyridine(g) was calculated as -3.6 +/- 2.7 kJ x mol(-1) and compared with the corresponding predictions by the B3LYP/cc-pVTZ (-3.6 kJ x mol(-1)), B3LYP/aug-cc-pVTZ (-3.7 kJ x mol(-1)), B3LYP/6-311++G(d,p) (-4.2 kJ x mol(-1)), G3MP2 (-4.3 kJ x mol(-1)), and CBS-QB3 (-4.0 kJ x mol(-1)) quantum chemistry models. The excellent agreement between the experimental and theoretical results supports the reliability of the Delta(f)H(m)(o) (NA, cr), Delta(sub)H(m)(o)(NA), and Delta(f)H(m)(o)(NA, g) recommended in this work. These data can therefore be used as benchmarks for discussing the energetics of nicotinic acid in the gaseous and crystalline states and, in particular, to evaluate differences imparted to solid forms by the production and processing methods. Such differences are perhaps at the root of the significant inconsistencies found between the published enthalpies of sublimation of this important active pharmaceutical ingredient and thermochemical standard. The molecular packing in the crystalline phase studied in this work was also discussed and its influence on the molecular structure of nicotinic acid was analyzed by comparing bond distances and angles published for the solid state with those predicted by the B3LYP/cc-pVTZ method. No advantage in terms of accuracy of the structural predictions was found by the use of the larger aug-cc-pVTZ or 6-311++G(d,p) basis sets.

Thermochemistry of aqueous pyridine-3-carboxylic acid (nicotinic acid)

“…The solution calorimetric experiments were performed by using the same nicotinic acid sample (NIST, standard reference material 2151) [9], previously employed in the determination of D f H m ðNA; crÞ and D sub H m (NA) [7]. This material had been characterized in terms chemical purity, phase purity, and morphology by elemental analysis, diffuse reflectance infrared Fourier-transform (DRIFT) spectroscopy, 1 H-and 13 C NMR, GC-MS, X-ray powder diffraction, scanning electron microscopy (SEM), and DSC [7].…”

“…This material had been characterized in terms chemical purity, phase purity, and morphology by elemental analysis, diffuse reflectance infrared Fourier-transform (DRIFT) spectroscopy, 1 H-and 13 C NMR, GC-MS, X-ray powder diffraction, scanning electron microscopy (SEM), and DSC [7].…”

“…We recently embarked on a systematic investigation of some key thermodynamic properties of nicotinic acid and its derivatives, which are relevant, for example, to evaluate the relative stability of different samples when the compounds are employed as solid APIs [6,7]. This led us to re-evaluate the standard molar enthalpy of formation of nicotinic acid in the crystalline state, D f H m ðNA; crÞ, and also its standard molar enthalpy of sublimation, D sub H m (NA), at T = 298.15 K [7] by using a combination of experimental and computational chemistry methods [7].…”

“…This led us to re-evaluate the standard molar enthalpy of formation of nicotinic acid in the crystalline state, D f H m ðNA; crÞ, and also its standard molar enthalpy of sublimation, D sub H m (NA), at T = 298.15 K [7] by using a combination of experimental and computational chemistry methods [7].…”

Heat capacity and thermodynamics of solid and liquid pyridine-3-carboxylic acid (nicotinic acid) over the temperature range 296K to 531K

“…In a series of previous publications we have reported on various aspects of the thermodynamics of nicotinic acid and some of its derivatives, namely (i) the relationship between structure and energetics of both the isolated molecules and anhydrous or hydrate forms of nicotinic acid, 2-, 4-, 5-, and 6-hydroxy nicotinic acids, and 5-chloro-6-hydroxynicotinic acid [13][14][15]; (ii) the concentration dependence of the enthalpy of solution of nicotinic acid in water [16]; (iii) the solubility of nicotinic acid in a series of solvents differing in polarity, polarizability and hydrogen-bonding ability [17]; (iv) the influence of temperature and ionic strength on the acidity constants of nicotinic acid in aqueous solution [18]; and (v) the determination of the standard molar enthalpies of formation of the three nicotinic acid species involved in aqueous protonation/deprotonation equilibria at infinite dilution [16].…”