Naproxen–Nicotinamide Cocrystals: Racemic and Conglomerate Structures Generated by CO₂ Antisolvent Crystallization

Cocrystallization of naproxen racemic mixture and nicotinamide was investigated in this work, using compressed CO₂ as antisolvent. A novel racemic cocrystal structure containing both enantiomers of naproxen linked to nicotinamide has been produced thanks to the CO₂ antisolvent batch crystallization process. The structure of the molecular complex and its intermolecular interactions were investigated by single-crystal X-ray diffraction and attenuated total reflectance Fourier transform infrared spectroscopy. The antisolvent feed rate was found to have a direct influence on the cocrystallization outcome. The racemic cocrystal was obtained at slow and moderate CO₂ feed rate, while very fast introduction of CO₂ resulted in the formation of a mixture of chiral cocrystals (conglomerate). Cross-seedings, thermal analysis, and temperature-resolved X-ray powder diffraction were used to probe the relationship between the different phases. In addition, all powders produced with CO₂ technology were obtained as cocrystal-pure, without significant excess of naproxen or nicotinamide homocrystals

Mechanisms of Reversible Phase Transitions in Molecular Crystals: Case of Ciclopirox

The detailed characterization of several subambient solid state transitions occurring in the pharmaceutical ingredient Ciclopirox between −20 °C and −85 °C was performed by using a combination of DSC, cold-stage optical microscopy, vibrational spectroscopies, solid state NMR at controlled temperature, structural analyses by single crystal X-ray diffraction, and temperature-resolved X-ray powder diffraction. The global analysis of the available data reveals that the mechanisms of these reversible transitions involve a subtle compromise between phenomena related to molecular disorder, cooperative release of strains induced by cooling, and structural reorganization associated with topotactic changes in crystal lattice and symmetry. However, no major change in the main features of crystal packings is observed during the successive single crystal-to-single crystal transitions, which highlights the difficulty to classify such transitions in the frame of conventional theoretical frameworks. The successive thermal events and related structural changes or relaxations can be seen as the consequences of a deconvolution phenomenon for the global phase transition between the dynamically disordered room temperature form (<i>C</i>2/<i>c</i>, Z = 8, Z′ = 1) and the ordered low-temperature form (<i>P</i>2₁/<i>c</i>, Z = 48, Z′ = 12). In this respect, the intermediate form(s) can be seen as transient states of kinetic origin with a questionable genuine crystallographic relevance

Molecular Relaxations in Supercooled Liquid and Glassy States of Amorphous Quinidine: Dielectric Spectroscopy and Density Functional Theory Approaches

In this article, we conduct a comprehensive molecular relaxation study of amorphous Quinidine above and below the glass-transition temperature (<i>T</i>_g) through broadband dielectric relaxation spectroscopy (BDS) experiments and theoretical density functional theory (DFT) calculations, as one major issue with the amorphous state of pharmaceuticals is life expectancy. These techniques enabled us to determine what kind of molecular motions are responsible, or not, for the devitrification of Quinidine. Parameters describing the complex molecular dynamics of amorphous Quinidine, such as <i>T</i>_g, the width of the α relaxation (β_KWW), the temperature dependence of α-relaxation times (τ_α), the fragility index (<i>m</i>), and the apparent activation energy of secondary γ relaxation (<i>E</i>_a‑γ), were characterized. Above <i>T</i>_g (> 60 °C), a medium degree of nonexponentiality (β_KWW = 0.5) was evidenced. An intermediate value of the fragility index (<i>m</i> = 86) enabled us to consider Quinidine as a glass former of medium fragility. Below <i>T</i>_g (< 60 °C), one well-defined secondary γ relaxation, with an apparent activation energy of <i>E</i>_a‑γ = 53.8 kJ/mol, was reported. From theoretical DFT calculations, we identified the most reactive part of Quinidine moieties through exploration of the potential energy surface. We evidenced that the clearly visible γ process has an intramolecular origin coming from the rotation of the CH­(OH)­C₉H₁₄N end group. An excess wing observed in amorphous Quinidine was found to be an unresolved Johari–Goldstein relaxation. These studies were supplemented by sub-<i>T</i>_g experimental evaluations of the life expectancy of amorphous Quinidine by X-ray powder diffraction and differential scanning calorimetry. We show that the difference between <i>T</i>_g and the onset temperature for crystallization, <i>T</i>_c, which is 30 K, is sufficiently large to avoid recrystallization of amorphous Quinidine during 16 months of storage under ambient conditions

Enhanced Second Harmonic Generation from an Organic Self-Assembled Eutectic Binary Mixture: A Case Study with 3‑Nitrobenzoic and 3,5-Dinitrobenzoic Acids

This work illustrates the use of powder second harmonic generation (powder SHG), temperature-resolved second harmonic generation (TR-SHG), and second harmonic generation microscopy (SHGM) in monophasic and multiphasic sample studies. The commercial powder of 3,5-dinitrobenzoic acid was found to exhibit a significant second harmonic generation signal, whereas only two centrosymmetric polymorphic forms have been reported for this compound. Second harmonic generation techniques were used in combination with chromatography, differential scanning calorimetry, and powder X-ray diffraction to show that the SHG activity of 3,5-dinitrobenzoic acid powder originates from a chemical impurity (3-nitrobenzoic acid) present in the commercial powder under the form of a new metastable noncentrosymmetric polymorph. The metastable equilibria between 3,5-dinitrobenzoic acid and 3-nitrobenzoic acid were studied, and SHG analyses performed on crystallized binary mixtures showed significant enhancements of the SHG signal compared to that of the pure noncentrosymmetric phase. This is due to the formation of a suitable eutectic microstructure that enables quasi phase matching (QPM). In particular, powders from near-eutectic compositions exhibit SHG signals up to 20 times higher than that of the powder containing pure 3-nitrobenzoic acid noncentrosymmetric phase. This observation could provide the basis for a new route to achieve new, efficient materials for second-order frequency conversion

Molecular Relaxations in Supercooled Liquid and Glassy States of Amorphous Quinidine: Dielectric Spectroscopy and Density Functional Theory Approaches

In this article, we conduct a comprehensive molecular relaxation study of amorphous Quinidine above and below the glass-transition temperature (<i>T</i>_g) through broadband dielectric relaxation spectroscopy (BDS) experiments and theoretical density functional theory (DFT) calculations, as one major issue with the amorphous state of pharmaceuticals is life expectancy. These techniques enabled us to determine what kind of molecular motions are responsible, or not, for the devitrification of Quinidine. Parameters describing the complex molecular dynamics of amorphous Quinidine, such as <i>T</i>_g, the width of the α relaxation (β_KWW), the temperature dependence of α-relaxation times (τ_α), the fragility index (<i>m</i>), and the apparent activation energy of secondary γ relaxation (<i>E</i>_a‑γ), were characterized. Above <i>T</i>_g (> 60 °C), a medium degree of nonexponentiality (β_KWW = 0.5) was evidenced. An intermediate value of the fragility index (<i>m</i> = 86) enabled us to consider Quinidine as a glass former of medium fragility. Below <i>T</i>_g (< 60 °C), one well-defined secondary γ relaxation, with an apparent activation energy of <i>E</i>_a‑γ = 53.8 kJ/mol, was reported. From theoretical DFT calculations, we identified the most reactive part of Quinidine moieties through exploration of the potential energy surface. We evidenced that the clearly visible γ process has an intramolecular origin coming from the rotation of the CH­(OH)­C₉H₁₄N end group. An excess wing observed in amorphous Quinidine was found to be an unresolved Johari–Goldstein relaxation. These studies were supplemented by sub-<i>T</i>_g experimental evaluations of the life expectancy of amorphous Quinidine by X-ray powder diffraction and differential scanning calorimetry. We show that the difference between <i>T</i>_g and the onset temperature for crystallization, <i>T</i>_c, which is 30 K, is sufficiently large to avoid recrystallization of amorphous Quinidine during 16 months of storage under ambient conditions