New Sodium Mefenamate - Nicotinamide Multicomponent Crystal Development to Modulate Solubility and Dissolution: Preparation, Structural, and Performance Study.

A cocrystal of mefenamic acid (MA) - nicotinamide (NA) has been reported to increase the solubility of MA, but it still does not exceed the solubility of sodium mefenamate (SM). Accordingly, this research dealt with a new salt cocrystal arrangement of SM - NA. Cocrystal screening was performed, followed by powder and single-crystal preparation. Solvent drop grinding and slow evaporation at cold and ambient temperatures were employed to produce the multicomponent crystal. Two new salt cocrystals were found as hemihydrates and monohydrates, named SMN-HH and SMN-MH, respectively. SMN-MH single crystals were successfully isolated and structurally analyzed using a single crystal X-ray diffractometer. Pharmaceutical properties were investigated, including hydrate stability, solubility, and intrinsic dissolution. The experiments showed that the hemihydrate was stable under ambient humidity and temperature, and that the monohydrate rapidly changed to hemihydrate. Both hydrates improved the solubility and intrinsic dissolution of SM, but SMN-HH was superior. The data showed that SMN salt cocrystals combine the advantages of salt and cocrystals and show potential for dosage form development.

Composing Novel Diclofenac Potassium and l-Proline Salt Cocrystal as a Strategy to Increase Solubility and Dissolution.

This research dealt with the multicomponent crystal developed from diclofenac potassium and l-proline to improve the pharmaceutical performance of this anti-inflammatory drug. Slow evaporation of the component mixture at a 1:1 M ratio, supported by ultrasonication, yielded a new salt cocrystal, which was characterized using thermal analysis, Karl Fischer titration, infrared spectrophotometry, powder diffractometry, and single crystal diffractometry. This salt cocrystal was confirmed as a tetrahydrate that comprised diclofenac potassium, l-proline, and water (1:1:4), named DKPH. The new salt cocrystal enhanced the solubility of diclofenac potassium by up to 3.56 folds and accelerated the intrinsic dissolution rate of 3.36 folds. It was supported by the solid and solution phase intermolecular interaction study. A different phase, which indicated a monohydrate form of the salt cocrystal, was found from the low humidity chamber during the isotherm sorption study. However, the tetrahydrate, DKPH, was proven as a stable form under ambient conditions.

Salt Cocrystal of Diclofenac Sodium-L-Proline: Structural, Pseudopolymorphism, and Pharmaceutics Performance Study.

Previously, we have reported on a zwitterionic cocrystal of diclofenac acid and L-proline. However, the solubility of this multicomponent crystal was still lower than that of diclofenac sodium salt. Therefore, this study aimed to observe whether a multicomponent crystal could be produced from diclofenac sodium hydrate with the same coformer, L-proline, which was expected to improve the pharmaceutics performance. Methods involved screening, solid phase characterization, structure determination, stability, and in vitro pharmaceutical performance tests. First, a phase diagram screen was carried out to identify the molar ratio of the multicomponent crystal formation. Next, the single crystals were prepared by slow evaporation under two conditions, which yielded two forms: one was a rod-shape and the second was a flat-square form. The characterization by infrared spectroscopy, thermal analysis, and diffractometry confirmed the formation of the new phases. Finally, structural determination using single crystal X-ray diffraction analysis solved the new salt cocrystals as a stable diclofenac-sodium-proline-water (1:1:1:4) named NDPT (natrium diclofenac proline tetrahydrate), and unstable diclofenac-sodium-proline-water (1:1:1:1), named NDPM (natrium diclofenac proline monohydrate). The solubility and dissolution rate of these multicomponent crystals were superior to those of diclofenac sodium alone. The experimental results that this salt cocrystal is suitable for further development.

Synthesis of Belt- and Möbius-Shaped Cycloparaphenylenes by Rhodium-Catalyzed Alkyne Cyclotrimerization.

A belt-shaped [8]cycloparaphenylene (CPP) and an enantioenriched Möbius-shaped [10]CPP have been synthesized by high-yielding rhodium-catalyzed intramolecular cyclotrimerizations of a cyclic dodecayne and a pentadecayne, respectively. This Möbius-shaped [10]CPP possesses stable chirality and isolated with high enantiomeric purity. It is evident from the reaction Gibbs energy calculation that the above irreversible cyclotrimerizations are highly exothermic; therefore establishing that the intramolecular alkyne cyclotrimerization is a powerful route to strained cyclic molecular strips.

Multicomponent Crystal of Mefenamic Acid and N-Methyl-d-Glucamine: Crystal Structures and Dissolution Study.

A novel multicomponent crystal (MC) of mefenamic acid (MA) and N-methyl-d-glucamine (MG) had been prepared to improve the physicochemical properties of poorly soluble drugs, and was characterized for its physicochemical properties by powder X-ray diffraction analysis, differential scanning calorimetry thermal analysis, FT-IR spectroscopy, in vitro dissolution rate, and physical stability. In addition, the crystal structure was determined by single-crystal X-ray diffraction analysis. The differential scanning calorimetry thermogram of the MA-MG binary system exhibits a single and sharp endothermic peak at 151.20°C, which was attributed to the melting point of a MC of MA-MG. FT-IR spectroscopy analysis showed the occurrence of solid-state interaction by involving proton transfer between MA and MG. The crystal structure analysis confirmed that MA-MG formed 1:1 ratio salt type MC. The formation of a MC of MA with MG significantly improved the dissolution rate of MA in compared to intact MA, and also the crystal demonstrated a good stability under a high relative humidity. These good properties would be attributed to the layer structure of MA and MG in the crystal.