Enhanced Dissolution of Naproxen by Combining Cocrystallization and Eutectic Formation

Abstract

Improving dissolution properties of active pharmaceutical ingredients (APIs) is a critical step in drug development with the increasing occurrence of sparingly soluble APIs. Cocrystal formation is one of the methods to alter the physicochemical properties of APIs, but its dissolution behavior in biorelevant media has been scrutinized only in recent years. We investigated the combined strategy of cocrystallization and eutectic formation in this regard and utilized the cocrystal model system of naproxen and three pyridinecarboxamide isomers. Binary melting diagrams were constructed to discover the eutectic compositions of the three cocrystals with excess amounts of pyridinecarboxamides. The melt–crystallized eutectics and cocrystals were compared in their dissolution behaviors with respect to neat naproxen. The eutectics enhanced the early dissolution rates of the cocrystals in both the absence and presence of biologically relevant bile salt and phospholipid components, whereas the cocrystal dissolution was expedited and delayed, respectively. The combined strategy in the present study will be advantageous in maximizing the utility of the pharmaceutical cocrystals.

Anti-hypertensive Effect of a Novel Angiotensin II Receptor Neprilysin Inhibitor (ARNi) -S086 in DSS rat model

“…NEPi and ARB combine to form a cocrystal, which reduces the risk of vascular edema caused by omapatrilat (NEPi and ACE). The cocrystal form has better drug properties than physical mixtures since it improves solubility, enhances compound PK properties, and increases absorption (Kim, Jang, et al, 2021;Cysewski, 2017). We developed S086-a novel ARNi cocrystal, which improved EXP3174's previously poor PK profile.…”

Mechanochemical synthesis of drug–drug eutectics of the antibacterial agent, linezolid

“…Thus, high shear forces and the compressive impacts generated in the process of mechanical milling in a ball mill not only break down the size of crystallites but also contribute to efficient chemical mixing and surface interactions. 38…”

“…Thus, high shear forces and the compressive impacts generated in the process of mechanical milling in a ball mill not only break down the size of crystallites but also contribute to efficient chemical mixing and surface interactions. 38 Because they influence drug bioavailability, the properties, solubility, and dissolution of pharmaceutical solids are critical physicochemical parameters. [39][40][41][42][43][44][45] Weak interactions and excess thermodynamic functions (free energy, enthalpy, and entropy) of eutectics confer these materials with higher solubility and faster dissolution rate vis-à-vis their pristine crystalline components.…”

Two Novel Co-Crystals of Naproxen: Comparison of Stability, Solubility and Intermolecular Interaction

“…Thus, pharmaceutical co-crystal technology has been demonstrated to be important in improving the poor solubility of NPX. NPX can form co-crystals or salts with the following CCFs or SFs, namely, nicotinamide [ 12 ], isonicotinamide [ 13 ] and picolinamide [ 14 ], duloxetine [ 15 ], and several chiral amino acids, including L-alanine [ 16 ], D-alanine, D-tyrosine, and D-tryptophan [ 17 ], arginine [ 18 ], zwitterionic prolinium [ 19 ], tramadol [ 20 ], bipyridine and piperazine [ 21 ], 4-amino pyridine and 2-amino pyridine [ 22 ], urea and thiourea [ 23 ]. SC XRD has been used to confirm the structures of most of these co-crystals or salts.…”