A threefold superstructure of the anti-epileptic drug phenytoin sodium as a mixed methanol solvate hydrate

Abstract

Phenytoin sodium, a salt of 5,5‐diphenylimidazolidine‐2,4‐dione, or phenytoin, is commercially available in various dosage forms for its anti‐epileptic properties to treat and prevent seizures. The title compound, poly[aquatris(μ3‐4,4‐diphenyl‐2,5‐dioxoimidazolidin‐1‐ido)trimethanoltrisodium(I)], [Na3(C15H11N2O2)3(CH4O)3(H2O)1.08]n, a methanol solvate and hydrate of phenytoin sodium, forms a modulated crystal structure that consists of a supercell made up of three close‐to‐identical repeat units. Each of the basic fragments consists of one phenytoin anion, a sodium cation, and either a methanol, or a methanol and a water molecule coordinated to the sodium ion, yielding a formula unit of Na(C15H11N2O2)(CH3OH)x(H2O)y for each of the three segments (x, y = 0 or 1; x + y = 1 or 2). Modulation along the b axis is introduced due to the presence or absence of water or methanol molecules at sodium and by the alternating torsion angles of one of the two phenytoin phenyl rings. Individual segments within the asymmetric unit are linked by covalent Na—O and Na—N bonds, with each sodium ion coordinated to one anionic amide N atom and three keto O atoms. The Na—N and one of the Na—O bonds connect (C15H11N2O2)·Na units along the modulation direction, creating an infinite [(C15H11N2O2)·Na] chain that is further stabilized by intramolecular N—H…O hydrogen bonding parallel to [010]. The second Na—O bond connects this chain with a symmetry‐equivalent copy of itself created by a screw‐axis operation, yielding double strands of [(C15H11N2O2)·Na] chains. Two of these double strands, propagating in opposite directions, constitute the content of the unit cell. Neighboring double strands are connected with each other to form layers perpendicular to the a axis, tethered together via O—H…O hydrogen bonds involving the water and methanol molecules. In addition to modulation, each of the repeat units also exhibits disorder of the modulated segments. Phenyl rings of each repeat unit are rotationally disordered, and sodium‐coordinated methanol and water molecules are also positionally disordered and/or partially occupied. The solvated structure reported here, while not matching the patterns reported for any of the known forms of phenytoin sodium, does provide a first insight into the complications and complexities involved in resolving the structure of anhydrous phenytoin sodium.

The crystal structure and Raman spectrum of the sodium salt of 5-Acetic acid hydantoin

“…First of all, the 5AAH molecules in the crystal give rise to a pseudo-octahedral coordinating geometry and bind via their oxygen atoms, instead of via a deprotonated ring nitrogen as is commonly found for hydantoins [26]. The lability of the carboxylic hydrogen atom of the acetic acid substituent justifies the preference of coordination via the carboxylic group, and also determines the very interesting formal charge of the hydantoin in the crystal, which is −0.5 e.…”

“…2) (see the illustrative example described in Ref. [26]). Coordination through the deprotonated carboxylic moiety of 5AAH, with the two NH groups of the ring being protonated, has been reported for the tetra-aqua-bis-5AAH Co II complex [34], showing that the most labile group to deprotonation in 5AAH is indeed the carboxylic moiety thus favoring complexation of the molecule where the structural integrity of the hydantoin ring is preserved.…”

“…(i) Does 5AAH coordinate sodium ions via the hydantoin ring (through a deprotonated ring nitrogen atom as it in general occurs for hydantoins, e.g. phenytoin [26]) or through the carboxylic acid substituent?…”

Influence of Co-amorphization on the Physical Stability and Dissolution Performance of an Anthelmintic Drug Flubendazole

“…Various strategies have been developed to improve the bioavailability of small molecules, such as pharmaceutical salts, − cocrystals, pharmaceutical solvates, − gels, and compositions with polymers and cyclodextrins. − Several techniques have been proposed in the literature for improving the pharmaceutically relevant characteristics of FluBZ, including the use of ionic liquids, binary crystals, and nanoemulsions, as well as incorporation in cyclodextrin cavities. − Amorphization is one of the most commonly utilized methods for increasing the apparent solubility and permeability of an active pharmaceutical ingredient (API). , However, amorphous pharmaceuticals are thermodynamically unstable phases that tend to crystallize during manufacture, storage, and dissolution. , Development of a homogeneous single-phase co-amorphous system consisting of an API and a second component, on the other hand, efficiently suppresses crystallization, prolonging the shelf life of a product while keeping the benefits of the amorphous form . Furthermore, combining two synergistic APIs into a co-amorphous system may boost treatment efficiency, potentially leading to attractive fixed-dose combinations. , …”

Solid-State Dehydration Mechanism of Diclofenac Sodium Salt Hydrates

“…Sodium API salts often form hydrate crystals in which the water coordination geometry around Na + is more flexible than the structure of the transition metal ion hydrate owing to the s-block atomic nature of Na [12]. This "pseudo-coordination bond" property of Na + -O(water) interactions contributes the specific hydration-dehydration behaviors of sodium API salts [13][14][15][16][17][18][19].…”