Enhancing the Hygroscopic Stability of S-Oxiracetam via Pharmaceutical Cocrystals

Abstract

Four cocrystals of (S-ox)(ga) (1), (RS-ox)(ga) (2), (S-ox)(pa) (3), and (RS-ox)(pa) (4) were prepared (S-ox = S-oxiracetam, RS-ox = racemic oxiracetam, ga = gallic acid, pa = 3,4-dihydroxybenzoic acid), and their structures were determined by single X-ray diffraction. In 1/2, two ga molecules link two S-ox/RS-ox molecules through intermolecular hydrogen bonds with a new R 2 2 (9) synthon to form a tetramer, the tetramers are further linked by intertetramer hydrogen bonds to generate a 2D sheet, and the adjacent 2D sheets are connected by intersheet hydrogen bonds to form the 3D structure of 1/2. In 3/4, the ox molecules form a 1D helical chain through intermolecular hydrogen bonds, and the helical chains are further linked by pa molecules through intermolecular hydrogen bonds to form a 2D sheet. The results of hygroscopic stability experiments indicate that the hygroscopic stability of Sox is much enhanced after the formation of cocrystal 1.

Cocrystallization of Nutraceuticals

“…58 An examination of the structure of protocatechuic acid-oxiracetam (1:1) cocrystals reveals that the acid-acid homodimer has been replaced by the acid-amide heterodimer (ZEBXOV and ZEBXUB) ( Figure 10). 51 The structure of vanillic acid displays the familiar acid-acid homodimer and the only phenolic substituent caps the hydroxyl moiety of the acid-acid dimer on both ends, thus giving rise to 2-D sheets (CEHGUS) (Figure 11). 60 Figure 11.…”

“…improving key physicochemical properties such as physical stability, 51,64,87,88,92,97,146 solubility 61,62,87,88,96,112 and bioavailability 96,112 of nutraceuticals, as well as of APIs. A summary of these studies is provided in Tables 4-5 and case studies discussed in more detail below.…”

“…Cocrystals containing gallic acid (1) and the API (S)-oxiracetam / (RS)-oxiracetam show much improved hygroscopic stability over prolonged periods of time relative to the API. 51 The (S) enantiomer is stable up to 75% relative humidity (RH) for eight weeks, whereas racemic oxiracetam is stable up to 87% RH for eight weeks. In comparison, gallic acid cocrystals with either enantiopure or racemic oxiracetam are stable up to 98% RH for eight weeks.…”

Transferability of cocrystallization propensities between aromatic and heteroaromatic amides

“…There are many examples of significant improvements of API behaviors both in vivo and in vitro [14,15] due to enhancement of pharmacokinetic properties as solubility [4,16,17] and bioavailability [18][19][20]. Also many other physicochemical properties can be modulated by cocrystallization including stability [21][22][23][24], hygroscopicity [25] and prolonged shelf life [26]. Among many drugs, aromatic amides acting either as APIs or as excipients attract nowadays substantial attention [27][28][29][30][31][32][33][34][35].…”

Co‐Crystal of Paracetamol and Trimethylglycine Prepared by a Supercritical CO2 Anti‐Solvent Process

“…During the past decade, the fabrication of co‐crystal microparticles has emerged as an effective strategy to improve physicochemical and mechanical performances, such as chemical stability , hygroscopicity , dissolution rate , mechanical properties , and bioavailability in pharmaceutical development without changing the chemical composition of the active pharmaceutical ingredients (APIs). Generally, the co‐crystals are stabilized by different interactions of intermolecular, i.e., hydrogen bonds, π‐π interactions, and van der Waals forces, but no proton transferred between the co‐former and the API.…”