Salt Cocrystallization of Loxoprofen Sodium with Sugar: Reduction of the Propensity for Hydrate Formation by Forming a Continuous One-Dimensional Chain Structure of Sodium and Sugar

Abstract

Compared to free base forms, salt forms are more frequently obtained as hydrates during solid form screening, although physically unstable hydrates are difficult to select for drug development. In this study, loxoprofen sodium dihydrate (LOXNa-2H2O), a widely used anti-inflammatory drug, was selected as a model drug to investigate the potential use of sugar as a coformer for cocrystallization with Na salts and the effect of salt cocrystallization with sugars on hydrate formation. In a screening study by liquid-assisted grinding with ethanol, two sugars, ribose (RIB) and fructose (FRU), formed new salt cocrystals with LOXNa. Differential scanning calorimetry, thermogravimetry, temperature-programmed powder X-ray diffraction, and water vapor sorption/desorption isotherm measurements revealed that the LOXNa·RIB and LOXNa·FRU salt cocrystals were a monohydrate and anhydrate, respectively. Single-crystal X-ray structural analysis of both salt cocrystals showed that direct ionic interaction did not occur between the Na cation and the carboxylate anion of LOX. Instead, sugars were coordinated around a Na cation, and a consecutive alternating structure of Na cations and sugars with a one-dimensional chain was formed along the b-axis. These characteristic chain structures prevented water molecules from approaching the Na cation and reduced the propensity for hydrate formation. FRU possesses one more hydroxyl group than the RIB molecule. The resulting strong hydrogen bonding network stabilized the LOXNa-FRU as an anhydrate without water molecules. Since sugars are safe and inexpensive excipients with various species, they can be useful coformers for salt cocrystals with various drug Na salts.

Comparative study on the effects of the inclusion complexes of non-steroidal anti-inflammatory drugs with 2-hydroxypropyl-β-cyclodextrins on dissociation rates and supersaturation

“…S4 † were obtained for neat LXP sodium salt dihydrate (LXP-Na), its mixtures, and plain HP-β-CD. That of neat LXP-Na was similar to the signals equivalent to the reported angles, 46,47 but no 3D crystallographic structure of the LPX-Na dihydrate was observed. The halo patterns of the mixtures were similar to those of plain HP-β-CD.…”

“…Because no crystalline entries had been retrieved for dihydrated loxoprofen sodium salt, the observed signals were verified to the 2 θ angles of 7.5, 11.1, 22.2, 30.0, and 33.8 degrees. 46,47…”

“…Because no crystalline entries had been retrieved for dihydrated loxoprofen sodium salt, the observed signals were verified to the 2θ angles of 7.5, 11.1, 22.2, 30.0, and 33.8 degrees. 46,47 2.3. Thermal analysis of neat API and API mixture with HPβ-CD Differential scanning calorimetry (DSC) was performed using a DSC8230 instrument (Rigaku Co., Tokyo, Japan).…”

Ciprofloxacin salt and salt co-crystal with dihydroxybenzoic acids

“…Recently, the co-crystallization of salt APIs or salt co-crystal formation has been increasingly studied. Salt co-crystallization has been utilized to suppress hydrate formation of salt APIs (Nugraha & Uekusa, 2018;Fujito et al, 2021). As a part of our study of salt cocrystals of APIs, we investigated multi-component crystals of ciprofloxacin.…”