Takayuki Fujito, Tsumugi Oshima, Kenjirou Higashi, Keisuke Ueda, Masataka Ito, Hyuma Masu, Shuji Noguchi, Kunikazu Moribe
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.
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.cgd.1c01050.
PXRD patterns before and after water vapor sorption/desorption isotherms measurements of LOXNa-2H2O, LOXNa-RIB-H2O, and LOXNa-FRU (Figure S1). PXRD patterns of LOXNa-2H2O, LOXNa-RIB-H2O, and LOXNa-FRU stored at each condition for 4 weeks (Figure S2). Experimental PXRD pattern and calculated PXRD pattern from the structure determined via SC-XRD measurements of LOXNa-RIB-H2O and LOXNa-FRU (Figure S3). The crystal structures of LOXNa-RIB-H2O (Figure S4) and LOXNa-FRU (Figure S5). PXRD patterns of LOXNa-RIB-H2O and LOXNa-RIB anhydrate (Figure S6). The packing structure of the NAPNa-LAC-4H2O salt cocrystal (Figure S7) (PDF)
This article has not yet been cited by other publications.
![[ASAP] 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](/image/eyJ1cmkiOiJodHRwczovL3MzLWV1LXdlc3QtMS5hbWF6b25hd3MuY29tL3N0YWNrYWRlbWljL3Byb2R1Y3Rpb24vcGFwZXIvOTM2NzE0Ny5wbmciLCJmb3JtYXQiOiJ3ZWJwIiwicXVhbGl0eSI6MTAwLCJub0NhY2hlIjp0cnVlfQ==.webp)
