Five anhydrous polymorphs (forms I−V) and one hydrate of furosemide−nicotinamide 1:1 cocrystal were discovered, and their solid-state properties were characterized using X-ray powder diffraction and differential scanning calorimetry. The crystal structures of forms I−IV were determined from the X-ray powder diffraction data and showed the structural differences between forms, which are mainly attributable to molecular conformations and supramolecular synthons. The slurry conversion experiments revealed that the order of thermodynamic stability of the polymorphs at 25 °C is I > III > II > V > IV. Dynamic vapor sorption analysis and X-ray single-crystal structure determination of the hydrate were conducted to study the dehydration mechanism. We observed structural similarities between the hydrate and its dehydrate, form IV, such as lattice parameters (except the a-axis length), synthons between furosemide and nicotinamide molecules, and the molecular conformation of furosemide; after dehydration, however, the a-axis contracted and nicotinamide molecules were displaced, along with the pyridine ring twisting.

The main purpose of this study was to investigate the solubilization enhancement properties of an amphipathic graft copolymer, Soluplus ® , on test compounds. Micellization of Soluplus ® in solution was characterized by evaluating the changes in the surface activity, turbidity, and thermodynamic behavior. To assess the feasibility of Soluplus ® as a polymeric carrier of solid dispersions, freeze-dried samples of ipriflavone were prepared, and the physicochemical properties of the carrier plus ipriflavone were evaluated in terms of solubility, dissolution, and crystallinity. The surface tension of the solution decreased depending on the polymer concentration, and gradual turbidity increase was observed. Isothermal titration calorimetry was used to measure the thermal reaction accompanying the micellization of Soluplus ® and indicated that a colloidal micelle formation improved solubility. The prepared formulations, particularly at a ratio of ipriflavone : Soluplus ® 1 : 10 (w/w) exhibited a dramatically improved solubility of ipriflavone that was ca. 70-fold higher than that of untreated ipriflavone. The solubilization mechanism of Soluplus ® was partially elucidated and suggested that its strategic application could improve the solubility of hydrophobic compounds.Key words isothermal titration calorimetry; ipriflavone; amphipathic graft copolymer; solubility Among the available technologies, the solid dispersion technique is commonly used as one of the most promising strategies for the enhancement of the solubility, dissolution rate, and bioavailability of poorly water-soluble compounds. A solid dispersion system can be defined as a distribution of active pharmaceutical ingredients as molecular amorphous particles and/or in the microcrystalline state into a carrier matrix-like polymer.1) The physicochemical characteristics of polymeric carriers could dominate the pharmaceutical properties of a solid dispersion system. 2,3) Based on the characteristic properties of a polymeric carrier, a number of solid dispersion systems possessing various functional properties such as sustained release, pH-dependent release, self-emulsifying properties, and site-specific release have been developed. [4][5][6][7] In particular, amphiphilic polymers have been found to be beneficial for the enhancement of not only solubility but also of the oral bioavailability of poorly water-soluble compounds because they form micellar structures that contain the compound. 6,8) Soluplus ® , a graft copolymer consisting of polyvinyl caprolactam, polyvinyl acetate, and polyethyleneglycol, has been applied to the design of solid-dispersion formulations with poorly water-soluble substances to improve their solubility and bioavailability.9,10) The copolymer exhibits an amphipathic property attributed to its hydrophilic and hydrophobic residues, which could contribute to the formation of micelles in water. Unlike conventional polymers such as polyvinylpyrrolidone and hydroxypropyl methylcellulose, Soluplus ® is bifunctional and can act as both a polym...

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We investigated the salt cocrystals formed by tofogliflozin with sodium acetate and potassium acetate by determining the crystal structures of the salt cocrystals and characterizing the solid states. The salt cocrystal screening using the slurry method and the liquid-assisted grinding method resulted in the formation of tofogliflozin-sodium acetate 1 : 1 and tofogliflozin-potassium acetate 1 : 1 salt cocrystals. Single-crystal X-ray diffraction revealed that, although each salt cocrystal belongs to a different space group, both of the salt cocrystals have almost similar structural features, including the conformation of tofogliflozin molecules, the coordination to Na /K ions, and hydrogen bonds. The salt cocrystals exhibited extreme hygroscopicity with deliquescence, which is also a property of sodium acetate and potassium acetate. In addition, tofogliflozinpotassium acetate salt cocrystal had two polymorphs, which were enantiotropically related.

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The crystal engineering approach based on isomorphism succeeded in crystallizing a pharmaceutical cocrystal in the early stage.

We studied the possibility of using ursodeoxycholic acid (UDCA) as an excipient to create an amorphous composite that can be administered to animals in preclinical studies of experimental drugs. Three UDCAbased amorphous samples composed of nifedipine (NIF), indomethacin (IND), and naproxen (NAP) were found by screening. The UDCA-based formulations were adjudged amorphous by solid-state analysis using X-ray powder diffraction and differential scanning calorimetry. In addition, amorphous samples of NIF-UDCA, IND-UDCA, and NAP-UDCA did not crystallize while in 1% methyl cellulose (MC) solution for 120 min, although an amorphous solid dispersion of NIF-poly(vinylpyrrolidone) (PVP) crystallized rapidly. The low hygroscopicity of UDCA helps NIF maintain an amorphous state in 1% MC solution. The UDCAbased amorphous composites can be administered as suspended formulations to animals in preclinical studies.