Preparation, characterization, and evaluation of dipfluzine-benzoic acid co-crystals with improved physicochemical properties.
OBJECTIVE
To prepare and characterize the co-crystal of dipfluzine and benzoic acid. To investigate the feasibility of the co-crystal for improving solubility and a faster dissolution rate in vitro and evaluate the bioavailability and tissue distribution of co-crystal in vivo.


METHODS
A novel dipfluzine-benzoic acid co-crystal prepared using the solvent-assisted co-grinding and the solvent ultrasonic methods were identified and characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA), as well as Raman, solid-state nuclear magnetic resonance (ssNMR), and terahertz (THz) spectroscopy. Pharmacokinetics and tissue distribution were tested in vivo using murine models. Statistics analysis for dissolution data of co-crystal in vitro and animal experiment data in vivo were evaluated using t-test.


RESULTS
Results of PXRD and DSC identified the dipfluzine-benzoic acid co-crystals were formed with a molar ratio of 1:2. The IR, Raman, and ssNMR spectra verified the formation of O-H · · · O and O-H · · · F hydrogen bonds. The complex constant, K, was evaluated to be 10(9) orders of magnitude with Δ r G < 0. The co-crystal solubility, the rate of drug dissolution and the relative bioavailability were approximately 500 times, five times and double that of dipfluzine, respectively. Increased solubility of co-crystal did not reduce distribution in the brain; the mean concentrations in the brain increased, but the differences had no statistic significance (p > 0.05).


CONCLUSIONS
The co-crystal of dipfluzine-benzoic acid improved the physicochemical properties of dipfluzine, such as solubility and dissolution rate. Furthermore, the increased relative bioavailability of co-crystal indicated the potential use in further clinical study.
School of Pharmaceutical Sciences, Hebei Medical University, Shijiazhuang, 050017, China.
Yulong
Y
Lin
Huan
H
Yang
Caiqin
C
Yang
Jing
J
Wang
D000818:Animals; D019817:Benzoic Acid / Q000737:chemistry* / Q000493:pharmacokinetics; D002121:Calcium Channel Blockers / Q000737:chemistry* / Q000493:pharmacokinetics; D002152:Calorimetry, Differential Scanning; D002936:Cinnarizine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D003460:Crystallization / Q000379:methods; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared; D014867:Water / Q000737:chemistry; D014961:X-Ray Diffraction
D002121:Calcium Channel Blockers; D014867:Water; D002936:Cinnarizine; C065758:dipfluzine; D019817:Benzoic Acid