title: Improvement of physicochemical properties of N-4472. Part III. VC/N-4472 complex formation and self-association in aqueous solution.
abstract: To improve the aqueous solubility of a poorly water-soluble drug, N-[2-(3,5-di-tert-butyl-4-hydroxyphenethyl)-4,6-difluorophenyl]-N'-[4-(N-benzylpiperidyl)]urea (N-4472), organic acid/N-4472 evaporates were prepared by using succinic acid, L-tartaric acid, citric acid and L-ascorbic acid (VC). Among these evaporates, only the VC/N-4472 evaporate at a molar ratio of more than 2 (VC/N-4472) formed stable colloidal particles (with a mean particle size <or=100 nm) in aqueous solution. In particular, the evaporate prepared at the molar ratio of 5 (VC/N-4472) formed a clear solution comprising fine particles with a narrow particle size distribution of 8-15 nm. On the basis of surface tension measurement, zeta potential determination and static light scattering measurement, it was conceivable that both N-4472 and VC contributed to the formation of a surface-active complex in aqueous solution, while the colloidal particles could be interpreted as the self-association product of these complexes. According to the findings on (1)H-NMR and attenuated total reflectance Fourier transform infrared spectra, it was postulated that upon combining both components at a molar ratio of 2 (VC/N-4472), a 1 : 1 association complex of N-4472 and VC was formed, whereas the higher order complexes were assumed formed with use of a molar ratio of more than 2 (VC/N-4472). Furthermore, it was evidenced that all of these complexes were composed of amphiphilic structures comprising both hydrophobic N-4472 moiety and hydrophilic VC moiety, thereby properly accounting for surface-active property of these complexes.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan. itok@nk-pharm.co.jp
authors.forename: Koichi
authors.initials: K
authors.lastname: Itoh
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Tozuka
authors.forename: Toshio
authors.initials: T
authors.lastname: Oguchi
authors.forename: Keiji
authors.initials: K
authors.lastname: Yamamoto
mesh_terms: D000143:Acids / Q000737:chemistry; D002264:Carboxylic Acids / Q000737:chemistry* / Q000494:pharmacology; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D010880:Piperidines / Q000737:chemistry*; D012996:Solutions; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry*; D014867:Water / Q000737:chemistry*
chemical_list: D000143:Acids; D002264:Carboxylic Acids; C457839:N-(2-(3,5-di-tert-butyl-4-hydroxyphenethyl)-4,6-difluorophenyl)-N'-(4-(N-benzylpiperidyl)) urea; D010880:Piperidines; D012996:Solutions; D014867:Water; D014508:Urea