Self-association properties of 4-[1-hydroxy-1-methylethyl]-2-propyl-1-[4-[2-[tetrazole-5-yl]phenyl]phenyl] methylimidazole-5-carboxylic acid monohydrate (CS-088), an antiglaucoma ophthalmic agent.
Self-association properties of CS-088, an antiglaucoma ophthalmic agent, were investigated. Various analytical methods, such as surface tension measurement, demonstrated that CS-088 is a self-associating compound with critical micellar concentration (CMC) of approximately 10 mg/mL. Light scattering analysis revealed that the micellar molecular weight (MMW) of CS-088 aggregates well above the CMC was approximately 2260, corresponding to a pentamer. In addition, the MMW corresponding to a dimer was detected by NMR spectroscopy, indicating that self-association of monomers to pentamers is via the formation of dimers. According to the Stokes-Einstein equation, hydrodynamic radii of the dimer and pentamer were calculated to be 0.87 and 1.16 nm, respectively. The concentration-dependent change in the NMR chemical shift indicated that hydrophobic interaction between biphenyl groups is an important factor in the self-association of CS-088 molecules. Furthermore, measurement of particle size distribution using a Nicomp Submicron Particle-Sizer revealed that the addition of either n-propanol or urea to CS-088 solution led to monomerization of the dimers and pentamers, suggesting that not only hydrophobic interaction but also hydrogen bonding is involved in stabilizing CS-088 aggregates. No bigger aggregate than a pentamer was formed in the absence of NaCl, whereas further aggregation was observed with increasing concentrations of NaCl.
Pharmaceutical Development Laboratories, Sankyo Co. Ltd., 1-12-1, Shinomiya, Hiratsuka, Kanagawa 254-0014, Japan. tkikuc@sankyo.co.jp
Takayuki
T
Kikuchi
Nobuya
N
Ito
Masahiko
M
Suzuki
Akira
A
Kusai
Ken
K
Iseki
Hitoshi
H
Sasaki
D000433:1-Propanol / Q000737:chemistry; D019281:Dimerization; D005901:Glaucoma; D007093:Imidazoles / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008823:Micelles; D008970:Molecular Weight; D009883:Ophthalmic Solutions / Q000737:chemistry*; D010316:Particle Size; D012965:Sodium Chloride / Q000737:chemistry; D013053:Spectrophotometry; D013500:Surface Tension; D013777:Tetrazoles / Q000737:chemistry*; D014508:Urea / Q000737:chemistry
D007093:Imidazoles; D008823:Micelles; D009883:Ophthalmic Solutions; D013777:Tetrazoles; D012965:Sodium Chloride; C437965:olmesartan; D014508:Urea; D000433:1-Propanol