title: Stabilization mechanism of limaprost in solid dosage form.
abstract: The effect of polymeric pharmaceutical excipients on the degradation of limaprost by hydrolysis was assessed by near infrared (NIR) spectroscopy and spin-spin relaxation time (T(2)) measurements of proton NMR. Freeze-dried limaprost-alfadex formulated with various polymeric pharmaceutical excipients was exposed under humidified condition at 25 degrees C and 75% relative humidity. The freeze-dried limaprost-alfadex formulated with cellulose derivatives, hydroxypropylmethylcellulose (HPMC) and hydroxypropylcellulose (HPC-L), degraded easily. However, degradation was suppressed in samples formulated with polysaccharides, dextran40, dextrin, and pullulan, although the water sorption was more than 10% (w/w). A second-derivative NIR study showed the changes in the water mobility in the mixtures. The absorption peak near 1900nm, which was assigned to water with high mobility, was observed in the humidified HPMC and HPC-L. The proton NMR spin-spin relaxation time measurements indicated that the structural relaxation of a polymeric excipient changed upon humidification. The polysaccharides showed only Gaussian relaxations, but the cellulose derivatives showed Lorentzian relaxations and Gaussian relaxations. The T(2) values of the Gaussian relaxation in HPMC and HPC-L were higher than those in dextran40, dextrin, and pullulan throughout the humidifying period. The higher molecular mobility of HPMC and HPC-L is related to the mobility of water, which may accelerate limaprost degradation.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan. moribe@p.chiba-u.ac.jp
authors.forename: Kunikazu
authors.initials: K
authors.lastname: Moribe
authors.forename: Noboru
authors.initials: N
authors.lastname: Sekiya
authors.forename: Takayuki
authors.initials: T
authors.lastname: Fujito
authors.forename: Masanobu
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Higashi
authors.forename: Chihiro
authors.initials: C
authors.lastname: Yokohama
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Tozuka
authors.forename: Keiji
authors.initials: K
authors.lastname: Yamamoto
mesh_terms: D000527:Alprostadil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D004355:Drug Stability; D005612:Freeze Drying; D006863:Hydrogen-Ion Concentration; D009682:Magnetic Resonance Spectroscopy; D019265:Spectroscopy, Near-Infrared
chemical_list: D000527:Alprostadil; C059238:limaprost