[Crystal forms, improvements of dissolution and absorption of poorly water-soluble (R)-1-[2,3-dihydro-1-(2'-methylphenacyl)-2-oxo-5-phenyl-1H-1, 4-benzodiazepin-3-yl]-3-(3-methylphenyl)urea (YM022)].
Polymorphs of (R)-1-[2,3-dihydro-1-(2'-methylphenacyl)-2-oxo-5-phenyl-1H-1,4- benzodiazepin-3-yl]-3-(3-methylphenyl)urea (YM022) were investigated. Two crystalline forms (alpha- and beta-forms) of YM022 were confirmed by powder X-ray diffractometry and differential scanning calorimetry. alpha- And beta-forms were obtained by recrystallization from ethanol and ethanol: water (5:1), respectively. Amorphous YM022 was obtained by spray drying of YM022 methanol solution. Since both crystalline and amorphous YM022 were sparingly soluble in water, solubilization of YM022 by solid dispersion and wet grinding methods were performed. In vitro dissolution study and in vivo absorption study in dogs were carried out using spray-dried solid dispersion, heat-treated solid dispersion and mechanical mixture. Spray-dried solid dispersion and heat-treated solid dispersion showed enhanced bioavailability, whereas mechanical mixture showed no improvement.
Yano
K
K
Novel Pharma Research Laboratories, Yamanouchi Pharmaceutical Co., Ltd., Yaizu, Japan.
Takamatsu
N
N
Yamazaki
S
S
Sako
K
K
Nagura
S
S
Tomizawa
S
S
Shimaya
J
J
Yamamoto
K
K
D000818:Animals; D000897:Anti-Ulcer Agents / Q000493:pharmacokinetics; D001569:Benzodiazepines / Q000493:pharmacokinetics; D001682:Biological Availability; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003460:Crystallization; D004285:Dogs; D007408:Intestinal Absorption; D008297:Male; D012995:Solubility; D014867:Water
D000897:Anti-Ulcer Agents; D014867:Water; D001569:Benzodiazepines; C087260:YM 022