Mechanism of optical isomerization of (S)-N-[1-(2-fluorophenyl)-3,4,6,7- tetrahydro-4-oxopyrrolo[3,2,1-jk] [1,4]-benzodiazepine-3-yl]-1H- indole-2-carboxamide (FK480) in soft capsules containing polyethylene glycol 400 and glycerol.
FK480 is a new synthetic non-peptide antagonist of cholecystokinin (CCK)-A receptors. The dosage form of FK480 is a soft capsule containing a solution of FK480 in a mixture of polyethylene glycol 400 (PEG 400) and glycerol to improve its bioavailability. Studies on the stability of this FK480 dosage form revealed that the main degradation occurred by optical isomerization at the asymmetric C-3 position of the pyrrolobenzodiazepine ring. The degradation reaction was accelerated by formic acid formed in a mixture of PEG 400 and glycerol. Addition of amino acids to the capsule solution retarded the isomerization by reacting with formic acid. Therefore, formic acid appears to accelerate optical isomerization of FK480.
Fukuyama
S
S
Analytical Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
Kihara
N
N
Nakashima
K
K
Morokoshi
N
N
Koda
S
S
Yasuda
T
T
D001570:Benzodiazepinones / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism; D002214:Capsules; D002766:Cholecystokinin / Q000037:antagonists & inhibitors*; D005561:Formates / Q000378:metabolism / Q000494:pharmacology; D005990:Glycerol / Q000008:administration & dosage; D007211:Indoles / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism; D007536:Isomerism; D011092:Polyethylene Glycols / Q000008:administration & dosage
D001570:Benzodiazepinones; D002214:Capsules; D005561:Formates; D007211:Indoles; C030544:formic acid; C082966:FR 120480; D011092:Polyethylene Glycols; D002766:Cholecystokinin; D005990:Glycerol