Stability of monoHER in an aqueous formulation for i.v. administration.
MonoHER is a semisynthetic flavonoid used successfully in modulating the cardiotoxic effect of doxorubicin but not its antitumor activity. The oral bioavailability of monoHER is <1%. Therefore, it should be prepared as an i.v. formulation for use in clinical trials. The solubility of monoHER in water is highly pH dependent. At pH</=8.3 the drug precipitates 4 h after preparation. DMSO was tested for enhancing the solubility of monoHER in aqueous solutions. In all DMSO-based aqueous solutions monoHER recrystalized again at pH<8.3 and room temperature within 4 h after preparation. Moreover, the stability of monoHER was lower in a DMSO stock solution than after dilution with an aqueous solution. The stability of monoHER was tested in alkaline solutions (pH 8.3 and 9.5) using an HPLC-DAD procedure to detect all possible degradation products within 10 min after injection. Minor degradation occurred to monoHER in alkaline solutions when exposed to daylight or 1% H(2)O(2). MonoHER intensively degraded when exposed to a high temperature (80 degrees C). The stability of monoHER was almost the same in saline or 5% glucose when kept at room temperature and an alkaline pH of 8.3 and 9.5. Under shelf-life conditions the stability of monoHER in 5% glucose (pH 8.4), decreased with about 10% during 48 h after preparation.
Abou El Hassan
M A
MA
Department of Medical Oncology, Free University Hospital, P. O. Box 7057, 1007 MB, Amsterdam, The Netherlands. m.abulhassan@azvu.nl
Touw
D J
DJ
Wilhelm
A J
AJ
Bast
A
A
van der Vijgh
W J
WJ
D000975:Antioxidants / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004355:Drug Stability; D005419:Flavonoids / Q000737:chemistry*; D005947:Glucose / Q000737:chemistry; D012431:Rutin / Q000031:analogs & derivatives* / Q000737:chemistry; D012965:Sodium Chloride / Q000737:chemistry; D012995:Solubility / Q000187:drug effects; D012997:Solvents / Q000494:pharmacology
D000975:Antioxidants; D005419:Flavonoids; D012997:Solvents; C056067:rutin sulfate; D012965:Sodium Chloride; D012431:Rutin; D005947:Glucose; D004121:Dimethyl Sulfoxide