Inclusion complexation of diazepam with different cyclodextrins in formulations for parenteral use.
A parenteral formulation for the water-insoluble benzodiazepine diazepam was developed. Different cyclodextrins (CDs) suitable for parenteral injection: hydroxypropyl-beta-cyclodextrin (HP-beta-CD), hydroxy-propyl-gamma-cyclodextrin (HP-gamma-CD), sulfobutylether-7-beta-cyclodextrin (SBE-7-beta-CD) and maltosyl-beta-cyclodextrin (malt-beta-CD) were used as alternatives to cosolvents to increase solubility. The increase in solubility displayed a concentration dependency for the four CDs used. Diazepam's solubility is enhanced linearly as a function of each CD concentration. The highest improvements in solubility (dissolved concentration circa 3.5 mg/ml in 40% CD) were found by adding HP-beta-CD or SBE-7-beta-CD. The additional use of polyvinylpyrrolidone (PVP) did not further increase the solubility of diazepam with HP-beta-CD. A parenteral aqueous diazepam solution was prepared containing 10 mg diazepam/5 ml 30% HP-beta-CD or SBE-7-beta-CD solution. The preparations are in agreement with the requirements for parenteralia. Sterilisation by filtration is required since autoclaving degrades the active compound. The stability of the preparations, with and without pH adjustment to pH 5, was investigated during 18 months and during this period no noticeable degradation was observed.
Holvoet
C
C
Department of Pharmaceutical Technology and Physical Pharmacy, Vrije Universiteit Brussel-VUB Brussels, Belgium.
Heyden
Y Vander
YV
Plaizier-Vercammen
J
J
D000465:Algorithms; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D003505:Cyclodextrins / Q000737:chemistry*; D003975:Diazepam / Q000008:administration & dosage / Q000737:chemistry*; D005079:Excipients; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000737:chemistry*; D007263:Infusions, Parenteral; D019999:Pharmaceutical Solutions; D012995:Solubility; D012997:Solvents; D013056:Spectrophotometry, Ultraviolet
D003505:Cyclodextrins; D005079:Excipients; D006993:Hypnotics and Sedatives; D019999:Pharmaceutical Solutions; D012997:Solvents; D003975:Diazepam