Cyclodextrin solubilization of the antibacterial agents triclosan and triclocarban: formation of aggregates and higher-order complexes.
It is well known that water-soluble cyclodextrins form inclusion complexes with many lipophilic water-insoluble drugs and that such complexation frequently enhances the aqueous solubility of drugs. It is also well known that various excipients, such as water-soluble polymers, organic acids and bases and metal ions can enhance the solubilizing effects of cyclodextrins. However, it is not clear how these excipients enhance the effects. The effects of cyclodextrins, 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD) and randomly methylated beta-cyclodextrin (RMbetaCD) on the aqueous solubility of triclosan and triclocarban were investigated. The phase-solubility profiles were all of type A(P) indicating formation of higher-order complexes or complex aggregates. Addition of lysine and other excipients enhanced the RMbetaCD solubilization of triclocarban. NMR spectroscopic studies, including 2D ROESY and 1D gROESY techniques, indicated that HPbetaCD and RMbetaCD, as well as their complexes, form aggregates of two to three cyclodextrin molecules. The critical concentration for the aggregate formation was determined to be 5.4% (w/v). Lysine, polyvinylpyrrolidone and magnesium ions formed non-inclusion complexes resulting in formation of multiple-component cyclodextrin complexes in aqueous solutions with triclocarban.
Duan
Matt S
MS
deCODE chemistry Inc., 2501 Davey Road, Woodridge, IL 60517, USA. mduan@decode.com
Zhao
Nelson
N
Ossurardóttir
Ina B
IB
Thorsteinsson
Thorsteinn
T
Loftsson
Thorsteinn
T
D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000737:chemistry*; D002224:Carbanilides / Q000008:administration & dosage / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical; D003505:Cyclodextrins / Q000737:chemistry*; D004121:Dimethyl Sulfoxide; D008239:Lysine / Q000737:chemistry; D008274:Magnesium; D009682:Magnetic Resonance Spectroscopy; D011205:Povidone; D012995:Solubility; D014260:Triclosan / Q000008:administration & dosage / Q000737:chemistry*; D047392:beta-Cyclodextrins / Q000737:chemistry
D000890:Anti-Infective Agents; D002224:Carbanilides; D003505:Cyclodextrins; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D014260:Triclosan; C009540:triclocarban; D011205:Povidone; D008274:Magnesium; D008239:Lysine; D004121:Dimethyl Sulfoxide