Use of cyclodextrins as solubilizing agents for simvastatin: effect of hydroxypropyl-β-cyclodextrin on lactone/hydroxyacid aqueous equilibrium.
The chemical conversion of simvastatin from the lactone (SVL) to the hydroxyacid (SVA) form is becoming an intriguing issue associated with the pharmacological use of SVL. On this matter, recent findings suggest that SVL complexation with cyclodextrins (CDs) may be a useful strategy to affect its aqueous solubility and chemical stability. In this work, a reverse-phase high-performance liquid chromatography (RP-HPLC) method able to selectively identify and quantify SVL and SVA has been set up, validated and applied to follow SVL hydrolysis in the presence of HPβCD. The combination of stability results with simvastatin/HPβCD stability constants achieved from UV-vis measurements and solubility/dissolution studies allowed to get an insight into SVL/HPβCD, SVA/HPβCD and SVL/SVA equilibria taking place in aqueous solution. Results show that in the presence of HPβCD the aqueous SVL/SVA equilibrium is shifted versus the hydroxyacid form. UV-vis results, showing that the lactone and the open-ring form of simvastatin interact with HPβCD in a similar extent, suggest that hydrolysis occurs also on SVL/HPβCD complex, thus supporting a mode of interaction that does not involve the lactone ring. This hypothesis is strengthened by NMR analysis performed on SVA, HPβCD and their inclusion complex, which indicates that the lactone ring is not included in HPβCD hydrophobic cavity. Finally, results suggest that particular attention must be paid to SVL lactonization in aqueous solution when using CD-based formulations and in demonstrating their effective benefit for a specific therapeutic use.
Department of Pharmaceutical and Toxicological Chemistry, University of Naples Federico II, Via D Montesano 49, 80131 Naples, Italy.
Francesca
F
Ungaro
Concetta
C
Giovino
Ovidio
O
Catanzano
Agnese
A
Miro
Andrea
A
Mele
Fabiana
F
Quaglia
Maria Immacolata
MI
La Rotonda
D000073738:2-Hydroxypropyl-beta-cyclodextrin; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D056148:Chromatography, Reverse-Phase; D004339:Drug Compounding; D004355:Drug Stability; D006868:Hydrolysis; D057927:Hydrophobic and Hydrophilic Interactions; D006880:Hydroxy Acids / Q000737:chemistry*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000737:chemistry*; D007783:Lactones / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D019821:Simvastatin / Q000737:chemistry*; D012995:Solubility; D013056:Spectrophotometry, Ultraviolet; D013678:Technology, Pharmaceutical / Q000379:methods; D047392:beta-Cyclodextrins / Q000737:chemistry*
D006880:Hydroxy Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007783:Lactones; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D019821:Simvastatin