Sildenafil/cyclodextrin complexation: stability constants, thermodynamics, and guest-host interactions probed by 1H NMR and molecular modeling studies.
Guest-host interactions of sildenafil (Sild) with cyclodextrins (CyDs) have been investigated using several techniques including phase solubility diagrams (PSD), differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), proton nuclear magnetic resonance (1H NMR) and molecular mechanical modeling (MM+). Estimates of the complex formation constant (K11) show that the tendency of Sild to complex with CyDs follows the order: beta-CyD>HP-beta-CyD>gamma-CyD, alpha-CyD, where K11 values at pH 8.7 and 30 degrees C were 150, 68 and 46, 43 M-1, respectively. Ionization of Sild reduces its tendency to complex with beta-CyD, where protonated (at pH 3.6) and anionic Sild (at pH 12.1) species have K11 values of 17 and 42 M-1, respectively, compared with 150 M-1 for neutral Sild (at pH 8.7). The hydrophobic character of Sild was found to provide 39% of the driving force for complex stability, while other factors including specific interactions contribute -7.9 kJ/mol. Complex formation of Sild with beta-CyD (DeltaG degrees=-22.9 kJ/mol) is largely driven by enthalpy (DeltaH degrees=-19.8 kJ/mol) and slight entropy (DeltaS degrees=10.3 J/molK) changes. 1H NMR and MM+ studies indicate formation of two isomeric 1:1 complexes: one involving complete inclusion of the phenyl-moiety into the beta-CyD cavity while the other pertaining to partial inclusion of the pyrimidinone moiety. The dominant driving force for complexation is evidently van der Waals with very little electrostatic contribution. DSC, XRPD and 1H NMR studies proved the formation of inclusion complex in solution and the solid state.
Al Omari
Mahmoud M
MM
The Jordanian Pharmaceutical Manufacturing Company, Naor, Jordan. momari@jpm.com.jo
Zughul
Mohammad B
MB
Davies
J Eric D
JE
Badwan
Adnan A
AA
D002152:Calorimetry, Differential Scanning; D003505:Cyclodextrins / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008958:Models, Molecular; D010879:Piperazines / Q000737:chemistry*; D011522:Protons; D011687:Purines; D000068677:Sildenafil Citrate; D013056:Spectrophotometry, Ultraviolet; D013450:Sulfones; D013816:Thermodynamics; D014961:X-Ray Diffraction
D003505:Cyclodextrins; D010879:Piperazines; D011522:Protons; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate