COMPUTATIONAL MODELING OF INCLUSION COMPLEX OF (R/S)-IBUPROFEN WITH ß-CYCLODEXTRIN AND ITS DERIVATIVES

• Main Author: Siti Nurhidayah, Enung
• Format: Dissertations
• Language: Indonesia
• Online Access: https://digilib.itb.ac.id/gdl/view/42233
• Institution: Institut Teknologi Bandung

Chiral separation is an important subject in analytical clinical chemistry, because of differences in the biological activity and pharmacokinetic properties of drug enansiomers. Ibuprofen, R,S-2-(4-isobutylphenyl)propionic acid, a derivative of 2-arylpropionic acids (profens), is a chiral non-steroidal anti-inflammatory drug (NSAID). Ibuprofen sold in the world markets be in the racemic form. Whereas has clinical function is S-enansiomer beside that R-enansiomer has many side effects. Experimentally the enansiomers of ibuprofen have been separated by GC, HPLC and CE method. GC method very challenge to develop continuously trough modify cyclodextrin as stationary phase. Computational method can use to calculate some parametric of complex inclusion, between stationery phase and analytes, being used to prediction stationary phase to separate ibuprofen racemic accurately also other of profens. Separation of IBP racemic is developing process still and no reported a great chiral selector to separate IBP racemic. Therefore this research will try to visual interaction complex inclusion, R/S-ibuprfen with ß-cyclodextrins and its derivative, with computational methode. During nowadays computational studying of complex inclusion beetwen ß-cyclodextrin and R/S-ibuprofen just use Molecular Dynamic (MD) methode. So of innovation from this research is applying quantum methode as approach to study complex inclusion beetwen ß-cyclodextrins and its derivative and R/S-ibuprofen. The purpose of this study is to calculate the thermodynamic parameters of the R/S-ibuprofen inclusion complex with ß-cyclodextrin and its derivatives, determine the geometry of the R/S-ibuprofen inclusion complex with ß-cyclodextrin and its derivatives, identify the way R/S-ibuprofen enantiomers take place or interact with ß-cyclodextrins and their derivatives and determine the dominant intermolecular interactions between ß-cyclodextrin and their derivatives with R / S-ibuprofen. The host compounds used are ß-cyclodextrin, DIMEB (2,6-di-O-methyl-?-cyclodextrin), TRIMEB (2,3,6-tri-O-methyl-?-cyclodextrin), TRIMEB-2-OH (2I–VI, 3I–VII, 6I–VII eicosa-O-methyl-?-cyclodextrin), TRIMEB-6-OH (2I–VII, 3I–VII, 6I–VIeicosa-O- methyl-?-cyclodextrin) and guest compounds used R-ibuprofen and S-ibuprofen. Host-guest inclusion complexes between R/S-ibuprofen and ß-cyclodextrin and their derivatives have been docking using AutoDock 4.2 and modeled using the semiempirical quantum method PM3 and ONIOM2 (B3LYP / 6-31g (d, p): PM3) and analysis NBO. Based on the value of ? obtained from stasionery phase computational modeling the most selective is TRIMEB. The order of selectivity from good to bad is as follows: TRIMEB; TRIMEB-6-OH; TRIMEB-2-OH; BCD; DIMEB. The results of thermodynamic parameter analysis such as ?H and ?S show that the R/S-ibuprofen inclusion complex with ?-cyclodextrin and its derivatives have negative ?H and ?S values which indicate that the formation of the inclusion complex is a process driven by enthalpy driven. In addition, it is also based on the NBO analysis of the most dominant intermolecular interactions between R/S-ibuprofen and ?-cyclodextrin and their derivatives are weak hydrogen bonds and van der Waals interactions. Thus, the factors driving the formation of R/S-ibuprofen inclusion complexes with ?-cyclodextrin include enthalpy driven, hydrogen bonds, and van der Waals interactions. Based on changes in distance between atoms and bond angles before and after the inclusion of complex inclusions, conformational changes occur. So qualitatively that R-ibuprofen is more flexible when forming inclusion complexes with ?-cyclodextrin and its derivatives, when compared to S-ibuprofen. Thermodynamic and other parameters resulting from computational modeling calculated by semiempirical quantum methods PM3 and ONIOM2, have the same trend. Therefore, it can be concluded that the semiempirical PM3 method is valid in modeling the R/S-ibuprofen inclusion complex with ?-cyclodextrin and its derivatives. Computational modeling in this research also has given confirmation for previous experimental and given some prediction for future research.