Soft Report - Dipartimento di Fisica - Sapienza

Vibrational properties of inclusion complexes: the case ofindomethacin-cyclodextrinCyclodextrins (CD) are a family of cyclicmolecules, consisting of six (α-CD), seven (β-CD) oreight (γ-CD) glucopyranose units which, in water,take on the peculiar 3-dimensional structure of atruncated cone, with a slightly soluble outer surfaceand a hydrophobic central cavity. A remarkableproperty of CD in aqueous solution, is their ability toform host-guest inclusion complexes with a widevariety of organic and inorganic molecules, providedthat the guest molecule is less polar than water. Inparticular, inclusion complexes of CD with non-polardrugs are a topic of current interest, because thesenon-covalent complexes increase the aqueoussolubility of drugs and also their chemical stabilityand bioavailability.Among the non-steroidal anti-inflammatorydrugs, indomethacin (IMC) is widely used as ananalgesic drug in the treatment of rheumatoidarthritis, as well as in other degenerative jointdiseases, and recently it has also shown anti-tumouractivity. Nevertheless, due to its chemical structure,IMC is poorly soluble in water and this reduces itstherapeutic applications. A strategy to affect itssolubility and chemical stability in water, which isactually employed in commercial drugs, consists inthe preparation of inclusion complexes with CD.In a recent paper [1] we discuss the resultsof Raman scattering experiments and numericsimulations on the IMC-CD inclusion complexes insolid state, which provide new insight into thestructure of the complexes, and into the effect of theinclusion process on the guest. Inclusion complexesof IMC with hydroxypropylβCD (IMC-HPβCD) andCD (IMC-βCD) have been prepared and preliminaryexperiments have been performed on the sampleusing electrospray-ionization mass spectrometry andNMR, in order to verify the effective formation of thecomplexes and their stoichiometry.also confirmed by the vibrational analysis performedby ab initio quantum chemical computation. Bycomparing the spectrum of free IMC (Fig.1 (a)) tothose of its inclusion complexes IMC-HPβCD (Fig.1(b)) and IMC-βCD (Fig.1 (c)), we note a markedbroadening of the peak corresponding to the amideC=O stretch, as well as a shift from ≈ 1700 cm -1 to ≈1670 cm -1 .From the above results one might infer thatit is the amide C=O group of IMC (and theneighbouring atoms) to be most affected by theinclusion process; similar results have been obtainedalso on the inclusion complex formed by βCD withIMC sodium salt. Moreover, in order to understandthe precise way in which such atoms are influencedby complexation, other possible effects should bediscussed, such as the possibility that the changes ofvibrational frequencies be due to the presence of theuncomplexed guest in dimer form. However, all theexperimental results indicate that the observed shiftof the amide C=O stretch is actually related tocomplexation and not to the cleavage of hydrogenbonding patterns of IMC dimers.Experimental results are in qualitativeagreement with the conclusion of simulation, asshown in Figure 2., where the effect of thecomplexation on the computed g(ω) is reported. Wenote that here the shift to lower energy of theeigenvalue at 1628 cm -1 (corresponding in thesimulation to the amide C=O stretch of IMC) is wellreproduced.g(ω)1628 cm -1free IMCfree βCDIMC-βCD complex1614 cm -11620 1650 1680Energy (cm -1 )Fig. 2 Calculated g(ω) for free IMC (full line), freeβCD (empty circles) and for IMC-βCD inclusioncomplex (dotted line)Fig. 1 Raman spectra of free IMC (a), IMC-HPβCDcomplex (b) and IMC-βCD complex (c).By comparing the Raman spectrum of freeIMC with that of other molecules which havechemical structure very similar to subunits of IMC,we have assigned the peak of the guest at 1698 cm -1to the amide C=O stretch. This assignment has beenReferences[1] B. Rossi, P. Verrocchio, G. Viliani, G. Scarduelli,G. Guella, I. Mancini, J. Chem. Phys. 125 044511(2006).Authors: B. Rossi (a,b), P. Verrocchio (a,b), G.Viliani (a,b), G. Scarduelli (a), G. Guella (a), I.Mancini (a) - (a) Dipartimento di Fisica Università diTrento, Italy; (b) INFM CRS-SOFT, c/o Università diRoma "La Sapienza", Roma, Italy77SOFT Scientific Report 2004-06