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Chemistry Journal of Moldova. V. Boldescu General, et al./Chem.J.Mold. Industrial and 2008, Ecological 3 (1), Chemistry. 85-88 2008, 3 (1), 85-88SPECTROPHOTOMETRIC STUDIES OF SANGUINARINE--CYCLODEXTRIN COMPLEX FORMATIONVeaceslav Boldescu, a,* Irina Kacso, b Ioan Bratu b and Gheorghe Duca aaDepartment of Industrial and Ecological Chemistry, State University of Moldova, 60, Mateevici str., MD 2009,Chisinau, Republic of Moldova*tel. (+373 79) 454062, fax (+373 22) 244248, e-mail: sboldescu@yahoo.combNational Institute for Research and Development of Isotopic and Molecular Technologies, 71-103, Donath str., P.O. Box700,RO-400293, Cluj-Napoca, RomaniaAbstract. The main aim of this study was to investigate the influence of pH and the presence of hydrophilicpolymer polyvinylpyrrolidone on the formation of sanguinarine--cyclodextrin (SANG--CD) inclusion complex.Spectrophotometric studies of the SANG--CD systems in the presence and without 0.1 % PVP at the pH 5.0 did notshow any evidence of the complex formation. However, the same systems showed several obvious evidences at thepH 8.0: the hyperchromic and the hypochromic effects and the presence of the isosbestic point in the region of 200 –210 nm. The association constants calculated by three linear methods: Benesi-Hildebrand, Scott and Scatchard, weretwo times higher for the systems with addition of 0.1% PVP than for the systems without it.Keywords: sanguinarine, -cyclodextrin, inclusion complex, UV-vis spectrophotometry, association constantIntroductionSanguinarine (SANG) is a quaternary benzo[c]phenanthridine alkaloid derived from the plants of Papaveraceaeand Fumaraceae families (Macleya cordata, Sanguinaria canadesis, Chelidonium majus). It has been found to be apotent antimicrobial, anti-inflammatory, antioxidant agent [1, 2]. Moreover, recent studies have shown its in vitro andin vivo antiproliferative activity toward skin and prostate cancer cells [3-5].Among the main obstacles of the pharmaceutical application of SANG are low solubility in water-based liquidsat the physiological pH and possible mucosal and skin irritation. The low solubility is caused by the prevalence ofSANG “pseudobase” form in the neutral and weak alkaline media (Figure 1). However, namely this form of SANG issupposed to penetrate membranes of the target cells.Figure 1. Sanguinarine iminium (I) and “pseudobase” forms (II)One of the methods that can be used to enhance the water solubility and to reduce the irritating properties ofdifferent drugs, is formation of drug-cyclodextrin inclusion complexes.Cyclodextrins (CDs) are cyclic oligosaccharides with a shape of truncated cone with a somewhat hydrophobiccavity and hydrophilic outside surface. -, c and -CDs, with six, seven and eight, -1,4-linked glucose residuesrespectively, are the most widely used. Inside of their cavity CDs can accommodate a wide range of lipophilic drugmolecules. The process of drug-cyclodextrin inclusion complexes formation depends on several factors: type ofcyclodextrin used (-, - or -CD), chemical and physical properties of the drug molecule, the complexation mediumproperties [6, 7].In order to influence the efficiency of the complexation process different methods have been used: controlledchange of pH of the complexation media [8, 9]; addition of different co-complexing agents to it: hydrophilic polymers(polyvinylpyrrolidone, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, polyethylene glycol) [10, 11],hydroxyacids [12], amino acids [13]; treatment of the complexation media with microwaves [14].The aim of this study is to evaluate the effect of the pH control and addition of hydrophilic polymerpolyvinylpyrrolidone on the complexation efficiency of -CD with SANG.85
V. Boldescu et al./Chem.J.Mold. 2008, 3 (1), 85-88ExperimentalPreparation of the SANG--CD systems for the spectrophotometric studiesThe studied systems of SANG at constant concentration 0.03 mM and CD at increasing concentrations 0.03,0.06, 0.10, 0.30, 0.50, 0.80, 1.00, 1.30, 1.50, 1.80, 2.00 mM have been prepared with and without addition of 0.1% (w/v)PVP in phosphate buffer-alcoholic solution (95:5 v/v) at different pH. The obtained solutions were mixed for 2 hours at35 °C wrapped in the aluminium foil to protect them from the direct light and then left for 24-hour equilibration.UV-vis spectrophotometry. UV-vis absorption spectra were recorded on a Jasco UV/VIS spectrophotometer,model V-550 equipped with a quartz cells with 1.0 cm optical path length.Results and discussionsThe spectrophotometric studies of the SANG--CD systems with and without addition of 0.1% (w/v) PVP atpH 5.0 did not show any evidence of stable complex formation. These results can be explained by the prevalence ofiminium form (Figure 1) of SANG in the studied systems at this level of pH. The iminium form is charged and is morehydrophilic than ‘pseudobase’ form, therefore, it can not be included into the hydrophobic cavity of the -CD.At the pH 8.0, close to physiological levels, SANG--CD systems with and without addition of 0.1% (w/v)PVP showed several significant evidences of the inclusion complex formation: the hyperchromic and the hypochromiceffects and the presence of the isosbestic point in the region of 200 – 210 nm (Figure 2. (a) and (b)).(a)Figure 2. (a) UV-VIS absorption spectra of 0.03 mM SANG at different concentrations of CD: 0.03, 0.06, 0.10, 0.30,0.50, 0.80, 1.00, 1.30, 1.50, 1.80, 2.00 mM, in phosphate buffer-alcoholic solution (95:5 v/v), pH 8.0; (b) UV-VISabsorption spectra of 0.03 mM SANG at different concentrations of CD: 0.03, 0.06, 0.10, 0.30, 0.50, 0.80, 1.00,1.30, 1.50, 1.80, 2.00 mM in the presence of 0.1% PVP, in phosphate buffer-alcoholic solution (95:5 v/v), pH 8.0(b)The simulated curves of the spectrophotometric titration (at 283 nm) of 0.03 mM SANG with CD in phosphatebuffer-alcoholic solution (95:5 v/v) with and without addition of 0.1% PVP, at pH 8.0, are shown in the Figure 3. (a)and (b). The hyperbolic character of the obtained curves is one of the indicators of the 1:1 stoichiometric ratio in theinclusion complex formation between the host (CD) and the guest molecule (SANG), according to the reaction shownin Scheme 1.SANG + CD SANG-CDThe curves resulted from the spectrophotometric titration of SANG with CD (at 283 nm) were processed toobtain the values of the association constant K aof SANG-CD systems, in the presence and without of 0.1% PVP. Theconstants were calculated using different linear methods: Benesi-Hildebrand, Scott, Scatchard [15]. The plots of thesethree methods for the studied host-guest complexes at pH 8.0, are shown in the Figures 4, 5 and 6. Among them, theScott method showed the highest levels of the correlation coefficients of the obtained results, ranging in the values 0.98– 0.99. The correlation coefficients for the Benesi-Hildebrand and the Scatchard methods were in the limits of 0.96 –0.98 and 0.93 – 0.94 respectively.86
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