Micellar effects on the complex formation reaction of copper (II) with ciprofloxacin

Transcription

1 Indian Journal of Chemical Technology Vol. 22, September 2015, pp Micellar effects on the complex formation reaction of copper (II) with ciprofloxacin Akshya umar Panda* & S D Bhattamisra Department of Chemistry, Berhampur University, Berhampur , Odisha, India akpanda09@yahoo.com Received 13 June 2013; accepted 17 February 2014 Complex formation between Cu (II) and ciprofloxacin in aqueous micellar media has been reported. Conventional spectroscopic and ph-metric methods have been adopted to investigate the micellar effects. Both cationic (cetyltrimethylammonium bromide, CTAB and cetylpyridinium chloride, CPC) and anionic (sodiumdodecylsulphate, SDS) surfactants have been used in the investigation. Results indicate considerable micellar effects with SDS, while the effects of CTAB and CPC are marginal. Deprotonation of ciprofloxacin hydrochloride is hindered in aqueous SDS medium, but the complex formation between Cu (II) and ciprofloxacin is considerably enhanced. The Cu (II) ciprofloxacin complex in SDS medium absorbs at 657 nm. The absorbance [SDS] profile exhibits double maxima, one below cmc and the other almost at the cmc of SDS. The results are explained in terms of pseudo-phase model whereby it is assumed that the complex formation reaction predominantly occurs on the negatively charged SDS micellar surface compared to the bulk aqueous phase. From the rate-[sds] profile, binding constant of ciprofloxacin-sds is found to be 20. eywords: Ciprofloxacin, Copper, Metal complex formation, Surfactant, Cmc, Binding constant Ciprofloxacin is a quinolone group drug used clinically for the treatment of a variety of bacterial infections including anthrax 1,2. The drug action involves inhibition of the function of bacterial DNA gyrase which is essential for DNA replication. The mechanistic pathway for the process is known 1,3 to involve metal-ciprofloxacin complex species as intermediates. Moreover, many other drugs in the form of metal complexes 3,4, particularly those of Cu 2+, have been known to possess enhanced pharmaceutical property 5-7. Hence studies on coordination property of ciprofloxacin with metal ions are of significance. Although there have been several reports on the metal ciprofloxacin complex formation 1,2,8-10, these are mostly limited to the synthesis, spectral properties and crystal structure of the complex. Some reports on biological activity against various microorganism are also available. The present paper deals with micellar effects on the thermodynamic spectral, and kinetic properties of Cu (II) complexes of ciprofloxacin. Both cationic and anionic surfactants have been used for the purpose. It is now well established that surfactants in aqueous media exert significant effects upon equilibria and rates of reaction by incorporating the reactants into their micellar pseudo-phases 11,12. Micelles also have potential role in biological systems where biochemical processes proceed in a microheterogeneous system containing an aqueous and liophilic moiety 13. Against this backdrop the present study on the acid dissociation of the drug as well as on the metal-drug complexation properties in micellar media is of special significance. This will help in understanding the drug properties in terms of their binding and transport as well as the chemical and metabolic activities of the bound species in physical systems. Experimental Section All the chemicals used were of AR grade, the drug ciprofloxacin was a gift from Ranbaxy, Mumbai. The surfactants viz., sodiumdodecylsulphate (SDS), cetyltrimethylammonium bromide (CTAB) and cetylpyridinium chloride (CPC) were recrystallised from ethanol or ethanol-acetone mixture and were stored over fused calcium chloride 14. ph metric titrations were carried out on a Systronics -361 assembly thermostatically maintained at 298. Carbonate free standard solution of OH was used for ph metric titration as well as for maintaining the ph of solution wherever necessary. Aqueous solution of Cu(NO 3 ) 2.3H 2 O was

2 254 INDIAN J. CHEM. TECHNOL., SEPTEMBER 2015 standardized complexometrically against disodium EDTA using fast sulphone black F as indicator. The stock solution of the drug of strength 0.05 mol dm -3 was prepared and stored at 277 when not in use. Titrations of drug solution as well as mixture of drug and metal solutions in various proportions were carried out using mol dm -3 OH solution from ph 2.0 to The visible absorption spectra of the metal complexes were measured on a Shimadzu 170A UV-visible spectrophotometer. The cell compartments were maintained thermostatically at 25 C. For spectrum in micellar media, equal amounts of surfactant solution were added separately to the drug and the metal solution. These were allowed to equilibrate for half an hour at the end of which the two solutions were mixed and the spectrum was taken. Results and Discussion The complex formation characteristics of ciprofloxacin with Cu (II) are known to be sensitive to the ph of solution 15. However, the absorption spectrum of Cu (II)-ciprofloxacin complex (Cu-cip) from nm, where the pure drug has negligible absorbance, could be gathered only up to ph 5.82 since above this ph ciprofloxacin solubility is too small to yield meaningful observation. The (max) values changes from (810) = 12.6 mol -1 dm 3 cm -1 for pure aqueous Cu 2+ ion to (743) = 34.8, (714) = 39.6, (703) = 48.6 and (691) = 60.1 mol -1 dm 3 cm -1 for Cu-cip complex at ph 2.95, 3.30, 4.62 and 5.84 respectively. (The figures in the bracket signify the wave length of maximum absorption). The blue shift in the wavelength of maximum absorption, (max), together with increasing values of (max) clearly indicate that both complex formation and its stability increase with increasing ph. When the complex formation reactions are carried out in surfactant solutions viz., cetyltrimethylammonium bromide (CTAB), cetylpyridinium chloride (CPC) and sodiumdodecylsulphate (SDS), each at a series of concentrations through its cmc, sizable changes in absorption properties of Cu-cip complex are observed but only with SDS (Table 1). With CTAB and CPC, the changes are negligible (Table 1) which suggest practically no effect of the respective micellar medium on the complexation process. In presence of SDS, the (max) value of Cu-cip complex shifts by almost 85 nm to 657 nm with =54.7 mol -1 dm 3 cm -1 compared to (max) = 743 nm and = 34.8 mol -1 dm 3 cm -1 for Cu-cip complex in pure aqueous medium at ph 3.00±0.1 (Fig. 1). This indicates enhanced complexation and increase in stability of the Cu-cip complex in SDS medium. Figure 2 shows the variation of (657) with increase in concentration of SDS from to mol dm -3. In these experiments the amounts Table 1 Spectrophotometric parameters of copperciprofloxacin complex in different media. [Ciprofloxacin]= and [Cu 2+ ] = mol dm -3. The concentration of the surfactant compounds: [CPC] and[ctab] = and [SDS]= mol dm -3. ph = 3.00±0.1. Species Medium max, nm, mol -1 dm 3 cm -1 Cu 2+ Water Cu-cip Water Cu-cip Water CPC Cu-cip Water CTAB Cu-cip Water SDS Fig. 1 Visible spectrum of copper-ciprofloxacin complex at different concentrations of SDS. Ciprofloxacin concentration = , Cu 2+ concentration = and SDS concentration: a = , b = , c= , d= mol dm -3. Curve e is the spectrum of same amount of Cu 2+ and ciprofloxacin in aqueous medium without any SDS. All measurements are made under thermostatic condition at 30C. Fig. 2 Variation of value in the absorption spectrum of Cu 2+ - ciprofloxacin complex as a function of SDS concentration (At = 657 nm). Reaction conditions are similar to those in Fig.1.

3 PANDA & BHATTAMISRA: MICELLAR EFFECTS ON REACTION OF COPPER (II) WITH CIPROFLOXACIN 255 of Cu 2+ and ciprofloxacin are taken in 1:10 molar ratio and in each case the absorbance value is recorded after five minutes from the time of mixing of the reactants. The change in (657) value of the Cu-cip complex with increase in SDS concentration is described by double maxima, one of the maxima occurring in the vicinity of cmc value of SDS (= mol dm -3 ). The [SDS] profile is explained by the fact that at low surfactant concentration ciprofloxacin forms a complex with the surfactant monomer which then activates it towards the metal ion thereby enhancing the rate of complex formation. As the surfactant concentration increases and the surfactant molecules arrange themselves to form micelles, the ciprofloxacin-surfactant monomer complex breaks. As a result the rate first increases and then decreases due to gradual formation of micelles. When the micellar concentration grows the concentration of both the reactants, the cationic Cu 2+ ions and the ciprofloxacin molecules increase in micellar pseudo-phase. The aggregation of both the reactants in a small volume of micellar pseudo-phase increases the rate of complex formation due to concentration effect 16. But after the micelles incorporate all the reactant molecules further increase in surfactant concentration only produces dilution effect and the rate finally decreases 17,18. Blasko and coworkers 19 also reported double rate maxima over a limited range of surfactant concentration and attributed their observation to the fact that such behavior are exhibited by substrates that are polarizable and can form reactive complexes with monomeric surfactants or submicellar clusters. Such complexes are reasonably reactive to make the overall effect visible. The overall rate of reaction is the sum total of those involving submicellar clusters as well as the micelles. The contribution of each is calculated by using the pseudo-phase model. The above explanation is further supported by results of kinetic study on the Cu-cip complex formation at different pre-micellar concentrations of SDS (Table 2). The kinetic experiments are carried out under conditions similar to those mentioned in Fig. 1. The pseudo first order rate constant values progressively increase with increase in SDS concentration. The plot of 1/(k ψ k 0 ) vs 1/[SDS] is linear with positive slope and intercept (Fig. 3). This suggests that the SDS catalyzed complex formation reaction may be treated in a manner analogous to that used for enzymatic catalysts 20,21. Table 2 First order rate constant values for the complex formation reaction between Cu(II) and ciprofloxacin at different pre-micellar concentrations of SDS. [Cu(II)] = , [Ciprofloxacin] = mol dm -3, ph=3.00±0.1, Temp=30C. Values of 1/(k ψ -k 0 ) and 1/[SDS] are also incorporated to explain Fig [SDS], 10 4 k ψ, sec (1/k ψ -k 0 ), sec 10-3 (1/[SDS]), mol dm -3 mol -1 dm 3 M + S k 0 Product MS Product where S is the reactive substrate (protonated ciprofloxacin), M is the surfactant molecule, MS is the substrate-surfactant complex and k 0 & k ψ are the rate constants for product formation in the bulk solvent and in the sub-micellar clusters. The pseudophase model yields the rate expression as: k P M k 0 P [SDS] (1) where P is some kinetic parameter and M is ciprofloxacin-sds binding constant. From the plot of 1/(k ψ k 0 ) vs 1/[SDS], the M is determined as (intercept/slope) and is found to be 20, which is moderately sufficient to account for rate acceleration in SDS medium. The equilibrium reactions between the metal ion and the drug have been studied ph-metrically. Analysis 22 of the titration data indicates the existence of only two metal complex species according to the following equilibria (Eqs. 2-4). HL 1 L H 2 2 L CuL k ψ... (2) Cu 2... (3)

4 256 INDIAN J. CHEM. TECHNOL., SEPTEMBER L CuL2 CuL 3... (4) where HL + is ciprofloxacin hydrochloride and L stands for the zwitterionic ciprofloxacin molecule, - R N H2COO(R C17H18 FN2O3 ), so that 1 is the equilibrium constant for carboxylate dissociation. The different equilibrium constant values in aqueous as well as aqueous micellar media are listed in Table 3. It is evident from the cited data that the various equilibrium constant values remain practically unchanged in presence of both cationic surfactants but undergo up to about 100 fold variations in SDS medium. The shift in magnitude of p 1 (= -log 1 ) values in micellar media compared to the aqueous solution is mainly due to the formation of a concentration gradient for drug molecules (HL + Cl - ) between the micelles and the bulk solution 23,24. The SDS micellar surface being negative, it stabilizes the positively charged species HL + thereby hindering its dissociation (Eq.1). This is evident in increasing p 1 value by almost two units in SDS medium. For CTAB and CPC, where the dissociation largely occurs in the bulk aqueous solution, a slight increase in the p 1 values may be attributed to decrease in dielectric constant of the medium in presence of surfactant molecules 23. However, the metal-drug complex formation is favored in SDS medium as evident from the 2 and 3 values in this medium compared to those in aqueous solution. This observation is in conformity with that from spectrophotometric study. It further supports the view that the complexation reaction occurs on the negatively charged micellar surface where both the cationic Cu 2+ ions and the drug molecules accumulate. The strong forces coupled with more effective collision raises the crystal field energy and hence the stability increases. Table 3 Acid dissociation constant of ciprofloxacin and stability constant values of Cu 2+ - ciprofloxacin complex in aqueous micellar media.at 298, I = 0.05, [ciprofloxacin] = , [Cu 2+ ] = , [SDS] = , [CTAB] = , [CPC] = mol dm -3. Medium - log 1 log 2 log 3 Water SDS CTAB CPC Conclusion Drugs in the form of metal complexes are known to have enhanced pharmaceutical activity. Metaldrug complex formation is greatly influenced in micellar media since micelles significantly affect equilibria and rates of reaction by incorporating the reactants into their micellar pseudo phases. Based on the estimation of thermodynamic stability and spectral properties in cationic and anionic surfactant media it is concluded that the anionic surfactant medium provides a favorable condition for metal-drug complex formation by incorporating both the Cu 2+ ions and the polar ciprofloxacin molecules into the micellar pseudo phase. The concentration effect enhances the complex formation. In the pre-micellar concentrations of the surfactant, there is also an increase in metal-drug complex formation with increase in surfactant concentration and this is attributed to surfactantdrug binding which acts as a precursor to metaldrug complex formation by activating the drug towards the metal ion. With the approach of the critical micelle concentration, such surfactant drug moieties break as surfactant molecules arrange themselves to form micellar aggregates. As a result the drug molecules are released to the bulk medium. Such sudden release of ciprofloxacin at a particular concentration of surfactant is significant and may be put to use in drug delivery in physiological systems. References 1 Zupancic M, Turel I, Bukovec P, White A J P & Williams D J, Croati Chem Acta, 74 (2001) Drevnsek P, Golobic A, Turel I, Poklar N & Sepcic, Acta Chim Slov, 49 (2002) Shen L L, Mitscher L A, Sharma P N, Donnel T J, Chu D W T, Coopr C S, Rosen T & Pernet A G, Biochemistry, 28 (1989) Shen L L & Pernet A G, Proc Natl Acad Sci, 82 (1985) Wu G, Wang G, Fu X & Zhu L, Molecules, 8 (2003) Ruiz M, Perello L, Ortiz R, Castineiras A, Maichlemossmer C & Canton E, J Inorg Biochem, 59 (1995) Brown D H, Lewis A J, Smith W E & Teape J W, Med J Chem, 23 (1980) Zupancic M, Arcan I, Bukovec P & odre A, Croati Chem Acta, 75 (2002) 1. 9 Turel I, Golic L & Ramirez O L R, Acta Chim Slov, 46 (1999) Mustafa J A, Acta Chim Slov, 49 (2002) Das A C & Nayak R C, Chem J Soc Faraday Trans, 83 (1987) Fendlar J H & Fendler E J, Catalysis in micellar and macro molecular systems (Academic Press, New York) 1975.

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