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Indian Journal of Chemical Technology Vol. 16, September 2009, pp. 426-430 Estimation of Ibuprofen solubilization in cationic and anionic surfactant media: 1Department of Chemistry, Berhampur University, Bhanja Bihar, Berhampur 760 007, India 2Department of Chemistry, Roland Institute of Technology, Surya Vihar, Golanthara, Berhampur 761 008, India Email: sreelekha_bu@yahoo.com; ranjanpadhy@aol.com Received 17 June 2008; revised 29 June 2009 Drug solubility is an important parameter for efficient drug delivery and absorption. Ibuprofen, α-methyl-4-[2-methyl- propyl] benzene acetic acid is a NSAID group of drug with antipyretic and analgesic properties. It has poor solubility in water. Its solubilisation properties in presence of cetyltrimethylammonium bromide (CTAB) and sodiumdodecyl sulphate (SDS) have been studied. Saturation solubilities in aqueous and aqueous-micellar media have been studied spectrophotometrically by measuring absorbance at 264 nm. Plot of solubility versus [SDS] shows a maximum in the pre-micellar region followed by the linear relationship between the variables in the region past critical micellar concentration (cmc). With CTAB, the solubility- [surfactant] profile shows double maxima, one each in pre- and post- micellar region. Appropriate explanation has been forwarded and the nature of solubilizate-surfactant interaction suggested. The pKa values of ibuprofen determined pH-metrically in aqueous and aqueous-SDS media have been used to supplement the inference. The association constant values and free energy change of solubilisation are reported. Keywords: Micelle, Surfactant, UV Spectroscopy, Absorption, Solubility, Ibuprofen
Drug solubility in aqueous medium is an important solubility of a poorly soluble compound in surfactant parameter for efficient drug delivery and absorption1,2. media remains very low till the cmc is reached and Of particular significance in this regard is the role played by surfactant solutions because of their ability concentration, here a maximum is obtained in the to increase the solubility of sparingly soluble solubility versus [surfactant] graph in the pre-micellar substances in water1. In aqueous solution, surfactant region with either SDS or CTAB as surfactant. Once molecules form organized assemblies or micelles over the cmc is reached the usual linear relationship a narrow concentration range called critical micellar between the two variables is observed only with SDS. concentration (cmc)3. The core of the micelles is However, with CTAB, the solubility-[surfactant] formed by hydrocarbon chain and is hydrophobic in profile shows a double maximum, one each in pre- nature while the outer polar head groups are and post-micellar regions. Thus the theory for hydrophilic and hence remain hydrated. Increase in increased solubilisation in surfactant media4,8 as the solubility of non-polar compounds in surfactant reversible interaction with the micelles of a surfactant medium is ascribed to their incorporation into either in water to form a thermodynamically stable isotropic the palisade layer or inner core of the micelles. solution is not sufficient. Based on the observations a However, compounds with some degree of polarity plausible theory to the mechanism of solubilisation of may be adsorbed at the micellar water interface4,5. ibuprofen in surfactant media is provided. Association Ibuprofen, α-methyl-4-[2-methylpropyl] benzene constants of the solubilizate with micelles as well as acetic acid, which is a non-steroidal, anti- dissociation constants of ibuprofen are also reported. inflammatory drug with analgesic and antipyretic properties, is selected for the present study. It has a Experimental Procedure
poor solubility in water6, 0.049 mg/mL. The present The drug ibuprofen was received as a gift from paper deals with solubilization properties of ibuprofen Apex Laboratories, Chennai. The cationic surfactant in both cationic (cetyltrimethylammonium bromide, (cetyltrimethylammonium bromide, CTAB) was from CTAB) and anionic (sodiumdodecyl sulphate, SDS) BDH while the anionic surfactant (sodiumdodecyl surfactant media. Contrary to the observations4,7 that sulphate, SDS) was from Qualigens. Saturated BHATTAMISHRA & PADHY: ESTIMATION OF IBUPROFEN SOLUBILIZATION IN SURFACTANT MEDIA solutions of ibuprofen in water and in surfactant minor change in the cmc value9 (9.2×10-4 mol dm-3). solutions of different concentrations were prepared by The change in the extents of solubilization with adding excess of the drug to the desired medium. To change in the concentrations of both SDS and CTAB ensure saturation solubility, each solution was is shown in Figs 3 and 4. In either case at pre-micellar subjected to shaking and this was accomplished in concentrations, there is an initial rise in solubility with three different ways; (i) by mechanical means, (ii) increase in surfactant concentration. The solubility using a magnetic stirrer or (iii) centrifuging at reaches a maximum then decreases and rises again at different rpm to a maximum of 4500 rpm at 27ºC. about the cmc value of the surfactant. With SDS as These saturated solutions were left for 24 h to the surfactant, in the region of [surfactant] > cmc, the equilibrate before being taken for spectroscopic solubility increases almost linearly with the increase estimation. Remi C-24BL Cooling Centrifuge was in concentration of the surfactant. However, with used for centrifuging the sample solutions. CTAB, a second maximum is obtained in the plot of The electronic spectrum of ibuprofen recorded by solubility versus [surfactant] in the region [surfactant] Shimadzu UV-visible spectrophotometer 1700, showed two peaks at 264 and 272 nm with extinction The relationship for association of a substrate coefficients as 299 and 257 mol-1 dm3 cm-1 respec- molecule in micellar medium is given by, tively. The concentration of ibuprofen in each saturated solution, measured (24 h) after mixing, was determined from its absorbance value at 264 nm. The conductance values of the saturated solutions of The equilibrium constant KM, also known as ibuprofen in water and in surfactant solutions of Systronics model 306 conductometer with extension conductivity cell, type CD-30 at 27ºC. The pKa values of ibuprofen in aqueous and aqueous-SDS media were determined pH metrically using Systronics µ 361 pH meter with extension glass, calomel electrode and temperature probe. Results and Discussion
Figures 1 and 2 show the conductance values of a number of solutions of SDS and CTAB respectively in presence of ibuprofen. The break at [SDS] = 4×10-3 mol dm-3 shows that the presence of ibuprofen in the surfactant medium lowers its cmc value9 Fig. 2 – Conductance values of CTAB solutions in presence of (8.1×10-3 mol dm-3). However, with CTAB there is Fig. 1 – Conductance values of SDS solutions in presence of Fig. 3 –Solubilization of ibuprofen as a function of [SDS] at 27ºC. INDIAN J. CHEM. TECHNOL., SEPTEMBER 2009 Fig. 4 –Solubilization of ibuprofen as a function of [CTAB] Fig. 5 – Plot of P versus (Dt – cmc) for ibuprofen solubilized in both [SDS] and [CTAB] media are included in where [SW] and [SM] stand respectively for the The presence of maxima in the plots of solubility solubility of the substrate (ibuprofen) in water and in versus [surfactant] in the region where [surfactant] the surfactant medium; [DM] is equal to [D]– cmc, [D] <cmc, may be explained on the basis of complex being the molar surfactant concentration in the formation between the substrate (ibuprofen) and the medium. This is because below cmc, the surfactant surfactant monomer11. As a result, the solubility molecules are largely in the monomeric form but increases. However, as the micelles start forming, the above cmc, these take up mostly the micellar form, substrate-surfactant complex breaks and so the the monomer concentration being approximately solubility decreases12,13. The electronic spectrum of equal to the cmc. The micelle-water partition ibuprofen in water and in 1.4×10-2 mol dm-3 SDS coefficient10, which is the ratio of substrate solution is shown in Fig. 6. There is no shift in concentration in micellar medium to that in water absorption maxima and the spectra are by and large the same. Resemblance of the absorption spectra of a solubilizate in the micellar medium to that in polar solvent implies a polar environment of the substrate in the micelle5. Obviously in an anionic surfactant like SDS, the linear increase in solubility of ibuprofen with increase in [SDS] in the post-micellar region P = K {[D ]−cm } may be ascribed to incorporation of the former in the so that the plot of partition coefficient against The following experiments further establish the site [Dt]-cmc will be a straight line of slope KM (Fig. 5). of adsorption of iburprofen in SDS micellar medium. Since in a micellar medium, the substrate is When SDS is added to ibuprofen solution an increase considered to be partitioned between two phases, the in pH is recorded. The pH change is smaller, in the micellar phase and the aqueous phase, the standard pre-micellar region but increases rapidly above the cmc to reach a saturation value at [SDS] concen- tration of about 5×10-2 mol dm-3. This implies that the acid dissociation of ibuprofen is hindered by the ibuprofen in a number of SDS solution with SDS where Pm is the molar partition coefficient between >cmc have been measured pH-metrically. There is a steady, almost linear increase in pKa values with BHATTAMISHRA & PADHY: ESTIMATION OF IBUPROFEN SOLUBILIZATION IN SURFACTANT MEDIA Table 1—Solubility of ibuprofen in aqueous solutions of SDS and CTAB at 27ºC. a: Either hand shaken or magnetically stirred b: Centrifuged at 4500 rpm. Table 2—Variation in the pKa value of ibuprofen with carboxylate anion of ibuprofen may compete with the anionic micelle for the H+ ion to form the neutral polar ibuprofen molecule, which then easily gets attracted to the micellar surface. This in turn explains both the observed phenomenon i.e. the increase of pKa value and solubility of ibuprofen with increasing SDS Fig. 6 – Electronic spectra of ibuprofen in water and in SDS solution (1.4×10-2 mol dm-3). The solubility pattern of ibuprofen in CTAB up to increasing [SDS] (Table 2), which further supports the cmc is explained exactly in a similar manner as in the above view that SDS micelles hinder deproto- nation. Several factors may be attributed to this concentration increases, the concentration of the behaviour14. Firstly, there may be a concentration ibuprofen increases in the micellar phase and so the gradient of protons between the bulk and interface. solubility increases. The cationic micellar surface Again the dielectric constant on the micellar surface is attracts the carboxylate anion of ibuprofen whose different from that of the bulk; the same on the formation is facilitated by formation of HBr, a micellar interface of SDS has been estimated14,15 as stronger acid compared to ibuprofen. Here the 32. In a medium of low dielectric constant compared electrostatic force is more effective compared to that to bulk water, acid dissociation is likely to be in SDS medium. This is evident from the decrease in hindered. Further, an anionic micellar surface like that pKa value of ibuprofen with increase in [CTAB]. But of SDS is expected to attract positively charged after micelles incorporate all the reactant molecules, species or polar neutral compounds. In such a further increase in micellar concentration only case rather protonation will be encouraged. The produces dilution effect and so the solubility INDIAN J. CHEM. TECHNOL., SEPTEMBER 2009 decreases forming the second maximum in the at concentration of about 5×10-3 mol dm-3 and 5×10-4 mol dm-3 for SDS and CTAB surfactants Table 1 shows some interesting results. When respectively. As a result, the solubility of ibuprofen centrifuged, solubility of ibuprofen in water increases decreases. The release of dissolved ibuprofen at a greatly, but its solubility in SDS solution of any particular concentration of the surfactant is extremely concentration is greatly suppressed compared to hand useful in drug delivery. However, the temperature and shaken or magnetically stirred solubility. The pH effects on solubility of ibuprofen in surfactant decrease in the rate of increase of solubility on media need to be conducted for better understanding centrifuging, is found to be directly proportional to the rpm value. It is felt that churning of the surfactant solution, especially at high rpm, most likely prevents References
formation of organized assemblies of micelles to a 1 Yagui C O R, Hsu H W L, APessoa-Jr & Tavares L C, Braz large extent. The system gets too disturbed to restore 2 Dalmora M E, Dalmora S L & Oliveira A G, Int J Pharm, to normalcy and so the solubility decreases. At any concentration, the solubility of either handshaken or 3 Moroi Y, Sato K & Matuura R, J Phys Chem, 86 (1982) magnetically stirred sample is same within acceptable 4 Yagui C O R, Hsu H W L, APessoa-Jr & Tavares L C, J Pharm Pharmaceut Sci, 8 (2005) 147. Conclusion
5 Fendler E J & Fendler J H, Catalysis in Micellar and Macromolecular Systems (Academic Press, New York), Micellar systems have important application in the field of pharmaceutical science particularly in drug 6 Drug Bank; Ibuprofen, APRD 00372 (www.drugbank.ca). solubility and delivery. Based on the estimation of 7 Yoshida N & Moroi Y, J Coll Inter Sci, 232 (2000) 33. ibuprofen solubilization in cationic and anionic 8 Rosen M J, Surfactants and Interfacial Phenomena (John surfactant media it is concluded that the anionic surfactant solution provides a better solubilizing 9 Mukherjee P & Mysels K J in Critical Micelle Concentration medium where in the post micellar region, interaction of Aqueous Surfactant Systems, Vol. 36 (NSRDS-NBS, between the polar ibuprofen molecule and the 10 Attwood D & Florence A T, Surfactant systems: Their micellar head group overcomes the electrostatic force Chemistry, Pharmacy and Biology (Chapman and Hall, New of repulsion between the anions leading to greater solubility. Considering the low toxicity of anionic 11 Bunton C A, Hong Y S, Romsted L S & Quan C, J Am Chem surfactants, the finding bears significance. In the pre- micellar regions, solubility of ibuprofen increases 12 Kahata Y O, Ando R & Kunitake T, J Am Chem Soc, 99 with increase in concentration of both anionic and cationic surfactants presumably due to complex 13 Kunitake T, Kahata Y O, Ando R, Shinkai & Hiakawa S, J formation between the drug and the respective 14 Sailaja B B V, Kebede T, Rao G N & Rao M S P, J Indian surfactant molecule. At the approach of cmc, the drug surfactant complex breaks, as the surfactant molecules 15 Bunton C A, Romsted L S & Supulveda L, J Phys Chem, 84 arrange themselves to form micelles. This occurs

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