Colloids and Surfaces B: Biointerfaces 88 (2011) 7277

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Colloids and Surfaces B: Biointerfaces

journal homepage: www.elsevier.com/locate/colsurfb

A comparative study of interaction of ibuprofen with biocompatible polymers

Iqrar A. Khan a , Kahkashan Anjum a , Mohd. Sajid Ali b , Kabir-ud Din a,
a b

Department of Chemistry, Aligarh Muslim University, Aligarh 202002, India Department of Chemistry, College of Science, King Saud University, Riyadh 11541, Saudi Arabia

a r t i c l e

i n f o

a b s t r a c t
In this paper we are reporting the interaction of a non-steroidal anti-inammatory drug ibuprofen (IBF) with various biocompatible polymers. Being amphiphilic, the drug interacts with the polymers similar to the interaction of surfactants and polymers. Therefore, we have considered the polymeramphiphile interaction approach using conductimetry. The polymers of different charges (cationic, anionic, and nonionic) have been taken for the study. It was found that the critical aggregation concentration (cac) decreases on increasing the polymer concentrations of cationic as well as nonionic polymers whereas it increases for anionic polymers. The results imply that anionic IBF interacts with cationic and nonionic polymers more strongly as compared to the anionic polymers. A possible anionicanionic repulsion is responsible for the weak interaction of IBF with anionic polymers. On the other side, the critical micelle concentration (cmc) increases for all polymers which is a usual indication of the interaction between amphiphiles and polymers. Free energies of aggregation ( Gagg ) and micellization ( Gmic ) were also computed with the help of degrees of micelle ionization obtained from the specic conductivity [IBF] isotherms. 2011 Elsevier B.V. All rights reserved.

Article history: Received 1 March 2011 Accepted 4 June 2011 Available online 21 June 2011 Keywords: Ibuprofen Drugpolymer interaction Critical aggregation concentration Polymer saturation point

1. Introduction The release of bioactive substances from polymeric materials has fascinated the signicant interest of investigators among the scientic community. Successful drug delivery necessitates concern of various factors and, therefore, different approaches have been developed which depend upon the route of administration, the indication at hand, the properties of the drug, and so on. Among these the effectiveness and safety of therapy are of foremost importance [13]. Essentially, the concentration of drug should be high enough at the targeted site to facilitate the therapeutic effect, but simultaneously it should not be too high, because this may result in unfavorable side effects. Keeping these effects in mind, the drug delivery systems should, therefore, be designed with proper knowledge of the properties of drugcarrier conjugates. The interaction of drugs with polymers (the most often used carrier) is also a very important aspect among these properties and plays an important role in the drug delivery formulations [48]. These interactions become more interesting when the drug is amphiphilic and have a tendency to form micelle-like aggregates [9,10]. A variety of drug molecules, such as antihistamines, antidepressants, tranquilizers, local anesthetics, and nonsteroidal

Corresponding author. Tel.: +91 571 2703515; fax: +91 571 2708336. E-mail address: kabir7@rediffmail.com (Kabir-ud-Din). 0927-7765/$ see front matter 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.colsurfb.2011.06.008

anti-inammatory drugs (NSAIDs) are known to be amphiphilic in character that form ordinary micelles or micelle-like associations above a critical concentration (the so called critical micelle concentration) [1115]. These drugs may interact with polymers in surfactant-like manner, i.e., there may exist critical aggregation concentration (cac) and critical micelle concentration (cmc) or polymer saturation point (psp) [9,10]. The cac, the onset of aggregation, is either near or well below the cmc of pure amphiphile while the cmc is assigned to the saturation of polymer domains by the monomers and/or micelle-like aggregates [1620]. Above the cmc, formation of normal micelles takes place. Both hydrophobic and electrostatic forces play an important role in the interaction of polymers and amphiphiles when either both or one of the entities are ionic in nature. The knowledge of cac may be of importance as the interaction of amphiphilic drug with polymer starts at this concentration. The present paper deals with the general problem of the aqueous association of surface active drugs and polymers. The sodium salt of ibuprofen (IBF) (Fig. 1) is NSAID which is surface active and was chosen as model drug. The results may be helpful in designing the drug delivery formulations of similar systems. The following biocompatible polymers were used: neutralpolyvinylpyrrolidone (PVP), polyethylene glycol (PEG), hydroxypropylmethyl cellulose (HPMC), hydroxyethyl cellulose (HEC); anionic-sodium carboxymethyl cellulose (NaCMC), dextran sulphate (DxS); cationic-hydroxyethyl cellulose ethoxylate (HECEQ).

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73

102 (S cm-1)

0 0.00 0.05 0.10 0.15

-3

0.20

0.25

[IBF] (mol dm )
Fig. 1. Structure of sodium salt of ibuprofen (IBF). Fig. 2. Plot of specic conductivity () versus [IBF] at 25 C.

2. Materials and methods 2.1. Materials The amphiphilic drug ibuprofen sodium salt (IBF) (99%, Sigma, USA, CAS Registry no. 31121-93-4), neutral polymers, i.e., polyvinylpyrrolidone K 30 (Fluka, Switzerland), polyethylene glycol K 35 (Fluka, Germany), hydroxypropylmethyl cellulose (Sigma, USA), hydroxyethyl cellulose (Otto, Mumbai), anionic polymers, i.e., sodium carboxy methyl cellulose (Sigma, USA), dextran sulphate (Merck, Germany), and cationic polymer, i.e., hydroxyethyl cellulose ethoxylate quaternized (Sigma, USA) were used as received. Demineralized double-distilled water of specic conductivity (12 106 S cm1 ) was used to prepare the stock solutions of the drug and polymers. 2.2. Conductivity measurements The conductivity measurements were executed on an ELICO (type CM 82T) bridge equipped with platinized electrodes (cell constant = 1.02 cm1 ). The conductivity runs were carried out by adding gradually concentrated IBF stock solution into the thermostated solvent or solvent including polymer at temperature 25 C. The critical micellar concentration of the pure IBF used was obtained from the plots of specic conductivity () as a function of the drug concentration. The cmc values were taken from the intersection of the two straight lines drawn before and after the intersection point in the plots (Fig. 2). As in case of the polymerdrug mixtures the plots of versus [drug] showed two breaks (Fig. 3), the cac was determined by the intersection of rst and second linear parts and the cmc was the intersection point of the second and third linear parts. 3. Results and discussion Fig. 2 shows a specic conductivity prole as a function of concentration of IBF. The intersection point of the two straight lines represents the usual critical micellar concentration (cmc) of IBF and

was found to be 0.90 mol dm3 . As we have used different polymers in this study which are either neutral or charged, we have got interesting results which depend on their charges as well as hydrophobicities. The specic conductivity proles of IBF in presence of various polymers are given in Figs. 39. We have used different concentrations of each polymer to get a complete insight on the interactions. Clearly, all plots show two breaks in presence of polymers in comparison to a single break observed in the absence.

12

102 (S cm-1)

6 % HPMC (w/v) 0.05 0.1 0.2 0.3 0.5 0.8 1.0

0 0.00

0.05

0.10

0.15

0.20
-3

0.25

0.30

[IBF] (mol dm )
Fig. 3. Plots of specic conductivity () versus IBF concentration at different concentrations of HPMC. The scale shown is for plot denoted as ( ). Other plots have been shifted upwards by 1.0, 2.0, 3.0, 4.0, 5.0 and 6.0 scale units (1 102 S cm1 ), respectively.

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12 12

102 (S cm-1)

102 (S cm-1)

6 % PEG (w/v) 0.05 0.1 0.2 0.3 0.5 0.8 1.0

% HEC (w/v) 0.05 0.1 0.2 0.3 0.5

0 0.00 0 0.00 0.05 0.10 0.15 0.20 0.25 0.05 0.10 0.15 0.20
-3

0.25

0.30

[IBF] (mol dm )
Fig. 6. Plots of specic conductivity () versus IBF concentration at different concentrations of PEG. The scale shown is for plot denoted as ( ). Other plots have been shifted upwards by 1.0, 2.0, 3.0, 4.0, 5.0 and 6.0 scale units (1 102 S cm1 ), respectively.

[IBF] (mol dm-3)

Fig. 4. Plots of specic conductivity () versus IBF concentration at different concentrations of HEC. The scale shown is for plot denoted as ( ). Other plots have been shifted upwards by 1.0, 2.0, 3.0, and 4.0 scale units (1 102 S cm1 ), respectively.

13 12 11 10

The two breaks in presence of polymer are ascribed to the occurrence of two kinds of aggregation phenomena. The rst break is called as the critical aggregation concentration (cac) where the interaction of macromolecule chain with the amphiphile (drug) starts. The second break point, cmc, is attributed to the saturation of polymer with drug monomers and/or micelle-like aggregates,

12

102 (S cm-1)

9 8 7 6 5 4 3 2 1 0 0.00 % PVP (w/v) 0.05 0.1 0.2 0.3 0.5 0.8 1.0 9

102 (S cm-1)

6 % HECEQ (w/v) 0.05 0.1 0.2 0.3 0.5 0.8 1.0

0.05

0.10

0.15

0.20

0.25

0.30

[IBF] (mol dm-3)

Fig. 5. Plots of specic conductivity () versus IBF concentration at different concentrations of PVP. The scale shown is for plot denoted as ( ). Other plots have been shifted upwards by 1.0, 2.0, 3.0, 4.0, 5.0 and 6.0 scale units (1 102 S cm1 ), respectively.

0 0.00

0.05

0.10

0.15
-3

0.20

0.25

[IBF] (mol dm )
Fig. 7. Plots of specic conductivity () versus IBF concentration at different concentrations of HECEQ. The scale shown is for plot denoted as ( ). Other plots have been shifted upwards by 1.0, 2.0, 3.0, 4.0, 5.0 and 6.0 scale units (1 102 S cm1 ), respectively.

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12

0.06
HPMC HEC

0.05 9

PVP PEG HECEQ

cac (mol dm-3)

NaCMC

102 (S cm-1)

0.04

DxS

0.03

% NaCMC (w/v) 0.002 0.003 0.005 0.008 0.01 0.015 0.02

0.02

0.01 0.0 0.2 0.4 0.6 0.8 1.0

0 0.00

% Polymer (wt/vol)
0.05 0.10 0.15
-3

0.20

0.25

[IBF] (mol dm )
Fig. 8. Plots of specic conductivity () versus IBF concentration at different concentrations of NaCMC. The scale shown is for plot denoted as ( ). Other plots have been shifted upwards by 1.0, 2.0, 3.0, 4.0, 5.0 and 6.0 scale units (1 102 S cm1 ), respectively.

Fig. 10. Critical aggregation concentration (cac) as a function of polymer concentration.

followed by formation of polymer-free aggregates on adding more amount of drug. It is remarkable to note that in presence of each polymer the rst break point, cac, is less than to the break point observed in absence of macromolecule, i.e., cmc of IBF in pure aqueous solution (Fig. 2).

12

% DxS (w/v) 0.05 0.1 0.2 0.3 0.5 0.8 1.0

0 0.00

0.05

0.10

0.15
-3

0.20

0.25

[IBF] (mol dm )
Fig. 9. Plots of specic conductivity () versus IBF concentration at different concentrations of DxS. The scale shown is for plot denoted as ( ). Other plots have been shifted upwards by 1.0, 2.0, 3.0, 4.0, 5.0 and 6.0 scale units (1 102 S cm1 ), respectively.

The appearance of rst break shifted to lower concentrations of the drug as the concentration of polymer increases, i.e., the cac decreases on increasing the polymer concentration. The second break point, on the other hand, is higher than the rst one and also more than the cmc of the drug in polymer free (pure aqueous IBF) solution. Thus, contrary to the decrease in cac, cmc increases on increasing the polymer concentration. A decrease in the cac value, mainly credited to the interactions between the macromolecule and amphiphilic drug, is the characteristic of polyelectrolytes and amphiphiles of opposite charges [2123]. But the interaction of amphiphiles with polymers which are either neutral or same charges (as of amphiphile) have also been observed, although upto a lesser extent [16,17,24]. As in this study we have taken the polymers of various natures, it can be concluded on the basis of results (given in Table 1 and Fig. 10) that cationic polymer HECEQ has more afnity towards the anionic drug IBF as implied by the lowest values of cac in this case. The larger decrement in the values of cac is obvious for HECEQ as both the entities present in the solution have opposite charges. Further, the neutral polymers were found to be of showing the intermediate extent of interaction, followed by the anionic polymers. Among the neutral polymers, cellulose HPMC and HEC derivatives interact strongly as compared to PEG and PVP. Furthermore, the extent of interaction of PVP was slightly greater than PEG. This seems to be a usual phenomenon as PVP is more hydrophobic as compared to PEG which is responsible for the stronger interaction of former as compared to the latter [25]. For the anionic polymers, i.e., NaCMC and DxS, despite a possibility of electrostatic repulsion between the constituents in these cases, hydrophobicity is supposed to play an important role behind the interaction between the polymers and the drug. Seemingly, the hydrophobic forces dominate over the electrostatic forces leading to the appearance of cac as a result of interaction between the drug and polymers of same charges. Although the values of cac are large as compared to the cationic and nonionic polymers, a decrease in cac is a clear indication of the drugpolymer interaction. Further, the decrease in cac for anionic polymers being not so sharp as compared to the cationic and nonionic ones supports the argument of weaker interaction. The values of cmc for all the polymers increase as the concentration of polymer increases (Fig. 11); this may be due to the fact

102 (S cm-1)

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Table 1 Free energies ( Gagg , Gmic , and Gt ) for IBF in presence of various polymers at 25 C evaluated on the basis of conductometric measurements. % Polymer (w/v) HPMC 0.05 0.1 0.2 0.3 0.5 0.8 1.0 HEC 0.05 0.1 0.2 0.3 0.5 PVP 0.05 0.1 0.2 0.3 0.5 0.8 1.0 PEG 0.05 0.1 0.2 0.3 0.5 0.8 1.0 HECEQ 0.05 0.1 0.2 0.3 0.5 0.8 1.0 NaCMC 0.002 0.003 0.005 0.008 0.01 0.015 0.02 DxS 0.05 0.1 0.2 0.3 0.5 0.8 1.0 Gagg (J mol1 ) 9652.2 10376.6 11451.4 11709.4 12531.4 12502.3 13324.0 11216.0 12042.4 12923.5 12924.4 13740.1 10271.9 11557.2 11024.1 12131.4 12486.1 12256.1 12278.5 10730.5 11428.4 11897.6 11705.2 12199.6 12234.8 12029.2 11371.0 11279.1 11917.9 11744.7 11210.9 11762.3 12810.6 9641.4 9278.0 9315.5 9215.1 9247.2 10745.1 9919.5 10323.5 10575.1 10986.6 10793.0 10336.6 10260.9 10395.0 Gmic (J mol1 ) 7570.2 7533.5 7107.0 6825.5 7142.7 6194.7 6383.4 7061.5 6759.6 6945.1 7015.0 6811.9 6852.3 6851.8 6551.1 6602.4 6534.7 6298.9 6350.8 8003.4 7813.4 7515.1 7682.4 7670.5 6998.4 6766.1 6790.4 6977.1 6508.4 6510.6 6108.9 6123.4 5775.3 7966.5 7147.3 7211.8 6915.2 6984.8 6592.7 6719.1 7808.7 7377.4 7103.7 6985.0 6651.9 6719.1 6423.0 Gt (J mol1 )

0.18

0.16

cmc (mol dm-3)

2082.0 2843.1 4344.4 4883.9 5388.7 6307.5 6940.7 4154.6 5282.8 5978.4 5909.4 6928.2 3419.7 4705.4 4473.1 5529.0 5951.4 5957.3 5927.8 2727.2 3615.0 4382.5 4022.8 4529.1 5236.4 5263.1 4580.6 4302.0 5409.6 5234.2 5101.9 5638.8 7035.3 1674.9 2130.7 2103.6 2300.0 2262.3 4152.4 3200.4 2514.8 3197.8 3882.9 3808.0 3684.7 3541.8 3972.1

0.14

0.12

0.10 0.0 0.2 0.4 0.6 0.8

HPMC HEC PVP PEG HECEQ NaCMC DxS

1.0

% P0lymer (wt/vol)
Fig. 11. Critical micelle concentration (cmc) as a function of polymer concentration.

was maximum. All these observations favor our discussion on the relative extent of interaction between various polymers and IBF. The degree of micelle ionization () was calculated by taking the ratio between the slopes of the linear portions above and below the break point in the conductivity proles [26]. Hence, two values, i.e., 1 and 2 , were obtained in our systems (Table S1, Supplementary data). The larger value of for the complex micelles is indication of an increased degree of ionic dissociation as a result of the interaction of amphiphile with macromolecule. The free energy of aggregation, Gagg , and the free energy of micellization, Gmic , can be calculated using (Eqs. (1) and (2)) [27] Gagg = RT (2 1 ) ln cac Gmic = RT (2 2 ) ln cmc (1) (2)

The free energy of transfer, Gt , associated with the binding interaction between the drug and macromolecule, is then given by Gt = Gagg Gmic (3)

that, as the amount of macromolecule increases, there is increase in the binding sites accessible to the drug monomers or drug aggregates (irrespective of charge), therefore, more amount of the drug is required to bind to the macromolecule. After the total binding sites are occupied, the drug monomers become free to form independent aggregates. It is to be noted that in studying polymeramphiphile interactions the value of cmc is just the saturation of polymer chains with the amphiphilic molecules, therefore, is not of much importance as compared to the cac (which is the starting point of interaction). But it seems from our results that the chain saturates rst for anionic polymers, followed by the nonionic polymers, and the amount of drug needed to saturate the cationic polymers

Though a complete account of the free energies associated with aggregation, micellization and transfer is not possible as various factors like, charges, polarity, hydrophobicity, etc., are associated with them and due to these factors the uncertainties in values are very large. However, we have discussed about these energies by considering the average values wherever required. In case of cationic polymer HECEQ, the value of Gagg varies from about 11210.9 to 12810.6 J mol1 , while for nonionic polymers the variation is from about 9652.2 to 13740.1 J mol1 . Anionic polymers have the least negative values of energy of aggregation 9215.14 to 10986.6 J mol1 . The aggregation is most favorable in case of cationic and nonionic polymers and causes the appearance of cac at very low concentrations. It is apparent from Table 1 that the feasibility of the aggregation was maximum in case of HEC. This might be due to the expected high hydrophobicity of the nonionic polymer and the possible Coulombic repulsion among counterions (of drug) and the cationic polymer. The most important among these, i.e., Gt , also follows the trend of Gagg and for all polymers it was found that it increases with the increase in the polymer concentration which is a strong indication of the interaction between the polymer and amphiphile.

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4. Conclusions The interaction between an anionic amphiphilic drug ibuprofen (IBF) with several polymers of various natures, viz., cationic, anionic and nonionic, was studied. It was found that the critical aggregation concentration (cac) decreases while the critical micelle concentration (cmc) increases on increasing the polymer concentration in all the cases. The decrease in cac on increasing the polymer concentration was much sharp in case of cationic and nonionic polymers as compared to the anionic polymers due to the possible repulsion between the anionicanionic pair (of the drug and the polymer). It was also observed that the cmc was maximum in case of cationic polymers and minimum for the anionic polymers. Gagg and Gt decrease while Gmic increases on increasing the polymer concentration. From the observed data it was found that the hydrophobicity plays important role in the polymeramphiphile interaction and is capable to dominate the repulsion between the same charges. Acknowledgement One of the authors (KA) acknowledges the UGC for nancial support in the form of scholarship. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.colsurfb.2011.06.008. References
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