Thermodynamic study of complex formation of β-cyclodextrin with ibuprofen by conductometric method and determination of ibuprofen in pharmaceutical drugs

1 Introduction

Pharmaceutical applications of cyclodextrins are widespread mainly for their effectiveness as solubilizing and stabilizing agents in various drug formulations. CDs have a relatively hydrophobic cavity, and are, therefore, able to form inclusion complexes in aqueous solution with a large variety of molecules of appropriate dimensions and low polarity. The compound into the CD cavity is able to change the physico-chemical properties of the former (Hamai and Satou, 2001) and this fact can be useful in different fields such as pharmaceutical, cosmetic, and food industries (Szejtli, 1998).

Host/guest complexation studies with cyclodextrins are of importance for drug delivery systems (Uekama et al., 1998; Loftsson and Brewster, 1996). Cyclodextrins have been used as complexing agents for chromatographic and capillary electrophoresis separations of ibuprofen, a non-steroidal anti-inflammatory drug (Rawjee et al., 1993). Drug-carrier interactions between ibuprofen and native and selected chemically modified β-cyclodextrins in solution and in the solid state have been also described (Mura et al., 1998).

Ibuprofen (Scheme 1) is a part of the propionic acid group of NSAID’s. It is an effective analgesic (pain relieving) and anti-pyretic (fever reducing) pharmaceutical drug. It is proven to work quickly and effectively to relieve pain almost anywhere in the body. Its most common use is as a reliever for fever symptoms, menstrual cramps, headaches, arthritis, and many other common pains.

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Scheme 1 Chemical structure of ibuprofen.

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Today a variety of techniques are available for the determination of ibuprofen in pure form or pharmaceutical formulations including potentiometric titration (Cakirer et al., 1999), liquid chromatography (LC) Ramos Payán et al., 2009; Canaparo1 et al., 2000 supercritical fluid chromatography (Bhoir et al., 1999; Johannsen, 2001), spectrophotometry (Sastry et al., 1989), NMR spectrometry (Hanna, 1997) and IR spectrometry (Tantishaiyakul et al., 1999) GC–MS (Way et al., 1997), but these techniques are expensive. The conductometric method is a very simple, sensitive and low cost method and recently some of the drugs were determined by this method (Campos Janegitz et al., 2008).

In the present paper, we report the results which are obtained from conductometric study of the complexation reaction of ibuprofen with β-cyclodextrin in water.

2 Experimental

β-Cyclodextrin (CD) was purchased from Aldrich. The solvent ethanol (Merck) was used with the highest purity. All reagents were of analytical grade, and the solutions were prepared using deionized water–ethanol binary mixture solvents. Ibuprofen was kindly supplied by Razi Pharmaceuticals (Iran). The stock solution of 1 × 10⁻² mol dm⁻¹ β-cyclodextrin was prepared by dissolving an appropriate mass of this reagent in deionized water. The solutions of β-CD in concentrations varying from 1 × 10⁻² to 1 × 10⁻⁴ mol dm⁻¹ were obtained by adequate dilution of the stock solution.

The experimental procedure to determine the stability constants of complexes is as follows (Arbab zavar et al., 2011) a solution of ibuprofen (1 × 10⁻⁴ mol dm⁻¹) was placed in a titration cell, thermostated at a given temperature and the conductance of solution was measured. Then a step-by-step increase of the cyclodexterin solution prepared in the same solvent (2 × 10⁻³ mol dm⁻¹) was carried out by a rapid transfer to the titration cell using a microburett and the conductance of the solution in the cell was measured after each transfer at the desired temperature.

The conductance measurements were performed using a digital AMEL conductivity apparatus, model 60, in a water bath thermostated at a constant temperature which maintained within ±0.03 °C .The electrolytic conductance was measured using a cell consisting of two platinum electrodes to which an alternating potential was applied. The cell constant was 0.73 cm⁻¹.

3 Results and discussion

The changes of conductivity (Λ) versus the ml of titrant for complexation of β-cyclodextrin and ibuprofen were measured in water and in each case for increasing the solubility of ibuprofen, 2 ml of ethanol was added to solutions. Fig. 1 represents a characteristic conductometric curve obtained for conductometric titration of the 1.0 × 10⁻³ mol dm⁻¹ ibuprofen solution using a 1.0 × 10⁻² mol dm⁻¹ β-CD solution.

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Figure 1 Conductometric titration of the 1.0 × 10⁻³ mol L⁻¹ ibuprofen solution using a 1.0 × 10⁻² mol L⁻¹ CD solution.

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With the time established as 30 s, three successive titrations were performed for each standard solution of ibuprofen in concentrations varying from 1 × 10⁻⁵ to 1 × 10⁻³ mol dm⁻¹ using the titrant CD solution, always ten times more concentrated than ibuprofen solution. As can be seen in Table 1, results obtained using the proposed conductometric method are in agreement with the theoretical values estimated for standard solutions of ibuprofen.

For the ibuprofen concentrations less than 1 × 10⁻⁵ mol dm⁻¹, the addition of the titrant caused small variations in the conductance, making the determination of the final point of the titration unreliable. So, the determination of the equivalence point can be determined until a content minimum of 1 × 10⁻⁵ mol dm⁻¹ of ibuprofen.

Also the changes of molar conductivity (Λ_m) versus the ligand to the cation molar ratio for complexation of β-cyclodextrin and ibuprofen were measured at different temperatures. From the data presented, it is obvious that addition of β-CD ligand to ibuprofen in water results in an increase in molar conductivity. This indicates that the β-CD-ibuprofen complex in water is more mobile than free solvated β-CD and ibuprofen. It is clear from Fig. 1 that the slope of curve changes sharply at the point where the ligand to cation mole ratio is about 1, which is an evidence for formation of a 1:1 [M:L] complex.

The stability constant of the complexes at each temperature was obtained from variation of molar conductance as a function of [L]_t/[M]_t molar ratio plots using a GENPLOT computer program (Genplot, 1989). The details of calculation of the stability constants of complexes by the conductometric method have been described in reference (Rounaghi et al., 1997). The values of the stability constant (log K_f) complexation of β-cyclodextrin and ibuprofen are listed in Table 2. The van^,t Hoff plots of ln K_f versus 1/T for all of the investigated systems were constructed. A typical example of these plots is shown in Fig. 2. The changes in standard enthalpy ( $\mathrm{\Delta }{H}_c^{°}$ ) for complexation reactions were obtained from the slope of the van^,t Hoff plots assuming that ΔC_p is equal to zero over the entire temperature range investigated. The experimental values of $\mathrm{\Delta }{H}_c^{°}$ show that the change in enthalpy for the complexation reactions between β-cyclodextrin and ibuprofen is negligible, therefore, it seems that the complexation processes in the water are probably athermic.

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Figure 2 van^,t Hoff plot for β-cyclodextrine-ibuprofen complex.

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The changes in standard entropy ( $\mathrm{\Delta }{H}_c^{°}$ ) were calculated from the relationship $\mathrm{\Delta }{G}_{c\text{,}298.15}^{°}$ = $\mathrm{\Delta }{H}_{c-}^{°}$ 298.15 $\mathrm{\Delta }{S}_c^{°}$ .The results are summarized in Table 3.

The values $\mathrm{\Delta }{S}_c^{°}$ for the complexation reactions between β-cyclodextrin and ibuprofen in solution are positive, therefore, the complexation reaction is entropy stabilized. It is reasonable to assume that the increase in entropy on complexation is due to additional solvent molecules which may be released from solvation shell of the studied cation upon complexation. It should be mentioned, however, that the complexation process involves not only a change in solvation of the ibuprofen, but also that of the β-cyclodextrin and the change in the flexibility of the β-cyclodextrin upon complexation.

4 Application

The proposed conductometric method was applied under the optimized conditions to determine ibuprofen concentration in a ibuprofen tablet (400 mg). Recoveries of analyte were examined by adding, ibuprofen reference solution at three concentrations (1.0 × 10⁻⁴ mol dm⁻¹, 10⁻³ mol dm⁻¹, and 5 × 10⁻³ mol dm⁻¹) to pharmaceutical product, and the results obtained were compared with the added concentrations. There is a close agreement between the concentration of ibuprofen determined by the proposed procedure (413 mg) and label value (400 mg), that its relative error (%) [(100 × (conductometric value – label value)/label value] was +3, that this result confirmed the accuracy of the procedure.

5 Conclusions

The proposed conductometric procedure for ibuprofen determination in pharmaceutical products is simple, fast, precise, and inexpensive. Moreover, the proposed method is easy and very useful for the rapid determination of ibuprofen in pharmaceutical products dispensing any pretreatment of sample, and it can be applied in laboratories of routine analysis.