Equilibrium solubility, solvent effect and preferential solvation of chlorhexidine in aqueous co-solvent solutions of (methanol, ethanol, N,N-dimethylformamide and 1,4-dioxane)

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Highlights

  • Solubility of chlorhexidine in four cosolvent mixtures was determined and correlated.

  • Solvent effect was studied based on solute-solvent and solvent-solvent interactions.

  • Preferential solvation of chlorhexidine in mixtures were derived by IKBI method.

Abstract

The equilibrium solubilities of chlorhexidine in four solvent mixtures of methanol (1) + water (2), ethanol (1) + water (2), DMF (1) + water (2) and 1,4-dioxane (1) + w water (2) at temperature range from (278.15 to 318.15) K were reported. At the same composition of methanol, ethanol, DMF or 1,4-dioxane and temperature, the mole fraction solubility of chlorhexidine was highest in DMF (1) + w water (2) mixtures, and lowest in ethanol (1) + w water (2) mixtures. By using the Jouyban-Acree model, van’t Hoff-Jouyban-Acree model and Apelblat-Jouyban-Acree model, chlorhexidine solubility was well correlated obtaining RAD lower than 1.69% and RMSD lower than 0.87 × 10−4. The dissolution process of chlorhexidine in solvent solutions was endothermic for the dissolution process. To study the solvent effect, solubility data were correlated to KAT parameters and cavity term on the basis of linear solvation energy relationships concept. Results indicate the key effect of cavity term and π in aqueous methanol and ethanol mixtures; cavity term in aqueous DMF mixtures; and cavity term, β and π in aqueous 1,4-dioxan mixtures. Quantitative values for the local mole fraction of methanol (ethanol, DMF or 1,4-dioxane) and water around the chlorhexidine were computed by using the IKBI method applied to the determined solubility data. Chlorhexidine was preferentially solvated by water for the four solvent mixtures in water-rich compositions; while in intermediate and co-solvent-rich composition for ethanol (DMF, 1,4-dioxane) (1) + w water (2) mixtures, chlorhexidine is preferentially solvated by the co-solvent. The preferential solvation magnitude of chlorhexidine was highest in 1,4-dioxane mixtures than in the other three solvent mixtures.

Introduction

Aqueous solubility is of significant importance that plays an important role in numerous biological and physical processes. Low solubility in water is likely to bring about formulation difficulties or low bioavailability in clinical discovery [1], [2]. Estimation of drug solubility at primary stages is thus essential in the drug discovery processes. The dependence of drugs’ solubility in mixtures upon temperature and composition is also very significant for design of liquid dosage forms, raw material purification, and knowing the mechanisms regarding the chemical and physical stability of pharmaceutical dissolution [3], [4], [5], [6]. Furthermore, drug solubility in mixed solvents is employed to performing a thermodynamic analysis to insight into the molecular mechanisms concerning the drug dissolution process [7] and to estimate the preferential solvation of a solute by solvent components in solutions [8], [9].

Chlorhexidine (CAS Registry No. 55-56-1, chemical structure shown in Fig. 1) is an active substance applied as a broad-spectrum disinfectant and antiseptic [10], [11], [12], [13]. The key problem of chlorhexidine in use is its very low solubility in water (8.309 × 10−5 mol⋅l−1) [14], [15], [16], which reduces its bioavailability. In an attempt to increase aqueous solubility, therapeutic activity and bioavailability of chlorhexidine, its salts are employed in medicine, which can increase significantly its aqueous solubility [17]. Alternatively, in spite of this drug’s wide usefulness, the physicochemical properties of chlorhexidine in organic and aqueous solutions have not been investigated systematically in literatures. For a long time numerous researchers had drawn their attention to study the solubility of chlorhexidine salts as well as several thermodynamic properties of chlorhexidine in water [14], [15], [16], [17]. A thorough literature study shows that only the solubility of chlorhexidine in water is available [14], [15]. Thus a new addition in this field is undoubling in enriching the region which still remains to be discovered. As a result this work tries to provide an idea relating to the thermodynamic properties of chlorhexidine in aqueous-organic mixtures with respect to water and the complex solvent-solvent and solute-solvent interactions therein.

Some co-solvency models have been put forward and used in predicting drug solubilities in mixtures, nevertheless the availability of experimental is still essential for the pharmaceutical scientists [3], [14], [18]. Although co-solvency has been widely used as the drug solubilizing technique in pharmacies, only just the mechanisms concerning in the decrease or increase in drug’ solubility start to be modeled from a deep thermodynamic point of view, comprising the analysis of preferential solvation of a solute by the components of solvent mixtures [7], [8], [9], [19].

Ethanol is a safe and common co-solvent in pharmaceutical industry. Its solubilization power is very high, so it is commonly applied in liquid formulations. In addition, it can also influence the drug’s metabolism, distribution, excretion and absorption [20]. Because of its aprotic and miscible with water, DMF is used as a co-solvent to investigate the interrelation between medium polarity and drug solubility [21]. The non-ideal of DMF‑water solutions is very strong, so it can act in the solute‑solvation procedure through preferential solvation and hydrophobic interactions [22]. It is noteworthy that 1,4-dioxane and methanol are not employed in developing liquid medicine because of its high toxicity. Nevertheless methanol is usually used in the drug purification process [23], as well as solvent in microencapsulation techniques of some drugs [24]. Furthermore, methanol is extensively used as a mobile phase in the high performance liquid chromatography [25]. Because 1,4-dioxane is completely miscible with water [26], it is broadly employed as a model co-solvent. Even more, the Jouyban-Acree model has been used to correlate the solubility for lots of drugs in 1,4-dioxane/methanol (1) + w water (2) mixed solvents [27]. In terms of the considerations described above, the main aim of this work is to report the equilibrium solubility of chlorhexidine (component 3) in binary mixtures of (methanol + water), (ethanol + water), (DMF + water) and (1,4-dioxane + water) at different temperatures in order to evaluate the respective thermodynamic quantities of the mixtures, as well as the preferential solvation of this drug by the organic solvents.

In treatment of the solvent effect, the polarity is commonly used as a general term to define the solvent capacity in all aspect for solvation of species. This definition covers the ability of solvent to interact through all possible non-specific electrostatic interactions such as Keesom dipole-dipole, Debye dipole-induced dipole and London instantaneous dipole-induced dipole, and specific interactions such as donor-acceptor hydrogen-bond and electron pair interaction, with exception of those leading to chemical and structural changes [28]. Attempts to describe quantitatively the solvent polarity in terms of macroscopic physical properties such as dielectric constant, refractive index, etc. in their single or combination form fail in most cases, because these properties characterize the solvent as a bulk medium, while the solvent polarity as thus defined is generally related to diverse interactions in which solvent molecules act on the molecular level. By exploiting some reference solvent-induced phenomena, methods have been proposed to establish the empirical solvent parameters for quantification of the polarity [28]. Among the well-known are Kamlet, Abboud and Taft parameters abbreviated by KAT [29], [30], [31]. KAT parameters include π*, α and β which quantify dipolarity/polarizability, hydrogen bonding acidity and hydrogen bonding basicity of the solvent, respectively. In fact, π* scales solvents based on their ability for making non-specific electrostatic interactions due to Keesom, Debye and London forces. Whereas α and β describe the relative ability of a solvent to donate and accept hydrogen-bonds in specific interactions, respectively. These parameters are determined from direct measurement of energy changes which take place on the molecular scale between solute and solvent. Therefore, it is generally expected being linear dependence of the solvent-induced free energy changes upon KAT parameters [32]. Such dependency has been presented by Kamlet, Abboud and Taft in the form of mathematical formulation named as the linear solvation energy relationships, KAT-LSER, which is of central importance in the solvent effect treatment [29], [30], [31], [32]. From a practical point of view, correlating the change in the Gibbs free energy of solvent-dependent properties to KAT parameters on the basis of KAT-LSER gives rise to information about solute-solvent as well as solvent-solvent interactions. Thus, one other aim in this work is to describe the solubility variation of chlorhexidine in aqueous solutions of methanol, ethanol, DMF and 1,4-dioxane through KAT-LSER model, in order to gain insight about the type and relative importance of the solvent descriptors and interactions influencing the solubility in these systems.

Section snippets

Materials

Chlorhexidine was provided by Shanghai Yuanye Biotechnology Co., Ltd., China with a mass fraction of 0.975. It was crystallized in methanol for three times. The final mass fraction of chlorhexidine used for solubility measurement was 0.997, which was confirmed by using a high-performance liquid chromatography (HPLC, Agilent 1260). The four organic solvents (methanol, ethanol, DMF and 1,4-dioxane) were provided by Sinopharm Chemical Reagent Co., Ltd., China, the purities of which were all no

X-ray powder diffraction analysis

The patterns of the raw material together with the solids equilibrated in liquid are shown in Fig. S1 of Supporting material. It can be seen that all the XRD patterns of solid phase of chlorhexidine in equilibrium with its solution have the same characteristic peaks with the raw material. Therefore, no polymorph transformation or solvate formation is observed during the whole experiment.

Solubility data

The determined mole fraction solubility (x) of chlorhexidine in methanol, ethanol, 1,4-dioxane, DMF and water

Conclusion

The equilibrium solubilities of chlorhexidine in co-solvent mixtures of methanol (1) + w water (2), ethanol (1) + w water (2), N,N-dimethylformamide (DMF, 1) + w water (2) and 1,4-dioxane (1) + w water (2) were determined experimentally by using the saturation shake-flask technique within the temperature range from 283.15 K to 323.15 K under atmospheric pressure (101.1 kPa). At the same temperature and mass fraction of methanol (ethanol, DMF or 1,4-dioxane), the mole fraction solubility of

Acknowledgements

The authors thank for the finical support from the National Natural Science Foundation of China (No. 21173188-515405-N11112), Henan Province Science and Technology Key Project of China (No. 152102210322), and the Starting Fund for Talents of North China University of Water Resources and Electric Power (No. 003019).

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