Solubility modelling, solvent effect and preferential solvation of carbendazim in aqueous co-solvent mixtures of N,N-dimethylformamide, methanol, ethanol and n-propanol

https://doi.org/10.1016/j.jct.2018.08.001Get rights and content

Highlights

  • Carbendazim solubility in four cosolvent mixtures was determined and correlated.

  • Solute-solvent and solvent-solvent interactions were investigated using KAT-LSER model.

  • Preferential solvation parameters were derived by IKBI method.

Abstract

The equilibrium solubility of carbendazim in solvent mixtures of N,N-dimethylformamide (DMF, 1) + water (2), methanol (1) + water (2), ethanol (1) + water (2) and n-propanol (1) + water (2) were determined experimentally by using the saturation shake-flask method at the temperatures ranging from (278.15 to 318.15) K under atmospheric pressure (101.1 kPa). The solubility of carbendazim increased positively with increasing temperature and molar fraction of organic solvents in each binary system. The minimum solubility was observed in neat organic solvents. The solid phase was tested by X-ray power diffraction, which showed that no polymorphic transformation, solvate formation or crystal transition during entire experiments conclusively. The drug’ solubility was mathematically represented by using the Jouyban-Acree model, van’t Hoff-Jouyban-Acree model and Apelblat-Jouyban-Acree model obtaining average relative deviations lower than 1.95% for correlative studies. The preferential solvation parameters were derived from their thermodynamic solution properties with the inverse Kirkwood–Buff integrals. The preferential solvation parameters for DMF, methanol, ethanol or n-propanol (δx1,3) were positive in the four solvent mixtures in intermediate and co-solvent-rich compositions, which indicated that carbendazim was preferentially solvated by co-solvent. It could act mainly as a Lewis acid interacting with proton-acceptor functional groups of the co-solvents. Temperature has a little effect on the preferential solvation magnitudes. Furthermore, the solvent effect was analyzed in the framework of linear solvation energy relationships by considering suitable combinations of solvent descriptors.

Introduction

The solubility of drugs in solvent mixtures as a function of composition and temperature is of crucial importance for raw material purification, design of liquid dosage forms, and understanding of the mechanisms relative to the physical and chemical stability of pharmaceutical dissolutions [1], [2]. So, the solubility of active ingredients is a significant physicochemical property in pharmaceutical design because it affects the drug efficacy, influencing several biopharmaceutical and pharmacokinetic properties [3], [4]. On the other hand, the solubility dependence on temperature allows performing a thermodynamic analysis to insight into the molecular mechanisms relating to the drug dissolution processes. Furthermore, drug solubility in solvent mixtures is employed to evaluate the preferential solvation of the solute by the solvent components in mixtures. This information provides a powerful tool in the understanding of molecular interactions relating to the drug dissolution processes [5], [6], [7].

Carbendazim (CAS Registry No. 10605-21-7, chemical structure shown in Fig. 1) is chemically described as 2-(carbomethoxyamino)benzimidazole. It is one of the benzimidazole fungicides widely-used broad-spectrum fungicide [8]. Carbendazim can be absorbed by plants and transferred to every part, to interfere mitosis of bacterial cell and inhibit its growth [9]. It is a widely used systemic fungicide against different fungi affecting fruits, vegetables and cereals [10], [11]. However, MBC has poor water solubility [12], [13], [14], [15], [16], [17], which have become a major constraining factor on its application of fungicidal activity. In order to improve its solubility in water, several methods have been proposed in the literatures, e.g. some pharmaceutically acceptable co-solvents, surfactants, and complexants, alone and in combination with pH [12], [17], [18], [19]. It is well known that co-solvents are the most commonly used excipients to improve the solubility of a nonpolar drug in aqueous media [2]. Nevertheless, in spite of the usefulness of this drug, the physic-chemical properties of carbendazim in aqueous and organic solutions have not yet been studied systemically in the previous works. Only the solubility of carbendazim in water [12], [13], [14], [15], [16], [17] and in lower alcohols at temperatures ranging from 278.15 K to 323.15 K [20] has been determined. The physic-chemical properties of carbendazim in aqueous and organic solutions have not been studied so far. So this work tries to give an idea about the relative stabilization of carbendazim in aqua-organic mixtures with respect to water and the comprehensive solute-solvent and solvent-solvent interactions therein.

Some theoretical and semiempirical models can be employed to predict drug solubilities in solvent mixtures, however the availability of experimental data is still fundamental for the pharmaceutical scientists [1], [21]. The solubility of carbendazim is low in neat water. Although cosolvency as the drug solubilizing technique has been widely employed in pharmacies long ago, recently the mechanisms involving in the increase or decrease in drugs’ solubility start to be approached from a deep thermodynamic point of view, including the analysis of the preferential solvation of solute by the components of mixtures [5], [6], [7], [22], [23]. As a generalized approach, the method of linear solvation energy relationships, LSER, treats the solvent effect by dividing the solute-solvent interactions into two types of non-specific (dipole-dipole, dipole-induced dipole and dispersion) and specific (hydrogen bonding) interactions. In addition, each of interaction terms has a linear contribution to Gibbs free energy of solvent dependent properties [24]. In this context, the empirical scales offer a convenient way to characterize the ability of the solvent to interact with the solute, defined as the polarity of the solvent, at the molecular level. Kamlet, Abboud and Taft (KAT) [24], [25] introduced an extensively used solvent scales through the solvatochromic studies of pairs of probing molecules in the set of solvents with different interacting properties. These scales comprises the dipolarity/polarizability, π*, the hydrogen bond basicity, β, and the hydrogen bond acidity, α, which are directly measured of the energy changes resulting from corresponding intermolecular solute-solvent interactions. Therefore, the study of solvent effect, in terms of LSER, reveals the nature and extent of solute-solvent interaction affecting a solvent-dependent properties. The KAT-LSER had shown notable successes in explaining a wide range of chemical phenomena, including the solubility in pure and mixed solvents [26], [27].

Methanol is not used to develop liquid medicines due to its high toxicity. But in some instances methanol is used in drug purification procedures, as well as solvent in some drug microencapsulation techniques [28]. Moreover, it is widely used as mobile phase in high performance liquid chromatography. Ethanol is a common and safe solvent to be used in pharmaceutical liquid formulations. Its solubilization power is reasonably high and usually used in the liquid formulations at concentrations lower than 50%. In addition to solubility enhancement of ethanol, it can affect a drug’s absorption, distribution, metabolism, and excretion. On the other hand, although n-propanol is not widely used as co-solvent for design of liquid medicines, it has been used as solvent in the pharmaceutical industry for resins and cellulose esters [29]. DMF is a very interesting co-solvent to study the interrelation between drug solubility and medium polarity because it is aprotic and completely miscible with water [30]. Water‑DMF mixtures are strongly non ideal and can act in the solute‑solvation process via hydrophobic interactions and preferential solvation [31], [32].

Considering these points-of-view, the main goal of this work is to report the equilibrium solubility of carbendazim (component 3) in binary solvent mixtures of (DMF + water), (methanol + water), (ethanol + water) and (n-propanol + water) at different temperatures in order to evaluate the respective thermodynamic quantities of the solution, as well as the preferential solvation of the drug by these organic solvents. This research expands the available solubility data about carbendazim [12], [13], [14], [15], [16], [17], [20] and also allows the thermodynamic analysis of the respective dissolution and specific solvation process.

Section snippets

Materials

Carbendazim was provided by Shanghai Dibai Biological Co., Ltd., China with a mass fraction of 0.985. It was purified three times via crystallization in methanol. The final composition of carbendazim used for solubility measurement was 0.997 in mass fraction, which was confirmed by using a high-performance liquid chromatography (HPLC, Agilent 1260). The four organic solvents (DMF, methanol, ethanol and n-propanol) were provided by Sinopharm Chemical Reagent Co., Ltd., China, the purities of

X-ray powder diffraction analysis

In order to validate the existence of the polymorph transformation or solvate formation of carbendazim during the mutual solubility determination, the equilibrium solid phase is collected and analyzed by XPRD. The patterns of the raw material and the solids crystallized in solvent mixtures are shown in Fig. S1 of Supporting material. It can be seen that all the XPRD patterns of solid phase of carbendazim in equilibrium with its solution have the same characteristic peaks with the raw material.

Conclusion

The equilibrium solubility of carbendazim in four solvent mixtures of DMF (1) + water (2), methanol (1) + water (2), ethanol (1) + water (2) and n-propanol (1) + water (2) at temperature range from 278.15 K to 318.15 K were reported. By using the Jouyban-Acree model, van’t Hoff-Jouyban-Acree model and Apelblat-Jouyban-Acree model model, carbendazim solubility was well correlated obtaining RAD lower than 1.95% and RMSD lower than 0.02 × 10-4. KAT-LSER model was successfully used to correlate the

Acknowledgment

This work was supported by the Natural Science Foundation of Guangling College, Yangzhou University (Grant No. ZKYB17007) and the innovation and Entrepreneurship Training Project for Undergraduate of Jiangsu Higher Education Institutions (Grant No. 201813987006Y).

References (44)

  • A. Jouyban et al.

    Solubility of fluphenazine decanoate in aqueous mixtures of polyethylene glycols 400 and 600 at various temperatures

    Fluid Phase Equilibr.

    (2014)
  • T.M. Krygowski et al.

    Empirical parameters of lewis acidity and basicity for aqueous binary solvent mixtures

    Tetrahedron

    (1985)
  • A. Jouyban

    Handbook of Solubility Data for Pharmaceuticals

    (2010)
  • J.T. Rubino

    Co-solvents and Cosolvency

  • A. Avdeef, Absorption and Drug Development, Solubility, in: Permeability and Charge State, Wiley-Interscience, Hoboken,...
  • M.E. Aulton

    Pharmaceutics. The Science of Dosage Forms Design

    (2002)
  • Y. Marcus

    Solvent Mixtures: Properties and Selective Solvation

    (2002)
  • Y. Marcus

    Preferential solvation in mixed solvents

  • J.M. Petroni et al.

    Sensitive approach for voltammetric determination of carbendazim based on the use of an anionic surfactant

    Electroanalysis

    (2016)
  • C.B. Chen, Composition for controlling leaf spot disease of cymbidium goeringii, CN Patent 104,920,405, September 23,...
  • C.B. Chen, Composition for controlling leaf spot disease of vanda sanderiana, CN Patent 104,920,436, September 23,...
  • D.J. Austin et al.

    High pressure liquid chromatography of benzimidazoles

    Pestic. Sci.

    (1976)
  • Cited by (20)

    • Thermodynamic insight in dissolution, distribution and permeation processes for some benzimidazoles in biologically relevant solvents

      2021, Journal of Molecular Liquids
      Citation Excerpt :

      A lower value at pH 7.0 was measured by Sangvi et al. [33] possibly due to different composition of buffer solution. At the same time, in comparison with pH 7.4, a slightly higher solubility of this compound in unbuffered water S2 = 8 mg·dm−3 (4.2·10−5 mol·dm−3) and 4.1·10−5 mol·dm−3 was published by Coscollà et al. [34] and Xu et al. [17], respectively. In their turn, Ge et al. [18] reported a lower value of CBZ aqueous solubility equal to 0.02 mmol·dm−3 (2·10−5 mol·dm−3).

    View all citing articles on Scopus
    View full text