Thermodynamic solubility modelling, solvent effect and preferential solvation of naftopidil in aqueous co-solvent solutions of (n-propanol, ethanol, isopropanol and dimethyl sulfoxide)

https://doi.org/10.1016/j.jct.2019.02.016Get rights and content

Highlights

  • Solubility of naftopidil in four co-solvent mixtures was determined and correlated.

  • Solvent effect analysis was made according to solute-solvent and solvent-solvent interactions.

  • Preferential solvation of naftopidil in four mixtures was derived by IKBI method.

Abstract

The naftopidil solubility in aqueous co-solvent mixtures of n-propanol, ethanol, isopropanol and dimethyl sulfoxide (DMSO) at temperatures from 278.15 K to 318.15 K was reported. At fixed composition of n-propanol, ethanol, isopropanol or DMSO and temperature, the mole fraction solubility of naftopidil was highest in DMSO (1) + water (2) mixture, and lowest in isopropanol (1) + water (2) mixture. The Jouyban-Acree model and van’t Hoff-Jouyban-Acree model provided well correlation results obtaining relative average deviation lower than 2.85% and root-mean-square deviation lower than 8.89 × 10−4. Furthermore, the method of linear solvation energy relationships was performed with a suitable combination of solvent polarity descriptors to elucidate the nature of intermolecular interactions giving rise to the solubility variation in co-solvent mixtures. Quantitative values for the local mole fraction of n-propanol (ethanol, isopropanol or DMSO) and water around the naftopidil were computed by using the Inverse Kirkwood–Buff integrals method applied to the determined solubility data. Naftopidil was preferentially solvated by water for the four solvent mixtures in water-rich compositions; while in intermediate and co-solvent-rich compositions for n-propanol (isopropanol and ethanol) (1) + water (2) mixtures, naftopidil was preferentially solvated by the co-solvent. The preferential solvation magnitude of naftopidil was highest in isopropanol mixtures than in the other three co-solvent mixtures.

Introduction

Aqueous solubility plays a significant role in many physical and biological processes. Low solubility of drugs in water is likely to lead to low bioavailability or formulation difficulties in clinical discovery [1], [2]. The drug solubility in solvent mixtures is quite crucial for the raw material purification, design of liquid dosage form, and understanding the mechanisms concerning the physical and chemical stability of pharmaceutical dissolutions [3], [4], [5], [6]. In addition, drug solubility in solvent mixtures can be used to perform a thermodynamic analysis to insight deeply into the mechanisms at molecular level during the drug dissolution process and to estimate the preferential solvation of a drug by solvent component in mixtures [7], [8], [9].

Naftopidil (CAS Registry No. 57149-07-2, chemical structure shown in Fig. 1), a new type of anti-hypertension drug and an antagonist of α1A/1D-adrenoceptor, has been developed as a drug for the treatment of benign prostate hyperplasia and hypertension [10], [11]. It exerts its antitumor action on a variety of cancers [12], [13], [14]. In addition, naftopidil induces apoptosis of MPM cells by interacting with protein kinase C [12], [13], [14], [15]. The key problem of naftopidil in use is its very low solubility in water (111.6 μg·ml−1) [16], [17], which decreases its bioavailability. In order to improve its aqueous solubility, therapeutic activity and bioavailability of naftopidil, microemulsification technique is used in medicine, which may increase significantly its aqueous solubility [17]. Instead, although this drug has been widely used for several years, the physicochemical properties of naftopidil in aqueous solutions have not been investigated systematically in the available works. A comprehensive literature review shows that only the solubility of naftopidil in water and some surfactant is available [17]. 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 present an idea regarding the thermodynamic properties of naftopidil in aqueous-organic mixtures and the solvent-solvent and solute-solvent interactions therein.

Several cosolvency models have been employed to predict drug solubility in co-solvent mixtures, however the availability of experimental is still vital for pharmaceutical scientists [3], [18]. Even though cosolvency has been widely used as a drug solubilizing method in pharmacies, the mechanisms relating to the increase or decrease in drug’ solubility start to be modeled in recent years, including the preferential solvation analysis of a solute by the components of mixed solvents [7], [8], [9], [19].

Ethanol has high solubilization power, so it is a common co-solvent and is applied in liquid formulations in pharmaceutical industry. Additionally, it may also impact the drug’s distribution, metabolism, absorption and excretion [20]. n-Propanol is not widely used as a co-solvent for the design of liquid medicine, however it has been employed as a solvent in the pharmaceutical industry for cellulose esters and resins [21]. Isopropanol is a flammable and colorless compound with a strong odor. It is miscible with ether, water, ethanol and chloroform, and dissolves many non-polar compounds. Isopropanol is used in solvent mixtures or solely for different aims [22], [23] including in penetration-enhancing pharmaceutical compositions for topical transepidermal and percutaneous uses. Solid solubility in dimethyl sulfoxide (DMSO) is one of the significant parameters during a drug discovery at early stage [24]. According to the above discussions, the chief aim of this work is to report the equilibrium solubility of naftopidil (component 3) in binary co-solvent mixtures of (n-propanol + water), (ethanol + water), (isopropanol + water) and (DMSO + water) at elevated temperatures in order to evaluate the respective thermodynamic quantities of the mixtures, as well as the preferential solvation of naftopidil by organic solvents.

In understanding the solvent effect on physic-chemical properties, special attention has been devoted to the solvent’s polarity. This phrase describes the overall capacity of the solvent to make non-covalent interactions with the solute. Since this definition covers a wide variety of non-specific (such as dipole-dipole, dipole-induced dipole, instantaneous dipole-induced dipole, and etc.) and specific (such as hydrogen bonding, electron donor-acceptor and etc.) interactions, the solvent’s polarity is a difficult concept to be quantified [25]. Physical properties of solvents (such as the relative permittivity and the index of refraction), whether in single or combined form, are inadequate descriptors of the polarity because solvents interact on the molecular level with the solute, but macroscopic concepts consider the solvent as a continuum environment. An alternative approach is the solvatochromic comparison method in which some well-designed solvatochromic probes serve to provide information on microscopic details of solvation phenomena [25], [26], [27], [28]. This approach allows Kamlet, Abboud and Taft to develop three solvent parameter scales, named as KAT parameters, in order to quantify the solvent’s polarity [26], [27], [28]. KAT parameters are π* = dipolarity/polarizability scale, α = hydrogen bonding acidity scale and β = hydrogen bonding basicity scale. In fact, π* is a measure of the ability of solvent to participate in universal interactions such as electrostatic Keesom orientation, Debye induction and London dispersion interactions. Whereas α and β measure the property of solvent to act as a donor and acceptor hydrogen-bonding in specific solute-solvent interactions, respectively. KAT parameters are derived from direct changes in the solvation energy of electronic states of probes. Kamlet, Abboud and Taft formulate the concept of linear solvation energy relationships as multi-parameter equations, named as KAT-LSER, for quantitative interpretation of the solvent effect [26], [27], [28], [29]. The use of KAT-LSER for quantitative analysis of solvent-induced properties provides knowledge on the nature of different solute-solvent and solvent-solvent interactions that affect the solvation phenomena. Therefore, as one of objectives of present study, the solubility of naftopidil was analysed in aqueous solutions of n-propanol, ethanol, isopropanol and DMSO by using KAT-LSER model, to unveil the nature and relative significance of intermolecular interactions that give rise to the solvent effect on the naftopidil solubility.

Section snippets

Materials

The crude naftopidil having a mass fraction of 0.983 was provided by Sangon Biotech (Shanghai) Co. Ltd., China. It was purified via re-crystallization in ethanol. The final mass fraction purity of naftopidil used for experiment was 0.996, which was confirmed by using a high-performance liquid chromatography (HPLC, Agilent 1260). In addition, the (S,S) and (R,R; CAS Reg. No. 127931-15-1) enantiomer ratio for the purified naftopidil was determined in our laboratory using a Chiralpak AD-H

X-ray powder diffraction analysis

The determined patterns of the raw naftopidil as well as the solid equilibrated with liquor are shown in Fig. S1 of Supporting material. As can be observed all XRD patterns of solid phase in equilibrium with their mixtures have the similar characteristic peaks with raw naftopidil. Therefore, no solvate formation or polymorph transformation takes place in experiment.

Solubility data

The determined mole fraction solubility (x) of naftopidil in n-propanol, ethanol, isopropanol and DMSO and water within the

Conclusion

The equilibrium solubilities of naftopidil in co-solvent mixtures of {n-propanol (1) + water (2)}, {ethanol (1) + water (2)}, {isopropanol (1) + water (2)} + and {DMSO (1) + water (2)} were determined experimentally by using the saturation shake-flask technique within the temperature range from 288.15 K to 328.15 K under atmospheric pressure (101.2 kPa). At the same temperature and mass fraction of n-propanol (ethanol, isopropanol or DMSO), the mole fraction solubility of naftopidil was greater

References (45)

  • A. Jouyban

    Handbook of Solubility Data for Pharmaceuticals

    (2010)
  • J.T. Rubino

    Co-solvents and cosolvency

  • A. Avdeef

    Absorption and drug development, solubility

    Permeability and Charge State

    (2003)
  • M.E. Aulton

    Pharmaceutics, The Science of Dosage Forms Design

    (2002)
  • F. Martínez et al.

    Preferential solvation of etoricoxib in some aqueous binary co-solvent mixtures at 298.15 K

    Phys. Chem. Liq.

    (2016)
  • Y. Marcus

    Solvent Mixtures: Properties and Selective Solvation

    (2002)
  • Y. Marcus

    Preferential Solvation in Mixed Solvents

  • K. Mikami et al.

    Naftopidil is useful for the treatment of malignant pleural mesothelioma

    Pharmacology

    (2014)
  • R. Takei et al.

    Naftopidil, a novel α1–adrenoceptor antagonist, displays selective inhibition of canine prostatic pressure and high affinity binding to cloned human α1-adrenoceptors

    Jpn. J. Pharmacol.

    (1999)
  • H. Kanda et al.

    Naftopidil, a selective α1–adrenoceptor antagonist, inhibits growth of human prostate cancer cells by G1 cell cycle arrest

    Int. J. Cancer

    (2008)
  • Y. Hori et al.

    Naftopidil, a selective α1–adrenoceptor antagonist, suppresses human prostate tumor growth by altering interactions between tumor cells and stroma

    Cancer Prev. Res.

    (2011)
  • A. Gotoh et al.

    Antitumor action of α1-adrenoceptor blockers on human bladder, prostate and renal cancer cells

    Pharmacology

    (2012)
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