Thermodynamic solubility modelling, solvent effect and preferential solvation of naftopidil in aqueous co-solvent solutions of (n-propanol, ethanol, isopropanol and dimethyl sulfoxide)
Graphic abstract
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)
- et al.
Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings
Adv. Drug Deliv. Rev.
(1997) - et al.
Role of the development scientist in compound lead selection and optimization
J. Pharm. Sci.
(2000) - et al.
Modelling the solubility and preferential solvation of gallic acid in co-solvent + water mixtures
J. Mol. Liq.
(2016) - et al.
Solubility of naproxen in 2-propanol + water mixtures at various temperatures
J. Mol. Liq.
(2015) - et al.
Solubility of fluphenazine decanoate in aqueous mixtures of polyethylene glycols 400 and 600 at various temperatures
Fluid Phase Equilibr.
(2014) - et al.
Solubility and thermodynamics function of vanillin in ten different environmentally benign solvents
Food Chem.
(2015) - et al.
Solubility modelling, solvent effect and preferential solvation of 6-chloropurine in several aqueous co-solvent mixtures between 283.15 K and 328.15 K
J. Chem. Thermodyn.
(2018) - et al.
Equilibrium solubility and preferential solvation of 1,1′-sulfonylbis(4-aminobenzene) in binary aqueous solutions of n-propanol, isopropanol and 1,4-dioxane
J. Chem. Thermodyn.
(2018) - et al.
Solute-solvent and solvent-solvent interactions and preferential solvation of hesperidin in aqueous co-solvent mixtures of ethanol, isopropanol, propylene glycol and n-propanol
J. Mol. Liq.
(2018) - et al.
Solute-solvent and solvent-solvent interactions and preferential solvation of limonin in aqueous co-solvent mixtures of methanol and acetone
J. Mol. Liq.
(2018)
Handbook of Solubility Data for Pharmaceuticals
Co-solvents and cosolvency
Absorption and drug development, solubility
Permeability and Charge State
Pharmaceutics, The Science of Dosage Forms Design
Preferential solvation of etoricoxib in some aqueous binary co-solvent mixtures at 298.15 K
Phys. Chem. Liq.
Solvent Mixtures: Properties and Selective Solvation
Preferential Solvation in Mixed Solvents
Naftopidil is useful for the treatment of malignant pleural mesothelioma
Pharmacology
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.
Naftopidil, a selective α1–adrenoceptor antagonist, inhibits growth of human prostate cancer cells by G1 cell cycle arrest
Int. J. Cancer
Naftopidil, a selective α1–adrenoceptor antagonist, suppresses human prostate tumor growth by altering interactions between tumor cells and stroma
Cancer Prev. Res.
Antitumor action of α1-adrenoceptor blockers on human bladder, prostate and renal cancer cells
Pharmacology
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