Preparation of a New Active Component 1,10-B10H8(S(C18H37)2)2 for Potentiometric Membranes, for the Determination of Terbinafine Hydrochloride

1. Introduction

The availability and purification of water resources is a basic priority for humanity in general, and for the scientific community in particular. According to the UN [1], 2.2 billion people do not have access to clean drinking water, 3.5 billion people do not have access to safe sanitation and 80% of wastewater is returned to the ecosystem without treatment. The issue of water resources is particularly acute in Africa, in arid climate zones [2], where there is also a steady and continuous population growth [3], as well as a significant requirement for water resources for the extraction of numerous minerals [4].

Anthropogenic nitrogen [5,6,7], which is contained in fertilisers, herbicides and fungicides, is an important factor in hydrosphere pollution, especially in water bodies located in the agricultural zone. Nitrogen-containing compounds play an important role in the modern world, but their content should be controlled.

Potentiometry is one of the best methods of control. Due to its rapidity, simplicity and low cost, the ionometric method can be implemented in field conditions, treatment plants and in analytical laboratories [8]. There is, however, a limited set of ions that can be determined by potentiometry [9]. Recently, the search for new active components for selective membranes has been re-emphasised [10]. The combination of the potentiometric method of analysis with other methods, such as HPLC [11], allows the design of highly accurate analytical systems with wide customisability and high application potential. The development of synthetic chemistry and materials science has made it possible to create complex macromolecular systems that are selective towards organic ions with a delocalised charge [12]. Such sensors are highly selective to a particular ion and enable analysis of systems consisting of similar molecules.

It has previously been shown that closo-decaborates with exopolyhedral functional substituents can be used in ion-selective membranes for the detection of various classes of organic compounds, such as local anesthetics, hormones and quaternary ammonium bases, including biodegradable compounds that can accumulate in aqueous media [13].

Terbinafine is an antifungal drug, first produced in 1984 [14] and tested in 1989 [15], which has shown promising results; its structure is shown in Figure 1. Included in the WHO list of essential drugs, it belongs to the class of derivatives of allylamine [16]. Its principle of action is to disrupt the integrity of the cytoplasmic membrane of fungi and block the synthesis of membrane sterols [17]. In tablet or ointment form, it is used for the treatment of variegated shingles, fungal infections of the nails and ringworm, and for addressing itching and mycosis. Terbinafine is an effective fungicidal agent that causes minimal adverse reactions [18,19], and is effectively used for the treatment of both humans and animals [20]. Many studies are currently underway to expand the use of this drug [21,22].

For the analytical determination of Terbinafine, HPLC [23] with a detection limit of up to 1.0 × 10^-8M is mainly used. In the literature, a limit of quantification up to 2.7 × 10^-7M [24] is indicated. The measurement uncertainty in the determination of Terbinafine by HPLC with UV detection was evaluated in [25]. Other methods used for the qualitative and quantitative analysis of terbinafine hydrochloride, in the form of tablets, creams, plasma and other biological samples, have included UV, LC/MS, UPLC, HPLC, GC/MS, HPTLC, GC, Ion pair Electrophoresis, Micellar chromatography and UFLC [26]. In 2013, for the first time, a potentiometric sensor based on tetraphenylborate was reported to have successfully determined Terbinafine in pharmacological preparations [27]. Since then, the electrochemical analysis of Terbinafine has been actively developed [28]. Potentiometric determination appears to be the most promising approach, due to its rapidity, portability, simplicity, low cost of analysis and low limit of detection [29].

As can be seen from Table 1, the ion-pair complex of the Terbinafine cation and tetraphenyl borate anion is the main active component for the potentiometric determination of Terbinafine. It has previously been shown that lipophilic boron cluster anions have greater selectivity to organic cations [31]. Therefore, the question of the functionalisation of boron cluster anions and the investigation of the electroanalytical properties of membranes with them in their composition remain relevant.

This study describes the synthesis of a new closo-borate compound, 1,10-B₁₀H₈(S(n-C₁₈H₃₇)₂)₂ – 1,10-di-(bis-octodecylsulfonio)-closo-decaborate, and investigates its physicochemical characteristics. Membranes selective to Terbinafine ions were obtained on the basis of the new compound, and their potentiometric parameters and operational characteristics were studied.

2. Materials and Methods

2.1. Analyzes and Reagents

Elemental analysis for carbon, hydrogen and sulfur was performed using a Carlo ErbaCHNS-3 FA 1108 automated elemental analyser.

¹H, ¹¹B and ¹³C NMR spectra of samples dissolved in CDCl₃ were recorded on a QOne AS400 (China) spectrometer, (at the Shared Facility Center for Physical Research Methods of the Kurnakov Institute of General and Inorganic Chemistry of the Russian Academy of Sciences), operating at a frequency of 399.88, 128.29 and 100.55 MHz, respectively, using an internal deuterium lock. Tetramethylsilane and boron trifluoride etherate were used as external references. NMR spectra of compound 1 are shown in Figures S1–S4.

IR spectra of complexes were recorded on a Lumex Infralum FT-02 Fourier-transform spectrophotometer in the range of 4,000–400 cm^–1, at a resolution of 1 cm^–1. Samples were prepared as pressed tablets with KBr. IR spectra of compound 1 are shown in Figure S5.

All reagents and chemicals used throughout this work were of analytical reagent grade and solutions were prepared with redistilled water. High molecular weight poly(vinyl chloride) (PVC), tetrahydrofuran (THF), dichloromethane (CH2Cl2), petroleum ether, bis(1-butylpentyl)adipate (BBPA), terbinafine hydrochloride, 1-bromooctadecane (C₁₈H₃₇Br), cesium carbonate (CsCO₃) and dimethylformamide (DMF) were purchased from Merck KGaA and used without prior purification. Cesium 1,10-bis(sulfanyl)-closo-decaborate Cs[1,10-B₁₀H₉(SH)₂] was synthesised and identified in the laboratory of the chemistry of light elements and clusters of the N.S. Kurnakov Institute of General and Inorganic Chemistry of RAS [32]. Stock standard solutions of terbinafine hydrochloride (0.1 M and 1,000 μg mL− 1) were prepared by dissolving precise amounts of each compound in water, 0.1 M HCl–NaOH or acetate buffer solutions. Working standard solutions were prepared daily from stock solutions by serial dilution. All stock solutions were refrigerated between uses. The commercial pharmaceuticals analysed in this study were purchased at a local pharmacy. Test samples of terbinafine hydrochloride were prepared by diluting 100–500 μL of each injectable solution up to 100.0 mL with 0.1 M acetate buffer solution (pH 4.67). These model solutions were subjected to the multiple standard additions procedure for determination.

2.2. Synthesis of 1,10-B₁₀H₈(S(n-C₁₈H₃₇)₂)₂

The salt Cs₂[1,10-B₁₀H₈(SH)₂] (200 mg, 0.45 mmol) was dissolved in 10 mL DMF in a 50-mL round bottom flask, after which 1-bromooctadecane (625 mg, 1.87 mmol) and cesium carbonate (307.9 mg, 0.95 mmol) were added. The reaction solution was heated at 80°C for 8 hours, with constant stirring, in an argon atmosphere. The mixture was then evaporated using a rotary evaporator and dried from residual DMF in a deep vacuum using a rotary vane pump. 10 mL of dichloromethane was added to the resulting residue, followed by treatment in an ultrasonic bath for 10 minutes. Then, the suspended mixture was centrifuged from the residue of cesium carbonate, so that cesium bromide was formed. The organic fraction was collected and evaporated again using a rotary evaporator. The residual octadecyl bromide was removed by flash chromatography on silica gel. For this, the substance was homogenised in 50 ml of petroleum ether and 1 gram of SiO₂ silica gel in a 100 ml flask. It was then carefully evaporated and the resulting powder was placed on a chromatographic column pre-filled with pure silica gel. Petroleum ether was used as a washing eluent. The substance was collected from silica gel using a CH₂Cl₂/petroleum ether 1:1 mixture. The second organic fraction was collected and evaporated using a rotary evaporator and dried in a deep vacuum. 1,10-B₁₀H₈(S(n-C₁₈H₃₇)₂)₂ (440.7 mg, 0.37 mmol) was obtained (yield 82%).

Calcd. for C₇₂H₁₅₆B₁₀S₂, %: C, 72.41; H, 13.17; S, 5.37. Found, %: C, 72.29; H, 13.08; S, 5.32.

¹¹B{¹H} NMR (СDCl₃, ppm): 9.2 (s, 2B, B1, B10), -24.4 (d, 8B, B2-B9).

¹H NMR (CDCl₃, ppm): 3.26 (dm, 8H, SCH₂), 2.02 (m, 8H, SCH₂CH₂), 1.54 (m, 8H, C3H₂), 1.26 (m, 112H, C4H₂-C17H₂), 0.89 (t, 12H, CH₃), 1.80-0.20 (m, 8H, B₁₀H₈).

¹³С NMR (CDCl₃, ppm): 43.67 (SCH₂), 32.07 (SCH₂CH₂), 29.85, 29.80, 29.75, 29.66, 29.54, 29.51, 29.15, 28.82, 26.34 (C3-C16), 22.83 (CH₂CH₃), 14.26 (CH₃).

IR (KBr, cm^-1): 2955, 2918, 2850, 2505, 1467, 1417, 1378, 1314, 1263, 1247, 1227, 1177, 1129, 1097, 1067, 990, 963, 923, 890, 874, 852, 823, 795, 755, 721.

2.3. Manufacturing Membranes

In order to fabricate the sensor with the best potentiometric response characteristics, several membrane compositions were used; these are specified in Table 2. The components were dissolved in distilled THF. Each resulting cocktail solution was carefully mixed and degassed for 5 minutes by sonication, then transferred into a glass ring (28 mm i.d.) located on a smooth glass surface. After total THF evaporation at room temperature for ~72 hours, a transparent polymeric membrane with an average thickness of ~0.3 mm was obtained. The reproducibility of membrane performance was ensured by thoroughly mixing the membrane ingredients and by controlling both the evaporation rate of the solvent and the resulting membrane thickness. The «master membrane» manufactured was separated from the glass plate, and disks of an appropriate diameter (≈6 mm) were cut. Then, the membrane disk was mounted in an electrode body (Type IS 561, Philips, Eindhoven, Netherlands) filled with the inner solution 1.0 mM terbinafine hydrochloride. Before use, the sensors were conditioned by being soaked in 1.0 mM solution of terbinafine hydrochloride, for 1 day, to establish the membrane–solution equilibrium. In the case of trace analysis, a faster response was obtained if the PVC membrane was conditioned in a solution that had a similar composition to that of the sample. Between measurements, the sensors constructed were washed with deionised distilled water and blotted with tissue paper. The electrodes were kept dry in an opaque closed vessel while not in use. The performance characteristics of the sensors were evaluated according to IUPAC recommendations [33]. Potentiometric selectivity coefficients were determined by using the separate solution method (SSM) and the matched-potential method (MPM), thus avoiding the limitations of the non-Nernstian behaviour of interfering ions [34].

2.4. Potentiometric Measurements

All potentiometric measurements were carried out, while stirring the test solutions at room temperature (25 ± 2°C), using a pH/ion analyser (Radelkis OP-300, Hungary). An electrochemical cell can be represented by the following diagram:

Ag/AgCl

1.0 mM terbinafine hydrochloride

PVC-membrane

Sample solution

AgClsatd, 3M KCl

AgCl/Ag

A Philips IS-561 electrode body was used to manufacture the potentiometric sensor and a silver chloride electrode (Radelkis OP-0820) was used as an external reference electrode. pH measurements were carried out with a Radelkis OP-0808R combined electrode, using Mettler Toledo calibration solutions.

3. Results

3.1. Synthesis of the Active Ingredient

The preparation of the disubstituted sulfonium derivative of closo-decaborate anion with octadecylalkyl substituents 1,10-B₁₀H₈(S(n-C₁₈H₃₇)₂)₂ can be carried out using a similar procedure to that used for the mono-substituted sulfonyl derivative [2-B₁₀H₉SH]^2- [35]. Due to the presence of two functional groups, however, a longer reaction time is needed. The general scheme of preparation is presented below (Figure 2).

The progress of the reaction can be monitored using ¹¹В NMR spectroscopy. In the ¹¹В NMR spectrum (Figure S2), all signals relative to the parent compound Cs₂[B₁₀H₈(SH)₂] [32] shifted to the weak field: from the apical vertices by 4.7 ppm, whereas from the equatorial ones by 0.6 ppm and are at 9.2 and -24.4 ppm, respectively. In addition, the shape of the signals changed significantly and a strong broadening of the signals was observed. The width of the signal at half its height was 586 Hz for apical vertices and 134 Hz for equatorial vertices; (for the anion [1,10-B₁₀H₈(SH)2]^2-, these values were 4.7 and 5.6 Hz, respectively).

According to ¹H NMR spectroscopy data for the final product, several signals relating to the organic part of the target compound can be observed. The signal at 3.26 ppm refers to methylene groups bound to the sulfur atom; these groups were diastereotopic and were located at the prochiral S-centre, resulting in the shape of this signal being a doublet of doublet triplets with constants J₁ = 91.5 Hz, J₂ = 12.8 Hz and J₃ = 7.2 Hz, with the presence of a roof effect (Figure S1). The signals at 2.02, 1.54, 1.35 and 1.26 ppm can be attributed to the remaining methylene groups in the alkyl substituent, with the signal at 0.89 ppm relating to the C18 methyl group. In the ¹³C NMR spectrum, a group of signals related to the octadecylalkyl substituent can also be observed. The signal at 43.67 ppm refers to the methylene group bonded to the sulfur atom.

3.2. Ion Sensor Development

According to fundamental considerations [36,37], the potentiometric behaviour of membrane sensors based on the ion-exchange mechanism depends on the selectivity of ion exchange processes at the membrane–test solution interface, the mobility of the respective ions in the membrane phase and hydrophobic interactions between ions and the organic membrane. The membrane potential of the ion sensor (E_m) can be represented by the following equation:

$$E_m=const+(RT/z_{X}F)ln(c_{aq}^X/c_m^X)=const+(RT/z_{X}F)[ln{c}_{aq}^X+ln(K_{ass}^{XY}{c}_m^Y/c_m^{XY}\left)\right]$$

where c_aq^X is the concentration of the Terbinafine cation (X) in the test aqueous solution; z_X is the charge of the Terbinafine cation; c_m^X, c_m^Y and c_m^XY represent the concentrations of the anesthetic cation (X), counter-anion (Y) and their ion-pair complex (XY) in the membrane, respectively; K_ass^XY is the association constant of the ion-pair complex; F, R and T are the Faraday constant, the gas constant and absolute temperature, respectively. This means that the lipophilicity of a primary ion (X) and a counter-ion (Y), and the association degree of their ion-pair complex in the membrane phase are the main factors affecting the electroanalytical characteristics of the sensor.

Another very important parameter that should be considered to achieve the best performance of ionic sensors is the nature of a plasticizer (solvent mediator) employed in the membrane composition. The plasticizer provides the mobility of the membrane-forming compounds, and the dielectric and mechanical properties of the polymeric membrane.

As it was shown earlier, the best potentiometric parameters are shown by membranes with low dielectric constant plasticizer according [12] to the Igen-Denison-Ramsey-Fuoss equation (T = 293 K) [38], so we've chosen aliphatic BBPA (εr = 5.3).

The potentiometric curve characterising the response of the sensor based on the PVC-membrane containing 1,10-B₁₀H₈(S(n-C₁₈H₃₇)₂)₂ in BBPA to the Terbinafine ion selected is shown in Figure 3. As can be seen, the sensor showed Nernstian response slopes of (57.2 ± 0.3) mV/decade over a wide linear concentration range, for all tested solutions.

The Terbinafine ion-selective membrane sensors were calibrated, and the potentiometric selectivity coefficients were determined. The potentiometric response characteristics of the sensor were found to be dependent on the amount of the Terbinafine salt in the membrane composition, (see Table 2).

As follows from the results obtained, the sensor based on membrane No. 5 had the best content. This sensor showed a Nernstian response in the concentration range of 4.0 × 10^-8 – 10^-2 mol/L and a lower detection limit (LOD) of 1.0 × 10^-8 mol/L. In addition, the sensor showed stability, good reproducibility and a fast response. The interference of some common cations in some sensors’ response was studied using the mixed solution method. Potentiometric measurements were carried out using test solutions containing the constant concentration of an interfering ion (0.01 mol/L). Calculated selectivity coefficient values are shown in Table 3. These values clearly indicate that the Terbinafine sensor was fairly selective towards Terbinafine cations, for different ions tested.

The active component 1,10-B₁₀H₈(S(n-C₁₈H₃₇)₂)₂ is a neutral carrier, but the membranes obtained showed no response to inorganic anions; this may have been because the boron backbone [B₁₀H₈]^2- has a constant negative charge. Due to their structure, the lipophilic S⁺(n-C₁₈H₃₇)₂ groups were embedded in the polymer matrix of PVC and the charge on the sulfur atom was partially shielded. It can be observed from Table 3 that the more lipophilic cations (TBA⁺) had a greater interfering effect.

Dynamic response time is the time required for the electrode to achieve values within ± 1 mV of the final equilibrium potential, after successive immersions in the sample solutions [39]. Its calculation involved varying and recording Terbinafine concentration in a series of solutions from 1.0 × 10^-2 to 1.0 × 10^-8M. Sensors were able to quickly reach their equilibrium response, in the whole concentration range. The time of this for the PVC membrane electrode was about 20 seconds, in the concentrated solutions.

To examine the effect of pH on electrode responses, potential was measured at specific concentrations of the Terbinafine solution (1.0 × 10^-4 M) for pH values ranging from 1.0 to 9.0, (concentrated NaOH or HCl solutions were used for pH adjustment), for each of the PVC membrane electrodes. The results have shown that potential remained constant despite pH changes within the range of 3 to 6, which indicates the applicability of this electrode in the specified pH range. Some quite noteworthy fluctuations in the behaviour of potential as pH changed were observed below and above the aforementioned pH limits. Specifically, fluctuations above a pH value of 6 might be justified by removing the positive charge on the drug molecule. Fluctuations below a pH value of 3 were caused by the removal of the membrane ingredients or the analyte in the solution. Figure 4

4. Conclusions

In summary, a new compound, 1,10-di-(bis-octodecylsulfonio)-closo-decaborate - 1,10-B₁₀H₈(S(C₁₈H₃₇)₂)₂, was obtained and a selective potentiometric sensor for terbinafine hydrochloride was obtained based on the new boron cluster compound. The sensor demonstrated advanced performance with a fast response time, a lower detection limit of 1.0 × 10^-8 M for the PVC membrane electrode and potential responses across the range of 4.0 × 10^-8 – 1.0 × 10^-2 M. The new active component has better characteristics than sodium tetraphenylborate, which provides great opportunities for modification of the sensor obtained. The study of potentiometric sensors with closo-borate compounds has contributed to the search for an effective rapid method for monitoring nitrogen-containing compounds in water resources.