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Estimating the Solubility, Solution Thermodynamics, and Molecular Interaction of Aliskiren Hemifumarate in Alkylimidazolium Based Ionic Liquids

Estimating the solubility and solution thermodynamics parameters of aliskiren hemifumarate (AHF) in three different room temperature ionic liquids (RTILs), Transcutol-HP (THP) and water are interesting as there is no solubility data available in the literature. In the current study, the solubility and solution thermodynamics of AHF in three different RTILs, THP and water at the temperature range from 298.2 to 318.2 K under air pressure 0.1 MP were evaluated. The solid phase evaluation by Differential Scanning Calorimetry (DSC) and Powder X-ray Diffraction (PXRD) indicated no conversion of AHF into polymorph. The mole fraction solubility of AHF was found to be highest in 1-hexyl-3-methylimidazolium hexafluorophosphate (HMMHFP) ionic liquid (7.46 × 10−2) at 318.2 K. The obtained solubility values of AHF was regressed by the Apelblat and van’t Hoff models with overall root mean square deviations (RMSD) of 0.62% and 1.42%, respectively. The ideal solubility of AHF was higher compared to experimental solubility values at different temperatures. The lowest activity coefficient was found in HMMHFP, which confirmed highest molecular interaction between AHF–HMMHFP. The estimated thermodynamic parameters confirmed endothermic and entropy driven dissolution of AHF in different RTILs, THP, and water.


Introduction
Renin is an enzyme secreted by the kidney and plays a key role in the pathogenesis of arterial hypertension and its consequent complication associated with cardiovascular and renal diseases [1]. Aliskiren hemifumarate (AHF) is the first clinically approved, orally active, highly potent, and selective renin inhibitor for the treatment of hypertension alone or in combination with other antihypertensive agents [2]. It is chemically designated as (2S,4S,5S,7S)-N-(2-Carbamoyl-2methylpropyl)-5amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]octanamidehemifumarate ( Figure 1). It is white to slightly yellowish crystalline powder having a molecular weight of 1219.61. In spite of high potency, aliskiren is poorly absorbed (2.5% oral bioavailability) and reflects a high inter-subject variability in their pharmacokinetic profile after oral bioavailability) and reflects a high inter-subject variability in their pharmacokinetic profile after oral administration [3,4]. Due to poor bioavailability, a comparatively higher dose of aliskiren (150-300 mg) is required for therapeutic management of hypertension. In addition, high fat food decreases the absorption of aliskiren and therefore patients use to establish a routine pattern for taking aliskiren with regard to meals (US PI). Room temperature ionic liquids (RTILs) are basically organic molten salts which exist in the liquid state at room temperatures [5]. RTILs are usually prepared by combining large organic cations with a variety of smaller organic or inorganic anions. It has many unique physicochemical properties in comparison to traditional solvents and therefore emerged as a multifunctional solvent for pharmaceutical and biomedical applications [6,7,8,9]. It exhibits very low/or negligible vapor pressure, low melting point with a wide liquidity range, a high thermal, chemical & electrochemical stabilities, unique solvating properties with excellent dissolution performance [10,11,12]. In addition, it has adjustable solvent viscosity, polarity, and hydrophobicity associated with low or high water miscibility which results from a matchless association of molecular characteristics of their constitutive ions [7,8]. Moreover, some RTILs behave as nano segregated fluids with polar networks permeated by a polar domain, which enables the understanding of their peculiar solvent behavior at a molecular level [9]. RTILs have been utilized for solubility enhancement of poorly aqueous soluble drug and efficacy enhancer of topical analgesic with increased thermal stability properties [13,14]. Therefore, RTILs can overcome various pharmaceutical problems, i.e., low solubility, low permeability, which results in low bioavailability of drugs, and the presence of polymorph/solvate, which severely effects the efficacy of commercially available drugs [8]. Among the variety of RTILs, alkylimidazoliumbased RTILs, in which the alkyl group of the ILs can be varied by selection of different halohydrocarbons is most commonly employed RTILs, and have become one of the research hot topics in recent years [6]. The solubility data of AHF in safe/non-toxic ionic liquids measured in this study could be useful in pharmaceutical dosage form development. In this study, we used three different alkyl imidazolium-based RTILs ( Figure 2). Therefore, the aim of this study was to evaluate Room temperature ionic liquids (RTILs) are basically organic molten salts which exist in the liquid state at room temperatures [5]. RTILs are usually prepared by combining large organic cations with a variety of smaller organic or inorganic anions. It has many unique physicochemical properties in comparison to traditional solvents and therefore emerged as a multifunctional solvent for pharmaceutical and biomedical applications [6][7][8][9]. It exhibits very low/or negligible vapor pressure, low melting point with a wide liquidity range, a high thermal, chemical & electrochemical stabilities, unique solvating properties with excellent dissolution performance [10][11][12]. In addition, it has adjustable solvent viscosity, polarity, and hydrophobicity associated with low or high water miscibility which results from a matchless association of molecular characteristics of their constitutive ions [7,8]. Moreover, some RTILs behave as nano segregated fluids with polar networks permeated by a polar domain, which enables the understanding of their peculiar solvent behavior at a molecular level [9]. RTILs have been utilized for solubility enhancement of poorly aqueous soluble drug and efficacy enhancer of topical analgesic with increased thermal stability properties [13,14]. Therefore, RTILs can overcome various pharmaceutical problems, i.e., low solubility, low permeability, which results in low bioavailability of drugs, and the presence of polymorph/solvate, which severely effects the efficacy of commercially available drugs [8]. Among the variety of RTILs, alkylimidazolium-based RTILs, in which the alkyl group of the ILs can be varied by selection of different halohydrocarbons is most commonly employed RTILs, and have become one of the research hot topics in recent years [6]. The solubility data of AHF in safe/non-toxic ionic liquids measured in this study could be useful in pharmaceutical dosage form development. In this study, we used three different alkyl imidazolium-based RTILs ( Figure 2). Therefore, the aim of this study was to evaluate the solubility, solution thermodynamic, and molecular interaction of AHF with different alkyl imidazolium-based RTILs.
the solubility, solution thermodynamic, and molecular interaction of AHF with different alkyl imidazolium-based RTILs.

Solid Phase Characterization of AHF
Solid phase characterization of the initial and equilibrated sample were performed by Differential Scanning Calorimetry (DSC) and Powder X-ray Diffraction (PXRD) spectral analysis to know about the crystallinity/amorphicity and various thermal parameters of the drug. The DSC spectra of initial and equilibrated AHF (obtained from water) are shown in Figure 3A,B, respectively. The DSC spectra of initial AHF showed a broad peak at the fusion temperature (Tfus) of 369.62 K, confirming AHF's amorphous nature ( Figure 3A). However, an equilibrated sample of AHF showed almost similar peaks at 371.62 K which suggested its amorphous nature ( Figure 3B). The enthalpy fusion (∆Hfus) of initial and equilibrated AHF were measured as 36.85 kJ mol −1 and 38.21 kJ mol −1 , respectively. The DSC thermograms of initial and equilibrated AHF were found to be almost similar and did not convert into polymorphs after reaching equilibrium. The Tfus and ∆Hfus of AHF by DSC analysis has been available in literature as 371.5 K and 30.28 kJ mol −1 , respectively [15], which were very close to our obtained data. The studied temperature range of 298.2 to 318.2 K was selected in the present work in such a way that the maximum studied temperature (i.e., T = 318.2 K) should not exceed the melting/fusion temperature of AHF. The melting temperature of AHF was obtained as 371.5 K in this work. The maximum studied temperature was much lower than the melting temperature of AHF, hence, the proposed temperature range was selected in this study. The XRD diffraction pattern of initial and equilibrated AHF are presented in Figure 4A and B, respectively. The diffraction pattern of initial AHF showed broad and diffused peaks suggesting its amorphous nature ( Figure 4A), as it has been also confirmed by DSC studies. However, the same broad and diffused peaks could be seen in the equilibrated sample, suggesting no change after equilibrium [15].

Solid Phase Characterization of AHF
Solid phase characterization of the initial and equilibrated sample were performed by Differential Scanning Calorimetry (DSC) and Powder X-ray Diffraction (PXRD) spectral analysis to know about the crystallinity/amorphicity and various thermal parameters of the drug. The DSC spectra of initial and equilibrated AHF (obtained from water) are shown in Figure 3A,B, respectively. The DSC spectra of initial AHF showed a broad peak at the fusion temperature (T fus ) of 369.62 K, confirming AHF's amorphous nature ( Figure 3A). However, an equilibrated sample of AHF showed almost similar peaks at 371.62 K which suggested its amorphous nature ( Figure 3B). The enthalpy fusion (∆H fus ) of initial and equilibrated AHF were measured as 36.85 kJ mol −1 and 38.21 kJ mol −1 , respectively. The DSC thermograms of initial and equilibrated AHF were found to be almost similar and did not convert into polymorphs after reaching equilibrium. The T fus and ∆H fus of AHF by DSC analysis has been available in literature as 371.5 K and 30.28 kJ mol −1 , respectively [15], which were very close to our obtained data. The studied temperature range of 298.2 to 318.2 K was selected in the present work in such a way that the maximum studied temperature (i.e., T = 318.2 K) should not exceed the melting/fusion temperature of AHF. The melting temperature of AHF was obtained as 371.5 K in this work. The maximum studied temperature was much lower than the melting temperature of AHF, hence, the proposed temperature range was selected in this study. The XRD diffraction pattern of initial and equilibrated AHF are presented in Figure 4A and B, respectively. The diffraction pattern of initial AHF showed broad and diffused peaks suggesting its amorphous nature ( Figure 4A), as it has been also confirmed by DSC studies. However, the same broad and diffused peaks could be seen in the equilibrated sample, suggesting no change after equilibrium [15].

Measured Solubilities of AHF
The obtained xe data of AHF in RTILs, Transcutol-HP (THP) and water at T = 298.2 K, 303.2 K, 308.2 K, 313.2 K, and 318.2 K under atmospheric pressure are shown in Table.1. There is no literature available on solubility of AHF in the RTILs, which would be the replacement of hazardous organic solvents for the development of dosage form.

Measured Solubilities of AHF
The obtained xe data of AHF in RTILs, Transcutol-HP (THP) and water at T = 298.2 K, 303.2 K, 308.2 K, 313.2 K, and 318.2 K under atmospheric pressure are shown in Table.1. There is no literature available on solubility of AHF in the RTILs, which would be the replacement of hazardous organic solvents for the development of dosage form.

Measured Solubilities of AHF
The obtained x e data of AHF in RTILs, Transcutol-HP (THP) and water at T = 298.2 K, 303.2 K, 308.2 K, 313.2 K, and 318.2 K under atmospheric pressure are shown in Table 1. There is no literature available on solubility of AHF in the RTILs, which would be the replacement of hazardous organic solvents for the development of dosage form.
The solubility of AFH in water at T = 298.2 K is approximately 100 mg/mL (converted to 1.47 × 10 −3 in mole fraction solubility) as reported in the literature [16]. While, solubility of AHF in RTILs and THP with respect to temperature is not reported elsewhere. The mole fraction solubility of AHF in water at T = 298.2 K was found to be 1.45 × 10 −3 which was much closer to reported solubility [16]. It was noted in our studies that mole fraction solubilities (x e ) of AHF increased with increases in temperature in experimental solvents. The x e values of AHF were obtained highest in HMMHFP followed by BMMHFP, THP, OMMHFP, and water at T = 298.2 K. The same trends were also seen at all studied temperatures (T = 303.2-318.2 K) (see Table 1). The highest solubility of AHF was observed in RTILs probably due to anion-cation combinations of RTILs, which are responsible for H-bonding, Van der Waals forces, and π-π interactions between solute and solvent [17]. Based on solubility studies, it is considered that AHF is freely soluble in all investigated solvents, as AHF is an amorphous powder, confirmed by DSC and PXRD.

Hansen Solubility Parameters
Hansen solubility parameters (δ) are very useful to correlate the solubility data of AHF with polarity of AHF and solvents. The values of δ for AHF and RTILs, THP and water were calculated with the help of Equation (1) [17]: In this Equation, δ d , δ p, and δ h represent dispersion, polar, and hydrogen-bonded parameters for Hansen solubility, respectively. The HSPiP software (version 4.1.07) was used to estimate these parameters (δ, δ d , δ p, and δ h ). The estimated data of these parameters are given in Table 2.
The δ value for AHF was obtained as 25.00 MPa 1/2 , suggesting that it is drug with medium polarity. The x e values of AHF were also found to be higher in all RTILs and THP as these RTILs and THP have medium δ values ( Table 2). The x e value of AHF was recorded as a maximum in HMMHFP. This observation was probably due to the close δ value of HMMHFP (22.70 MPa 1/2 ) with that of AHF. However, the x e value of AHF was found minimum in water and this observation was probably due to the maximum δ value of water (47.80 MPa 1/2 ).

Measurement of Ideal Solubilities and Activity Coefficients
The ideal solubility of pure AHF (x idl ) was measured by using equation (2) [18]: In this equation, R = universal gas constant and ∆C p = difference in the molar heat capacity of solid form with that of liquid form [18,19]. The ∆C p value for AHF was approximately calculated using Equation (3) [18]: The values of T fus and ∆H fus for pure powder AHF were measured by DSC thermal analysis and recorded as 369.62 K and 36.85 kJ mol −1 , respectively. By applying Equation (4), the ∆C p data for AHF was measured as 99.69 J mol −1 K −1 . The measured data of x idl are documented in Table 2. The ideal solubilities of AHF were measured much higher in comparison to mole fraction solubilities of AHF in different RTILs, THP, and water at all investigated temperatures. The ideal solubilities of AHF were measured in the range of 7.61 × 10 −2 to 1.65 × 10 −1 . The higher ideal solubilities of AHF could be due to lower fusion temperature of amorphous AHF powder. Among the different solvents studied, RTILs (HMMHFP) was found to be the ideal solvent for the solubilization of AHF.
The activity coefficients data of (γ i ) for AHF in all experimental solvents were measured by using Equation (4) [19,20]: The values of activity coefficients (γ i ) of AHF were investigated in all solvents at T = 298.2 K, 303.2 K, 308.2 K, 313.2 K, and 318.2 K and are documented in Table 3. The values of the activity coefficients (γ i ) of AHF are very important parameters to explain solute-solvent interaction at the molecular level. The highest value of γ i for AHF in water was determined in comparison to other investigated solvents. While, data of γ i for AHF was found much lower in RTILs (HMMHFP) as it could be seen in Table 3. A slight fluctuation in γ i was observed in water with change in temperatures. While, γ i values were found almost constant in other investigated solvents with a variation in temperatures. The determined γ i data for AHF were measured in accordance with mole fraction solubility in all solvents studied. According to γ i values, the highest molecular interactions were obtained in AHF-HMMHFP in comparison to other solute-solvent interactions. While, the weak molecular interactions were obtained in AHF-water due to its highest γ i obtained values in water.

Correlation of x e Values of AHF
The obtained x e values of AHF in this work were correlated by using the Apelblat and van't Hoff models [21][22][23][24]. Apelblat model solubility (x Apl ) for AHF was calculated by using Equation (5) [20,23]: In this Equation, the symbols A, B and C are parameters of the Apelblat model which were calculated by non-linear multivariate regression analysis of x e values of AHF and are listed in Table 4.
The values x e of AHF were correlated with x Apl of AHF in terms of the root mean square deviations (RMSD) and R 2 . The values of RMSD were calculated by using Equation (6): In this equation, N is the number of experimental data points. The correlation between values of Inx e and Inx Apl of AHF against 1/T are given in Figure 5. It could be seen in Figure 5 that a good correlation/curve fitting obtained between values of Inx e and Inx Apl of AHF in all investigated solvents. The measured values of "A, B, C, RMSD, and R 2 " are listed in Table 5. The obtained values of RMSD in different solvents were found in the range of 0.57% to 0.91%. The overall RMSD for Apelblat correlation was measured as 0.62%. The highest (0.91%) and lowest (0.57%) RMSD values for AHF were obtained in BMMHFP and OMMHFP, respectively. The obtained R 2 values for AHF were found as 0.9996 to 0.9999. These obtained data revealed an excellent curve fitting of values of x e and x Apl for AHF using the Apelblat model. In this equation, N is the number of experimental data points. The correlation between values of Inxe and Inx Apl of AHF against 1/T are given in Figure 5. It could be seen in Figure 5 that a good correlation/curve fitting obtained between values of Inxe and Inx Apl of AHF in all investigated solvents. The measured values of "A, B, C, RMSD, and R 2 "are listed in Table 5. The obtained values of RMSD in different solvents were found in the range of 0.57% to 0.91%. The overall RMSD for Apelblat correlation was measured as 0.62%. The highest (0.91%) and lowest (0.57%) RMSD values for AHF were obtained in BMMHFP and OMMHFP, respectively. The obtained R 2 values for AHF were found as 0.9996 to 0.9999. These obtained data revealed an excellent curve fitting of values of xe and x Apl for AHF using the Apelblat model.  The van't Hoff model solubility (x van't ) for AHF were calculated using Equation (7) [22]: In the above Equation, symbols a and b are coefficients of the van't Hoff model. These coefficients values were obtained by simple regression of graphs plotted for Inx e data of AHF against 1/T. The measured x e values of AHF also correlated with x van't values using RMSD and R 2 values. The curve correlation between x e and x van't values of AHF as a function of 1/T is given in Figure 6. The data represented in Figure 6 again showed an excellent correlation/curve fitting between x e and x van't values of AHF. The calculated values of a, b, RMSD, and R 2 are documented in Table 5. The RMSD values for AHF in all investigated solvents were obtained as 0.74% to 1.70%. The overall RMSD was obtained as 1.42%. The maximum and minimum values of RMSD for AHF were obtained in the RTILs (HMMHFP) as 1.70% and RTILs (OMMHFP) 0.70%, respectively. The coefficient of correlation (R 2 ) values for AHF in all investigated solvents were calculated as 0.9953 to 0.9998. These results again indicated an excellent curve fitting of x e values of AHF with the van't Hoff model.

Measurement of Apparent Thermodynamic Parameters
The solubilization behavior of AHF in all investigated solvents was studied by determination of apparent standard thermodynamic parameters. The thermodynamic parameters namely: apparent standard dissolution enthalpy (∆ sol H 0 ), apparent standard Gibbs free energy (∆ sol G 0 ) and apparent standard dissolution entropy (∆ sol S 0 ) for dissolution behavior were obtained with the help of apparent thermodynamic analysis. The ∆ sol H 0 data for AHF solubilization in all solvents were determined at the "mean harmonic temperature (T hm ) with the help of van't Hoff analysis using Equation (8) [20,25].
The "∆ sol H 0 " values for dissolution of AHF in all solvents were calculated by van't Hoff curve constructed for Inx e values of AHF as a function of 1/T − 1/T hm. The ∆ sol G 0 values for dissolution behavior of AHF in all investigated solvents were estimated at T hm by using Krug et al. analysis using Equation (9) [26]: The value of intercept for AHF in each investigated solvent was calculated from thevan't Hoff plot. The values of ∆ sol S 0 for dissolution behavior of AHF in all investigated solvents were calculated with the help of combined approach of van't Hoff and Krug et al. analysis using Equation (10) [26,27].
The obtained values of ∆ sol H 0 , ∆ sol G 0 , ∆ sol S 0 , and R 2 for dissolution behavior of AHF in all solvents are documented in Table 6. The ∆ sol H 0 values for dissolution behavior of AHF in all investigated solvents were calculated as 29.01-33.41 kJ/mol. The highest and lowest ∆ sol H 0 values for AHF were obtained as 33.41 kJmol −1 and 29.01 kJ/mol in BMMHFP and water, respectively. The ∆ sol G 0 values for AHF solubilization in different investigated solvents were observed as 7.71-15.83 kJ/mol. The ∆ sol G 0 values for AHF solubilization was observed highest in water followed by OMMHFP, THP, BMMHFP, and HMMHFP solvents. The lowest values of ∆ sol G 0 for AHF solubilization in HMMHFP ionic liquids, which was probably due to the highest solubility of AHF in HMMHFP. The positive obtained values of ∆ sol H 0 and ∆ sol G 0 for AHF solubilization in all investigated solvents confirmed an endothermic dissolution of AHF [22,24]. The ∆ sol S 0 values for AHF solubilization behavior in all solvents was obtained in positive values as 42.80-83.15 kJ/mol. The average values of ∆ sol H 0 , ∆ sol G 0 , and ∆ sol S 0 were calculated as 31.22 kJ/mol, 10.70 kJ/mol, and 66.62 kJ/mol with relative uncertainties of 0.06 kJ/mol, 0.28 kJ/mol, and 0.23 kJ/mol, respectively. The positive ∆ sol S 0 values for AHF in all solvents indicated an entropy driven solubilization [22,27]. Table 6. Thermodynamic quantities (∆ sol H 0 , ∆ sol G 0 , and ∆ sol S 0 ) and R 2 values for AHF dissolution in three different ILs, Transcutol-HP, and water b .

Materials
AHF, BMMHFP, HMMHFP, and OMMHFP were purchased from Mesochem Technology (Beijing, China). Transcutol-HP ® was obtained from Gattefosse (Lyon, France). Purified water (conductivity less than 1 µS·cm −1 ) was taken from Milli-Q Water Purification Unit in College of Pharmacy, Prince Sattam Bin Abdul-Aziz University, Al-Kharj Saudi Arabia. The data of physical properties and characterization used in the experiment are listed in Table 7.

Analysis of AHF
The samples were quantified by using UV Spectroscopy (JASCO, Japan) at lambda max of 280 nm after dilution with suitable solvents [26]. A linear standard curve of AHF was plotted between concentration 10-150 µg g −1 and absorbance with coefficient of correlation of R 2 = 0.9990. A regression equation was obtained as y = 0.005x + 0.010 (where, y = measured absorbance of AHF and x = concentration of AHF). The concentrations of AHF samples were determined with help of regression equation of standard plot.

Solid Phase Characterization of AHF
Solid phase characterization of initial and equilibrated AHF was performed by Differential Scanning Calorimetry (DSC) and Powder X-ray Diffraction (PXRD) analysis. DSC and PXRD evaluation were done to know the many thermal properties of initial and equilibrated samples of AHF [26][27][28]. DSC spectral analysis of the samples were recorded by Perkin Elmer DSC-8000, Waltham, MA, USA equipped with autosampler and controlled by Pyris software (Waltham, MA, USA). Accurately weighed amount of initial AHF (5mg) and equilibrated AHF (5mg) was pressed into hermetically sealed aluminum pan. DSC spectral analysis of both samples were performed in inert nitrogen gas environment with a flow rate of 50 mL/min. The temperature scan was used as 10 degree min −1 T = 313.2-433.2 K. PXRD spectral analysis of both AHF sample were performed on instrument Ultima IV (Rigaku Inc., Tokyo, Japan). The 2θ values were set in the range of 3 • to 120 • with a scan rate of 0.5 degree/min. The powder XRD of both samples were analyzed at a "tube voltage of 40 kV and 40 mV current".

Solubility Studies of AHF
Mole fraction solubility of AHF in three different room temperature ionic liquids (BMMHFP, HMMHFP, and OMMHFP), transcutol-HP, and water was determined by shake flask method [29,30]. The solubility of AHF in these solvents was measured at T = 298.2 K, 303.2 K, 308.2 K, 313.2 K, and 318.2 K under atmospheric pressure. In brief, excess amount of AHF drug was dispersed in each investigated solvents enclosed in screw capped glass flask. Each AHF solution mixture was kept on a biological shaker (Julabo, Allentown, PA, USA) for shaking at 100 rpm for 72 h to reach equilibrium. After complete saturation of AHF in each solvents, sample was taken from shaker and kept to sediment the drug particles [17]. Then, required volume of supernatant samples were withdrawn, filtered and analyzed the AHF after suitable dilution with respective solvents by UV spectrophotometry at 280 nm [26]. Each experiments were done in triplicate.
Mole fraction solubilities of AHF (x e ) were calculated with the help of Equation (11) [30].
x e = m 1 /M 1 m 1 /M 1 + m 2 /M 2 (11) Here, m 1 and m 2 represents the masses of AHF and solvents used, respectively. M 1 and M 2 represent the molar masses of AHF and solvents used, respectively.

Conclusions
In this study, the solubility of AHF in different alkyl imidazolium-based ionic liquids, THP and water were measured at 298.2-318.2 K. The solubility was found to increase with respect to increases in temperature in all investigated solvents. The obtained solubility data were well fitted/correlated with the Apelblat and van't Hoff models. The data confirmed that solubilization of aliskiren hemifumarate was endothermic, spontaneous, and entropy driven in all solvents. In conclusion, aliskiren hemifumarate has been considered free soluble in all solvents due to its amorphous nature as confirmed by DSC/PXRD. However, maximum solubility was observed in 1-hexyl-3-methylimidazolium hexafluorophosphate (HMMHFP) ionic liquid.