Effect of additives on the aggregation phenomena of amphiphilic drug and hydrotrope mixtures

MOLLIQ-112049; No of Pages 14 Journal of Molecular Liquids xxx (xxxx) xxx

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Effect of additives on the aggregation phenomena of amphiphilic drug and hydrotrope mixtures Malik Abdul Rub Chemistry Department, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia

a r t i c l e

i n f o

Article history: Received 13 August 2019 Received in revised form 25 October 2019 Accepted 1 November 2019 Available online xxxx Keywords: Antidepressant drug Electrolytes Hydrotrope Fluorescence FT-IR

a b s t r a c t Association behavior between the cationic antidepressant drug imipramine hydrochloride (IPH) and anionic hydrotrope - sodium benzoate (NaBez) mixtures in aqueous solutions, along with the electrolytes NaCl (50 mmol·kg−1) and NaBr (50 mmol·kg−1) were studied using a conductometric technique at four different temperatures. The results showed a decrease in critical micelle concentration (cmc) of IPH (drug) in combination with NaBez, viewing a remarkable interaction amongst studied constituents along with cmc values of IPH drug further lessens through raised in mole fraction (α1) of NaBez. The electrolytes NaCl and NaBr reduced the cmc of IPH, NaBez together with their mixture (IPH-NaBez) in diverse ratio and NaBr was additionally effectual in reducing the cmc of the system in comparison to NaCl. Moreover, the cmc values of IPH and NaBez mixtures showed a lower than ideal cmc (cmcid) value characterizing the non-ideality in system. Additional parameters of the conductometric method such as the micellar mole fraction employing the Rubingh and Rodenas models, interaction parameter (β), activity coefficients of the mixed micelles, and excess Gibbs free energy using the Rubingh and Rodenas models and so on were evaluated. The activity coefficients values were lessened in electrolyte solvent in the entire systems showing the enhanced non-ideality of mixed system in electrolyte solution. At various temperatures, thermodynamic parameters were also evaluated in aqueous along with electrolyte solutions. The interactions amongst the studied constituents in the aqueous system were also evaluated by fluorescence and FT-IR studies and explored in detail. © 2018 Elsevier B.V. All rights reserved.

1. Introduction Surfactants have both hydrophilic and hydrophobic components in the same monomers, which make them multipurpose compounds that are broadly utilized for house-hold proposes as well as in manufacturing industrial products [1–3]. Surfactant monomers not only produce monolayers at interfacial surfaces by diminishing the Gibbs energy of a solution, but they also promote self-association to form micelles that can be measured at critical micelle concentrations (cmc) [4–7]. Micelles are constructed of a hydrophilic exterior and hydrophobic interior that are capable of mimicking biomembranes. Therefore, micelles are both polar and nonpolar molecules. The cmc value, along with association phenomena, can be overwhelmed via a variety of factors, including the type of amphiphile used to produce micelles, the chain length of hydrophobic part, the charge of the hydrophilic portion, temperature, and inorganic/organic solvents [1]. In comparison to singular amphiphiles, an amphiphile mixture system can be characterized by having lower cmc values, advanced surface actions and lower surface energy, which are often found in detergents

E-mail address: [email protected].

[8]. As a result, in aqueous or non-aqueous systems the evaluation of the interaction properties of oppositely charged amphiphile molecules is importance for basic science as well as improving their technological applications [1]. Considering the noteworthy application and economic function of mixed amphiphile systems, much effort has been dedicated to exploring and exposing the physicochemical characteristics of these systems. The thermodynamic and physicochemical characteristics of mixed amphiphile systems are crucial properties for understanding their principal functions and relevant applications, such as cmc formation, degree of dissociation, and number of monomers in one micelle, which are dependent on temperature and the occurrence of other inorganic and organic compounds in the system [9–12]. In pharmaceutical sciences, the absorption of a range of drugs can be detected or enhanced via mixed micelles [13,14]. Hydrotropes are well-known amphiphilic organic molecules with structures similar to common surfactants, with the only difference between them being that the non-polar portions of hydrotrope monomers are much shorter compared to common surfactants [15]. Like common surfactants, hydrotrope monomers self-aggregation into micelles due to their amphiphilic nature and at concentrations above which produce aggregation, or minimum hydrotropic concentration (mhc) [16]. Hydrotropes increase the solubility of hydrophobic compounds in

Please cite this article as: M.A. Rub, Effect of additives on the aggregation phenomena of amphiphilic drug and hydrotrope mixtures, Journal of Molecular Liquids, https://doi.org/10.1016/j.molliq.2019.112049

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water because of their self-association property [16]. Sodium benzoate (NaBez) is an important electrolyte with hydrotropic properties (Scheme 1) that is used in many fields. NaBez was the first preservative the FDA allowed in foods and is still a widely used food additive [1]. NaBez inhibits the development of potentially dangerous germs in food, preventing spoilage. NaBez is used as a preservative in some over-the-counter and prescription medications, particularly in liquid medicines like cough syrup [1,17]. Despite of many applications of hydrotropes, they also have some drawbacks. Aggregation phenomena of the antidepressant imipramine hydrochloride (IPH) drug have been conductometrically studied in the current system in absence and presence of the hydrotrope NaBez, in aqueous solutions and with different salts (NaCl and NaBr) at different temperatures. This drug is odorless and crystalline powder that contains a tricyclic ring and a small hydrocarbon chain that includes a terminal N atom (Scheme 2) [17]. IPH is widely used for the effective treatment of depression associated with agitation or anxiety, bed wetting (which is also called nocturnal enuresis), hyperactivity and behavioral problems [17]. In the case of bed-wetting, IPH possibly will job through blocking the consequence of an acetylcholine usual compound on the bladder. This drug tasks on the central nervous system to enhance the extents of particular substances in brain [17]. Apart from this, drug has some side effects also. When used in combination of various types of drug carriers such as hydrotropes, the unwanted or toxic side effects of this group of drug have been minimized, while their bioavailability has been increased, indicating that the hydrotropes can potentially change or alter drug pharmacological activities [18]. The micellization of IPH has already been conductometrically studied at dissimilar temperatures in the occurrence of bile slats, and with conventional and gemini surfactants [19–21]. However, the outcome of diverse inorganic and organic compounds on the mixed micellization of cationic IPH and anionic hydrotropes is yet to be accounted. In this work, the micellar and thermodynamic behavior of the mixed micelles formed by IPH and NaBez in aqueous solution, along with two different salts (NaCl and NaBr), has been investigated to shed light on various interactions affecting the drug delivery system. The current method was also worked out to inspect the thermodynamic parameters of micellization of amphiphiles mixtures. Additives participate a considerable function in finely alteration intra- and inter-micellar interactions amongst amphiphilic molecules, as a result affecting solution characteristics like cmc [1,22]. Since biologically essential compounds like NaCl are found in the body, the study of their outcome on the association phenomena of drug-hydroptrope mixed systems is of significant interest. We also conducted a supporting assessment of the binding between IPH and hydrotrope in an aqueous system using fluorescence and IR spectroscopic methods.

Scheme 1. Molecular structure of the anionic hydrotrope - sodium benzoate (NaBez).

Scheme 2. Molecular structure of imipramine hydrochloride (IPH).

2. Experimental section 2.1. Materials All materials were of analytical grade and used without further purification. The purity of the materials is provided as mass fractions. The antidepressant drug IPH was acquired from (Sigma, USA) and had a purity N0.98. The hydrotrope NaBez (Merck, India) and the electrolytes sodium chloride (NaCl; BDH, India) and sodium bromide (NaBr; Loba Chemie, India) had purities of 0.995, 0.998, and 0.998, respectively. The entire solutions were formulated using double-distilled deionized water with specific conductivity 0.8–2.0 μS cm−1. 2.2. Techniques 2.2.1. Conductivity measurement The interaction amid IPH and the employed anionic hydrotrope NaBez in aqueous and electrolytic solutions were evaluated using conductivity measurements by determining the cmc values of the mixed systems [23,24]. The conductivity of IPH alone, NaBez alone and IPHNaBez mixtures of proportions in H2O or electrolyte solutions (50 mmol kg−1 NaCl/NaBr) were recorded using a digital Jenway 4510, UK conductivity meter equipped through a dip cell with a 1.0 cm−1 cell constant. The solution temperature was maintained by flowing H2O through the cell griping solution and the accuracy was maintained at ±0.2 K. The accuracy was found to around ±0.5% of the conductivity meter used in this study. The conductivity meter instrument was calibrated prior to starting the new system experiment by means of 0.1 N KCl. The conductivity of the solvent (i.e. H2O in case of the pure amphiphiles; a fixed concentration of NaBez in H2O; a set concentration of NaBez in NaCl/NaBr) was recorded first before the prepared stock solution of IPH in H2O or 50 mmol kg−1 salt/drug-NaBez mixtures in H2O or 50 mmol kg−1 NaCl/NaBr was used as the solvent. After equipment was calibrated and the temperature of the resulting solution was equilibrated, conductivity was recorded and process was repeated many times until the increment in conductivity values reduced too much. The conductivity values were then plotted against their employed amphiphile concentration using Origin software. The values of cmc from these plots were obtained and the errors in cmc values were generally b3%. 2.2.2. Surface tension measurements An attension tensiometer (Sigma 701, Germany) was used for determining the surface tension (γ) of IPH drug by means of a platinum ring detachment process at 293.15 K. Temperature was managed by flowing

Please cite this article as: M.A. Rub, Effect of additives on the aggregation phenomena of amphiphilic drug and hydrotrope mixtures, Journal of Molecular Liquids, https://doi.org/10.1016/j.molliq.2019.112049

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H2O from a thermostat and the error in temperature was below 0.2 K. The γ of double distilled water (DDW) was measured first and then the γ of the pure IPH drug was evaluated via consecutive additions of stock solutions of the drug in DDW. The γ value decreased with every addition of the drug solution in DDW and after a certain decrease in value, the value became constant. The concentration at which γ became constant or the intersection point between γ versus concentration was defined as the cmc value of pure IPH in the aqueous system. The accuracy of measurements of γ was near ±0.2 mN m−1. 2.2.3. Fluorescence measurement A Hitachi F-7500 fluorescence spectrometer was used to measure fluorescence of the IPH solution with and without different concentrations of NaBez in an aqueous system. The whole fluorescent measurements were conducted by fixing the excitation/emission slit width at 5.0 nm and using a quartz cuvette cell with a 10-mm path length. Fluorescence measurements were recorded at a 250 nm excitation wavelength with a maximum obtained by a UV–visible spectrometer for the pure drug. 2.2.4. FT-IR measurement A Thermo Scientific NICOLET iS50 FT-IR spectrometer (Madison, USA) was utilized for measurement of spectra. The FT-IR spectra were noted in the range amongst 4000 and 400 cm−1 and only a chosen section of the wavelength is given. The stock solutions of individual amphiphiles (IPH (drug) and NaBez hydrotropes) as well as their mixed systems were prepared in DDW. The H2O spectrum was deduced from the employed system. 3. Results and discussion 3.1. Mixed micellization study The mixed micellization in aqueous and non-aqueous solutions had various physicochemical amends because of the interactions between the amphiphiles and gives up improved aggregation properties. Amongst many methods a conductivity method is one of the fine techniques that habitually used for the determination of the cmc of singular and mixed amphiphile systems in aqueous and non-aqueous solutions [1]. A strong coulombic interaction was measured in the mixed systems of cationic and anionic amphiphiles, which resulted in unusually lower cmc values in comparison to those predicted by the ideal theory [25]. In general, in the cationic and anionic amphiphile mixtures, complex formation or precipitation occurs in the aqueous system, which inhibits their application. However, such systems are possible when either constituent of the mixture are used in excess, which allows for stable mixtures of solutions with opposite charge to be produced [26]. The cmc values of single constituents and their binary mixtures at different concentrations or mole fractions of NaBez in aqueous solutions with or without electrolytes were tested using the conductivity technique. The specific conductivity of a studied system of pure and mixtures of two amphiphiles (i.e. drug and hydrotrope) that were dependent on the amphiphile concentration of were evaluated at four different temperatures (288.15 K, 293.15 K, 298.15 K and 303.15 K). The characteristic plots of specific conductivity against the concentration of IPH in the presence of various mole fractions (α1) of NaBez at 298.15 K in aqueous solution are illustrated in Fig. 1. At the beginning of the experiment, the conductivity of the solution increased linearly with the addition of prepared stock solutions of solvent. After addition of the stock solution beyond a definite concentration, the conductivity of the systems because to decrease, indicating a change in slope value. The breaking point of both lines indicated the cmc value of the particular system. The evaluated cmc values of the studied system with mole fractions of NaBez (α1) in aqueous and salts solutions at all studied temperatures are shown in Tables 1–3. The cmc value of pure IPH was also evaluated via surface tension at 293.15 K (Fig. 2). The obtained cmc

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values of pure IPH measured with both conductivity and surface temperature were similar to each other. At 293.15 K, the cmc value of IPH alone was 41.01 mmol kg−1, consistent with previously published measurements [17,19,21], while the surface tension method reported a value of 41.70 mmol kg−1. The concentration of hydrotropes beyond which monomers aggregate is called the minimum hydrotrope concentration (mhc) despite cmc [27]. In the current study, the mhc value of NaBez was in agreement with values reported in the literature (Table 1) [28] and it is clearly seen from the structure of both components that the hydrophobic segment of NaBez is very small compared to the hydrophobic part of the drug monomers (Schemes 1 and 2). Therefore, IPH begin forming micelles at much a lower concentration compared to the hydrotropes tested in this study. We used concentrations of NaBez were much lower compared to their mhc value, indicating the concentrations of NaBez used in this study contributed to IPH micelles by forming mixed micelles or remaining as monomers in the solvent. The data shown in Tables 1–3 indicate that that as the mole fraction of hydrotrope NaBez (α1) in solution mixture increased, the value of cmc of mixtures (IPH + NaBez) decreased and the cmc values of mixtures were usually in between the cmc of the pure constituents. This result validated the mixed micelle formation in solution mixtures through attractive interactions amongst the studied constituents. Tables 2 and 3 show that compared to an aqueous system, the cmc values of single constituents and their mixtures decreased in the presence of electrolytes (NaCl and NaBr). The decrease in cmc values of single components along with their mixed systems was reported more with NaBr compared to NaCl. The decrease in the cmc value of the studied system in the presence of salts reduced micellar charge surface density that further reduced Coulombic repulsion amongst the head groups. Counter ions attach a significant quantity to ionic micelles and they are attached with micellar surfaces mainly through electrical field produced through head groups, as well as via particular interactions between the head group and the counter ion [29]. A small change in cmc can be observed in the change of micelle head group; conversely, a more obvious outcome has been observed by changing the counter ion [30]. Interestingly, cmc rapidly decreased when the counter ion was changed from a univalent to bi- and trivalent variants [30]. Indeed, this response to counter ion charge occurs because of the enhanced binding of counter ions to the micelles, which results in a decrease in electrostatic repulsion amongst the charged micelle head groups. We report that NaBr was additionally efficient at reducing the cmc value of pure and mixed drug systems compared to NaCl (Tables 2 and 3). Chloride and bromide ions are counter ions of IPH (cationic) and NaBez (anionic) micelles. The extent of counter ion binding with micelles depends on the Hofmeister series, which states that bromide ions bind with micelles more strongly compared to chloride ions [1]. Hypothetically, the hydrated ion radius is inversely proportional to size, and the self-association of amphiphiles is largely based on the hydrated radius of the counter ion [31]. The size of bromide counter ion is more than that of a chloride ion because a hydrated radius of bromide ion (3.30 Å) is less than that of a chloride ion (3.32 Å) [1]. As a result, the addition of sodium bromide to amphiphile solutions results in a more significant reduction of the electrostatic repulsion between head groups when compared to sodium chloride [1]. The cmc values of our studied system show that the enhanced mole fraction of hydrotropes (α1) was reduced both in the absence and presence of salts, indicating a significant interaction between the studied constituents. The acute reduction in the cmc values for IPH by the small α1 of NaBez were attributed to the negatively charged surfactant environment that reduced the charge density around the micelle surface. When cmc values of mixed systems are reduced in the presence of electrolytes than their absence, this indicates that the salts changed the electrostatic interaction amongst oppositely charged molecules by reducing the width as well as the potential of the electric double layer at the air-interface [32]. Accordingly, the salts added to mixed micelle solutions encourage a

Please cite this article as: M.A. Rub, Effect of additives on the aggregation phenomena of amphiphilic drug and hydrotrope mixtures, Journal of Molecular Liquids, https://doi.org/10.1016/j.molliq.2019.112049

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Fig. 1. The plots of specific conductance against the concentration of IPH in the presence of mole fractions (α1) of sodium benzoate (NaBez) at 298.15 K in aqueous solution.

reduction in electrostatic repulsion between the charged head groups; furthermore, it’s direct to a remarkably lesser in cmc value as compared to aqueous system [33,34]. Ideal cmc values (cmcid) were estimated using Clint's theory for mixed systems of IPH and NaBez in both studied media, and then calculated values were compared with the cmc values determined with the conductometric technique. Clint's theory states that there is no interaction between constituents and the cmcid values were calculated with Eq. (1) [35]: 1 α1 α2 ¼ þ cmcid cmc1 cmc2

ð1Þ

In Eq. (1), α1 and α2 are the mole fractions of NaBez and IPH, respectively. cmc1 and cmc2 are the mhc of NaBez and cmc of IPH, respectively. Deviations of the cmc values for interactions between NaBez and IPH from cmcid were used to determine (i) if cmc values were less than cmcid, a synergistic or attractive interaction occurred between the constituents; (ii) if cmc values were greater than cmcid, repulsive or antagonistic interactions occurred between the components; and (iii) if cmc values were equal to cmcid, no interaction occurred between the components in the mixed system. Tables 1–3 show that in our conditions, the evaluated cmc values were lower than cmcid, indicating their values deviating from the ideal and that synergistic interactions occurred between IPH and NaBez in the solution mixtures both in presence and

Please cite this article as: M.A. Rub, Effect of additives on the aggregation phenomena of amphiphilic drug and hydrotrope mixtures, Journal of Molecular Liquids, https://doi.org/10.1016/j.molliq.2019.112049

M.A. Rub / Journal of Molecular Liquids xxx (xxxx) xxx t1:1 t1:2 t1:3 t1:4 t1:5 t1:6 t1:7 t1:8 t1:9 t1:10 t1:11 t1:12 t1:13 t1:14 t1:15 t1:16 t1:17 t1:18 t1:19 t1:20 t1:21 t1:22 t1:23 t1:24 t1:25 t1:26 t1:27 t1:28 t1:29 t1:30 t1:31 t1:32 t1:33 t1:34 t1:35 t1:36

t2:1 t2:2 t2:3 t2:4 t2:5 t2:6 t2:7 t2:8 t2:9 t2:10 t2:11 t2:12 t2:13 t2:14 t2:15 t2:16 t2:17 t2:18 t2:19 t2:20 t2:21 t2:22 t2:23 t2:24 t2:25 t2:26 t2:27 t2:28 t2:29 t2:30 t2:31 t2:32 t2:33 t2:34 t2:35 t2:36

5

Table 1 The different parameters for IPH–NaBez mixed systems in aqueous solutions at different temperature along with concentration.a cmc/mmol∙kg−1

α1

cmcid/mmol∙kg−1

g

f1Rub/f1Rod

f2Rub/f2Rod

ln(cmc1/cmc2)

0.61 0.59 0.57 0.56 0.55 0.54

0.0012/0.0012 0.0013/0.0011 0.0013/0.0010 0.0013/0.0008 0.0012/0.0007

0.9769/0.9794 0.9295/0.9516 0.8709/0.9215 0.7961/0.8751 0.6887/0.8511

1.83

0.62 0.61 0.59 0.58 0.56 0.55

0.0013/0.0013 0.0014/0.0012 0.0014/0.0012 0.0014/0.0011 0.0014/0.0009

0.9798/0.9763 0.9355/0.9422 0.8804/0.9057 0.8165/0.8631 0.7154/0.8259

1.82

0.63 0.62 0.61 0.59 0.57 0.56

0.0011/0.0012 0.0012/0.0011 0.0012/0.0010 0.0012/0.0009 0.0012/0.0007

0.9781/0.9764 0.9331/0.9458 0.8758/0.9101 0.8081/0.8678 0.7032/0.8336

1.91

0.65 0.63 0.62 0.61 0.59 0.57

0.0010/0.0010 0.0011/0.0009 0.0011/0.0008 0.0011/0.0007 0.0011/0.0006

0.9776/0.9796 0.9288/0.9479 0.8698/0.9151 0.7993/0.8725 0.6924/0.8453

2.02

T = 288.15 K 0 0.45 0.90 1.35 1.79 2.69 1

10−3 10−3 10−3 10−3 10−3

38.40 35.45 32.35 29.30 25.90 21.45 238.55

× × × × ×

10−3 10−3 10−3 10−3 10−3

41.01 38.10 34.90 31.75 28.55 24.05 252.40

× × × × ×

−3

10 10−3 10−3 10−3 10−3

× × × × ×

−3

× × × × ×

38.39 38.39 38.38 38.37 38.37 T = 293.15 K

0 0.45 0.90 1.35 1.79 2.69 1

41.00 40.99 40.98 40.97 40.97 T = 298.15 K

0 0.45 0.90 1.35 1.79 2.69 1

39.80 36.85 33.75 30.60 27.40 22.90 268.35

39.79 39.79 39.78 39.77 39.77 T = 303.15 K

0 0.45 0.90 1.35 1.79 2.69 1 a

10 10−3 10−3 10−3 10−3

38.75 35.85 32.65 29.55 26.30 21.85 291.15

38.74 38.73 38.72 38.72 38.71

Relative standard uncertainties (ur) limits are ur(cmc/cmcid) = ±3%, ur(g) = ±3%, ur(f1Rub/f1Rod) = ±4% and ur(f2Rub/f2Rod) = ±4%.

Table 2 The different parameters for IPH–NaBez mixed systems in 50 mmol·kg−1 NaCl solutions at different temperature along with concentration.a cmc/mmol∙kg−1

α1

cmcid/mmol∙kg−1

g

f1Rub/f1Rod

f2Rub/f2Rod

ln(cmc1/cmc2)

0.60 0.58 0.57 0.56 0.54 0.53

0.0011/0.0008 0.0011/0.0007 0.0011/0.0007 0.0011/0.0006 0.0010/0.0004

0.9734/0.9943 0.9191/0.9812 0.8471/0.9581 0.7629/0.9276 0.6283/0.9412

1.86

0.61 0.60 0.58 0.57 0.55 0.54

0.0011/0.0010 0.0012/0.0009 0.0012/0.0008 0.0012/0.0007 0.0011/0.0006

0.9757/0.9863 0.9271/0.9675 0.8631/0.9407 0.7853/0.9019 0.6625/0.8845

1.85

0.62 0.61 0.59 0.58 0.57 0.55

0.0010/0.0008 0.0011/0.0008 0.0011/0.0007 0.0010/0.0006 0.0010/0.0005

0.9744/0.9888 0.9228/0.9709 0.8562/0.9464 0.7756/0.9096 0.6475/0.9034

1.94

0.64 0.62 0.60 0.59 0.58 0.56

0.0009/0.0007 0.0010/0.0006 0.0010/0.0006 0.0009/0.0005 0.0009/0.0004

0.9733/0.9928 0.9203/0.9803 0.8504/0.9581 0.7652/0.9231 0.6317/0.9318

2.06

T = 288.15 K 0 0.45 0.90 1.35 1.79 2.69 1

−3

× × × × ×

10 10−3 10−3 10−3 10−3

× × × × ×

−3

36.06 33.05 29.85 26.45 23.0 18.05 232.45

36.05 36.04 36.04 36.03 36.03 T = 293.15 K

0 0.45 0.90 1.35 1.79 2.69 1

10 10−3 10−3 10−3 10−3

38.55 35.50 32.35 29.05 25.55 20.55 246.30

10−3 10−3 10−3 10−3 10−3

37.50 34.45 31.25 27.95 24.45 19.50 262.25

10−3 10−3 10−3 10−3 10−3

36.48 33.45 30.30 26.95 23.40 18.45 285.05

38.54 38.53 38.52 38.51 38.50 T = 298.15 K

0 0.45 0.90 1.35 1.79 2.69 1

× × × × ×

37.49 37.48 37.47 37.46 37.46 T = 303.15 K

0 0.45 0.90 1.35 1.79 2.69 1 a

× × × × ×

36.47 36.46 36.45 36.44 36.43

Relative standard uncertainties (ur) limits are ur(cmc/cmcid) = ±3%, ur(g) = ±3%, ur(f1Rub/f1Rod) = ±4% and ur(f2Rub/f2Rod) = ±4%.

Please cite this article as: M.A. Rub, Effect of additives on the aggregation phenomena of amphiphilic drug and hydrotrope mixtures, Journal of Molecular Liquids, https://doi.org/10.1016/j.molliq.2019.112049

6 t3:1 t3:2 t3:3 t3:4 t3:5 t3:6 t3:7 t3:8 t3:9 t3:10 t3:11 t3:12 t3:13 t3:14 t3:15 t3:16 t3:17 t3:18 t3:19 t3:20 t3:21 t3:22 t3:23 t3:24 t3:25 t3:26 t3:27 t3:28 t3:29 t3:30 t3:31 t3:32 t3:33 t3:34 t3:35 t3:36

M.A. Rub / Journal of Molecular Liquids xxx (xxxx) xxx

Table 3 The different parameters IPH–NaBez mixed systems in 50 mmol·kg−1 NaBr solutions at different temperature along with concentration.a cmc/mmol∙kg−1

α1

cmcid/mmol∙kg−1

g

f1Rub/f1Rod

f2Rub/f2Rod

ln(cmc1/cmc2)

0.58 0.57 0.56 0.55 0.53 0.52

0.0009/0.0006 0.0010/0.0006 0.0010/0.0005 0.0009/0.0004 0.0008/0.0003

0.9679/0.9993 0.9045/0.9928 0.8197/0.9743 0.7227/0.9501 0.5631/0.9986

1.91

0.6 0.59 0.57 0.56 0.54 0.53

0.0010/0.0007 0.0011/0.0006 0.0010/0.0006 0.0010/0.0005 0.0009/0.0004

0.9702/0.9981 0.9118/0.9922 0.8359/0.9772 0.7454/0.9539 0.5989/0.9984

1.90

0.61 0.60 0.58 0.57 0.55 0.54

0.0009/0.0006 0.0009/0.0005 0.0009/0.0005 0.0008/0.0004 0.0008/0.0003

0.9695/0.9997 0.9050/0.9868 0.8262/0.9726 0.7321/0.9476 0.5779/0.9875

2.01

0.62 0.61 0.59 0.58 0.56 0.55

0.0008/0.0005 0.0008/0.0005 0.0008/0.0004 0.0008/0.0004 0.0007/0.0003

0.9673/0.9975 0.9046/0.9908 0.8235/0.9762 0.7268/0.9503 0.5729/0.9964

2.10

T = 288.15 K 0 0.45 0.90 1.35 1.79 2.69 1

10−3 10−3 10−3 10−3 10−3

33.60 30.45 27.15 23.60 20.05 14.85 225.55

× × × × ×

10−3 10−3 10−3 10−3 10−3

35.80 32.60 29.30 25.80 22.20 17.0 239.40

× × × × ×

−3

10 10−3 10−3 10−3 10−3

× × × × ×

−3

× × × × ×

33.59 33.58 33.57 33.56 33.56 T = 293.15 K

0 0.45 0.90 1.35 1.79 2.69 1

35.79 35.78 35.78 35.77 35.77 T = 298.15 K

0 0.45 0.90 1.35 1.79 2.69 1

34.35 31.25 27.8 24.4 20.85 15.65 255.35

34.34 34.34 34.33 34.32 34.32 T = 303.15 K

0 0.45 0.90 1.35 1.79 2.69 1 a

10 10−3 10−3 10−3 10−3

34.10 30.90 27.60 24.15 20.55 15.35 278.10

34.09 34.08 34.08 34.07 34.06

Relative standard uncertainties (ur) limits are ur(cmc/cmcid) = ±3%, ur(g) = ±3%, ur(f1Rub/f1Rod) = ±4% and ur(f2Rub/f2Rod) = ±4%.

absence of electrolytes. The cmc values also showed that mixed micellization occurred at inferior concentrations. A considerable variation in cmc occurred when the hydrophobicity was enhanced as a result of the interaction between the constituents. The nonideal conditions of the solution mixtures were observed more in the presence of electrolytes compared to the aqueous system, and the nonideality of the conditions were ordered: IPH-NaBez in NaBr N IPH-NaBez in NaCl N IPH-NaBez in water.

Fig. 2. Plots of surface tension against the log [IPH] in aqueous solution at 293.15 K.

3.2. Effect of temperature on the IPH-NaBez system Aqueous as well as non-aqueous solutions can affect the cmc value of the surfactant in a temperature-dependent manner based on hydrophobic and hydrophilic hydrations [1]. Hydrophobic and hydrophilic hydrations of monomeric amphiphiles or solution mixtures are achievable, but in micellar solutions only hydrophilic hydration is possible. Hydrophobic and hydrophilic hydrations decrease as temperature increases [36]. At low temperatures, only hydrophilic dehydration supports the micellization process, while hydrophobic dehydration opposes micellization [1,36]. Accordingly, the extent of both conditions affects cmc values depending on the temperature at which the solution is maintained. The result of temperature on cmc value (or mhc value in the case of NaBez) of single and mixed constituents (IPH-NaBez) in both media conditions are given in Tables 1–3. Nonionic surfactant cmc values were found to decrease as temperature increased because of the hydrophobicity of the monomers also increased with temperature [1]. However, ionic amphiphiles had cmc values with U-shaped behaviors that showed minima as temperature increased [37]. Additionally, a continuous increase in cmc value was reported in the literature with increases in temperature [38]. For the micellization of pure NaBez, the mhc values increased as temperatures increased because hydrophobicity of the monomers decreased as temperatures increased, indicating a second factor contributes to micellization of pure hydrotropes (Tables 1–3). Albeit the IPH used in the present study is cationic, but the cmc values changed with temperature in an unusual manner compared to a common surfactant. Initially, as the temperature increased from 288.15 K to 293.15 K, the cmc value of IPH increased, indicating disorder in the structure of H2O in the presence of the hydrophobic portions, and this phenomenon was larger than the dehydration of the hydrophilic portion (Tables 1–3). However, as the temperature increased from

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293.15 K to 303.15 K, a reduction in cmc value was detected, suggesting dehydration of the hydrophilic portion of IPH monomers was the governing factor in excess of H2O particle disorder in the hydrophobic portion (Tables 1–3). In other words, this particular behavior of IPH was obtained because of the difference in the extent of hydration amongst the saturated hydrocarbon and the aromatic portion of IPH monomers (Scheme 1). We observed a strong release of H2O at higher temperatures from the aromatic portion of the molecule, making the drug additionally hydrophobic and hence, decreased the cmc value. Some other amphiphilic drugs as well as nonionic surfactants have a similar cmc versus temperature curves, further supporting the temperature dependency of these molecules in solution [39,40]. Similar to the drug, the behavior of cmc versus temperature in IPHNaBez mixtures was found to be the same because of the concentration or α1 of NaBez was very low in the aqueous and electrolyte solutions. As a result, NaBez did not have an effect on the cmc-temperature relationship. The presence of salt and NaBez in the IPH solution reduced cmc values. 3.3. Micellar mole fraction of NaBez in mixed IPH-NaBez micelles Amongst the number of procedures that can measure the nonideality in a mixed micellization system, the Holland and Rubingh theory evaluates the micellar mole fraction of constituents in mixed micelles using Eq. (2) [41,42]:
2
 X Rub ln α 1 cmc=X Rub 1 1 cmc1
2 h
 i¼1 cmc2 ln ð1−α 1 Þcmc= 1−X Rub 1−X Rub 1 1

ð2Þ

In Eq. (2) XRub is the micellar mole fraction of the first constituent 1 (i.e., NaBez). The ideal micellar mole fraction (Xid 1 ) of the first constituent (NaBez) was computed using the Eq. (3) [43]. X id 1 ¼

α 1 cmc2 α 1 cmc2 þ α 2 cmc1

ð3Þ

The determined cmc values of the current system were investigated using a different model described by Rodenas [44], which is based on Lange's theory [43]. The micellar mole fractions (XRod 1 ) of the

t4:1 t4:2 t4:3

7

first constituent (NaBez) uses the Rodenas model calculated with the equation: X Rod ¼ −ð1−α 1 Þα 1 1

∂ ln cmc þ α1 ∂α 1

ð4Þ

Table 4 shows that the micellar mole fractions of hydrotropes (NaBez) using both models (XRub and XRod 1 1 ) and the ideal micellar mole fractions (Xid 1 ) were achieved more than the ⍺ 1 in the presence/absence of electrolytes, and their values were enhanced as NaBez concentration increased in the mixtures. This proposes that NaBez contributes to the mixed micelle formation by replacing the IPH monomers to reduce the steric hindrance in the micellar interior, resulting in a decrease in cmc of the system. The values for X1 of NaBez in the current system could be organized in the following Rub order: XRod N XRub N Xid and XRod values were also larger 1 1 1 . The X 1 1 id than X1 , indicating that compared to ideal mixing, the contribution of NaBez was found more in mixed micelles than ideal mixed state. In the presence of electrolytes in solution mixtures, the level of all evaluated micellar mole fractions were increased compared to aqueous systems. The change in micellar mole fractions was due to the reduced coulombic repulsions amongst the mixture constituent head groups from the charge neutralization at the micellar surface. For this reason, electrolytes induced the interaction between the constituents, which resulted in lower cmc values of mixtures and Rub higher XRod and Xid 1 , X1 1 values compared to conditions that did Rub not include electrolytes. The evaluated values of XRod and Xid 1 , X1 1 were higher with NaBr than NaCl, suggesting that NaBr was more effective in reducing the coulombic repulsions between the head groups of NaBez and IPH mixtures. 3.4. Interaction parameter (β) The interaction parameter (β) is a way to evaluate the nature and extent of interactions between constituents that compose solution mixtures. The β values were assessed via using the values of XRub as shown 1 in Eq. (5) [42].
 ln α 1 cmc=X Rub 1 cmc1 β¼
2 1−X Rub 1

ð5Þ

Table 4 Different micellar mole fraction (X1) of NaBez for IPH-NaBez mixed systems at different temperature, media along with concentration.a α1

t4:4

104·Xid 1

Rod XRub 1 /X1

104·Xid 1

288.15 K

Rod XRub 1 /X1

104·Xid 1

293.15 K

Rod XRub 1 /X1

104·Xid 1

298.15 K

Rod XRub 1 /X1

303.15

t4:5 t4:6 t4:7 t4:8 t4:9 t4:10 t4:11 t4:12 t4:13 t4:14 t4:15 t4:16 t4:17 t4:18 t4:19 t4:20 t4:21 t4:22 t4:23 t4:24

IPH-NaBez mixed systems in aqueous solution 0.45 × 10−3 0.72 0.0556/0.0578 0.90 × 10−3 1.45 0.0948/0.1155 1.35 × 10−3 2.17 0.1261/0.1732 1.79 × 10−3 2.89 0.1559/0.2307 2.69 × 10−3 4.34 0.1912/0.3454

0.73 1.46 2.19 2.92 4.38

0.0524/0.0489 0.0913/0.0976 0.1221/0.1463 0.1491/0.1949 0.1841/0.2918

0.67 1.33 2.01 2.66 4.01

0.0540/0.0522 0.0922/0.1043 0.1234/0.1563 0.1512/0.2081 0.1865/0.3117

0.60 1.20 1.79 2.39 3.59

0.0542/0.0560 0.0941/0.1120 0.1251/0.1678 0.1531/0.2235 0.1882/0.3347

IPH-NaBez mixed systems in 50 mmol∙kg−1 NaCl solution 0.45 × 10−3 0.70 0.0591/0.0786 0.90 × 10−3 1.39 0.1004/0.1571 1.35 × 10−3 2.09 0.1353/0.2354 1.79 × 10−3 2.79 0.1659/0.3136 −3 2.69 × 10 4.18 0.2061/0.4696

0.71 1.41 2.11 2.81 4.22

0.0568/0.0668 0.0961/0.1334 0.1291/0.1996 0.1591/0.2664 0.1977/0.3989

0.64 1.28 1.93 2.57 3.85

0.0578/0.0713 0.0979/0.1425 0.1311/0.2135 0.1613/0.2845 0.2005/0.4259

0.58 1.15 1.72 2.30 3.45

0.0585/0.0768 0.0986/0.1534 0.1325/0.2299 0.1635/0.3063 0.2032/0.4587

IPH-NaBez mixed systems in 50 mmol∙kg−1 NaBr solution 0.45 × 10−3 0.67 0.0641/0.0935 0.90 × 10−3 1.34 0.1076/0.1869 −3 1.35 × 10 2.01 0.1448/0.2801 −3 1.79 × 10 2.68 0.1771/0.3731 −3 2.69 × 10 4.01 0.2211/0.5586

0.67 1.34 2.01 2.69 4.03

0.0620/0.0880 0.1040/0.1759 0.1391/0.2635 0.1707/0.3511 0.2128/0.5257

0.61 1.21 1.81 2.42 3.62

0.0622/0.0904 0.1067/0.1806 0.1417/0.2707 0.1735/0.3606 0.2165/0.5399

0.55 1.10 1.65 2.20 3.30

0.0638/0.0920 0.1063/0.1838 0.1419/0.2755 0.1741/0.3670 0.2166/0.5494

t4:25

a

Relative standard uncertainties (ur) limits is ur(X1) = ±3%.

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In any system, the values of β have three possible interpretations: β values can be positive in some systems, indicating antagonistic or repulsive interactions; β can be negative in some systems, which represent synergistic or attractive interactions; and β can be zero, which can also indicate no interactions or ideal mixing between solution constituents. Therefore, the more negative the β values are, the stronger the interaction between the constituents [1]. In our study, β values were negative in both media conditions, suggesting a reduction of electrostatic self-repulsion between IPH drug head groups in the presence of NaBez, further demonstrating that the interactions between the constituents were attractive in nature (Fig. 3). The attractive interactions in all systems studied could be considered “synergistic” if the system includes these given two states [1]: (i) the value of β should always be negative and (ii) the magnitude of β should always be more than the magnitude of ln(cmc1/cmc2) value (i.e. here, cmc1 = mhc). Therefore, both states are observed in our studied systems in almost all cases and as a result, “synergism” can be applied our systems to describe the interactions in aqueous and electrolyte systems (Fig. 3 and Tables 1–3). An increase in the concentration of NaBez in the system promotes negative β values that increased in both system conditions (Fig. 3), indicating that the addition of anionic NaBez hydrotrope ions to cationic drug head groups reduced repulsion between the micellar solution of the drug and caused additional interactions between the constituents. It is clear from Fig. 3 that the addition of electrolytes (NaCl/NaBr) to the aqueous mixtures of IPH and NaBez enhanced the values of β, which showed that their negative value enhanced the interaction between the

ionic head groups due to the increase in ionic strength of the system, and further reduced the already negative β values [45,46]. The β values became more negative in the presence of NaBr compared to NaCl in solution mixtures. 3.5. Activity coefficients Rub The activity coefficients (fRub (IPH)) were evaluated 1 (NaBez), f2 using the Rubingh model for the studied media conditions by substituting interaction parameters and micellar mole fraction values in the Eqs. (6) and (7).

Rub


2  ¼ exp β 1−X Rub 1

ð6Þ

Rub


2  ¼ exp β X Rub 1

ð7Þ

f1

f2

(NaBez) and fRod (IPH) The values of the activity coefficients fRod 1 2 were also evaluated by substituting micellar mole fraction values evaluated by the Rodenas theory in Eqs. (8) and (9): Rod

f1

¼

α1 cmc X Rod 1 cmc1

ð8Þ

Fig. 3. Effect of temperature and NaBez mole fraction (α1) on the β of IPH–NaBez mixed systems in different solvents: (A) aqueous, (B) 50 mmol kg−1 NaCl and (C) 50 mmol kg−1 NaBr.

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M.A. Rub / Journal of Molecular Liquids xxx (xxxx) xxx

ð1−α1 Þcmc  ¼
1−X Rod cmc2 1

9

The analyzed values of both activity coefficients using these theories were less than one, indicating the non-ideal behavior of the studied systems in both media conditions and accordingly, the synergistic interactions between IPH and NaBez happened at the entire mole fraction of NaBez (Tables 1–3). Therefore, the obtained cmcid was less than cmc, β was less than zero, and the activity coefficient was less than one; these results were all in consistent with synergistic interactions between the studied constituents in both studied media systems. The f2 (IPH) values were higher in all cases in comparison to f1 (NaBez). The f1 (NaBez) and f2 (IPH) were reduced in the presence of electrolytes at all studied α1. These results show that non-ideality of solution mixtures were enhanced in the presence of electrolytes (Tables 1–3). Moreover, the non-ideality of solution mixtures increased more with NaBr compared to NaCl in the IPH-NaBez mixed systems.

electrolytes. In an ideal system, the value of Gex becomes zero, while the Gex values in the experimental cases were negative at every α1 of NaBez, which became more negative value as the α1 of NaBez increased in the presence and absence of salts (NaCl/NaBr). These results confirmed that mixed micelles formed by IPH-NaBez mixtures were more stable than their individual constituents. Moreover, mixed micelle stability also increased with increasing NaBez α1 because repulsion decreased and hydrophobic interactions increased between the ionic head groups of IPH, which stabilized the mixed micelles, and this phenomenon is well sustained via their β. The variation in temperature of solution mixtures did not significantly change the values of ΔGex (Fig. 4). In the presence of electrolytes (NaCl/NaBr), the values of ΔGex were more negative in comparison to their aqueous solutions, indicating that the stability of mixed micelles was further increased through salt-dependent ionic strength, which led to a decrease in repulsion [58]. We also found that the values of ΔGex were more negative with NaBr compared to NaCl, suggesting that IPH-NaBez mixed micelles were more stable with NaBr in the solution.

3.6. Degree of dissociation (g)

3.8. Thermodynamics of mixed micelles

Reduced values of conductivity past the cmc point were due to the binding of the counterion through the micelle. For single and mixed micellar solutions, the value of the degree of dissociation (g) was determined from the plots of specific conductance against concentration from the post-micellar and pre-micellar slope ratios in both studied media conditions [47,48]. This method for determining g is commonly used because of its simplicity and accuracy. The thermodynamic parameters depend on the values of degree of dissociation. The experimental values of g for IPH alone and as IPH-NaBez mixtures in both studied media at various temperatures are shown in Tables 1–3. The value of g decreased with the rise in salt concentration [49] and increased with temperature [47,50]. We observed an increase in g in the IPH alone and IPH-NaBez mixed solution systems as the temperature increased, while the value of g decreased in the presence of salts (Tables 1–3). The decrease in g occurred more with NaBr compared to NaCl because bromide ions are big in size and have a small hydrated radius in comparison to chloride ions [51]. The decrease in g values due to the presence of a salt suggests there is a better packing of the associated structure formed by drug molecules. Salt increased the charge density on the micellar surface by increasing the amount of salt anions bound with micelles [52]. We found that the higher the value of cmc, the higher the value of g, indicating that cmc is directly comparable to the g value. Moreover, smaller g values indicate that micellization occurs at lower concentrations. Therefore, the g values for IPH-NaBez mixed systems were lower compared to IPH alone, suggesting that compared to pure IPH, early micellization occurred in drug and hydroptrope mixtures and their values means cmc value of mixtures further decreased as α1 of NaBez in solution mixtures increased, but the values of g for both conditions did not vary too much because of very small α1 of NaBez (Tables 1–3).

Thermodynamic parameters determine the structural as well as situational outcome of mixed micelle formation. To estimate the diverse thermodynamic parameters, we determined the cmc values of individual and mixed IPH-NaBez system was required. The Gibbs free energy of micellization (ΔG0m) for singular constituent and mixed micelles with NaBez in presence/absence of electrolytes were computed with the following equation [1,59,60].

Rod

f2

ð9Þ

3.7. Excess free energy The excess free energy of micellization (Gex) for both models was estimated with the Eqs. (10) and (11) using the activity coefficient and micellar mole fraction parameters that were evaluated with the Rubingh and Rodenas theory [53–57]. h
 i Rub Rub Rub ΔGRub ln f 2 ln f 1 þ 1−X Rub ex ¼ RT X 1 1

ð10Þ

h
 i Rod Rod Rod ln f 2 ΔGRod ln f 1 þ 1−X Rod ex ¼ RT X 1 1

ð11Þ

Fig. 4 shows the values of ΔGRub (Rubingh model) and ΔGRod ex ex (Rodenas model) for the IPH-NaBez system with and without

ΔGom ¼ −ð2−g ÞRT lnX cmc

ð12Þ

In Eq. (12) Xcmc is the cmc computed in mole fraction, R and T has usual meaning. The evaluated values of ΔGom were negative for single and mixtures of constituents in both aqueous and electrolyte systems (Table 5) [61]. These negative values indicate the association phenomena are spontaneous and that this process is thermodynamically stable. The spontaneity of mixed systems increased as the α1 of NaBez in the solution mixtures increased because the negative value of ΔGom enhanced along with the mole fraction of NaBez in aqueous and electrolyte solutions (Table 5). The experimental systems had low α1 of NaBez and therefore, mixed micelles also consistently had lower quantities of NaBez in comparison to IPH, which determined the ΔG0m of solution mixtures are near to that of IPH alone values. The interaction amongst the charged head groups of the constituents accounted for the negative value of ΔGom and their negative value increases because of decrease in degree of dissociation with increased in the α1 of NaBez. As a result, aggregation phenomena are most likely to start at a low cmc value. Temperature did now show any significant effects on ΔGom values the tested media conditions. The values of ΔG0m for pure IPH were in good agreement with those from the literature [17,19,62] and was also comparable with those reported for similar classes of drugs [41,46]. In the mixed systems, the values of ΔG0m were more negative than the ΔG0m value of IPH alone, demonstrating that the association phenomena of mixtures were more spontaneous in these environments. In the presence of electrolytes (NaCl/NaBr), the values of ΔG0m were more negative, suggesting that the system was more spontaneous with salt, which was a result of the enhanced interactions between constituents that form mixed micelles and decreased electrostatic repulsions (Table 5). The magnitude of ΔG0m values for all studied systems was greater with NaBr compared to NaCl, suggesting that the process of micellization and mixed micellization were more spontaneous with NaBr (Table 5). This result illustrates that ΔG0m values follow a similar trend as cmc values in systems that include electrolytes, indicating that the electrolyte which reduces the cmc of studied system more, negative ΔGom value of that system is also found to be more.

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−1 Rod Fig. 4. The variations in ΔGRub NaCl and ex and ΔGex with NaBez mole fraction (α1) in IPH-NaBez mixed systems in different media at different temperatures. (A) aqueous, (B) 50 mmol kg (C) 50 mmol kg−1 NaBr. Filled symbols indicate Rubingh model analysis and open symbols indicate the Rodenas model analysis.

t5:1 t5:2 t5:3 t5:4

Table 5 The thermodynamic parameters (Gibbs free energy (ΔGom/kJ·mol−1), enthalpy (ΔHom/kJ·mol−1) and entropy (ΔSom/JK−1 mol−1)) for IPH–NaBez mixed systems at various temperatures and concentration in different media.a α1

t5:5

ΔGom/ΔHom/ΔSom

ΔGom/ΔHom/ΔSom

ΔGom/ΔHom/ΔSom

ΔGom/ΔHom/ΔSom

288.15 K

293.15 K

298.15 K

303.15 K

t5:6 t5:7 t5:8 t5:9 t5:10 t5:11 t5:12 t5:13 t5:14 t5:15 t5:16 t5:17 t5:18 t5:19 t5:20 t5:21 t5:22 t5:23 t5:24 t5:25 t5:26 t5:27 t5:28

IPH-NaBez mixed systems in aqueous solution 0 −24.23/−12.61/40.33 0.45 × 10−3 −24.85/−14.02/37.57 −3 0.90 × 10 −25.52/−14.97/36.61 1.35 × 10−3 −26.04/−15.95/34.99 −3 1.79 × 10 −26.65/−19.49/24.84 2.69 × 10−3 −27.50/−23.05/15.42

−24.25/−12.95/38.53 −24.68/−14.31/35.37 −25.34/−15.27/34.31 −25.85/−16.28/32.61 −26.58/−20.03/22.34 −27.38/−23.69/12.56

−24.59/5.73/101.69 −25.03/6.20/104.76 −25.52/6.84/108.54 −26.23/7.48/113.07 −26.99/8.67/119.61 −27.83/10.21/127.56

−24.73/5.84/100.83 −25.36/6.36/104.66 −25.88/7.02/108.52 −26.42/7.62/112.29 −27.21/8.83/118.89 −28.27/10.47/127.81

IPH-NaBez mixed systems in 50 mmol∙kg−1 NaCl solution 0 −24.62/−12.89/40.68 0.45 × 10−3 −25.27/−14.01/39.07 0.90 × 10−3 −25.79/−15.87/34.45 1.35 × 10−3 −26.39/−18.63/26.95 1.79 × 10−3 −27.25/−21.18/21.06 2.69 × 10−3 −28.29/−26.32/6.87

−24.64/−13.25/38.85 −25.10/−14.29/36.86 −25.78/−16.31/32.31 −26.34/−19.15/24.53 −27.16/−21.77/18.38 −28.13/−27.05/3.67

−24.98/5.63/102.65 −25.45/6.10/105.83 −26.16/6.82/110.59 −26.74/7.87/116.08 −27.40/9.29/123.07 −28.60/11.55/134.68

−25.12/5.74/101.79 −25.79/6.26/105.75 −26.52/6.99/110.55 −27.13/8.08/116.13 −27.82/9.54/123.24 −29.08/11.86/135.06

IPH-NaBez mixed systems in 50 mmol∙kg−1 NaBr solution 0 −25.21/−12.43/44.37 0.45 × 10−3 −25.73/−13.46/42.56 0.90 × 10−3 −26.30/−15.14/38.73 1.35 × 10−3 −26.98/−17.84/31.72 −3 1.79 × 10 −27.92/−20.66/25.19 −3 2.69 × 10 −29.18/−27.62/5.41

−25.07/−12.67/42.27 −25.57/−13.73/40.37 −26.31/−15.56/36.65 −26.94/−18.33/29.37 −27.85/−21.24/22.54 −29.01/−28.39/2.07

−25.46/4.99/102.14 −25.97/5.53/105.68 −26.76/7.31/114.28 −27.41/6.98/115.36 −28.36/8.27/122.86 −29.60/11.01/136.21

−25.73/5.12/101.76 −26.26/5.68/105.36 −27.04/7.51/113.96 −27.71/7.17/115.06 −28.69/8.49/122.65 −29.96/11.31/136.13

t5:29

a

Relative standard uncertainties (ur) limits is ur(ΔGom), ur(ΔHom), and ur(ΔSom) are ±3%, ±4% and ±5% respectively.

Please cite this article as: M.A. Rub, Effect of additives on the aggregation phenomena of amphiphilic drug and hydrotrope mixtures, Journal of Molecular Liquids, https://doi.org/10.1016/j.molliq.2019.112049

M.A. Rub / Journal of Molecular Liquids xxx (xxxx) xxx 3500

The value of standard enthalpy (ΔH0m) of our experimental aqueous and electrolyte solution systems was estimated with Eq. (13) [63]. ð13Þ

2500

With the values of ΔG0m and ΔH0m calculated, the values of entropy (ΔS0m) were determined using Eq. (14).  o  ΔH m −ΔGom ΔSom ¼ T

NaBeZ -1 (mmol.Kg ) 0 2.49 4.95 7.39 9.80 12.20 14.56 19.23 28.30

3000

ð14Þ

At lower temperature (i.e. 288.15 K and 293.15 K), the values of ΔH0m of IPH alone and in a mixture with NaBez were negative, indicating an exothermic process. However, at temperatures 298.15 K and 303.15 K, these values were positive, which showed that the process can also be endothermic but at higher temperature (Table 5). For negative ΔHom values in any system, London-dispersion forces play a significant role in the association phenomena [64], while positive ΔHom values represent the splitting of ordered H2O into hydrophobic monomers [65]. At 298.15 K and 303.15 K, positive ΔHom values indicated an endothermic process potentially due to dehydration of H2O particles correlated with the tricyclic ring of IPH. Although this unusual behavior of IPH is still not clear (i.e. endothermicity and a reduction in cmc at 298.15 K and 303.15 K), the most probable reason for this behavior is the liberation of H2O particles from the hydrophobic part of the IPH molecule. With the enhanced α1 of NaBez in solution mixtures, the magnitude of ΔHom values increased, showing that the aggregation phenomena in solution mixtures had comparatively less entropy (Table 5). In the presence of an electrolyte, the negative values of ΔHom in IPH-NaBez mixed systems were enhanced at higher mole fractions of NaBez at 288.15 K and 293.15 K, indicating that electrolyte-dependent aggregation is not as entropy driven as that of aqueous systems. The values of ΔSom for micellization of IPH and in IPH-NaBez mixtures were achieved positive at each employed temperature. However, the ΔSom values were much lower at 288.15 K and 293.15 K compared to temperatures of 298.15 K and 303.15 K, which were significantly enhanced approximately eight times in magnitude (Table 5). Clearly, this behavior of IPH was due to its special structure and indicates it is the main component of mixed micelles. Indeed, there was dissimilarity in the hydration level between the saturated and aromatic hydrocarbon segments of the IPH monomers. The high ejection of H2O particles from the aromatic ring of IPH caused random entropy enhancement at upper temperatures and drug hydrophobicity also increased, which initiated a decrease in cmc of the system at elevated temperatures. The IPH ΔSom values were lower with NaBez, which shows that the randomness of the system diminished in the presence of hydrotropes but electrolyte (NaCl/NaBr) did not affect greatly the values of ΔSom of mixed systems (Table 5). 3.9. Fluorescence study The fluorescence spectra of the antidepressant drug IPH with or without the anionic hydrotrope NaBez at different concentrations were recorded (Fig. 5) [66–68]. In an aqueous system, the absorption spectrum of IPH was 245 nm. Usually antidepressant drug have charge-transfer transitions as well as emission from these fluorophores at higher wavelengths compared to those in which absorption takes place. The emission maxima were additionally reliant on the polarity of the neighboring atmosphere of the probe compared to the analogous absorption maxima because the molecule maintains its excited form for longer time compared to the absorbance spectra [69]. The maximum or peak at wavelength 245 nm was indicated as a π-π⁎ transition. The pure IPH demonstrated emission maxima at ~396 nm with a shoulder at ~502 nm (Fig. 5). Different concentrations of NaBez reduced the fluorescence spectra of IPH, suggesting that NaBez concentration promoted

Intensity

ΔH om

  ∂ ln X cmc ¼ −ð2−g ÞRT 2 ∂T

11

2000

1500

1000

500

0 350

400

450

500

Wavelength / nm

550

600

Fig. 5. Fluorescence spectra of IPH excited at 250 nm in the absence/presence of increasing concentrations of NaBez in an aqueous system.

diversity in the possible molecular interactions between constituents at excited states, which could induce molecular reorganization, shifts in energy, and formation of complexes at ground states. The reduced fluorescent intensity therefore occurred due to quenching from the interactions between these constituents and increased polarity of the neighboring environment [70]. 3.10. FT-IR study FT-IR has also been used to investigate the interactions between mixed micelles components [71,72]. Fig. 6 (a) and (b) show the background-subtracted FT-IR spectra of pure IPH and IPH-NaBez equal ratio mixtures in an aqueous system. The frequencies of the headgroups and hydrophobic parts of the amphiphiles provide information on the structural alteration in the micelle monomers [73]. The probable interaction between IPH and NaBez in solution could shift the C\\N stretching, C\\H bending and C\\H stretching frequency of the IPH head group. For pure drug IPH and IPH-NaBez mixtures, we selected the frequency region in between 1200 and 1490 cm−1 (Fig. 6a) to test the effect of NaBez on aliphatic C\\N stretching and C\\H bending in the drug molecule. IPH has the positively charged N atom that is directly connected to three alkyl groups. In the pure IPH spectra, the exposed C\\N stretching occurred at 1212 and 1225 cm−1 and the frequency of C\\H bending occurred at 1468.07 and 1484.94 cm−1. However, in the presence of NaBez, the C\\N bond stretching shifted from 1212 to 1218 cm−1 and 1225–1230 cm−1; while C\\H bond bending shifted from their initial position of 1468.07 and 1484.94 cm−1 to 1474.33 and 1486.87 cm−1 correspondingly. On the contrary, we chose the frequency region of 2900–2970 cm−1 to evaluate the outcome of NaBez on C\\H stretching of drug and their graph is shown in Fig. 6 (b). IPH had C\\H stretching at 2910.10 and 2931.80 cm−1 and this value was moved to 2918.30 and 2943.37 cm−1, respectively, with the addition of NaBez. These shifting of band stretching and bending frequency of the selected IPH functional group of IPH, on addition of NaBez indicates an interaction between these components (IPH and NaBez) [74]. The spectra of NaBez along or mixed with identical ratios of IPH are presented in Fig. 6 (c) and (d). In Fig. 6 (c), the spectra in the frequency range of 1350–1430 cm−1 represents the effect of IPH on C\\O stretching in NaBez. The C\\O bond of NaBez had a strong and broad stretching band at 1399 cm−1, which shifted toward a higher frequency of 1410 cm−1 with the addition of IPH, indicating an interaction between these constituents. Fig. 6 (d) illustrates the spectra of NaBez

Please cite this article as: M.A. Rub, Effect of additives on the aggregation phenomena of amphiphilic drug and hydrotrope mixtures, Journal of Molecular Liquids, https://doi.org/10.1016/j.molliq.2019.112049

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Fig. 6. FT-IR spectra of IPH in the absence/occurrence of NaBez in selected wavenumber regions (cm−1) (a) and (b). The spectra of NaBez in the absence/absence of NaBez in selected wavenumber regions (cm−1) (c) and (d).

and NaBez-IPH mixtures in the frequency range of 1590–1600 cm−1 to test the effect of IPH on C_O stretching band of NaBez. The pure NaBez demonstrated a strong C_O stretching band at 1594.38 cm−1. However, the addition of IPH in solution with NaBez, promoted a shift in this band to a higher frequency (1595.35 cm−1), which indicated an interaction between these components. As a result of these interactions between IPH and NaBez, the frequency changes were small but reproducible [74]. The interaction between NaBez and IPH was further confirmed by the shift in frequency observed more in the C\\O bond rather than C_O bond of NaBez. 4. Conclusions We examined the mixed micellization behavior of the antidepressant drug IPH and the anionic hydrotrope NaBez with low mole fraction in aqueous and electrolyte (NaCl/NaBr) solutions using conductivity and fluorescence techniques at various temperatures. The conductivity measurements on IPH and NaBez mixtures in absence/ presence of salt revealed a synergistic behavior over the entire mole fraction range of the solutions. Additionally, micellar mole fraction (XRod and XRub 1 1 ) values of NaBez were higher than those of NaBez α1 in mixed systems in both studied media. These findings indicate that the involvement of NaBez in mixed micelles is greater than what has been predicted from the α1 of NaBez. Attractive interactions between these constituents occurred in both aqueous and electrolyte solutions as indicated by the considerable deviation of the

experimentally determined cmc from the ideal cmc (cmcid) values. The reduction in cmc values of pure and mixed systems occurred due to the presence of electrolytes, especially more with NaBr compared to NaCl. The negative ΔGom values indicate that the micellization phenomena are thermodynamically possible in both media. The evaluated ΔHom value for IPH-NaBez mixtures were negative at lower temperatures but became positive as temperatures increased. The current studied interactions are of immense importance for biological and pharmaceutical understanding of how hydrotropes like NaBez assist in the delivery of amphiphilic drugs. The decrease in fluorescent intensity of drugs like IPH associated with hydrotropes like NaBez is as a result of their strong binding through a hydrophobic interaction. FT-IR results of pure drug solution and IPH-NaBez mixtures show that change stretching and bending frequencies occur, which confirm the interaction between these constituents. Declaration of competing interest The author has declared that no competing interests exist. Acknowledgements This project was funded by the Deanship of Scientific Research (DSR), King Abdulaziz University, Jeddah, under grant No. (DF-056130-1441). The authors, therefore, gratefully acknowledge DSR technical and financial support.

Please cite this article as: M.A. Rub, Effect of additives on the aggregation phenomena of amphiphilic drug and hydrotrope mixtures, Journal of Molecular Liquids, https://doi.org/10.1016/j.molliq.2019.112049

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Please cite this article as: M.A. Rub, Effect of additives on the aggregation phenomena of amphiphilic drug and hydrotrope mixtures, Journal of Molecular Liquids, https://doi.org/10.1016/j.molliq.2019.112049