Interaction of antipsychotic drug with novel surfactants: Micellization and binding studies

    Interaction of antipsychotic drug with novel surfactants: Micellization and binding studies Naved Azum, Malik Abdul Rub, Abdullah M. Asiri PII: DOI: Reference:

S1004-9541(17)30541-4 doi:10.1016/j.cjche.2017.09.009 CJCHE 926

To appear in: Received date: Revised date: Accepted date:

3 May 2017 24 July 2017 14 September 2017

Please cite this article as: Naved Azum, Malik Abdul Rub, Abdullah M. Asiri, Interaction of antipsychotic drug with novel surfactants: Micellization and binding studies, (2017), doi:10.1016/j.cjche.2017.09.009

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Chemical Engineering Thermodynamics

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Interaction of antipsychotic drug with novel surfactants: micellization

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and binding studies

1

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Naved Azum1,2*, Malik Abdul Rub1,2, Abdullah M. Asiri1,2

Center of Excellence for Advanced Materials Research, King Abdulaziz University, Jeddah

2

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21589, Saudi Arabia

Chemistry Department, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi

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Arabia

*Corresponding author. Tel.: +966 126473648 E-mail address: [email protected]

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ABSTRACT

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The interaction of cationic gemini surfactants (alkanediyl-α,ω-bis(alkyl dimethylammonium

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bromide)) with an antipsychotic drug (chlorpromazine hydrochloride (CPZ)) has been investigated. Various micellar and interfacial parameters have been deliberated by surface

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tension measurement to report the nature of interactions between drug and novel surfactants mixtures. The behavior of mixed systems, their compositions and activities of components have

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been analyzed in the light of Rubingh’s theory. The results indicate synergism in the binary

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mixtures. The binding study between CPZ and surfactants has been done by spectroscopic

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techniques such as UV-visible and fluorescence. The results are discussed in the light of the use of gemini surfactants as promising drug delivery agents for phenothiazine drugs and hence improve their bioavailability.

Keywords: Gemini surfactants; Antipsychotic drug; Chlorpromazine hydrochloride; Mixed micellization

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1. Introduction

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Amphiphiles or surface active compound have both hydrophilic and hydrophobic properties. The amphiphiles have the unique capability of making nano size clusters in solutions,

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known as micelles. The micelles formed by amphiphiles are capable of solubilizing the sparingly

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soluble substances. They are able to modify the interfacial properties of the liquid (non-aqueous or aqueous) in which they are present. Amphiphiles are ubiquitous materials, which exhibit a

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fascinating range of applications in chemical processes, industries, in the formulation of pharmaceuticals, in mineral processing technologies, and in the food processing industries [1-5].

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When amphiphiles present in low concentration, act much as normal electrolytes, but at higher concentrations deviated. The solubility of surfactants in water is low because of the presence of

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the hydrophobic hydrocarbon tail. These compounds when dissolved in a solvent the hydrophobic portion the segregate from the solvent by self-aggregation leading to the formation of micelles. This phenomenon, known as the hydrophobic effect, spontaneously minimizes the unfavorable hydrocarbon-water contacts and increases the entropy of the system. Two or more types of amphiphiles mixed together, to make a mixed micelle. The mixed micelle is a result of self-assembly of different amphiphiles monomers present in a solution. Many applications from household to industrial are associated with mixed micelle because of having great properties of a mixed system in comparison to single [6-17]. In recent times, a new generation of surfactants has been evolved named as gemini or novel surfactants [18-24]. In these novel surfactants, the two conventional surfactants are chemically bonded together by a spacer group (Fig. 1). The spacer may be a flexible or rigid

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ACCEPTED MANUSCRIPT structure [25]. These surfactants have globally concern to solve the environmental problems by preparing ester and amide group gemini surfactants. These surfactants are used in carbon steel

(B) 16-5-16

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(A) 14-5-14

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pipelines in the acidic medium as corrosion inhibitor [26-28].

Fig. 1. Chemical structure of (A) 14-5-14 and (B) 16-5-16.

Noteworthy

among

these

gemini

surfactants,

the

cationic

alkanediyl-α,ω-

bis(alkyldimethylammonium bromide) type, designated m-s-m, where the length of the alkyl tails designated by “m” and s refers to the number of methylene units that make up the alkyl spacer, has received more attention because of their low critical micelle concentration (cmc) values, superior surface activity, higher solubilizing capacity, bio-degradable and non-toxic in nature. The hydrophobic interactions in surfactants are driven by the micellization while the repulsion of charged head groups and hydration are the voluntary. In gemini surfactants two amphiphilic moieties joined by a spacer group, when the spacer is short these moieties are closed to each other. Due to chemical bond connection, the hydrophobic chains interactions enhance; on

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ACCEPTED MANUSCRIPT the other hand, repulsion between the hydrophilic groups reduced. That’s why gemini surfactants are more readily to form aggregates.

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Chlorpromazine (CPZ) is an amphiphilic drug [29, 30], marketed with the name

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Thorazine. It is an antipsychotic drug used to treat psychotic disorders such as schizophrenia. It is also used to treat bipolar disorder, nausea, vomiting, and anxiety before surgery. CPZ is a

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tricyclic amphiphilic compound, which contains hydrophobic part as an amino group (Fig. 2).

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CPZ has anticholinergic, cardiovascular and antihistamine side effects [29, 31] and induces phospholipidosis (accumulation of excessive intracellular phospholipids) [32]. The interaction

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occurs between the negative phosphate oxygen of the lipids found in the body and protonated

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amine group of CPZ.

Fig. 2. Chemical structure of Chlorpromazine hydrochloride (CPZ). To lessen these side effects, phenothiazine drugs are used with a carrier (surfactants, polymers, block co-polymers etc.) [33-41]. Thus, the aim of our study is to interrogate the adsorption and mixed micellization study of cationic amphiphilic drug (CPZ) with gemini 5|Page

ACCEPTED MANUSCRIPT surfactants (alkanediyl-α,ω-bis(alkyldimethylammonium bromide, m-s-m). Such explorations are guided to depict the involvement of the drug monomers in the mixed adsorbed monolayer

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and mixed aggregates [42, 43]. The appropriateness of energetic model for binary systems also

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perceived. Various theoretical models are being used to analyze the data.

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2. Materials and Methods

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2.1. Materials

All chemicals were of analytical grade and employed as obtained without further

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purification. Important information on the resource and purity of the employed chemicals are revealed in Table 1. De-ionized double distilled water (DDW) having specific conductivity (1 to

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2)·10-6 S cm-1 at 298.15 K was consumed throughout the study to prepare the stock solution. Amphiphile solutions were prepared by dissolving accurately weighed quantities of amphiphiles

Table 1

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(drug and gemini surfactants) in requisite volumes of DDW solution for experiments.

Source and purity of the compounds employed in this work. Chemical name

Source

CAS number Mass fraction purity

Analytic methods

Chlorpromazine hydrochloride (CPZ)

Sigma (USA)

69-09-0

≥ 0.98

TLCa

N,N-Dimethylhexadecylamine

Sigma (USA)

112-69-6

0.95

GCb

N,N-Dimethytetradecylamine

Sigma (USA)

112-75-4

≥ 0.95

GCb

1, 5-Dibromopentane

Sigma (USA)

111-24-0

0.97

NA

Ethanol

Sigma (USA)

64-17-5

≥ 0.99

GCb

Ethyl acetate

Sigma (USA)

141-78-6

-

NA

a

Thin-layer chromatography (provided by supplier). bGas chromatography (provided by supplier). 6|Page

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2.2.Synthesis of gemini surfactants (m-s-m)

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The synthesis and purification are the two factors, which are important in its preparation.

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The bis (quaternary ammonium) surfactants were synthesized by adopting the procedure outlined

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in reference [44, 45] and showing in the Fig. 3:

Fig. 3. Protocol for the synthesis of gemini (m-5-m) surfactants (m = 14 for 14-5-14 and m = 16 for 16-5-16). A 1:2.1 equivalent mixture of corresponding 1, 5-dibromo alkane with N, N-dimethyl alkyldecylamines in dry ethanol was refluxed (at 353.15 K) for 48h. Thin-layer chromatography method was employed to check the progress of the reaction. The solvent removed from the reaction mixture under vacuum to obtain the product. The hexane/ethyl acetate mixture was used to re-crystallized the solid and get the product in pure form. The overall yield of the gemini

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ACCEPTED MANUSCRIPT surfactants ranged from 70%-90%. The synthesized gemini surfactants (m-s-m) was checked by HNMR (Table 2) spectroscopy using CDCl3 as a solvent.

HNMR data for gemini surfactants.

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1

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Table 2

δ

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Group

No. of protons

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14-5-14

0.86-0.89

6

1.25-1.35

36

1.58-1.61

4

1.73

8

N-CH2-(CH2)3-CH2-N

2.03-2.07

6

N-CH3

3.38

12

3.51-3.55

8

CH2-(CH2)9-CH3

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(CH2)2-CH2-

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-CH2-(CH2)9

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-CH3

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1

N-CH2

16-5-16

-CH3

0.85-0.90

6

CH2-(CH2)9-CH3

1.26-1.35

44

-CH2-(CH2)9

1.61-1.66

4

(CH2)2-CH2-

1.85

8

N-CH2-(CH2)3-CH2-N

2.07-2.12

6

N-CH3

3.34

12

N-CH2

3.44-3.50

8

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2.3. Surface tension measurements

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The platinum ring detachment technique is used to get the surface tension of CPZ, gemini as well as their binary mixed systems by using Attension tensiometer (Sigma 701, Germany) at

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298.15 K. The temperature of the studied solution was kept constant having error ± 0.1 K by

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frequently circulating thermo stated H2O through a jacketed vessel. The Attension tensiometer work on Du Nouy principle. We have added the different aliquot volume of stock solution to a

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fixed amount of solvent (water) in the vessel. The ethanol flame was used to clean the ring after each set of experiments. The precision of the measurements was around ± 1.0 m Nm–1. The Fig.

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concentration.

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4 represents a relation between measured surface tension and logarithm of surfactant

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Fig. 4. Plots of surface tension (γ) vs. the logarithm of total amphiphile concentration (STotal) of

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binary mixtures at various mole fractions of CPZ (A) CPZ+14-4-14 (B) CPZ+16-5-16

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at 298.15 K.

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2.4. Fluorescence measurements

All fluorescence measurements were performed on Hitachi F-7000 spectrometer. This apparatus is equipped with 150 W Xenon lamp as the excited source. Fluorescence data were collected by using excitation wavelength of 315 nm. We choose the size of both emission and excitation slits 5 nm by using a 10-mm quartz cell for all experiments. 2.5. UV-visible measurements The absorbance of CPZ solution with increasing concentration of surfactants measured by using double beam UV-visible spectrometer (Thermo Scientific, Evolution 300). The double distilled and de-ionized water was used for baseline correction. The temperature was kept constant (298.15 K). Results and Discussion 3.1. Critical micelle concentration 10 | P a g e

ACCEPTED MANUSCRIPT The representative plots of surface tension vs. lg [amphiphile] for binary mixtures are shown in Fig. 4. The cmc values for pure 14-5-14, 16-5-16 and CPZ amphiphiles tally with the earlier

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literature values [44-48]. The drug molecules hardly adjust in the curve area of the micelle

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because the hydrophobic portion of the drug is rigid. It is not easy for the drug molecule to amend in the curve area of micelle because of its rigid hydrophobic part, hence make micelle at

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higher concentration. The hydrophobic interaction is the major driving force of micelle

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formation. At the time of micellization activity, water molecules from the hydration shells in the region of the hydrophobic portions of a monomer, are liberated and entropy increases. The chain

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of the surfactant breaks the water structure around it as a result increase in entropy; therefore, on increasing the chain length of the surfactant molecule the micellization takes place at a lower

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concentration. Hence, the cmc of 16-5-16 is less than that of 14-5-14. Further, it is also clear that the cmc values for all CPZ-14-5-14/16-5-16 mixtures fall in between the cmc values of pure

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components. In mixed geminis-CPZ systems, the cmc values increase with increasing the mole fractions of CPZ. It means gemini formed micelles first and the CPZ molecules penetrate into the gemini micelle and the hydrophobic interactions between the rigid hydrophobic part of CPZ and alkyl chains of the gemini increase. The Clint model [49] can be used to predict the cmc of an ideal mixture (the individual components are non-interacting), where the ideal cmc of mixed amphiphiles is shown by the Eq. (1) 1 𝑐𝑚𝑐ideal

𝛼

= ∑𝑛𝑖 [𝑐𝑚𝑐𝑖 ] 𝑖

(1)

Where αi and cmci are the stoichiometric mole fraction and cmc of ith component in the mixture. The comparison between ideal and non-ideal mixtures can be easily predicted by this model. It is

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ACCEPTED MANUSCRIPT confirmed from (Fig. 5), that experimental values (cmcexp) are lower than that of ideal values (cmcideal), signifies synergistic interaction among components in the mixture. There is a

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hydrophobic interaction between the hydrophobic part of CPZ and the two hydrophobic chains

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of gemini surfactant, hence, aggregation takes place at inferior concentrations in comparison to

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an ideal state.

Fig. 5. Plots of experimental cmc (cmcexp) and ideal cmc (cmcideal) versus mole fraction of CPZ (αCPZ) for (A) CPZ+14-5-14 and (B) CPZ+16-5-16. 3.2 Interaction and interaction parameter (β) 12 | P a g e

ACCEPTED MANUSCRIPT In the light of regular solution theory (RST), the mutual interaction between amphiphiles in the mixed systems leading to nonideality has been evaluated theoretically by Rubingh [50].

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The micelle mole fraction of CPZ (X1), as well as interaction parameter (β), can be calculated

(𝑋1 )2 ln(𝛼1 𝑐𝑚𝑐exp /𝑋1 𝑐𝑚𝑐1 )

(2)

ln(𝛼1 𝑐𝑚𝑐exp /𝑋1 𝑐𝑚𝑐1 ) (1−𝑋1 )2

(3)

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𝛽=

=1

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(1−𝑋1 )2 ln[(1−𝛼1 )𝑐𝑚𝑐exp /(1−𝑋1 )𝑐𝑚𝑐2 ]

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using the following equations:

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The magnitude of interaction operating between components of mixed systems compare to their self-interaction before mixing in akin situations, can be judged by the using a parameter of

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interaction (β). A negative β value shows that the attractive interaction between two different

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amphiphiles (Table 3) because the value of the β is comparative to the free energy of mixing.

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Table 3

Different physicochemical parameters at bulk for CPZ + 14-5-14/16-5-16 mixtures at 298.15 K and pressure p=0.1 MPa.a α1

104 cmcexp /

104 cmcideal /

mol∙kg-1

mol∙kg-1

X1

X1,ideal

–β

f1

f2

CPZ+14-5-14 0.0

1.560

0.1

1.70

1.73

0.018

0.001

2.851

0.0641

0.999

0.3

2.04

2.22

0.070

0.005

3.247

0.0603

0.984

0.5

2.49

3.09

0.141

0.011

3.786

0.0610

0.927

0.7

3.30

5.07

0.219

0.024

4.308

0.0725

0.812

0.9

8.73

14.2

0.281

0.088

3.184

0.1928 13 | P a g e

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145

0.38

0.1

0.24

0.42

0.184

0.0003

10.500

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0.0009

0.701

0.3

0.26

0.55

0.223

0.0011

9.977

0.0024

0.609

0.5

0.36

0.76

0.235

0.0026

8.989

0.0052

0.608

0.7

0.48

1.27

0.272

0.0061

8.991

0.0085

0.514

0.9

0.69

3.74

0.351

10.461

0.012

0.275

1.0

145

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0.0

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CPZ+16-5-16

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0.0232

a

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Standard uncertainties (u) are u(T) = 0.20 K and u(p) = 5 kPa (level of confidence = 0.68). Relative standard uncertainties (ur) are ur(cmcexp / cmcideal) = ±3%, u(X1/ X1,ideal) = ±3%, ur() = ±3%, and ur(f1/ f2) = ±4%.

The strong attraction among components in the mixed systems comes out by the higher

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negative β values while approximately ideal mixing by zero. A positive value indicates that the attractive interaction between amphiphiles is weaker. The strength of interaction between the different molecules, not alone responsible for the existence of synergism in the mixtures of amphiphiles but synergism also depends on the association properties of all amphiphile in the solution. Due to more hydrophobic nature of 16-5-16 compared to 14-5-14, it generates strong synergistic interactions with CPZ as the clear from the more negative value of βav of the 16-516+CPZ system (βav = –9.784). It may be due to longer hydrophobic twin tails of gemini surfactant which interact more favorably with CPZ to form the core of mixed micelles. Similar synergistic effects in m-2-m + CTAB mixtures have been reported by Sood et al. [51]. The mole fraction of component 1 (X1, ideal) in the mixed micelle in an ideal condition can be calculated as: 14 | P a g e

ACCEPTED MANUSCRIPT 𝑋1,ideal =

α1 𝑐𝑚𝑐2

(4)

α1 𝑐𝑚𝑐2 +α2 𝑐𝑚𝑐1

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The values of X1 and X1,ideal are shown in Table 3. The evaluated X1 values are higher than X1,ideal for all mole fractions. It is concluded that the mixed micelle of geminis+CPZ has the large

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involvement of CPZ than in its ideal state. The activity coefficients (f1, f2 ) for present binary

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systems inside the micelle are connected to interaction parameter (β) can be calculated from the

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following equations

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𝑓1 = exp[𝛽(1 − 𝑋1 )2 ] 𝑓2 = exp[𝛽(𝑋1 )2 ]

(5) (6)

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The activity coefficients are thermodynamic quantities without unit and for an ideal solution

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have a unity value. The values greater or lower than one indicates the increase of attractive or

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repulsive interactions. The micellar mole fraction of the CPZ is higher in the mixed systems even in the high concentration of the gemini in the mixtures, as a result, signifying their higher tendency to take part in mixed micellization and well supported by their activity coefficients. The activity coefficients are found to be below 1, indicating non-ideal behavior as well as attractive interaction.

3.3. Mixed monolayer formation In the binary amphiphilic systems, the interfacial composition and interaction parameter between two amphiphiles at the Langmuir monolayer formation was evaluated by using Rosen model [52]. In the case of an ideal monolayer, a negative value of interaction parameter (βS) indicates synergistic while a positive value indicates antagonistic amphiphile-amphiphile interaction. However, for an ideal monolayer, interaction parameter is zero. The 𝑋1𝑆 and βS value 15 | P a g e

ACCEPTED MANUSCRIPT in case of the mixed monolayer at the interfacial surface are evaluated by means of using Eqs. (7) and (8) (7)

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𝑆 /𝑋 𝑆 𝐶 𝑆 ) ln(𝛼1 𝐶exp 1 1

(1−𝑋1𝑆 )2

(8)

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𝛽𝑆 =

=1

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𝑆 /𝑋 𝑆 𝐶 𝑆 ) (𝑋1𝑆 )2 ln(𝛼1 𝐶exp 1 1 𝑆 𝑆 /(1−𝑋 𝑆 )𝐶 𝑆 ] (1−𝑋1 )2 ln[(1−𝛼1 )𝐶exp 1 2

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𝑆 Where 𝑋1𝑆 is mole fraction of CPZ in the total mixed monolayer and𝐶1𝑆 , 𝐶2𝑆 and 𝐶exp are the

molal concentrations in the solution phase of CPZ, 14-5-14/16-5-16 and their mixture,

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respectively, at the mole fraction α1 of CPZ. Equation (7) solved numerically for 𝑋1𝑆 , which is then substituted into Eq (8) to calculate βS. The βS and 𝑋1𝑆 values of mixtures are given in Table

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4. Table 4

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Different physicochemical parameters at interface for CPZ + 14-5-14/16-5-16 mixtures at 298.15 K and pressure p=0.1 MPa.a α1

0.0

𝑆 104 𝐶exp /

𝑆 104𝐶ideal /

mol∙kg-1

mol∙kg-1

𝑋1𝑆

–𝛽 𝑆

𝑓1𝑆

𝑓2𝑆

CPZ+14-5-14

0.473

0.1

0.501

0.525

0.040

4.461

0.027

0.956

0.3

0.641

0.674

0.045

3.174

0.211

0.751

0.5

0.736

0.940

0.151

4.776

0.303

0.303

0.7

1.000

1.550

0.226

5.346

0.618

0.072

0.9

2.850

4.480

0.266

3.836

0.962

0.045

1.0

76.200 CPZ+16-5-16

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0.062

0.1

0.089

0.090

0.007

4.184

0.034

0.959

0.3

0.112

0.120

0.027

4.359

0.118

0.675

0.5

0.155

0.162

0.038

3.935

0.374

0.374

0.7

0.213

0.269

0.136

5.679

0.599

0.062

0.9

0.281

0.802

0.320

9.879

0.905

0.0003

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0.0

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1.0 76.200 a

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Standard uncertainties (u) are u(T) = 0.20 K and u(p) = 5 kPa (level of confidence = 0.68). 𝑆 𝑆 Relative standard uncertainties (ur) are ur(𝐶exp / 𝐶ideal ) = ±3%, u(𝑋1𝑆 ) = ±3% , ur(S) = ±3%, and ur(𝑓1𝑆 / 𝑓2𝑆 ) = ±4%.

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The negative value of βS, indicates synergistic interaction in the mixed monolayer. Higher

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the values of α1 compared to 𝑋1𝑆 indicates more propensities of gemini surfactants to

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preferentially populate the interface as compared to CPZ.

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The activity coefficients 𝑓1𝑆 and 𝑓2𝑆 of the amphiphiles in mixed monolayer are related to βS 𝑓1𝑆 = exp[𝛽 𝑆 (1 − 𝑋1𝑆 )2 ] 𝑓2𝑆 = exp[𝛽 𝑆 (𝑋1𝑆 )2 ]

(9) (10)

From Table 4, it was observed that all the systems exhibit values of activity coefficients less than one, which shows a synergistic effect between components of mixed surfactant systems at the interface. 3.4. Adsorption behavior The surface tension of pure or mixed solution decreases when amphiphiles adsorb at the air-water interface. The breakdown of hydrogen bonds at the surface is responsible for the reduction in surface tension. On increasing the concentration of amphiphiles after the saturation

17 | P a g e

ACCEPTED MANUSCRIPT at the interface, the amphiphilic molecules start to aggregates into nanostructured assemblies called as the micelle. After this association, the surface tension remains constant (Fig. 4). The

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Gibbs adsorption isotherm can be used to calculate the amounts of adsorbed amphiphiles per unit area at various concentrations by the fundamental Gibbs adsorption equation [53] d𝛾

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1

(11)

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𝛤max =– 2.303𝑛𝑅𝑇 lim𝐶→𝑐𝑚𝑐 (dlg𝑚 )

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where R, T and m is the gas constant (8.314 J mol–1 K–1), the temperature in Kelvin and concentration (STotal) in mol kg-1 respectively and n is the number of ionic species whose

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concentration at interface varies with the change in the [amphiphile] in the solution. For CPZ, n is taken as 2, and for geminis n is taken as 3. For mixtures, n is calculated by using the relation n

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= X1n1+X2n2. The surface excess is a measure of the effectiveness of the surfactant adsorption at

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the interface. The packing and tightness of molecules at the interface depends on the value of

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𝛤max , higher value of corresponds to maximum packing and strong tighten surfactant molecules at the interface. The physico-chemical properties like foaming, wetting, and emulsification can be determined by the adsorption effectiveness. The surfactant concentration required to reduce the surface tension by 20 mNm-1 is a useful measure of efficiency a surfactant. It is a negative logarithm of C20 values, pC20 = –lg C20. The pC20 for pure CPZ is lower than the mixtures, indicates that the concentration required to decrease the surface tension of water in 20 mNm-1 is lower in the presence of CPZ (Table 5). Table 5 Interfacial parameters CPZ+ 14-5-14/16-5-16 mixtures at 298.15 K and pressure p = 0.1 MPa.a αCPZ

106 Γmax / mol m–2

Amin / nm2

Aideal / nm2

γcmc / mN m–1

πcmc / mN m–1

pC20

18 | P a g e

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0.7 0.9 1.0

31.937

4.3

38.207

31.793

4.193

38.555

31.445

4.133

38.177

31.823

4

38.282

31.718

3.545

45.32

24.68

2.118

39.174

30.826

5.207

42.251

27.749

5.049

43.728

26.272

4.95

43.193

26.807

4.81

43.604

26.396

4.671

44.056

25.944

4.551

1.280

1.231

1.417

1.171

1.230

1.266

1.311

1.209

1.481

1.121

1.194

1.671

0.994

1.186

1.593

1.042

PT

0.5

38.063

1.297

RI

0.3

4.325

1.239

SC

0.1

30.746

1.339

0.730

2.273

NU

0.0

CPZ+14-5-14 39.254

1.092

1.519

2.263

1.007

1.648

2.238

1.196

1.388

0.5 0.7 0.9 1

1.129 0.951

D

0.3

2.224

1.470

2.104

1.745

1.878

TE

0.1

AC CE P

0

MA

CPZ+16-5-16

45.32 24.68 2.118 1.593 1.042 a Standard uncertainties (u) are u(T) = 0.20 K and u(p) = 5 kPa (level of confidence = 0.68). Relative standard uncertainties (ur) are ur(Γmax) = ±5%, ur(Amin/ Aideal) = ±5%, ur(cmc) = ±2%, ur(πcmc) = ±2% and ur(pC20) = ±3%.

The efficiency increase with increasing length of the gemini surfactant. The values of minimum area per molecule (Amin) for all the studied mixed systems were calculated using Eq 𝐴min = 1018 /(𝑁𝐴 𝛤max )

(12)

Where NA is the Avogadro’s number. Γmax and Amin are expressed in mol m–2 and nm2 units, respectively. Table 5 lists the Γmax and Amin for these systems. The data show that the Γmax of CPZ is more than gemini surfactants. The lower Γmax values in the case of gemini are due to the

19 | P a g e

ACCEPTED MANUSCRIPT fact that these molecules, having two hydrophobic head groups covalently bonded with the help of a spacer and thus occupy more area. Moreover, with the increase in chain length of these

PT

surfactants, the surface area occupied by each molecule increase further and hence 16-5-16 has

RI

less Γmax value in comparison to 14-5-14. The data recorded in Table 5 specify that the CPZ has higher surface adsorption (less Amin), while the adsorption tendency of CPZ molecule in the

SC

binary mixtures decreases. The balance between hydrophilicity and hydrophobicity of a

NU

particular amphiphile is responsible for the surface activity of that surfactant. The adsorbed molecules at solution-air interface occupy more at lower values of the 𝛤max (higher Amin), due to

MA

the lower compactness. The Table 5 data show, the area occupied per molecule in the mixtures is more than those taken by CPZ, confirmed that the interacting components are loosely packed at

TE

D

the interface and their orientation is almost perpendicular to the interface. The obtained outcomes also advocate that the gemini surfactants somewhat engaged in the adsorption on the surface.

AC CE P

Table 5 also lists the ideal mixing values, Aideal, calculated from the equation Aideal = 𝑋1𝑆 A1+𝑋2𝑆 A2

(13)

where 𝑋1𝑆 and 𝑋2𝑆 are the micellar molar fraction of component 1 and 2 at the interface, respectively. We found that the ideal values (Aideal ) in maximum cases are larger than the corresponding experimental values (Amin). It means that there is some van der Waals selfattraction among the hydrophobic parts of gemini molecules before mixing, which decreased upon mixing with CPZ. The areas occupied by the amphiphiles heads are greater than ideal state, as a result of loose monolayer formation by binary mixtures. The difference between the interfacial tension of water (γo) and interfacial tension at cmc (γcmc) is known as surface pressure (πcmc). It is a measure of the effectiveness of interfacial tension reduction. It can be expressed as 20 | P a g e

ACCEPTED MANUSCRIPT 𝜋𝑐𝑚𝑐 = 𝛾𝑜 – 𝛾𝑐𝑚𝑐

(14)

effectiveness of the amphiphiles in lowering the surface tension.

RI

3.5. Thermodynamics of micellization

PT

The πcmc values of mixtures are larger than CPZ (Table 5), indicates a significant reduction in the

SC

The standard Gibbs free energies of micellization and adsorption have been calculated as

NU

per the following equations [54, 55]: 𝑜 ∆𝐺𝑚 = 𝑅𝑇 ln 𝑋𝑐𝑚𝑐 𝜋

MA

𝑜 𝑜 ∆𝐺𝑎𝑑 = ∆𝐺𝑚 − 𝛤𝑐𝑚𝑐

(15)

max

(16)

AC CE P

Table 6

TE

𝑜 values of ∆𝐺𝑚 are given in Table 6.

D

Where Xcmc is the cmc in mole fraction unit obtained from surface tension studies. The calculated

Thermodynamic parameters of CPZ + 14-5-14/16-5-16 mixtures at 298.15 K and pressure p = 0.1 MPa.a αCPZ

o –∆𝐺𝑚 / kJ mol-1

o –∆𝐺ad / kJ mol-1

0.0

31.668

54.619

29.301

0.1

31.455

56.081

29.349

0.127

1.783

0.3

31.004

53.434

26.956

0.523

1.723

0.5

30.512

55.347

30.450

1.133

1.813

0.7

29.812

51.300

25.778

1.812

1.721

0.9

27.402

46.386

22.913

1.594

1.693

𝐺min / kJ mol-1 CPZ+14-5-14

–Δ𝐺ex / kJ mol-1

o o ∆𝐺ad / ∆𝐺𝑚

1.725

21 | P a g e

ACCEPTED MANUSCRIPT 1

20.439

35.932

28.447

1.758

CPZ+16-5-16 77.347

53.623

0.1

36.265

61.667

38.677

0.3

36.107

62.192

43.415

0.5

35.326

57.737

36.109

0.7

34.588

57.967

0.9

33.689

60.967

1

20.439

35.932

3.903

1.700

4.280

1.722 1.634

38.619

4.4113

1.675

46.321

5.904

1.809

SC

4.008

NU

a

2.200

PT

35.151

RI

0.0

28.447

1.757

D

MA

Standard uncertainties (u) are u(T) = 0.20 K, and u(p) = 5 kPa (level of confidence = 0.68). Relative standard uncertainties (ur) are ur(ΔGom) = ±3%, G m ur(ΔGoads) = ±4%, ur(Gmin) = ±4% and ur( ex ) = ±5%.

TE

o The ∆𝐺m are found to be negative for pure amphiphiles as well as mixed amphiphiles,

AC CE P

indicating that the process of micellization is spontaneous. The adsorption process can be o measured as a distribution between the bulk and surface phases. The value of ∆𝐺ad of the

mixtures are more negative than those of pure CPZ, signify that in the attendance of surfactants o molecules are dragged up to the interface more easily. The more negative values of the ∆𝐺ad o than ∆𝐺m confirm that the micellization is secondary in nature as compared to surface

adsorption. Sugihara et al. [56] have projected a thermodynamic quantity, Gmin, for evaluating synergism in mixed systems and given as 𝐺min = 𝐴min 𝛾𝑐𝑚𝑐 𝑁𝐴

(17)

Gmin is considered as the work required for making an interface or the free energy change accompanied by the transition from bulk phase to the interface of the components in the solution. In other words, the lower the value of Gmin, the more thermodynamically stable surface is 22 | P a g e

ACCEPTED MANUSCRIPT formed. The value of Gmin also measures the evaluation of synergism in the mixed systems. It is clear from the Table 6 that the values Gmin are lower in magnitude. It means thermodynamically

PT

stable surfaces are formed with synergistic interaction.

RI

The excess free energy of mixing (ΔGex) can be calculated by using the activity

SC

coefficients by the relation [57]:

(18)

NU

Δ𝐺ex = [𝑋1 ln 𝑓1 + (1 − 𝑋1 )ln𝑓2 ]

The values are given in Table 6. The Δ𝐺ex values are found to be negative confirms that the

formed from pure single amphiphiles.

TE

D

3.6. UV-visible spectroscopy

MA

formed mixed micelles are additional thermodynamically stable in comparison to micelles

The two-adsorption band belongs to a neutral phenothiazine compound, first at 250-265

AC CE P

nm region correspond to the 𝜋 → 𝜋 ∗ transition and second in the longer wavelength range (300320 nm) region attributed to the 𝑛 → 𝜋 ∗ transitions due to the presence of the nitrogen lone pair

5

4

Absorbance

(Fig. 6) [58].

14-5-14

3

2

1

0 250

275

300

325

350

375

400

Wavelength/nm

23 | P a g e

ACCEPTED MANUSCRIPT

5

2

275

300

325

SC

1

0 250

PT

16-5-16

3

RI

Absorbance

4

350

375

400

NU

Wavelength (nm)

MA

Fig. 6. Electronic absorption spectra of pure CPZ in the presence of increasing the concentration of 14-5-14/16-5-16.

D

In our case, the first peak appears at 259 nm and other at 306. The adsorption spectrum

TE

of CPZ has been studied in the presence of increasing equivalents of the surfactants to study the

AC CE P

interactions between CPZ and gemini surfactants. It is important to state here that pure gemini surfactants do not show any peak in the UV-visible spectra. The characteristic peak at 306 nm, which is due to the tricyclic region of CPZ, on the addition of gemini surfactants, the absorption intensity of CPZ decreases, but no shifting occurs. These results indicate that the binding of surfactants with CPZ molecule. In the mixed micellar systems, the gemini surfactants taken by the micelle of CPZ is often insufficient to produce high absorbance. 3.7. Fluorescence quenching To get firm conclusions about the interactions between CPZ and cationic gemini surfactants needs more experimentation. Therefore, we carried out fluorescence measurements by using the same solution prepared for the UV-visible measurements. Fig. 7 show that the addition of gemini surfactants, fluorescence intensity increases with increasing the concentration of gemini surfactants with a slightly red shift of spectra from 458 to 464 nm (14-5-14) and 45824 | P a g e

ACCEPTED MANUSCRIPT 460 nm (16-5-16). The red shift of spectra denotes the binding. The red shift in 14-5-14 is more

PT

than 16-5-16, implies that the binding of 16-5-16 with CPZ is not so strong compared to 14-5-14.

3750

11

14-5-14

SC

3000

Intensity

RI

4500

1

2250

NU

1500

0 350

400

MA

750

450

500

550

600

3500

11

AC CE P

3000

TE

4000

D

Wavelength (nm)

16-5-16

Intensity

2500

1

2000 1500 1000 500

0 350

400

450

500

550

600

Wavelength (nm)

Fig. 7. Fluorescence spectra of pure CPZ at λex = 315 nm in the presence of increasing concentration of 14-5-14/16-5-16.

3.

Conclusions The mixed micellization, spectroscopic and thermodynamic properties of the amphiphilic

drug (CPZ) and cationic novel surfactants (14-5-14 and 16-5-16) has been studied. The cmcs of 25 | P a g e

ACCEPTED MANUSCRIPT the mixed amphiphiles were measured by surface tension measurement. The results suggested that the two components formed mixed micelles and mixed monolayer. The values of

PT

experimental cmc (cmcexp) are lower than ideal (cmcideal) suggested that the mixed micelles

RI

formed due to attractive interactions with greater contribution from CPZ. The spontaneity of the current systems is confirmed by the negative values of the standard free energy of micellization

SC

o (∆𝐺m ). Values of free energies indicate that the process of adsorption at the interface is primary

NU

whereas micellization is secondary. The rapid increase of fluorescence intensity of CPZ with

MA

surfactants is due to strong binding of surfactants with CPZ by a hydrophobic interaction. Acknowledgments

D

Chemistry Department and Centre of Excellence for Advanced Materials Research, King

[1]

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[2]

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TE

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SC

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Graphical Abstract

Fluorescence spectra of pure CPZ in the presence of increasing concentration of gemini surfactant.

34 | P a g e