Interaction between a Nonsteroidal Anti-inflammatory Drug (Ibuprofen

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B: Biomaterials, Surfactants, and Membranes

The Interaction Between a Non-Steroidal Anti-Inflammatory Drug (Ibuprofen) and Anionic Surfactant AOT and Effect of Salt (NaI) and Hydrotrope (4-4-4) Apensu Dey, Victoria Sandre, Daniel Gerrard Marangoni, and Soumen Ghosh J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/acs.jpcb.8b00687 • Publication Date (Web): 07 Mar 2018 Downloaded from http://pubs.acs.org on March 8, 2018

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The Journal of Physical Chemistry

The Interaction Between a Non-steroidal Anti-inflammatory Drug (Ibuprofen) and Anionic Surfactant AOT and Effect of Salt (NaI) and Hydrotrope (4-4-4) Apensu Dey, Victoria Sandre, Daniel Gerrard Marangoni and Soumen Ghosh* Centre for Surface Science, Physical Chemistry Section, Department of Chemistry, Jadavpur University, Kolkata −700 032, India; E-mail: [email protected]

Department of Chemistry, St. Francis Xavier University, Antigonish, Nova Scotia, B2G 2W5,

Canada *Author for correspondence Abstract Ibuprofen (IBF), 2-(4-isobutylphenyl) propionic acid, is a surface active, common non-steroidal anti-inflammatory drug (NSAID); IBF possesses a high critical micelle concentration (cmc) when compared to conventional surfactants. The interactions of this common NSAID with an anionic surfactant, sodium octyl sulfosuccinate (AOT) were studied by tensiometric, fluorimetric, and calorimetric measurements in order to investigate this system as a possible model drug delivery system for an NSAID like IBF, particularly in a high dose regime for IBF. The interactions between the drug and the surfactant were modelled using a regular solution theory approach in the presence and absence of a model electrolyte (sodium iodide) and a novel nonaromatic,

gemini

hydrotrope,

tetramethylene-1,4-bis(N,N-dimethyl-N-butylammonium

bromide (4-4-4). Both the simple and the hydrotropic electrolyte were shown to have an effect on the solution properties (aggregation parameters, interfacial properties, and thermodynamics of aggregate formation) of the drug-surfactant mixtures, and on the interaction between the drug and the surfactant. Surface charges of all self-assembled systems were estimated from ζ-potential measurements; while density functional theory (DFT) calculations showed the interaction energy

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comparison among all the binary and ternary combinations. All these results were interpreted in terms of how altering the subtle balance of hydrophobic and electrostatic forces can significantly improve the ability of these self-assembled systems to transport drug molecules. 1. Introduction In aqueous solution, certain amphiphilic drugs can self-assemble into small aggregates that possess many similarities to surfactant micelles, due to the presence of a small hydrophobic group like an aromatic ring system1. Surfactants are widely used as emulsifiers, solubilizers, and detergents in diverse applications in the pharmaceutical, chemical, material science and energy industries. Many applications of surfactants take advantage of the innate ability of the micelles and other aggregates thus formed in solubilizing material that are otherwise insoluble in solvent systems. In pharmacology, surfactants have long been used as agents for the transport of drug molecules to target organs, due to their ability to solubilize many water-insoluble drugs.2-3 Surfactant micelles possess a number of advantages as drug carriers including: a) the ability they can solubilize poorly soluble drugs and thus increase their bioavailability; and b) retention in the body (particularly in the blood) providing gradual accumulation in the target organ. The synthesis of new / novel surfactants and the use of mixed micelles of existing surfactants may prove important in improving the effectiveness of drug delivery systems, and reducing the amount and cost of these surfactants used, as well as to reduce their environmental impact. In several cases, amphiphilic mixtures are used to achieve the reduction of surface tension of water which is not possible by a single surfactant; consequently, different types of amphiphilic mixtures are used. In the past thirty years, a number of thorough investigations have been undertaken to study the effectiveness of mixtures of amphiphilic systems (e.g., surfactant-surfactant, surfactant-polymer,


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polymer-polymer, surfactant-drug, drug-drug etc.)4-11 as drug-delivery agents. The development of controlled release systems is an attractive use of this field.12 A perfect controlled release system should have the potential to reach its intended targets and release the drug in awellcontrolled manner. Within this context, the use of surfactant micelles presents some significant advantages over other types of drug carriers, such as polymers and liposomes. Ibuprofen (IBF), 2-(4-isobutylphenyl) propionic acid is a well-known non-steroidal antiinflammatory drug (NSAID) that is used extensively in the management of chronic pain and inflammation11. IBF is also surface active13 with a high critical micelle concentration (180 mM). Previous studies of NSAIDs like IBF have reported on their dissolution properties,14-16 solubility behavior,17 release,18 and other thermodynamic properties16,19 of the drugs. Oral consumption of NSAIDs like IBF, however, can result in a number of deleterious side effects including gastrointestinal aggravation, ulceration, and in some cases, bleeding. Moreover, IBF is a poorly water-soluble drug. However, the sodium salt of ibuprofen used here is anionic in nature and can be easily solubilized in aqueous medium. The molecular architecture of the drug is presented in Scheme 1. The controlled release of IBF can be helpful for a formulation of a drug delivery system particularly in high dose treatments for diseases like rheumatoid arthritis. The use of sorption promoters and surfactants as accelerants are a couple of examples of attempts to help to control the release of IBF to improve bioavailability while reducing its common side effects.11 Given the advantages of surfactant mixtures in surface tension lowering and solubilization over their pure surfactant components, it may be possible for an appropriate mixture of the drug and a surfactant to increase the bioavailability of NSAID.20 A number of studies have shown that certain chemicals in a mixture interact synergistically and induce skin permeation enhancements higher



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than that induced by the individual components.21-23 A wide variety of surfactants have been actively pursued as skin permeation enhancers.23-25 Synergies between chemicals can be exploited to design potent permeation enhancers that overcome the efficacy limitations of single enhancers. Ionic surfactant molecules in particular tend to interact well with keratin in the corneocytes, open up the dense keratin structure and make it more permeable.26 In general, anionic surfactants are more effective than cationic and nonionic surfactants in enhancing skin penetration of target molecules. Anionic materials tend to permeate relatively poorly through stratum corneum upon short-time exposure, but permeation increases with application time.27 These all are the basic causes of choosing anionic surfactant AOT as an enhancer. In the present work, we have performed tensiometric, fluorimetric and calorimetric measurements on the interaction of IBF with an anionic surfactant sodium octyl sulfo succinate (AOT) in the absence and presence of 10 mM NaI and 10 mM tetramethylene-1,4-bis (N,Ndimethyl-N-butylammonium bromide) (4-4-4). The 4-4-4 molecule is treated here as a cationic hydrotrope having a twin shape containing small hydrophobic part28. Hydrotropes are well known solubilization enhancers in the detergent and pharmaceutical industries, and can also have a profound impact on solution properties such as viscosity, conductivity, and surface tension.29 In all cases, presence of the additives has an effect on the micellar and solution properties (aggregation parameters, interfacial properties, and thermodynamics of aggregate formation) of the drug-surfactant mixtures, as well as on the interaction between the drug and the surfactant molecules themselves. All these results are interpreted in terms of the alterations of hydrophobic and electrostatic effects and how they alter the energetics of the micellization and solubilization and how this can impact the use of these systems as controlled release formulations. 2. Experimental


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2.1 Materials All reagents used in this study are given below with their manufacturer and purity. AOT(≥98%), supplied by Aldrich, was used as received. The sodium salt of IBF was the product of TCI with purity(>98%). Pyrene and 1,6-diphenyl-1,3,5-hexatriene (DPH) used as micellar probes in the luminescence

probing

experiments,

were

Aldrich

products

with

a

purity

>98%.

Tris(hydroxymethyl)aminomethane (Tris-buffer) was purchased from Merck. Cetyl pyridinium chloride (CPC, purity = 99%) was received from Sigma. Pyrene was re-crystallized thrice from hexane-water.

2.2 Synthesis of cationic hydrotrope (4-4-4)

1,4-dibromobutane was reacted with a 2.1 molar equivalents of N,N-dimethylbutylamine in acetonitrile. The reaction was refluxed for 48h. Upon cooling, the hydrotrope precipitated out of solution as white crystals and they were collected by filtration. The product was further recrystallized (minimum two times) from an acetone/ethanol mixture. The crystals are then separated by filtration, washed with cold ethyl acetate, and dried in a desiccator. The yield is generally better than 70%.



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2.3 Methods 2.3.1 Tensiometry Tensiometric measurements weretaken with a du Noüy tensiometer (Krüss, Germany) using a platinum ring detachment method. The detailed procedure is available in the literature30,

31

.

During the addition of surfactants, a very small volume change was observed, so the dilution effect could be neglected. The measurements were duplicated to get reproducible results. The determined surface tension (γ) values were accurate within ±0.1 mN m-1.

2.3.2 Isothermal Titration Calorimetry (ITC) A Micro-Cal VP-ITC instrument (Malvern, U.K.) was used for thermometric measurements at the temperature range of 298−323 K. The value of standard enthalpy of micellization, ∆H0m was determined using this technique. Detailed discussion of the procedure is available in literature3032

. The measurements were done at least in triplicate and the reported thermodynamic parameters

represent the average and the standard deviations of the repeated trials. 2.3.3 Fluorimetry Steady-state fluorescence measurements were performed using a Perkin-Elmer LS 55 (USA) fluorescence spectrophotometer with a glass cell of 1 cm path length. The steady-state fluorescence quenching method was used for the determination of mean micelle aggregation number (N). Pyrene was used as a probe. The temperature was maintained at 298 K using Fluorescence Peltier System PTP-1. Details of the technique can be obtained in literature30,33. In all experiments, CPC was used as the quencher and is considered that the probe and the quencher (CPC) are located in the same environment of micelle and dispersed among aqueous and micellar pseudo-phases following Poisson statistics.


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The steady-state anisotropy (rss) were found from the relation34, 35 rss =

IVV − GIVH IVV + 2GI VH

(1)

where IVV and IVH are the emission intensities of the vertically and horizontally polarized components of the probe, respectively. In the expression of G factor, the IVV and IVH are the vertically and horizontally polarized emissions, respectively resulting from horizontally polarized excitation. 2.3.4 Time resolved fluorescence measurements Fluorescence life times were determined from time-resolved intensity decays by the method of time-correlated single-photon counting (TCSPC) using nanosecond diode excitation sources at 355 nm (IBH, UK, nanoLED-17, nanoLED-07), and TBX-04 as the detector,~80 ps instrument response function (IRF)36. All the transients for anisotropy measurements were collected at the wavelength of emission maxima and G factor was calculated from long time tail matching technique. 2.3.5. Dynamic light scattering (DLS) study: DLS measurements were performed with a Nano ZS Zetasizer (Malvern, U.K.) at a 90° scattering angle using a He−Ne laser (λ = 632.8 nm) at 303 K. All of the experimental solutions were filtered two to three times through membrane filters (with a pore size of 0.25µm).

3. Results and discussions 3.1. Critical micelle concentration (cmc) The solubility of IBF in solution was determined via back titration of the sodium salt by HCl.(Fig.1). The pKawas estimated from the pH at half neutralization to be 4.82 which is in reasonable agreement with the literature value 4.4437. The ionization constant is an important 7 ACS Paragon Plus Environment


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physicochemical property of drug molecule in understanding their site of adsorption, distribution to various organs, and elimination.38-40 We checked the pH of drug and surfactant mixture solutions and its values were found to be the same in the solution mixtures, indicating that the ionization of IBF was unaffected in the presence of the second surfactant and the additives. To completely mitigate any effect of the presence of additives might have on the ionization of the IBF, and any concomitant changes it may have on its interactions with other components, we chose to buffer the solutions to a pH ~ 7.6 using a tris-buffer system. The cmc values for the pure amphiphiles and their binary mixtures in the presence and absence of 10 mM NaI salt and 4-4-4 cationic hydrotrope were obtained from the break points in the surface tension-log[total amphiphile] plots, as shown in Fig. 2. The cmc values obtained from these plots are tabulated in Table 1. The values of cmc of pure IBF in the absence and presence of NaI and 4-4-4 are found to be 187.14,31.6 and 60.12 mM respectively whereas those respective values of AOT are 1.87, 0.51, and 1.58 mM. The cmc values of pure IBF and AOT are in good agreement with the literature values.33,41 Table 1 and Fig. 2 show that with an increase of mole fraction of AOT (αAOT), the cmc of the mixed combination decreases. In mixed micelles, the mixed amphiphiles may show either ideal or non-ideal behavior at the cmc. The properties of ideal or non-ideal behavior of mixed micelles of drug with ionic surfactants can be analyzed by applying the pseudo-phase model. If the micelles are regarded to be a macroscopic phase in equilibrium with a solution containing the corresponding monomers, then under the equilibrium condition, the ideality can be decided from Clint’s model42 as:

α 1 =Σ i cmcideal cmc i

(2)


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where αi and cmci are the stoichiometric mole fraction and cmc of ith component under the similar experimental conditions. For the binary drug–surfactant systems, the equation (2) becomes

α α 1 = 1 + 2 cmcideal cmc1 cmc2

(3)

where cmcideal, cmc1 and cmc2 are the cmc values of the mixed micelle, AOT and IBF, confirming with Table 1 respectively, α1 and α2 are the stoichiometric mole fractions of AOT and IBF, respectively. For ideal mixed systems, equation 3 is valid whereas for non-ideal system, there should be deviations from the experimental values. This theory is simple and considered as ideal one where non-interacting nature of individual amphiphiles is expected.We can clearly see in Table 1 that the experimental cmc (cmcexp) values deviate from the ideal cmc values (cmcid) calculated using equation 3, denoting some specific interactions between the surfactants. The cmc values of the mixed systems are indeed lower than those predicted by Clint’s equation, suggesting the formation of mixed micelles of the IBF and the AOT owing to synergistic interactions between them. Drug molecules for reducing the cmc are solubilized in the outer portion of the micellar core, and, hence, this can lead to a both an increase in the hydrophobic effects and a decrease in the electrostatic interactions between charged head groups, leading to a more thermodynamically favourable mixed system. The value of cmcid > cmcexp for aqueous solution containing 0.2 and 0.6 mole fractions of AOT (αAOT = 0.2 and 0.6) and for whole mixed systems in presence of hydrotropes 4-4-4, while, cmcid < cmcexp for the whole solutions of mixed systems in presence of electrolyte NaI and for aqueous solutions of 0.4 and 0.8 mole fractions of AOT (αAOT = 0.4 and 0.8).



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An increase in the values of cmc is observed in Table 1 with an increase in the mole fraction of IBF in the mixtures. This indicates that in the formation of the mixed micelle, drug molecules are penetrating into the micelle formed by AOT, which is consistent with the basic concept of the formation of sorption-promoter interactions. The penetration of drug molecules depends on the nature and polarity of the micellar core and the structure of drug molecules. In case of ionic surfactants, the penetration of the drug molecule into the core is difficult due to electrostatic repulsions between similar charges on the head groups. Here, both the sodium salt of IBF and AOT are anionic in nature; hence, the ionic surfactant shows lower binding affinity. This situation is more pronounced more in the presence of an electrolyte like NaI, therefore, an antagonistic interaction is observed. The long hydrophobic chain of ibuprofen is quite rigid, and hence, we would expect some difficulty in packing these chain into a spherical micelle like a conventional surfactant, and the micelles it does form will be at high surfactant concentrations. .11 As per our earlier discussion, we expect that the mechanism of solubilization consists of surfactant molecules forming micelles and drug molecules penetrate into them, resulting in the cmc of the mixed system is higher with respect to the surfactant, but smaller compared to the cmc of the drug molecule. The drug molecules can reside between the stern layer and shear surface of AOT micelles by the interaction of Na+counter ion present in the stern layer and so in presence of electrolyte, a cmc of IBF decreases due to screening effect. As a result, repulsion decreases between the head groups of the micelle of the salt with respect to aqueous solution. Details can be explained by the Davis and Rideal43 model that was modified by Borwanker and Wanson.44 This interaction becomes less prevalent in the presence of the hydrotrope 4-4-4 with respect to the NaI electrolyte solution due to its lower screening effect than that of the NaI, as 4-


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4-4 acquires some hydrophobicity owing to its small hydrophobic chain comparing with electrolyte solution. 3.2.Surface Tension Measurements The analysis of the energetics of amphiphile adsorption at the air-water interface is important for proper analysis of their physico-chemical physical characteristics. Understanding the mechanism behind surface tension reduction is key to understanding a number of industrial applications that depend upon colloidal dispersions like emulsion, suspension, alloy, and foam formation. The amount of amphiphile adsorbed per unit area of the surface can be calculated with the help of Gibbs adsorption equation. For surfactant mixtures in water, the Gibbs surface excess is related to the surface pressure. Π cmc = γ sol − γ cmc

(4)

where γ sol and γ cmc are surface tensions of pure solvent and solution at cmc respectively. Table 1 shows that the values of Π cmc are maximum for pure AOT and IBF combinations whereas these values are lowest for that combination in presence of hydrotropes. The number of amphiphilic molecules at the air-water interface can be determined from the Gibbs surface excess ( Γmax )4,41,45 Γmax = −

1 2.303nRT

 dγ   d log C   

(5)

where(dγ/dlogC) is the slope of the surface tension-log concentration profile below the cmc region, and R and T are the universal gas constant and absolute temperature respectively. The term n corresponds to the number of cations and anion coadsorbed at the surface; for such system having AOT as an anionic surfactant, the value of n =2, but in the presence of NaI and 4-4-4, containing an excess amount of Na+ in 10 mM NaI and cationic part in 4-4-4, n = 146. Table 1 shows that the values of surface excess of the binary system IBF-AOT in presence of NaI and 11 ACS Paragon Plus Environment


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hydrotrope (4-4-4) are larger than that of pure aqueous solution because the cationic parts of the salt and hydrotropes are present at the adsorption layer which reduces the repulsive force of interaction among the head groups of the system at the interface. Hence, the amount of surfactant adsorbed at the interface becomes high. Γmax is observed to decrease in aqueous solution with an increase in the proportion of surfactant due to the increase of the ionic character of the system; so consequently, repulsive interactions among the head group is increased. In NaI solution, this increase of ionic character is compensated due to the counter ion binding at the adsorption layer and an opposite result is observed. In the presence of hydrotropes, both the hydrophobic and electrostatic interactions are contribute to the change in the interactions presents among the amphiphile and the drug molecule, and a different trend is observed in the number of surfactant molecules adsorbed. From the Γmax values, the minimum area per surfactant molecule, Amin at the air/water interface were obtained from the following, Amin =

1018 N A Γmax

(6)

where NA is Avogadro's number. The Amin values of the mixture are in reverse order. In pure aqueous medium, the Amin values the mixtures are lower than AOT but higher than IBF (Table 1). In the presence of 10 mM NaI and 4-4-4, all the values are more or less constant. Again, the values of Amin of mixed amphiphile in pure aqueous medium are larger than other two systems due to greater electrostatic repulsions between the ionic head groups. The fact that the Amin values of mixed amphiphiles are lower in presence of salt and hydrotropes indicates the mixture molecules are more closely packed at the air-water interface. PC20 =

-logC20

(7)


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C20, the molar concentration of surfactant is required to reduce the surface tension of mixed media by 20 mN m-1. It is also the measurement of the efficiency with which surfactant molecules get adsorbed at the air-water interface.37 Table 1 shows that the values of PC20 do not follow any particular trend in case of AOT-IBF combination, but the values increase for that system in presence of NaI and 4-4-4 denoting higher efficacy of adsorption of amphiphiles at the interface. 3.3. Drug-Surfactant interaction Synthesis of a new surfactant is always a noble work, but from the past few years, it has been already proved that formation of mixed amphiphiles has a large impact due to its property to reduce the amount of used surfactants and its cost as well as to reduce their environmental impact.4-11 If CMC of the mixed drug-surfactant falls between the values of the corresponding pure components, mixed micelles formation is confirmed.47 In the present work, cmcideal>cmcexpt for aqueous solution containing 0.2 and 0.6 mole fractions of AOT and for the mixed system in presence of hydrotopes 4-4-4; so synergistic interaction is present. As cmcideal

Interaction between a Nonsteroidal Anti-inflammatory Drug (Ibuprofen

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