Surfactants (surface active agents)

Surfactants (surface active agents) are amphiphilic compounds which have the ability to reduce the surface tension of two phases; liquid and liquid, liquid and gas or liquid and solid.1 It is important to note that not all amphiphiles behave as surfactants, only those with somewhat equilibrated hydrophobic and hydrophilic regions.2 Principally, surfactants are made up of a polar hydrophilic head group and a non-polar hydrocarbon tail. In solution, they gather at the interface and arrange themselves so that the polar head group is in contact with the aqueous phase, and the non-polar hydrophobic chain forms weak bonds with the insoluble phase. At and above the critical micelle concentration (CMC), the interface becomes saturated with surfactant and as a result, micelles form encapsulating the insoluble drug. This in turn enhances stability, and shelf life of liquid formulations hence its widespread use. Pharmaceutical companies currently design and synthesise surfactants, one of the most recent types of novel synthetic surfactants are gemini surfactants.

Since the initial scientific literature on gemini surfactants was published in 1971, there has been growing interest on the design and synthesis of these gemini surfactants; a family of synthetic molecules made up of two identical or different amphiphilic moieties connected by a spacer group near or on the head group.3-7 These surfactants often have lower CMC’s and superior surface-active properties compared to the corresponding conventional surfactants of equal chain length.8-13 Surfactant solutions with lower CMC’s exhibit greater solubilisation and stability at low surfactant concentrations, and are therefore more desirable in the pharmaceutical industry.10 This has further given rise to the extensive study of dimeric and oligomeric surfactants which incorporate two (dimeric) or more (oligomeric) amphiphilic moieties covalently linked by a spacer group.8-10,14 Some dimeric surfactants with short spacer groups exhibit high viscosity at relatively low concentrations compared to their monomeric counterparts which is further amplified by shear-induced viscoelasticity.8,9,11 In essence, the chemical structure, length, hydrophobic or hydrophilic nature, and rigidity or flexibility of the spacer group, along with the associated amphiphiles, play a vital role in determining the properties of solutions, which include the aggregation behaviour, and interfacial characteristics.5,8,11

Oligomeric surfactants have not been studied in detail despite their promising benefits in the formulation of stable colloidal dispersions.10 This is mostly due to their more complex synthesis and purification.15 Since dimeric surfactants possess properties superior to the corresponding monomers, it is theoretically predicted that these properties would be further amplified with an increasing degree of oligomerization, with small spherical micelles forming at low concentrations, and wormlike or threadlike micelles forming at higher concentrations.11,16,17 Oligomeric surfactants can be classed into 4 different types according to their chemical compositions; anionic, cationic, non-ionic and zwitterionic. Polyoxyethylene type surfactants have a wide variety of commercial and industrial applications such as in agro-chemical, cosmetic, household, and therapeutic products.15,18-20 In this investigation, the polyoxyethylene type non-ionic oligomeric surfactant Tyloxapol (4-isooctylpolyoxyethylene phenol formaldehyde polymer) and its monomeric counterpart Triton X-100 were studied. Tyloxapol consists of a maximum of 7 units of Triton X-100 (octoxynol 9), covalently bonded with methylene spacer groups (Scheme 1) and has been used as a formulation ingredient in topical ocular drug delivery and as a nanocarrier of systemic anti-tubercular drugs.19,21,22 Also Zhang et al. has explained the effect of solubilisation and diffusion-based drug transport of potassium naproxenate in Tyloxapol micelles.23 Furthermore, the use of Tyloxapol solely as a polymer has been reported to have mucolytic effects in the treatment of Chronic Obstructive Pulmonary Disease.24 The monomeric version Triton X-100, is also commonly used in the solubilisation of poorly water-soluble compounds for example in household and industrial cleaners.25-27

Although both surfactants are composed of the same monomer units, they show significant differences in their physico-chemical properties.27-29 (solubilising power, CMC, stability, viscosity, shape and size). Tyloxapol has a CMC between a wide range of concentrations (0.0016 nM ??? (27)0.008 and 0.028 mM), as opposed to Triton X-100 which has a much higher CMC (∼0.2mM). This is due to the hydrophobic regions in Tyloxapol having greater thermodynamic preference to the micelle pseudo-phase comparing to these regions in Triton X-100 surfactant, and therefore, lower concentrations of Tyloxapol are required for micelle formation as opposed to Triton X-100.10,27 The solubilisation power of Tyloxapol is reportedly greater than that of Triton X-100. (more examples) Dharaiya et al. reported that Bisphenol solubilised to a higher degree in Tyloxapol micelles compared to Triton X-100 micelles.10 However, there is a lack of reports which describe the differences in solubilisation power of each of the surfactants with water-insoluble drugs. In this study, the solubility and physico-chemical properties of water-insoluble drugs in solution of micelle-forming surfactants; Triton X-100 and its polymeric version, Tyloxapol were measured to investigate the hypothesis that drug solubilisation is improved if the structures of the drug and surfactant are matched. The drugs studied were the non-steroidal anti-inflammatory agents, ibuprofen and indomethacin. It was predicted that ibuprofen would exhibit greater solubility in Triton X-100 than/and Tyloxapol due to the similarities in structure of the hydrophobic regions, whereas indomethacin would exhibit low solubility in water regardless of the surfactant used.

Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) with strong analgesic and anti-pyretic activity. It is currently being used in the treatment of rheumatoid arthritis, menstrual cramps, headaches, toothache, back pain or minor injury and can be found over the counter under the trade name Nurofen in liquid, capsule and tablet forms.30 Indomethacin is also an NSAID, however used to treat more serious anti-inflammatory conditions such as osteoarthristis, rheumatoid arthritis, and gouty arthritis.31 The chemical structures of these drugs as well as the surfactants studied are shown in Scheme 1. Ibuprofen and indomethacin are insoluble in water hence the need for surfactants. Although the pharmacological actions of ibuprofen and indomethacin are similar, their chemical structures vary significantly. Ibuprofen has a molecular weight (MW) of 206.29 g/mol and contains one benzene ring, whilst indomethacin has a MW of 357.79 g/mol and is composed of a benzene ring, indole, and several other functional groups. Both drugs are hydrophobic and therefore insoluble in water. The surfactants, Triton X-100 and Tyloxapol, have hydrophobic isooctyl chains which are mostly similar to ibuprofen, containing one benzene ring and a MW of 191.11 g/mol. Therefore it is expected, according to the hypothesis, that ibuprofen would exhibit greater solubility than indomethacin in both Triton X-100 and Tyloxapol. Ibuprofen has a greater solubility in water than indomethacin however both drugs are hydrophobic and considered insoluble. (should I tabulate this info instead? Eg As below)

Drug Molecular Weight (g/mol) Solubility in water at 25˚C (mg/L)

Ibuprofen 206.29 0.937

Indomethacin 357.79 21

Scheme 1. Chemical structures of a) Triton X-100, b) Tyloxapol, c) ibuprofen, d) indomethacin

2. Materials:

Non-ionic surfactants Triton X-100 and Tyloxapol were purchased from The Dow Chemicals (city, country) and Sigma-Aldrich (Dorset, UK) respectively, and used as received. Anti-inflammatory drugs, ibuprofen (99%) and indomethacin, were supplied from Acros Organics (city, country) and Sigma (city, country) respectively. Methanol was obtained from Fisher Chemical.

Full name then product code, then city and country

3. Methods:

3.1 Quantification of ibuprofen and indomethacin

Each of the drugs ibuprofen and indomethacin were separately dissolved in solvent and diluted to produce a range of concentrations ranging from 0.005 mg/mL to 0.5 mg/mL. The absorbance of the dilutions was measured using UV-Visible spectrometry (PerkinElmer, UK) at a wavelength of 265 nm for ibuprofen solutions, and 360 nm for indomethacin solutions. The absorbance values were plotted against concentration and linear regression analysis was performed with Microsoft Excel 2017. The calibration curve obtained was extrapolated to determine unknown concentrations of drug in samples with varying concentrations of surfactant, and the regression coefficient was used to assess the quality of the calibration curve.

3.2 Assessment of solubility/UV-Visible spectroscopy

Stock solutions of surfactants – Triton X-100 and Tyloxapol – were prepared by dissolving each surfactant in deionised water to produce the following concentrations: 1, 2.5, 5, 10 and 15 % w/w, and allowed to mix for 12 hours on a magnetic stirrer (IKA R010, UK). An excess of 50-100 mg of Ibuprofen and indomethacin were separately added to 1mL of each surfactant at each of the concentrations into microcentrifuge Eppendorf tubes. Samples were rotated at 20 rpm on a rotating wheel (Stuart Biocote, UK) for an incubation period of 3 or 4 days. Samples were then centrifuged (Biofuge Heraeus, Germany) at 13,000 rpm for 15 mins to separate undissolved drug prior to filtering using syringe-driven filters of size 0.22 µm. The supernatant was diluted with methanol and the concentration of each drug determined using absorbance values obtained from UV-Visible spectrophotometry, alongside calibration curves.

3.3 Assessment of particle size/Light Scattering

Samples prepared as above were twice filtered into plastic cuvettes to eliminate dust, and particle diameter was measured using light scattering (Zeta Potential Analyzer, Brookhaven Instruments Corporation) at room temperature (25 ℃) with a refractive index of 1.59.

3.4 Assessment of viscosity/Viscometry

Samples containing ibuprofen and indomethacin in 10 % w/w of Triton X-100 and Tyloxapol separately were prepared and diluted to various concentrations. The relative viscosity of the each solution was measured at 25 ℃ by using Calibrated viscometers ( viscometer x). All measurements were done by keeping the viscometer in a temperature controlled water bath and measuring the flow time in seconds. The kinematic relative viscosity (centi-stokes) of each sample was calculated using Poiseuille’s law and used to determine the reduced and inherent viscosities. Huggins and Kraemers plots were then plotted and extrapolated to obtain the intrinsic viscosity for each solution.

3.5 Statistical analysis

Statistical analysis was performed using Excel 2017. A two-tailed, unpaired Student’s t-test was used to determine statistically significant differences. p<0.05 was considered significant.

4. Results:

4.1 Assessment of solubility

Fig. 1. The influence of surfactant concentration (% w/w) of Tyloxapol and Triton X-100 on the concentration of ibuprofen (mg/mL) in solution. Data points plotted represent the mean of n=8 samples. Error bars indicate the standard deviation of each value and the correlation coefficient is given as R2= 0.98361 for Triton X-100 and R2= 0.98214 for Tyloxapol.

Fig. 1. shows the effects of surfactant concentration on the concentration of ibuprofen and thus gives an indication on the solubility of the drug at each concentration. There is a clear positive correlation as expected, with high correlation coefficients exhibited by both surfactants thus indicating a strong linear relationship, whereby the experimental data is closely related to the linear model. The standard deviations are shown as error bars on each of the data points. It can be noted that there are some samples which exhibited greater deviation about the mean than others, especially those at higher concentrations of surfactant. At low concentrations of each of the surfactants – Tyloxapol and Triton X-100 – the error bars are relatively small, thus indicating low dispersion of data and high reliability, as opposed to those exhibited by samples of Triton X-100 at 10 and 15 % w/w.

The graph clearly shows that samples containing Triton X-100 exhibited greater solubilisation of the ibuprofen drug. The highest solubilisation of ibuprofen was observed to be 50 mg/mL at 15 % w/w of Triton X-100, whereas the highest concentration in Tyloxapol was at approximately half the value (28 mg/mL). This does not correspond to previous literature which stated that the solubilisation is enhanced with an increasing degree of oligomerisation.2,8,10

Should I change Fig 1 & 2 units to make y and x axis match?? For convenience?

Does the MSR have to have the same units?

Fig. 2. The influence of surfactant concentration (% w/w) of Tyloxapol and Triton X-100 on the concentration of indomethacin (mg/mL) in solution. Data points plotted represent the mean of n=8 samples. Error bars indicate the standard deviation of each value and the correlation coefficient is given as R2= 0.97784 for Triton X-100 and R2= 0.9395 for Tyloxapol.

Fig. 2 represent the effects of varying surfactant concentration on the concentration of indomethacin drug solubilised in solution. There is a clear positive correlation exhibited by samples containing each of the surfactants, as expected. Samples containing indomethacin and Triton X-100 demonstrate a strong linear relationship with a correlation coefficient of 0.97784, and are shown to have greater solubilisation of indomethacin as opposed to Tyloxapol. The standard deviations for samples of Triton X-100 can be seen to increase when the concentration of surfactant is increased from 1 to 15 % w/w, with a relatively large deviation of 0.95 at 15 % w/w. Samples at higher concentrations exhibited high viscosity and some appeared to have phase separation, hence the large deviation in the data. Samples containing Tyloxapol and indomethacin also show a strong linear trend with a correlation coefficient of 0.9395, however, the error bars are much smaller in size compared to those of Triton X-100 data points. Finally, the slope of Triton X-100 is steeper than that of Tyloxapol in Fig. 2, thus indicating that there is a greater increase in solubilisation of indomethacin per unit of surfactant.

Referring to Fig. 2, the concentration of indomethacin in Triton X-100 ranges from 0.34 to 6.27 mg/mL, compared to that of Tyloxapol which increases from 0.1 to 2.39 mg/ml. However, the maximum concentration of ibuprofen shown in Fig.1 for Triton X-100 at 15 % w/w is 50.36 mg/ml, and 25.96 mg/ml for Tyloxapol, both of which are much larger. This indicates that ibuprofen exhibited higher solubility in water than indomethacin in water, regardless of which surfactant was used and thus provides evidence for the hypothesis that matching drug and surfactant structure increases solubilisation power. Ibuprofen samples were more viscous than indomethacin samples, and this may have given rise to error in precision when carrying out dilutions before measuring absorbance of samples using UV-vis spectrometry.

In summary, the results represented in Fig.1 and 2 showed that the solubilisation capacity is enhanced if the drug structure matches the surfactant structure, as hypothesised. However, the trends observed also suggest that the solubilisation of drugs is greater for the monomeric surfactant Triton X-100, compared to the oligomeric Tyloxapol. This was not predicted according to previous research.

Fig. 3. Solubilisation capacity of surfactants Tyloxapol and Triton X-100 with two drugs – indomethacin and ibuprofen.

Traditionally, the solubilisation capacity is expressed as the molar solubilisation ratio (MSR) defined as the number of moles of solubilisate per mole of surfactant above the CMC. However, for the purpose of drug formulation, where the amount of material used is of importance, the percentage weight of solubilisate per volume of solubiliser is a more useful unit of expressing the solubilisation capacity. This was obtained from the gradient of the solubilisation curves (Fig. 1 and 2), and was plotted in Fig. 3.

The solubilisation capacity of Triton X-100 is greater than Tyloxapol in both cases of ibuprofen and indomethacin. This does not correspond to literature, as Tyloxapol was expected to exhibit greater solubilisation capacity due to its increasing degree of oligomerisation. Indomethacin exhibited a greater increase in solubilisation from Tyloxapol micelles to Triton X-100 micelles (182 %), compared to ibuprofen (86 %).

Micelle water partition coefficient???

4.2 Assessment of particle size

Drug (mg/mL) Surfactant Concentration of Surfactant (%w/w) Reference mean effective diameter (nm) Mean effective diameter (nm) Standard deviation

Ibuprofen Tyloxapol 1.00 8.90 16.20 0.30

2.50 8.10 19.20 0.10

5.00 7.70 18.90 0.20

10.00 6.70 14.30 0.10

15.00 7.10 11.80 0.20

Triton X-100 1.00 10.70 174.10 20.20

2.50 10.50 364.20 19.20

5.00 11.30 – –

10.00 11.20 – –

15.00 10.40 – –

Table 1. Effective diameter (nm) of ibuprofen samples in each of the surfactants Tyloxapol and Triton X-100. Values represent the mean of n = 10 measurements

Explain why they were viscous and why the results are unreliable and you cant add to data

Stokes einstein relationship to analyse results?

Table 2. Effective diameter (nm) of indomethacin samples in each of the surfactants Tyloxapol and Triton X-100. Values represent the mean of n = 10 measurements

Drug (mg/mL) Surfactant Concentration of Surfactant (%w/w) Reference mean effective diameter (nm) Mean effective diameter (nm) Standard deviation

Indomethacin Tyloxapol 1.00 8.90 8.70 1.40

2.50 8.10 57.00 7.30

5.00 7.70 8.70 0.10

10.00 6.70 8.20 0.10

15.00 7.10 8.90 0.20

Triton X-100 1.00 10.70 14.60 0.50

2.50 10.50 16.00 0.20

5.00 11.30 13.50 0.20

10.00 11.20 12.00 0.10

15.00 10.40 10.40 0.30

T tests

Not sure how to analyse this data other than stating trends observed. Should I do a t test on all the concentration for each combination of drug and surfactant so in total ill have 4 values, one for each combo?

4.3 Assessment of viscosity

Table 3. Intrinsic viscosities of samples containing different surfactants Triton X-100 and Tyloxapol, with or without the drugs ibuprofen or indomethacin. The intrinsic viscosities were calculated from the reduced and inherent viscosities of samples of varying concentrations of surfactant between 0.003 and 0.01 mg/mL.

Surfactant Drug Intrinsic viscosity (mL/g)

Triton X-100 Reference 5.25

Indomethacin 6.98

Ibuprofen 43.2

Tyloxapol Reference 5.34

Indomethacin 5.59

Ibuprofen 10.3

The intrinsic viscosities [η] were obtained from Huggins and Kraemer plotting of the reduced and inherent viscosities, respectively, at varying concentrations of surfactant. These values give an indication of the viscosity of the dissolved macromolecule, which is independent of concentration unlike the reduced and inherent viscosities. Therefore, the intrinsic viscosities can be used to determine the contribution of a solute to the viscosity of the solution.

Table 3 shows that the intrinsic viscosity for each of the surfactants increases as drug is added to the solution. The ‘reference’ solutions contain surfactant alone dissolved in pure water. The table also shows that the intrinsic viscosities of surfactant solutions containing ibuprofen are much higher than the same solutions with indomethacin. In the case of Triton X-100, there is an 723 % increase in the intrinsic viscosity when ibuprofen is added, and a 33 % increase when indomethacin is added to the surfactant solution. The same trend is observed with Tyloxapol samples, however at a much smaller magnitude, with an increase of 93 % when ibuprofen is added, and 5 % when indomethacin is added. Therefore, it can be deduced that both drugs, ibuprofen and indomethacin, contribute to an increase in viscosity, however, ibuprofen has a much larger contribution compared to indomethacin. This is further acknowledged by the large standard deviations in the solubility data obtained from samples containing ibuprofen, compared to those containing indomethacin (Fig. 1 and 2).

Fig. 3. The influence of addition of drug ibuprofen or indomethacin on the viscosity of Triton X-100 surfactant solution.

Label unit for y axis??

Fig. 4. The influence of addition of drug ibuprofen or indomethacin on the viscosity of Tyloxapol surfactant solution.

Fig. 3 and Fig. 4 represent the data in Table 3 to show the difference in intrinsic viscosities of each of the solutions. Fig. 3 shows that the addition of indomethacin does not have a large impact on the viscosity of the solution as opposed to the addition of Triton X-100. Also, it can be seen that both Triton X-100 and Tyloxapol exhibit very similar intrinsic viscosities originally (5.25 and 5.34 respectively). It can be assumed that Tyloxapol has little effect on the viscosity, and this remains fairly constant regardless of the surfactant used, however Triton X-100 has an unpredictable much larger effect on the viscosity of any of these surfactants. Further viscosity studies would need to be carried using a variety of other surfactants and comparing the magnitudes of change in their intrinsic viscosities with the addition of surfactant.

5. Discussion:

5.1 Solubilisation of drugs

The purpose of this study was to investigate the hypothesis that drug solubilisation is enhanced when the structure of the drug is similar to the hydrophobic region of the surfactant. The surfactants used in this investigation were Triton X-100 and its oligomeric version, Tyloxapol. The drug of similar structure studied was ibuprofen, and this was compared to the solubilisation of another NSAID with a very different chemical structure to the surfactants, indomethacin. The structures of each drug and surfactant is represented in Scheme 1 of this report for convenience. The solubilisation capacities of each of the surfactants with each drug was determined from UV-Vis spectrophotometry. The results from Fig. 1-3 showed that ibuprofen exhibited higher solubilisation than indomethacin in both of the surfactants, Triton X-100 and Tyloxapol, thus proving the hypothesis. Fig. 3 illustrates indomethacin exhibiting much lower solubility than ibuprofen in both surfactants, Tyloxapol and Triton X-100. This further acknowledges the hypothesis previously stated as indomethacin has a much larger structure compared ibuprofen, and differs greatly from the hydrophobic region of the surfactants.

For each drug; ibuprofen and indomethacin, the solubilisation is greater in micelle solutions of Triton X-100 compared to Tyloxapol. This suggests that the monomeric counterpart, Triton X-100, has a greater ability to solubilise drugs than the oligomeric surfactant Tyloxapol. On the contrary, previous studies have concluded that dimeric surfactants display superior properties to their conventional monomers. By principle, dimeric surfactants are distinguished from the conventional surfactants due to their lower CMC’s, greater surface-active properties, and enhanced viscoelasticity. In addition, dimeric surfactants appear to have better solubilizing, wetting, and foaming properties than conventional surfactants.2,8,10 Zana et al. reported that extending the dimeric surfactants to oligomeric surfactants would enhance these properties further. For the quaternary ammonium bromide surfactant oligomers investigated by Zana et al. it was found that as the degree of oligomerisation was increased, the CMC decreased, whilst the microviscosity and surface activity increased. Dharaiya et al. investigated the micellar solubilisation of Tyloxapol and its monomer Triton X-100 with the drug Bisphenol A (BPA). It was reported that BPA exhibited greater solubilisation with Tyloxapol than Triton X-100. 10 However, in the same investigation the shape of the Tyloxapol micelles formed were found to be more spherical, compared to Triton X-100 which formed ellipsoidal micelles.10 Since Tyloxapol forms smaller spherical shaped micelles, there is a smaller portion inside the micelles hydrophobic core. Therefore, the solubilising capacity may vary depending on the locus of solubilisation of the solubilisate.32 This in turn is highly dependent on the polarity of the solubilisate, and the hydrophilic and hydrophobic interactions formed between the solubilisate and the surfactant.10,32-35 Therefore, it is understood that the molecular structure of the surfactant as well as the physico-chemical properties such as the shape, size and similarities in structure of the drug and micelle, play vital roles in the solubilisation act.

In the case of the drug BPA, it is assumed that the drug distributes itself in the palisade layer of the micelles, with the polar hydroxyl groups forming hydrogen bonds with the polyoxyethylene chain head groups and the remaining non-polar moiety forming Van Der Waals interactions with the hydrocarbon hydrophobic core.10,32However, in this investigation since both drugs – ibuprofen and indomethacin – are non-polar, it may be assumed that the drugs are mostly situated inside the micelle’s hydrophobic core, and thus a micelle with larger interior space is expected to exhibit higher solubilisation. With this into account, and the understanding that Triton X-100 forms larger micelles than Tyloxapol, it can be presumed that both drugs may exhibit higher solubilisation in Triton X-100 than in Tyloxapol.10 This is further acknowledged by the trends in particle size represented in Table 1 and 2 of this report, where the mean effective diameter of the Triton X-100 micelles encapsulating each of the drugs was much larger than Tyloxapol micelles.

5.2 Effect of drugs on viscosity

The intrinsic viscosities for each of the formulations were calculated and results showed that ibuprofen had a significant effect on the viscosity of the samples. This suggests that the addition of ibuprofen led to an increase in the hydrophobic interactions, thus favouring micelle growth.10 This is in agreement with the large increase in the sizes of the micelles containing ibuprofen shown in Table 1. According to Fig. 3 and 4, Tyloxapol alone exhibited higher viscosity than Triton X-100, however, with the addition of drugs the viscosity of Tyloxapol was remained within a smaller range compared to the viscosity of Triton X-100 which increased by approximately 7 fold. This may be due to the more rigid structure of the Tyloxapol micelle compared to Triton X-100 micelles as Tyloxapol is made of up to 7 monomers of triton X-100 covalently bonded together by spacer groups. For this reason, Tyloxapol is less flexible to form larger micelles upon the addition of drugs.10

5.3 Limitations and future research

The results from the assessment of solubilisation are in agreement with the results obtained from light scattering techniques and viscosity measurements, however, not all the results correspond with literature. For this reason, it would be appropriate to further test this hypothesis and determine the reproducibility of results. One way in which this could be done would be to repeat the same investigation, using different combinations of surfactants and drugs, or to synthesise a new surfactant whose hydrophobic region is identical or similar to an existing drug and compare solubilisation capacities. If the drug exhibits greater solubility in the novel surfactant then the hypothesis can be validated. In addition, the hypothesis could be tested with different types of surfactants, such as cationic or anionic surfactants to help solidify the trends observed in this investigation. Also, a lower range of concentrations of surfactants can be used in future investigations to ensure increase viscosity is lowered and phase separation does not occur.

Results from further investigations could be used to help rule out the effects of other contributing factors such as temperature, and pH and thus enhance the reliability, as well as help to determine truth in the hypothesis. Note: an increase in temperature causes dehydration of the polyoxyethylene hydrophilic head group of the surfactants by breaking some of the hydrogen bonds, thus lowering the CMC and leading to micelle growth.10 This then leads to an increase in the aggregation number and micelle diameter.34 It may be useful to also measure the effects of temperature on micelle size, and viscosity by dynamic light scattering techniques. The results from this can be used to assess whether the increase in micelle size is mostly due to the introduction of drugs, i.e. ibuprofen, or also highly influenced by temperature. Lowering the pH can also lead to micelle growth and increase viscosity of solutions.34 Therefore, it is important to carry out future research in controlled conditions by for example, placing samples into a temperature controlled water bath prior to UV-vis spectrophotometry.

In addition, Small Angle Neutron Spectroscopy (SANS) can be carried out and used alongside DLS results to determine the precise morphology of the micelles formed from each surfactant and enhance the reliability of the results obtained from the light scattering technology used. Although results were precise, they may have not given accurate measurements of the mean effective diameter, as was seen with ibuprofen at higher concentrations of Triton X-100. The use of SANS can be used to determine the size, shape, and aggregation number of the solutions, hence giving an indication of the 3D structure of the micelles formed from each of the surfactants.10

6. Conclusions:

Surfactants are amongst the most widely used products in chemical industry,36,37 and their emerging use in pharmaceutical formulations has led to the extensive research on their mechanisms in solution. This study focuses on the use of gemini and oligomeric surfactants in drug formulations to enhance the solubilisation of water-insoluble drugs. Results from this study suggest that drugs which match the structure of the surfactant used exhibit greater solubilisation capacities. Ibuprofen – a drug with a similar chemical composition to the surfactants, Triton X-100 and Tyloxapol – showed better solubilisation compared to indomethacin – a drug with a relatively different structure, thus providing evidence for the hypothesis. However, another trend observed in this study was that the monomeric surfactant, Triton X-100, exhibited greater solubilisation capacities than its oligomer, Tyloxapol for both drugs – ibuprofen and indomethacin. Recent investigations have shown that surfactant solubilisation capacity is expected to increase as the degree of oligomerisation increases, however, this study has provided evidence against this. Future work should be carried in order to establish and provide further evidence for the original hypothesis regarding solubilisate and surfactant structure, as well as the new finding that the degree of oligomerisation may not have a causal relationship with the extent of solubilisation, and that there may be other important factors which play a vital role in the solubilisation of drugs.

Supplementary information:

Fig. S1. UV calibration curve for ibuprofen with sample absorbance (at 𝛌 = 265 nm) plotted against drug concentration (% w/w). The equation of the line of regression is: A(265 nm) = 1.7206ibuprofen mg/mL – 0.0234 (R2 = 0.98932). Data points plotted were derived from single samples.

Fig. S2. UV calibration curve for indomethacin with sample absorbance (at 𝛌 = 360 nm) plotted against drug concentration (% w/w). The equation of the line of regression is: A(360 nm) = 20.547indomethacin mg/mL = 0.1285 (R2 = 0.99437). Data points plotted were derived from single samples.

What else should I include in supplementary information? 

Acknowledgements:

Abstract:

Purpose. In this study, the relationship between drug and surfactant structure and its influence on solubilisation was investigated for anti-inflammatory agent’s ibuprofen and indomethacin with the surfactant Triton X-100 and its polymeric form Tyloxapol.

Materials and methods. Solubility of each drug at various concentrations of surfactant solution was investigated using UV spectrophotometry, and particle size was examined using light scattering technology.

Results. Results indicated that …

Conclusion.

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