Other Hydrotropes

It's time to admit it - the term "hydrotrope" is now used so indiscriminately by so many different people that it is in danger of being meaningless. After all, "hydrotropic" simply means "turning towards water" so it's not surprising that different people have turned the word to their own use.

In cosmetics, for example, it has become fashionable to add "hydrotropes" to formulations on the grounds that "surfactants" are "bad". In pharma, if a surfactant such as Tween-80 (seen as being pharmacologically safe, though the "ethoxylate scare" is now calling that judgement into question) acts as a reasonable hydrotrope in surfactant mode, but is even better when some modest-sized molecule is included in the formulation, which is the hydrotrope - the Tween-80 or the modest-sized molecule? Another definition of hydrotrope (relevant to cosmetics) has no relationship to solute solubility; the definition is: "A hydrotrope is a substance that improves the solubility of surfactants in water, particularly those systems containing high levels of builders or alkalinity." There is no consistency in use.

Further confusion is provided by the popular term "solubilizer". This term at least has the merit of being clear what the added molecule is supposed to be doing - increasing solubility. The trouble, again, is that a solvent, a surfactant, a small molecule like urea and a complex polymer such as BASF's Soluplus can all increase solubility of difficult-to-dissolve solute. Cyclodextrins can be considered as solubilizers and the ever-trendy dendrimers can also increase solubility of solutes in water.

Those who like further sophistication should be aware that with the aid of scattering (light or neutron) techniques all sorts of interesting "hydrotrope" phenomena can be found. Here are some examples:

• The Kunz group in Regensburg¹ do marvellous work with "surfactant-free microemulsions". These tend to operate near phase boundaries. On one side is separated oil, water, hydrotrope, on the other is a simple co-solution of all three. But near the boundary the oil starts to form nanodrops similar to those of microemulsions. This is all tied up with the Ouzo Effect, which in turn requires that the water and hydrotrope are fully miscible, that the oil and hydrotrope are fully miscible but, of course, that the oil and water are immiscible. There are undoubtedly many interesting opportunities for this form of hydrotropy if that is what you are looking for. In particular it has allowed some "green" formulations of things like mosquitoe repellents².
• The Eastoe group in Bristol³ have been able to show that some "bad surfactants" do form surfactant-like clusters. The interesting question (which isn't answered in that particular paper) is whether those clusters help solubility (as in classic surfactant mode) or hinder it (as shown for small-molecule hydrotropes). An excellent and extensive review of hydrotropy from the same group⁴ is a reminder of how confusing the whole area can be and helps greatly to distinguish between different modes of hydrotropy. The contribution of Practical Hydrotropes to the debate within that review is to emphasise that for many of the small molecules cited the clustering that undoubtedly occurs is not, as tends to be assumed, necessary for but actually harmful to overall solubility
• Astonishingly it has been shown⁵ that one can make stable o/w emulsions with no surfactant if the water has been thoroughly degassed. It is possible to make alcohol-free fragrances using this technique, though degassing water to the required extent is rather difficult/expensive and keeping the water degassed is also a problem. Whether this is connected to the mysterious world of nanobubbles is unclear.

What we all really want is the answer to the question: "What can I add that is safe and cheap (and/or in small quantities) to my water-insoluble solute to get the concentration I require for, e.g., drug delivery?"

The hope is that this section on hydrotropes will help you answer that question for your particular solute by clearing away the confusion. You can ask yourself the following:

• Do I really want to add something like 3M urea, sodium benzoate or niacinamide (all classic small-molecule hydrotropes) to my formulation?
• Do I want to go down the surfactant route, probably gaining solubility in the interfacial region, and perhaps having to add some extra molecules (typically alcohols or other surfactants) to decrease the CMC and increase the overall solubility for minimum total surfactant?
• Do I want a microemulsion?
• Do I want to operate at a boundary of oil (in)solubility?
• Do I just want to use lots of a safe solvent?
• Do I want to use the nano-bubble effect?

Once you know which approach to choose you can then use the appropriate theory - small molecule FST (here), surfactant theory (here), HLD-NAC (Practical Surfactants), HSP or COSMO-RS (use your favourite search engine to find, e.g. HSPiP or COSMOtherm), or get yourself some light/neutron scattering to work on the more interesting boundaries of the subject.

It's not easy to reach the right answer. But it is a lot easier if you keep clear in your mind what mechanism(s) you actually want to apply to achieve your desired result.