top of page

What Extraction Solvents should I use for Extractable Studies? - Careful it's a trick question.

Hi, this blog entry is a continuation of my previous posts on extractable study design here together with my other blogs.

My last post talked a little about solvent choice around ratio of solvents to samples. In this article I would like to discuss the related topic of solvent selection in extractable studies.

As with all things E&L, there are opinion on this topic but not much in the way of agreement.

This can be a barrier for people new to the topic area as perhaps people are looking for a quick answer before moving on to with their busy lives.

I understand this point of view but asking, “What solvent should I use for extractable studies?” runs the risk of missing the point – An extractable study is an experiment and each experiment should be to test a hypothesis.

This is a fundamental to the scientific method which has been around since 17th century and based on much earlier foundations of science and mathematics. So, before I go too far off track and give a lecture on the history of science let’s return to the point at hand:

What solvent should I choose for my extractables study?

Let look at one potential choice:

I’ll choose a solvent which (substitute here with; my boss / colleague told me to use / I used last time / first one in the solvent cupboard / heard mentioned in guide or blog

Well this one, is an interesting choice! Your boss might be an E&L expert so they might know exactly the right one to use and of course my blogs are excellent!

The more serious answer is you need to carefully consider you choice and be prepared to justify it on the basis of knowledge and understanding.

OK, now we have that out of the way let’s consider what knowledge and understanding are involved here.

The purpose of the solvent in an extractable study must be clearly defined.

Unfortunately, as I have discussed before the term “extractable study” is poorly defined and is used to cover a lot of difference uses. An extractable study might be used to attempt to “de-formulate” a material or it might be used to create a set of targets for a leachable method or it might be used to provide insight into the probability for some (not all) substances within a material to leach into a drug product under the conditions of use of the drug product or indeed a medical device.

All these examples (and a few more) would potentially require a different type of extractable studies and a different solvent choice.

Therefore, the correct response to the question “What solvent should I use?” should respond to with the typical politician’s trick of responding to a question with another question, “What sort of extractable study are you doing?”

Solvents have, like any chemical substance, a range of identifiers and properties which define them. Therefore, in making a selection it is important to consider the ones which are helpful to extractable studies.

Below is a list which comes immediately to mind, but I am sure there are others. I have listed them in an approximate order of importance (at least in my opinion)

A Measurement of Polarity, Log P and Log D

This is my top consideration but one of the more complex. There are many physicochemical descriptors which have been developed which can be correlated to polarity and I have reviewed and read many papers and books devoted to this subject.

For example, I have a 546-page book by Charles M Hansen devoted to the Hansen solubility parameters. Needless to say, it’s a “interesting” read and itself builds on earlier work by Hildebrand and fundamental topics such as thermodynamics and diffusion, but why is it important in E&L?

It’s because it can be reduced to the phrase “Like dissolves, like” this rule of thumb is in stark contrast to the 546 pages by Dr Hansen but it takes us to the same place. Solvents which aid extraction from a polymeric material will need to be able to have solubility for the substances you wish to remove from the material and to promote the diffusion and transport through that material. Parameters which describe a solvent polarity allow you to match a solvent to the material you wish to study and the substance(s) you wish to remove from that material.

The Goldilocks Problem

This leads us to discuss the next point. When conducting an extraction, you do not want to degrade or dissolve the material from which you are extracting. You are seeking only to successfully remove the substances contained within it. So, the solvent must like the children’s story of goldilocks must find this mid-point between too-little and too-much extraction (not porridge!).

This equilibrium of concentrations between different solvents and materials is another key point of understanding and Parameters such as log P and its related descriptor for ionised substances log D are the next topic I shall mention. A major use of Extractable studies are to predict how a drug product formulation might leach substances from a material either during manufacture, storage or use. This prediction will be aided from an understanding of the solvent properties of the drug product formulation. In turn, these drug product formulations have be developed to deliver the API into a patient from knowledge and understanding of transport mechanism within the body. These equilibria are controlled in part by relative solubilities and these relative solubilities ratios are modelled by measurement or prediction described by LogP and LogD which takes two difference polarity solvents (Water and Octanol) and look at the equilibrium concentrations for a given substance.

Thus, selecting a solvent system which is close to the drug product formulation (as described by parameters such as Log P) provides a justification for expecting the extractable study to be a good predictor of likely leachables.

If your aim is not simulation of leachables but rather a more wholesale removal of substances from a material (Exhaustive / Exaggerated Extraction) then the polarity of your extracting solvent is better matched to material and not the drug product. But care must be exercise not to completely dissolve the polymer.

Why not dissolve the material completely you might ask? Well there are good practical reasons to avoid this approach. Once a polymer is fully or partially dissolved in a solvent you are very likely to worsen the likelihood successful of detection extractables since you will being trying to detect trace levels of substances in the presence of large quantity of the polymer, this certainly affects the effectiveness of the analytical equipment and changes the physical characteristics of the solvent extracts such as forming emulsions or gels.

These analytical considerations lead me on to other parameters of importance

Boiling Point

When conducting an extractable experiment, you will need to consider both the method of extraction and the mechanisms for preparation of the analytical sample. Thus, the solvent choice can be very influential here. Boiling point will be a determinant of extraction temperature if you select extraction methods which operate under atmospheric pressure such as reflux or Soxhlet extraction. So if you are extracting in N-methyl pyrrolidone that extraction will be occurring at a temperature of around its boiling point of 202°C compared to a temperature of 39.6°C for dichloromethane.

Thus, the combination of polarity and solvent boiling point (and of course they are intertwined) are very significant. Additional I will add



Purity of selected solvent is another analytical consideration; extractable studies are an exercise in trace analysis. Therefore, extraction solvents are a major obstacle to detection and quantitation particularly if they contain impurities. Both the solvent and its impurities can interfere with successful analysis so solvent selection should not ignore the quality of the solvents and their potential for impurities. This potential is linked to methods of analysis undertaken. Analysis for metals needing a different impurity requirement than an analysis for volatiles, semi-volatiles and non-volatiles.

Well as you can see is not simple! And if you were looking for simple answers today all I can do is offer sympathy. On the flip side, I hope this article has helped you understand the drivers and knowledge which must be considered the next time you think about that question: What solvent shall I use for extractable study?

If you want to continue to discuss this and all things E&L please join my E&L forum (it’s free!). That all for now, these kinds of topics and others will be no doubt be discussed at Conferences and Webinars.

101 views0 comments

Recent Posts

See All


bottom of page