Partitioning & Partition Coefficient: Definition and explanation by Pharma Drama
After solubility, partitioning is probably the most useful behaviour that allows selection of a potential drug candidate. But how is partitioning behaviour actually quantified? Through the partition coefficient! In this snug, we look at why partitioning behaviour is important and how partition coefficients, and log P values, are defined.
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Transcript:
Welcome to Pharma Drama, the channel where we look at the science of healthcare and healthcare products. In this video I want to explain an important, but often misunderstood, concept that is critical to whether a molecule will be a good drug substance or not – partitioning. How a molecule partitions between solvents is often denoted by a log P value. You might have heard of this term but may not know where it derives from. So, if you’re ready to find out, get yourself a beverage and let’s make a start.
The properties of a drug substance will be listed in a pharmacopoeia, and the first three you will usually see are melting point, log P and solubility. The melting point is usually given because it is an easy way to identify a compound – melt it and see if the melting point of your sample is the same as that stated in the pharmacopoeia, but log P and solubility are much more important in giving an indication of how likely the drug substance is to be absorbed following oral administration. I have a separate video where I discuss solubility – the link is in the comments below – because today I want to talk about log P.
When we swallow a medicine, the drug it contains cannot act in the body until (one) it is in solution and (two) it has been absorbed. The relative ease with which a drug substance dissolves is indicated by its solubility (the higher the better) but absorption is more tricky to quantify. Your body is made of cells, and cells are really just bags containing a myriad of biochemical compounds. How do cells manage to keep all their cargo inside themselves? They have an outer layer called a membrane. The membrane is made of special molecules called lipids. We don’t need to worry too much about what membranes are right now, we just need to know that lipid molecules are non-polar. Nearly all the liquid in your body, including that inside cells, is water and water is polar.
Polar and non-polar materials do not mix and if you try and mix them, they will remain as separate phases. To be absorbed into the bloodstream, however, a drug must dissolve in water and then cross multiple cell membranes. To do this, the drug substance must have some affinity for water, but also some affinity for lipid. If a drug substance had total affinity for water and none for lipid, it could never enter the cell membrane, and if it had total affinity for lipids it would never dissolve in water in the first place.
So to understand the likelihood that a drug substance will be able to dissolve in water and cross cell membranes, we need a way to quantify its relative affinity for each. We do this by defining a special term called a partition coefficient. The ‘P’ in log P stands for partition coefficient.
Before I tell you what a partition coefficient actually is, let’s consider first a thought experiment. Imagine I have dissolved some drug substance in water to a known concentration and I add an equal volume of an oil. The oil is not miscible with the water, so will sit on top of the water as a separate phase – you can see that in this mixture of water and olive oil. If you can’t remember whether oil floats on water or water floats on oil, think about the awful images on the TV when an oil tanker runs aground – huge volumes of oil float on the water, which kind of makes the clean up easier but badly affects any birds that land in it. If the drug substance has absolutely no affinity for the oil phase at all, no drug molecules will dissolve in the oil and the concentration of drug in water will remain the same as it was initially. In reality, most drug substances have some affinity for water and some for oil, so if we were to shake the two phases together for a while, some of the drug molecules will transfer, or partition, from the water phase to the oil phase. We will reach a position of equilibrium, where we have a new, lower, concentration of drug in the water phase and a concentration of drug in the oil phase. The relative concentrations in the two phases will be directly proportional to the relative affinities of the drug substance in the two phases. Hence, if we take the ratio of the two concentrations, we will get a constant value. That value is the partition coefficient.
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Because it’s a ratio, we can put the concentration in oil above the concentration in water or vice versa. Which is correct? Mathematically, both are! But we need to have some sort of convention, so we all calculate the same thing. To make life easy, we calculate partition coefficients as the concentration in oil over the concentration in water (oil floats on water remember).
Imagine, for instance, that at the start of our thought experiment we had a concentration of drug in water of ten grams per litre and we add a litre of oil and shake. If, at the end, the drug substance had an equal affinity for water and oil, half the drug molecules would be in the oil and half would remain in the water. The concentration in each phase would then be five grams per litre. Five divided by five is one. Therefore, if we have a partition coefficient of one, it indicates a drug substance has equal affinity for oil and water. If the drug substance had a greater affinity for water than oil, then at the end we might measure a concentration in oil of two grams per litre and in water of eight grams per litre. Our partition coefficient would be nought point two five. Conversely, if the drug had a greater affinity for oil that water, our final concentrations might be eight grams per litre in oil and two grams per litre in water, and our partition coefficient would be four.
Can you see that if our partition coefficient is greater than one then the drug has more affinity for oil than water and if the partition coefficient is less than one the drug has more affinity for water than oil?
To make life easier, usually the log of the partition coefficient is given. That is because the log of one is zero, the log of a number greater than one is positive and the log of a number less than one is negative. Therefore a positive log P value indicates a drug has more affinity for oil than water and a negative log P value indicates a drug has more affinity for water than oil.
So when you see a log P value given for a drug, now you know what it means! It indicates the relative affinity of that drug for either oil or water.
Of course, the use of log P values has some issues. Firstly, although it is easy to measure it doesn’t actually tell you directly how a drug will be absorbed in the body; it’s just a guide as to whether a drug prefers water or oil. The closer the value of log P to zero, the more likely it is the drug will be absorbed OK. Secondly, when we make the measurement in the laboratory we don’t add equal volumes of cell membranes and water – we have to use an oil phase which is a close mimic of cell membranes and that is usually octanol (although other oil phases can be used). Finally, one big issue is where a drug can ionise (we will talk about this in a separate video, but salts often ionise in water) – ionised drugs have zero affinity for oil, and this has the effect of ‘skewing’ the partition coefficient. If we take into account the effect of ionisation, what we calculate is called a distribution coefficient, and again I will talk about that in a separate video.
So, remember that most drug substances will have some affinity for water and some for oil, so when both phases are present a drug will distribute (or partition) between each. The ratio of concentrations in the two phases, assuming equal volumes, is the partition coefficient. To keep the numbers simple, the log of the partition coefficient is usually stated. A negative log P indicates a greater affinity for water and a positive log P indicates a greater affinity for oil.
Right, I hope you found that brief description useful. If you did, please hit the ‘like’ button and consider subscribing – I will be posting many videos explaining fundamental science concepts and if there are any particular topics you’d like me to explain, please leave a comment below. Otherwise, thank you so much for watching, and I’ll see you again soon.
Source: Pharma Drama