What is pHmax?

Salt chemistry is pretty complicated, and one of the more abstract concepts to understand is pHmax! Here, Pharma Drama looks at what pHmax is and what changes a salt will undergo on either side of it. This knowledge is super-useful when understanding salt stability! So even though the concept is a little abstract, it’s well worth trying to understand it!

See the video and read the transcript below:

Welcome to Pharma Drama, the channel where we look at the science of healthcare and healthcare products. In this video I’m going to talk about an interesting parameter that is very important to how salts behave in buffered solutions – pHmax. Once you understand what happens at pHmax, you will understand a lot more about salt stability! So, if you’re ready to get to your head around it, get yourself a drink and let’s make a start.

Pharmaceutical salt chemistry is both interesting (well, to me at least!) and complex and as a result I have posted several videos looking in detail at specific aspects of how salts behave. The links to these videos are below. One interesting aspect of drug salts is that their solubility will often increase, relative to the free acid or base, because dissolution results in the generation of either a conjugate acid or base, as I have discussed previously. The conjugate acid or base will change the pH of the solution and, as a consequence, increase the solubility of the salt. The stronger the conjugate acid or base and/or the greater the amount of salt dissolved the greater the change in pH. The change in pH can be quite significant and we should remember this for three reasons; one, because it hugely affects solubility; two, because if we dissolve a salt in a buffer there should be no change in pH (and so no effect on solubility); and three, because were we to cause such a pH change in the body the patient would experience a lot of discomfort (luckily the body is buffered, so this often doesn’t happen, but this then means the improvement in solubility is often not seen in-vivo either!).

In any event, the change in pH changes solubility and if we plot values of solubility versus pH we would see graphs like these for salts of acidic and basic drugs respectively. The plots have quite a peculiar shape; if I consider the plot for an alkali salt for instance, solubility is lowest at low pH values, rises as the pH approaches the pKa of the free acid and reaches a plateau at high pH values. What is going on with the salt that causes this profile, I hear you ask? The answer is, quite a lot!

The low solubility at low pH values is a result of Le Chatelier’s principle; because ionisation of an acidic drug will generate protons, and there are a lot of protons already in solution at low pH, ionisation is prevented. Thus, solubility is at its lowest. As the pH rises, the extent to which the drug can ionise increases – since ions are usually quite soluble in water, more drug molecules are able to dissolve and the solubility increases. In principle solubility should increase exponentially as the pH rises, but in practice there will be other factors (such as solvent-solute interactions) that ultimately limit solubility and that is what causes the plateau.

So that (I hope) explains the shape of the profile. But there is one very important point of the curve that we should talk about – pHmax. This is the pH at which the plateau starts and it’s a very interesting value because of what happens to any excess solid present either side of it. On one side of pHmax any excess solid will be a salt and on the other it will be free acid/base. Now that’s a big concept to get your head around! What is going on?

I think it helps to imagine how the data for a plot like this would be measured experimentally. Firstly, remember that solubility is defined as the concentration of a saturated solution in equilibrium with excess solid. This point will become very important in just a moment. Secondly, to generate the solubility plot we need to measure the solubility of a salt at a number of pH values. We could do this by adding excess salt to a number of solutions of different pH, but imagine you were an efficient scientist and you wanted to measure the solubilities using the least amount of material possible. One way to do this would be to add excess salt to an acidic solution, say pH 1; once equilibrium has been established, the solubility can be measured. That gives the data point for pH 1. Next, you could raise the pH of the solution by adding some base (sodium hydroxide would do), say to pH 2. Again, once equilibrium is established, the solubility can be measured. This is the data point for pH 2. This process can be repeated, adding base to raise pH, and the solubility can be measured at each pH value. We have only used one solution of salt, which is handy in preformulation when not much compound may be available.

So far, so good.

BUT, if we were to analyse the chemical nature of the excess solid as we did the measurements we would find that at low pH values the excess solid is all free acid, and at high pH values the excess solid is all salt! Why is that and when did the change happen? The easiest part of that to answer is the second part; the excess solid converts from free acid to salt at pHmax. Now for the why! Imagine the start of the experiment I just described; we are measuring the solubility at pH 1. When we add some base, every molecule of base added causes a rise in pH. We add sufficient base to get to pH 2 and measure solubility again. We will find that the addition of base always causes a rise in pH, until we get to pHmax. At this particular pH value we will find that as we add base there is no apparent rise in pH – rather, each molecule of base that is added converts one molecule of the excess solid from free acid to salt. Once all the excess solid has been converted to the salt form, addition of further base causes a rise in pH once more. We would see the same conversion if we repeated the experiment in reverse, starting from high pH and adding acid to lower pH; addition of acid will lower pH until we reach pHmax, whereupon each molecule of acid added converts one molecule of excess solid from salt to free acid.

And, you might say to me, do we see the same phenomenon for acidic salts? The answer is, of course, we certainly do! The only difference with acidic salts is that the excess solid will be free base at pH values above pHmax and salt at pH values below pHmax.

And that is all we need to say about pHmax right now. It is, even I accept, an abstract and complex concept! However, it’s super-important to know about it, because it can have a massive influence on the stability of salts. For now though, all I want you to remember is that if there is any solid salt in contact with water, then whether it remains as a salt or converts to the free acid/base will depend on the pH of the solution and which side of the pHmax it lies.

OK, I hope that was helpful and you are inspired to hit the like button and, if you haven’t already, consider subscribing. It really helps the channel. Otherwise, thank you so much for watching and I’ll see you again soon.

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Tags: formulation