pH and Drug Design

Today’s Google Doodle celebrates the Danish biochemist S.P.L. Sørensen (1868-1939) (Figure 1). He came up with the famous pH scale that is taught to high school chemistry students and is an important property to consider when using chemicals. The Doodle is a game which gets you to guess how acidic or basic some common household items are.

google doodle#
Figure 1 S.P.L. Sørensen Google Doodle1

The pH scale varies from 1-14 (Figure 2). A neutral solution (e.g. water) is considered to have pH 7 and any pH lower than 7 is deemed to be an acidic solution and anything more than 7 a basic/alkaline solution. The pH scale is logarithmic so something with a pH of 6 is 10 times more acidic than something with a pH of 7.

pH scale
Figure 2 The pH scale

The average pH of our body is slightly alkaline at pH 7.4, “physiological pH” but it actually varies across different parts of the body:

  • Mouth: pH 6.5-7.5
  • Stomach: pH 1.5-4
  • Intestines: pH 4-7
  • Blood: pH 7.4

This is important in drug design because as the pH environment changes, a drug molecule may undergo chemical changes because of the acidic/basic solution it is in.

If an environment is too acidic, a drug may become “protonated”. Chemists use the term proton/hydrogen interchangeably because a hydrogen ion is by definition a proton as it has lost its single electron to form H+.

An acid is defined as a proton/hydrogen donor, it loses hydrogen atoms to other species. This means any acid present in an environment, say gastric acid in our stomach, may react with the drug, adding a proton to the molecule (Figure 3). This forms a drug salt.

basic drug and acid
Figure 3 A basic drug reacting with an acid to form a protonated salt

Similarly, if an environment is too basic, a drug may become “deprotonated”. Bases react with acidic protons present on the drug molecule and remove them from the drug molecule, again causing it to become a salt (Figure 4). A drug salt will behave differently to the neutral drug and might not get to where it needs to be in the body.

acidic drug and base
Figure 4 An acidic drug reacting with a base/alkali to form a deprotonated salt

Have you ever tried mixing oil and water? They don’t tend to like mixing together very well (Figure 5). This phenomenon is important for how a drug behaves in the body. The neutral form of the drug will typically be happier dissolved in the oil over the water, whereas the protonated/deprotonated salt form of a drug would be happier dissolved in the water.

clear long stem wine glass with yellow liquid
Figure 5 Oil and water do not mixPhoto by Pixabay on

Our body is made up of a mixture of oily and watery (“aqueous”) environments. For example, the outside of our cells is an oily phospholipid membrane whereas the inside and outside of our cells are water-based. A drug needs to be sufficiently oil soluble to be able to cross the cell membrane to get inside the cell (Figure 6).

If the drug has been chemically altered by the acidic/basic environment around it and is in its salt form, it is highly unlikely to cross the cell membrane to get into cells and have the desired effect. This is because salts are much happier dissolved in water. The non-salt version of the drug may well dissolve in water too but it is more likely to also dissolve in oily substances to cross a cellular membrane.

drug absorption pH
Figure 6 Drug form vs cell permeability (i.e. its ability to cross a cell membrane)

There are a number of different ways of administering a drug to a patient (topical creams, intravenous injections, slow-release patches, inhalers etc.) but the preferred method is oral dosing, that is, a tablet you swallow with water. Each delivery method has its own set of advantages and disadvantages. Regarding oral tablets, the drug then needs to bypass the gastrointestinal tract (GIT) (Figure 7) to get to where it needs to be in the body to have its desired biological effect.

Figure 7 Gastrointestinal Tract (GIT)2


The GIT is made up of the mouth, throat, stomach and upper and lower intestines. When the drug first enters the body by mouth, it is in a neutral environment (pH 6.5-7.4). Some of the drug may be absorbed into the lining of our mouths but most of it travels down our throats to our stomach which is relatively much more acidic (pH 1-4).

If we don’t want the drug to be absorbed into the stomach lining, we design our drug such that it contains groups of atoms that will be protonated to form the salt. This means the drug will be happier in the stomach acid than the oily stomach lining. Similarly, it is important to make sure a drug is sufficiently stable to survive this acidic environment and not be broken down by our body’s metabolism processes.

The drug then moves on to the intestines which are relatively more basic than the stomach (pH 4-7). Usually any protonated parts of the drug will be deprotonated again to give the neutral form of the drug and this is where many drugs travel through the oily intestine lining and into the blood (pH 7.4).

As you can see, knowing about pH and how it can affect molecules is very important in drug design. Sørensen’s pH scale is a helpful way of quantitatively measuring how acidic or basic a chemical environment is. Chemists use this to predict how a drug might behave in that environment.

  1. Google homepage, accessed 29th May 2018
  2. Image used under creative commons license using Bing Image Search software

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