Ionization and pKa Value – Physicochemical Properties

Ionization and pK_a value

Ionization is an important physiochemical property for a drug molecule. Most of the drugs are either weak acid or base and can exist in either ionized or unionized state. The ionization of the drug depends on its pka and pH. The pka value is important for its pharmacological activity, as it influences both absorption and the passage of the drug through cell membrane. The rate of drug absorption in the biological fluids is not proportional to the concentration of the drug at the absorption site but the concentration of the absorbable form of the drug.

For example, Aspirin in stomach will be more than 99% unionized and hence it gets more readily absorbed in the stomach. Same way, barbituric acid is inactive because it is a strong acid (unionized form). But 5, 5′-disubstituted barbituric acid has CNS depression action as it is weak acid and exist in ionized form.

Using drug pka, the formulation can be adjusted to pH to ensure maximum solubility in water (ionic form) or maximum solubility in non-polar solvent (unionized form).

The pH of a substance can be adjusted to maintain water solubility and complete ionization. For example Phenytoin injection adjusted to pH12 with sodium hydroxide to obtain 99.98% of the drug in ionized form. Tropicamide eye drops, an anticholinergic drug has a pka of 5.2 , and the drug has to be buffered to pH4 to obtain more than 90% ionization.

Those drugs in an ionized form will tend to distribute throughout the body more than the unionized molecule. In general drug pass through the non-polar membranes of capillary walls, cell membranes and blood brain barrier in unionized form. A drug must cross many lipid barriers as it travel to the receptor that is its site of action. Cell membranes contain many ionic species (phospholipid, protein) that can repel/or bind ionic drugs. The ion channel receptor is usually lined with polar functional groups can act in an analogue manner. Ionic drugs are also more hydrated; therefore they are more bulky than non-ionic drugs.

According to the rule of Thumb, the unionized form of drug pass through membranes, but act as ions if ionization possible. A pKa in the range of 6 to 8 would therefore be most advantageous, because the non-ionized species that pass through then lipid membrane have good probability of becoming ionized and active within this pKa range. A high degree of ionization can prevent drugs from being absorbed from the GI tract and thus decreases systemic toxicity. This is advantage for externally applied disinfectant or antibacterial sulfanilamide which is meant to remain in the intestinal tract to fight infection. Therefore, when conducting experiments on drug-receptor binding, protein dissociation must be regulated using buffer.

Ionization also plays an important role in the electrostatic interaction between ionic drugs and ionized protein side chain in cell surface or receptors. The changes in pH may affect the reactivity of acidic and basic groups on the cell surface or within the cell. At isoelectric point, anion and cation in protein exist as Zwitter ions; increasing the pH of the medium will increase the concentration of the anion on the cell thereby increasing the activity of biologically active cation. Similarly decrease in pH, increase the concentration of cation and the activity of anion.