Ionisation constant

Preformulation studies ;Ionisation constant

1. Ionisation constant

2. Acids and bases Arrhenius theory of acids and bases: Acids are substances which produce hydrogen ions in solution. Bases are substances which produce hydroxide ions in solution. Bronsted-Lowry Theory of acids and bases: An acid is a proton (hydrogen ion) donor. A base is a proton acceptor. Lewis Theory of acids and bases: An acid is an electron pair acceptor . A base is an electron pair donor

3. Pka value Ionisation constant ( pka ) is a term that describes the tendency of compounds or ions to dissociate and is also known as dissociation constant Whereas pH is simply a measure of the hydrogen ion concentration in a give solution

4. pH solubility profile Acid Base Compounds Increases No change Basic No change Increases Acid No change No change Neutral Increases Increases Amphiphile

5. GI absorption of weakly acidic or basic drugs Unionised form pH at the site of absorption Pka value of the drug Lipid solubility of unionised species

6. pH in different parts of the body Plasma : 7.35-7.45 Buccal cavity : 6.2-7.2 Stomach : 1.0-3.0 Duodenum : 4.8-8.2 Jejunum and ileum : 7.5-8.0 Colon : 7.0-7.5

7. Determination of Pka Potentiometric titration Henderson hasselbalch equation Solubility measurements HPLC techniques Capillary zone electrophoresis Foaming activity UV-VIS spectra

8. Henderson-hasselbalch equation For acidic drugs, pH = pKa + log ([ ionized ]/[unionized]) For basic drugs, pH = pKa - log ([ionized]/[unionized])

9. Derivation of Henderson-hasselbalch equation

10. Importance of pka Effect on kinetic profile Only the unionised form of a drug can partition across biological membranes (providing the unionized form is lipophilic) The ionised form tends to be more water soluble [required for drug administration and distribution in plasma] Effect on lipophilicity When the drug become ionized, this will increase its water solubility because there will be a better solvation by ionic-dipole interaction between ionized drug and water molecule. So, once the drug get ionized it will have lower logP than the unionized from (more polar).

11. Importance of pka Because most drugs are ionizable at different body pH ranges, the % ionization must be taken into consideration when we are about to synthesize or develop certain drug. For Acids: pH < pKa by 2 units, 99% unionised pH > pKa by 2 units, 99% ionised For bases: pH < pKa by 2 units, 99% ionised pH > pKa by 2 units, 99% unionised