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