Ph, Solubility, Ionization affecting absorption
a. Physical state:
liquid materials are absorbed better than solids and amorphous solids are absorbed at a faster rate than crystalloids which are absorbed better than colloids. This is because the solid have to disintegrate then only they can absorb.
Example: novobiocin absorb faster if present as amorphous than crystalline form.
Some drugs shows polymorphism (steroids, barbiturates), they are not chemically different, but different in physicochemical properties like m.p, solubility, b.p etc. Metastable polymorphs exhibit greater dissolution and hence better absorption and therapeutic activity than stable polymorphs. Example: methylprednisolone.
b. lipid or water solubility:
Drugs in aqueous solution mix more readily than those in oily solution with the aqueous phase. This is because in the lumen of GIT water is presents. Hence, these types of drugs absorbed faster through it (intercellular).
However, at a surface of a cell, made up of phospholipids, the lipid soluble drugs penetrate in to the cell more rapidly than water soluble drugs (intracellular).
Bile salts are very useful for absorption of fat soluble vitamins and fatty substances. [ bile salts are amphipathic ; they have both polar and non polar portions. Thus, they can form tiny spheres called as micelles, which are 2 – 10 nm in diameter and include 20 – 50 bile salt molecules.
Due to polar portion, bile salt molecules dissolve in intestinal fluid and dietary lipids or drugs can dissolve in non polar central core of micelles. By this form, the fatty acids reach the epithelial of villi]
It is known that mucosal lining of GIT is impermeable to the ionized form of weak acids or bases. Most of the drugs are available as weak acids or weak bases.
The weak base is absorbed at a faster rate from the intestine (pH 7.50 – 8), this is because the basic substances can’t be ionized in basic medium. So the uncharged substances can be passed easily due to its lipid solubility. Similarly, weak acid is absorbed at a faster rate from stomach (pH 1.4 – 2).
But, many uncharged drugs can’t be absorbed or they are insufficiently lipid soluble like aminoglycosides. This is because of occurrence of H – bond which converts the uncharged molecules to hydrophilic.
For ionization of weak base,
BH+ <===> B + H+
By Handerson – Hasselbach equation,
pH = pKa + log10 [B]/[BH+]
pKa = pH + log10[BH+]/[B]
For weak acid,
AH <===> A- + H+
pKa = pH + log10[AH]/[A-]
Now suppose for basic drug ( same for weak acids ), no. of dissociate and no. of undissociate drugs conc. is same, then [BH+]/[B] = 1 . So, in this case pH = pKa.
Hence, when pH is equal to pKa, the drug is ionized halfly.
If pH is decreasing only by 1,
log10[BH+]/[B] = 1 or [BH+]/[B] = 10
If pH is increasing only by 1,
[BH+]/[B] = 1/10
Ionization of drug effects not only the rate at which the drug permeate membrane but also steady state distribution of drug between the body compartments, if pH difference is present between them.
If we assume that the unionized species can absorb through the cell membrane, then the drug being concentrated in some suitable pH like acidic drugs are concentrated more in acidic pH (the unionized drug crosses the gastric mucosa and converted to ionize species and passes slowly through cell membrane, called as ion trapping).
If there is large pH difference between two compartments then ion trapping is very common. Example: drugs like aspirin (weak acid) can cause ulcer by this phenomenon only. So, the drugs which favours gastric
emptying can enhance the absorption of aspirin from ileum due to large surface area than stomach, despite the fact that the acidic pH of stomach helps to absorb weak acid.
This is because, conc. gradient can’t be established between two compartments ever. The charge ions can also cross the cell membrane and compartment’s conc. gradient rarely reaches to equilibrium due to gastric content and renal fluid never stand. So conc. gradient is decreased.