HYDROLYSIS

The reaction of water with esters and salts of weak acids or weak bases is called hydrolysis. It is a chemical process in which a molecule is cleaved into two parts  by the addition of a water molecule. One fragment of the molecule gains H⁺ ion from water and other group gains OH^- ion.

There are two types of hydrolysis:

• Ionic hydrolysis
• Molecular hydrolysis

Ionic hydrolysis:

It occurs when salts of weak acids or bases interact with water to give an alkaline basic solution e.g. Sodium Acetate hydrolyzes in water into acetic acid and NaOH. The solution is alkaline (because of NaOH).

NaC₂H₃O₂  + H₂O ==> NaOH + HC₂H₃O₂

Na⁺  + C₂H₃O₂^-  + H₂O ==> Na⁺ + OH^- + HC₂H₃O₂

Molecular hydrolysis

We are more concerned with molecular hydrolysis e.g. aspirin, procaine, atropine etc. In daily life hydrolysis process is involved in different reactions e.g. in saponification, triglyceride (fats) are hydrolyzed with an aqueous base like NaOH. Fatty acids react with base to form soaps.

Hydrolysis is also used in liberation of energy from ATP, where phosphate linkage is broken down by hydrolysis to release energy which is used in the biosynthesis of molecules and active transport of ions or molecules through cell membrane.

 Aspirin is particularly susceptible to hydrolysis above pH 10.

According to Higuchi et al, procaine decomposes mainly by hydrolysis, the degradation being due, primarily to the breakdown of the uncharged and singly charged forms. The reaction is catalyzed by hydroxyl ions.

It was found that atropine (C₁₇H₂₃NO₃) undergoes alkaline and acidic hydrolyses at different pH levels. Above pH 4.5, the catalytic reaction involves hydroxyl ions and below pH 3, hydrogen ions are involved. pH for maximum stability is between 4.1-3.2 at 100^oC

Factors affecting hydrolysis:

• Moisture
• pH
• Temperature
• Solvent

Protection against hydrolysis:

Adjusting pH:

Drugs may be stabilized by adjusting the pH of the solution to a value at which the compound is found to exhibit lowest rate constant. If the reaction is subjected to general acid- base catalysis, the buffer used for pH adjustment must be chosen carefully. The buffer should provide an optimum pH for both maximum stability and greatest therapeutic activity of the drug. In most cases the therapeutic activity depends upon the presence of free base rather than ionized salt in solution. e.g. pylocarpine exists as 99% base at pH 9 and only 0.1% at pH 4.

Aspirin buffered solution is maximum stable at a pH of 2.4, above a pH of 10 the decomposition rate rapidly increases.

Complexation:

Some dugs form complexes with others which inhibit their hydrolysis e.g. benzocaine in aqueous solution forms a complex with caffeine to form benzo-caffeine complex. Only the benzocaine which is free in the solution will be hydrolyzed.

Suppressing the solubility of drug:

By suppressing the solubility, the concentration of drug in solution decreases e.g. the rate of degradation of penicillin in procaine penicillin solution was shown to be due to that portion which is in solution form. It is found that solubility may be reduced by the use of various additives such as gluconate, sorbitol, dextrose and citrates.

Removal of H₂O:

Hydrolytic decomposition may further be prevented by the removal of water. The drug may be stored in dry form and used as such or suspended as an insoluble powder in a suitable vehicle. Even in the solid state, drug may decompose e.g. decomposition of solid aspirin due to temperature and humidity.

Surfactants

Nonionic, cationic and anionic surfactants when added to solutions containing drugs form micelle and the drug particles become trapped in the micelle.

The hydrolytic groups such as OH cannot penetrate this micelle cover and reach the drug particles, hence hydrolysis rate is decreased.