Question

What additives may be used to prevent acid catalyzed hydrolysis of drugs containing ester moieties in drug formulations?

Answer 1

Hydrolysis means the reaction of a molecule with water resulting in the cleavage of a chemical bond within that molecule. Although there are a large number of functional groups that are susceptible to hydrolysis, esters and amides are the most common ones found in drugs prone to hydrolysis.

Hydrolysis can be prevented by chemically modifying the structure of the active compound in the early drug development stage, providing that the problematic hydrolysis is identified early enough.

However, for inherently unstable drugs, preventive measures can include altering the dosage form in a number of ways. For liquid dosage forms, the hydrolysis of drugs is dependent on the presence of water, and thus storage of dry powders followed by reconstitution in water before dispensing minimises hydrolysis.

Similarly, if a drug is known to be susceptible to hydrolysis at room temperature, its storage in a cool place is advised, and patients can be counselled on this practice. Additionally, pharmacists should provide the correct labelling on the packaging.

Moreover, the rate of hydrolysis is temperature-dependent and thus heat sterilisation of such drugs could be a problem. For semi-solid dosage forms (ointment and creams), the stability of the active ingredient can be controlled by changing the nature of the ointment or cream base in the formulation.

The sensitivity of a drug to hydrolysis in a solid dosage form can be controlled in a similar manner by preparing a less hygroscopic salt of the drug or by reducing the water content in the excipients used in the formulation.