Chemical Degradation

It is the separation of chemical compound into elements or simpler compounds. Change in the chemical nature of the drug is called as chemical degradation.

Chemical degradation includes:

• Hydrolysis
• Oxidation
• Decarboxylation
• Isomerization
• Polymerization

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1. HYDROLYSIS :

• Hydrolysis means splitting of pharmaceutical product by the action of water.
• It is the main problem with the pharmaceutical systems such as emulsions, suspensions, solutions etc.
• This is carried out by water vapours from atmosphere.
• Hydrolysis is catalyzed by hydrogen ions or hydroxyl ions and also by acidic or basic species commonly encountered as components of buffers.

The main classes of drugs that undergo hydrolysis are the:

• Esters
• Amides
• Ring

A. Esters Hydrolysis:

• Upon hydrolysis of esters acyl-oxygen is cleaved and acid and alcohol is produced

B. Amide Hydrolysis:

• Although amides are relatively stable than esters but these are susceptible to specific and general acid-base hydrolysis.
• Amide hydrolysis usually involves the cleavage of the amide linkage to give an amide giving alcohol and amine as hydrolyzed products.

C. Ring Hydrolysis:

• Compounds containing ring undergo hydrolysis to make hydrolyzed products.
• For example, β-lactam antibiotics such as penicillins which are cyclic amides or lactams undergo rapid ring opening due to hydrolysis

Protection against Hydrolysis:

1. By packing drugs into controlled humidity containers
2. By incorporating a suitable desiccant in the pack
3. By addition of buffers in liquid dosage forms.
4. By minimizing buffer concentration to the minimum required for maintaining pH
5. By altering dielectric constant of system by using non-aqueous solvents such as alcohol, glycerin and propylene glycol

2. ISOMERIZATION :

• Isomerization is a degradation process in which a drug degrades to form a product with an identical chemical formula (i.e., isomers).
• Isomers have the same chemical composition but a different configuration or structure and possess different physicochemical properties.

TYPES OF ISOMERISATION

1. Optical isomerisms
2. Geometrical isomerisms

1.OPTICAL ISOMERISMS :

• Optical Isomerism is defined as the property of organic compounds in which they have same molecular and structural formula but have non- superimposable mirror images.
• It is further divided in:
• Racemization
• Epimerization

• Racemization is a process in which optically active compounds (consisting of a single enantiomer) are converted into an equal mixture of enantiomers with zero optical activity (a racemic mix).
• The rate of racemisation depends on the molecule and conditions such as pH and temperature.

• Epimerization in pharmaceutics refers to the process by which one epimer is converted into another.
• Epimers are a specific type of stereoisomer that differ in configuration at only one stereogenic center.
• This process can affect the pharmacological properties of drugs, including their efficacy, metabolism, and toxicity. Understanding epimerization is crucial in drug formulation and development, as it can influence drug stability and therapeutic outcomes.

2.GEOMETRICAL ISOMERISMS :

• Geometrical isomerism, also known as cis-trans isomerism, occurs in compounds with restricted rotation around a bond, typically a double bond or a cyclic structure. In geometrical isomers: 1. Cis Isomers: Similar or identical groups are on the same side of the double bond or ring. 2. Trans Isomers: Similar or identical groups are on opposite sides

• These different arrangements can lead to distinct physical and chemical properties, such as boiling points, solubility, and reactivity. Geometrical isomerism is important in various fields, including organic chemistry and pharmacology, as it can influence the biological activity of molecules.

3. OXIDATION:

• 1. Instabilities in a number of pharmaceutical preparations are due to oxidative degradation of the active ingredients of these preparations when exposed to atmospheric oxygen.

2.Removal of an electropositive atom, radical or electron, or the addition of an electronegative atom or radical is called as oxidation.

Oxidation is of two types: o Auto-oxidation o Photo-oxidation

A. Auto-Oxidation:

• 1.It is the most common form of oxidative degradation that occurs in many pharmaceutical preparations and involves a free radical chain process. 2.In an auto-oxidative degradation, only a small amount of oxygen is required to initiate the reaction and thereafter oxygen concentration is relatively important

B. Photo-Oxidation / Photolysis:

• 1. Exposure to light may produce oxidation-reduction, ring rearrangement or modification and polymerization. 2. The shorter the wave-length of light, the greater is the effect of light in initiating the chemical reaction because of higher energy. 3. The thermal (induced by light) reaction may continue even after the light source has been withdrawn. 𝐶𝑦𝑎𝑛𝑜𝑐𝑜𝑏𝑎𝑙𝑎𝑚𝑖𝑛𝑒 𝐿𝑖𝑔ℎ𝑡 𝐻+ ↔ 𝐷𝑎𝑟𝑘 𝐶𝑛− 𝐻𝑦𝑑𝑟𝑜𝑥𝑦𝑐𝑜𝑏𝑎𝑙𝑎𝑚𝑖𝑛 + 𝐶𝑁− 𝑂𝑥𝑖𝑑𝑎𝑡𝑖𝑜𝑛 → 𝐵𝑖𝑜𝑙𝑜𝑔𝑖𝑐𝑎𝑙𝑙𝑦 𝐴𝑐𝑡𝑖𝑣𝑒 𝑃𝑟𝑜𝑑𝑢𝑐𝑡�

4. POLYMERIZATION:

• Combination of two or more identical molecules to form a much larger and more complex molecule is called as polymerization.
• e.g: Degradation of antiseptic formulations and aldehydes is due to polymerization. Formaldehyde solution may result into formation of white deposit when stand in cold.

5. DECARBOXYLATION:

• Elimination of CO2 from a compound is called as Decarboxylation.
• Drug substances having a carboxylic acid group are sometimes susceptible to Decarboxylation

4-AMINOSALICYLIC ACID

EXAMPLE :

ASPIRIN (ACETYLSALICYLIC ACID :

WHEN STORED IMPROPERLY OR EXPOSED TO MOISTURE, ASPIRIN CAN DEGRADE, AND DECARBOXYLATION CAN LEAD TO THE FORMATION OF SALICYLIC ACID, REDUCING ITS EFFICACY

EFFECTS OF DECARBOXYLATION ON DRUG STABILITY :

• LOSS OF EFFICACY; IF A DRUG UNDERGO DECARBOXLATION PREMATURELY, IT CAN LOSE ITS THERAPEUTIC POTENCY . THIS CAN BE AN ISSUE DURING STORAGE OR TRANSPORTATION, ESPECIALLY IN DRUGS THAT ARE SENSITIVE TO HEAT OR PH.
• FORMATION OF TOXIC BY-PRODUCTS; IN SOME CASES, DECARBOXYLATION MAY RESULT IN THE FORMATION OF TOXIC OR LESS DESIRABLE COMPUNDS, WHICH CAN AFFECT THE SAFETY PROFILE OF THE DRUG.

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Prevention of Decarboxylation

• 1) Proper storage conditions :(cool,dry, and light-protected environments) are crucial for preventing unwanted decarboxylation. 2) pH control :can help stabilize drugs that are prone to decarboxylation under acidic or basic conditions. 3) Use of stabilizersor inhibitors :in the drug formulation can reduce the risk of decarboxylation during storage and handling. Managing decarboxylation is an important consideration in pharmaceutical chemistry to ensure drug stability and maintain therapeutic efficacy.