Mechanism of Degradation

Title : Mechanism of Degradation

Course Co ordinator : Dr. Smt. Jayanti Vijaya Ratana.

Let us now see why and how the drugs placed in the products are decomposing. Are they splitting into two? Are they changing into other inactive or toxic forms? Why is this happening and can we prevent it?
Degradation happens by a few pathways but the most often seen mechanism is Hydrolysis. Oxidation and photolysis are the next two mechanisms most often seen.

Contents

1, Hydrolysis
Ester hydrolysis
Amide hydrolysis
2, Oxidation

Hydrolysis

The word “hydrolysis” literally means “splitting by water”. Before the mechanism of hydrolysis was properly understood scientists thought when some compounds are added to water, the water splits them. For example, a solution of sodium acetate produces acetic acid and hydroxide ions. At one time, the equation for this process would have been written (assuming that there is a chemical reaction between water and sodium acetate).

AcONa + H2O <=> ?AcOH + NaOH —— (1)

But today we know that what is involved is not a reaction with water, in the presence of water sodium acetate is dissociating into acetate ion and sodium ion and the resultant acetate ion is reacting with water to form acetic acid, but this reaction is not fast at all; it happens only to a small extent.

So this process is better represented as

AcONa <=> ?AcO + Na+ —— (2)

AcO- + H2O <=> ?AcOH + OH- —— (3)
Equation (2) is essentially complete and the acid base reaction of equation (3) happens only to a small extent. Equation (3) represents “hydrolysis” and we say that the acetate ion is slightly “hydrolyzed” in water to form acetic acid and hydroxide ion. Similarly chemists say that ammonium ion (NH4+) is hydrolyzed by water to form ammonia and hydronium ion.

H4N+ Cl- => ?H4N+ + Cl-

H4N+ + H2O <=> NH3 + H3O+

The term “hydrolyze” is used to include almost any reaction with water. So we must see that though water may be involved in some reactions as the reacting species, in many cases it plays a passive supporting role, that is, it is something like a facilitator. It many times acts as a solvent vector between two reacting species in solution. In solid dosage forms the reactions will be taking place in saturated solutions. Now I want you to observe a few facts regarding hydrolysis:
(1) Hydrolysis reactions involve, nucleophilic attack of labile bonds by water on the drug in solution.
(2) The reactions involving lactam groups are fastest and are followed by those involving esters, amides and imides in that order.
(3) These reactions usually follow first order.
(4) If this type of reaction happens due to any other solvent it is called solvolysis.
(5) These reactions are catalyzed by H3O+ (c) presence of divalent metal ions (d) ionic hydrolysis (Protolysis) (e) heat (f) light (g) solution and (h) high drug concentrations.

The molecules having ester or amide functional groups are most susceptible to hydrolysis. Anesthetics, antibiotics, vitamins and barbiturates are examples for drugs that decompose due to hydrolysis. The ester and amide groups have so many similarities that they are called “bioisosteres”.

Let me tell you a few things about local anesthetics so that you will know that we are talking about real drugs. Most of the local anesthetic drugs are either benzoic acid or aniline derivatives. The benzoic acid derivatives are esters developed from cocaine, whereas the aniline derivatives are amides developed from isogramine. These drugs have chemical structures that usually have the following formula:

Lipophilic center => Ester or amide group =>?Bridge =>?Hydrophilic center

The lipophilic center helps in the penetration of the cell membrane and the hydrophilic center helps in transportation and in binding to the receptor. When the two centers are in good balance the best local anesthetic action is obtained.
So esters or amides are really providing links between two other moieties and as the saying goes “any chain is only as strong as its weakest link”. So it is at the point of an ester or an amide that decomposition or splitting usually happens.

Ester hydrolysis
Esters are compounds having the structure R – C – O – R1 , where R and R1 are carbon groups. An ester can be thought of as being derived by reaction of an alcohol with a carboxylic acid, with the elimination of a molecule of water. The hydrolysis of an ester into a mixture of an acid and alcohol involves the rupture of a covalent bond between a carbon atom and oxygen atom. These reactions usually happen in the presence of water but happen much faster when either an acid or an alkali is present. Acids, alkalies and certain enzymes, which are capable of supplying the hydrogen or hydroxyl ions to the reaction mixture catalyse this hydrolysis. The alkaline hydrolysis of an ester is irreversible and an acid hydrolysis is reversible.

Let us take a brief  look at the scheme of ester hydrolysis given by Walters and explained very clearly by Leon Lachman and Patrick De Luca in “Theory and practice of Industrial Pharmacy”.
The ester usually is cleaved at the acyl – oxygen linkages, that is between the carbonyl carbon and the oxygen of C2H5 (O- C2H5). The scheme of ester hydrolysis is this

 

 

 

 

 

So the general form of the kinetic equation to express acid or base – catalyzed hydrolysis are as followsSo the general form of the kinetic equation to express acid or base – catalyzed hydrolysis are as follows

d(ester)/dt = K (ester) (H+)

d(ester)/dt = K (ester) (OH-)

So, since the rate seems to depend on the concentrations of two ingredients, it looks as through they are second order equations. But in reality we keep the acid or the alkali in huge excess, so that the small change in the concentration is negligible. Hence the concentration of (H+) or (OH) is constant throughout the reaction. So we treat it as a pseudo – first order equation and the above two equations reduce to the form.
d(ester)/dt = -K (ester)

This is an expression for a first order equation. Many drugs have been studied with respect to their decomposition by hydrolysis, but I will take the example of aspirin. Aspirin was most widely studied and a thorough study was performed by Edwards and is discussed by Lachman. The degradation of aspirin in various buffer solutions was studied and the reaction rate was treated as pseudo first – order.

Aspirin hydrolysis takes place even when the drug is in the solid powder form and if we take an old sample of aspirin and open the lid the unmistakable smell of acetic acid is sure to hit us. The presence of free salicylic acid is recognized and a test for fee salicylic acid is a required test on all samples of aspirin powder. Another advantage in studying the reaction rate of aspirin hydrolysis is that we can follow the concentration of salicylic acid, i.e. the product of the reaction and from that calculate the remaining amount of aspirin. We must remember to calculate in molar quantities

Amide hydrolysis

 

Nylon and a number of other synthetic fibers and films are amides. Proteins are also amides. In all these substances, the constituent units are very large molecules, in which amide groups are the principal building blocks.
Hydrolytic cleavage of an amide results in the formation of an acid and an amine.

 

 

Amides are more stable than the esters. Drugs such as niacinamide, phenethicillin, barbiturates, and chloramphenicol have been reported to degrade by amide hydrolysis.
Kosky studied the stability of salicylamide and some N-substituted derivatives, and postulated both basic and acid hydrolysis for degradation.

Kosky found that in the acid medium, salicylanilide was more stable than salicylamide, which in turn was more stable than benzamide. Aminoalkyl substituents on the nitrogen increased the stability of benzamide. Salicylamide was more stable in basic than in acidic medium, probably due to the protection given by the negative charges on the phenolate ion. The N-alkyl and N – amino alkyl salicylamides were highly resistant to acid and base hydrolysis. This was probably because of the combined steric hindrance by the hydroxyl group in the orthoposition and the alkyl and aminoalkyl group on the nitrogen.

Drugs having ester groups and amide groups in their molecular structure degrade via hydrolysis in the presence of water. Common ester labile bonds are formed between an alcohol and a carboxylic acid. The ester bond is hydrolyzed by hydrogen and hydroxyl ions as shown in the following reactions:
The acyl oxygen in the ester group is protonated and the carboxyl group is further polarized. Nucleophilic attack at the acyl carbon is increased by water. A base, which is a powerful nucleophile, attacks on the acyl carbon and the carbon oxygen bond is broken.

The rate of degradation of an ester labile group is dependent on the characteristics of R1 and R2. For a given R1, the rate of degradation decreases with the higher ackyl group of R2OH because the higher the alkyl, the fewer electrons are withdrawn whereas for a given R2 the degrdation rate increases with the increase in electron – withdrawing group (eg. Cl, NO2) of R, COOH.

The rate of degradation by hydrolysis increases by replacing methyl to ethyl and propyl. The higher alkyl groups possessing the greater electron – donating characteristics increase the electron density at the acyl carbon and thus the attack of OH- is inhibited. On the contrary electron attracting groups such as chlorine and NO2 increase the rate of degradation.

Substituents can have a dramatic effect on reaction rates. For example, the test – butyl ester of acetic acid is about120 times more stable than the methyl ester which in turn is approximately 60 times more stable than the vinyl analog.

Amides
An amide is a compound of the type and is formed by reaction between a carbonylic acid and an amine and is less susceptible than ester groups to hydrolysis. This is because of the lesser electrophilicity of the carbon – nitrogen bond. The amide group is hydrolyzed


The rate of degradation of the amide group by hydrolysis is dependent on the characteristics of the substituents R1, R2 and R3.

Lactam

Antibiotics possessing the ?-lactam structure, which is a cyclic amide are hydrolyzed rapidly by ring opening of the ?–lactam group. The ring opening of the ? – lactam is much faster than that of other amide groups because a four membered ring is joined to a five or six membered ring and a weaker bond exists between carbon and nitrogen of ? – lactam.

The following table taken from page 182 of modern Pharmaceutics (Third Edition) by Gilbert S. Banker and Christopher T. Rhodes gives all the types of drug compounds that are susceptible to hydrolysis and also gives good examples.

Some Functional Groups Subject to Hydrolysis:

Drug type Examples
Esters 

Lactones

Amides

Lactams

Oximes

Imides

Malonic ureas

Nitrogen
mustards

Aspirin, alkaloids 

Dexmethasne sodium phosphate

Estrone sulfate

Nitroglycerin

Pilocarpine

Spironolactone

Thiacinamide

Chloramphenicol

Penicillins

Cephalosporins

Steroid oximes

Glutethimide

Ethosuximide

Barbiturates

Melphalan

Oxidation

Oxidation is the next mot important path way of drug decomposition. Oxygen is present everywhere in the atmosphere and exposure to oxygen will decompose drug substances that are not in their most oxidized state through auto oxidation. Oxygen is a diradical and most auto oxidations are free radical reactions. A free radical is a molecule or atom with one or more unpaired electrons.

Oxidation/reduction reactions involve the transfer of electrons or the transfer of oxygen or hydrogen from a substance. Oxidation of inorganic and organic compounds is explained by a loss of electrons and the loss of a molecule of hydrogen, respectively as, Inorganic compounds:

(SO3)-2 + 2 OH  <=>  (SO4)-2 + H2O + 2 e-

Organic Compounds: Loss of hydrogen

When an oxidation reaction involves molecular oxygen, the reaction occurs spontaneously under mild conditions. It is known as auto oxidation. In an auto oxidation process, free radicals formed by thermal or photolytic cleavage of chemical bonds (eg: peroxide (ROOH) or redox processes with metal ions presenting raw material impurities are involved.

Fe++ + ROOH Fe+++ + OH- + RO.

The free radical formed RO reacts with oxygen to produces a peroxide radical, and the reaction propagates as:

RO. + O2 =>?ROOO.

ROOO. + RH => ROOH + RO.
The free radical reaction continues until all the free radicals are consumed or destroyed.
If we go through page 183 of Banker we learn very interesting things. As little as 0.0002 M copper ion will increase the rate of Vitamin C oxidation by a factor of 105. Hydroperoxides contained in polyethylene glycol suppository bases have been implicated in the oxidation of codeine to codeine – N – oxide. Many oxidation reactions are catalyzed by acids and bases.

The following table taken from page 183 of Banker gives a list of functional groups susceptible to Auto oxidation.

Table  : Some Functional Groups Subject to Autoxidation:

Functional group Examples
Phenols 

Catechols

Ethers

Thiols

Thioethers
Carboxylic acids

Nitrites

Aldehydes

Phenolsin steroids 

Catecholamines
(dopamine, isoproterenol)
Diethylether

Dimercaprol (BAL)

Phenothiazines (Chlorpromazine)

Fatty acids

Amyl nitrite

Paraldehyde

The products of oxidation are usually electronically more conjugated; thus the appearance of, or a change in, color in a dosage form is suggestive of the occurrence of oxidative degradation.

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