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Stability of drugs and medicines Oxidation

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Stability of drugs and medicines. Oxidation and Hydrolysis
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PHARMACEUTICAL CHEM. II
Stability of drugs and medicines
Samer Housheh; Ph.D in QC & Pharm. Chem., S.housheh@au.edu.sy
1
Lecture
nd
2
Stability of drugs and medicines
Oxidation and Hydrolysis
Contents
1. Preface .................................................................................................................................................. 2
2. Oxidation ............................................................................................................................................... 2
2.1. Initiation ........................................................................................................................................ 2
2.2. Propagation ................................................................................................................................... 2
2.3. Termination ................................................................................................................................... 2
2.4. Stability of free radicals ................................................................................................................ 3
2.5. Prevention of oxidative deterioration .......................................................................................... 8
2.5.1. Exclusion of oxygen ............................................................................................................... 8
2.5.2. Use of amber or coloured glass containers .......................................................................... 8
2.5.3. Use of chelating agents ......................................................................................................... 8
2.5.4. Use of antioxidants ............................................................................................................... 8
2.6. Autoxidation of fats and oils ......................................................................................................... 9
2.7. Ageing ......................................................................................................................................... 10
PHARMACEUTICAL CHEM. II
Stability of drugs and medicines
Samer Housheh; Ph.D in QC & Pharm. Chem., S.housheh@au.edu.sy
2
1. Preface
rugs sometimes have quite complicated chemical structures and are biologically active
compounds. It should not, therefore, come as a surprise that these reactive molecules
undergo chemical reactions that result in their decomposition and deterioration, and that
these processes begin as soon as the drug is synthesized or the medicine is formulated.
Decomposition reactions of this type lead to, at best, drugs and medicines that are less active than
intended (i.e. of low efficacy); in the worst-case scenario, decomposition can lead to drugs that are
actually toxic to the patient. This is clearly bad news to all except lawyers, so the processes of
decomposition and deterioration must be understood in order to minimize the risk to patients.
2. Oxidation
Oxidation is the process whereby an atom increases the number of bonds it has to oxygen,
decreases the number of bonds it has to hydrogen, or loses electrons.
The types of drugs that are affected include phenols (such as morphine), catecholamines (for
example, adrenaline (epinephrine) and noradrenaline (norepinephrine)) as well as polyunsaturated
compounds such as oils, fats and fat-soluble vitamins (e.g. vitamins A and E). Radical chain
reactions of this type are called autoxidation reactions and can be quite complicated. All, however,
proceed via a number of discrete steps, namely, initiation, propagation and termination.
2.1. Initiation
2.2. Propagation
2.3. Termination
D
PHARMACEUTICAL CHEM. II
Stability of drugs and medicines
Samer Housheh; Ph.D in QC & Pharm. Chem., S.housheh@au.edu.sy
3
2.4. Stability of free radicals
It is useful to be able to look at the structure of a drug molecule and be able to predict which sites,
if any, in the molecule are susceptible to oxidative deterioration.
The most common bond in a drug molecule to be broken during an autoxidation process is a
covalent bond between hydrogen and another atom, usually carbon.
A rank order can be drawn up that lists the relative stabilities of free radicals; a highly substituted
tertiary (3) radical is considerably more stable than a secondary (2) or a primary (1) radical.
The least stable alkyl radical is the methyl radical, which has no alkyl substituents and therefore
no mechanism whereby the unpaired electron can be stabilized:
Drugs that are susceptible to oxidation of carbonhydrogen bonds include ethers (which oxidise
to form highly explosive peroxides), aliphatic amines (which oxidise at the a hydrogen atom) and
aldehydes (which are easily oxidised to carboxylic acids and peroxy acids). Examples of these
reactions are shown in Figure 8.6.
PHARMACEUTICAL CHEM. II
Stability of drugs and medicines
Samer Housheh; Ph.D in QC & Pharm. Chem., S.housheh@au.edu.sy
4
PHARMACEUTICAL CHEM. II
Stability of drugs and medicines
Samer Housheh; Ph.D in QC & Pharm. Chem., S.housheh@au.edu.sy
5
Other bonds that oxidise easily are the oxygenhydrogen bond found in phenols and the nitrogen
hydrogen bonds found in aromatic amines Figure 8.7.
Drugs containing phenolic groups include the analgesics morphine (and related opiates) and
paracetamol as well as the bronchodilator salbutamol, widely used in the treatment of acute
asthma. See Figure 8.9. Drugs that contain two phenolic groups, such as adrenaline (epinephrine)
and other catecholamines such as noradrenaline (norepinephrine) and isoprenaline are particularly
susceptible to oxidation and have to be formulated at acidic pH. All of these compounds are white
crystalline solids that darken on exposure to air.
Adrenaline forms the red coloured compound adrenochrome on oxidation (Figure 8.10), which
can further polymerise to give black compounds similar in structure to melanin, the natural skin
pigment. Injections of adrenaline that develop a pink colour, or that contain crystals of black
compound, should not be used for this reason. Adrenaline for injection is formulated as the acid
tartrate (Figure 8.10), which, in aqueous solution, gives a pH of approximately 3.
It is called the acid tartrate since only one carboxylic acid group of tartaric acid is used up in salt
formation with adrenaline. This leaves the remaining carboxylic group to function as an acid.
PHARMACEUTICAL CHEM. II
Stability of drugs and medicines
Samer Housheh; Ph.D in QC & Pharm. Chem., S.housheh@au.edu.sy
6
Cleavage of the nitrogenhydrogen bond in aromatic amines occurs in a similar manner to that
described for phenols, to give a complex mixture of products due to coupling reactions of the type
shown in Figure 8.11.
PHARMACEUTICAL CHEM. II
Stability of drugs and medicines
Samer Housheh; Ph.D in QC & Pharm. Chem., S.housheh@au.edu.sy
7
PHARMACEUTICAL CHEM. II
Stability of drugs and medicines
Samer Housheh; Ph.D in QC & Pharm. Chem., S.housheh@au.edu.sy
8
2.5. Prevention of oxidative deterioration
2.5.1. Exclusion of oxygen
This is pretty obvious; if oxygen in the air is causing the oxidation, then exclusion of oxygen from
the formulation will minimize oxidative deterioration. This is usually achieved by replacing the
oxygen with an inert gas atmosphere (e.g. nitrogen or argon). The container should also be well
filled with product and closed tightly to minimize the possibility of air getting to the medicine.
2.5.2. Use of amber or coloured glass containers
Amber glass excludes light of wavelengths _470 nm and so affords some protection to light
sensitive compounds. Special formulations, such as metered dose inhalers used in the treatment of
asthma, also offer protection from light and oxygen since the drug is dissolved or suspended in
propellant and stored in a sealed aluminium container.
2.5.3. Use of chelating agents
Oxidation reactions can be catalyzed by the presence of tiny amounts of metal ions (for example,
0.05 ppm Cu2_ can initiate decomposition of fats) and so stainless steel or glass apparatus should
be used wherever possible during manufacture of susceptible compounds. If the presence of metal
ions cannot be avoided, then chelating agents, such as disodium edetate, are used to chelate and
remove metal ions. Disodium edetate is the disodium salt of ethylenediaminetetraacetic acid, or
EDTA, and is shown in Figure 8.12.
2.5.4. Use of antioxidants
Antioxidants are compounds that undergo oxidation easily to form free radicals but which are then
not sufficiently reactive to carry on the decomposition chain reaction. They selflessly sacrifice
themselves to preserve the drug or medicine. Most antioxidants are phenols and two of the most
commonly used are shown in Figure 8.13. Ascorbic acid (vitamin C) also functions as an
PHARMACEUTICAL CHEM. II
Stability of drugs and medicines
Samer Housheh; Ph.D in QC & Pharm. Chem., S.housheh@au.edu.sy
9
antioxidant and is added to medicines and foodstuffs for this reason. Food manufacturers
enthusiastically label their products as having ‘added vitamin C’. What they are not so keen to tell
you is that the vitamin is not there for the consumers’ benefit but rather as an antioxidant to stop
their product decomposing oxidatively (see Figure 8.14).
2.6. Autoxidation of fats and oils
Fixed oils and fats are naturally occurring products, usually of plant origin, that are used
extensively in pharmaceutical formulation. They are very susceptible to oxidative decomposition
(a process called rancidity) and special precautions must be taken to control their stability and
prevent their decomposition. Compounds of this type exist as complex mixtures of structurally
similar oils, the composition of which can vary from year to year depending on factors such as
climate, time of harvest, etc. Chemically, fixed oils and fats are esters of the alcohol glycerol
(propane-1,2,3-triol) with three molecules of long-chain carboxylic acids, called fatty acids, which
may all be the same or may differ depending on the oil (Figure 8.15).
PHARMACEUTICAL CHEM. II
Stability of drugs and medicines
Samer Housheh; Ph.D in QC & Pharm. Chem., S.housheh@au.edu.sy
10
Compounds of this type are called triglycerides and contain several sites within the molecule where
autoxidation can occur to cause breakdown of the molecule. This is especially true if the fatty acids
are unsaturated (i.e. contain at least one carboncarbon double bond; if the carbon chain contains
several double bonds, the oil is said to be polyunsaturated).
The stability of oils is very important in pharmaceuticals since nonpolar drugs (for example,
contraceptive steroids and neuroleptic tranquillisers) are often formulated in oily injection vehicles
for intramuscular or depot injection. Injections of this type can be given, for example, once a
month, and the drug exerts its pharmacological effect as it leaches out of the injection site into the
bloodstream. Oils used as injection vehicles include arachis oil, from the peanut plant, olive oil,
castor oil and ethyl oleate, the ethyl ester of the 18-carbon fatty acid oleic acid (Figure 8.16).
These oils, if they are to be used parenterally, need to be chemically pure and free from microbial
contamination. As stated above, plant oils are often complex mixtures of chemically similar
compounds and so require special forms of pharmaceutical assay (e.g. determination of their acid
and saponification values) as well as physical methods of assay such as determination of density
(i.e. weight per millilitre) and measurement of their refractive index. Increasingly, modern
instrumental methods of analysis, such as gas chromatography, are being used to identify
component oils and ensure purity (e.g. see the BP assay of Arachis Oil).
2.7. Ageing
The effects of oxygen are not limited only to the oxidation of small molecules found in drugs and
medicines. It is now thought that most of the chemical effects of human ageing are as a result of
sustained and cumulative oxidative damage on important macromolecules present in our cells
(particularly DNA). The old joke to the effect that air is poisonous everyone who breathes the
stuff dies does have some truth in it. As soon as we are born, the cells in our bodies begin to
suffer damage from reactive oxygen species (such as hydroxyl and superoxide radicals). These
reactive species are formed by the breakdown of oxygen present in all our cells and, once formed,
can react with essential cell components such as phospholipid membranes, cellular proteins and
DNA. Damage to DNA results in genetic mutations, which can be passed on to subsequent
generations of cells. If the oxidative damage is severe, the cell in question will enter a programme
of cell death, called apoptosis, and effectively commit suicide. To counteract these onslaughts by
reactive forms of oxygen, the body has evolved a number of elegant defense mechanisms. Repair
enzymes can detect damaged DNA bases and repair them in situ without disrupting the function
of the DNA. Similarly, damaged membrane is repaired to restore cell integrity. These repair
enzymes are essentially catalyzing an intracellular REDOX process and require a number of
essential nutrients such as vitamins C and E to act as antioxidants. The ageing effects of oxidative
damage cannot be reversed (yet!) and no amount of expensive cosmetic preparations will stop skin
from ageing, but the amount of damage to cells may be reduced by an adequate intake of vitamins
and antioxidants in the diet. The most recent nutritional advice is to consume at least five helpings
PHARMACEUTICAL CHEM. II
Stability of drugs and medicines
Samer Housheh; Ph.D in QC & Pharm. Chem., S.housheh@au.edu.sy
11
of fresh fruit and vegetables every day to maintain an adequate dietary intake of essential
antioxidants. It is a sad reflection on our society that much more time, money and advertising are
spent on expensive cosmetic ‘remedies’ for ageing than are spent ensuring a healthy diet for all in
the population.
………To be continued
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