STABILITAS OBAT

OKSIDASI

Suwaldi Martodihardjo
(Prof. Dr. MSc. Apt)

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 Oxidation
Oxidation of inorganic and organic compounds is
explained by a loss of electrons and the loss of a
molecule of hydrogen.

The oxidation of drug substances can be affected by

the availability of oxygen.

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 Some Functional Groups Subject to
Autoxidation

Functional Examples
group
Catechols Catecholamines (dopamine)

Ethers Diethylether

Thiols Dimercaprol (BAL)

Thioethers Chlorpromazine

Carboxylic acids Fatty acids

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 Oxidation
Oxidation is a major drug degradation pathway, second only to
hydrolysis.
Examples:
– Amines: R
O O
R R 1 O O
R 1 1 1
+ -
H N HO N N N O
R2 R2 R2
R2

– Alcohols: R1 O O R1 R1 O O R1
H OH O H OH O
R2 R2 H HO
– Sulfur moieties:
R1 R1
R1 O O R1
R3 R2 O O O O
S R2 R3 R2 R3
R2 SH S
R1 R3 S O S OH
R3 R2 O OH
– Alkenes & alkynes: O

R1 H O O R1 H H2O H H

H R2 R1 OH
H R2 O OH R2

Minggu, 04 Maret 2018 SUWALDI MARTODIHARDJO

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 INITIATION

Initiator
RH R.

Free radicals are generated in the initiation stage

•The initiation stage takes a certain period of time to occur

(= the induction period).

•The catalyst may be metal ions, light, heat, and base.

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•METAL ION-CATALYZED INITIATION

Metal ions initiate the autoxidation by direct reaction with substrates

and/or hydroperoxide present in the system as an impurity or formed in
the propagation step.

Ascorbic acid undergoes autoxidation reaction and is strongly catalyzed

by metal ions such as Fe+3 and Cu+2.

ArCH3 + Co+3 [ ArCH3]+. + Co+2 ArCH2. + H+

Electron transfer initiation between metal ions (Co +3) and

organic compounds (alkylbenzenes) benzyl cation radicals
formed and deprotonate to yield a benzyl radical.

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LIGHT INITIATION
•Upon light exposure, organic molecules may adsorb energy (E) :

E = hc/ =hv

c = the speed of light (3.0 x 1010 cm s-1)

h = Planck’s constant (6.625 x 10–27 erg-s)
 = the wavelength of the light

The energies of UV light (=200 – 400 nm) are

 143 – 71.5 kcal/mole;
The energies of visible light ( = 400 – 700 nm) are
71.5 – 40.8 kcal/mole.

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 Hydroperoxides and peroxides are readily cleaved.

RCOOH hv RO . + HO .
hv
ROOR 2 RO .

Activated C-C and C-N bond may also cleave.

hv
ArCOOH Ar . + .COOH

hv
ArCOO- Ar . + COO-

Aqueous solutions of tetracycline are stable at low pHs, but

deaminate readily at pH  pKa .

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 Addition ROO . + C = C ROO – C – C .

Propagation R . + O2 ROO .

FREE RADICAL INITIATORS

•Azo compounds such as azobisisobutyronitrile (AIBN),

2,2`-azobis[2-(methylcarboxy)propane] (ACP), and t-butyl
hyponitrite contain a weak –C-N=N-C- bond that can easily be
broken by light or heat to generate free radicals.

Abstraction ROO . + RH ROOH + R .

R–N=N–R 2 R . + N2

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 R . + R. R–R
R . + O2 ROO .

TERMINATION

•In the termination step, free radicals are consumed to form molecular
products.
•Three main types of termination reactions between free radicals can
occur, and their relative importance is determined by the oxygen
concentration  at very low oxygen pressures, reaction of an alkyl
radical with another alkyl radical or peroxy radical dominates

R . + ROO . ROOR
•at reasonable oxygen pressure, most alkyl radicals are quenched by
oxygen, and the primary termination step is the self-reaction of
peroxy radicals.

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 2 ROO . Molecular products

For primary and secondary alkylperoxy radicals,

the mechanism of termination probably involves a
tetraoxide intermediate that undergoes disproportionation
through a concerted mechanism to give an alcohol and a
carbonyl product :
1.aldehyde for a primary alkylperoxy radical
2.ketone for a secondary alkylperoxy radical.

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The kinetics of the oxidation of drug substances can
be affected by the availability of oxygen.

Effect of oxygen concentration on the apparent first-order rate

constants for ascorbic acid oxidation at 25°C.
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 • Oxidation of phenothiazines.

Oxidation of ascorbic acid.

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 INHIBITION OF AUTOXIDATION
•Degradation of the drug substance results in loss of potency and
thereby formation of degradation products that may be toxic or
incompatible with the formulation.

In addition to initiating oxidation of the drug, excipient oxidation can

result in a variety of changes in the formulation, including color, pH,
solubilizing properties, and viscosity.

Several approaches have been developed to inhibit the autoxidation

reaction and thus stabilize the drug and formulation.

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 ANTIOXIDANTS
•Antioxidants are substances that can be added in a small
quantity to products to retard oxidation reactions.
In pharmaceutical products they are commonly used to
protect the drug and/or excipients from autoxidative
degradation.

•PHENOLIC ANTIOXIDANTS
Phenolic antioxidants are sometimes called primary or true
antioxidants.

These antioxidants most commonly used in pharmaceutical

products are :
1.butylated hydroxytoluene (BHT),
2.butylated hydroxyanisole (BHA),
3.the tocopherols (vitamin E), and
4.propyl gallate.

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 Structures of some common antioxidants.

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 Stabilization of drugs against
oxidation

Antioxidants commonly used for

Aqueous systems Oil systems
Sodium metabisulfite Ascorbyl palmitate
Sodium thiosulfate Butylaled hydroxy toluene
Ascorbic acid Butylated hydroxy anisole

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 Structures of some common antioxidants.

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•Hindered phenols are the phenolic antioxidants containing tert-
butyl or methyl groups adjacent to the hydroxyl on the phenolic
ring. They are BHA, BHT, and the tocopherols and insoluble in
water but soluble in nonpolar solvents such as lipids and oils.

•Propyl gallate, a trihydroxy phenol is more polar than the

hindered phenols and thus is slightly soluble in water. This
compound forms a highly colored complex with Fe3+.

REDUCING AGENTS
•Reducing agents used in the pharmaceutical industry include:
ascorbic acid, ascorbyl palmitate, sodium bisulfite, sodium
metabisulfite, sodium sulfite, acetone sodium bisulfite, sodium
formaldehyde sulfoxylate, thiglycerol, and thioglycolic acid.

Two other reducing agents and chelators that are used in the
food industry are thiodipropionic acid and its dilauryl ester.
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 Structures of some common antioxidants.

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•Reducing agents consume oxygen and they are
sometimes referred as oxygen scavengers.

•These reducing agents (antioxidants) are particularly

useful in closed systems.

Some reducing agents can decompose peroxides,

chelate metal ions, and act as chain-breaking
antioxidants.

•The sulfite family of antioxidants reacts with oxygen

in aqueous solution to give sulfate by a complex free-
radical process that is catalyzed by transition metal
ions.
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 Bisulfite acts as an oxygen scavengers

M+
SO3–2 + O2 SO4–2

The bisulfite ion is also nucleophilic and can react with and
degrade drugs that contain susceptible functionalities, resulting
in unwanted gedradation.

Several compounds have been shown to react with bisulfite,

including :
•morphine . physostigmine
•epinephrine . dobutamine
•dopamine . tryptophan.

The sulfite ion can also act as a strong general base catalyst for
ester hydrolysis.

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CHELATING AGENTS
•Trace metal ions can play a major role in initiating autoxidation reactions.
 A particularly effective strategy to slow autoxidation is to add a
chelating agent to the formulation.
The most effective chelator for use in pharmaceutical product is EDTA.
EDTA as the calcium disodium salt or disodium salt is usually added in
combination with an antioxidant.

•EDTA is soluble in water and alcohols, but practically insoluble in oils.

EDTA has been used in many types of formulation, including oils in
the amounts of 0.002 – 0.05%.
Other pharmaceutical excipients that act as chelators include:
citric acid, tartaric acid, and amino acids.

These are used in relatively high concentrations ( up to 1% or more).

The efficient complexation between a chelating agent and metal ion is

favored by higher pH values;
 at lower pH, protons compete with free metal ions in complexing with
the chelating agent.
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OTHER INHIBITION APPROACHES
•The use of an antioxidant is the most common method of inhibiting
autoxidation reactions. The other methods may also be used such as
protecting the formulation from reactants and conditions that initiate or
accelerate the autoxidation reaction.

TEMPERATURE

•The temperature dependence of autoxidation reactions is usually lower

than that of many types of degradation reactions.

•Cooling or freezing drug products or the drug substance may not

provide significant lowering of reaction rates.

•Lowering the temperature can also increase the concentration of

oxygen in solution, leading to increased reactivity.

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 pH ADJUSTMENT
•The anionic form of weak acids such as phenols, carbon acids,
and thiols is usually more easily oxidizable than the neutral
form.

Lowering the pH can reduce or slow the autoxidation.

•The increased stability of a drug formulated at lower pH can be

explained by the pH dependence of the electrode potential.

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REMOVAL OF OXYGEN

•The available oxygen in the head space of a

container may be controlled to reduced the
extent of degradation.

•In a study of morphine degradation in various

formulations stored for 1 to 3 years showed a
strong correlation between the volume of air
included in the package and degradation or
discoloration.

Removal of oxygen from the vehicle is therefore

an obvious way of reducing or eliminating
autoxidation.

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LIGHT PROTECTION
•Light-initiated autoxidation can occur only at sites of light exposure. The
use of light-resistant containers provides a convenient way of protecting
light-sensitive drugs.

•The USP defines light-resistant glass and plastic containers as those that
do not allow more than 10% of the incident light for any wavelength
between 290 nm and 450 nm.

•Typical amber glass with 2-mm thickness is qualified for light-resistant

containers. If more light needs to be excluded, thicker amber glass may be
used.

•One possible adverse effect of using amber glass containers for light
protection is that metal ions such as iron and manganese may leach out of
the glass, thus catalyzing the autoxidation.

Ascorbic acid, thimerosal, and amitriptyline were all found to be less

stable in amber glass containers than in flint glass containers.
For this reason, products should be stress tested by light in various types
of light-resistant containers.
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• THE END OF LECTURE

• THANK YOU FOR PAYING ATTENTION

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