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CHEMICAL STABILITY OF DRUGS

CHEMICAL STABILITY
OF DRUGS
TOMMY JULIANTO
FACULTY OF PHARMACY
UNIVERSITI TEKNOLOGI MARA

Determine a time interval of drugs to be


remain in sufficient potency after
manufactured, especially for unstable drugs.
Concentration should be not less than 95 %
after prepared
prepared.
To predict the shelf life of drugs, we need to
understand the kinetics of drugs
decomposition process.
How reactions can be classified into various
order.

Many drugs are susceptible to some form of


chemical decomposition in their dosage
forms.
Solid and liquid dosage form
loss
l
off drugs
d
potency
t
changes in the physical appearance
- discoloration (photochemical
decomposition)
Classes of drugs susceptible to decomposition
Precautions to minimize the loss of potency

Calculate the rate constant in certain


environment conditions.
Stress conditions: temperature and
humidity.
Accelerated
drugs
breakdown
(save
cce e ated d
ugs b
ea do
(sa
e ttime).
e)
Result will determine the conditions of
storage.
Stability can be improve by formulation/
packaging modification.

Chemical decomposition of
drugs
Type of the main decomposition process.
Conditions of drugs in both liquid and solid
formulations can loss their potency.
T be
To
b aware to
t some chemical
h i l groups
which when present in drug molecules can
cause stability problem.
How to minimize the chemical breakdown.

Type Drug degradation can be occur in


formulations:
- Hydrolysis
- Oxidation
- Isomerisation
- Photochemical decomposition
- polymerisation

Hydrolysis
Drugs are susceptible to this type of
degradation:

Examples of chemical
groups susceptible to
hydrolysis. :

Derivate of carboxylic acid


Contains functional groups
Ester, amide, lactone
lactone,, lactam
lactam,, imide and carbamate.
carbamate.
Ester;
physostigmine
E t e.g. Acetilsalisilic
A til li ili acid,
id physostigmine,
h
ti i , methyl
th l
dopate,, tetracaine and procaine.
dopate
a bimolecular reaction involving acylacyl-oxygen
cleavage.
Amide; e.g. chinchocaine
chinchocaine,, chloramphenicol,
chloramphenicol,
ergometrin etc.
cleavage the amide linkage
Lactam
Lactam;; nitrazepam and chlordiazopoxide,
chlordiazopoxide, penicillin,
etc.

water plays a dominant role in hydrolysis


as a solvent vector between to reacting
solutes in solution.
Hydrophilic reactions involve nucleophilic
attack of labile bonds;
e.g.: lactam>ester>amide>imide,
l t
t
id i id b
by water
t
on the drug in solution, and first order.
If the attack is by a solvent other than
water it is known as solvolysis
solvolysis..

Hydrolysis catalyzed by hydrogen ions


(acid) or hydroxyl ions (base).
Acid base catalysis.

can be prevent by adjusting pH at


maximum stability kinetic of drugs.
alteration of dielectric constant by the
addition of non
non--aqueous solvent; glicerin,
alcohol, PG etc.

reduce the solubility of drugs by the


addition of additives such as, sorbitol
sorbitol,,
citrates, dextrose etc.
addition of caffeine to aqueous solution
of benzocaine
benzocaine,, procaine and amethocaine
to decrease betabeta-catalysed hydrolysis.
by solubilisation of a drug by
surfactants.
by modifying chemical structure of drugs
without reduce therapeutic efficiency.

A number of conditions catalyse the


breakdown:
 The presence of OH The presence of H3O The presence of divalent metal ions
 Ionic
I i h
hydrolysis
d l i (P
(Protolysis)
t l i ) iis quicker
i k th
than
molecular
 Heat
 Light
 Solution polarity and ionic strength
 High drug concentrations

The oxidation process has usually been


eliminated by storage under anaerobic
conditions without an investigation of the
oxidation mechanism.
Actually oxidation is one of the major
cause of drug instability.

Phenolic compounds; morphine and


phenyleprine..
phenyleprine
Catecholamines;; dopamine and adrenaline.
Catecholamines
Steroid, antibiotic, vitamins, oils and fats.

H removes from organic compound to


form a hydro peroxide, ROOH.
And the process continue by producing
new free radical.
The reaction proceeds until the free
radicals destroyed by inhibitors or by side
reactions which eventually break the chain
The rancid odour that is a characteristic of
oxidised fats and oils due to aldehydes,
ketone and short
short--chain fatty acid which
are the breakdown products of the
hydroperoxides.

Oxidation
Oxidation is the next common pathway for
drug breakdown and the process usually
control by the environment.
E.g. light, trace metal, oxygen and oxidizing
agent.
there are little attention on oxidation
simultaneous hydrolitic and oxidative
degradation also can occur

Oxidation involves the removal of an


electropositive atom, radical or electron, or the
addition of an electronegative atom or radical.
Autooxidation;; unanalysed reaction.
Autooxidation
Oxidation chain reactions is quite slow under the
influence of oxygen molecular.
Chain reaction; initiation, propagation and
termination.
termination
Initiation can be via free radicals formed from
organics compounds by the action of light, heat
or transition metals.
Propagation of the reaction involves the
combination of molecular oxygen with the free
radical R- to form radical ROO-.

Autooxidation

Another type of oxidation involves the reversible loss


of electrons without the addition of oxygen.
morphine; the undissociated and the protonated
forms of morphine, M, are both oxidised by
atmospheric oxygen to give a free radical peroxide
and a semiquinone,
semiquinone, SQ.
> free radical quinone
quinone,, Q.
Q undergo coupling with M to give the dimer of
pseudomorphine,, PM, resulted in elimination of a
pseudomorphine
hydrogen free radical HFR.
HFR react with HFR to form hydrogen peroxide HP.
HP can react with morphine to form morphinr Noxide, MNO, or
may decompose to produce a free radical oxygen
which can also react with morphine base to give the
N-oxide.

Stabilisation of drugs against


oxidation
Various precautions during manufacture and
storage.
Oxygen in the containers should be replace with
nitrogen
g or carbon dioxide.
Contact of drugs with heavy metals should be
avoided.
Storage should be at reduced temperatures.
Difficult to remove all oxygen from a containers, and
even traces of oxygen are sufficient to initiate the
oxidation chain.

By the addition of compound that can act as


inhibitors which can delay or prevent the
chain reaction of oxidation process of drugs
is the best solution; antioxidants.
Tocopherols, ascorbic acid, gallic acid, etc
Sodium methabisulphite also can act as
antioxidant.
These compound readily oxidised than the
drugs and so protect it from oxidation.
Oxidation is catalysed by unprotones
amines; aminophylline, avoid to admixture
with easily oxidise drugs.

Isomerisation
Process of conversion of a drug into its
optical or geometric isomers.
May regarded as a form of drug degradation.
Often resulting in a serious loss of
therapeutic activity.
Adrenaline in solution form at low pH has
been attributed to racemination that lead to
loss of activity. Conversion of the
therapeutically active form, from laevolaevo-rotary
form into its less active isomer.

In acidic conditions the tetracycline


undergo epimerisation at carbon 4 to form
an equilibrium mixture of tetracycline and
the epimer, 4 epiepi-tetracycline.

Pilocarpine undergoes simultaneous base


catalyzed hydrolysis and epimerization in
aqueous solution.
Epi-tetracycline have much lower
Epitherapeutic activity than natural isomers.
The degradation rate is pH dependence
(max. epimerisation at pH 3.2) and the
reaction is also catalysed by phosphate
and citrate ions.

Both the hydrolysis and the epimerisation


reactions followed pseudo first
first--order rate
equations.
Other drug is cephalosporin ester CE.
CE are used as intermediates in
cephalosporin synthesis and as prodrugs
for oral administration of parentral admin.
CE undergoes reversible basebase-catalysed
isomerisation..
isomerisation

Cis--trans isomerisation may be a cause of loss


Cis
of potency of a drug if the two geometric isomer
have different therapeutic activities.
Isomerisation of a vitamin A to form cis isomers
at the 22- and 66-position leads to decreased
activity compared with the allall-trans molecule.

Photochemical decomposition
(Photolysis)
Light is often catalised oxidation and hydrolysis
When molecules are exposed to electromagnetic
radiation they absorb light (photons) at
characteristic wavelengths
g
which an increase in
energy, which can:
- cause decomposition
- be retained or transferred
- be converted to heat
- result in light emission at a new wavelength
(fluorescence, phosphorescence)

Many drugs, including the phenothiazine


tranquallisers, hydrocortisone,
prednisolone, riboflavine, ascorbic acid
and folic acid are light sensitive.
Phenothiazine chlopromazine (CLP)
(CLP), is
rapidly decomposed under the action of
UV light, follow by discolorisation of the
solutions.

The lost of an electron to yield the


semiquinone free radical R.
Degradation yield the phenazathonium ion
P, react with water to yield
chlorpromazine sulphoxide (CPO).
CPO is itself photolabile and further
decomposition occurs.
Other products are chlorpromazine NN-oxide
and hydroxychlorpromazine.

Chlorpromazine behaves differently under


UV irradiation in anaerobic conditions.
A polymerisation has been proposed.
The polymer isolated after intracutaneous
injection of some patient that have receive
prolonged chlorpromazine medication.
bluishbluish-purple discoloration,
may be a result of the HCl liberation
during photodecomposition.

Drugs can be protected from oxidation by


the use of coloured glass bottle and
storage in the dark.
Amber glass exclude light of wavelength
<470nm, considered can give optimum
protection for drugs that sensitive to light
light.
Coating tablets with a polymer film
containing UV absorbers as additional.

Vinyl acetate containing oxybenzone;


sulphasomidine tablets

Polymerisation
The process by which two or more
identical molecules combine together to
form a complex molecule.
Concentrated aqueous
q
solution of
ampicillin sodium
The reactive -lactam bond of ampicillin
molecule is opened by reaction with the
side--chain of a second ampicillin molecule
side
and a dimer is formed > higher polymer.

Antigenic in animal, they are considered to


play a part in eliciting pencilloylpencilloyl-specific
allergic reactions to ampicillin in man.
Dimerising tedency of ampicillin increases
with the increase in the basicity of the sidesidechain group.
In term of increasing rates;
cyclacillin<ampicillin<epicillin<amoxycillin

Trace metal catalysis


The hydrates of formaldehyde
Under certain conditions polymerise in
aqueous solution to form
paraformaldehyde, which appears as a
white deposit in the solution.
The polymerisation may be prevented by
adding to the solution 10 15 % of
methanol.

the presence of metal can induce some


reaction on drug, such as oxidation.
Other Drug degradations

Temperature
Influence of pH
The degradation of most drugs is catalysed
by extreme pH.
Solvolysis
Chelating agents
Hygroscopicity
Solid--state stability
Solid
ORDER OF REACTION

KINETIC OF CHEMICAL LYSIS


The changes may be;
Before we can predict the shelf life of a
dosage form it is essential to determine the
kinetics of the breakdown of the drug under
carefully
y controlled conditions.
Kinetics is the study of the rate at which
processes occur.

Chemical; decomposition of a drug,


Chemical;
radiochemical decay)
Physical;; transfer across a boundary, such
Physical
as the intestinal lining or skin)

Kinetic study are useful in providing


information that:

gives an insight into the mechanisms of the


change involved
allows a prediction of the degree of change
that will occur after a given time has elapsed

Pre--formulation stability assessment


Pre

Stress condition for stability of assessment

By investigation the intrinsic stability of the


drug it is possible to advise on formulation
approaches and indicate types of excipient,
specific protective additives and packaging
which are likelyy to maintain the stability
y of
drug and product.
The assessment use a stress conditions to
predict drug stability.
Solid;; Heat, Moisture uptake and Physical
Solid
stress.
Aqueous solution;
solution; pH, Light and Oxidation.

Solid
- Heat (
(C); 4, 20, 30, 40, 40/75% RH, 50 and 75.
- Moisture uptake; 30, 45, 60, 75 and 90% RH at
room temperature.
- Physical stress; ball milling.
Aqueous solution
- pH; 1, 3, 5, 7, 9 and 11 at RT and 37 C. Reflux in 1
M HCl and 1 M NaOH.
- Light; UV (245 and 366 nm) and visible at RT
- Sparging with oxygen at RT; UV.

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