Principles and kinetics of drug

stability (PHR 416)

Nahla S Barakat, PhD

Professor of Pharmaceutics
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 Pure drugs, solids, liquids, or gases are usually more

stable than their formulations.

When they are formulated into medicines decomposition
happens faster because of the presence of excipients, and
moisture and because of processing .

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Factors affecting drug stability

Each ingredient, whether therapeutically active or

pharmaceutically necessary can affect the stability of

drug and dosage forms.
The primary environmental factors that can reduce
stability include exposure to adverse temperature ,
light, humidity, oxygen, carbon dioxide.
The major dosage form factors that influence drug
stability include particle size (emulsion, suspension),
pH, solvent composition (% of free water and polarity),
solution ionic strength, compatibility of anion and
cation, primary container, specific chemical additive.

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The chemical decomposition of the

drug
In this lecture we examine various ways in which drugs in both
liquid and solid formulations can lose their activity, so that we
can be aware of those chemical groups which, when present in
drug molecules, can cause stability problems.
We will later see how to prevent or minimize the chemical
breakdown for each type of decomposition process.
It should be noted that with some drug molecules more than one
type of decomposition may be occurring at the same time; this,
of course, complicates the analysis of the system.

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Drugs susceptible to hydrolytic

degradation
How can we tell whether a drug is likely to be
susceptible to this type of degradation?
If the drug is a derivative of carboxylic acid or
contains
functional groups based on this moiety,
for example an ester, amide, lactone,
lactam,
imide or carbamate,
Examples of chemical groups susceptible to hydrolysis
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 Drugs that contain ester linkages include acetylsalicylic acid (aspirin),

physostigmine, methyldopate, tetracaine and procaine.

Ester hydrolysis is usually a bimolecular reaction involving acyloxygen
cleavage. For example, the hydrolysis of procaine is shown in Scheme 1
The hydrolysis of amides involves the cleavage of the amide linkage as
but at slower rate than esters, for example, in the breakdown of the local
anaesthetic procaine, cinchocaine (Scheme 2)
This type of link is also found in drugs such as chloramphenicol,
ergometrine and benzylpenicillin sodium.
As examples of lactam ring hydrolysis we can consider the decomposition
of nitrazepam and chlordiazepoxide, penicillin, cephalosporine.
The major chemical accelerator or catalysit of hydrolysis of lactam are
adverse pH and specific chemicals (e.g. dextrose and copper in case of
ampicillin hydrolysis)
Lactones, or cyclic esters pilocarpine, dalvastatin and warfarin undergoes
hydrolysis due to ring opening.
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.Hydrolysis of the ester group of procaine

Hydrolysis of the amide linkage of cinchocaine

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 Barbiturates, hydantoins, and imides contain

functional groups related to amides but tend to be

more reactive.
Barbituric acids such as barbital, phenobarbital
and amobarbital, undergo ring-opening hydrolysis.
Decomposition products formed from these drug
substances are susceptible to further decomposition
reactions such as decarboxylation.

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Controlling drug hydrolysis in solution

Optimisation of formulation
Hydrolysis is frequently catalysed by hydrogen ions (specific acidcatalysis) or hydroxyl ions (specific base-catalysis) and also by
other acidic.
Several methods are available to stabilize a solution of a drug
which is susceptible to acidbase catalysed hydrolysis. The usual
method is to determine the pH of maximum stability from kinetic
experiments at a range of pH values and to formulate the product
at this pH .
Alteration of the dielectric constant by the addition of no-naqueous
solvents such as alcohol, glycerin or propylene glycol may in many
cases reduce hydrolysis.
In many cases solubilization of a drug by surfactants protects
against hydrolysis

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 it is possible to suppress degradation by making the

drug less soluble. The stability of penicillin in

procainepenicillin suspensions was significantly
increased by reducing its solubility by using additives
such as citrates, dextrose, sorbitol and gluconate.
Adding a compound that forms a complex with the
drug can increase
stability.
Ex. The addition of caffeine to aqueous solutions of
benzocaine, procaine and tetracaine was shown to
decrease the base-catalysed hydrolysis of these
local anaesthetics in this way.
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2- Oxidation

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Oxidative degradation can occur by autoxidation, in

which reaction is uncatalysed and proceeds quite slowly
under the influence of molecular oxygen, or may involve
chain processes.
Steroids and sterols represent an important class of drugs
that are subject to oxidative degradation through the
possession of carboncarbon double bonds
polyunsaturated fatty acids, commonly used in drug
formulations, are particularly susceptible to oxidation
Polyene antibiotics, such as amphotericin B which
contains seven conjugated double bonds (heptaene
moiety), are subject to attack by peroxyl radicals,
leading to aggregation and loss of activity.
The ether group in drugs such as econazole nitrate (III)
and miconazole nitrate (IV) is susceptible to
oxidation
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 Stabilisation against oxidation

Various precautions should be taken during manufacture

and storage to minimize oxidation. The oxygen in

pharmaceutical containers should be replaced with
nitrogen or carbon dioxide; contact of the drug with
heavy-metal ions such as iron, cobalt or nickel, which
catalyse oxidation, should be avoided; and storage
should be at reduced temperatures.
Antioxidants
It is very difficult to remove all of the oxygen from a
container and even traces of oxygen are sufficient to
initiate the oxidation chain. by adding low concentrations
of compounds that act as inhibitors.
Such compounds are called antioxidants
Reducing agents such as sodium metabisulfite may also
be added to formulations to prevent oxidation. These
compounds are more readily oxidized than the drug
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3- Isomerisation
Isomerisation is the process of conversion of a drug

into its optical or geometric isomers. Since the

various isomers of a drug are frequently of different
activity, such a conversion may be regarded as a
form of degradation, often resulting in a serious loss
of therapeutic activity. For example, the appreciable
loss of activity of solutions of adrenaline at low pH
has been attributed to racemisation the
conversion of the therapeutically active form, in this
case the levorotary form, into its lessactive isomer.

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In acidic conditions the tetracyclines undergo

epimerisation at carbon atom 4 to form an

equilibrium mixture of tetracycline and the
epimer, 4-epi-tetracycline .
The 4-epi-tetracycline is toxic and its content
in medicines is restricted to not more than
3%.
Vitamin A (all-trans-retinol) is enzymatically
oxidized to the aldehyde and then isomerised
to yield 11-cis-retinal , which has a decreased
activity compared with the all-trans molecule

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4- Photochemical decomposition
Many pharmaceutical compounds, including

the phenothiazine tranquillizers,

hydrocortisone, prednisolone, riboflavin,
ascorbic acid and folic acid, degrade when
exposed to light.
As a result there will be a loss of potency of
the drug, often accompanied by changes in
the appearance of the product, such as
discoloration or formation of a precipitate.

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sunlight is able to penetrate the skin to a

sufficient depth to cause photodegradation

of drugs circulating in the surface
capillaries or in the eyes of patients
receiving the drug.
The rate of the photodegradation is
dependent on the rate at which light is
absorbed by the system and also the
efficiency of the photochemical process

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Stabilization against photochemical decomposition

Pharmaceutical products can be adequately protected from
photo-induced decomposition by the use of coloured glass
containers and storage in the dark.
Amber glass excludes light of wavelength 470 nm and so
affords considerable protection of compounds sensitive to
ultraviolet light.
Coating tablets with a polymer film containing ultraviolet
absorbers has been suggested as an additional method for
protection from light.
In this respect, a film coating of vinyl acetate containing
oxybenzone as an ultraviolet absorber has been shown to
be effective in minimizing the discoloration and photolytic
degradation of sulfasomidine tablets.

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5. Polymerisation
Polymerisation is the process by which two or

more identical drug molecules combine

together to form a complex molecule. It has
been demonstrated that a polymerisation
process occurs during the storage of
concentrated aqueous solutions of
aminopenicillins, such as ampicillin sodium.
The process can continue to form higher
polymers. Such polymeric substances have
been shown to be highly antigenic in animals

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The hydrate of formaldehyde, HOCH2OH,

may under certain conditions polymerise in

aqueous solution to form
paraformaldehyde, HOCH2(OCH2)nOCH2OH,
which appears as a white deposit in the
solution.
The polymerisation may be prevented by
adding to the solution 1015% of methanol.

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6- Dehydration
The preferred route of dergradation of Prostaglandin E2 and

tetracycline is the elimination of water molecule from their

structures. Acid catalyzed dehydration of tetracycline form

epianhydrotetracycline, a product that lack antibiotic

activity and causes toxicity.
The driving force for this type of covalent dehydration is the

formation of a double bond .

In physical dehydration such as those occurring in theophyline
hydrate and ampicillin trihydrate, water removal does not create
new bond but often change s the crystalline structure of the
drug.
Dehydration reactions involving water of crystallization may
potentially affect the absorption rate of the dosage form.

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7- Incompatibilities
Chemical interactions between two or more

drug components in the same dosage form, or

between active ingredient and a
pharmaceutical excipient, occur frequently.
Ex., inactivation of cationic aminoglycoside
antibiotic and anionic penicillins in IV
admixture . The formation of inactive complex
between these two classes of antibiotics
occurs not only in vitro but also in vivo in
patients with severe renal failure.

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Incompatibilities have also been observed in

solid dosage forms. A typical tablet contain

binders, disintegrant, lubricant and fillers.
Screening model may predict interaction of
drug substances with excipients.
Many pharm. Incompatibility are the result of
reactions involving the amine functional group
Table 1

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Reaction of bisulphite and antioxidant

epinephrine, a catecholamine, undergoes

displacement of its hydroxyl group by

bisulfite.
Dexamethasone 21-phosphate, an /unsaturated ketone, is known to undergo
addition by bisulfite.

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Table 1. some potential drug

incompatibility

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Other chemical degradation reactions

Such as hydration, decarboxylation, or pyrolysis

are also potential routes for drug degradation. E.g.

Cyanocobalamin may absorb about 12% of water
when exposed to air, and p-aminisalicylic acid
decomposes with evolution of carbon dioxide to
form m-aminophenol when subject to
temperature above 40 C.

Decarboxylation-some dissolved carboxylic acids,

such as p-aminosalicylic acid, lose carbon
dioxide from the carboxyl group when heated.
The resulting product has reduced
pharmacological potency.
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Physical degradation route

Polymorphic transformation:
Exposure to changes in temperature, pressure, relative

humidity and comminution during drying, granulation,

milling and compression may lead to polymorphic
transformation
Steroids, sulfonamides and barbiturates can form
polymorphs
Polymorph may exhibit significant differences in
physicochemical parameters such as solubility, melting
point, dissolution rate.
Ex. Conversion of more soluble crystal form (form II) of
cortisone acetate to a less soluble crystal form (form V)
when the drug is formulated as an aqueous suspension.

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The phase change leads to caking of the

cortisone acetate suspension

conversion from solvated to nonsolvated form
or hydrate to anhydrous can lead to change in
solid-state properties.
For example: a moisture-mediated phase
transformation of carbamazepine to the
dihydrate has been reported to be responsible
for whisker growth on the surface of tablets.
The effect can be retarded by inclusion of
Polyoxamer in the tablet formulation.
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Another physical property that affect the

appearance, bioavailability and chemical

stability is degree of crystalinity.
Amorphous materials tend to be more
hygroscopic than their crystalline form.
Also amorphous form of drugs are less stable
than their crystalline form.
Example: the crystalline cyclophosphamide is
much more stable than the amorphous form.
The amorphous form of biosynthetic human
insulin is more stable
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Vaporization
Flavours, are mainly ketones, aldehyde, and

ester and cosolvents may be lost from the

formulation
Example: nitroglycerine, significant drug loss to
the environment can occur during patient
storage and use.
(FDA)
The addition of macromolecules such as PEG,
PVP and MCC allows for preparation of
stabilized nitroglycerin SL tablet
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Aging
Changes in the disintegration and dissolution

characteristics of the dosage forms are caused by

alteration in the physicochemical properties of
the inert ingredients or the active drug in the
dosage form,
Changes in the processes as a function of the age
of the dosage form may result in corresponding
changes in the bioavailability of the drug product
Melting time of aminophylline supp increase from
20 min- 1 hr after 24 weeks storage at 22 C.
Aging of solid dosage form can cause a decrease
in their in vitro rate of dissolution

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Adsorption
Up to drug loss can occur after nitroglycerine is

stored in PVC infusion bags for 7 days at room

temperature. This loss can be attributed to
adsorption
More than 40% of a dose of quinidine gluconate
when the drug was administered with a
conventional PVC intravenous administration
set.
Drug loss was reduced by using a winged iv
cather and short tubing
Diazepam, isosorbide dinitrate, insulin has
shown substantial adsorption to PVC

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