Pharmaceutical formulation is the means whereby a drug is converted into a medicine, i.e., to a suitable form for administration to a patient by a particular route. The conversion of a drug into a medicine often involves the addition of pharmaceutical adjuvants (excipients) such as binding agents, disintegrating agents, antioxidants, antimicrobial preservative and emulsifying agents etc. The stability of a medicine relates to the various changes that may occur in the medicine during preparation and storage and to the impact of those changes on its fitness for use.

1. Stability of
Pharmaceuticals
Malay Pandya
Dosage Form Development
B.Pharm
K.B.I.P. E.R.

2. Introduction
 Pharmaceutical formulation is the means whereby a
drug is converted into a medicine, i.e., to a suitable
form for administration to a patient by a particular
route.
 The conversion of a drug into a medicine often involves
the addition of pharmaceutical adjuvants (excipients)
such as binding agents, disintegrating agents,
antioxidants, antimicrobial preservative and emulsifying
agents etc.
 The stability of a medicine relates to the various
changes that may occur in the medicine during
preparation and storage and to the impact of those
changes on its fitness for use.
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3. Some of the possible result of
product instability
 Loss of active drug (e.g. aspirin hydrolysis, oxidation of
adrenaline).
 Loss of vehicle (e.g. evaporation of water from o/w
creams, evaporation of alcohol from alcoholic
mixtures).
 Loss of content uniformity (e.g. creaming of emulsions,
impaction of suspensions).
 Loss of elegance (e.g. fading of tablets and colored
solutions).
 Reduction in bioavailability (e.g. ageing of tablets
resulting in a change in dissolution profile).
 Production of potential toxic materials (e.g. breakdown
products from drug degradation).
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4. Objective
 To provide evidence on how the quality of a drug
substance or drug product varies with the time under
the influence of variety of environmental factors such as
temperature, humidity and light.
 Stability testing permits the establishment of
recommended pack, storage condition, retest periods
and shelf life.
 Useful in development of the product
 Required for registration of application
 Then the FDA was contacted to relay this drug product
quality concern and to provide the necessary facts to
investigate this production lot.
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5. Definition
 Stability is the capacity of a drug product to remain
within specifications established to ensure its identity,
strength quality and purity.
 Instability may cause
 Undesired change in performance, i.e.
dissolution/bioavailability
 Substantial changes in physical appearance of the
dosage form
 Causing product failures
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6. Types of stability studies
1. Physical
2. Chemical
3. Microbiological
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7. Physical stability
 Physical stability implies that
The formulation is totally unchanged throughout
its shelf life and has not suffered any changes by way of
appearance, organoleptic properties, hardness,
brittleness, particle size etc.
 It is significant as it affects:
1. pharmaceutical elegance
2. drug content uniformity
3. drug release rate.
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8. Chemical stability
 Chemical stability implies:
The lack of any decomposition in the chemical
moiety that is incorporated in the formulation as the
drug, preservatives or any other excipients.
This decomposition may influence the physical and
chemical stability of the drug
 Factors
 Temperature • pH • Buffers • Ionic strength •
Dielectric constant of solvent • Oxygen • Light •
Polymorphism • Moisture & Humidity • Excipients
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9. Microbiological stability
 Microbiological stability implies that:
The formulation has not suffered from any
microbiological attack and is meeting the standards
with respect to lack of contamination/sterility.
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10. MALAY PANDYA 10
Reaction rate and order

11. Reaction rate and order
 Reaction rate is the velocity of reaction to convert the
reactants into its product.
 Reactions may be classified according to the order of
reaction, which is the number of reacting species whose
concentration determines the rate at which the reaction
occurs.
 The most important orders of reaction are zero-order
(breakdown rate is independent of the concentration of
any of the reactants), firstorder (reaction rate is
determined by one concentration term) and second-
order (rate is determined by the concentrations of two
reacting species).
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12. Zero-order reactions
 As the name suggests the
decomposition proceeds at a
constant rate and is independent of
the concentrations of any of the
reactants.
 The rate equation is: dx/dt = ko
 Integrating this equation with respect
to time from t=0 to t=t, we get x = kot
 Comparing this equation with y=mx +
c, the plot of concentration(x) vs
time (t) gives a straight line with the
slope ko
 Many decomposition reactions in the
solid phase or in suspensions
apparently follow zero-order kinetics.
 The photo degradation of
sulphonamides drug also follow zero
order rate reaction.
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13. First-order reactions
 As the name suggests the rate depends on the
concentration of one reactant.
 The rate equation is
 Integrating this equation with respect to time from t=0 to t=t
 Where a is the amount of drug degraded at time t, x is the
initial amount of drug, k1 is the rate of reaction.
 The rate of decomposition of a drug A is the change of
concentration of A over a time interval, t, i.e., –d[A]/dt (note
that this is negative because the drug concentration is
decreasing). However, it is more usual to express the rate as
dx/dt, where x is amount of drug which has reacted in time t.
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14.  The rearrangement of the
previous equation gives
 Comparing this equation with
y = mx + c, a plot of time (t)
vs log (a-x), we get
Slope = -2.303/k1
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First-order reactions

15. Second-order reactions
 As the name suggests the rate depends on the
concentration of two reacting species, A and B.
 For the usual case where the initial concentrations of
A and B are different, the rate equation is:
 Where,
a is the initial concentration of A,
b is the initial concentration of B,
x is the amount of drug decomposed
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16. Second-order reactions
 Integrating this equation with
respect to time from t=0 to t=t,
 Rearrangement of the above
equation gives
 Comparing this equation with
y = mx + c, a plot of time (t) vs
log [(a-x)/(b-x)], would yield a
straight line with
slope = 2.303/k2(a – b).
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17. MALAY PANDYA 17
Acid Base Catalysis

18.  The rate of reaction is frequently influenced by the presence
of catalyst.
 i.e. Hydrolysis of sucrose in of water with hyrogen ions as
catalyst.
 Two types
1. Specific acid base catalysis: When the rate law of an
equation involves change in the concnetration of hydrogen
or hydroxyl ions the reaction is said to be specific acid base
catalysis.
2. General acid base catalysis: In addition to the effect of pH
on the reaction rate, there may be catalysis by one of the
more species of buffer, this is called general acid base
catalysis. The effect of the buffer components can be large.
For example, the hydrolysis rate of codeine in 0.05 M
phosphate buffer at pH 7 is almost 20 times faster than in
unbuffered solution at this pH.
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Acid Base Catalyst

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20. Decomposition reactions
 The most causes of decomposition are :
◦ Hydrolysis
◦ Oxidation
◦ Isomerization
◦ Photochemical decomposition
◦ Polymerization
• It is possible to minimize breakdown by optimizing
the formulation and storing under carefully controlled
conditions.
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21. Hydrolysis
 Drugs containing ester, amide, lactam, imide or
carbamate groups are susceptible to hydrolysis.
 Hydrolysis can be catalyzed by hydrogen ions (specific
acid catalysis) or hydroxyl ions (specific base catalysis).
 Solutions can be stabilized by formulating at the pH of
maximum stability or, in some cases, by altering the
dielectric constant by the addition of non-aqueous
solvents.
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22. Oxidation
 Oxidation involves the removal of an electropositive atom, radical or
electron, or the addition of an electronegative atom or radical.
 Oxidative degradation can occur by auto- oxidation, in which reaction
is unanalyzed and proceeds quite slowly under the influence of
molecular oxygen, or may involve chain processes consisting of three
concurrent reactions: initiation, propagation and termination.
 Examples of drugs that are susceptible to oxidation include steroids
and sterols, polyunsaturated fatty acids, phenothiazines, and drugs
such as simvastatin and polyene antibiotics that contain conjugated
double bonds.
 Various precautions should be taken during manufacture and storage
to minimise 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.
 Storage should be at reduced temperatures.
 Antioxidants should be included in the formulation.
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