Reaction kinetics

By
A. S. Adebayo, Ph. D.

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KINETICS
 Applications
 Chemical reactions such as
decomposition of medicinal
compounds
 Processes of drug absorption,
distribution and elimination from the
body
 Shelf life determination.
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Shelf life determination
 In determining the shelf life of a preparation,
tests are carried out on the active ingredient,
the additives and the finished product to
determine:
 Whether decomposition will occur
 The type of decomposition
 Factors that affect the rate of decomposition
such as light, air, moisture, temperature, etc.
 The influence of formulation additives
 The rate at which breakdown occurs.

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Rate of Reaction
Expressing speed of a reaction:
 as the decrease in concentration of any reacting
substance
 as the increase in concentration of the product per
unit time.
 If C is the concentration, then the rate of
reaction:
dC
C n

dt
 where n=0,1 or 2 for zero, first & second order
reactions respectively
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Order of Reaction
 Manner in which the rate of reaction
varies with the concentration of the
reactants
 Most processes involving ADME can be
treated as first- order processes
 Some drug degradation processes can
be treated as either First or zero order
processes
 Some drug substances obey Michaelis-
Menten kinetic process

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First Order Kinetics

 n=1 and the reaction rate is dependent

on the concentration of one of the
reactants in the formulation.
dC
   kC
dt
 C is the concentration remaining un-
decomposed, unabsorbed, yet to be
distributed, metabolized or excreted at
time t as the case may be
 k is the first order rate constant.

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First Order Kinetics (cont.)

 On integration, the equation above gives:

ln C  ln Co  k t  0
 On rearrangement and conversion to log
in base 10:
kt
log C  log Co 
2.303

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Log concentration versus time

Log
Conc Slope = -k/2.303
.

Time

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Exercises??

 Determine the expression for rate

constant, k
 Determine the expression for process
half-life, t1/2
 Write the exponential forms of the
equation in natural log and log in base
10.
 What is the significance of process half-
life?
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Zero order reaction

 In this type of reaction, n=o and the

reaction rate is independent of the
concentration of the reacting substance.
 The rate of change is constant.
 Here, factors other than concentration of
reactants constitute the limiting factor
e.g. solubility or absorption of light
(photochemical reactions).

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Zero order reaction (cont.)
 When solubility is the limiting factor, only
the proportion of drug in solution
undergoes degradation:
 As the drug is consumed in the degradative
reaction, more drug goes into solution until
all solid (C) has reacted.
 Until this has happened, the degradation
process will not be dependent on the total
conc. of drug but on the proportion in
solution, thereby producing a zero order
process.

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Zero order reaction (cont.)

 Zero order Equation:

 dCo
k
dt

 Co= original concentration of reacting

material, k=reaction rate constant, dt=
change in time.

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Zero order processes

 Expression of zero order equation:



Ct  Co  kt
 Ct=conc. at time t, Co=conc. at time o.
 Plot of C against t gives a straight line
with slope of -ko

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Concentration versus time (Zero-
order plot)

Conc
Slope = -k0

Time

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Reaction half-life (Zero-order)

 For a zero order reaction, the time for

50% reaction, t½, is given as:
1Co Co
t1 / 2  2

ko 2k o

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Apparent Zero Order Reaction
Kinetics

 Suspensions are a special case of zero order

kinetics, in which the concentration of drug in
solution depends on its solubility.
 As the drug in solution decomposes, more of it
is released from a reservoir of suspended
particles thereby making the concentration in
solution constant.
 The effective concentration is the drug
equilibrium solubility in the solvent of
formulation at given temperatures

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Apparent Zero Order Reaction
Kinetics (Cont.)
 Ordinarily, the equation for
decomposition is first order:
 d C 
 k C 
dt

C=the conc. of drug remaining un-

decomposed at time t
 k=the known first order rate constant.

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Apparent Zero Order Reaction
Kinetics (Cont.)
 When concentration is rendered constant
by suspended particles offering
replacement, then

k C   ko
 thereby turning the first order rate law
into;  d C 
 ko
 dt
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Chemical instability

 Can present as;

 Loss of potency
 Accumulation of toxic degradative products
 Degrardation of excipient responsible for product
stability e.g. emulsifying agents, preservatives
 Conspicuous colour change e.g. marked
discoloration of adrenaline although very slight
change in adrenaline content, is unacceptable to
patients, pharmacists, physicians and the nurses.

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Solid state versus solution stability

 Generally, chemical reactions proceed

more readily in liquid state than in solid
state
 Serious stability problems are more
commonly encountered in liquid
medicines e.g. order of dosage form
stability is generally: solution <
suspension < tablet.

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Determination of Order of Reaction

 Use of rate equation – The data

collected in a kinetic reaction should be
substituted into the integrated form of
equations of various orders.
 The process under test should be
considered to be of that order where the
calculated k value remains constant within
limits of experimental error.

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Determination of Order of Reaction..

 Half life method – For a zero order or pseudo

first order reaction, t ½ is proportional to initial
concentration of reactant (Co),
 t½ for a first order reaction is independent of
Co, .
 Graphical method – For a zero order or
pseudo first order reaction, plot of C vs. t is
linear; for first order reaction, plot of log (Co-
Ct) vs. t is linear.

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Factors Affecting Rate of Reactions

 The rate of reaction (degradation of

pharmaceutical products) can be influenced
 temperature,
 moisture,
 solvent (pH, dielectric constant, etc),
 light (radiation),
 catalysts,
 oxygen and
 concentration of reactant (s).

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Temperature

 Temperature – Rate of most chemical

reactions increase with rise in
temperature up to 2 to 3 times with each
10° rise in temperature.
 The relationship is expressed by
Arrhenius equation: E
 RTa
k  Ae

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Arrhenius equation
 Log transformation gives:
Ea 1
log k  log A 
2.303 RT
 k is the rate of reaction
 A is a constant known as the frequency factor
Ea is the activation energy,
 R is the gas constant (1.987 calories deg-
1mole-1 OR 8.314 J mole-1)

 T is the absolute temperature.

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Arrhenius equation….

 Plot of log k against 1/T gives a straight

line with slope of –Ea/2.303R and
intercept of log A.
 For a reaction carried out at 2 diff. temp.,
(subtracting eqn. 1 from 2 gives:
k2 Ea T2  T1 
log 
k1 2.303R T2T1

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Activation Energy: Arrhenius
Equation
 The degradation of a new cancer drug
follows first-order kinetics and has
degradation rate constants of 0.0001 H-1
at 60 ºC and 0.0009 H-1 at 80 ºC. What is
its Ea?

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Stability Projection for Shelf Life

 The time required for 10 % of the drug to

degrade with 90 % of intact drug
remaining is based on Arrhenius
equation: k 2 Ea (T2  T1 )
log 
k1 2.303RT1T2

k = reaction rate, T = temperature,

 R = gas constant, Ea = activation
energy

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Concept of Q10
k (T 10)
Q10 
KT

 Q values of 2 (Ea ≈ 12.2 kcal/mole), 3

(Ea ≈ 19.4 kcal/mole), and 4 (Ea ≈24.5
kcal/mole) are commonly used
 They represent the energies of activation
of the reactions around room
temperature.

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Concept of Q10…..
 Q10 estimates can be t 90 (T1 )
made with the equation: t 90 (T2 )  T 
 where t90T2 is the Q10 10
estimated shelf life
 t90T1 is the shelf life at a
given temperature
 ∆T is the difference in
temperature between T1
and T2 (i.e. T2 – T1)
 Increase in ∆T will
decrease shelf life while
a decrease in ∆T will
increase shelf life

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Shelf-life Prediction
 Shelf-life at different storage temperature can
be estimated as:
t 90 (T1 )
t 90 (T2 )  T 
Q10 10
 t90T2 is the estimated shelf life
 t90T1 is the shelf life at a given temperature
 ∆T is the difference in temperature between T1
and T2
 Increase in ∆T will decrease shelf life while a
decrease in ∆T will increase shelf life

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TUTORIAL QUESTIONS
1 An ophthalmic solution has a shelf life of 6
hours at room temperature (25 °C).
Calculate the estimated shelf-life in a
refrigerator (5 °C)
2 An antibiotic has a shelf life of 48 hours in
the refrigerator (5 °C). What is its estimated
shelf-life at room temperature (25 °C)?
3 In what ways can chemical instability be
manifested on formulated products? List and
discuss four main types of reactions involved
in chemical degradation.

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TUTORIAL QUESTIONS
4. A drug suspension (125 mg/ml) decays by zero-order
kinetics with a reaction rate constant of 0.5 mg/ml/hr.
What is the concentration of intact drug remaining
after 3 days?
5. How long will it take for the suspension in question 4
above to reach 90 % of its original concentration?
6. An ophthalmic solution of a mydriatic drug present at
5 mg/ml concentration exhibits first order degradation
with a rate of 0.0005/day. How much drug will remain
after 120 days? How long will it take for the drug to
degrade to 90 % of its original concentration?

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TUTORIAL QUESTIONS

7.The rate constant for decomposition of 5-

hydroxymethylfurfural was 1.173 H-1 at
120 ºC and 4.860 H-1 at 140 ºC. What is
the activation energy and frequency
factor, A in sec-1 for the breakdown of
5HMF in this temperature range?

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TUTORIAL QUESTIONS
8. Analysis of the rate of ºC K
degradation of a
colourant in a multi-sulfa
drug preparation shows
40 0.00011
the following results:
 Assuming a first- 50 0.00028
order process,
compute the 60 0.00082
activation energy and
the value of K at 25
ºC 70 0.00196

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THANK YOU FOR YOUR
ATTENTION

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