Chapter 14

CHEMICAL KINETICS
AND STABILITY
Stability testing provide evidence on how the
quality of a drug varies with time under the
influence of a many environmental factors as:
- Temperature
- Humidity
- Light
and to estimate the shelf life for the drug and
recommended storage conditions
This chapter introduces the rates and mechanisms
of reactions with particular emphasis on
decomposition and stabilization of drug products.
 Rates, Order, and Molecularity of
Reactions
aA + bB cC + dD

Rate constant Order of reaction

 Molecularity and order of reaction

A reaction occurs through several elementary steps . If a

reaction proceeds through several steps, the order and
not the molecularity is used in the rate law.

, unimolecular reaction

, Bimolecular reaction

, Rare, Termolecular reaction

The order and molecularity are identical only for
elementary reactions. Bimolecular reactions may or may
not be second order.
Determine the rate law for the reaction and identify any intermediate or
catalyst in the reaction.

, rate determining step.

+2 +
 Specific Rate Constant
The constant, k, is called the specific rate constant.
Any change in the conditions of the reaction as
temperature, solvent, or a slight change in one of the
reacting species, will lead to a rate law having a different
value for the specific rate constant.
Rate constants derived from reactions consisting of a
number of steps of different molecularity are functions
of the specific rate constants for the various steps. Any
change in the nature of a step due to a modification in
the reaction conditions or in the properties of the
molecules taking part in this step could lead to a change
in the value of the overall rate constant
 Units of the Basic Rate Constants

zero-order reaction

first-order reaction ,

second-order reaction ,
 Zero-Order Reactions

When this linear equation is plotted with [A] on the

vertical axis against t on the horizontal axis, the slope of
the line is equal to -k0

the half-life is the time required

for one-half of the material to
disappear
Integrated Rate Law
Suspensions. Apparent Zero-Order Kinetics
Suspensions are another case of zero-order kinetics
The concentration in solution depends on the drug's
solubility. As the drug decomposes in solution, more
drug is released from the suspended particles so that
the concentration remains constant. This concentration
represents the drug's equilibrium solubility in a
particular solvent at a particular temperature. The
important point is that the amount of drug in solution
remains constant despite its decomposition with time.
The reservoir of solid drug in suspension is responsible
for this constancy
The equation for an ordinary solution, with no reservoir
of drug to replace that depleted, is the first-order:

As [A] is the concentration of undecomposed drug at

time t, and k is known as a first-order rate constant. But
if the concentration [A] remains constant, as in a
suspension then
 First-Order Reactions

If linear equation is obtained when is plotted

versus t the reaction is considered to be first order
reaction and the slope = -
A solution of a drug contained 500 units/mL
when prepared. It was analyzed after 40 days
and was found to contain 300 units/mL.
Assuming the decomposition is first order, at
what time will the drug have decomposed to
one-half of its original concentration?
 Half-Life for first order reaction
The period of time required for a drug to decompose to
one-half of the original concentration.
The half life of first order reactions is
independent of the initial
concentration of reactants

A substance decomposes at 320 oC with a rate

constant of 3.72 × 10-5 s-1.
a) Calculate the half-life of the reaction.
b) What fraction will remain undecomposed if the
substance is heated for 2.5 hours at 320 oC?
Second-Order Reactions:
A → P or A + B → P when [A]₀ = [B]₀

• The equation is given as: • Half-Life for second

order reaction

• By integration:
Example 14-5
Saponification of Ethyl Acetate

The reaction of saponification of ethyl acetate at 25°C

is given as:
CH3COOC2H5 + NaOH CH3COO-+Na + C2H5OH
The initial concentrations of both ethyl acetate and
sodium hydroxide in the mixture were 0.01000 M. The
change in concentration, x, of alkali during 20 min
was 0.000566 mole/liter.
Compute
(a) the rate constant
(b) the half-life of the reaction
The following data have been obtained for the decomposition of
N2O5 at 340 K according to the following reaction
2 N2O5(g) → 4 NO2(g) + O2 (g)

Time/min 0 1 2 3 4 5
)mol/L( ]N2O5[ 1.000 0.705 0.497 349 .0 0.246 0.173

•What is the order of the reaction?

•What is the value of the rate constant?
The gas-phase reaction:
NO3 NO2 + ½O2
obeys second order kinetics. At a temperature of
20oC the initial concentration on NO3 equal to
0.50 mol/L and after 60 minutes the
concentration is equal to 0.35 mol/L.
•What is the rate constant of this reaction?
•What is the half-life of the above reaction?
A hypothetical chemical reaction with a single reactant is
40.0% complete after 185 s at some fixed temperature and
at initial concentration is 0.100 mol L−1.
•If the reaction is first order, find the rate constant and the
half-life.
•If the reaction is second order, find the rate constant and
the half-life.
Pseudo-first order reaction
 The time and amount of decomposition of 0.056 M
glucose at 140°C in an aqueous solution containing 0.35 N HCl
were found to be:

What are :
- order
- half-life
- specific reaction rate
of this decomposition?
Can one unquestionably
determine the order from
the data given?

Pseudo-first order reaction

] A[ ln[A] ]A[/1 delta ln delta 1/[A]

551 6.311735 0.001815 0.03697- 6.83571E-05

531 6.274762 0.001883 0.02479- 4.72628E-05

518 6.249975 0.001931 0.03138- 6.15299E-05

502 6.2186 0.001992 0.03034- 6.13562E-05

487 6.188264 0.002053 0.07458- 0.000159001

452 6.113682 0.002212 0.04757- 0.000107796

431 6.066108 0.00232 0.04751- 0.000112904

411 6.018593 0.002433

 6.3

6.2
ln [glucose]

Equation y = a + b*x
6.1 Weight No Weighting
Residual Sum 3.48496E-4
of Squares
Pearson's r -0.99771
Adj. R-Square 0.99467
Value Standard Error
Intercept 6.32663 0.00487
C
Slope -0.02574 7.12328E-4
6.0

0 5 10 15
time
 Second-Order Reactions: A + B→ P

[A]₀ ≠ [B]₀
A second order reaction of the type: A + B → P was
carried out in a solution that was initially 0.050 M
of A and 0.080 M of B. After 1.0 h the
concentration of A had fallen to 0.020 M.
a) Calculate the rate constant.
b) What is the half-life of the reactants?
For A + B → products

For A + 2B → products
 Complex Reactions
Reactions that have more than one
elementary reaction are known as complex
reactions. Examples of these reactions are:
a) Reversible reactions
b) Parallel reactions
c) Consecutive reactions.
 Reversible Reactions A B

At any time [A] + [B] = [A]o

As t
 k
Problem: A B
For a hypothetical reaction: k'

That is first order in both directions with k=17.7 min−1 and k'=32.2 min−1. If
the initial concentration of A is equal to 0.175 mol L−1 and the initial
concentration of B is equal to zero find [A]eq and [B]eq.
Parallel or Side
Reactions

k = k1 + k2
Series or Consecutive Reactions
k1 k2
A B C

(14-54)

(14-55)
The Steady-State Approximation

Michaelis–Menten Equation
A number of kinetic processes cannot have their rate laws
integrated exactly so approximation or numerical analysis can be
used. If the derived rate law is reasonably accurate it should
match the rate law that obtained experimentally.

The steady-state approximation is used to reduce the labor in

derivation of a rate law. Example of this approximation is the
Michaelis–Menten equation.

k1 k3
E+S ES P+E
k2
Thus, under steady-state conditions, the rate of product formation
is given by

The maximum velocity for the Michaelis–Menten

Vm = (dP/dt)maximum
When S is very large, all enzyme E0 is present as E·S (all enzyme is combined
with the substrate) and the reaction proceeds at maximum velocity. As
dP/dt becomes Vm then
Vm = k3E0
because E · S is equivalent to E0 and equation 14-65 becomes:
Equation (14-66) can be inverted to obtain a linear expression
known as the Lineweaver–Burk equation

A plot of 1/V versus 1/S yields a straight line with an intercept

on the vertical axis of 1/Vm and a slope of Km/Vm
Example:
The velocity, V, of an enzymatic reaction at increasing substrate
concentration [S] was experimentally determined to be as follows:
Rate-Determining Step Overall reaction
In a reaction sequence in which one step A+C P
is much slower than all the subsequent
steps leading to the product, the rate at
which the product is formed may
depend on the rates of all the steps
preceding the slow step but does not Applying steady-state approximation
depend on any of the steps following.
The slowest step in a reaction sequence
is called the rate-determining step
k1
A B
k2

k3
B+C D
k4
D P
If step 3 is the slow step if step 2 (the reverse
(the rate-determining reaction) is the slow step,
step) then: then:
k2 ≫ k3 C k3C ≫ k2
equation (14-69) is equation (14-69) reduces to
simplified to a second- a first-order expression
order expression:
Quiz (first lecture)

In the Michaelis-Menten equation show that when = then

Quiz (second lecture)

Derive the rates of the intermediates from the following

Mechanism:

Slow
 Temperature Effects
Factors that affect the reaction velocity are temperature, solvents,
catalysts, and light.
Reaction rates α number of collisions per unit time.
Number of collisions ↑ as the temperature ↑
Reaction rate is expected ↑ as temperature ↑.
The speed of many reactions increases about two to three times
with each 10°C rise in temperature. As a reaction proceeds from
reactants to products, passing a “barrier” is what prevents the
reactants from immediately becoming products. The activation
energy, Ea is a measure of this barrier. The effect of temperature
on reaction rate is given by Arrhenius equation:

(14-72)
k : specific reaction rate
A : a constant known as Arrhenius
factor or the frequency factor
Ea : energy of activation
R : gas constant (8.314 J/K mol)
T : the absolute temperature
Example 14-7
Decomposition of 5-HMF

The rate constant k1 for the decomposition of 5-

hydroxymethylfurfural at 120°C is 1.173 hr-1 and k2 at
140°C is 4.860 hr-1.
a) What is the activation energy, Ea
b) Find the value of frequency factor, A for the
breakdown of 5-HMF within this temperature range?
Additional example:
A first-order decomposition reaction is observed to have the
following rate constants at the indicated temperatures.
Estimate the activation energy.
Classic Collision Theory of Reaction Rates

The Arrhenius equation is an empirical relation giving

the effect of temperature on an observed rate
constant.
When collisions between molecules occur, only certain
fraction of the molecules when collide have kinetic
energy > activation energy which may lead to
products.
According to Boltzmann distribution law
Z: collision number or number of collisions/s cm³
P: steric or probability factor

Energy factor
 Q10 Calculations
Connors et al. described a straightforward calculation to
understand the temperature effects. Using this method, one can
estimate the effect of a 10° rise in temperature on the stability
of pharmaceuticals.
Q10 approximation: a method useful for making quick
calculation
As noted by Connors et al:
Activation energies for drug decompositions ≈12 to 24
kcal/mole ≈ 50 to 100 kJ/mol
Typical values 19 to 20 kcal/mole ≈ 80-85 kJ/mol
Q10 = 2, 3, and 4 when Ea = 12.2, 19.4, and 24.5 kcal/mol
As temperature rises from 20°C to 30°C.
Degradation rate of most pharmaceutical agents increases
by 2 to 4 times (average 3 times) for a 10°C rise in
temperature (from 20°C to 30°C) that typical consumers
will experience. The more advanced student may be
interested in generalizing the Q10 approach to estimate the
effect of increasing or decreasing the temperature by
variable amounts.
 Transition-State Theory
An alternative to the collision theory is the transition-
state theory

A + B A B P

Normal reactant molecules Activated complex Product

The Arrhenius activation energy, Ea, is related by the enthalpy of
activation of the transition state:
Eyring showed that the quantity v can be considered,
to a good approximation, as a universal factor for
reactions, depending only on temperature that it can
be written as:

The collision theory and the transition-state theory are seen to

be related by comparing equations

The collision number (Z) probability factor, P

Example 14-11
Acid-Catalyzed Hydrolysis of Procaine
In the study of the acid-catalyzed hydrolysis of procaine, Marcus
and Baron obtained the first-order reaction rate (k), from a plot of
log c versus t and the activation energy (Ea), from an Arrhenius plot
of log k versus 1/T. The values were k = 38.5 × 10-6 sec-1 at 97.30°C
and Ea = 16.8 kcal/mole (70.3 kJ/mol)
Compute ΔS‡ and the frequency factor, A, using equations (14-97)
and (14-98), and the probability factor P. It is first necessary to
obtain RT/Nh at 97.30°C or about 371 K:

Plank constant (h) = 6.626 × 10−34 J∙s

Boltzmann constant (kB or k) = 1.38× 10−23 J/K
 Medium Effects: Solvent, Ionic Strength,
Dielectric Constant
The influence of the solvent on the rate of
decomposition of drugs is very importance although the
process is complicated. The dissolving is related to the
relative internal pressures (solubility parameters) of the
solvent and the solute. Factors as ionic strength and the
dielectric constant of the solvent are also significant.
where V2 is the molar volume of the solute and δ1 and
δ2 are the solubility parameters for the solvent and
solute, respectively.
Influence of Ionic Strength
In a reaction between ions, reactants A and B have charges zA and zB
respectively. The activated complex (A ··· B)‡ has a charge of (zA + zB).
A reaction involving ions can be represented as
where k0 is the rate constant in an infinitely dilute
solution in which µ= 0.
A plot of log k against õ should give a straight line with
a slope = 1.02zAzB
If one of the reactants is a neutral molecule, zAzB = 0,
and the rate constant, as seen from equation (14-113),
should then be independent of the ionic strength in
dilute solutions. Good agreement has been obtained
between experiment and theory
 Equation (14-113) express the kinetic salt effect, the variation of
the rate constant of a reaction between ions with ionic strength
of the solution. If the reactant ions have the same sign (as the
reactions between cations or anions) then increasing the ionic
strength by the addition of inert ions increases the rate constant.
The formation of a single, highly charged ionic complex from two
less highly charged ions is favored by high ionic strength because
the new ion has a denser ionic atmosphere and interacts with
that atmosphere more strongly. But if ions of opposite charges
react more slowly in solution of high ionic strength. The charges
cancel and the complex has a less favorable interaction with its
atmosphere than the separated ions.
If the reacting molecules are uncharged in a solution
having a reasonable ionic strength, the rate expression is:

where b is a constant obtained from experimental data.

The rate constant for the base hydrolysis of
[CoBr(NH3)5]2+ varies with ionic strength as tabulated
below. What can be deduced about the charge of the
activated complex in the rate-determining stage?
Catalysis: Specific and General Acid–Base and pH Effects

Rate of a reaction is frequently influenced by the presence of a

catalyst. Hydrolysis of sucrose in the presence of water at room
temperature proceeds has a –ve value of ΔG° but the reaction is
so slow as to be negligible. The inversion proceeds at a measurable
rate by adding a small amount of acid.
Catalyst: a substance that influences the speed of a reaction
without itself being altered chemically. The catalyst does not
change the overall ΔG° of the reaction so:

The catalyst increases the velocity of the reverse reaction to the

same extent as the forward reaction so the equilibrium is reached
more quickly in the presence of the catalyst
Catalytic may be homogeneous or heterogeneous.
Homogeneous catalysis: occurs when the catalyst and
the reactants are in the same phase. Acid–base
catalysis are the most important type of homogeneous
catalysis.
Heterogeneous catalysis: occurs when the catalyst and
the reactants form separate phases in the mixture. The
catalyst may be a finely divided solid (Pt) or it may be
the walls of the container. The catalysis occurs at the
surface of the solid and called contact catalysis. The
reactant molecules are adsorbed at various points
or active centers on the surface of the catalyst.
Adsorption weakens the bonds of the reactant
molecules and lowers the activation energy.
Catalysts may be poisoned by certain substances that
are strongly adsorbed at the active centers of the
catalytic surface where the reactants would normally
be held during reaction. Carbon monoxide is known
to poison the catalytic action of copper in the
hydrogenation of ethylene. Other substances, known
as promoters, are found to increase the activity of a
catalyst. For example, cupric ions promote the
catalytic action of ferric ions in the decomposition of
hydrogen peroxide.
The end of chapter 14