SECTION 9: Kinetics

Chapter 12 in Chang Text

Outline for Section 9 Part I

9.1. Kinetics in Pharmaceutical Science

9.2. Rates of Reactions

9.3. Reaction Order:

Zero-Order, 1st Order

9.1. Chemical Kinetics in Pharmaceutical Science

Why do we, as pharmaceutical scientists, care about Chemical

Kinetics and Kinetics in General ?

We use rate equations and rate laws to define and describe processes
involved in everything from ..

Making the Drug to Formulation to Drug Administration

in Animals
Rates are important for the following:
rate of reaction to synthesize a drug molecule
....rate of side reactions under specific conditions

rate of decomposition, degradation, biotransformation,

and inactivation of a drug

rate of precipitation of a drug from a formulation under

specific conditions

rate of release of a drug from a delivery system

rate of uptake of drug into cells

rate of reaction between drug and biological target

(or other molecules)

rate of clearance of drug from bloodstream

rate of elimination of drug from body

Rate of Decomposition of Drug

characterization of the decomposition or stability of drugs is

of critical importance

decomposition may proceed by hydrolysis, oxidation, isomerization,

epimerization, photolysis etc.

many groups study the effect of ingredients of dosage forms or

formulations and environmental factors (i.e. temperature, pH )
on the chemical and physical stability of drugs
 Examples:
1. Higuchi studied the decomposition of Chloramphenicol.

Chloramphenicol decomposes via hydrolytic cleavage of the amide

bond (shown above).
rate of degradation of is low and independent of pH for pH
range 2 7
hydrolysis is catalyzed by presence of acids
maximum stability occurs at pH 6 at room temperature.the
half-life under these conditions is 3 years
2. Stability of Doxorubicin (anti-cancer drug)

very difficult drug to study as it chelates with metal ions,

self-associates in solution (DOX-DOX), absorbs to plastic
and glass, undergoes oxidative and photolytic decomposition

Beijnen et al. studied the kinetics of degradation of DOX as a

function of pH, ionic strength, temperature and concentration of
drug.

decomposition followed first order kinetics at constant

temperature

pH rate profile demonstrated that maximum stability was

achieved at about pH = 4.5
 DOX is an anthracyclineincludes Doxorubicin
chromophoric anthraquinone moiety
and a charged sugar within structure

anthracyclines are generally light

sensitive (many have investigated
photodegradation of DOX when
exposed to room light)

exposure to light, increase in pH and

and adsorption to container known to
result in DOX loss (decrease in concentration
of intact DOX in solution)

kinetics of photodegradation of DOX has been studied in buffer,

and biologically relevant media

incorporation of DOX into a delivery system, termed liposomes,

has been found to reduce rate of photodegradation of drug
can make
DOXIL (Caelyx in Canada)
liposomes
such that
internal
pH = 4.5

Liposome -
encapsulated
Doxorubicin

Doxil is approved for refractory ovarian cancer and AIDs-related

Kaposis sarcoma
Bandak et al. studied the UV-induced degradation of DOX as a
free agent and as a liposome-encapsulated agent
(Pharm. Res. 1999, 16, 841)

.very important study as administration of DOXIL

(liposome-encapsulated DOX) is known to result in localization of
high concentrations of DOX under the skin

.actually one of the dose-limiting toxicities of DOXIL is

called hand-foot syndrome.
Photodegradation of Encapsulated DOX is Reduced

(Pharm. Res. 1999, 16, 841)

Why is Encapsulated DOX More Stable ????

protection by lipid bilayer

high concentration of DOX inside liposome leads to aggregate

formation (DOX-DOX aggregates)

low pH of the intra-liposomal aqueous phase

 Rate of Reaction of Drugs with Biological Components

Cisplatin (CDDP) is an
anti-cancer drug that mitochondria

exerts anti-cancer activity

by binding to cellular DNA nucleus

MT
drug enters the cell, passes
through cytosol and enters
nucleus where it binds DNA
Cytosol

CDDP in cytosol may also

bind metallothionein (MT) Figure 1: Schematic of CDDP entry into cell, passage through cytosol
and other endogenous thiols and binding to DNA in nucleus. (not drawn to scale)

binding of CDDP to MT limits amount available for binding to DNA

therefore reducing anti-cancer activity
MT is a small cellular protein (6 kDa) that binds strongly to metal ions
(CDDP molecule contains platinum within chemical structure)
 Hagrman et al. (Drug Metabolism and Disposition 2003)
studied the kinetics of the reaction of CDDP with MT

their studies included characterization Cisplatin

of the rate of reaction between CDDP (CDDP)
and MT under specific conditions

also dependence of reaction rate on

concentration of CDDP and MT was
examined.

..this data is critical as it provides understanding of ability

of MT to trap CDDP.and thus alter the therapeutic
effect of this drug.
 Rate of Clearance of Drug from Circulation

Liposome
-encapsulated Free drug
drug 350
Liposome Encapsulated Drug

Drug Concentration in Plasma

300 Free Drug

250

(ug /mL)
200

150

100

50

0
0 1 2 3 4 5
Time (hours)
Sample blood at time points
t = 15 mins, 30 mins, 1 hr, 4 hrs etc.
 9.2. Rates of Reactions

Rate of a reaction is expressed as change in reactant concn. with time

R P

Rate of reaction over time interval (t2 t1) may be expressed as

Follows:

{[R]2 - [R]1} / {t2 t1} = [R] / t

..where [R]1 is the concentration of R at t1

and [R]2 is the concentration of R at t2

Since [R]2 < [R]1 we introduce a minus sign so rate has a positive value:

Rate = - [R] / t
Rate can also be expressed in terms of concentration of product:

Rate = {[P]2 - [P]1} / {t2 t1} = [P] / t

since [P]2 > [P]1 we dont need minus sign in equation.

actually we are not usually interested in rate over a time interval

because this is an AVERAGE..rather we are interested in
instantaneous rate

The rate of a reaction at a specific time may be given by:

rate = - d [R] / dt = d [P] / dt

Units of reaction rate are usually M s-1 or M min-1

For reactions where we have coefficients in front of the reactants or
products.

2R P

..in this case the reactant disappears twice as fast as the product
appears

Rate = - ( d [R] / dt ) = d [P] / dt

The rate for reactions is then:

a A + b B c C + d D

Rate = - (1/a) ( d [A] / dt ) = - (1/b) ( d [B] / dt )

= + (1/c) ( d [C] / dt ) = + (1/d) ( d[D] / dt )

(t is time after start of reaction)

9.3. Reaction Order:

relationship between rate of a chemical reaction and the concns.

of reactants and products is complicated and must be determined
experimentally..

For reaction: a A + b B c C + d D

In general:
rate [A]x [B] y

The Rate Law :

= k [A]x [B] y
rate is proportional to conc.
of reactants raised to some
.where k is the rate constant. power

The rate constant does not depend on concentrations it is only

dependent on Temperature.
How do we define the order of a reaction ?

.for example

Rate = k [A] x [B] y

.in this case the reaction is x order with respect to A and

y order with respect to B.

..the reaction has an overall order of x + y

IMPORTANT: in general there is NO relationship between

order of reaction and stoichiometric coefficients in reaction.
Example:

2 N2O5 (g) 4 NO2 (g) + O2 (g)

..the Rate Law for this reaction is known to be:

Rate = k [N2O5 ]

reaction is first-order with respect to N2O5

ORDER of REACTION..gives dependence of Rate on concns.

9.3.1. Zero Order Reactions

Rate law for a zero-order reaction is given by

A Products

rate = - d [A] / dt = = k [A] 0 = k

k (in units of M s-1) is the zero- order rate constant.

for a zero-order reaction the rate is independent of reactant

concentration.
d [A] = - k dt

Integration between t = 0 and t = t at concentrations of [A]t=0

and [A]t gives the following expression:

[A] t t
d [A] = [A] t [A] t=0 =- kdt = - kt
[A] t=0 0

[A] t = [A] t=0 - kt

[A] = [A]0 - kt
Example:
Conversion of ethanol to acetaldehyde by the enzyme
LADH (liver alcohol dehydrogenase). Oxidizing agent is
NAD+ (nicotinamide adenine dinucleotide):

LADH

CH3CH2OH + NAD+ CH3CHO + NADH + H+

In the presence of an excess of alcohol over the enzyme

and with the NAD+ buffered via metabolic reactions that
rapidly restore it, the rate of this reaction in the liver is
zero order over most of its course.
The reaction cannot be of zero order for all times; because,
obviously, the reactant concentration cannot become less than
zero and the product concentration must also reach a limit.

For the oxidation of alcohol by LADH, the reaction is zero

order only while alcohol is in excess !!
Plot of concentration versus time for a zero order reaction.
The magnitude of the slope of each straight line is equal to
the rate constant, k0 . The order must eventually change from
being zero as [CH3CH2OH] approaches zero.
For a zero-order
reaction the Rate
is independent of
concentration of the
reactant.
9.3.2. First - Order Reactions

rate = - d [A] / dt = = k [A]

rate of reaction depends on concn. of reactant raised to the

first power.

.in this case the units of k are s-1

 k1
A B

d[A] d[B]
= + = k1 [A]
dt dt

d[A]
= k1 [A]
[A]

Integrate both sides:

[ A ]2
d[A] t 2

= k1 dt
[ A ] [A]
1 t 1

ln [A] = k1 t + C
 If: [A]0 occurs at t = 0 then:

ln [A]0 = C

[A]
Therefore: ln = k1 t
[A]0

Or:

[A] = [A]0 exp( k1 t)

 [A] = [A]0 e kt

this equation shows us that in first order reactions there

is an exponential decrease in reactant concentration with time.

Plot of ln { [A] / [A]0 } versus t gives a straight line with a slope

that is given by k .
Exponential Decay of [A] with Time

Chang Text. Page 449

Example (1). The Kinetics of Radioactive Decay is First Order

222 218
Rn Po +
86 84

is the helium nucleus (He 2 +)

Table 12.1 in your text gives examples of other radioactive

decay reactions.
HALF LIFE (t 1/2) of a Reaction

.half life of a reaction is defined as the time it takes for the

concentration of the reactant to decrease by half of its original
value.

Therefore for a 1st order reaction the concentration of A would

be [A] = [A]0/2 at t = t 1/2

ln { [A] / [A] 0 } = - k t 1/2

When t = t 1/2 the equation becomes:

ln { ([A]0/2 )/ [A] 0 } = - k t 1/2

t 1/2 = (ln 2) / k = 0.693 / k

 t 1/2 = (ln 2) / k = 0.693 / k

.from this equation we see that t 1/2 is independent of the initial

concentration of the reactant.

Thus for A to decrease from 2 M to 1 M will take just as much

time as decrease from 0.1 M to 0.05 M.

For other types of reactions the half-lives do depend on the

initial concentration of reactant.

In general the expression describing relationship between

[reactant] and half-life is as follows:

t 1/2 ( 1 / ( [ A]0 n 1))

where n is the order of the reaction

Chang Text # 12.6

(a) The half-life of the first-order decay of radioactive 14C is about

5720 years. Calculate the rate constant for the reaction.

Solution:

(b) The natural abundance of 14C is 1.1. X 10-13 mol % in living matter.
Radiochemical analysis of an object obtained in an archaeological
excavation shows that the 14C isotope content is 0.89 x 1014 mol %.
Calculate the age of the object. STATE ASSUMPTIONS MADE.
Solution

[14C] / [14C]0 = e - kt

t = - (1/k) ln {[14C] / [14C]0 }

.the mol % of 14C for all living matter is assumed to be the same

when matter dies, it no longer exchanges material with the

environment and the mol % of 14C will decrease according to 1st order
decay kinetics.

..the ratio of [14C] / [14C]0 depends on time elapsed since death.

Chang Text # 12.5

A certain first-order reaction is 34.5 % complete in 49 minutes

at 298 K. What is the rate constant ?
Chang TEXT # 12.49: The activity of a radioactive sample is the
number of nuclear disintegrations per second, which is equal to the
first order rate constant times the number of radioactive nuclei
present. The fundamental unit of radioactivity is curie (Ci), where
1 Ci corresponds to exactly 3.70 x 1010 disintegrations per second.

This decay rate is equivalent to that of 1 g of Ra-226. Calculate the

rate constant and the half life for the radium decay. Starting with
1.0 g of the radium sample, what is the activity after 500 years ?
The molar mass of radium-226 is 226.03 g/mol.

Solution: