STABILITY

CHEMICAL KINETICS
Pharmaceutics III
s.khamanga@ru.ac.za

1
 LEARNING OBJECTIVES
• To understand the effect of temperature on degradation of
active pharmaceutical ingredients
• Explain the Arrhenius equation and the meaning of the
variables
• Discuss the concept of activation energy and transition state
• To determine activation energy graphically or algebraically
• To determine rate constant graphically or algebraically
• To calculate t90 and t1/2
• Describe the impact of reaction kinetics in the context of drug
formulations
• To gain a thorough understanding of the principles required to
establish the shelf life of packaged pharmaceutical products
using Q10 concept
• To explain the principles that form the basis of extension of
storage life of pharmaceutical products at low temperatures
2
 LEARNING OBJECTIVES
• To explain the different types of catalysis in pharmaceutics
• To sketch a potential energy profile showing the Ea for the
forward and reverse reactions and show how they are
affected by the addition of a catalyst
• To understand the different degradation mechanisms
• To understand and discuss the different pH rate profiles
• Evaluate the log k versus pH profile of drugs and identify
the pH at which a drug is most stable

3
 LECTURE 1
• To understand the effect of temperature on
degradation of active pharmaceutical
ingredients

4
 1. TEMPERATURE
EFFECT OF TEMPERATURE

• Have looked at the rate equations pertaining to the degradation of

an API

• Represents degradation reactions occurring under specific

conditions e.g. at a specific temperature or pH

• k values are specific for a specific set of conditions

• What influences k?

• NB - Temperature and pH

• To explain the effect of temperature on reaction rates and the

associated rate constants we have to look at activation energy
theory
5
 1. TEMPERATURE
• Consider the reaction:

• A + H+ → B

• Rate of reaction is prop to:

– # of collisions between A and H+

– # of collisions with sufficient energy to favour the reaction

• Energy required within collisions before the reaction can proceed is

determined by the ACTIVATION ENERGY of the reaction

• Reacting molecules must attain the energy of the TRANSITION STATE

6
 LECTURE 2
• Discuss the concept of activation energy and
transition state

7
 2. Transition State Theory
Transition State Theory
M‡

•
ΔG1‡ ΔG1‡
Influences Rate

ΔG-1‡
Reactants

ΔG0
ΔG0
Influences Extent Products
Gibbs free E

k (k+1 and k-1)

A+B P
K+1 k (k+1 and k-1)
A+B M‡ P
K-1
M‡
Activated complex is unstable and can break to form product 8
 2. Transition state theory
• Reaction occurs only if there is enough E
• Initial energy needed to be able to win the final
exothermic total E gain
• The transition state is highly unstable and cannot be
isolated

9
 2. Transition state theory

Three basic features of transition state theory

•Transition state theory has been successful in calculating
the
o standard enthalpy of activation,
o the standard entropy of activation, and the
o standard Gibbs energy of activation
•Between products and reactants, there exists the
transition state
•Activated complex is a higher-energy, reactant-product
hybrid
• It can convert into products, or revert to reactants

10
 2. Transition state theory
Transition State Theory
• Postulates that a hypothetical transition state occurs after the
state in which chemicals exist as reactants, but before the
state in which they exist as products
• Activated complex
• A higher-energy species that is formed during the transition
state of a chemical reaction

11
 2.Transition state

• The activation energy (Ea), labeled ΔG‡, is the E difference between reactants and the
activated complex, also known as transition state
• In a chemical reaction, transition state is defined as the highest-E state of
the system
• If molecules in the reactants collide with enough KE and this E is higher than the
transition state energy, then the reaction occurs and products form
• In other words, the higher the Ea, the harder it is for a reaction to occur and vice versa
12
 2.TRANSITION STATE
• Points to note on Transition State and Activation Energy:

A ↔ B

• 1 A must attain the activated state A++ in order to go to B

• 2 B can go to A – reverse reaction BUT the activation energy

required is greater than going from A to B

i.e. the forward reaction is favoured

• 3 As ΔG0 increases the reaction tends towards B

If the energy of B<<<A then the reaction approaches
completion

i.e. the difference in energy between A and B determines the

extent of reaction at the end point
13
 2.TRANSITION STATE
• 4. The lower the Ea the greater the number of
collisions which will attain the activation complex energy level
in a unit time interval

• 5. Therefore - the Ea determines the rate of reaction at a

particular temperature i.e. the stability of the API

• The SMALLER the Ea, the FASTER the rate of reaction

• 6. Overall - ↑ Temp → ↑ collisions → ↑ [A++] → ↑ Rate.

↓ Ea → ↑ [A++] → ↑ Rate
In other words, there is a minimum amount of energy required for
reaction: the activation energy, Ea.

7. The relationship between T, reaction rate and activation energy is

described by the Arrhenius equation
14
 LECTURE 3, 4, 5
• Explain the Arrhenius equation and the
meaning of the variables
• To determine activation energy graphically or
algebraically using Arrhenius equation
• To determine rate constant graphically or
algebraically
• To calculate t90 and t1/2

15
 3. Arrhenius equation

ARRHENIUS EQUATION

• k = Ae -Ea/RT
• Where k= reaction rate constant (any order).
• A= Arrhenius constant/pre exponential factor
• Ea = Activation energy of reaction (kcal/mol) = kJ
mol−1
• T= absolute temperature (K)
• i.e. 273.16 °C + t °C at which the reaction is Note
taking place. units
• R= Universal gas constant.
• i.e. R = 8.31446 J K−1  mol−1

16
 Arrhenius equation
• The stability of drug molecules is one of the
most important areas of the drug
development process
• Arrhenius studies can be used in order to
predict the stability of compounds by
performing forced degradation studies at
elevated temperatures and then extrapolating
the data to room temperature

17
 Arrhenius equation
• Real-time and accelerated stability tests are used to assess shelf-
life of products
• Accelerated tests are preferred for industrial uses since they
shorten time required to get product to market
• Principle of accelerated stability testing is to expose a product to
stress conditions in order to increase rate of degradation (i.e.,
samples of the materials stored at elevated Tͦ⁰ will degrade more
rapidly than at normal Tͦ⁰ )
• By measuring degradation rate at high Tͦ⁰, and by modeling or
assuming a degradation rate–temperature relationship,
extrapolation at the storage Tͦ⁰ will predict shelf-life of the
material
• Thus, accelerated stability modeling consists of the following
steps:
1) estimating the degradation rate at each elevated temperature,
2) Relating the degradation rate to the temperature, and
3) predicting stability at the intended storage temperature
18
 Arrhenius equation
• Products show different degradation patterns as they age
• There are three main types of degradation reactions:
– zero-,
– first-, and
– second-order
• Only one kind of molecule is involved in zero- and first order
reactions, and the degradation rate is constant
• The exponential degradation pattern in time of first order
reaction is probably the most common in literature, although at
optimum storage conditions the differences between patterns
of the first- and second-order reactions are indistinguishable
• Furthermore, the degradation rate of zero- and first-order
reactions can be related to Tͦ⁰ by Arrhenius equation
19
 3. Arrhenius equation
• This equation can be re-arranged into a log linear equation which
are easy to use:

• log K = log A - Ea Ea . 1
2.303 R T 2.303R T

• y = c - mx where 1/T = x

• This indicates that a plot of log k vs 1/T will be LINEAR with a slope
of
-Ea
2.303R

• This is known as a Arrhenius Plot

ln k = ln A - (Ea/RT)
20
 Ea and Arrhenius equation

• To gain an understanding of activation energy

• To determine activation energy graphically or
algebraically
• Ln k=Ln(Ae−Ea/RT)
=Ln A + Ln(e−Ea/RT)
= Ln A + −Ea/RT

21
 Exercise
• It takes about 3.5 minutes to cook a hard-boiled egg in
one city (X), but at the higher altitude of another city (Y),
where water boils at 91°C, the cooking time is 4.9
minutes.
• Use this information to estimate the activation
energy for the coagulation of egg albumin protein
(The proteins in the egg start to thicken, a process known as coagulation).

22
 Solution
• The ratio of the rate constants at the elevations of City (X) and City (Y) is 4.9/3.5 = 1.4, and
the respective temperatures are 373K and 364K .
• With the subscripts 2 and 1 referring to City X and City Y respectively:

• Ea=(8.314)(Ln1.4)/1/364K–1/373K)
• =(8.314)(0.3365)/0.00274K−1–0.00268K−1 = 2.797661/6x10-5
• = 4663 J mol–1 = 4.66 KJ mol-1

COMMENT
• This low value seems reasonable because thermal denaturation of
proteins primarily involves the disruption of relatively weak hydrogen
bonds; no covalent bonds are broken (although disulfide bonds can
interfere with this interpretation.

23
 3. Arrhenius equation
Summary:  E 
k  A exp  a  where A = frequency factor.
 RT 
• Linear form: . E
ln k  ln A  a
RT
• Plot ln k vs. 1/T; the slope gives Ea/R.
E.g. determine the activation energy for the decomposition of X from the temperature
dependence of the rate constant.
Arrhenius Plot
-5

-6

ln k
-7

-8
• Two point equation sometimes used also: 0.00300 0.00305
1/T, K 
0.00310 0.00315

E.g.2: Determine the rate constant at 35°C for the hydrolysis of sucrose, given that at 37°C
it is 0.91mL/(mol*sec). The activation energy of this reaction is 108 kJ/mol.
• Rate constant increases when T2>T1

24
 −𝐸 −12484
=
𝑅 1

12484 X 8.314 = 103 791. 976 J/K. mol

Ln k vs 1/T
-4
0,00295 0,00297 0,00299 0,00301 0,00303 0,00305 0,00307 0,00309 0,00311 0,00313 0,00315 0,00317

-4,5

-5

y = -12484x + 31.599
-5,5 R² = 1

-6

-6,5

-7

-7,5

-8

Ln k Linear (Ln k) 25
USEFUL EQUATIONS

26
Example

27
Using the Arrhenius Equation

28
 EXERCISE
Determine the Ea of the to form the degradation product of the drug

29
 4. Arrhenius plot
• From an Arrhenius Plot, the Ea of a reaction can be calculated.

• Once the Ea is known, the reaction rate constant k can be calculated

for any T

• t90 and t½ can then be calculated at any T

Note:
• Ea of a reaction is specific for a reaction conducted under specific
conditions.

• However, it does not change with T

30
 4. Arrhenius plot
• The Arrhenius Equation can be re-arranged into several useful forms:

• log ( k2 ) = - Ea ( 1 - 1 )
( k1 ) 2.303 R ( T2 T1 )
log of the ratio of k2 / k1

• or log k2 = Ea (T2 – T1)

k1 2.303 R.T2.T1
• Where k1 and k2 are the rate constants at temperature T1 and T2 in °K
(°C+273).

31
 4. Arrhenius plot
• Ea’s for some Common Pharmaceutical Degradation Reactions.

Compound Reaction Ea (kcal/mol)

Ascorbic Acid Oxidation 23
Aspirin Hydrolysis 14
Atropine Hydrolysis 14
Benzocaine Hydrolysis 19
Chloramphenical 20
Epinephrine Hydrolysis 23
Procaine Oxidation 14
Thiamine Hydrolysis 20
Hydrolysis

Range of Ea for pharmaceuticals is generally between

14 - 23 kcal/mol

1 Cal = 4.184 J
32
 Arrhenius plot- EXERCISE
Sulphacetamide

• Antibacterial agent used as the Na+ salt in ophthalmic solutions.

– Ea = 22.9 kcal/mole at pH 7.4

• Degradation is pH independent between pH 5 and 11.

k1 at 120° = 9.0 x 10-6 sec-1 (temp. for sterilisation)

• In the pH range of 5-11, sulphacetamide exists as an anion with a pKa

of 5.21 (acidic)

The ionised form is more stable than the unionised form

• Degradation is by hydrolysis – i.e. addition of water, which is catalysed

by H+ and OH- at the extremes of pH
33
 Arrhenius plot- EXERCISE
• k120 at 120°C = 9 x 10-6 s-1 1st order

• 120°C = 393°K = T1
• 25°C = 298°K = T2
• k at 25° = k25

• Question – What is the shelf-life of this ophthalmic solution at 25°C?

• Question – What percentage will be degraded during the sterilisation

process at 120°C for 30 minutes?

34
 Arrhenius plot- PLOT
ARRHENIUS EXERCISE
• 1. Calculate k2 ie k at 25°C

• log k25 = - Ea (1 - 1)
k120 2.303 R (T2 T1 )

• log k25 = - 22 900 (1 - 1)

k120 2.303 x 1.987 (298 393)

= -4.06 -ve / +ve NB

• Therefore k25 = 8.7 x 10-5 (antilog of -4.06)

k120

• Therefore k25 = 8.7 x 10-5 x 9 x 10-6 S-1

= 7.85 x 10-10 s-1

35
 Arrhenius plot- EXERCISE
• Now t90 = 0.105 First Order
k25

• Therefore t90 = 0.105

7.85 x 10-10 s-1
t90 = 1.34 x 108 s

t90 = approx. 4.25 years.

• This agrees with the monograph shelf life of 4.2 years at 25°C

36
 Arrhenius plot- EXERCISE

• What percentage would degrade during the sterilisation process at 120°C for 30
mins?

• Will it be significant?

k120 at 120°C = 9.1 x 10-6 s-1 first order

t = 30min = 1800 s

Ln [D]t = Ln [D]0 – k1 t
Ln [D]t - Ln [D]0 = – 9.1 x 10-6 x (30 x 60) units NB

Ln (D/D0) = - 0.01638 -ve NB

D/D0 = 0.9838

Therefore % degraded = 1.62%

37
 LECTURE 6, 7
• To gain a thorough understanding of the
principles required to establish the shelf life of
packaged pharmaceutical products using Q10
concept
• To explain the principles that form the basis of
extension of storage life of pharmaceutical
products at low temperatures

38
 4. Shelf-life
• Shelf life studies are used to determine how long a product can
reasonably be expected to maintain its quality, safety, and
character
• Test methods
– There are two test methods for conducting a shelf life study
– The direct method involves storing the product under specific
conditions for a period of time that is longer than its expected shelf
life and checking it at regular intervals to see when it begins to spoil
– Two indirect methods allow for shelf life prediction without
conducting a full-length storage trial, and are useful for products with
a long shelf life
The first indirect method
• uses a predictive model based on information from a
database that predicts bacterial growth under specific
conditions, which can then be used to calculate shelf life
39
 4.Shelf-life
• Second indirect method: is an accelerated shelf life study
• Involves deliberately increasing rate at which a product will spoil,
usually by increasing the storage T
• Tool used in accelerated studies is “the rule of ten,” or Q10, which
is factor by which rate of spoilage increases when the T is raised
by 10° C
• Q10 allows for prediction of a product’s shelf life under real-life
conditions based on results of testing conducted at high T

40
 5. Q-10
Q10 values and their use in the estimation of shelf-life

• A Q10 value is the ratio of reaction rate constants (k) for two
reactions 10°C apart
Ln[D] 300°
• i.e. 310°

Time

• This ratio is essentially constant for a particular reaction irrespective of

which 10°C interval is considered

• i.e.

• However, the Q10 value depends on the Ea of the reaction

41
 5. Q-10
• If the Ea is high then the Q10 value is high and vice versa

• Approximate Q10 values for a range of Ea values are as follows:

Ea Q10 ΔT ΔT / 10 QΔT Δk
Kcal/mol rate
constants
14 2 +10°C 1 (21) X2 Doubles

19 3 +10°C 1 (31) X3 Triples

24 4 +10°C 1 (41) X4 Quadruples

14 24
19 300°

300°
Ln[D] 300° Ln[D] Ln[D]
310° 310°
310°
42
Time Time Time
 5. Q-10
40°C 30°C
313°K 303°K

Q10 = k40 = 2
k30
Q10 = k40 = 3
k30
Q10 = k40 = 4
k30 Ea = 14 Kcal/mole

Ea = 19 Kcal/mole

Ea = 24 Kcal/mole
3.20 3.30 3.40
1/T (°K) x 10-3

43
 5. Q-10
• If temperature change is more than +10°C then:

• If ΔT = 25°C ΔT = 25 = 2.5
10 10

Therefore

44
 5. Q-10
• If storage T is increased above stated storage T then:
Ea Q10 ΔT ΔT / 10 QΔT Δk
Kcal/mol rate
constants
14 2 +10°C 1 (21) X2 Doubles

19 3 +10°C 1 (31) X3 Triples

24 4 +10°C 1 (41) X4 Quadruples

Ea Q10 ΔT ΔT / 10 Q10ΔT/10 Δk t90

Kcal/mol =

QΔT

14 2 +25 2.5 5.7 x 5.7 1/5.7

(22.5)
19 3 +25 2.5 15.6 x 15.6 1/15.6
(32.5)
24 4 +25 2.5 32 x 32 1/32
45
(42.5)
 5. Q-10
• If storage T is decreased below the stated storage temperature then:

• ΔT = -25°C ΔT = -25 = -2.5

10 10

• Therefore

Ea Q10 ΔT ΔT / 10 Q10ΔT/10 Δk t90

Kcal/mol =QΔT

14 2 -25 -2.5 1/5.7 x 0.175 x 5.7

(2-2.5)
19 3 -25 -2.5 1/15.6 x 0.064 x 15.6
(3-2.5)
24 4 -25 -2.5 1/32 x 0.031 x 32
(4-2.5)

46
 5. Q-10
• However, in the Pharmacy you DO NOT generally know k
but you do know t90 (shelf-life)

• You know that there is an indirect relationship between k

and t90 therefore k can be substituted for 1/t90 so:

47
 5. Q-10
• Q10 values can be used to calculate very approximate changes in shelf-life
when products are stored at higher or lower T than stipulated
• When calculating a new shelf-life the safest possible estimate with respect
to patient safety should be used

• Considering that pharmaceutical degradation reactions are generally in

the range of 13 to 24 kcal/mol with respective Q10 values of 2 to 4:

• A Q10 of 4 should be used to calculate a decrease in the shelf-life after

storage at elevated T as this will generally over-estimate the rate of
degradation and under-estimate the new shelf-life

• A Q10 of 2 should be used to calculate an increase in the shelf-life after

storage at reduced temperature as this will generally over-estimate the
rate of degradation and under-estimate the new shelf-life

48
 Pharmaceutics III – Stability
EXERCISE
1. The expiration period of a reconstituted product is 18
hours at room T. Estimate the expiration period when
the product is stored in the fridge.

2. A newly reconstituted product is labeled to be stable

for 24 hours in the fridge. What is the estimated shelf-
life at room temperature?

3. A product has an expiry date of 1 year when stored in

the refrigerator. The product has been stored for one
month at room temperature. If the product is returned
to the refrigerator what is its new expiry date?

49
 Pharmaceutics III – Stability
EXERCISE
4. A reconstituted suspension of Ampicillin is stable for 14
days in the refrigerator. If the product is left out of the
fridge for 12 hours what is the reduction in the expiry
date?

5. If we know that the Ea of ampicillin at pH=5 is 18.3

kcal/mol then calculate the actual expiry date
reduction.

50
 5. Q10
1. The expiration period of a reconstituted product is 18 hours at room T (25°C).
Estimate the expiration period when the product is stored in the fridge.
0 18 hrs at 25°C
0 X hrs at 5°C

ΔT =T2-T1 = 5 -25 = -20°C

Therefore if Q10 = 2 then If Q10 = 4 then

so since so since

Therefore X = 72 hours Therefore X = 288 hours

Use 72 hours as a conservative estimate (decrease temp: use 2) 51
 5. Q10
2 A newly reconstituted product is labeled to be stable for 24 hours in the
fridge. What is the estimated shelf-life at room temperature.
0 24 hrs at 5°C
0 X hrs at 25°C

ΔT = T2-T1 = 25-5 = 20°C

Therefore if Q10 = 2 then If Q10 = 4 then

so since so since

Therefore X = 6 hours Therefore X = 1.5 hours

Use 1.5 hours as a conservative estimate (increase temp: use 4)
52
 5. Q10
3 A product has an expiry date of 1 year when stored in the refrigerator. The
product has been stored for one month at room temperature. If the product is
returned to the refrigerator what is its new expiry date.
0 12 months at 5°C
0 1 month at 25°C
0 equivalent to X months at 5°C

ΔT = -20°C (25°C to 5°C) ΔT =T2-T1 = 5 -25 = -20

Therefore if Q10 = 2 then If Q10 = 4 then

so since so since

Therefore X = 4 months Therefore X = 16 months

Use 16 months as a conservative estimate so the product should be discarded.
53
 5. Q10
4 A reconstituted suspension of Ampicillin is stable for 14 days in the refrigerator. If
the product is left out of the fridge for 12 hours what is the reduction in the
expiry date.
0 14 days at 5°C
0 12 hours at 25°C
0 equivalent to X months at 5°C

ΔT = -20°C (25°c TO 5°c)

Therefore if Q10 = 2 then If Q10 = 4 then

so since so since

Therefore X = 2 days Therefore X = 8 days

Use 8 days as a conservative estimate so the product can be stored at 5°C for a
further 6 days.
54
 LECTURE 8, 9, 10
• To explain the different types of catalysis in
pharmaceutics
• To sketch a potential energy profile showing the
activation energies for the forward and reverse
• reactions and show how they are affected by the
addition of a catalyst.
• To understand the different degradation mechanisms
• To understand and discuss the different pH rate profiles
• Evaluate the log k versus pH profile of drugs and identify
the pH at which a drug is most stable

55
 6. Catalysis
The Effect of Catalysis on Reaction Rate

• Does a Catalyst - Effect rate?

Effect equilibrium?
Get transformed?
Get consumed?
Get regenerated?

• Catalysis and transition state theory

- Explained by effect on activation
energy

Catalysis is the process of increasing the rate of a chemical reaction by adding a

substance known as a catalyst, which is not consumed in the catalyzed reaction and
can continue to act repeatedly

56
 6. Catalysis

If a catalyst is added to a reaction, the Ea is

lowered because a lower-energy transition
state is formed

Enzymes affect the rate of reaction in both the forward and reverse directions; the
reaction proceeds faster because less energy is required for molecules to react when they
collide. Thus, the rate constant (k) increases.

ΔH‡, represents the difference in energy between the ground state and the transition state
in a chemical reaction. The higher the activation enthalpy, the more energy is required
for the products to form.
57
 6. Catalysis
• Types of Catalysis in Pharmaceutics
1. Specific Acid Catalysis
Catalyst is the solvated proton from an acid i.e. H+ which is H3O+
in solution. Eg HCl H+ + Cl- then H+ + H2O H3O+
A solvated proton is essentially H+
2. Specific Base Catalysis
Catalyst is the solvated hydroxyl ion from a base i.e. OH- in
solution. Eg NaOH Na+ + OH-

3. General Acid Catalysis

Catalyst is a proton other than an hydronium ion.
Any “Bronstead Acid” or compound which can donate a proton eg.
NH4 +

4. General Base Catalysis

Catalyst is a proton acceptor other than OH- such as a “Bronstead
Base” which acts as a proton acceptor by sharing an electron pair.
58
 6. Catalysis
• Reactions in soln that are not catalysed are slow since charge
development and separation occurs in transition state
• When bonds are made or broken, charged intermediates are
often formed which are higher in E than reactants
• Since intermediate is higher in E than the reactants, the
transition state would be even higher in E
• Hence more closely resemble the charged intermediate
• Anything that can stabilize charges on intermediate and
hence developing charges in transition states will lower E of
transition state and catalyze the reaction
• Charge development in the TS can be decreased by
either donation of a proton from general acids

59
 6. Catalysis
• Value of studying catalysis

1. ascertain effect of catalyst on reaction rate

2. ascertain what compounds in a formulation act as catalysts

3. can recognise potential catalysts in proposed formulations

4. can formulate to minimise a catalytic effect on stability.

60
 6. Catalysis
• The Effect of pH on Reaction Rate and H+ and OH- as catalysts

• pH is a major factor affecting reaction rates in solution as reactions are

often catalysed by H+ and/or OH- ions

Other factors such as

1) -T
2) -ionic strength of solution
3) -solvent composition and additives
• The effect of pH on reaction rate can be determined by determining
– the degradation profiles and
– first-order rate constants of reactions (solutions) at various pHs.

• If the log of the rate constants obtained at various pHs are plotted against
pH, a pH rate profile is obtained
• pH of drug solution has effect on stability
• 1 pH shift may cause a 10x fold in change in K
61
 6. Catalysis
• pH rate profiles are generally one or a combination of three basic
shapes:

1 V-graph
Log K

pH

2 Sigmoidal Log K

pH

3 Bell-Shaped Log K

pH
62
 6. Catalysis
• V-Graphs
Obtained for specific acid and specific base catalysis of NON-IONISABLE
compounds in aqueous solution .

OR of IONISABLE COMPOUNDS where ionisation does not affect stability.

Consider the reaction of D Products

e.g. The hydrolysis of an ester with water

• Three possible reaction pathways co-exist :

1 Catalysis by H+ - reaction proceeds under specific acid catalysis
2 Catalysis by 0H- - reaction proceeds under specific base catalysis
3 Un-catalysed – reaction proceeds without catalysis.
i.e. Hydrolysis by water without any influence from H+ or OH- ions.

• Overall rate of reaction at a particular pH will be the sum of the individual

rates of reaction for the three possibilities above.
63
 6. Catalysis
• Hypothetical Rate Equation is:
D

H+ Un-C OH-

P P P

rate = k1 [D][H+]n + k2 [D] + k3 [D][0H-]m [H2O] omitted

acid catalysed un-catalysed base catalysed

• Since this is hydrolysis, H2O is also involved in the reaction but kn takes this
into account as the concentration of H2O remains constant.
• The concentrations of H+ and OH- are also constant at a specific pH
(buffered).

• Remember Rate or –d[D] = k2 [D][H+] 2nd order

dt
= k1 [D] 1st order
64
 6. Catalysis
The overall rate equation will be: rate = k [D]

• Therefore

k [D] = k1 [D][H+]n + k2 [D] + k3 [D][0H-]m

k = k1 [H+]n + k2 + k3 [0H-]m

• Or k = k1 [H+]n + k2 + k3 . Kw m
[H+]

Since Kw = [H+][OH-] = 1.0 x 10-14 at 25°C (ion product of water)

• n and m are the orders of reaction with respect to H+ and OH- and are = 1

• k1, k2 and k3 are the rate constants of the specific acid, base or uncatalysed
reactions.

65
 6. Catalysis
• Now Consider if the pH of the reacting solution is low:
H+ is high so
– only first term is significant
– the second and third terms can be ignored

• Therefore k = k1 [H+]n

• Taking Logs and rearranging for H+ log k = log k1 – npH

• Therefore a plot of log k vs pH will be a straight line with a gradient

of n.

• For specific acid catalysis n = 1 therefore the gradient will be -1.

66
 6. Catalysis
• Now Consider if the pH of the reacting solution is high:
OH- is high so
only third term is significant
the first and second terms can be ignored

• Therefore k = k3 [0H-]m

• Taking Logs and rearranging for H+ log k = log k3 – m.p0H

log k = log k3 + m.pH -14

• Therefore a plot of log k vs pH will be a straight line with a gradient

of +m.

• For specific base catalysis m = 1 therefore the gradient will be +1.

67
 6. Catalysis
• If degradation studies are conducted at high and low pHs then the
complete profile can be constructed and k2 determined.

• When all three ks are known the overall k can be accurately

calculated for any pH.

k = k1 [H+]n + k2 + k3 [OH]m

• Any pH – rate profile is only valid for one temperature.

Calculation of rates at temperatures different from which the pH-

rate profile was determined will require the use of the Arrhenius
equation as you have already seen.

68
 6. Catalysis
Log k3

Log k1

n (-1) m (+1)
Log k
(overall)

pH of max. stability
Log k2

1 pH 14

• Straight lines with gradients of -1 and 1 demonstrate direct relationship

between pH or pOH and k(overall) and specific acid or base catalysis
respectively.

• Position of the inflection point is dependent on the relative magnitudes of

k1 and k3 .

69
 6. Catalysis
• Usually k1 << k3, therefore inflection point is usually on acidic side of
neutral

• If k1 >> k3 then the inflection point will be on the alkali side of

neutral.

• For specific acid and specific base catalysis, maximum stability

occurs at the inflection point when:
k1[H+]n = k3[OH-]m

• k (overall) at the point of inflection is approximately equal to k2 ,

however, k2 actually resides below the inflection point, the extent
of which depends on the magnitudes of k2 relative to the other two
ks.

70
 6. Catalysis
• Sigmoidal Graphs
This shape of pH-rate profile is usually obtained for weak
acids and weak bases (ionisable) where degradation is not
significantly catalysed by H+ or OH- but ionisation plays a
major role in the uncatalysed degradation of the molecule

71
 6. Catalysis
Bell Shape - 1
• This shape of pH-rate profile can be obtained for weak acids
or bases (ionisable) which are di-acidic or di-basic (release or
accept two protons) i.e. the compound has two pKa’s
• occurs when two ionisable functional groups in molecule

Where degradation is not significantly catalysed by H+ or

OH- but ionisation plays a major role in the uncatalysed
degradation of molecule.

72
 6. Catalysis
• Practically, pH-Rate profiles are useful as they:
1. Provide information on rate vs pH (obvious).

2. Provide info on the degradation process – specific acid/base

catalysis or general acid/base catalysis.

3. Provide info on how to limit degradation

4. Can be determined by measuring the concentration vs time

under different conditions over the pH range if the rate
equation is complex.

5. Can be calculated from minimal experimental data if the rate

equation is known.

73
 6. Catalysis
• Eg. 1 Determine at what pH AMPICILLIN in solution is most
stable.

• Method: 1. Determine the degradation rate at high and

low pHs where degradation is fast.

2. Derive the rate equation from knowledge of

the reaction.

3. Calculate points on the pH-rate profile and

plot Log k vs pH.

4. May need to determine pH-rate profile at

different temperatures.

5. Can calculate Activation Energy at any

temperature and therefore k and t90 at any
temperature.
. 74
 EXERCISE

Summary of rate constants for degradation of drug X in aqueous solution at pH and temperatures
The Unit of K is min–1.

25˚C 37˚C 45˚C 60˚C 75˚C

pH
Ln(Ka) Ln(Ka) Ln(Ka) Ln(Ka) Ln(Ka)

1.25 –3.11 –3.66 –3.42 –3.70 –3.15

2.25 –2.924 –4.11 –4.63 –5.47 –5.02

4.64 –4.62 –5.12 –4.89 –3.94 –4.86

6.67 –4.95 –6.19 –5.67 –4.65 –2.55

7.4 –4.89 –7.74 –3.80 –4.77 –5.58

8.06 –3.04 –4.77 –4.21 –6.50 –4.04

9.53 –4.66 –4.31 –4.71 –5.93 –4.09

75
 EXERCISE
pH Rate Constant (k) × 10−4 (min−1)

1 13.6

2 45.0

3 1.17

4 0.90

5 0.91

6 1.77

7 4.56

8 6.60

9 6.68

10 6.69

11 6.71

12 6.702

76
 6. Catalysis
55°C Does activation energy change with pH?
45°C
35°C
-4

Log k Log k
sec-1

pH of Max Stability
-6.6
1 pH 14

77
 EXERCISE
Eg. 2 The pH=rate profile of Aspirin is presented below. Is this
product suitable for reconstitution with water before dispensing.
- Unbuffered or buffered at what pH?
- Estimate the t90 of an Aspirin solution at the pH of maximum stability and
buffered at pH 7.0 where pH change with time would not be significant.
-4 -4

-5 -5

Log k Log k
sec-1 sec-1
-6 -6

-7 -7
1 3.5 7 14
pH

78
 EXERCISE
• Log k at pH 3.5 = -6.5 check graph therefore k = 3.00 x 10-7 s-1 ORDER
• Log k at pH 7.0 = -5.5 therefore k = 3.10 x 10-6 s-1

• At pH 3.5 t90 = 0.105/3.00x10-7

= 3.5x105 s
= approx. 4 days

• At pH 7.0 t90 = 0.105/3.10x10-6

= 3.3x104s
= approx. 9 hours

For a reconstituted product, only reconstitution at the time of

dosing is really feasible. Otherwise, alternative methods of
stabilising aspirin solution must be employed.

79
 EXERCISE
• This profile represents:
1. pH 1 – 3.0 Specific acid catalysis (H+)
2. pH 3.0 – 11 Sigmoid due to ionisation with
plateau where ionisation is complete but
without OH- catalysis
4 pH 11 – 14 Specific base catalysis (OH-)
-4

-5

Log k Log k
sec-1
-6

-7
1 3.5 7 14
pH
80
 EXERCISE
• Assuming RC00H represents aspirin then

k1
• 1. RCOOH H+
Products Specific acid catalysis

kI Not catalysed significantly by H+ or OH-

• 2. RCOOH H2O Products but ionisation decreases stability due
to increased ionised moiety
kII
• 3. RCOO- H2O Products
k3
OH-
• 4. RCOO- Products Specific base catalysis

• 1 and 4 represent the V-shaped portion of the profile where [H+] and [OH-]
are in high concentration respectively.

• 2 and 3 represent the sigmoid portion of the profile where the less stable ionised
form which has decreased stability increases in concentration. 81
 EXERCISE
• pH independent: several reactions going on each causing an effect
on its own-results in cancelation of H+ an OH-, which gives a
uniform rate over this pH range
• The use of pseudo-first order is sufficient to define and study the
degradation of ASA-hydrolysis proceeds through a complex
mechanism over the pH range studied

• The rate equation which accounts for this profile can then
be written as:

• koverall [RCOOH] = k1[RCOOH][H+] + kI[RCOOH] + kII[RCOO-] + k3[RCOO-][OH-]

From the profile it is evident that k3 > k1 and kII > kI

82
 EXERCISE
Eg. 2 What will an acceptable pH be for a solution of pilocarpine (eye
drops) to have a t90 of 4 months if stored at 25°C.
Want a t90 = 4 months = 10 368 000 seconds
Since t90 = 0.105/k
k = 1x10-8 s-1
-2 Log k = -8
acceptable range = 4.5 – 7.0
-4

Log k Log k
sec-1 -6

-8

-10
1 3 5 7 9 11 14
pH
83