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STABILITY CALCULATION AND RATE EQUATION

SRAVANKUMAR NARLA

M PHARMACY ,PHARMACEUTICS

VIKAS COLLEGE OF PHARMACY

STABILITY CALCULATION AND RATE EQUATION SRAVANKUMAR NARLA M PHARMACY ,PHARMACEUTICS VIKAS COLLEGE OF PHARMACY 1

General Outline

  • Definition of drug stability and drug kinetics

  • Influence of temperature on drug stability

  • Importance of studying kinetics

  • Shelf life and half life

  • Basic math principles

  • Drug kinetics reaction orders

  • Determination of reaction orders

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Definition of drug stability and drug kinetics

Stability

Drug Stability refers to the capacity of a drug substance or

product to remain within established specifications of

identity, strength quality, and purity in a specified period of time.

factors that affect drug stability include temperature

condition, moisture, light, microbes, packaging materials, transportation, components of drug composition and the nature of the active ingredient.

.

Arrhenius Equation

  • Arrhenius developed a mathematical relationship between k and E a :

Arrhenius Equation  Arrhenius developed a mathematical relationship between k and E : where A is

where A is the frequency factor, a number that represents the likelihood that collisions would

occur with the proper orientation for reaction.

Arrhenius Equation

Taking the natural

logarithm of both sides,

the equation becomes

y = mx + b
y
=
mx + b

When k is determined experimentally at several temperatures, E a can be calculated from the slope of a plot of ln k vs. 1/T

Activation Energy

In other words, there is a minimum amount of energy required for reaction: the activation energy, E a

Just as a ball cannot get over a hill if it does not roll up the hill with enough energy, a reaction cannot occur unless the molecules possess sufficient energy to get over the activation energy barrier.

Activation Energy  In other words, there is a minimum amount of energy required for reaction:

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Accelerated stability studies
Accelerated stability studies

Stability study is to predict the shelf life of a product by

accelerating therate of

decomposition, preferably by

increasing the temperature of

reaction conditions.

With the advancement in branch of kinetics shelf life of dosage form can be predicted with in months based on accelerated stability reports

Storage condition of 40 0 C and relative humidity

of 75% has been recommended for all the four

zones for drug substances and drug products. Studies carried out for 6 months.

Accelerated storage conditions must be at least 15 0 C above the expected actual storage temperature and appropriate

relative humidity

Objectives of accelerated stability tests:

the rapid detection of deterioration in different initial formulations of the same product - this is used in selecting the best formulation from a series of possible choices

the prediction of shelf life, which is the time a product will remain satisfactory when stored under expected or

directed storage condition;

Drug Kinetics

  • It is defined as how drug changes with time i.e., study of rate of change. Many drugs are not chemically stable and the principles of chemical kinetics are used to predict the time span for which a drug (pure or formulation) will maintain its therapeutic effectiveness or efficacy at a specified temperature

    • The rate, velocity or speed of a reaction is given by + or dc/dt

      • Here dc is small changes in the concentration with in a given

time interval dt.

Importance of studying kinetics

It determines:

  • Stability of drugs (t 1/2 )

  • Shelf life ((t 0.9 )

  • Expiration date

Stability of drugs (t 1/2 ) The half life (t 1/2 ) is defined as the time necessary for a drug to decay by 50% (e.g., From 100% to 50%, 50% to 25%, 20% to

10%)

Shelf life (t 0.9 )

It is defined as the time necessary for the drug to decay to

90% of its original concentration.

Half-Life

Half-Life Half-life is defined as the time required for one-half of a reactant to react. Because

Half-life is defined as the time required for one-half of a reactant to react. Because [A] at t 1/2 is one- half of the original [A],

[A] t = 0.5 [A] 0

SHELF LIFE
SHELF LIFE

It is defined as the time required for the concentration of the reactant To reduce to 90% of its initial concentration.

Shelf life is represented as t 90

As per defination the term in equation change to C =90a/100 ; t =t 90

Basic Math principles

  • i) The straight Line:

General equation: Y = mx+ b

Y = dependent variable m = slope

X = independent variable

b = intercept

also

Ordinate = dependent variable axis abscissa = independent variable axis

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m = slope = ∆Y / ∆X 15 15

m = slope = ∆Y / ∆X

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Advantages of use of straight line

  • Easier to determine parameters (slope and intercept)

  • Simultaneous determination of two parameters (m + b) Logarithms:

ii)

  • (a) Common log (base10)

log 100 = log 10 2 = 2 log 1000 = log 10 3 = 3

  • (a) Natural log (base e = 2.72)

In 100 = In e x In 100 = In 2.72 x

= 4.61

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Straight Line:

Straight Line: Slope = m = ∆Y / ∆X = constant 17 17

Slope = m = ∆Y / ∆X = constant

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Curve:

Curve: Slope is not constant but function of X Slope = 1 derivative of y with

Slope is not constant but function of X Slope = 1 st derivative of y with respect to X

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Integration

Determination of area under the curve i.e., sum or amount.

b a AUC =
b
a
AUC =

Where; Y is the function of the graph

b = upper limit a = Lower limit

Order of Reactions

Law of mass action

The rate of a reaction is proportional to the molar concentrations of the reactants each raised to power equal to the number of molecules undergoing reaction.

a A + b B Rate α [A] a .[B] b Rate = K [A] a .[B] b

Order of Reactions Law of mass action The rate of a reaction is proportional to the

Product

Order of reaction = sum of exponents

Order of A = a

and B = b

Then Overall order = a + b

Example:

The reaction of acetic anhydride with ethyl alcohol to form ethyl acetate and water

(CH 3 CO) 2 + 2 C 2 H 5 OH

Example: The reaction of acetic anhydride with ethyl alcohol to form ethyl acetate and water (CH

2 CH 3 CO 2 C 2 H 5 + H 2 O

Rate = K [(CH 3 CO) 2 O] . [C 2 H 5 OH] 2 Order for (CH 3 CO) 2 O is 1 st order Order for [C 2 H 5 OH] 2 is 2 nd order Overall order of reaction is 3 rd Order

Types of reaction orders (a) Zero order reaction:

It is a reaction where reaction rate is not dependent on the

concentration of material i.e concentration is not changing (i.e. negligible amount of change).

Example:

Fading of dyes ,

Oxidation of vitamin A in an oily solution etc….

- dc/dt =Ko

Equation for zero order:

a [A] k
a [A]
k

Product (P)

Rate = - dc/dt = K [c] 0

- dc/dt = k

dc = - k dt

Equation for zero order: a [A] k Product (P) Rate = - dc/dt = K [c]

co = Initial concentration ct = Concentration at time t

Equation for zero order: a [A] k Product (P) Rate = - dc/dt = K [c]

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C T Units of the rate constant K:
C
T
Units of the rate constant K:

c = co Kt K = co c /t K = Concentration / time = mole / liter . second = M. sec -1

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Determination of t1/2

Let c = co /2 and t 1/2 = t substitute in equation;

  • c = co k t

t 1/2 = co / 2K

Note: Rate constant (k) and t 1/2 depend on co

Determination of t 0.9

Let c = 0.9 co and t= t 0.9 substitute in equation;

  • c = co k t

t 90% = t 0.9 = 0.1

co / k

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(b) First order reaction

The most common pharmaceutical reactions; e.g;

drug absorption

& drug degradation The reaction rate of change is proportional to drug concentration i.e.

  • drug conc. is not constant.

a [A] k Product (P)
a [A]
k
Product (P)

Equation:

Rate = - dc/dt = K [c]1

(b) First order reaction The most common pharmaceutical reactions; e.g; drug absorption & drug degradation The

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C = co e –kt Difficult to determine slope Lnc Log co Log c = log
C = co e –kt
Difficult to determine slope
Lnc
Log co
Log c = log co – kt / 2.303
Slope = c 1 – c 2 / t 1 – t 2
Slope = -k / 2.303
Logc

C

lnc = lnco kt Slope = c 1 c 2 / t 1 t 2 Slope = -k

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Determination of t 1/2

Let

t = t 1/2 and c = co /2

substitute in ln c = ln co Kt t 1/2 = ln 2/ K = 0.693 / K K units = 0.693 / t 1/2 = time -1

Determination of t 0.9

Let

t = t 0.9 c = 0.9 co

substitute in ln c = ln co Kt t 0.9 = 0.105 / K and K = 0.105/ t 0.9

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Example: A drug degrades according to the following:

Time (min.)

Conc. (%)

0

100

1

65.6

2

43.0

3

28.19

4

18.49

10

1.50

Plot c against t on semi log paper and determine slope, K and t1/2

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Solution: log 28.195 = 1.45 and log 1.5 = 0.176 slope = 1.45 – 0.176 /

Solution:

log 28.195 = 1.45 and log 1.5 = 0.176

slope = 1.45 0.176 / 3 10

=

1.27 / -7 = - 0.181

Equation; log c = log co Kt / 2.303 slope = -K/ 2.303

- 0.181 = - K / 2.303 K = 0.417 min -1

t 1/2 = 0.693 /

K

t1/2 = 0.693 / 0.417 = 1.66 minute

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Special Case

Apparent zero order of reaction

In aqueous suspensions of drugs, as the dissolved

drug decomposes more drug dissolve to maintain drugconcentration

i.e. drug concentration kept constant, once all undissolved drug is

dissolved, rate becomes first order.

Another special case: Pseudo 1 st order:

When we have two components, one of which is changing appreciably from its initial concentration and the other is present in excess that it is considered constant or nearly constant. Note: In first order reactions, neither K or nor t 1/2 is dependent on concentration

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2 nd Order reaction

When you have two components reacting with each other or one component reacting with itself.

2 Order reaction When you have two components reacting with each other or one component reacting

Units of K:

2 nd order graph
2 nd order graph

1/C = 1/Co + Kt K = (1/C - 1/Co) / t K = M-1. sec -1

i.e, K is dependent on initial drug concentration.

Half life:

Shelf life:

t 1/2 = 1 / KCo

t 0.9 = 0.11 / KCo