1 DRUG STABILITY & KINETICS General Outline 1) Definition of drug stability and drug kinetics 2) Importance of studying kinetics 3) Basic math principles 4) Drug kinetics reaction orders 5) Determination of reaction orders 6) Shelf life and half life 7) Overage 8) Degradation pathways 9) Influence of packaging on drug stability 10) Influence of temperature on drug stability 11) Influence of catalysts on drug stability
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DRUG STABILITY & KINETICS
General Outline
1) Definition of drug stability and drug kinetics
2) Importance of studying kinetics
3) Basic math principles
4) Drug kinetics reaction orders
5) Determination of reaction orders
6) Shelf life and half life
7) Overage
8) Degradation pathways
9) Influence of packaging on drug stability
10) Influence of temperature on drug stability
11) Influence of catalysts on drug stability
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1) Definition of drug stability and drug kinetics
Stability
It is defined as the study of the extent to which the properties
of a drug substance or drug product remain within specified limits at
certain temperature. Properties may be physical, chemical,
microbiological, toxicological or performance properties such as
disintegration and dissolution.
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.
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2) Importance of studying kinetics
It determines:
Stability of drugs (t1/2)
Shelf life ((t0.9)
Expiration date
Stability of drugs (t1/2)
The half life (t1/2) 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 (t0.9)
It is defined as the time necessary for the drug to
decay to
90% of its original concentration.
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3) Basic Math principles
i) The straight Line:
General equation: Y = mx+ bY = 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
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Advantages of use of straight line
Easier to determine parameters (slope and intercept)
Simultaneous determination of two parameters (m + b)
ii) Logarithms:
(a) Common log (base10)
log 100 = log 102 = 2
log 1000 = log 103 = 3
(a) Natural log (base e = 2.72)
In 100 = In ex
In 100 = In 2.72x = 4.61
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Relation between Log and Ln
Ln X = 2.303 Log X
Rules for calculating with Log
log (a . b) = log a + log b
log (a / b) = log a - log b
log an = n log a
log ex = X
(iii) Differentiation:
Determination of the rate of change ( ≈ slope in graph)
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Slope = m = ∆Y / ∆X = constant
Straight Line:
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Curve:
Slope is not constant but function of X
Slope = 1st derivative of y with respect to X
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Rules of differentiation
y = axn dy/dx = anxn-1
e.g., y = x2 dy/dx = 2x
y = n eax dy/dx = an eax
e.g., y = 3e-2x dy/dx = -6e-2x
y = ln x dy/dx = 1/x
y = 1/x dy/dx = - 1/x2
y = ex dy/dx = ex
Example:
y = 10 x3 + 2 x2 + 5x + 5
dy/dx = 30 x2 + 4 x + 5
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(iv) Integration
Determination of area under the curve i.e., sum or amount.
AUC =
a b
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Where; Y is the function of the graph
b = upper limit
a = Lower limit
Rules of Integration:
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Example
Determine the area under the curve for the relationship
y = mx + b, upper limit = a and Lower limit = 0
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If you do not know the equation of the line you can use the trapezoidal
rule to calculate the area under curve (AUC)
4) 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 Product
Rate α [A]a .[B]b
Rate = K [A]a .[B]b
Order of reaction = sum of exponents
Order of A = a and B = b
Then Overall order = a + b
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Example:
The reaction of acetic anhydride with ethyl alcohol to form ethyl acetate and water
(CH3 CO)2 + 2 C2H5OH 2 CH3 CO2 C2H5 + H2O
Rate = K [(CH3 CO)2 O] . [C2H5OH]2
Order for (CH3 CO)2 O is 1st order
Order for [C2H5OH]2 is 2nd order
Overall order of reaction is 3rd Order
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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
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Equation for zero order:
a [A] k Product (P)
Rate = - dc/dt = K [c]0
- dc/dt = k dc = - k dt
co = Initial concentration
ct = Concentration at time t
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Units of the rate constant K:
c = co – Kt
K = co – c /t
K = Concentration / time
= mole / liter . second
= M. sec-1
C
T
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Determination of t1/2
Let c = co /2 and t1/2 = t
substitute in equation;
c = co – k t
t1/2 = co / 2K
Note: Rate constant (k) and t1/2 depend on co
Determination of t0.9
Let c = 0.9 co and t= t0.9
substitute in equation;
c = co –k t
t90% = t0.9 = 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)
Rate = - dc/dt = K [c]1
Equation:
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C = co e –kt
Difficult to determine slope lnc = lnco – kt
Slope = c1 – c2 / t1 – t2
Slope = -k
lnco
Log co
Log c = log co – kt / 2.303Slope = c1 – c2 / t1 – t2
Slope = -k / 2.303
Or use semi log paper
C Lnc
Logc
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Semi log paper
Slope = -K / 2.303
Slope = log c1 – log c2 / t1 – t2
NOT c1 – c2 / t1 – t2
Units of K:
lnc = lnco – Kt
K = ( lnco – lnc ) / t
Unit = time-1
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Determination of t1/2
Let t = t1/2 and c = co /2
substitute in ln c = ln co – Kt
t1/2 = ln 2/ K = 0.693 / K
K units = 0.693 / t1/2 = time-1
Determination of t0.9
Let t = t0.9 c = 0.9 co
substitute in ln c = ln co – Kt
t0.9 = 0.105 / K and K = 0.105/ t0.9
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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