Drug Stability and Kinetics
Drug Stability and Kinetics
Drug Stability and Kinetics
General Outline 1)
2) 3) 4) 5) 6) 7) 8) Definition of drug stability and drug kinetics Importance of studying kinetics Basic math principles Drug kinetics reaction orders Determination of reaction orders Shelf life and half life Overage Degradation pathways
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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
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)
also
Ordinate = dependent variable axis abscissa = independent variable axis
m = slope = Y / X
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
(iii) Differentiation:
Determination of the rate of change ( slope in graph)
Straight Line:
Slope = m = Y / X = constant
Curve:
Slope is not constant but function of X Slope = 1st derivative of y with respect to X
y = n eax
e.g., y = 3e-2x y = ln x y = 1/x y = ex
Example:
dy/dx = an eax
dy/dx = -6e-2x dy/dx = 1/x dy/dx = - 1/x2 dy/dx = ex
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 =
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Where;
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.
aA+bB
Rate [A]a .[B]b Rate = K [A]a .[B]b
Product
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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Equation for zero order: a [A] k Product (P) Rate = - dc/dt = K [c]0 - dc/dt = k dc = - k dt
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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
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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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Lnc
Log co
Logc
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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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2 3 4 10
65.6
43.0 28.19 18.49 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 / 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 t1/2 = 0.693 / K t1/2 = 0.693 / 0.417 = 1.66 minute
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Special Case
(c) 2nd Order reaction When you have two components reacting with each other or one component reacting with itself.
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i.e, K is dependent on initial drug concentration. Half life: Shelf life: t1/2 = 1 / KCo
t0.9 = 0.11 / KCo
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