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DRUG STABILITY

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It is defined as how drug changes with time i.e., study of rate. of change. ... The most common pharmaceutical reactions; e.g; drug absorption & drug degradation ... – PowerPoint PPT presentation

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Title: DRUG STABILITY


1
  • DRUG STABILITY KINETICS
  • General Outline
  • 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
  • Influence of packaging on drug stability
  • Influence of temperature on drug stability
  • Influence of catalysts on drug stability

1
2
  • 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.

2
3
  • 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.

3
4
  • 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

4
5
m slope ?Y / ?X
5
6
  • Advantages of use of straight line
  • Easier to determine parameters (slope and
    intercept)
  • Simultaneous determination of two parameters (m
    b)
  • 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

6
7
  • 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)

7
8
Straight Line
Slope m ?Y / ?X constant
8
9
Curve
Slope is not constant but function of X Slope
1st derivative of y with respect to X
9
10
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
10
11
(iv) Integration Determination of area under
the curve i.e., sum or amount.
a
b
AUC
12
Where Y is the function of the graph b
upper limit a Lower limit Rules of
Integration
13
  • Example
  • Determine the area under the curve for the
    relationship
  • y mx b, upper limit a and Lower limit 0

14
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15
  • 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 a Aa .Bb
  • Rate K Aa .Bb
  • Order of reaction sum of exponents
  • Order of A a and B b
  • Then Overall order a b

16
  • 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 . C2H5OH2
  • Order for (CH3 CO)2 O is 1st order
  • Order for C2H5OH2 is 2nd order
  • Overall order of reaction is 3rd Order

17
  • Types of reaction orders
  • 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

18
Equation for zero order a A k
Product (P) Rate - dc/dt K c0 - dc/dt
k dc - k dt co Initial
concentration ct Concentration at time
t
18
19
C
T
Units of the rate constant K c co
Kt K co c /t K Concentration / time
mole / liter . second M. sec-1
19
20
  • 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

20
21
  • (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 c1
  • Equation

21
22
C co e ktDifficult to determine slope
lnco
lnc lnco kt Slope c1 c2 / t1 t2 Slope
-k
C
Lnc
Log co
Log c log co kt / 2.303 Slope c1 c2 / t1
t2 Slope -k / 2.303
Logc
Or use semi log paper
22
23
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
23
24
  • 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

24
25
  • 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

25
26
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
26
27
  • 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 1st 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
    t1/2 is dependent on
  • concentration

27
28
  • (c) 2nd Order reaction
  • When you have two components reacting with
    each
  • other or one component reacting with itself.

29
  • 2nd order graph

Units of K 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 t1/2 1 /
KCo Shelf life t0.9 0.11 / KCo
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