9/26/2012

Principles and kinetics of drug stability (PHR 416)

Gamal El Maghraby, Ph.D.

Molecularity
Molecularity describes the mechanisms or the pathways of reaction (i.e the number of molecules, atoms or ions entering the reaction). Reactions may be:
complex (multistep) reaction in which the reaction takes place in a series of steps the product of each step cannot be isolated and serves as starting material for the next step. Finally, relatively unreactive materials are obtained and constitute the final product. Elementary reaction (single step reaction)

The order is identical to molecularity in elementary reaction as it gives the number of molecules entering the reaction.
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Specific rate constant

The constant k appearing in the rate law associated with a single step reaction (elementary) reaction is called the specific rate constant. Any change in the conditions of the reaction (solvent, temperature, .) will lead to different value for the specific rate constant.
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Half life and shelf life

Half life (t1/2)
Is the time required for one-half of the material to disappear; it is the time at which A has decreased to A.

Shelf life (t90)

Is the time required for 10% of the material to disappear; it is the time at which A has decreased to 90% of its original concentration (i.e., 0.9A).
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Units of the basic rate constants

The rate equations are rearranged to have the value of the rate constant. For zero order reaction:

K0 = Moles liter-1 second-1

Units of the basic rate constants

For first order reaction:

K = second-1
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Units of the basic rate constants

For second order reaction:

K = liter second-1 mole-1

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Zero order reactions: e.g. the loss of color of multisulfa product

Zero order reaction means constant rate and independence on the concentration of reactant.

A (colored) Product (colorless) The intensity of color decreases with time. This can be monitored spectrophotometry.
The reaction was found to be zero order (i.e. constant rate irrespective to reactant conc.)

So Reaction rate = K0

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Zero order reactions: The loss of color of multisulfa product

The rate equation can be integrated between the initial concentration A0 at t0 and At (conc. at time = t) to produce:

So:

At A0 = k0t At = A0 k0t

Zero order reaction

At = A0 k0t

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Suspension, apparent zero-order kinetics

Suspensions are examples of apparent zero order kinetics in which the concentration in solution depends on drug`s solubility. As the drug decomposes in solution, more drug is released from the suspended particles so that the concentration remains constant. This conc. is the drug`s equilibrium solubility in particular solvent at particular temperature.
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Suspension, apparent zero-order kinetics

The important point is that the amount of drug in solution remains constant despite its decomposition with time. The reservoir of solid drug is responsible for this consistency Apparent zero order. In absence of reservoir particles, the drug is depleted with time and the reaction is first order which can be described using the following equation:

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Suspension, apparent zero-order kinetics

Where A is the concentration of intact drug at time t and k is first order rate constant When the concentration [A] is rendered constant as in case of suspension we may write: K[A] = k0 So that the first order rate equation becomes a zero order equation and is said to be : Apparent zero order equation. Once all particles have been converted to solution the system changes to first order reaction.
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Suspension, apparent zero-order kinetics

Example: A prescription of liquid aspirin containing 325mg/5ml (6.5 g/100ml) is called for. The solubility of aspirin at 25 oC is 0.33g/100ml; so the preparation will be suspension. The preparation has pH 6. The first order rate constant for aspirin degradation in this solution is 4.5 x 10-6 sec-1. Calculate the zero order rate constant. Determine the shelf life (t90). k0 = K[A] = (4.5 x 10-6 sec-1) x (0.33g/100ml) K0 = 1.5 x 10-6 g/100ml sec-1.
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First order reactions

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1st order reactions

A k1 B (+ C)

Rate: -

d[c] = k[c] dt
d[c] = kdt [c]

C= concentration of reactant at time t. C0 = initial concentration of the reactants.

Rewriting: -

Integration gives:

1 d[c] = kdt [c] C0 0

So: ln[c] ln[c]0 = -kt [c] = [c]o e k t

or:

ln [c] = ln [c]o k t

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1st order reactions

ln [c] = ln [c]o k t Plotting ln[A]t against t gives a straight line with slope -k: log [c] = log [c]o k t /2.303
k= 2.303 a log (a x) t

Where a = c0 and (a-x)= c The halflife, t1/2, is defined as the time that is needed to reduce the concentration of the reactant to 50% of its original value. In formula:
ln 1 / 2[c]0 = -kt1/2 so [c]0
t1/ 2 = ln 2 0.693 = k k

Concentration and time of 1st order reaction

[c] Describe the features of plot of [c] vs. t and ln[c] vs. t for 1st order reactions. Apply the technique to evaluate k or [c] at various times. ln[c] [c] = [c]o e k t ln [c] = ln [c]o k t

t t t
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Concentration and time of 1st order reaction

[c] Describe the features of plot of [c] vs. t and ln[c] vs. t for 1st order reactions. Apply the technique to evaluate k or [c] at various times. log[c] log [c] = log [c]o k t /2.303 k t [c] = [c]o e

t t t
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