KINETICS OF DRUGS

Dandamun, Benbellah Ali Y. BSCHE-5 Engr. Elaine G. Mission

KINETICS OF DRUGS

Contents
Introduction ...................................................................................................................................... 2 Drug kinetics ..................................................................................................................................... 2 Rate, Order, and Molecularity .................................................................................................. 2 Zero-Order, First-Order, and Second-Order Reactions and Their Rate Equations, HalfLife and Shelf-Life ......................................................................................................................... 3 Zero-Order Reaction................................................................................................................ 4 First-Order Reaction ................................................................................................................. 7 Second-Order Reactions ...................................................................................................... 10 Special Cases ......................................................................................................................... 13 Sample Problems ....................................................................................................................... 13 Solutions to Problems ................................................................................................................ 15 References...................................................................................................................................... 17

KINETICS OF DRUGS

KINETICS OF DRUGS
Introduction
For us to be able to predict the shelf-life of a dosage, it is essential to determine the kinetics of the breakdown of the drug under carefully controlled conditions. Drug kinetics is essential because it determines the following: Stability of Drugs (Half-life or t1/2) Shelf Life (t0.90)

It is even used in the determination of the drugs expiration date. But the discussion will only focus on the basic principles of Drug Kinetics.

Drug kinetics
Drug kinetics is simply defined as how drug changes with time. 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.

Rate, Order, and Molecularity

The underlying principle on which all of the science of kinetics is built is the law of mass action (Cairns, 2008). The law of mass action states that, 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. + = [] [] The Rate of a chemical reaction is the speed of the reaction or simply, how fast the reaction occurs. It is, in a dilute solution, proportional to the concentrations of the various reactants each raised to the power of the number of moles of the reactant in the balanced chemical equation. Reactions are classified according to number of reacting species whose concentration determines the rate at which the reaction occurs (Florence and Attwood, 2006). The Order of the reaction (Overall Order) is the sum of the powers to which these concentrations are raised. The individual order of the reactant is simply the exponent of the reactant. = 2

KINETICS OF DRUGS = = = + In practice, the rate of a chemical reaction depends only on a small number of concentration terms, and the sum of the powers to which these concentrations are raised. This is because chemical reactions occur in a number of steps, or stages (called a mechanism) and the rate of the overall reaction is often governed by the rate of the slowest step (called, not surprisingly, the rate-determining step). Even if every other stage of a chemical reaction occurs essentially instantaneously, the rate of the reaction as a whole cannot exceed that of the slowest stage. (Cairns, 2008) The order of a chemical reaction cannot be predicted from the chemical equation, even if it has been balanced. The order of a reaction is determined experimentally from accurate measurements of the rate under different conditions (Cairns, 2008). Typically, drugs react in the zero, first, and second order. There are also rare cases wherein the drugs undergo a third order reaction, or even a fractional order of reaction. The Molecularity is the total number of molecules taking part in the slowest of the elementary reaction steps. In most chemical reactions, two molecules collide and react; the molecularity is 2 and the reaction is said to be bimolecular. e.g.: + Reactions in which only one molecule is involved (unimolecular) are known, but usually occur in the gas phase. e.g.: Reactions with a molecularity higher than 2 are very rare, since this would require three or more reactants all encountering each other at the same time.

Zero-Order, First-Order, and Second-Order Reactions and Their Rate Equations, Half-Life and Shelf-Life
Taking an example of a reaction: = [] Rate can be rewritten as: = [] Differential rate equations like these are not much use to the practicing chemist, so it is usual to integrate the differential form of the rate equation, shown above, to obtain more 3

KINETICS OF DRUGS useful expressions (Cairn, 2008). The next discussion will be all about the derivation of the rate reactions for zero, first, and second order reactions. For the following derivations, we let: = = (@ = 0) = = 1/2 = 0.9 = The shelf life of a pharmaceutical product is the length of time the product may safely be stored on the dispensary shelf before significant decomposition occurs. This is important since, at best, drugs may decompose to inactive products; in the worst case the decomposition may yield toxic compounds. The shelf-life is often taken to be the time for decomposition of 10% of the active drug to occur, leaving 90% of the activity. The unit for the rate constant (k) can be determined using the formula: ()1 ()1

Zero-Order Reaction
There are some reactions in which the rate of the reaction is independent of the concentration of the reactants but does depend on some other factor, such as the amount of catalyst present. These reactions are termed zero-order reactions, and rate equations can be derived as follows: [] = []0 [] =
0

[] = = or = We can also rewrite the equation in terms of the mole fraction of A (Xa). =

KINETICS OF DRUGS Zero-order process takes place at a constant rate independent of the existing concentration or initial concentration. Example: A patient was given 100 mg drug A orally. Assume that the drug absorption follows zeroorder kinetics at a rate of 10 mg/min. In the example, 10 mg of drug will undergo absorption for every minute. It does not matter even if the initial concentration administered to the patient is higher or lower than 100 mg. The same rate (10 mg/min) will be followed. Eventually, the process will come to an end when the amount of drug administered is absorbed by the body completely (for the example, the process ends in 10 minutes.) In zero-order reactions the amount of product formed varies with time so that the amount of product formed after 20 minutes will be twice that formed after 10 minutes. Reactions that follow zero-order kinetics are quite rare, but they do occur in solid-phase reactions such as release of drug from a pharmaceutical suspension.

FIGURE 1 PLOT OF T VS CA

FIGURE 2 HYDROLYSIS OF A SUSPENSION OF ACETYLSALICYLIC ACID AT 34C. A plot of the amount remaining (as ordinate) against time (as abscissa) is linear with a slope of k0. Many decomposition reactions in the solid phase or in suspensions apparently follow zero-order kinetics. (Florence and Attwood, 2006) 5

KINETICS OF DRUGS Drugs that follow Zero-order kinetics Phenytoin Phenylbutazone Warfarin Heparin Ethanol Aspirin Theophylline Tolbutamide Salicylates

Half-life for a Zero-Order Reaction

The half-life of a reaction can be derived by letting =0.5 and = 1/2 . = 0.5 = 1/2 0.5 = 1/2 / = .

Note that for the half-life of a zero-order reaction, rate constant (k) and half-life (t1/2) depend on the initial concentration of the reactant ( ).

FIGURE 3 SAMPLE PLOT FOR THE HALF-LIFE OF A ZERO-ORDER REACTION 6

KINETICS OF DRUGS

Shelf-life for a Zero-Order Reaction

The shelf-life of a reaction can be derived by letting =0.9 and = 0.90 . = 0.9 = 0.90 0.1 = 0.90 . = .

Same as the half-life, rate constant (k) and shelf-life (t0.90) depend on the initial concentration of the reactant ( ).

First-Order Reaction
This type is the most common in the pharmaceutical industry (e.g.: drug absorption and drug degradation). The rate of first-order reactions is determined by one concentration term and may be derived as follows: [] = []

[] = []
[] = [] 0

ln ln = =

In terms of the mole fraction of A (Xa), the equation becomes: ( ) = First-order process takes place at a constant proportion of the drug concentration available at that time so the process is depending on the initial concentration. Example: A patient was given 100 mg of drug B orally and it was assumed to be following first-order kinetics, a proportion of 10% per minute of the existing concentration at that time. For this example, the dose given to the patient is again 100 mg but the proportion being absorbed is 10% per minute. This means that in the first minute, 10% of the initial drug will be absorbed (10 mg in the example). For the second minute, again 10% of the drug that remained for absorption will be absorbed (10% of 90 mg = 9 mg, meaning, after the 7

KINETICS OF DRUGS second minute, only 81 mg of the reactant will remain). And this process goes on. This means that the first-order process never comes to an end.

FIGURE 4 PLOT OF T VS LN(CA/CAO)

FIGURE 5 FIRST-ORDER PLOT FOR HYDROLYSIS OF HOMATROPINE IN HYDROCHLORIC ACID (0.226 MOL DM-03) AT 90C. If a plot of equation is made, with t on the horizontal axis and ln

on the vertical axis,

a straight line passing through the origin will be obtained for a reaction obeying first-order kinetics. The slope of this straight line will be equal to k, the rate constant for the reaction.

KINETICS OF DRUGS

FIGURE 6 GRAPHS SHOWING THE DIFFERENCE OF FIRST AND ZERO-ORDER KINETICS IN TERMS
OF ELIMINATION OF DRUGS

As can be seen in the figure, the main difference between a first-order and a zero-order reaction is that in zero-order reaction, the process will end eventually while in a first-order reaction, the process does not end.

Half-life for a First-Order Reaction

The half-life of a reaction can be derived by letting =0.5 and = 1/2 . ln =

ln

0.5 = 1/2

ln 0.5 = 1/2 / = .

Note that for the half-life of a first-order reaction, rate constant (k) and half-life (t1/2) does not depend on the initial concentration of the reactant ( ).

KINETICS OF DRUGS

FIGURE 7 SAMPLE PLOT FOR THE HALF-LIFE OF A FIRST-ORDER REACTION

Shelf-life for a First-Order Reaction

The shelf-life of a reaction can be derived by letting =0.9 and = 0.90 . ln ln =

0.9 = 0.90

ln 0.9 = 0.90 0.90 = ln 0.9

Same as the half-life, rate constant (k) and shelf-life (t0.90) does not depend on the initial concentration of the reactant ( ).

Second-Order Reactions
For reactions of the type: 2 or + The rate of the reaction will be first order with respect to each reactant and hence second order overall. The rate of a second-order reaction is determined by the concentrations of two reacting species. The rate equation for a second-order reaction is derived as follows:

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KINETICS OF DRUGS [] = []2

[] = []2
[] = []2 0

= In terms of the mole fraction of A (Xa), the equation becomes: = The equations derived are only valid for second-order reactions in which the concentrations of the reactants are equal. In most cases it is possible to arrange for the concentrations of the reactants to be equal and the equations may be used.

FIGURE 8 PLOT OF T VS 1/CA

The equation derived is a straight line of the type y = mx + b, so that a plot of 1/Ca against t yields a straight line of slope k, with an intercept on the vertical axis of 1/Cao.

Half-life for a Second-Order Reaction

The half-life of a reaction can be derived by letting =0.5 and = 1/2 . 1 1 = 1 1 = 1/2 0.5 0.5
2 0.5

= 1/2

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KINETICS OF DRUGS 1 = 1/2 / =

The half-life for a second-order reaction is inversely proportional to the initial concentration.

FIGURE 9 SAMPLE PLOT FOR THE HALF-LIFE OF A SECOND-ORDER REACTION

Shelf-life for a Second-Order Reaction

The shelf-life of a reaction can be derived by letting =0.9 and = 0.90 . 1 1 = 1 1 = 0.90 0.9 0.9
2 0.9

= 0.90

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KINETICS OF DRUGS 0.1 = 0.90 0.9 0.90 = . .

The shelf-life for a second-order reaction is inversely proportional to the initial concentration.

Special Cases
Apparent Zero-Order of Reaction
In aqueous suspensions of drugs, as the dissolved drug decomposes more drug dissolve to maintain drug concentration i.e. drug concentration kept constant, once all undissolved drug is dissolved, rate becomes first order.

Pseudo First-Order
In some second-order reactions the concentration of one of the reactants is many times more than the concentration of the other, too large in fact as to be considered constant throughout the reaction. In these cases, the reaction appears to follow first-order kinetics, even though, strictly speaking, it is still a second-order process. The majority of decomposition reactions involving drugs fall into this category, either because the species reacting with the drug is maintained constant by buffering or because, as in the case of uncatalysed hydrolysis reactions, the water is in such large excess that any change in its concentration is negligible. Example: In a Hydrolysis Reaction catalyzed by [ + ]: [] = [][ + ] When the solution is buffered at constant pH, [ + ] is constant and we can write the equation as: [] = []

Sample Problems
1. A solution of a drug was freshly prepared at a concentration of 300 mg/ml, after 30 days, the drug concentration in the solution was 75 mg/ml. a. Assuming First-order kinetics. What is the rate constant? When will the drug decline to one-half of the original concentration? b. Assuming Zero-order kinetics. What is the rate constant? When will the drug decline to one-half of the original concentration?

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KINETICS OF DRUGS c. Assuming Second-order kinetics. What is the rate constant? When will the drug decline to one-half of the original concentration?

2. If the half-life for decomposition of a drug is 12 hr., how long will it take for 125 mg of the drug to decompose 30%? Assume First-order kinetics and constant temperature.

3. A pharmacist dissolved a few milligrams of a new antibiotic drug into exactly 100 ml of distilled water and placed the solution in a refrigerator (5 C). At various time intervals, the pharmacist removed a 10 ml aliquot from the solution and measured the amount of drug contained in each aliquot.

a. What is the order of the decomposition process of this antibiotic? b. What is the rate of decomposition of this antibiotic? c. How many milligrams of antibiotic were in the original solution prepared by the pharmacist?

4. Determine the first-order rate constant for the hydrolysis of acetyl--methylcholine at 85C from the information given below.

5. Hydrogen peroxide solutions are normally stable, but when metal ions are added, hydrogen peroxide decomposes: 14

KINETICS OF DRUGS 22 2 22 + 2 In a solution containing FeCl3, the concentration of H2O2 varied as follows:

Using these data, determine the order of the reaction with respect to peroxide, and the value of the rate constant (include appropriate units).

Solutions to Problems
1. = 75 / = 300 / = 30 a.

75 = (30 ) 300 = . / 1/2 = 1/2 = / 0.5

0.5 4.62 102 / =

b. = (75 300)/ = (30 ) = . /( ) 0.5 0.5(300 ) 1/2 = 7.5 /( ) / = 1/2 =

c.

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KINETICS OF DRUGS 1 1 = (30 ) 75 300 ) = . () ( 1/2 = 1/2 = 300 1 1 1 (3.33 104 ()1 ( )

/ =

2. 1/2 = 12 0.5 1/2 = 0.5 12 = = . / (1 ) = 0.06 (1 0.30) = = .

3. a. The plot of t vs Ca formed a straight line, therefore the reaction is at zeroorder. b. The slope of the graph (-k) is -6.55. Therefore, rate constant (k) = 6.55 (mg/ml) hr c. The intercept of the graph is 87.30. Therefore, Cao= 87.30 mg/ml

4. The slope (k) of the graph is 0.35. Therefore, rate constant (k) = 0.35/day

5. The plot of t vs ln(Ca/Cao) formed a straight line, therefore the reaction order is first-order. The slope (k) of the graph is 3.99 x 10-3. The rate constant (k) is 3.99 x 10-3.

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KINETICS OF DRUGS

References
Attwood, D. and Florence, A. (2006). Physicochemical Principles of Pharmacy, 4th ed. Retrieved from: http://www.scribd.com

Cairns, D. (2008). Essentials of Pharmaceutical Chemistry, 3rd ed. Retrieved from: http://www.4shared.com/office/_wd4P3B4/Essentials_of_Pharmaceutical_C.htm

Differences between Zero-order kinetics and First-order kinetics. Retrieved from: http://www.pharmainfo.net/og/rcp/downloads

Drug Stability and Kinetics. Retrieved from: http://www.scribd.com

Drugs following zero order pharmacokinetics. http://www.lifehugger.com/moc/84/Drugs_following_zero_order_pharmacokinetics

First and zero order kinetics. Retrieved from: https://sites.google.com/site/pharmacologyinonesemester/2-drug-distributionmetabolism-and-elimination/2-5-blood-levels/2-5-3-first-and-zero-order-kinetics

Half-lives. Retrieved from: http://chemwiki.ucdavis.edu/Physical_Chemistry/Kinetics/Reaction_Rates/Halflives_and_Pharmacokinetics

Levenspiel, O. Chemical Reaction Engineering, 3rd ed. Retrieved from: http://www.scribd.com

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