Chemical Kinetics and Stability (22)

Why is stability testing needed?

To provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity, and light

Stability testing includes testing what attributes of drugs?

Those that are suscpetible to change during storage over time and are likely to influence safety and potency

Stability needs to be evaluated over time in _________ container-closure system that will be used for marketing the drug

the same

1 multiple choice option

Stability testing should cover?

Chemical, physical, biological, and microbial attributes, preservative content, and functionality tests

Describe physical attributes

Changes to the physical nature of the drug (appearance, properties, hardness, brittleness, particle size)

Describe chemical attributes

Separation of the chemical compound into elements or simpler compounds or change in the chemical nature (hydrolysis, oxidation, isomerization, polymerization, photodegradation)

Describe microbial attributes

Contamination of the product (depends on time of microbe and level of toxicity)

What are the three frequencies types of testing?

Long-term, accelerated, and intermediate

Long-term testing

Every 3 months in the first year, every 6 months in the second, and annually thereafter

Accelerated testing

Minimum of three time points (0, 3, and 6 months) (minimum of 6 months)

Intermediate testing

Minimum of four time points (0, 6, 9, and 12 months) (minimum of 6 months)

What is allowed to happen if the drug has no significant changes in the six-month's accelerated testing?

The product can be placed in market with a provisional shelf-life of up to 2 years

What is shelf-life?

Time at which the average drug characteristic remains within an approved specification after manufacture

What is potency?

The amount of drug needed to produce a given effect (strength)

What is degradation?

Condition or process of degrading. Decline to a lower quality, condition, or level.

What is expiry date?

Time in which a drug product in specific packaging will remain stable when stored in recommended conditions

What is efficacy? Safety?

Optimum therapeutic level for a specified period of time; minimum or no side effects

Describe the storage conditions for long-term stability testing

25°C (±2)/ 60% RH (±5) or 30°C (±2)/ 65% RH (±5) or

Describe the storage conditions for accelerated stability testing

40°C (±2)/ 75% RH (±5)

Describe the storage conditions for intermediate stability testing

30°C (±2)/ 65% RH (±5)

What is drug stability?

The resistance of the drug to the various chemical, physical, and microbial reactions that may change the original properties

Define shelf life

The time during which the medicinal product is predicted to remain fit for its intended use under specified storage conditions

Define shelf life quantitatively

The time until the original potency or content of the active ingredient has been reduced by 10%. Time for 10% of drug to disappear/decreased to 90% the original volume

Why are accelerated stability tests utilized?

It is not always practical to wait years until 10% of the drug activity is lost

What is the purpose of accelerated stability tests?

To quickly evaluate the drug degradation process, physical change, and to predict a shelf life.

How can you accelerate stability tests?

By adding various types of stresses to speed the degradation process

What are some common types of stresses that can be implemented in accelerated stability tests?

Temperature, humidity, and light

What is kinetics?

Reaction rates and the sequence of steps by which a reaction occurs

What is the rate of a reaction for a given chemical change?

The speed with which its reactants disappear and its products form

Why do we study kinetics?

Allows a prediction of the degree of change that will occur after a given time has elapsed.

Why do we study drug stability?

Safety of the patient, to know how stability is affected by factors, such as temperature, humidity, and light, and to establish a shelf-life for the drug product.

What is the application of chemical kinetics in pharmacy?

the production of more-stable drug preparations and recommended storage conditions/packaging/formulations

Rate of reaction

Speed or velocity of a reaction with which a reactant(s) undergoes a change

How is the rate of reaction determined?

By the change in the concentration of the reactants or products as a function of time

What is the equation for rate?

change in concentration/change in time (-dc/dt)= K^a

What is K?

The rate constant

What is exponent a?

The number of molecules and represents the order of the reaction

What are the different orders of reactions?

zero, first, second, third, and pseudo first

What is the order of a reaction?

Indicates how the rate of a chemical reaction depends on the concentration of each reactant involved

Zero order rate reactions

The loss of drug is independent of the concentration of the reactants and is constant with respect to time (-dc/dt)= K0

What is the integrated form of the zero order rate constant, K0?

C=-K0t + C0

What is C0?

The initial concentration of the drug

What is C?

The concentration of the drug after a period of time (t)

What are the units for K0?

Concentration per unit time

Why is it common to use the half life in zero order reactions?

Don't want to wait for all the material in a reaction to decompose

What is the equation for half-life in zero order reactions?

t1/2=(1/2)(C0/K0)

What is the equation to find time in a zero order reaction?

C=-K0t + C0 → K0t + C= C0 → K0t= C0-C → t=C0-C/K0

How are t=C0-C/K0 and t1/2= (1/2)(C0/K0) similar

They give the same answer regardless of which you use when looking for half-life (1/2 x C0 is equal to C0-C)

Describe the graph of a zero order reaction (-dc/dt versus t)

The line is horizontal when plotted as -dc/dt (K0) against time (t). It is independent of the change in concentration. Decreases by the same amount each time (slope= C0-Ct)

Describe the graph of a zero order reaction (C versus t)

When plotted as concentration against time: As time increases, concentration decreases at a constant rate.

C= -K0t + C0

C decreases as t increases. C0 is the original concentration and intercepts the y-axis.

What is the equation to find the time of shelf life in zero order reactions?

t(90%)=C0-(0.9)C/K0

First order rate reactions

The loss of drug is directly proportional to the concentration remaining with respect to time. Rate of reaction is proportional to concentration of drug remaining (-dc/dt)= KC

What is the integrated form of the first order rate constant, KC?

logC= (-Kt/2.303) + logC0

What is the integrated of the first order rate constant, KC, in natural log form?

ln C= -kt + ln C0

What is the half life equation for first order reactions?

ln C (50)= -kt + ln C0 (100) → kt + ln 50= ln 100 → t= ln 100- ln 50/ k → t1/2= 0.693/k

What is the equation to find the time of shelf life in first order reactions?

t(90%)= 0.105/k = (ln 100- ln 90)/k

Describe the graph of a first order reaction (log C versus t)

When plotted as concentration versus time, the line decreases and is represented by -K/2.303 or the change in concentration over the change in time. The y-intercept is the original concentration.

compare rate of elimination in first order and zero order reactions

First order reactions have a constant fraction of drug eliminated per unit of time dependent on concentration while zero order reactions have a constant rate of elimination independent of concentration

Give an example of first order elimination

0 hours= 80 mcg

12 hours= 40 mcg

24 hours= 20 mcg

36 hours= 10 mcg

48 hours= 5 mcg

Dependent on concentration, fractional decrease

Give an example of zero order elimination

0 hours= 80 mcg

12 hours= 65 mcg

24 hours= 50 mcg

36 hours= 35 mcg

48 hours= 20 mcg

Inependent on concentration, constant decrease

Describe the two graphs in zero and first order reactions

Linear and curved. The curved graphs between zero and first order differ based on concentration dependency

What is the energy of activation?

High energy barrier that a reaction must reach in order to go from reactants to products such as in a degradation reaction

Describe how increased temperature effect drug degradation rate

It increases it. Rate normally increases 2-3 times with each 10 °C increase

The effect of temperature on reaction rate is given by what equation?

Arrhenius

What is the Arrhenius equation?

k=Ae^(-Ea/RT)

What is k?

The rate constant of the reaction

What is A?

The frequency of correctly oriented collisions between reacting species

What is e?

The base of the natural logarithm

What is Ea?

The activation energy

What is R? T?

Universal gas constant; absolute temperature

What other forms can the Arrhenius equation exist in?

lnk= lnA - (Ea/RT) or logk= logA - (Ea/2.303RT)

What is the Q10 equation for shelf life?

What is t90(T2)?

The shelf life at time 2

What is t90(T1)?

The shelf life at time 1

What is a common value for Q10?

3

Example: An antibiotic solution has a shelf-life of 48 hours at 5°C, what is the shelf-life at 25°C?