Lecture 22 - Chemical Kinetics and Drug Stability

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What should stability studies include testing of, according to the FDA?

Testing of attributes of the active substance that are susceptible to change during storage

What physical attributes should be tested during stability studies?

Changes to the physical nature of the drug, occurring in tablets, capsules, or semisolids

• Appearance

• Properties

• Hardness

• Brittleness

• Particle Size

What chemical attributes should be tested during stability studies?

Separation of the chemical compound into elements or simpler compounds, or change in the chemical nature

• Hydrolysis

• Oxidation

• Isomerization

• Polymerization

• Photodegradation

What microbiological attributes should be tested during stability studies?

Contamination of a product

• Dependent on the type of microbe, and

• Level of toxicity

What is Potency?

Amount of drug needed to produce a given effect; usually expressed in dosage, such as mg

Also known as Strength

What is Degradation?

Condition or process of degrading or being degraded (decline to a lower quality, condition, or level)

What is Shelf Life?

Time at which the average drug characteristics remains with an approved specification after manufacture (decay to 90% of its original concentration)

What is Expiry Date?

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

What is Efficacy?

Safety?

Efficacy — optimum therapeutic level for specific period of time

Safety — minimum or no side effects

What are the basic requirements for Stability Testing of drug products?

1. Include testing of attributes susceptible to change during storage and are likely to influence potency and safety

2. Should cover chemical, physical, biological, and microbiological attributes; preservative content (antioxidant, antimicrobial); and functionality tests (drug dissolution)

3. Needs to be evaluated over time in SAME container-closure system proposed for marketing

What is the frequency of testing required for Drug Products, according to each of these testing types?:

• Long-Term Stability Testing

• Accelerated Stability Testing

• Intermediate Stability Testing

What happens if there is no significant change during the 6-month accelerated or real-time stability testing?

Long-Term:

• Every 3 months over first year, every 6 months over second year, then annually after

Accelerated:

• Minimum of three time points

Intermediate:

• As a result of significant change at accelerated storage condition

• Minimum of four time points

IF NOT SIGNIFICANT CHANGE DURING 6-MONTH ACCELERATED AND REAL-TIME STABILITY, product will be allowed to place in market with provisional shelf life of up to 2 years

What is ‘significant change’ determined as in drug stability?

Failure to meet its specification

What are the storage conditions required for Long-Term Stability Testing?

What is the minimum time period covered by the data at submission (how long of testing)?

Storage Conditions:

• 25˚C ± 2˚C OR 30˚C ± 2˚C

• 60% RH ± 5% RH OR 65% RH ± 5% RH

• Where RH = long-term condition

• Up to applicant which conditions to test with

Minimum Time Period:

• 12 months

What are the storage conditions required for Intermediate Stability Testing?

What is the minimum time period covered by the data at submission (how long of testing)?

Storage Conditions:

• 30˚C ± 2˚C

• 65% RH ± 5% RH

• If these are the long-term conditions, then there is no intermediate condition

Minimum Time Period:

• 6 months

What are the storage conditions required for Accelerated Stability Testing?

What is the minimum time period covered by the data at submission (how long of testing)?

Storage Conditions:

• 40˚C ± 2˚C

• 75% RH ± 5% RH

Minimum Time Period:

• 6 months

How is Drug Stability quantified?

Via Shelf-Life

What is Shelf-Life?

How does it relate to active ingredient concentration?

Time in which the product is predicted to remain fit for its intended use, under specified storage conditions

Time until the original potency or content of the ACTIVE ingredient has been reduced by 10%

Time required for 10% of material to disappear; time at which a drug has decreased to 90% of its original conc.

What is the purpose of Accelerated Stability Testing?

What are common stresses used?

Used to quickly evaluate the drug degradation process, physical changes, and to predict a shelf life

Common stresses include temperature, humidity, and light

What is Kinetics?

What is the Rate of Reaction?

Kinetics — concerned with reaction rates and sequence of steps with which a reaction occurs

Rate of Reaction — for a given chemical change, speed with which reactants disappear and products form

Why do we study Kinetics?

Why do we study drug stability?

Kinetics allow us to predict the degree of change that will occur after a given time has elapsed

Drug stability allows us to determine:

• Safety of patient (toxicity and potency)

• Stability affected by specific factors (temp, humidity, light)

• Establish shelf-life for products

• Production of more stable drug preparations and recommended storage conditions / packaging / formulations

What determines the rate of a reaction?

Determined by the change in the conc. of the reactants of products as a function of time

What is the expression used to show rate?

What is the order of a reaction?

Rate = dc / dt, where

dc — increase or decrease in conc. over the time interval dt

dt — time interval

Order of a reaction demonstrates how the concentration affects the rate of the reaction

What are the units of the rate constant, k, for a Zero Order reaction?

First Order reaction?

Zero Order — k = moles / L*s = moles x liters^-1 x second^-1

First Order — k = 1/s = second^-1

What is the Q10 Method of Shelf-Life Estimation?

Something something change in rate with a 10˚C increase in temp

Allows you to determine change in shelf-life based on change in temp.