Drug Stability

Drug stability

the extent to which a product retains within specified limits and throughout its period of storage and use

5 types of drug stability

1. chemical stability

2. physical stability

3. microbial stability

4. therapeutic stability

5. toxicologic stability

Chemical stability

the API retains chemical integrity and labeled potency within the specified limits

Physical stability

the original physical properties, including appearance, palatability, uniformity, dissolution, and suspendability are retained

Microbial stability

sterility or resistance to microbial growth is retained according to the specified requirements

Therapeutic stability

the therapeutic effect remains unchanged

Toxicologic stability

no significant increase in toxicity occurs

Hydrolysis

drug molecules interact with water molecules to yield breakdown products

Ways to prevent hydrolysis

• using substitute nonaqueous liquids

• using anhydrous vegetable oils as solvent

• supply the drug in a dry form for reconstitution

• film coating of tablets

• avoid humidity

• buffers

Oxidation

increases number of carbon-oxygen/hydrogen bonds in a molecule or number of bonds involving an oxygen/hydrogen

How to prevent oxidation

• replace the air in the container’s headspace with inert gas such as nitrogen

• control pH

• add chelating agent

• store drug at low temperature

• add anti-oxidants

Photolysis

light-induced degredation

What wavelengths tend to be most damaging?

300 nm to 400 nm

What compounds are most susceptible to photodegredation?

carbonyl, nitro, alkene, aryl chloride, phenol, extensive conjugation

How to prevent photolysis

• amber glass containers

• storage in dark place

• film coating of tablets

Microbial instability

contamination by water or air

Microbial preservatives properties

• antimicrobial activity

• low toxicity for humans

• good solubility in water, low solubility in oil

• stable and effective over a wide pH range

• compatible with excipients

• nonvolatile, odorless, tasteless

Microbial preservatives examples

alcohols & glycols, parabens, quaternary ammonium salts

Shelf life

to delineate the period by which a drug product, following manufacture, remains suitable for its intended use by patients

Typical shelf life

2-3 years

Expiration date

the date at which the manufacturer can still guarantee the full potency and safety of the drug

What are the stability and expiration dating of a drug based on?

chemical reaction kinetics

Reaction kinetics

the rate of chemical change and how it is influenced by solvent, pressure, and temperature

What must occur in order to react?

molecules must collide

What increases the probability of collisions & thus reactions?

an increase in the concentration of reactants

Zero-order degradation rate

happens when the rate is constant meaning it doesn’t depend on drug concentration

Zero order degradation expression

C = C0 - k0t

Decomposition half life

the time at which the drug has decreased to 50% original concentration

Half life expression for zero order

t1/2 = C0/2k0

First order degradation rate

depends on how much drug is left dependent of drug’s concentration

First order drug degradation expression

lnC = lnC0 - kt

Half life expression for first order

t1/2 = 0.693/k

t90

the time required for 10% of the drug to degrade with 90% of the intact drug remaining

t90 expression for zero order

t90 = 0.1C0/K0

Shelf-life for zero order rate is proportional to

initial concentration

Shelf-life for first order rate

constant

Effect of temperature on degradation rate

increased temperature, increased degradation rate

Q10 temperature coefficient

a measure of the rate change of the chemical reaction because of the temperature being increased by 10℃

Q10 expression

Q10 = k2/k1

For most reactions, Q10 is equal to

3

Application of the Q10 method

estimates shelf life for a product that has been stored or is going to be stored under a different set of conditions than specified in the product labeling

Estimated shelf-life at new temperature expression

Known shelf life at a given temperature/Q10^0.1(new temp-given temp)

Stability testing

required by FDA for a demonstration of drug stability for products undergoing development

Stages of stability testing

pre-clinical and clinical

Three attributes tested for stability

chemical, physical, and microbiological

How must stability be evaluated over time?

in the same container proposed for marketing

Factors considered in stability studies

temperature, humidity, pH, light intensity, and drug concentration

Stability testing guidelines

FDA’s current good manufacturing practice regulations (U.S. market), international conference on harmonization guidelines (ICH)

Real-time stability testing

long term stability testing

Accelerated stability testing

testing at high temperature and/or humidity to speed up drug’s degradation process to allow faster submission process of data to FDA

Frequency of long-term stability testing

every 3 months over the first year, every 6 months over the second year, annually thereafter

Frequency of accelerated stability testing

minimum of three time points

Stability testing technology

Stability chamber - stimulates storage condition & enables evaluation of product stability based on accelerated & long-term protocols

Uniform exposure

the set conditions to all the samples in stability chamber

Stability chambers control

temperature & humidity