END-PRODUCT STABILITY & COMPATIBILITY

“The extent to which a product retains (within a specified limit and throughout its storage and use) the same properties and characteristics that it possessed at its time of manufacture.”

stability

“The measure of how stable a substance is when mixed with another substance. If two substances mix together and undergo a chemical reaction, they are considered incompatible.”

compatibility

the change in or degredation of active ingredients

instability

USP states the four most common and critical factors that affect stability are

1. heat

2. light

3. oxidation

4. hydrolysis

We don't want to see any changes in our compounded preparation prior to its ________________

beyond-use date

“An undesirable reaction between two drug substances, a drug and excipient used in drug product, or a drug substance or excipient with the container used to store the final drug product.”

Incompatibility

Formation of an undesirable byproduct which may affect _____________________________ of final product

safety, efficacy, or appearance

A change in physical state of drug substance which may affect the physical properties of the drug substance

Physical Incompatibility

types of Physical Incompatibility

1. Crystallization

2. Precipitation

3. Sorption or leaching

A change from amorphous form to crystalline form. Ex: Mannitol crystallizing at room temperature

Crystallization

When a previously dissolved solid/solute reforms in a liquid/solvent Ex: Calcium phosphate in prepared TPN

Precipitation

Drug molecules adhere at surface or penetrate their container’s matrix Ex: Amiodarone stored in PVC bags

Sorption and leaching

characteristics of chemical incompatibility

1. Active drug product lost as a result of unwanted chemical reaction

2. Loss of drug potency

3. Production of undesirable toxic substance or byproduct

4. These incompatibilities can produce visible changes such as odor or color, but many do not

types of chemical compatibility

1. hydrolysis

2. oxidation

3. complexation

4. displacement

Cleavage of chemical bonds due to water. Ex: Beta-lactam antibiotics at room temperature

Hydrolysis

Loss of electrons due to ions or other molecules Ex: Ascorbic acid in the presence of oxygen gas

Oxidation

Reaction between ligand and metal ion that forms a coordination complex Ex: Tetracycline will complex in presence of calcium

Complexation

Replacement of one element by another in a compounded product Ex: Cisplatin in presence of aluminum cation

Displacement

A drug product is considered unstable when the active ingredient loses sufficient potency to adversely affect _______________ of the drug (falls outside specified studied parameters)

efficacy

There can be exceptions, but __________ of labeled potency is generally accepted as the minimum acceptable potency level

90%

examples of intrinsic factors of stability meaning the active ingredient's chemical structure and formation

1. Crystallization structure

2. solubility

3. melting point

examples of extrinsic factors meaning the environment to which the drug was exposed

1. temperature

2. pH

3. concentration

4. light

5. order of mixing

For every 10 °C rise in temperature, the rate of ________________ increases

degradation

Per the USP 797, if a sterile product is stored or exposed to a temperature that exceeds its recommended storage temperature or a temperature of ____________, then that product must be discarded

>40 °C

If drug becomes too warm; _________________________ and speeding up unwanted chemical reaction with heat/temp

increases chemical degradation process

If drug becomes too cold; ___________________________ and solutes readily dissolved can come out of suspension

increases drug crystallization or precipitation

If drug is inappropriately frozen; _______________________ and damage occurs upon freezing process when active ingredient structure compromised

can inactivate, denature, or crack emulsions

a deviation from the manufacturer’s labeled storage condition for ANY duration of time

temperature excursion

consequences of temp excursion

1. Increased impurity or altered byproducts can lead to decreased active ingredient

2. Cracked emulsions or lipid layer separation

3. Product discoloration

Alterations in pH can affect drug

solubility

Consider when mixing two drugs each drug has its own pH. This mixture may change the final overall pH over the resultant solution. Drugs may change their ____________________ depending on their pH

purity or precipitation

Increasing the drug concentration will increase the rate of degradation because of the increase in the ______________________ to react with each other

availability of ingredients

Drugs can undergo photo degradation when exposed to_____________

light

______________ are susceptible to photolysis

Vitamins A and B12

to protect from light there can be use of _______________ of prepared parenteral products

amber vials/containers or opaque sleeves

consider what when mixing drugs

1. Consider the miscibility

2. consider charge of particles

3. consider melting point alterations as components are added together

_____________ serve as a mechanism to administer multiple drugs simultaneously while minimizing contact

Y-sites

pharmacist roles in stability

1.Dispensing oldest stock first with eye on expiration dates

2.Storing products under appropriate environmental conditions according to supplied monographs or labels

3.Observing products for evidence of instability

4.Dispensing product in the proper container with the proper closure

5.Informing and education patients about product storage