Arrhenius and Drug Degradation (Final)

10%

No more than _________ decrease in the active content should take place within the shelf life at the recommended storage temperature

accelerated stability testing

Drug product is exposed to (stress conditions) extremes of temperature, humidity, and light in order to predict the shelf life

k increases

In the Arrhenius equation if A is increased what happens to k?

k decreases

In the Arrhenius equation if Ea is increased what happens to k?

it increases

In the Arrhenius equation if temperature increases then what happens to k?

k

specific reaction rate constant at temperature T

A

-arrhenius factor or frequency factor
-indicates how many collisions have the correct orientation for product formation

Ea

energy of activation (cal. mol ^-1)

R

gas constant (1.987)

T

temperature (degree K)

Arrhenius equation

is based on the collision theory which supposes that particles must collide with both the correct orientation and with sufficient kinetic energy if the reactants are to be converted into products

they lower Ea

What effect do catalysts have on Ea?

Activation energy (Ea)

is the minimum kinetic energy a molecule must possess in order to undergo a reaction

increase

Lowering Ea will lead to an ________ in the k or rate of the reaction.

Increases

__________ in T leads to an increase in k. Roughly, rate of reaction doubles with every 10 degrees C rise in temperature.

Arrhenius plot

used to determine activation energy

Q10 approach

-is based on Ea but independent of reaction order
-method that can estimate shelf-life

Q10

the ration of 2 different reaction rate constants

12.2

A Q value of 2 corresponds to an Ea value of what?

19.4

A Q value of 3 corresponds to an Ea value of what?

24.5

A Q value of 4 corresponds to an Ea value of what?

T90 (T2)

estimated shelf life

T90 (T1)

the given shelf like at a given temperature

Delta T

the difference in the temperature between T1 and T2

1. Hydrolysis
2. Oxidation
3. stabilization against photolysis
4. thermal degradation
5. racemization

What are the mechanisms of drug degradation?

-specific acid catalyzed hydrolysis
-specific base catalyzed hydrolysis
-solvent catalyzed hydrolysis
-general acid base catalyzed hydrolysis

Drug moiety could be susceptible to what?

ways to stabilize against hydrolysis

•Select pH of optimum stability
•Select buffers that do not catalyze hydrolysis
•Complexation - Only uncomplexed drug will undergo hydrolysis
•Decrease solubility - formulate as suspensions
•Use of surfactants - Micellar entrapment
•Use of co-solvents
•Decrease drug in solution
•Formulate as solid dosage forms
•Lyophilized products

reaction rates

If you alter activity coefficients what is directly affected?

change in pKa and viscocity

What indirectly affects the reaction rate?

polar

More polar solvents will favor reaction proceeding in a direction that produces ________ products.

nonpolar

non polar solvents will favor reaction proceeding in a direction that produces ___________ products.

yes

Does dielectric constants effect the co-solvents on reaction rates?

oxidation

-removal of electrons
-involves free radical chain reactions
-influenced by heat and light

-antioxidants
-chelating agents
-optimum pH
-avoid light
-store at low temps

How can you stabilize a molecule against oxidation?

oxygen scavengers

antioxidants: sulfites, ascorbic acid, mono thioglycerol

chain reaction terminators

preferentially become stable radical which can be combined with other radicals to terminate chain reactions
ex: BHA or BHT

reducing agents

reducing oxidized drugs
ex: ascorbic acid

chelating agents

removes metal catalysts, EDTA

displace oxygen with nitrogen or other inert gases

How can you protect a molecule from dissolved oxygen?

-amber colored bottles
-aluminum foils

What are different things we use to protect a drug from photolysis/light?

Furosemide

What is an example of a drug that must be stabilized against photolysis?

Covid-19 vaccines

What is an example of a drug that must have thermal degradation?

racemization

tetracycline by epimerization