Stevens Material - Lecture 17, 18, 19

How is the speed of a reaction measured?

By its rate

What is thermodynamics concerned with?

The difference between the products and the reactants

I.e. the difference between final and initial

What does thermodynamics tells us?

The spontaneity of a chemical reaction, whether it will be positive or negative

What does thermodynamics NOT tell us?

The pathway/mechanism by which the reactants turn into products Rate of conversion 

What is chemical kinetics?

The study of the rate and mechanism of chemical reactions

What types of ways will drugs degrade over time?

Photodegradation, oxidation, hydrolysis, acid base catalysis

Why is kinetics so important to drug products?

It is important to understand this process to ensure the drug product dosed is the SAME as the product originally manufactured

What factors can affect how quickly degradation reactions proceed?

Relative humidity/water

Temperature

pH

Why are drug products packaged the way they are?

To specifically mitigate potential degradation

Will have defined storage conditions, antioxidants, and buffers

What does rate define?

How fast a reaction proceeds

What is average rate?

The slope

Change in A/Change in Time

What is instantaneous rate?

A more precise definition of the rate of a chemical reaction

The tangential slope at a specific time

-d[A]/dt

When do most reactions fastest instantaneous rate occur?

At the beginning of the reaction when the tangential slope is the steepest

What are rate laws?

The relationship between instantaneous rate and time dependent reaction concentration 

The stoichiometry of a balanced chemical reaction does?

NOT identify the order of the reaction, unless a single step reaction

Steady State?

Are processes that do not display a time dependence

Flat line with no slope

Rate=-d[A]/dt=0

What are steady state events?

Events where -d[A]/dt=0

Common in reactions with more than one step

What do integrated rate laws measure?

Uses the entire time window to fully describe concentration vs time relationship and predict drug concentration at any time 

Zero order reactions?

The rate law is independent of the reactant concentration

Change in [A]/Change in T=k

Are successive t1/2’s constant in zero order reactions?

No, both t1/2 and t90 are dependent on the initial concentration

So at different times you’ll get different t1/2 t90

Shelf life measures what?

The time it takes for 10% of the drug to degrade

First order reactions units are what?

In time^-1

When do you use the ln function of first order?

When calculating k or [A]

When do you use the e function in first order?

Exponential decay or calculating t

What is weird about first order t1/2 and t90?

There is NO concentration dependence on either equation

Pseudo order?

When two reactants are provided but one has a disproportionately large initial concentration

Generally the drug concentration is small relative to water 

Suspension?

Always assume zero order

Why are suspensions zero order?

How much drug actually in the solution is capped by the solubility, so it is dependent on concentration

So as the drug in solution degrades, the solid drug in the suspension is released back into the solution

Stability

Is a drugs ability to maintain its specified identity, strength, quality, and purity within its established limits throughout its shelf life

Physical instability

Non covalent changes to the product components

Molecules remain the same

Chemical Instability

Changes to the covalent bonding of the product components

Molecules are changed, no longer dealing with the same molecule

Hydrolysis

Water attacking acyl groups

Esters, amides, lactams, imides

What basically happens during neutral hydrolysis?

Water attacks an acyl group, kicks off leaving group and -OH gets connected to carbonyl carbon

Biggests to smallest potential for hydrolysis 

Acyl Halide

Acid Anhydride

Ester

Laxtone

Lactam

Imide

Amide

What is a prodrug?

A drug compound that are produced inactive forms that become activated by hydrolysis

How are the structure of prodrugs different than the structures of salts?

The cleavable part of the prodrug is always apart of the molecule, never separate unlike salts

What group is the most suspectable to hydrolysis?

Esters

What is possible if a drug has both a carbonyl and a primary amine? 

A carbonyl-amine oligomer formation

Amine will act as a nucleophile and form a new chemical bond with the carbonyl

What two functional groups can produce an imine?

Aldehydes and ketones

What groups can be attacked by a primary amine?

Acyl halides, esters, lactams, lactones, anhydride and carboxylic acids

What happens during oxidation?

Initiation: Event triggers formation of a drug radical (metal, heat, light)

Propagation: Radical propagates the reaction, more radicals form

Termination: Two radicals join together to form non-radical chemical bond

What molecules are the targets for oxidation?

O and S

What is formed with oxygen during oxidation?

OH- basically turn into O=C

What are the rules for carbons during oxidation?

Every bond to another C does not change the oxidation state

Every bond to H decreases the oxidation state by 1

Every bond to a more electronegative atom increases the oxidation state by 1

How does sulfur oxidize?

May form sulfoxides or disulfide linkages

Photolysis 

Most at risk are aromatic amines, easily broken bonds

Can lead to radical formation to further initiate oxidative decomposition 

What is kobs influenced by?

Directly by solvents, presence of a co-solvent/pH, solutes, temperature, product packaging

If you change the pH what will also change?

kobs

How does pka relate to hydrolysis?

As pka increases the potential risk for hydrolysis reactivity decreases

What happens in acid catalysis when pH increases?

kobs decrease

Getting more basic, the reaction is happening slower, so t1/2 and t90 increase 

What happens when pH increases in base catalysis?

kobs increase

Getting more basic, reaction will happen faster, so t1/2 and t90 decrease

What is Ea?

Energy of activation, it separates the reactants from products

Smaller Ea means?

Less the reaction as the overcome to occur

The arrhenius equation main idea is?

Probability

For the reaction to occur the molecules have to physically collide with enough energy to generate a product 

Is the arrhenius equation rate dependent?

No its rate independent so you can use it for whatever order

What does Q10 measure?

A method for measuring shelf life variation with temperature

Q10?

Is a ratio of two rate constants that differ by 10 degrees

90% of all drugs have a Ea between?

10-30 kcal/mol

Why is understanding stability important for compounding?

Any adjustments could impact product performance and patient outcomes

Who regulates compounding?

State pharmacy boards