1 - Stability Flashcards by Sam Myers

Define drug stability

extent to which a product retains, which in specified limits and throughout its period of storage and use, the same properties and characteristics it possessed at the time of manufacture

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What are the 3 areas of concern when describing drug stability

chemical (active ingredients retain chemical integrity and potency within limits)
physical (properties such as dissolution and appearance are retained)
microbiological (sterility or resistance to microbial growth retained)

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(Chemical) - product specifications have limits usually ______% of the label

+- 2-10%

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What can physical degradation lead to?

-can lead to reduced bioavailability and reduced efficacy

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What does microbiological stability refer to?

basically keeping a product sterile or resisting microbial growth

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Describe hydrolysis (chemical degradation)

decomposition of a drug through a rxn with water

- water acts as a nucleophilic agent and attacks electrophilic sites of drug molecule

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What are the most common functional groups involved in hydrolysis?

carboxyl derivatives

lactams
esters
amides

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Describe oxidation (chemical degradation)

often mediated through atmospheric oxygen
most are free radical and occur spontaneously under ordinary conditions (auto oxidative)
color/aroma changes seen (oxidative processes are usually more conjugated)

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In what solutions/states can oxidation occur in?

aqueous solution
non-aqeous solution
solid state

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Oxidation is viewed as ?

loss of electrons
loss of hydrogen
gain of oxygen

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Give examples of functional groups subject to oxidation

phenols
catechol
ether
thiols
thioether
aldehyde

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Describe photolysis (chemical degradation)

-light provides energy (photon) for initiation of an oxidative process

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When electromagnetic radiation absorbed by a molecule the following may occur: (4 things)

1) molecule decomposes with release of free radical
2) energy retained - chemical change
3) energy converted to heat and no reaction occurs
4) absorbing molecules emit light of different wavelength

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Dehydration ?

loss of a water molecule

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Is dehydration a chemical change?

No - just changes the crystal habit of the drug (pseudo polymorphism) which may result in solubility changes

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Formation of a pseudopolymorph may affect _____ due to solubility changes.

It may also affect _____.

bioavailability

stability

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Racemization

changes in optical activity may result in very significant changes in biological activity

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Can the body metabolize l or d amino acids?

It can only metabolize l-amino acids

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Can DXM (dextromethorphan) be dangerous?

not at medically-recommended doses (there are almost no psychoactive effects)

-but at high doses - has euphoric, psychedelic, and dissociative properties

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What is the recreational use of DXM referred as?

robo-tripping

Triple Cs

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______ is an opioid analgesic

levomethorphan

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B-lactam group of penicillins/cephalosporins with amino group of an amino glycoside antibiotic = ???

inactive amide

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Drug containing primary amine and one with aldehyde functional group = ???

Schiff’s base

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Drug with amine functional group and hydroxyl group of a sugar = ??

Maillard reaction

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Polymorphism is a type of ____ degredation

physical

How do polymorphs differ and result in solubility differences?

they differ in crystal structure and crystal energies

Polymorphism may result in an ___ product

unusable *could result in caking of product

What are 4 examples of physical degradation?

- polymorphism - vaporization - aging - adsorption

Explain vaporization (physical degradation)

- some drugs have high vapour pressure and drug is lost through vaporization - severe changes in tablet content and uniformity may occur

Explain aging (physical degradation)

- changes can occur in the disintegration/dissolution properties of the formulation - hardening or softening alters the disintegration/dissolution and bioavailability

Explain adsorption (physical degradation)

drug loss to packaging materials as well as documented in IV solutions in PVC plastic

How are adsorption problems avoided?

-care must be taken in container selection

Define shelf life (t90)

the time when the initial concentration of active drug bas decreased by 10%

Order of a rxn must be determined _____

experimentally

T or F: Expiration dates are usually based on zero or first order kinetics.

true

First order calculations: plot of Log[D] vs time gives a straight line with a slope equal to ?

-K1/2.303

formula for shelf life for first order calculations

t90 = 0.105/k1

units for a first order rate constant ?

t^-1 or 1/time

loss of drug directly ____ to the concentration remaining with respect to time

proportional

t1/2 is ____ for first order calculations

constant

see slide 27 for first order equation

Zero order calculations: plot of concentration vs time is ____ and gives a slop of __

linear Ko

shelf life formula for zero order calculations

t90 = 0.1[D]o/ko

unit of rate constant for zero order rxns

concentration/time

zero order rxns: loss of drug _____ of concentration and ____ with respect to time

independent constant

see slide 30 for zero order equation

List factors affecting rxn rate

- temperature - catalysis - pH effects - solvent effects - solubility effects

Explain how temperature affects rxn rate

rxn rates are proportional to the number of collisions so expect rxn rate to increase with increasing temperature

Explain how a catalyst has increases rate of rxn

a catalyst is a substance which increases rate constant of a rxn but does not change the equilibrium constant

Is a catalyst transformed or consumed?

Neither - it interacts with the reactants to facilitate reaction

A catalyst decreases ??

activation energy

How does pH affect reaction rates?

certain pH's can be better for certain rxn rates they can measure rxn rate while changing pH and keeping other variables (temp, ionic strength, and solvent composition) held constant and then determine what pH indicates the best rxn rate

What do you plot for a pH profile for a first order rxn?

log k vs pH

What do you plot for a pH profile for a zero order rxn?

k vs pH

What kind of pH profiles can you see?

1) V-shaped curve - seen with non-ionizable substrate subject to hydrolysis - in this case put rxn at the lowest rxn rate (so it will go the slowest) 2) sigmoid shaped curve - seen when the drug molecule can undergo acid/base dissociation so this is the typical curve for an ionizable substrate - we want it buffered somewhere near the tail of the curve **see diagram for pic** - we don't want the rxn to go too fast or too quickly

Always pick the pH that allows the lowest reaction rate

okay man

water miscible solvents that can be added into formulation to solubilize the drug - examples?

- alcohol - propylene glycol - glycerol - polymeric acids (PEG)

increase in solvent polarity ____ the rates when a charge is developed in the activated complex

accelerates

increase in solvent polarity _____ the rates when there less charge in the activated complex

decreases

Give some examples of how you could stabilize drug products

-prepare insoluble salt and formulate it as a suspension

What does reduced solubility in a suspension do?

decreases amount of drug available for rxn

T or F: drug can undergo apparent first order rxn in solution and then when formulated as a suspension, it decomposes through apparent zero order kinetics

true

What are two stabilization strategies?

hydrolysis | oxidation

Drug must be in ____ for hydrolysis to occur

solution

Therefore exclusion of water will ____ the rate

slow

control of ___ allows some control over hydrolysis rate

Storing a product at a ____ temperature may be used to increase product stability

reduced *note this does not mean freezing - can only freeze a limited amount of drugs

What can't you freeze?

emulsions protein drugs ampicillin

T or F: complexes can accelerate decomposition and some may alter solubility and variability

true

If you have a complex - how can you overcome decomposition?

- can formulate it as a suspension | - this may be a useful tactic since drug will probably degrade through apparent ZERO order kinetics

List 4 ways you can overcome oxidation

1 - protect from light 2 - exclusion of oxygen 3 - addition of antioxidants 4 - control of pH

How can you protect something from light?

- amber glass - opaque plastics - foil wrapping on IV infusions

How can you exclude oxygen?

- useful for parental | - purge with inert gas (usually nitrogen) and sealed

How can you add antioxidants?

-inclusion of a chelating agent such as EDTA which will consume trace amounts of metal ions which can function as catalysts (can be useful) **an antioxidant is a material which is more easily oxidized than the product or free radical inhibitors ?? da fuck man

What is usually a good pH range that will provide no deleterious effect on product and is physiologically acceptable?

3-4

1 - Stability Flashcards

(75 cards)