pencils DDS drug stability

drug product

finished dosage form that contains active & inactive ingredients (excipients)

three main types of drug or drug product degradation

chemical

physical

microbiological

pharmacological effects

molecular changes can alter interaction w/target receptor

ADME effects

ADME processes changed

fanconi syndrome

tetracyline can degrade to a potential fatal nephrotoxic compound fanconi syndrome= nephrotoxicity

penicillins in solution can degrade to allergenic compounds 

benzyopenicillin to benzylpenicillinic acid (TOXIC)

chemical degradation mechanisms

hydrolysis, oxidation, & photolysis

functional groups susceptible to hydrolytic cleavage

ester, amides, lactams, lactones

oxidation

THINK REMOVAL OF ELECTRONS

reactive oxygen species 

hydrogen peroxide, superoxide, hydroxyl radical

functional groups susceptible to oxidation

phenols, catechols, thiols, tertiary amines, polyunsaturated hydrocarbons

thiols

thiols when oxidized lead to disulfide bonds RSH to RSSR

tretinoin

used for acne can PHOTOXIDIZE apply in the evening 

polyunsaturated hydrocarbons 

conjugated double bonds w/high energy electrons 

take home photons

photon w a wavelength of 300nm has 400kj/mol of energy comparable to a bond energy of organic molecules suggesting that these PHOTONS CAN HELP MAKE OR BREAK BONDS

most common photolytic mechanism is photo-oxidation

light can help create free radicals

caking of powders and its effects

“caking” the drug clumps up and particles become united

take home drug states 

drugs are generally more stable in the solid state bc in their solid state stability chemical rxns faster in solution 

stressing solid

solid is stored in high temp & humidity stress

degradation kinetics

kinetics play a role in determining the shelf life

rxn rates & temp

rxn rates depend on temp

rxn order 

the overall sum of the rxn order (n) may be defined as n= a + b… sum of the exponents 

1st order degradation

rate proportional to conc and the plot is exponential decay starts high gradually lowers

pseudo 1st order degradation

order for most hydrolytic rxns

the degradation is apparently independent of the conc of one of the reactants, even though it is consumed in the rxn

take home zero order degradation

zero order drug degradation can occur when there is a reservoir of drug to replace the drug that is lost to decomposition (suspensions)

shelf life 

shelf life is defined as the time for 10% degradation (t90) 

10% not considered therapeutically significant 

pH & acid catalysis

protonation of the carbonyl O makes the C more electrophilic (+)

negative slope up down

when you reduce the pH the degradation rate goes up

pH & base catalysis

hydroxyl ion is very nucleophilic

increase in pH increase in degradation rate

pH concerns 

solubility & pt concerns 

arrhenius equation

used to model the effect of temp on degradation & make useful predictions of the effects of diff temps on the products shelf life

useful for accelerated stability studies, which can be used to establish a tentative expiration date

A (arrhenius equation)

constant “frequency factor”

how many collisions have the proper orientation

Ea (arrhenius equation)

is the energy of activation for the rxn 

energy needed for a rxn to occur 

drug stabilization approaches (reduced temps) 

consider potential problems w freezing and that is there will be increased drug conc 

drug stabilization approaches (stable pH) (adjust pH in bulk)

formulate at a pH of max stability

NaOH SB HCl SA

drug stabilization approaches (dry product) (include desiccants) (lyophilization)

drying the product forms it into a solid… drug is most stable in a solid state

silica gel helps w moisture

“solvent loving”= freeze drying

lyophilization process

1. start w a liquid that includes drug plus excipients ex: sugar to add bulk

2. samples are frozen then sublimed under vacuum (vacuum needed to remove frozen water slow process)

3. porous matrix usually results (pores remain where water crystals were)

additional measures

remove/replace oxygen

boiling removes most O causing inert gas nitrogen/argon

use of antioxidants 

oil soluble

-vitamin E

-BHT

-propyl gallate

water soluble-

-ascorbic acid (vit c) 

-sodium sulfite (common, allergenic in 0.2% of population

reasons for antioxidants

stop propagation (chain terminators) “free radical scavengers”

preferentially oxidize- more easily oxidized

metal content and chelators

chelators are used to minimize metal content

role of metals in oxidation

metals help create chain initiating radicals

metal can come from many sources 

trace amounts in chemicals & containers 

chelators

citric acid, tartaric acid, EDTA

REMEMBER THESE BIND TO METALS

they work synergistically w/antioxidants

review of light

lower wavelength means higher energy

UV range 185-380nm= high energy absorbed by most drugs