exam 4 Flashcards
hydrolysis
drug interacts with water to cleave and break into two fragments
water reacts to degrade drug so do not store in humid environments
ex - chloramephenicol
chemical kinetics and stability
drug degrades faster at higher temps
stability NAPLEX
solution stable: at given concentration, for certain time, temperature, degree of light exposure. decompose faster than solids
solid stable: for certain time, temperature, degree of light exposure
drug compatability
compatability issues for longer infusion times like piperacillin/tazobactam, antibiotics like z-pack, cipro, tobramycin, vancomycin, insulin and vasopressors
temperature and stability
higher temps break down proteins and speed up chemical reactions
most IV drugs are refrigerated for longer stability
exceptions: furosemide and phenytoin crystallize if kept cold
IV drugs like flagyl, moxifloxacin, acetominophen, acyclovir, pentamidine, valproate can be kept at room temp
light exposure NAPLEX
light exposure causes photodegradation and can increase toxicity
amber vials protect from light
Vit. K , nitroprusside, doxycycline must be protected from light during admin
check drug for color changes
stability and degradation NAPLEX
stability: product retains properties and characteristics throughout its period of storage
certain functional groups are susceptible to degradation
degradation: oxidation-reduction, hydrolysis, photolysis
oxidation - naplex
ex - oxidation of epinephrine
other known oxidations include carmelization of onions where OH groups oxidize and turn brown
prevent oxidation - protect temp changes, control pH, light protection, low temp, chelating agents (ETDA), antioxidants to remove free radicals
hydrolysis NAPLEX
water causes cleavage of a bond in molecule
likely hydrolyzed: carbonyl, amide, cyclic amide
function of dosage forms
provide accurate dose
promote drug dissolution
promote delivery to site of action
ensure drug stability
control drug deliver to body
determine dosing intervals
hydrolysis mechanism in basic conditions
amide hydtrolysis
nucleophillic attack of hydroxide anion (OH-) on ester of carbonyl group
this forms carboxylic acid and alcohol
nucleophillic attack of hydroxide anion on amide carbonyl group
carboxylic acid and amine formation
how can hydrolysis of esters and lactones be prevented
how can hydrolysis of amides and lactams be prevented
protect from moisture (solid dosage forms like tabs and caps)
protect from heat (hydrolysis is faster at higher temps)
control pH in solution formulations (ester/lactone hydrol is ph-dependent)
oxidation summary
oxidation is a common, complicated route of drug degradation
photolysis is drug degradation caused by exposure to light
many functional groups oxidize
oxidation can be minimized by protecting from air, light, metals and excipients added to formulation
zero order kinetics
degradation of drug in suspension
when the drug concentration in solution is constant like in a suspension
independent of concentration
in the solid state
stability issues for biologics (proteins)
proteins tend to be more fragile than small molecule drugs
biologics are bigger so they have more bonds that can break
biologics can lose activity if they unfold
biologics can aggregate: increase or decrease potency and increase potential for adverse immune response
proteins summary
recombinant proteins like vaccines, stem cells, gene therapy
made from AA and have folded structure
tend to be more fragile than small molecule drugs
one of fastest growing drug classes
protein degradation
chemical degradation: breaks covalent bonds and forms incorrect ones, hydrolytic reactions, oxidation reactions
physical degradation: changes in protein structure without breaking bonds, unfolding, aggregation
hydrolytic reactions
oxidation reactions
aggregation
hydrolytic (chemical): asparagine deamination, peptide bond hydrolysis
oxidation (chemical): methionine oxidation
disulfide bond scrambling
aggregation (physical)
solubility
solubility should be considered with dose
poorly soluble drug can completely dissolve under physiological conditions if dose is small, so dose solubility may be more important
bioavailability
depends not only on having drug in solution but also on drugs permeability
if drug cannot get into solution it will not be bio available
enteric coating polymers
release drug in small intestine
matrix tablet
drug embedded in polymer matrix
errosion and diffusion
errosion: where polymer is degraded and drug is released
diffusion: polymer remains and drug swells and diffuses out
elementary osmotic pump (OROS) in Concerta
semipermeable membranes
drug containing osmotic core
water enters membrane but drug cannot escape
there is a delivery orifice that allows drug to enter body
single chamber and double chamber
single: drug just diffuses out
double: water fills up chamber and pushes drug out
GI transit time of OROS
stomach (fasted): .5 hr .25 - 4 hr
stomach (fed): 2-3 hr .75 - 10hr
small intestine: 3 hr 2-4 hr
colon: 32 hr 4 - 96 hr
dissolution of methylphenidate vs oros
methylphenidate: taken three times spikes than levels out
oros: more consistent dissolution
drug release forms
immediate release: drug peaks immediately
delayed release: has same peak but release is delayed
extended release: does not peak as high but release is longer. can also allow us to not peak as high or dip as low
problems with generic concerta
giving immediate release can cause more side effects compared to extended release
types of innovation
group A: most are group a. involve incremental tweaking of existing products - change tablet shape
group B: based on analogy
group C: wild ideas
mind manager
concept map
model for inventive ideation - convert, change, copy, separate, combine
ritalin innovation
want to change BID to QD
change: formulation
copy: use OROS
combine: beads of different release
seperate: use beads of different release
innovation pipeline
idea
concept
experiment
pilot
launch
blue ocean strategy
map needs and differentiate
which needs you meet
lean startup
build products or services that meet needs of early customers
try, test, fail quickly
don’t overplan
go for minimum viable product
customer feedback and do not invest time in designing features
disruptive innovation
no one sees it coming
early prototypes were not very functional, but niche consumer segment won over
topple industry leaders
simpler
best approach is to spin off new compant to introduce these - IBM in florida
us life expectancy
from 1950-2014 it has been increasing
males - 76.4 y.o
females - 81.2 y.o
us life expectancy with covid
both male and female life expectancies dropped due to COVID
antiviral drugs
very insoluble, so difficult to get into bloodstream
solutions for insoluble antiviral drugs
prodrug: drug that is inactive and then converted to active form due to physico-chemical transformation in the body
formulation: melt extrusion and spray drying
sofosbuvir
prodrug that is converted to triphosphate and inhibits the NS5B polymerase
antiviral drugs poor solubility reasons for failing
39% poor bioavailability
30% low efficacy
11% high toxicity
10% adverse effects
10% others
melt extrusion
make amorphous dosage from by melt extrusion
improve solubility and bioavailability
itraconazole
not soluble in crystalline form
more soluble as pellets or melted
spray drying
improves solubility and bioavailability
spray solution into hot dryer
particles fall down and become processed into fine powder
antiviral molecules
makes molecules that will inhibit virus
molecules has little effect on normal cells and is non toxic
formulation is important in making these molecules soluble
abuse prevention
abuse-deterant tech makes product manipulation more difficult
improve tamper resistance
incorporate deterrent
abuse-deterrent must be referenced by comparator
abuse deterrent formulations
oxycontin has polyethylene oxide (PEO) that is very hard and does not break that makes it very hard to inject.
polyethylene glycol
PEO turns into gel when water is added and hard to inject
reformulation to decrease drug diversion
before reformulation it was higher
after reformulation it was much lower
