lecture 6c Flashcards
what is included in drug formulation to manufacturing
stages that occur to get from a lead compound to it being manufactured and used by consumers.
when do drug formulation studies occur
thoughout the whole process
from preclinical studies to launch!!
what must be known before drug formulation
the drugs intended use must be known in order to be optimised!!
we must know it’s use before preclinical studies
examples of drug administration routes
oral dose
nasal spray
injection
what differs between drugs that are administered differently
their formulation differs.
they will be formulated differently in order to be optimised for their intended use
is the drug the main part of medicine
no!!
there are excipients in the medicine aswell!!
what 3 factors control bioavailability ‘F’
- the drugs rate and extent of release from its dosage form
- absorption from solution state
- bio transformation during absorption
what does the shape of a plasma conc profile depend on
relative rates of absorption and elimination
what do plasma conc profiles vary between
they vary depending on the route of administration
what administration leads to an early peak due to fast absorption on a plasma conc profile
intravenous
intramuscular
what administration route leads to a delayed peak on a plasma conc profile
oral, rectal, subcutaneous
is the rate of elimination constant
yes!
it depends on the nature of the active ingredient
3 things that make up drug disposition
distribution
metabolism
excretion
a drugs disposition is itsssss
ADME!!
absorption
adsorption
metabolism
extraction / elimination
plasma conc profile for multiple doses
furry graph
conc changes up and down with time
plasma conc profile for single dose
normal graph
increases, peak, decreases
conc increases then decreases with time
what are the visible phases of a plasma conc profile
absorption phase
elimination phase
what is Css
steady state concentration
when the absorption of the drug is equal to the elimination of the drug
what happens to the drug when it is administered using multiple doses
- drug accumulates in the body until plateau is reached
what happens when the plasma conc is too high for multiple doses
excessive adverse side effects occur
conc increases too high too fast
in multiple doses, where do we want the drug conc to be at
the therapeutic window.
the conc where effects are seen but there are no excessive side effects.
plasma drug conc increases slowly + therapeutic success is seen
areas of preformulation research
aka things we think about before formulating the drug
- physiochemical properties
- bulk characterisation
- solubility analysis
- stability analysis
preformulation research: physiochemical properties
physical properties
PURITY
SURFACE AREA
PARTICLE SIZE
PARTICLE SHAPE
preformulation research : bulk characterisation
powder flow properties
bulk density
preformulation research: solubility analysis
pka
dissolution
pH solubility profiles
preformulation: stability analysis
solution
solid state
bulk
compatibility stability
what must we think about when optimising a drugs formulation
we must think about it’s intended use.
aka if it’s use is to stop a sore throat and u need to suck on it, we must formulate it to taste nice
the active principle must be studied,, what else must be studies
the excipients
everything other than the active principle
when do preformulation research occur
all the time!!
from preclinical to launch
what’s solubility must be studied
the active principle + excipients in an aqueous media
when solubility is tested,, what condition are used
37*C
aqueous buffer to reach equilibrium
what is max saturation // solubility
the max amount of a drug/excipient that can be dissolved in a fixed volume.
fully saturated = it can’t dissolve anymore
why must solubility be studied at different pHs
solubility of ionisable groups changes under certain pHs.
the body also has environments of different pHs.
COOH vs COO- have diff solubilities
why must a solubility profile be made
to see the diff states the active principle is in diff pHs.
allows us to optimise the drugs formulation basing it of its use.
aka the use of a certain solvent for nasal sprays
what does pKa equal to and when
it equals pH
when 50% of the drug is ionised
ionic drugs have diff what???
diff solubilities in diff environments
how does COOH change between pHs and body environments
pH 1: mainly COOH can enter the plasma
pH 7: mainly COO- can’t return back to stomach.
no longer membrane soluble
what does testing solubility help us do
- find correct solvents to use when manufacturing the active ingredient
name one dosage form ‼️‼️‼️
solid!!
name the diff types of solid dosage forms
- buccal tables
- chewable tablet
- sugar coated
- film coated
what are the advantages of a solid oral dosage form
- accurate
- good shelf life
- easy to store + distribute
- ppl can administer it themselves
what are the disadvantages of a solid oral dosage form
- hard to administer it to unconscious ppl
- may take longer for the drug to be absorbed
what determines the way a drug is delivered to the site of action
it’s physical state + chemical composition
aka a solid with 0 solubility cannot be administered intravenously
what gives a drug it’s suitable consistency
the active principle and the excipients // the vehicle.
the vehicle takes the drug to the target
what is a excipient // a target
a non therapeutic
gives the drug its suitable consistency
lists of drug consistency’s
solid
liquid
gas
semisolid
what is important about the active principle and the excipient
- they must be physically and chemically compatible!!
they must not react and cause side effects
they must be tested for this under lots of pH values
solid capsule
gel coating
gelatine covering
colourant included
solid tablets
compressed + molded with the excipient
anticaking agents
can be sugarcoated to mask bad flavour
when does polymorphism occur
when a chemical compound crystallises with different internal structures
diff types of possible polymorphisms
crystalline (crystal arrangement)
polycrystalline ( many crystals joined)
amorphous ( bit of a mess but we love her x)
out of the 3 polymorphic forms,, what structure is least soluble
crystalline
then polycrystalline
then amorphous
what is the difference between the 3 polymorphic forms
- diff physiochemical properties
aka solubility, melting point
effects their ‘F’ and stability
what does the rate at which a drug or excipient dissolve in any particular medium depend on
- particle size + particle size distribution
- particle porosity // surface area
- wettability of surface (initiates dissolution)
- nature of dissolution fluid
dissolution meaning
breaking down
dispersing itself
what size of particle dissolves at a faster rate
a smaller particle
moisture uptake and sorption
measured to see how a medicine (drug + excipient) should be stored and packaged based on moisture uptake findings
moisture uptake / sorption
gives insight into how a medicine ( drug + excipient) should be packaged
what is an excipient
- inactive substance with no therapeutic use
- used as a vehicle or medium for drugs
should be inert - must also be tested alongside the drug
example of an excipient
colourant
bulking agent
anti-caking agent
binders
why must excipients be included in the ingredients section
someone could be allergic to the excipient but not the drug itself (the active principle)
what are drugs that are formulated as extended release
they release the active principle over a longer period of time.
most commonly seen for oral doses
- TI, solubility, potency + rate of absorption/ excretion must be considered
when are extended release dosage forms of drug usually used
for chronic conditions
not for acute conditions
sterile formulation product examples
medical devices
sterile fluids
what is pharmacopoeia + certified analysis
- list of the quantitative and qualitative compositions of medicines
- series of tests that the medicine and raw materials must undergo
- must occur in order to be fda approved into clinical trials
medicine quality control role
- drugs must obey high quality standards
what 2 things play a crucial part in a lab study
- the procedures
- the ppl in the lab
the manufacturing industry is full of..
Good Practice Standards
all steps of the lab must be covered under,,
GXP
what does the X in GXP stand for
LABORATORY
MANUFACTURING
what is GOOD LABORATORY PRACTICE
- established by the fda to:
• assess non clinical pharmceutical lab study safety
• protect integrity of scientific data (moral principles + honestly) - provide open end research for product advancement (long answers)
what lab studies does GLP regulate
non clinical lab studies for future human / animal drugs, perfumes, biologics etccc
what do u need when handling live organisms or plants
GLP
good laboratory practice
what must be tested under GLP
safety and efficacy
what studies don’t require GLP
discovery
basic research
screening
in vitro studies
studies where safety is not a concern
things included in GLP
- audit + inspection (internal and external- FDA) to see if procedures are being followed
- standard operating procedures (guidelines labs should follow - must be clearly written and accessible)
- data must be recorded physically (what was done, how it was done, where it was done)
- staff must be trained!!
GLP examples:
notes made on temperature gives info on how drugs should be stored.
what do GMP regulations apply to
they apply to every step of the manufacturing process!! not just the testing
what does the FDA say about GMP
that manufacturers should reevaluate their practices to stay up to date with new technology
when should GMP be applied
when smt is being manufactured for consumers!
batches and ingredients must be tested!!
data on safety of smt applies to what GXP
GLP
manufacturing aka batch/kit release and associated safety testing applies to what GXP
GMP
- anything with making stuff for ppl/ consumers = GMP
what happens after preclinical testing
- after preclinical we have clinical tests!!!
before the drug is transported to diff countries to start clinical trials what must occur
drug must be subject of an approved marketing application by EU IMPD, IND, CTA
marketing application : EU IMD
european investigational medicinal product dossier
marketing application: IND
Investigational new drug
marketing application: CTA
clinical trial authorisations
what happens before u can start clinical trials
get document from clinical trial sponsor!! u wait 30 days for the FDA to analyse the data to see if ur clinical trial is safe + won’t put anyone in harms way. then after 30 days u can start clinical trials
medicine and GMP
used to make sure that products are consistently produced under good standards
why are GMPs important in medicine
- ensures that medicine is high in quality
- makes sure there are no health hazards, prevents time wasting, prevents money waste, makes sure no toxic compounds were added unintentionally
- countries can refuse to sell drugs that aren’t under GMP.
