L7 - physiochemical properties of small drugs Flashcards
the body can’t absorb solids, so what must happen to a drug to have its biological effect?
- must be released from its dosage form at the site of administration
- undergo dissolution
what can liberation (release of drug from dosage form) cause?
can affect drugs bioavailability (quantity of drug that reaches site of action + rate at which drug get there)
what is bioavailability influenced by?
- dosage form (+ excipients & manufacture method)
- physiology of site of administration
steps of release of oral dosage form (tablet with insoluble permeable coating)
the drug dissolves inside the tablet (osmotic pump)
steps of release of oral dosage form (coated tablets)
- dissolution of coating
- it then disintegrates
- disaggregation (fine granules/ primary particles)
- go into solution
steps of release of oral dosage form (drug suspensions)
- particles of drug suspended in liquid
- don’t have to released from dosage form
- can just diffuse to epithelium
how does drug dissolution occur from crystal to liquid?
- salvation of drug molecules at crystal surface makes a STAGNANT layer of drug solution
- this is the diffusion layer
- drug molecules will diffuse across the diffusion layer into the bulk dissolution medium
- this can be the contents of the GI tract
what is the rate of dissolution dependent on?
the slowest step out of salvation of drug molecules at crystal surface and diffusion across diffusion layer
what can dissolution at a constant temperature and pressure be described as?
Noyes-whitney equation
notes-whitney equation
dm/dt = D A (Cs - C) / h
dm/dt
dissolution rate of drug (kg s-1)
D
diffusion coefficient of solute in dissolution medium (m s-1)
A
surface area of drug particle (m2) (part in the middle inside the diffusion layer)
Cs
solubility of the drug (kg m-3)
C
concentration of drug in bulk solution at time (kg m-3)
h
thickness of the boundary layer (diffusion layer) (m)
generally C () CS
C «_space;Cs
conc of drug in bulk sol is usually a lot smaller than the solubility of the drug
key parameters that affect the rate of dissolution of a drug
- surface area of particles (particle size + wettability)
- molecular weight
- solubility (hydro and liphphilicity, crystal structure)
- GI tract (viscosity, volume of liquid, movement, secretions, pH)
brief overview o
- drug diffuses from site of release to epithelium
- across epithelium
- drug in sol passes mucus layer on epithelium
- through apical layer, through cell, through basolateral layer
- into systematic circulation
transcellular pathway (major)
across (through) the cells into the blood
paracellular pathway (minor)
alongside the cell (between cells) to the bloodstream
what makes paracellular pathway difficult?
- tight junctions between neighbouring cells
- adherens junctions which join cytoskeleton of cells together
- desmosomes where proteins cross gap between cells
rate limiting junction
what drugs can be absorbed across paracellular pathway?
small hydrophilic (due to aqueous medium in between the cells) drugs can pass between cells but rate of diffusion is affected by tight junctions
3 main ways that drugs go through transcellular pathway
- passive diffusion: solutes diffuse into cells down a conc gradient and go through lipid bilayer and then cytoplasm
- facilitated diffusion (selective) - down a conc gradient - uses transporter/carrier protein
- active transport - against a concentration gradient - needs energy - carrier mediated transport
why does the rate of absorption plateau for active transport at at a certain drug concentration?
there is only a limited number of carrier proteins (carriers becomes saturated)
endocytosis (minor pathway)
- plasma membrane folds in on itself
- forming endosomes (vesicles)
- endoscopes can fuse with lysosomes
- contents degraded by enzymes
passive diffusion
- a system not in equilibrium moves towards equilibrium
-so flow (flux occurs) - e.g dye in water, diffusion of dye in liquid
- low entropy ordered system becomes high entropy disordered (increase in entropy due to random movement of molecules)
equation for movement of molecules
J = C x V x A
(flux = conc x velocity x area)
J
flux (mol s-1). movement of molecules
C in flux
conc (mol cm-3)
v in flux
velocity (cm s-1)
A in flux
area (cm2)
passive diffusion - fick’s first law - describes rate of diffusion
J = -D x dc/dx
D in ficks first law
diffusion coefficient (diffusivity)
dc/ dx
concentration gradient
what is flux proportional to?
potential energy gradient (conc gradient which is the driving force towards eqm)
what does a higher dc/dx mean?
- bigger conc gradient
- so system ifs further away from eqm
what does the negative sign in fick’s first law indicate?
flow from high conc to low conc
when you mix solutes in uniform what happens?
- conc gradient = 0 so flux = o
- free energy is minimised
- entropy is maximised
what is the stokes einstein equation for?
- relates diffusivity to local environment conditions
- properties of the diffusing molecule
stockes einstein equation
D = KB x T / 6pi x n x r
D in stokes einstein equation
diffusion coefficient (diffusivity)
KB in stokes einstein equation
Boltzmann constat
T in stokes einstein equation
temperature
n in stokes einstein equation
viscosity of solvent (more viscous = smaller diffusivity)
r in stokes einstein equation
particle radius
how do particles move?
very quick but they are “blind” so move randomly + collide with other molecules
in a collection of diffusing molecules how do you find the mean distance moved (x)?
x = √(2𝐷 𝑡)
D= diffusivity
t = time
small vs larger drug x
smaller drug has larger diffusivity so it will travel faster
passive diffusion across epithelia
- drug released from dosage form
- drug diffuses to epithelium
- then through it
(aq to lipid to aq)
what is the conc gradient (dc/x) maintained by across the epithelia?
by drug absorption into blood
extended ficks first law to examine drug passing through biological membrane
J = A D K (Co - Ci) / h
A in ficks first law
membrane area
K in ficks first law extended
partiton coefficient
Co - Ci in ficks first law extended
concentration gradient (one side of membrane to another)
h in ficks first law extended
membrane thickness
membrane properties
- flux is INVERSELY proportional to membrane thickness, h (as flux inc, membrane thickness decreases, so rate inc)
- flux is proportional to membrane area, A (as flux inc so does membrane area, e.g villi in small intestine)
drug properties
- flux is proportional to conc gradient (Co - Ci)
- flux is proportional to partition coefficient, K
drug and membrane properties
- flux is proportional to diffusivity of drug in the membrane, D
so drug size (MW) + membrane nature affects it
what is the partition coefficient?
- quantifies the distribution of drug between aq phase and lipid membrane
- measure this partition between oil + water
- shows how lipophilic a drug is
P is il water partition coefficient
P = Coil / Cwater
expressed as logo
how to determine oil/ water partition coefficient via solubility
- find drug solubility in oil (Soil) and in water (Swater)
- partition coefficient = oil/water
how to find lipophilicity via shake flask method?
- add drug to equal volume of water and oil
- shake for time
- allows phases to separate
- find conc of drug in oil + water
- P = coil/cwater
(oil phase usually octane) so can be octane water partition coefficient
if drug is more soluble in octanal than water?
log p is bigger than 0
P is higher than 1.
high lipophilicity
if drug is more soluble in water than octanal?
- Lop P is lower than 0
- P is lower than 1
log p below 1?
- high sol
- low permeability
- low oral absorption
log p 1-3
- moderate sol
- moderate perm
- good oral absorption
log p 3-5
- low sol
- high perm
- variable oral absorption
log p above 5
- poor sol
- high perm
- poor oral absorption
optimum log p ranges for oral delivery?
around 1 to 3
