L7 - Physiciochemical Properties Flashcards
What must a drug do for it to have a biological effect? And why?
It must be released from its dosage form
- the body doesn’t absorb solids
What is the drug’s bioavailability influenced by? (2)
- the dosage form, including excipients
- the physiology of the site of administration
What 2 steps does drug dissolution involve?
- solvation of drug molecules at the crystal surface
- drug molecules diffuse across diffusion layer to bulk dissolution medium
What is the Noyes-Whitney eqn?
dm/dt = DA(Cs-C)/h
What do the letters stand for in the Noyes-Whitney eqn?
m - mass of drugd released into solution (kg)
t - time (s)
dm/dt - dissolution rate of the drug (kg s-1)
D - diffusion coefficient into dissolution medium (m s-1)
A - SA of drug particle (m2)
Cs - solubility of drug (kg m-3)
C - conc of drug in bulk solution at time (kg m-3)
h - thicknedd of boundary layer (m)
What are the key parameters for the Noyes-Whitney eqn? (4)
- effective SA
- molecular weight (MW)
- solubility (hydro-/lipohilicity, crystal structure)
- GI tract (viscosity, vol of liq, movement, etc)
What are the 2 drug absorption pathways?
- transcellular pathway (across cells)
- paracellular pathway (alonside cells)
What are the 3 different types of junctions?
- tight junctions
- adherens junctions
- desmosomes
What are tight junctions?
Membranes of neighbouring cells fused by intimate connections between cell surface proteins
What are adherens junctions?
They connect actin filaments in the cytoskeletons of neighbouring cells together
What are desmosomes?
Fibrous proteins cross the gap between cells and anchor keratin filaments in the cytoskeletons together
What is the rate limiting for the paracellular pathway?
The passing through tight junctions
What are the 3 ways that drugs get absorbed through transcellular absorption?
- passive diffusion
- facilitated diffusion
- active transport
What is passive diffusion?
(Main pathway of drug absorption)
Solutes diffuse into cells DOWN a conc grad
- must partition into the lipib bilayer and out again into cytoplasm
What is facilitated diffusion?
Selective, carrier-mediated transport of a drug DOWN a conc grad
What is active transport?
Selective, carrier-mediated transport of a drug DOWN or AGAINST a conc grad
- requires energy input
What is endocytosis?
(Very minor pathway)
Internalisation of the plasma membrane, engulfing extracelular fluid
- limited relevance to absorption of small drugs in GI tract
What is passive diffusion in terms of equilibrium?
A system not in equilibrium moves towards equilibrium, which means the flor (flux) must occur
- low entropy (ordered) to high entropy (disordered)/homogenous as they diffuse
What is Fick’s First Law?
J = -D dc/dx
J - flux
D - diffusion coefficient
dc/dx - conc grad
What are details about Fick’s First law? (4)
- flux is proportional to potential energy grad
- the further a system is from eq (high dc/dx) the faster it moves towards it
- -ve sign - flow from high to low conc
- free energy minimised, entropy maximised when mixing of solutes is uniform
What is the Stokes-Einstein eqn?
D = kb x T/ 6pi x n x r
D - diffusion coefficient
Kb - Boltzmann constant
T - temp
n - viscosity of solvent
r - particle radius
What does the stokes-einstein eqn relate diffusivity to? (3)
- local environmental conditions
- properties of solvent which molecules is diffusing
- properties of the diffusing molecule
What is the speed of diffusion like?
Molecules move really quickly, moving randomly and colliding with other molecules
What is mean distance moved propertional to in a collection of diffusin molecules?
Mean distance moved (x) in a specific direction is proportional to the square root of time
x = sqrt(2D t)
What is passive diffusion like across epithelia?
Aq -> lipid -> aq
Dosage form released, drug needs to diffuse to the epithilium and then through it
What is Fick’s first law on passive diffusion?
J = ADK(Co-Ci)/h
K - partition coefficient
Co-Ci = conc grad
What are the membrane properties regarding fick’s first law in passive diffusion? (2)
- flux is inversely proportional to membrane thickness
- flux is proportional to membrane area
What are drug properties like regarding fick’s first law in passive diffusion?
Flux is proportional to the
- conc grad
- partition coefficient
What are the drug and membrane properties like regarding fick’s first law in passive diffusion?
Flux is proportional to the diffusivity of drug in the membrane
- influenced by drug size and nature of the membrane
What does K quantify?
The distribution of a drug between the aq phase and the lipid membrane
What does lipholicity measure in practice?
The partitioning of a drug between oil and water
- indication of how lipophilic a drug is
What is P?
The oil/water partition coefficient
P = Coil/Cwater
Determined using octanol and water, expressed as LogP
What are the methods for determining P?
- solubility
- shake/flask method
What is the solubility method like for determining P?
Determine drug solubility in oil and its solubility in water
P = Soil/Swater
What is the shake/flask method like for determining P? (4)
- Add drug to equal vols of water and oil
- Shake for extended period of time
- Allow phases to separate
- Determine conc of drug in each phase
What is LogP when the drug is more soluble in octanol than water?
P > 1
Log P > 0
What is LogP when the drug is less soluble in octanol than water?
P < 1
LogP < 0
What LogP do approximately 90% of small molecule drugs on the market have?
LogP between 0 and 5
What is the optimum Logp range for oral delivery
LogP 1 to 3
