Drug Delivery Hyp2 Flashcards
What are the four factors important for shelf life and stability?
- Drug content remains above specified level
2.No accumulation of degradation products that could
represent a risk to patient
3.Physical characteristics remain suitable - Biological and microbiological stability critical for sterile products
What are the three common chemical routes of degradation?
- Hydrolysis
- Oxidation
- Photolysis
What factors can increase the rate of hydrolysis?
Heat, light , trace metals
What is the shape of the rate reaction of reaction curve for hydrolysis and why?
U- shaped, due to it being catalysed by acids and bases
Which ones, out of esters and amides, are less susceptible to hydrolysis and why?
Give an exception to this:
Amides are less because N less electronegative than O
Lactams are less stable than esters due to ring strain
What is the difference between proteolysis and deamidation?
Proteolysis is the breaking of amide bonds in backbone
Deamidation is the breaking of amide bonds in Gln, Asn
What are five strategies to reduce the chance of hydrolysis?
Solid or suspension instead of solution formulation
Buffers to ensure optimal pH
Reduced solvent polarity (e.g. ethanol or polypropylene glycol added to water)
Low temperature storage
Packaging to exclude humidity
What is oxidation?
The loss of electrons to an oxidizing agent
What happens to organic compounds when they are oxidised?
The molecule gains oxygen, loses hydrogen
Which compounds are commonly oxidised?
Alcohols, amines, thiols, thioethers, compounds with multiple bonds
What are thiols/ thioethers,
They have an S rather than an O
What are five factors oxidation is influenced by?
exposure to oxygen (or other oxidizing agents) exposure to light trace metals (catalysis) temperature (less than hydrolysis) free radicals
What is a free radical?
An atom or molecule with an unpaired electron (A•)
What are the stages of reaction with free radicals?
- Initiation stage- bond breaks to make a free radical
- Propagation stage- Free radical reactions with a paired radical to give a different free radical and paired radical
- Termination- Two free radicals pair up
What are four strategies to reduce oxidation?
- Antioxidants are compounds that are oxidised more easily than the drug or that form relatively stable free radicals (e.g.ascorbic acid)
- Chelating agents form complexes with trace metals and prevent their catalytic activity (e.g. ethylenediamine tetraacetic acid – EDTA)
- Low pH can stabilise liquid formulations
- Packaging in inert atmosphere, light excluded
What is photolysis?
Chemical degradation induced by exposure to light and the absorption of photons
What excipient can catalyse the photodegradation of a drug?
Titanium dioxide
What are two ways to decrease photodegradation?
Packaging to reduce exposure to light (e.g. amber glass containers, aluminium foil blister packs, external cardboard container)
Temperature has only a small influence on the rate of photolysis reactions
What are three other types of degradation and describe what they are:
- Isomeric changes- Geometrical isomers (cis/trans, e.g. retinol)
- Chiral centres - Reduction- the molecule gains electrons, gains hydrogen or loses oxygen
- Dimerization and polymerization: the molecule reacts with another molecule of the same kind
What does ADME stand for?
Absorption
Distribution
Metabolism
Excretion
What is absorption?
The process of getting the drug from the delivery site to the bloodstream
What is distribution?
A description of where in the body the drug goes to after administration and absorption
What is metabolism?
How the body chemically changes foreign compounds so that they can be more easily removed from the body
What is excretion?
How the body removes drugs or metabolites, also called elimination
What is the Therapeutic Window?
As the drug exposure increases, the more adverse the effects. In the therapeutic window, this is where the drug has the best/ safest effect.
What are the types of testing occurring in the industrial perspective?
Pre- clinical testing: - In vitro and animal testing Clinical (human) testing: - Phase 1 - Phase 2 - Phase 3
Name six sites of where drugs can be tested from the body:
- blood plasma
- blood serum
- whole blood
- breath
- milk
- urine
How is blood plasma separated to find the drug concentration in the blood?
Whole blood is centrifuged after adding an anticoagulant. Cells are precipitated. The supernatant fluid, contains proteins that often bind drugs. The concentration in plasma comprises bound and unbound drugs.
What type of drugs can pass through the membrane?
Unionised nonpolar drugs
What are the five types of routes of absorption from the gastric lumen?
- Transcellular route: passive diffusion
- Transcellular route: active transporter utilisation
- Paracellular route (tight junctions)
- Lipid absorption via micelles / bile salts
- Particulate absorption via GALT: (Gut-Associated Lymphatic Tissue)
What are the three factors of a drug for it to be orally absorbed?
- pKa of drug
- pH of gastric site
- Log P of drug
What is the equation to find the oral absorption of acidic drugs?
% of [A-] = 100 x 10^ ( pH -pKa)/ 1 + 10^ ( pH -pKa)
What does transcellular mean in drug transport?
Involves passage of the drugs through cells
What does paracellular mean in drug transport?
Between blood and lumen ( gap junctions) as too polar
What is the partition co-efficient?
P = conc in water/ conc in oil
What do the values from the partition co-efficient mean in regards to solubility?
Log P = 0 = Equally soluble in both
Log P = -ve = More soluble in water
Lop P = +ve = More soluble in oil
What is a disatvantage of using LogP in the partition co-efficient and what is used instead?
Only considers un-ionised material
Use Log Papp,
What is the equation to work out the rate of oral absorption?
Rate= P x A x (C1- C2)
P = partition coefficient
A = effective surface area
(C1- C2) = conc gradient
What is the correlation between molecular weight and solubility?
The larger the molecular weight the lower the permeability
What is the normal pH of blood plasma?
7.4
What are the two types of plasma protein in the blood?
Globulins and albumin
Which is the most important binding protein and describe its characteristics:
Albumin
- soluble in water
- soluble in dilute salt solutions
- mw approx 69,000
- pI=4.9
• Binds anionic, cationic and non-ionic drugs
• High affinity : low capacity - “specific” binding sites and
low affinity : high capacity - “non-specific” binding sites
Can bound/ unbound drugs be distributed?
Only un bound
Describe the one compartment model:
Simplest possible representation of PK - drug goes in - drug comes out - no complications No metabolism, no protein binding, no sequestration by other tissues
What are the main five pharmacokinetics parameters?
- Volume of Distribution
- Clearance
- Exposure
- Mean residence time
- Fraction of dose remaining
In first order kinetics, what does the rate depend on?
The concentration
What is the equation to work out the initial concentration of a drug in reservoir?
𝐶= e^y intercept
What is the equation to work out the rate of elimination (clearance) of a reservoir and annotate:
Vd x Ke
Vd= volume of distribution Ke= elimination constant
What are the equations to determine the extraction ratio, E?
E = 𝑅𝑎𝑡𝑒 𝑜𝑓 𝑒𝑙𝑖𝑚𝑖𝑛𝑎𝑡𝑖𝑜𝑛/ Rate of presentation
𝐸=𝑄 (𝐶−𝐶out)/ Qx C = (𝐶−𝐶out)/ C
What is clearance?
Clearance is the volume of the fluid presented to the eliminating organ (extractor) that is effectively completely cleared of the drug per unit of time.
ml/min or L/hr
What does volume of distribution predict?
The concentration for a given amount of drug in the body in the plasma.
Theoretical, how much volume would drug be in if whole dose would be equally distributed at initial conc.
What is the equation to work out the fraction rate of elimination?
k = rate of elimination/ amount in reservoir
k = CL/ V
What is the other equation to measure the rate of first order elimination?
Put this equation into a linear equation:
− 𝑑𝐶/dt = 𝑘elim x 𝐶
𝑙𝑛𝐶(𝑡) =ln𝐶(0) −𝑘elim x 𝑡
What does the gradient in an IV bolus plasma vs time graph represent?
Elimination contant, kelim
How would you calculate the half life of a drug in plasma from a normal graph?
e.g.
get a large conc e.g. 80μg/mL and draw horizontal line to curve, then draw vertical line down to time
do the same with half the conc, so 40μg/mL
t 80μg/mL - t 40μg/mL = half life
What is the equation to calculate half life from an equation?
𝑙𝑛2/ kelim = t1/2
What are three important pharmacokinetics parameters?
- Volume of Distribution
- AUC (Exposure)
- Clearance
What is the apparent volume of distribution and how is it calculated?
The total volume of fluid the drug would occupy if the total amount of drug in the body was in solution at the same conc it is in the plasma
Vd= dose/ initial plama conc (sometimes also over weight in kg)
What do high, low and intermediate values of volume of distribution indicate?
Low= vascular system e.g plasma Medium = distributed to other tissues High= tightly bound to very specific tissues
What is another way of calculating the volume of distribution and what does it mean?
Using the Area Under the Curve (AUC)
Larger areas under the curve, has a larger exposure to the drug as it is a slower process
Initial conc/ kelim
What is another equation to calculate half life?
t1/2 = In2 x V/ CL
What is the mean residence time?
The average time molecules of drug stay in the body
What is the equation to calculate mean residence time (MRT)?
MRT= 1/kelim
How do you calculate the kelim from a plasma conc vs time graph?
Find the gradient
How do you calculate the initial concentration from a plasma conc vs time graph?
e^-y intercept
How do you calculate the half life from a plasma conc vs time graph?
ln2/kelim
How do you calculate the area under the curve, also known as exposure from a plasma conc vs time graph?
Initial conc/ kelim
How do you calculate volume of distribution from a plasma conc vs time graph?
Dose/ initial conc
What is the volume of distribution?
Theoretical value of how much is in plasma
How much volume would drug be in if the whole dose would be equally distributed at initial conc
How do you work out clearance from a plasma conc vs time graph?
Volume of distribution x kelim
