pharmacokinetics and toxicology of lead optimisation+ preformulation studies combined

two lecture in one

how much rat bioavailability should be found to increase the chance of a success in humans

30% or higher

what are some strategies to improve solubility?

increase the amount of ionizable groups

polar groups

hydrogen bonding groups- can be acceptors or donors

MW less than 500

reduction in particle size

polymorphous state( amorphous is more soluable)

formulating into a salt

what are some commonly used ions to make salts?

chloride and sodium

what are some negative impacts of low soluability?

poor absorption and bioavailability

may require increase volume of administration to improve solubility

fake low activity from bioassay

frequent high dosing administration

expensive formulation

erratic assay results- reading may be different to when compound precipitates

what size of molecule can pass through the paracellular route?

8 armstrong

what is the major pathway of drug permeation?

transcellular

what are some physicochemical properties of compound that pass through the transcellular route?

MW less than 300

unionized

soluble

lipophilic- Log P greater than 0

what are some physicochemical properties of compound that pass through the paracellular route?

small, less than 8 A

positively charges

Log p less than 0 - hydrophillic

why are positively charged molecules more likely to cross through the paracellular route

the tight junctions are negatively charged

what are some strategies to improve permeability?

change ionizable to non ionizable

increase lipophilicity, by adding methyl group

replace polaraity

prodrug

what is an isoester of COOH?

tetrazole

what group can be added to increase lipophilicity?

methyl group

what are class one molecules in the BCS system

high solubility high permeability

what are class two molecules in the BCS system

low solubility high permeability

what are class three molecules in the BCS system

high solubility low permeability

what are class four molecules in the BCS system

low solubility and low permeability

based on the BSC system what is defined as having high soluability?

when the highest dose is fully soluable in less than 250ml over the pH range 1-7.5

what techniques can be done in the lab to understand polymorphism?

DSC, thermogravimetic analysis, x ray diffraction

according to the ICH guidelines how should stability be tested?

the drug substance be tested under different stress conditions that are indicative of environmental challenges to which the drug will be exposed.

examples of stress, pH, temperature, humidity, light, oxidizing agents

how can hydrolytic degradation be tested ?

refluxing the drug in 0.1HCL and 0.1 NaOH for 8-12 hours

According to the ICH guidelines, how should photostability be tested?

1.2 million lux-hours of visible light exposure, along with 200 W-h/m2 of UV

for pH stability in solution what duration of time is stability tested for

up to one month

what compounds are prone to free radical chain oxidation?

unsaturated compound, oils, compounds that contain a double bond

how can redox reaction be tested for oxidative stability?

test in solution in the presence of hydrogen peroxide or other free radical initiators