Partition Coefficents

Question 1

Lipid Bilayers

Answer 1

• Polar groups project outward toward the aqueous environment
• Non polar region point toward each other

Question 2

Drugs that are charged

Answer 2

• Too water soluble
  – Poor lipid soluble
• Difficulty crossing lipid bilayer
  Ex. Quaternary ammonium

Question 3

Drugs that are uncharged

Answer 3

• Too lipophilic
  – Poor water soluble
• Tend to partition into fatty deposit in the body

Question 4

Petition Coefficients

Answer 4

Ratio of polar characteristics to non polar characteristics
- Very critical physico-chemical property
P= Conc. of drug in lipid phase/Conc. of drug in water

Question 5

n-octanol

Answer 5

Surrogate for lipids
- Lipid refers to a class of compound rather than a single compound
- Can be determined experimentally by distributing a known amount of a drug between equal vol of n-octanol and water in a separator funnel
– After equilibration the conc. of drug is determined
— P=Drug Octanol/Drug water
P= Conc. of drug in n-Octanol/Conc. of drug in water

Question 6

Hansch Partition Coefficient

Answer 6

• Quantitative measure of the effect of a substituent on the partition coefficient of the molecule as a whole
  Pi(x)=log (Px/Ph)=Log Px - Log Ph=> Log Px = Log Ph + Pi (x)
  LogPx is the Partition coefficient of the substituted compound
  LogPh is the partition coefficient of the unsubstituted compound
• Positive Pi(x) => the Substituent (x) makes the compound more lipophilic (less polar)
• Negative Pi(x) => the Substituent (x) makes the compound more water soluble (more polar)

Question 7

Log P

Answer 7

Low P= More water soluble
- Double bonds leads to more water solubility
High P = More Lipid soluble
- Each additional Carbon raises the log P by 0.5 unit
- This mean for two compound with identical functional groups the one with more carbons will be more lipophilic
- Compounds lacking a branch will be more lipophilic than those with a branch

Question 8

Delta G

Answer 8

Lower entropy means larger Delta G (positive)
- K will be smaller
- Compound morre likley to stay in th organic phase

Question 9

Factors that Increase Log P

Answer 9

• Groups that Do Not readily form hydrogen bonds
  – +pi groups (carbons (CH3, CH2, CH, C), even saturated carbons)
  – Halogen (CI, Br, I); F will to only if attached to an unsaturated (or aromatic) carbon
  – Trifluoromethyl (CF3 - strongest +pi)
  – Thiols (mercaptans) and this ethers (sulfides)
  — Sulfur is much larger than hydrogen and cannot easily form hydrogen bonds

Question 10

Factors that decrease Log P

Answer 10

Groups that readily form hydrogen bonds
- (-pi groups)
- O and N containing functional groups (the lone pair are very efficient at hydrogen bonding)
– Alcohols, ether, any functional groups with a carbonyl bond, amine, nitriles, nitro, etc.
- Charged Functional groups
– Positive charges are attracted to O of water while negative are attracted to H of water
- F attached to saturated carbon
- Unsaturation
– Double and triple bonds
- Branching
– at any point other than at the end

Question 11

Log D

Answer 11

Distribution constant
Log ((drug)oct/ (drug)H2O +(ionized drug)H2O)
Log D= 3@pH 7.4
- Log D is smaller or equal to Log P
acid => Log D= Log P(HA) - Log (1+10^pH-pKa)
base => Log D= Log P(B) - Log (1+10^pKa-pH)