117: Partition Coefficient pt 1

Partition Coefficient

• how a drug distributes at equilibrium btw 2 iisicble phases

• octanol (lipid-like) & water

• at a fixed temp using only neutral, UN-Ionized form

partiion coefficient is independent of what

concentration, within dilute limits

what does partiion coefficient reflect

a molecule's intrinsic lipophilicity (fat-loving) versus hydrophilicity (water-loving) character.

P = [C] octanol / [C] water

logP = log10(P)

meaning of P values

P >1: compound favors organic (octanol), lipophilic phase

P=1: equal affinity for both phases

P<1: compound favors aqueous phase, hydrophilic

why is n-Octanol the standard ref solvent

mimics the amphipathic environment of biological membranes better than any simpler alternative

octanol amphipathic structure

Its long hydrocarbon tail (lipophilic) and polar hydroxyl head (capable of H-bonding) resemble phospholipids in cell membranes

Why does water-saturated octanol retain water?

Holds approximately 2 M water, allowing hydrogen bonding with polar solutes and mimicking a real membrane environment

Why is octanol considered a historical standard?

Used for decades in regulatory and pharmacological studies (Hansch and Lipinski) to provide standardized drug comparisons.

What properties of octanol make it easy to work expeerimentally?

• Low volatility

• Low water solubility

• UV transparency

Why can LogP be misleading for drugs at physiological pH?

• measures only the neutral form of a drug.

• Most drugs partially ionize at physiological pH (7.4)

• ionized forms are charged, prefer water, and partition poorly into octanol.

Log P vs Log D

• LogP: Constant; measures lipophilicity of the neutral drug only and does not change with pH.

• LogD: Variable; measures effective lipophilicity at a specific pH, accounting for both ionized and unionized forms.

what happens w/ non-ionizable compounds (or fully un-ionized)

LogD = LogPat every pH

log D ((distribution coefficient)

logP<0

Highly polar / water-soluble

• Poor membrane permeability; often renally excreted quickly

logP 0-3

most oral drug

• balanced/ drug-like

• hydrophilic enough to stay in solution

• lipophilic enough to cross mem

log P >5

Highly lipophilic

Risk of poor solubility, high protein binding, toxicity, bioaccumulation

log P values ref

what increases logP (lipidphilic)

• Longer alkyl / aliphatic chains (each -CH2- adds ~0.5)

• Aromatic rings and halogens (Cl, Br, I)

• Branching and increased molecular bulk

• Fewer hydrogen bond donors/acceptors

what decreases logP

• Ionizable groups

  • (-COOH, -NH2) when charged

• Hydroxyl (-OH), amine, and amide groups

• Hydrogen bond donors and acceptors

• Polar functional groups

  • (-CN, -NO2 to a lesser extent)

what shapes a drug’s journey thru body at every step

lipophilicty

Absorption logP

high, improves passive diffusion acx gut wall

• too high can harm dissolution in gut fluid

Distribution

• Lipophilic drugs partition into fatty tissue and cross the blood-brain barrier more readily;

• hydrophilic drugs stay in plasma/extracellular fluid.

Metabolism

• Lipophilic compounds are typically better substrates for CYP450 oxidation,

- faster hepatic clearance.

Excretion

Hydrophilic drugs (and lipophilic drugs after metabolism to polar

metabolites) are more readily cleared renally.

How Is Partition Coefficient Measured?

• Shake-Flask Method

• RP-HPLC Retention

• Computational (in silico)

Shake-Flask Method

• Classic reference method

• Drug shaken to equilibrium in octanol + buffered water

• Phases assayed by UV/HPLC

• Best for log P range −2 to 4

RP-HPLC Retention

• Retention time on C18 column correlates with log P

• Fast, small sample size

• Calibrated against reference standards

• Good for high-throughput screening

Computational (in silico)

• Fragment-based: ClogP, AlogP

• Atom-based & QSPR models

• No compound needed — used pre-synthesis

• Guides early drug design choices

Incomplete Phase Separation

Residual emulsification traps droplets of one phase in the

other, contaminating the assay of both

Insufficient Equilibration Time

Stopping before true equilibrium under-estimates transfer into the organic phase, especially for larger molecules

Wrong Solvent System

Octanol may not represent every biological barrier —

skin, GI mucus, and CNS membranes can need different

reference solvents.

Uncontrolled / Unbuffered pH

Without a buffer, ionization shifts mid-experiment, turning a P measurement into an uncontrolled mix of P and D.

Interfacial Adsorption

Surface-active solutes adsorb at the oil-water interface rather than truly partitioning, inflating apparent recovery

Temperature Drift

KD is temperature-dependent; assays run at inconsistent temperatures are not directly comparable