LogP vs LogD

  • logD instead of logP – more valuable predictor during drug discovery (when lipophilicity is correlated with in vivo permeability).
  • Partition coefficient (P)- measure of differential solubility of a compound in two immiscible solvents. logP is the descriptor of lipophilicity for neutral compounds, or where the compound exists in a single form.
  • Distribution coefficient (D) – measure of pH-dependant differential solubility of all species in the octanol/water system. It is the appropriate descriptor for ionizable compounds. 
  • The ionization of a compound greatly affects octanol-water partitioning and that lipophilicity cannot be simplified to a constant. Scientist must take care in measurement of logP at a pH where the compound exists in its neutral form , and/or report logD at a specific pH.
  • Example-conclusion we draw from predicting the logD profile of 5-methoxy-2-(1-piperidin-4-ylpropyl)pyridine is contradictory to that derived from  logP alone.
  • Neutral form of 5-Methoxy-2-(1-piperidin-4 ylpropyl) pyridine is almost non-existent at physiologically relevant pH (1–8). The neutral form only dominates after ~pH 13.
  • Predicted logP is 2.7 leads to conclusion that compound shows a preference to be associated with the lipid phase (>30 fold affinity for octanol over water), and will permeate through biological membranes spontaneously.
  • Negative values of logD (-1.44 to 0) in the physiologically relevant pH range (pH 1–8) leads to conclude that this compound would be more susceptible to higher aqueous solubility and of lower lipophilicity and poor membrane permeability. Lipophilicity of the compound is low below pH 12 when the majority of the compound exists in an ionized form.
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True vs Apparent Partition Coefficient

  • True partition coefficient is defined for an unionized/ neutral system (assumes that all drug is present in ionized form).
  • Apparent partition coefficient is defined for an ionized system.
  •  Papp = P x funionized
  • Example- 100 mg drug is added to an immiscible mixture of water and organic solvent. 40 mg drug is found in organic phase and remaining drug in water phase is (100-40) = 60 mg. The mass of the ionized and unionized drug in water= 40 mg and 20 mg repectively.
  • The concentration of the drug in the organic phase (in 50.0 mL of organic solvent) is (40/50) = 0.8 mg/L.
  • The concentration of unionized drug in water is (20/50) = 0.4 mg/L.
  • Concentration of the total drug in water is (60/50) = 1.2 mg/L.
  • The percentage of the drug extracted into the organic phase is (40 mg/ 100 mg) x 100 = 40%.
  • True partition coefficient of the unionized drug is (drug in organic phase / unionized drug in water) = 0.8/0.4 = 2.
  • Apparent partition coefficient is (drug in organic phase / total drug in water phase) = (0.8/1.2) = 0.67.
  • Papp = P x funionized
  • Papp = 2 x (20/60) =2x 0.33 = 0.67

REFERENCES

https://www.acdlabs.com/download/app/physchem/logp_vs_logd.pdf

 

  • https://www.differencebetween.com/difference-between-true-and-apparent-partition-coefficient/