Physicochemical properties 8.3.2018 LIPOPHILICITY LogP depends on: Molecular volume Dipolarity Hydrogen bond acidity Hydrogen bond basicity LIPOPHILICITY LogP depends on: Molecular volume -related to molecular weight and affects the overall size of the cavity that must be formed in the solvent LIPOPHILICITY LogP depends on: Molecular volume Dipolarity -affects the polar alignment of the molecule with polar solvent (dipole-dipole interaction with molecules of water) Hydrogen bond acidity Hydrogen bond basicity LIPOPHILICITY LogP depends on: Molecular volume Dipolarity Hydrogen bond acidity -hydrogen bond donation – hyrogens with polar bonds (OH, NH2, NH) Hydrogen bond basicity -hydrogen bond acceptance (O, N, F atoms) Both affects the hydrogen bonding rate with environment LIPOPHILICITY LIPOPHILICITY pKA Most of drugs are ionizable Most of drugs are basic pKA pKa determines the degree of ionization and affects both solubility and permeability, but in opposite way pKA pKA pKA Effect of mesomeric effect on sulfonamide activity : most acidic compounds are most potent almost linear dependence pKA Effect of mesomeric effect on sulfonamide activity : most acidic are most potent pKA basic drugs permeates blood-brain barrier, acidic do not so pKA pKa effect on water solubility of bile acids: pKA The strenght of acid can be increased by electron withdrowing group on α carbon (halogen, carboxy, cyano, nitro...) The strenght of base can be decreased by adding conjugated double bond system close to nitrogen (nitrogen lone electron pair is delocalized) Basicity of aniline can be increased by -OCH3 and decreased by -NO2 substitution SOLUBILITY Solubility is a determinant of intestinal absorption and oral bioavailability Solubility is increased by adding ionizable groups or reducing logP and MW Salt formation increse dissolution rate SOLUBILITY Problems of low-soluble compounds: design problem: -lipophillic groups are often added to enhance target binding -most active compounds are often poor soluble SOLUBILITY Structural properties affecting solubility: SOLUBILITY Effect of solubility on oral bioavailability: SOLUBILITY Changing one property affest other properties: SOLUBILITY Permeability tends to vary over a more narrow range than does solubility. The difference between a high-permeability and low-permeability compound can be 50-fold (0.001- 0.05 min-1) The difference between a high-solubility and lowsolubility compound can be million-fold (0.1 µg/mL-100mg/mL) Therefore, if a structural modification improves solubility by 1000-fold while reduces permeability by 10-fold, there will be still 100-fold improvement of absorption SOLUBILITY Approaches to improve solubility – structure modification is the first choice SOLUBILITY Structure modification strategies for solubility improvement: SOLUBILITY 1. Addition of ionizable groups typically basic amine or carboxylic group is added SOLUBILITY 1. Addition of ionizable groups typically basic amine or carboxylic group is added SOLUBILITY 1. Addition of ionizable groups SOLUBILITY 1. Addition of ionizable groups SOLUBILITY 1. Addition of ionizable groups - acids SOLUBILITY 1. Addition of ionizable groups - base SOLUBILITY 1. Addition of ionizable groups - base SOLUBILITY The most active compound in vitro is not necessarily the most active in vivo A succesfull drug candidate posesses balanced potency and suitable physico-chemical properties SOLUBILITY 2. Reduction of logP SOLUBILITY 3. Increasing hydrogen bonding properties SOLUBILITY 3. Increasing hydrogen bonding properties rapid increase of solubility due to disruption of aggregate formation SOLUBILITY 4. Addition of polar group ester or carboxylic group (epoxide hydrolase inhibitors) SOLUBILITY 4. Addition of polar group SOLUBILITY 4. Addition of polar group polyethylene glycol SOLUBILITY 5. Reduction of the molecular weight SOLUBILITY 6. Out-of-plane substitution planar molecules forms tight crystall lettice and aggregates in water solutions SOLUBILITY 6. Out-of-plane substitution SOLUBILITY 7. Prodrug construction addition of carged or polar groups SOLUBILITY 8. Salt formation Solubility of salts are generally higher than of free acid or base After dissolving, free acid or base may crastallize due to pH of environment. However, compound may stay at supersaturated solution and do not precipitate immediately Salt increases bioavailability due to increasing dissolution rate SOLUBILITY 8. Salt formation SOLUBILITY 8. Salt formation SOLUBILITY 8. Salt formation SOLUBILITY 9. Crystalline solid formation structure modification gains crystalline derivatives of liquid active compounds or increases low m.p. PERMEABILITY 95% of drugs permeates by passive diffusion generally, uncharged molecules are able to permeate but small part of ionizated molecules are able to permeate too, while forming neutral pairs with suitable counterions PERMEABILITY PERMEABILITY The only way to improve permeability is structure modification Formulations are not effective in fixing poor permeability PERMEABILITY 1. Reducing ionizable groups PERMEABILITY 2. Increasing lipophilicity PERMEABILITY 3. Isosteric replacement of polar groups tetrazole for carboxylic group PERMEABILITY 3. Isosteric replacement of polar groups isosteres of carboxylic group PERMEABILITY 3. Isosteric replacement of polar groups isosteres of carboxylic group PERMEABILITY 4. Esterification of craboxylic groups PERMEABILITY 5. Reduction of hydrogen bonding and polarity PERMEABILITY 6. Reduction of size PERMEABILITY 6. Reduction of size PERMEABILITY 7. Addition of non-polar side chain increasing membrane affinity by long saturated chain cyclic peptide: PERMEABILITY 7. Addition of non-polar side chain PERMEABILITY 8. Prodrug construction example of modifications increasing lipohilicity/reducing number of ionizable groups