Chapter 6. pKa & Chapter 7. Solubility 2015.10.07 목희연 Chapter 6. pKa 6.1 • pKa Fundamentals 6.2 • pKa Effets 6.3 • pKa Case Studies 6.4 • Structure Modification Strategies for pKa • Problems Chapter 6. pKa 6.1 pKa Fundamentals • pKa = -logKa • For acids: • For bases: 6.1 pKa Fundamentals • Henderson-Hasselbach equation 6.2 pKa Effets • Highly permeable compounds Low solubility Acidic compound with pKa 5 6.3 pKa Case Studies • Effect of pKa and size on activity 6.3 pKa Case Studies • Effect of pKa on activity of a structural series 6.3 pKa Case Studies • Basic drugs tend to permeate the bloodbrain barrier 6.3 pKa Case Studies • Acidity and basicity effects water solubility 6.4 pKa Case Studies • At acids :adding α-halogen or EWG → increase acidity • At bases :adding EDG → increase basicity :adding aromatic group → decrease basicity Problems • 1. For acids, as pH decreases, are there: (a) more anions, (b) more neutral molecules, (c) higher solubility, (d) lower solubility, (e) higher permeability, (f) lower permeability? • 2. For bases, as pH decreases, are there: (a) more cations, (b) more neutral molecules, (c) higher solubility, (d) lower solubility, (e) higher permeability, (f) lower permeability? • 3. At pH 6.8, a basic compound of pKa 9.5 is mostly in what form?: (a) ionized, (b) neutral. Problems • 4. For benzoic acid (pKa 4.2), estimate the degree of ionization in the fasted state for the stomach, duodenum, and blood. For HA=H++A−, use the relationship: [HA]/[A−]=10(pKa−pH) Location pH [HA]/[A−] = 10(pKa-pH) Ionization Stomach 1.5 102.7 Neutral Duodenum 5.5 10-1.3 (-) Blood 7.4 10-3.2 (-) Problems • 5. For piperazine (pKa 9.8), estimate the degree of ionization in the fasted state for the stomach, duodenum, and blood. For BH+ =H++B, use the relationship: [BH+]/[B]=10(pKa−pH) Location pH [BH+]/[B] = 10(pKa-pH) Ionization Stomach 1.5 108.3 (+) Duodenum 5.5 104.3 (+) Blood 7.4 102.4 (+) Problems • 6. If the pH is 2 units above the pKa of an acid, the predominant species is: (a) neutral, (b) anion. • If the pH is 2 units below the pKa of a base, the predominant species is: (c) neutral, (d) cation. Chapter 7. Solubility 7.1 • Solubility Fundamentals 7.2 • Effects of Solubility 7.3 • Effets of Physiology on Solubility and Absorption 7.4 • Structure Modification Strategies to Improve Solubility 7.5 • Strategies for Improving Dissolution Rate 7.6 • Salt Form • Problems Chapter 7. Solubility • Solubility is one of the most important properties in drug discovery. • Negative effects of low-solubility compounds: - Poor absorption and bioavailability after oral dosing - Insufficient solubility for IV dosing - Artificially low activity values from bioassays - Erratic assay results (biological and property methods) - Development challenges (expensive formulations and increased development time) - Burden shifted to patient (frequent high-dose administrations) 7.1 Solubility Fundamentals Compound structure Physical state of compound that is introduced into solution • Solid: Amorphous, crystalline, polymorphic form • Liquid: Predissolved in solvent (e.g., dimethylsulfoxide [DMSO]) Composition and physical conditions of solvent(s) • Types of solvents • Amount (%) of co-solvents • Solution components (e.g., salts, ions, proteins, lipids, surfactants) • pH • Temperature Methods of measurement • Equilibration time • Separation techniques (e.g., filter, centrifuge) • Detection (e.g., ultraviolet, mass spectrometry, turbidity) 7.1 Solubility Fundamentals • Structural properties affect solubility -Lipophilicity, Size, pKa, Crystal lattice energy • Log S = 0.8 – LogPOW – 0.01(MP-25) LogP increses by 1 unit or Melting Point increases by 100℃ Solubility decreases 10-fold 7.1 Solubility Fundamentals • Derivation of Henderson-Hasselbalch equation for solubility S = S0 (1+10(pH-pKa)) (Acid) S = S0 (1+10(pKa-pH)) (Base) 7.2 Effects of Solubility • Solubility classification ranges for human oral absorption <10㎍/mL Low solubility 10-60㎍/mL >60㎍/mL Moderate solubility High solubility • Solubility for animal dosing 7.4 Structure Modification Strategies to Improve Solubility • How to improve solubility through structure modification 7.4 Structure Modification Strategies to Improve Solubility • Add Ionizable Groups SGF, simulated gastric fluid (pH 1.2) PB, phosphate buffer (pH 7.4) 7.4 Structure Modification Strategies to Improve Solubility • Reduce Log P Maximum concentrations in the blood 7.4 Structure Modification Strategies to Improve Solubility • Add Hydrogen Bonding introducing hydrogen bond donors or acceptors ex) OH, NH2 7.4 Structure Modification Strategies to Improve Solubility • Add Polar Group 7.4 Structure Modification Strategies to Improve Solubility • Reduce Molecular Weight 7.4 Structure Modification Strategies to Improve Solubility • Out-of-Plane Substitution 7.4 Structure Modification Strategies to Improve Solubility • Construct a Prodrug 7.5 Strategies for Improving Dissolution Rate Dissolution rate how fast a compound can dissolve into solution 7.6 Salt Form Salt forms can modify physicochemical properties (e.g., dissolution rate, crystallinity, hygroscopicity) p-amino-salicylic acid mechanical properties (hardness, elasticity, etc.) Problems • 1. A free acid (pKa4) and its sodium salt are tested for solubility. Will they have the same solubility in water? Why? Will they have the same solubility in pH 7.4 potassium phosphate buffer? In pure water, the pH will change when the compound is added, so salt will be more soluble / Same solubility • 2. Compound A was dosed in rat as an oral suspension at 100 mg/kg, 200 mg/kg, and 300 mg/kg. Cmax and AUC of all three doses were the same. What is the potential cause? Solubility-limited absorption • 3. An acidic compound has intrinsic solubility of 2 μg/mL and pKa of 4.4. What is the approximate solubility of the compound at pH 7.4? S = S0 (1+10(pH-pKa)) 2,000 μg/mL • 4. Why does the solubility of subsequent analog compounds in a lead series tend to be lower during lead optimization? In order to improve target binding, lipophilic groups are often added to the template, which reduces aqueous solubility Problems • 5. List structural properties that affect solubility. Lipophilicity, molecular size, pKa, charge, crystal lattice energy • 6. What is the difference between solubility and dissolution rate? Solubility is the highest sustainable concentration; dissolution rate is how much of the compound dissolves per unit time • 7. Structural modifications to improve solubility often decrease what other property? Permeability • 8. What usually is the most successful structure modification to improve solubility? Add ionizable group • 9. Making a salt improves the: (a) intrinsic solubility, (b) dissolution rate. Problems • 10. For the following lead structure, what structural modifications could you make to improve solubility? Remove groups not needed for binding (reduce lipophilicity and MW) Add amines to existing chains Add H-bond donors and acceptors in locations that also increase binding • 11. Low solubility can cause which of the following?: (a) low oral bioavailability, (b) low metabolism, (c) low permeability, (d) increased burden on patients, (e) less expensive drug product formulation.