Lecture 3: salt and solubility III

Partition coefficient (P)

measures how much a non-ionized drug prefers fat (lipid) over water

P is a constant at a specific temperature, Usually expressed as log10P or logP

high, positive log P

Lipophilic, prefers fat

low, negative log P

Hydrophilic, prefers water

zero log P

Equal preference for fat and water

log P formula

Dissolution of drug

drug must dissolve in GI fluids so it has to have good water solubility

absorption of drug

needs to cross lipid GI membrane so it has to be lipid soluble

Low log P: More hydrophilic

drug can dissolve in GI fluid but hard to cross lipid membranes

High log P: More lipophilic

drug can cross lipid membrane but bard to dissolve in GI fluid

drug needs a balance

b/t hydrophilicity and lipophilicity for effective oral absorption

4 factors affecting drug absorption (decreases)

Acid Instability

Enzymatic Degradation

Large Molecular Size

First-Pass Metabolism

Acid Instability (Acid-Labile Drugs)

Some drugs are destroyed by stomach acid, makes the drug becomes inactive before it can be absorbed which decreases bioavailability

Enzymatic Degradation

Enzymes in the GI tract can break down drugs before absorption.

This is especially important for proteins and peptides, which can be broken down by digestive enzymes

Large Molecular Size

Large drug molecules have difficulty crossing GI membranes which leads to poor absorption and low bioavailability

First-Pass Metabolism

After absorption, a drug may undergo metabolism in the intestinal wall and liver before reaching systemic circulation which causes decreased oral bioavailability

routes where lipid solubility is important

nasal/oral inhalation, drug for CNS (bbb), topical creams, intramuscular or subcutaneous injections

routes where water solubility is important

IV solution and ophthalmic/otic solution

high lipid solubility has more metabolism

Lipophilic drugs are extensively metabolized by the liver, it converts lipid-soluble drugs into more water-soluble metabolites

Advantages of Increasing Water Solubility

Better Dissolution in the GI Tract

Easier Preparation of Drug Solutions

Higher Drug Concentrations in Urine

Less Metabolism and Fewer Drug Interactions

advantages of increasing lipid solubility

Better GI Membrane Penetration

Better Blood-Brain Barrier (BBB) Penetration

Longer Duration with Depot Injections

Increased Plasma Protein Binding

Better Absorption Through Other Routes

distribution coefficient (D)

measures how a drug distributes between lipid and water environments, including both ionized and non-ionized forms

depends on pH

distribution coefficient (D) formula

Log D = 0 to 3

Optimal range for balanced hydrophilicity/lipophilicity

Log D = 2

Optimal Log D value for blood brain barrier
permeation

Log D < 0

Hydrophilic compounds

Log D > 5

Highly lipophilic compounds

3 main ways to change a drug's water or lipid solubility

1.Use Inorganic or Organic Salts

2.Alter the Drug Structure (Make Analogs)

3.Convert the Drug Into an Ester Prodrug (lipid soluble)

Use Inorganic or Organic Salts

can add water soluble salt to increase dissolution in water or add lipid solubility salts to increase lipid solubility and prolong drug release

drug analog

molecule that has a similar chemical structure to another drug but with small structural modifications

prodrug

inactive or less active form of a drug that gets converted into its active form inside the body

-commonly used lipid-soluble ester prodrugs

Lipinski’s Rule of 5

Molecular weight ≤ 500 Da

log P ≤ 5

Hydrogen bond donors (HBD) ≤ 5

Hydrogen bond acceptors (HBA) ≤ 10

sugars

exceptions to Hydrogen bond donors (HBD) ≤ 5

but have special transportations