More Introduction

Question 1

Why is solubility important?

Answer 1

Formulation; free bases and acids are often liquid (oils). Salts are also soluble in water, so they dissolve out of solid dosage forms. However, drug absorption across biological membranes is better in unionized state. Finally transit to the site of action may require the drug to be ionized and binding to the receptor could require either ionized or unionized form

Question 2

How do we classify drugs (based on solubility)?

Answer 2

Hydrophilic (water loving, polar)
Lipophobic (lipid hating, polar)
Lipophilic (lipid loving, non polar)
Hydrophobic (water hating, non polar)

Question 3

What is required for dissolution of a chemical?

Answer 3

For a chemical to dissolve in a particular solvent, the compound must form attractive forces with the molecules of the solvent

Question 4

How do we estimate solubility?

Answer 4

It is possible to estimate the solubility properties of a drug by examining its structure. Some functional groups promote and others reduce interaction (bonds) with the solvent

Question 5

Can we alter the solubility of a drug?

Answer 5

We can use an acid or a base to make the drug into a salt. We can add substituents that are very water soluble (but there’s a limit to this). Typically this means: adding groups that are H-bond donors and acceptors and/or adding groups that can ionize. We can also alter the dosage form

Question 6

Name the attractive forces involved in solubilization

Answer 6

1. Disperson forces (aka London Forces)
2. a) Dipole-dipole bonding
3. b) H-bonding (a special kind of dipole-dipole bonding)
4. Ionic bonding
5. Ion-dipole bonding

Question 7

What are dispersion forces?

Answer 7

Weak bonds that occur between induced and instantaneous formed dipoles. They are often wrongly referred to as Van der Waals forces

Question 8

Why are dispersion forces important?

Answer 8

They are important for interaction between non polar groups (e.g., hydrocarbons). However, some component of attraction between all molecules is dispersion.

Question 9

Describe dispersion forces

Answer 9

Generally they get larger as the molecule gets bigger. Generally they increase as the total area for interaction between molecules increases.

Question 10

What are dipole-dipole interactions?

Answer 10

Stronger bonds that happen between permanent dipoles

Question 11

What are H-bonds?

Answer 11

They are stronger than ordinary dipole-dipole interactions. They happen between atoms with highly electronegative atoms attached to H. It’s a major contributor to hydrophilicity, hence molecules with many H-bond donors and acceptors are more water soluble (there’s a limit to this)

Question 12

Explain how H-bonds occur (i.e., acceptors and donors)

Answer 12

H-bonds happen between an electronegative atom with an attached hydrogen (the donor) and another electronegative atom with a lone pair of electrons (the acceptor)

Question 13

Describe the geometry of an H-bond

Answer 13

The ideal geometry between the lone pair on the acceptor and the hydrogen of the donor is 180º but they can form weak interactions at 130º or less
H-bond length is 1.5 to 2.2 angstroms (while typical covalent bond is between 1 and 1.5 angstroms)

Question 14

What are examples of H-bond acceptors?

Answer 14

Carboxylic acid (ionized and unionized)
Phosphate
Ethers
Esters
Amides (only the oxygen, not the nitrogen!)
Ketone
Aldehyde
Alcohols
Amines

Question 15

What are not H-bond acceptors?

Answer 15

S, Cl and F are surprisingly weak H-bond acceptors because halogens are so electronegative that they want to hang onto their electrons (unideal geometry)
The N of amides is not an acceptor (partial double bond character)
SH is not an H-bond acceptor

Question 16

What is more common intermolecular H-bonds between drug molecules or intramolecular H-bonds formed in water?

Answer 16

H-bonds between drug molecules in solutions of water are uncommon. There are lots of water molecules that out compete intermolecular H-bonding. A drug would have to break H-bonds with water first (which requires energy) in order to form new H-bonds with other drug molecules in solution. Intramolecular H-bonds form in water because the H-bonding pair is always part of the same molecule they are always in close proximity and more easily formed. This is sometimes referred to as the effect of local concentration

Question 17

How do H-bonds affect absorption?

Answer 17

A drug forming many H-bonds with water means that those bonds need to be broken and the drug must be unionized for absorption to happen. Breaking H-bonds is thermodynamically unfavourable. In general, you do not want to have too many hydrogen bond donors or acceptors or the drug will not absorb

Question 18

What is ionic bonding?

Answer 18

Electrostatic attraction between cations and anions
Common in salts of organic molecules
They are strong (700-800 kJ/mole)

Question 19

What is ion-dipole bonding?

Answer 19

Electrostatic between a cation/anion and a dipole
Can be strong (40-600 kJ/mole)
Important attraction between drugs and water

Question 20

Where do we find covalent bonds in medicinal chemistry?

Answer 20

They don’t happen between drugs and solvents
They can be a part of drug receptor interactions, however this is rare and generally avoided (by altering the protein with the drug, it would trigger an immune response because the immune system would no longer recognize the protein as “self”)
Covalent bonds are strong (150-1100 kJ/mole)

Question 21

How can solubility be predicted?

Answer 21

The solubility of a drug is a function of the lipophilic and hydrophilic groups within its structure. These groups determine the extent of interaction of the drug with lipophilic or hydrophilic solvent. The relative solubility of a drug can be determined with the partition coefficient

Question 22

Mathematically, what is the partition coefficient?

Answer 22

P= [drug] in octanol/[drug] in water

Values are often reported as log P = pi

Question 23

How can solubility be predicted mathematically?

Answer 23

There are mathematical formulae that can estimate the relative solubility of an organic molecule based upon substituents on a molecule. The relative solubility of a drug is the sum of the contributions to the overall solubility

Question 24

What does increasing the logP affect?

Answer 24

It increases the binding to enzymes/receptors (good)
It decreases aqueous solubility (bad)
It increases binding to P450 metabolizing enzymes (bad)
It increases absorption through membrane (good)
It increases binding to blood/tissue proteins - less drug free to act (bad)
It increases binding to heart ion channels - cardiotoxicity (bad)

Question 25

What is something important that logP affects?

Answer 25

One of the most important factors affecting the potency of a drug is the logP

Question 26

How do drugs cross membranes?

Answer 26

Passive diffusion can happen through aqueous channels (i.e., channels that are aqueous on the inside)
Passive diffusion through lipid (this is the most important mechanism of absorption across membranes)
Facilitated transport via transporters that transport endogenous compounds (e.g., amino acid transporters - note this mechanism is important when drugs “look” like endogenous compounds; if the drug “looks” like an amino acid (particularly aromatic drugs), it may be taken up via an amino acid transporter

Question 27

How does local blood flow affect the crossing of biological membranes?

Answer 27

Local blood flow will transport drugs that just crossed biological membranes displacing the equilibrium so as to drag more drug across the membrane

Question 28

How does solubility affect drug absorption/why is it important?

Answer 28

A good drug has a balance between lipophilic and polar (ionized) forms. Drugs need to be hydrophilic enough for reasonable water solubility, but they also need to be lipophilic enough to be membrane permeable.
Both pKa and pi play important roles in determining drug absorption

Question 29

Why do drugs need to be hydrophilic?

Answer 29

To have sufficient solubility so that they dissolve out of solid dosage forms (dissolution)
Also needs to have some solubility in biological fluids to transport to the site of action (blood plasma, etc.; distribution)

Question 30

What happens to drugs that are too hydrophilic?

Answer 30

They won’t be absorbed across biological membranes (absorption) - this is because they form too many interactions with water that need to be broken before absorption can occur

Question 31

Why is ionization important?

Answer 31

The ability to ionize represents a good happy medium between having sufficient lipophilicity to cross membranes when unionized and being water soluble enough for dissolution and distribution when ionized. A drug can have hydrophilic properties when ionized and the same drug can have hydrophobic properties when unionized

Question 32

What controls ionization?

Answer 32

pKa and pH

Question 33

What is the pH of the: blood, saliva/sweat, stomach (fasting), stomach (fed), duodenum (fasting), duodenum (fed), colon?

Answer 33

Blood: 7.4
Saliva/sweat: 6
Stomach (fasting): 1
Stomach (fed): 3-7
Duodenum (fasting): 5
Duodenum (fed): 6
Colon: 7-8

Question 34

What conditions promote the unionized form of an acidic drug?

Answer 34

For acidic drugs decreasing the pH (addition of acid or hydrogen ions) will increase the unionized form of the drug which is generally better at crossing biological membranes

Question 35

What conditions promote the unionized form of a basic drug?

Answer 35

For basic drugs, increasing the pH (addition of base or hydroxide ions) will increase the unionized form of the drug which is generally better at crossing biological membranes

Question 36

What happens when you mix water and oil?

Answer 36

Putting a lipophilic compound in water disturbs the network of water-water hydrogen bonds. You then get fewer, but stronger, water-water H-bonds at the non-polar/water interface. This is called interfacial tension (it’s similar to surface tension). Water molecules at the interface are more orientationally restricted which results in a decrease in entropy (delta S). This increases free energy (delta G = delta H - T*deltaS) making dissolution of non-polar compounds into water unfavourable