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Flashcards in More Introduction Deck (36):
1

Why is solubility important?

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

2

How do we classify drugs (based on solubility)?

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

3

What is required for dissolution of a chemical?

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

4

How do we estimate solubility?

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

5

Can we alter the solubility of a drug?

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

6

Name the attractive forces involved in solubilization

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

7

What are dispersion forces?

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

8

Why are dispersion forces important?

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

9

Describe dispersion forces

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

10

What are dipole-dipole interactions?

Stronger bonds that happen between permanent dipoles

11

What are H-bonds?

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)

12

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

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)

13

Describe the geometry of an H-bond

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)

14

What are examples of H-bond acceptors?

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

15

What are not H-bond acceptors?

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

16

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

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

17

How do H-bonds affect absorption?

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

18

What is ionic bonding?

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

19

What is ion-dipole bonding?

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

20

Where do we find covalent bonds in medicinal chemistry?

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)

21

How can solubility be predicted?

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

22

Mathematically, what is the partition coefficient?

P= [drug] in octanol/[drug] in water
Values are often reported as log P = pi

23

How can solubility be predicted mathematically?

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

24

What does increasing the logP affect?

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)

25

What is something important that logP affects?

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

26

How do drugs cross membranes?

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

27

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

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

28

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

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

29

Why do drugs need to be hydrophilic?

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)

30

What happens to drugs that are too hydrophilic?

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

31

Why is ionization important?

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

32

What controls ionization?

pKa and pH

33

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

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

34

What conditions promote the unionized form of an acidic drug?

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

35

What conditions promote the unionized form of a basic drug?

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

36

What happens when you mix water and oil?

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