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Medicinal Chemistry > Lecture 2 - Drug Solubility > Flashcards

Lecture 2 - Drug Solubility Flashcards

1
Q

What state are free bases or acids normally in?

A

Liquid

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2
Q

What does hygroscopic mean?

A

Absorbs moisture from air

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3
Q

Drug absorption across biological membranes is better in the ____ state

A

Unionized

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4
Q

Are lipophilic drugs polar?

A

Non-polar

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5
Q

How does a chemical dissolve in a particular solvent?

A

The compound forms attractive forces with the solvent molecules

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6
Q

What is one way to estimate solubility of a drug?

A

Examine its structure

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7
Q

How can you alter the solubility of a drug?

A
  • Add acid or base to make the drug into a salt
  • Add substituents that are very water soluble
  • Alter dosage form
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8
Q

What types of water soluble substituents should you add to alter solubility?

A
  • Add groups that are H-bond donors and acceptors

- Add groups that can ionize

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9
Q

Which forces are the weakest?

A

Dispersion/london forces

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10
Q

Dispersion forces are important for interaction between ____ groups

A

Nonpolar

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11
Q

Are dispersion forces the same as van der waals attractions?

A

No, van der waals attractions include dispersion, dipole-dipole, and others

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12
Q

What causes dispersion forces to increase?

A
  • Increased size of molecule

- Increased total area for interaction between molecules

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13
Q

Methane, ethane, and propane are gases; butane, hexane, and octane are liquids; long chain hydrocarbons are waxes (solids). Why?

A
  • Molecular weight

- Increased dispersion forces between them

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14
Q

Dispersion forces occur between _____

A

Induced and instantaneous formed dipoles

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15
Q

Dipole-dipole interactions occur between ____

A

Permanent dipoles

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16
Q

What are H-bonds?

A

A special kind of dipole-dipole

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17
Q

Are normal dipole-dipole or H-bonds stronger?

A

H-bonds

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18
Q

H-bonds occur between ___

A

An electronegative atom w/ an attached hydrogen (donor) and another electronegative atom w/ a lone pair of electrons (acceptor)

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19
Q

H-bonding is a major contributor to ______

A

Hydrophilicity

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20
Q

Molecules with many H-bond donors and acceptors are ____ water soluble

A

More

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21
Q

Are intermolecular H-bonds between drug molecules in solutions of water common and why?

A
  • No
  • 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
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22
Q

Why do intramolecular bonds form in water?

A

B/c the H-bonding pair is always part of the same molecule, so they are always in close proximity and can more easily form H-bonds

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23
Q

What are the 2 types of intermolecular bonds and which is more common?

A

1) Drug + drug (less common)

2) Drug + water (more common)

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24
Q

What is the difference between intermolecular and intramolecular bonds?

A

Intermolecular occurs between 2 separate molecules; intramolecular occurs between 2 atoms of the same molecules

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25
What must happen to the drug and H-bonds for absorption to occur?
- H-bonds must be broken | - Drug must be in unionized form
26
Is it favourable to break H-bonds with water?
No
27
Is it good to have a lot of H-bond donors and acceptors in a solution?
No because the drug won't absorb
28
What is ionic bonding?
Electrostatic attraction btwn cations and anions
29
Ionic bonding is common in ____
Salts of organic molecules
30
What is strongest type of attractive force?
Ionic bonding
31
What is ion-dipole bonding?
Electrostatic attraction btwn cation/anion and dipole
32
Ion-dipole bonding is an important attraction btwn ____
Drugs and water
33
What are some weak H-bond acceptors?
Sulfur, chlorine, and fluorine
34
Is SH an H-bond donator?
No
35
Is the N of an amide an H-bond acceptor?
No
36
Do covalent bonds occur between drugs and solvent?
No
37
What determines solubility of a drug?
The lipophilic and hydrophilic groups w/in its structure
38
How can relative solubility of a drug be determined?
Partition coefficient
39
What is the formula for the partition coefficient?
P = [drug]octanol / [drug]water
40
What is octanol?
A lipophilic organic solvent
41
What is pi with respect to partition coefficient?
The log of the partition coefficient
42
What is relative solubility of a drug?
The sum of the contributions of each group of a molecule to its overall solubility
43
How do functional groups w/ N and O affect solubility and why?
- Generally increase water solubility | - They polarize the molecule and act as H-bond acceptors and donors
44
How do functional groups w/ ionizable groups affect solubility?
Increase water solubility
45
How do functional groups w/ alkyl chains, rings, and aromatic groups affect solubility?
Increase lipid solubility
46
What does a negative pi value mean?
Functional group is hydrophilic
47
What does a positive pi value mean?
Functional group is lipophilic
48
What is the pi value for a carbon in an aliphatic chain?
+0.5 (must count that for each carbon)
49
What does it mean when a compound has a logPcalc value greater than +0.5?
It is considered water insoluble (lipophilic)
50
What does it mean when a compound has a logPcalc value less than or equal to +0.5?
Considered water soluble
51
How does a high logP affect binding to an enzyme/receptor?
Increases binding
52
How does a high logP affect aqueous solubility?
Decreases it
53
How does a high logP affect binding to P450 metabolizing enzymes?
Increases binding
54
How does a high logP affect absorption through membrane?
Increases absorption
55
How does a high logP affect binding to blood/tissue proteins?
Increases binding, so less drug is free to act
56
How does a high logP affect binding to heart ion channels and what does this lead to?
- Increases binding | - Causes cardiotoxicity
57
logP is one of the most important factors effecting _____
Drug potency
58
What happens once a drug crosses a membrane?
Local blood flow will transport the drug, which displaces eq'm so as to drag more drug across the membrane
59
Is a good drug very hydrophilic?
- Needs to be hydrophilic enough for reasonable water solubility and to make a dosage form - Needs to be lipophilic enough to be membrane permeable
60
Why do drugs need to be hydrophilic?
- To have sufficient solubility, so they dissolve out of solid dosage forms (dissolution) - Needs some solubility in biological fluids to transport to the site of action (distribution)
61
Why can't hydrophilic drugs be absorbed across membranes?
They will form too many interactions w/ water that need to be broken for absorption to occur
62
What controls ionization?
pKa and external pH
63
When will a drug need to be in its IONIZED form?
Distribution through blood
64
When will a drug need to be in its UNIONIZED form?
- Receptor binding | - Distribution into another tissue type
65
What does a low pH mean for ionization of acidic drugs?
Low pH will increase the unionized form of the drug
66
What does a low pH mean for ionization of basic drugs?
Low pH will increase the ionized form
67
What occurs when a lipophilic compound is put in water?
It disturbs the network of water-water H-bonds, causing fewer but stronger water-water H-bonds at the non-polar/water interface called INTERFACIAL TENSION
68
What occurs at the non-polar/water interface?
Water molecules are more orientationally restricted, causing decreased entropy and increased G making dissolution of non-polar compounds into water unfavourable

Medicinal Chemistry (14 decks)

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