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Medicinal Chemistry > Lecture 2 - Drug Solubility > Flashcards

Lecture 2 - Drug Solubility Flashcards

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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
Q

What must happen to the drug and H-bonds for absorption to occur?

A
  • H-bonds must be broken

- Drug must be in unionized form

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26
Q

Is it favourable to break H-bonds with water?

A

No

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27
Q

Is it good to have a lot of H-bond donors and acceptors in a solution?

A

No because the drug won’t absorb

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28
Q

What is ionic bonding?

A

Electrostatic attraction btwn cations and anions

29
Q

Ionic bonding is common in ____

A

Salts of organic molecules

30
Q

What is strongest type of attractive force?

A

Ionic bonding

31
Q

What is ion-dipole bonding?

A

Electrostatic attraction btwn cation/anion and dipole

32
Q

Ion-dipole bonding is an important attraction btwn ____

A

Drugs and water

33
Q

What are some weak H-bond acceptors?

A

Sulfur, chlorine, and fluorine

34
Q

Is SH an H-bond donator?

A

No

35
Q

Is the N of an amide an H-bond acceptor?

A

No

36
Q

Do covalent bonds occur between drugs and solvent?

A

No

37
Q

What determines solubility of a drug?

A

The lipophilic and hydrophilic groups w/in its structure

38
Q

How can relative solubility of a drug be determined?

A

Partition coefficient

39
Q

What is the formula for the partition coefficient?

A

P = [drug]octanol / [drug]water

40
Q

What is octanol?

A

A lipophilic organic solvent

41
Q

What is pi with respect to partition coefficient?

A

The log of the partition coefficient

42
Q

What is relative solubility of a drug?

A

The sum of the contributions of each group of a molecule to its overall solubility

43
Q

How do functional groups w/ N and O affect solubility and why?

A
  • Generally increase water solubility

- They polarize the molecule and act as H-bond acceptors and donors

44
Q

How do functional groups w/ ionizable groups affect solubility?

A

Increase water solubility

45
Q

How do functional groups w/ alkyl chains, rings, and aromatic groups affect solubility?

A

Increase lipid solubility

46
Q

What does a negative pi value mean?

A

Functional group is hydrophilic

47
Q

What does a positive pi value mean?

A

Functional group is lipophilic

48
Q

What is the pi value for a carbon in an aliphatic chain?

A

+0.5 (must count that for each carbon)

49
Q

What does it mean when a compound has a logPcalc value greater than +0.5?

A

It is considered water insoluble (lipophilic)

50
Q

What does it mean when a compound has a logPcalc value less than or equal to +0.5?

A

Considered water soluble

51
Q

How does a high logP affect binding to an enzyme/receptor?

A

Increases binding

52
Q

How does a high logP affect aqueous solubility?

A

Decreases it

53
Q

How does a high logP affect binding to P450 metabolizing enzymes?

A

Increases binding

54
Q

How does a high logP affect absorption through membrane?

A

Increases absorption

55
Q

How does a high logP affect binding to blood/tissue proteins?

A

Increases binding, so less drug is free to act

56
Q

How does a high logP affect binding to heart ion channels and what does this lead to?

A
  • Increases binding

- Causes cardiotoxicity

57
Q

logP is one of the most important factors effecting _____

A

Drug potency

58
Q

What happens once a drug crosses a membrane?

A

Local blood flow will transport the drug, which displaces eq’m so as to drag more drug across the membrane

59
Q

Is a good drug very hydrophilic?

A
  • 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
Q

Why do drugs need to be hydrophilic?

A
  • 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
Q

Why can’t hydrophilic drugs be absorbed across membranes?

A

They will form too many interactions w/ water that need to be broken for absorption to occur

62
Q

What controls ionization?

A

pKa and external pH

63
Q

When will a drug need to be in its IONIZED form?

A

Distribution through blood

64
Q

When will a drug need to be in its UNIONIZED form?

A
  • Receptor binding

- Distribution into another tissue type

65
Q

What does a low pH mean for ionization of acidic drugs?

A

Low pH will increase the unionized form of the drug

66
Q

What does a low pH mean for ionization of basic drugs?

A

Low pH will increase the ionized form

67
Q

What occurs when a lipophilic compound is put in water?

A

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
Q

What occurs at the non-polar/water interface?

A

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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