Physiochemical reactions

Question 1

What are solutions (3)

Answer 1

1. Liquids that can dissolve solids, liquids and gases to make a solution
2. Solution – a mixture of two or more components that forms a homogeneous monophasic system
3. A solution can occur in any phase, but we will be focusing on the liquid phase

Question 2

What are the types of solutions (3)

Answer 2

1. Saturated solution – Solute is in equilibrium with the solid (or other distinct component)
2. Unsaturated or sub-saturated solution – the dissolved solute is in a concentration below that necessary for complete saturation
3. Supersaturated solution – contains more of the solute than is normal (at a defined temperature)

Question 3

What is the definition of solubility (2)

Answer 3

1. The maximum amount of a substance that can be dissolved in water (usually at a defined temperature, pressure, pH, crystal form, etc.)
2. The most relevant solubility is from the most stable crystal form (polymorph) – the least soluble form – This is likely to be the form in the final product as the most reliable to manufacture

Question 4

What happens to factors that destabilise the solid state (1)

Answer 4

Factors that destabilise the solid state (lattice energy, amorphous versus crystalline, etc.) increase the amount in the solution.

Question 5

What are the properties of water that affect solubility (5)

Answer 5

1. Water is polar
2. It has two potential hydrogen bond donors.
3. Hydrogen bond donor = group containing polarised hydrogen (H-electronegative atom such as N, O, F)
4. Has two potential hydrogen bond acceptors
5. A hydrogen bond acceptor is an atom with lone pairs of electrons that can form attractive interactions with hydrogen bond donors.

Question 6

What type of compounds does water prefer to dissolve (3)

Answer 6

1. polar compounds
2. compounds with hydrogen bond donors
3. compounds with hydrogen bond acceptors in them

Question 7

How do charge groups affect solubility (4)

Answer 7

1. The most polar groups are charged groups.
2. Some chemical groups are acidic or basic and can exist in charged forms.
3. Charged forms are much more soluble than uncharged.
4. pH, therefore, changes the amount of compound that can dissolve

Question 8

What is intrinsic solubility (1)

Answer 8

Is the equilibrium solubility of the free acid or free base form of an ionisable compound at a pH where it is fully un-ionised

Question 9

What is the two-phase property of solubility (4)

Answer 9

1. Certain structural types prefer to associate with themselves rather than with water.
2. They prefer to be in a solid state.
3. Non-polar groups
4. Dominated by hydrocarbon groups - hydrophobic

Question 10

What are hydrophobic groups (4)

Answer 10

1. repel water
2. Tend to contain only carbon and hydrogen.
3. Include aromatic rings like benzene.
4. Halogen atoms, especially Cl, Br and I

Question 11

What are polar groups (3)

Answer 11

1. Tend to contain more electronegative elements O, N, F.
2. Include hydrogen bond donors and acceptors.
3. Include acidic and basic groups that can become charged.

Question 12

What is the solid-state effect (2)

Answer 12

1. Sometimes, polar groups prefer to interact with other polar groups in the molecule than with water – they like to be in a solid state.
2. Sometimes, molecules do not pack so well.

Question 13

What shapes do molecules have that don’t pack together well in the solid state (3)

Answer 13

1. Molecules that do not pack well are unsymmetrical – molecules with chiral centres.
2. Molecules that do not pack well have uneven shapes.
3. Molecules that do not pack well are hard to diffract use-CryoEM

Question 14

What shapes do molecules have that pack together well in the solid state (3)

Answer 14

1. Symmetrical
2. Flat
3. Disrupting packing can increase solubility.

Question 15

What is permeability (3)

Answer 15

1. Permeability involves compounds moving from an aqueous to a lipid environment - aqueous to hydrophobic.
2. To be permeable, compounds must then move back out of the membrane into water.
3. Many drugs need to be soluble in water and hydrophobic solvents.

Question 16

What is partitioning (2)

Answer 16

1. Some solvents are essentially completely insoluble in one another – immiscible.
2. Some hydrophobic solvents and water (e.g. Oil and vinegar)

Question 17

What is the partition coefficient (4)

Answer 17

1. The partition coefficient was first defined in “On the Laws that Operate for the Partition of a Substance between two Solvents”
2. The partition coefficient can be very sensitive to temperature.
3. Immiscible solvents can be used to measure how easily a compound can move from one type of environment into another.
4. If a hydrophobic solvent and water, this can be a good “model” for cell membrane permeability –Aqueous to hydrophobic.

Question 18

How do we measure partitioning between hydrophobic and hydrophilic groups? (3)

Answer 18

1. D = Conc. in hydrophobic layer/Conc. In aqueous layer
2. D = distribution coefficient
3. Usually use Log10(D) called LogD

Question 19

How do we measure partitioning between acidic and basic groups? (4)

Answer 19

1. P= Conc. of neutral form in hydrophobic later/Conc. In neutral form in an aqueous layer
2. P = partition coefficient
3. Usually use log10(P) called logP
4. For compounds without acidic or basic groups, logP = logD.

Question 20

What do logP values mean (4)

Answer 20

1. A compound with a higher log P value prefers to be in the hydrophobic solvent more than a compound with a lower logP
2. A compound with a higher logP tends to be less soluble in water.
3. A compound with a higher logP tends to move into membrane environments more readily.
4. BUT! 1-octanol is not the same as any of these other environments

Question 21

What log P values are acceptable for (most) drugs (3)

Answer 21

1. Drug not absorbed - LogP less than 2
2. Good ADME - LogP greater than 2 but less than 5
3. Drug accumulation-toxicity -LogP greater than 5

Question 22

According to Lipinski’s rule, what are the criteria that an orally active drug must not violate more than one of (6)

Answer 22

1. No more than 5hydrogen bond donors (the total number ofnitrogen–hydrogen andoxygen-hydrogenbonds)
2. No more than 10hydrogen bond acceptors (allnitrogen oroxygenatoms)
3. Amolecular mass of less than 500daltons
4. Anoctanol-water partition coefficient [6] (logP) that does not exceed 5
5. Note that all numbers are multiples of five, which is the origin of the rule’s name.
6. Many exceptions are known natural products.

Question 23

How do shape and size affect drug molecules (3)

Answer 23

1. shape and size are also important to fit into the target site
2. Drug molecules ameliorate diseases by binding to target sites to modulate their biological function.
3. Knowledge of the 3D shape of the freeligand is therefore valuable in guiding thedesignof the bestdrugmolecules.