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Flashcards in Biopharmaceutics Oral Deck (56)
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1

Describe the simple model of dissolution

- drug molecules diffuse from the saturated diffusion layer into different compartments (e.g. the blood)
- this sets up a concentration gradient
- as the drug molecules move into the bulk fluid from the diffusion layer, more molecules are drawn into the diffusion layer meaning that it will remain saturated (sink conditions)
- the rate of dissolution is the rate limiting step
- sink conditions = first order kinetics

2

What needs to be considered with the diffusion layer?

- pH of the diffusion layer around each drug particle may be different

by NOT considering this you may over-estimate the rate of ionisation and therefore dissolution of weak acids in the intestine and weak bases in the stomach

3

Why are the dissolution rates of weak acids in the stomach low?

- environment has an abundance of protons
- all of the weak acid molecules will be protonated, and therefore unionised
- diffusion layer will not possess a charge
- drug is therefore poorly soluble

4

What would improve the dissolution rates of weak acids in the stomach?

- making an ALKALINE salt of the weak acid (as it dissolves it would release hydroxide ions, which are basic, making a more alkaline environment in the diffusion layer)
- Na and K salts dissolve more rapidly than free acids, regardless of the local pH and will release hydroxide ions, which will promote drug ionisation and therefore dissolution

5

How do small hydrophilic compounds permeate the gut wall?

PARAcellular water channels, between cells

6

How do lipophilic compounds permeate the gut wall?

TRANScellular route, partition into the lipid bilayer of cell membranes, through cells

7

What is Log P?

a measure of lipophilicty, the partition coefficient of only the UNIONISED drug between aqueous and lipophilic phases

8

What is pKa?

describes the extent to which a drug is ionised

- when the pH is the same as the pKa, 50% of the drug will be ionised

9

What is D/Log D?

the distribution coefficient (the partition coefficient) expect that it accounts for the degree of ionisation

10

What is the D calculation for weak acids?

unionised organic/(unionised aqueous + ionised aqueous)

[HAorganic] / { [HAaqueous] + [A-aqueous] }

11

What is the D calculation for weak bases?

unionised organic/(unionised aqueous + ionised aqueous)

[Borganic] / { [Baqueous] + [BH+aqueous] }

12

What is the Log D calculation?

Log D = Log P - Log (1 + Antilog (pKa - pH))

13

Log D is pH dependent, true or false?

True
- because it takes into account the ionised and the unionised form, so is dependent on pH as this would affect the ionisation

14

How is the Log D calculation limited?

it doesn't take into account
- unstirred conditions
- connective flow
- absorption of ionised species
- different pH at the membrane surface
- disruption of the lipid membrane

the calculation gives a good APPROXIMATION of Log D

15

What is the absorption rate of carrier-mediated transport?

absorption rate = Vmax C/ (Km + C)

- C is the free drug concentration at the site of absorption (not complexed to the carrier)
- Km is a constant relating to the affinity of the carrier that binds the drug
- Vmax is a constant relating to the maximum rate of transport (saturation of the carriers)

this assumes that the absorption rate = the rate of the carrier mediated transport

16

What are the generalisations of a weakly basic drug in the stomach?

- the weakly basic drug will be IONISED, and will therefore have high dissolution in the stomach
- this means that the permeability of the drug will be lower as the drug is now less lipophilic
(however the drug is not designed for permeation with a low SA)
- the presence of food ENHANCES the dissolution and therefore the solubility:
1. slows the gastric emptying time, so that the drug stays in the stomach for longer, giving it more time to dissolve
2. presence of food stimulates the stomach to produce more acid, reducing the pH and increasing the ionisation

17

What are the generalisations of a weakly basic drug in the intestine?

- the weakly basic drug will be UNIONISED, and will therefore have low solubility in the intestine
- this means that the drug will be more lipophilic as it is uncharged, and has a higher permeability
- the intestine has a high SA and a good blood flow, which will set up sink conditions and therefore a concentration gradient for the drug to be absorbed

18

What varies blood flow?

- varies from person to person
- after a meal there is a higher blood flow
- if ill/resting/in shock there is a lower blood flow

19

What are the generalisations of a weakly acidic drug in the stomach?

- the weakly acidic drug will be UNIONISED, as there is a high concentration of protons in the stomach
- this means that the drug has low solubility but high permeability (however the stomach is not designed for permeation as it has a low SA)
- presence of food will NOT enhance solubility, and will only increase the retention time

20

What are the generalisations of a weakly acidic drug in the intestine?

- the weakly acidic drug will be IONISED, as there is an increase in the pH
- this means that the drug is less permeable, but increased solubility
- although less permeable, there will still be enough of the unionised form being absorbed in order to set up a concentration gradient

21

What is the pKa of a strong acid and strong base, and are they influenced by changes in the pH?

strong acid: < 2
strong base: > 11

they are UNLIKELY to be affected by changes in the pH as they will be ionised at most pH values

22

What is the pKa of a very weak acid and a very weak base, and are they influenced by changes in the pH?

very weak acid: > 8
very weak base: < 7

they are UNLIKELY to be affected by changes in the pH as they will be unionised at most pH values

23

What is the pKa of moderately weak acids and bases, and are they influenced by changes in the pH?

moderately weak acid: 2.5 - 7.5
moderately weak base: 7 - 10

these will be affected by changes in the pH

24

What is the effect of pH on ionisation, or pKa on moderately weak acids?

pH value of 2 ABOVE the pKa of an acid will mean that there will be 99% IONISED

pH value of 2 BELOW the pKa of an acid will mean that there will be 99% UNIONISED

25

What is the effect of pH on ionisation, or pKa on moderately weak bases?

pH value of 2 ABOVE the pKa of a base will mean that there will be 99% UNIONISED

pH value of 2 BELOW the pKa of a base will mean that there will.be 99% IONISED

26

What is the volume of fluid in the stomach when it is empty?

100mL

27

What is the BCS classifications?

1. High Solubility and High Permeability
2. Low Solubility and High Permeability
3. High Solubility and Low Permeability
4. Low Solubility and Low Permeability

28

What is a biowaiver?

where you don't need to submit bioavailability data to get product approval

29

What BCS classifications are eligible for a biowaiver?

- Class 1 - fewer of these compounds are being identfied
- Class 2 IF they are weak acids, and highly soluble at pH 6.8
- Class 3 IF they are rapidly dissolving

30

When is a drug considered to be highly soluble?

when the HIGHEST dose required dissolves in < 250mL of water over a pH range of 1 - 7.5