Oral Biopharmaceutics 1 Flashcards
A drug cannot be absorbed if it is hasn’t been what?
Dissolved
What are the stages of dissolution of a solid dosage form?
Dose form → disintegration of granules → deaggregation into fine particles → solubilised drug molecules → complexation/precipitation into fine particles
What is the boundary layer?
The area directly next to the drug particle where there is a high concentration of the drug in solution
Moving away from the boundary layer you have what layer?
Diffusion layer
When a drug is rapidly absorbed/partitioned into another compartment, the concentration ________ with distance from the drug molecule.
Decreases
How is the equilibrium maintained when drug is being rapidly absorbed/partitioned into another compartment?
As drug molecules diffuse away from the boundary later into bulk fluids, new drug molecules replace them to maintain the equilibrium, rapidly saturating the diffusion layer
What is the rate limiting step under these conditions (sink conditions)?
Rate of dissolution
What can be said about the pH of the diffusion later, in vitro vs. in vivo?
In vitro - pH around each drug particle is constant
In vivo - the pH of the unstirred diffusion layer around each drug particle may be different and the dissolution of the particle may not be the same
What could be the problem in assuming in vitro and in vivo diffusion layers to be identical?
Could lead to an overestimation of ionisation, dissolution and uptake rates
WA drugs are more likely to dissolve in…
The higher higher pH of the intestine
WB drugs are more likely to dissolve in…
The acidic pH of the stomach
How can dissolution rate of WA drugs in the stomach be increased? How does this work?
Formation of an alkaline salt of the drug
Would put OH⁻ ions into the system allowing more of the WA to be dissolved
E.g. Na⁺ and K⁺ salts
What are some of the generalisations for permeation made for oral drugs (small hydrophilic)? Do they hold true?
Small hydrophilic drugs permeate through paracellular water channels - very few drugs actually do this
What are some of the generalisations for permeation made for oral drugs (lipophilic)? Do they hold true?
Lipophilic compounds permeate by partition into and through the lipid bilayer of biological membranes (transcellular route) - in some circumstances
What are some of the generalisations for permeation made for oral drugs (other routes)? Do they hold true?
Some compounds permeate via membrane transporters - increasingly observed as we develop more complex and charged drugs, inc. efflux transporters
Transport through other epithelial and endothelial barriers, e.g. BBB, relies on more advanced understanding and novel drug delivery methods
What are some of the generalisations for permeation made for oral drugs (large compounds)? Do they hold true?
Large compounds e.g. synthetic peptides and protein-based biologics, raise a no. of problems due to their size and instability/sensitivity to pH
The pH partition hypothesis of absorption of ionised drug depends on?
Dissociation constant, Ka or pKa
Partition coefficient [P]
What is pKa?
pH at which ionised = unionised
What is logP a measure of?
Lipophilicity and how lipid soluble a drug is
LogP only describes the ionisation of a drug in which form?
Unionised form
What is a more accurate measure of permeation than logP?
LogD or distribution coefficient (D)
What is distribution coefficient (D)?
The ‘effective’ partition coefficient accounting for degree of ionisation
What are some limitations to these calculations (Ka, logP, logD etc.)? (5)
Unstirred/no sink conditions
Convective flow
Absorption of ionised species (at a differing rate to unionised)
Different pH at the membrane surface (to elsewhere in your dissolution compartment)
Disruption of the lipid membrane (results in dissolution through damaged sites)
What is carrier mediated facilitated transport?
Exchange of drug with some other molecule, usually an ion
What is active transport?
ATP-involved
What are the 4 generalisations made for WB drugs in the stomach?
1) Food increases time for dissolution (by delaying gastric emptying)
2) Acidity increases % protonated
3) This increases solubility
4) Protonated drug is less lipophilic and so less permeable
What is the transit time for the small intestine?
1 second after food
5 seconds at rest
30 seconds after shock (blood diverted elsewhere)
What are the 3 generalisations made for WB drugs in the intestine?
1) Emptying into increased pH reduces % protonated
2) Solubility also reduced and precipitate particles may form
3) Uncharged base is more lipophilic and permeable
How is the high diffusion gradient maintained in the intestine?
Rapid blood flow
How much absorption occurs in the stomach and why?
Little absorption as the stomach has a low s.a. and is covered by a layer of mucus
Presence of food in the stomach is beneficial for WB drugs in which 2 ways?
Delays gastric emptying so allows more time for dissolution
Induces the release of gastric secretions which further lower the pH promoting ionisation
How is the small intestine designed for absorption?
Large surface area and highly vascularised establishing sink conditions
Means that any problems with drug solubility because the majority is unionised (WB) are overcome
What are sink conditions?
Essentially means sufficient media to ensure unimpaired dissolution (sugar and water example)
How is blood flow to the intestine affected when exercising, ill or in shock?
Blood is diverted away from the intestines reducing the permeability of drugs
What is the problem with WA drugs (dissolution)?
Mostly unionised in the stomach impairing dissolution
Unionised molecules are more lipophilic and permeable but this isn’t useful in the stomach due to the low s.a. and mucus coverage
Drug is also more likely to precipitate and aggregate if it does not dissolve, further reducing s.a.
Is the presence of food favourable or not when dealing with WA drugs?
No, the presence of food delays gastric emptying, this isn’t favourable for WA as we want them to move into the alkaline compartment of the intestine ASAP to allow for dissolution
Once in the small intestine, WA drugs become ionised, how does this affect their permeation (more or less likely, level of impact)?
Less likely to partition into gut wall due to their ionisation
Doesn’t have too much of an effect due to the larger s.a. and high vascularisation of the small intestine allowing the establishment of sink conditions
How does permeation of WA ionised drugs occur in the small intestine?
A small proportion of the drug does exist in its ionised form
This proportion can permeate and when this happens, more of the drug is converted to the unionised form to maintain the eqᵐ and can enter the bloodstream
What can be said about the _______ of very weak acids?
- pKa
- Ionisation
- Solubility
- Permeability
> 8 (hates being ionised)
Unionised at most pH values
May be poor or little affected by pH
May be ok and little affected by pH
What can be said about the _______ of moderately weak acids?
- pKa
- Ionisation
- Solubility
- Permeability
2.5-7.5
Unionised at gastric pH, ionised at intestinal pH
Poor in stomach and improved in intestine
Ok in stomach but declines in intestine
What can be said about the _______ of stronger acids?
- pKa
- Ionisation
- Solubility
- Permeability
<2 (loves to be ionised)
Ionised at most pH values
May be ok or little affected by pH
May be poor and little affected by pH
What can be said about the _______ of weak bases?
- pKa
- Ionisation
- Solubility
- Permeability
7-10
Ionised at gastric pH, largely unionised at intestinal pH
Ok at gastric pH but decline at intestine
Poor in stomach and improves in intestine
What can be said about the _______ of stronger bases?
- pKa
- Ionisation
- Solubility
- Permeability
> 11
Ionised at most pH values
May be ok or little affected by pH
May be poor and little affected by pH
How is knowing the pKa of a drug useful?
Can tell you what proportion of the drug will be ionised
Once you know this, you can make some conclusions about the extent of solubility and permeability
From a formulation perspective, which categories are the least feasible drug candidates for drug development?
Very weak acids and very weak bases
What is BCS?
Biopharmaceutical Classification System (BCS)
Classifies drugs into 4 classes dependent on solubility and permeability
What is a ‘biowaver’?
Means a drug does not need to show in vivo bioavailability data in order to get product approval
What makes a drug eligible for biowaver?
If the drug has a very predictable response, such as a Class I drug
It behaves very similarly in vitro as it does in vivo
What is a class I drug? (solubility, permeability and eligibility)
High solubility
High permeability
Eligible for biowaver
What is a class II drug? (solubility, permeability and eligibility)
Low solubility
High permeability
Eligible if WA, highly soluble at pH 6.8, plus dissolution
What is a class III drug? (solubility, permeability and eligibility)
High solubility
Low permeability
Eligible if very rapidly dissolving
What is a class IV drug? (solubility, permeability and eligibility)
Low solubility
Low permeability
Not eligible
When is a drug considered ‘highly soluble’?
When the highest required dose dissolves <250ml of water over a pH range of 1-7.5
When is a drug considered ‘highly permeable’?
When >90% administered dose is absorbed
Compounds with a solubility less than what causes significant problems?
<10mg/ml
More and more new compounds have solubility issues, why is this?
Increased use of combinatorial chemistry and high throughput screening
Solubility issues create a greater reliance on what?
Patented formulation processes
What are some of the in vivo consequences of poor solubility? (5)
Decreased bioavailability
Increased chance of food effects
Increased issues in patients with diseases
More frequent incomplete release of drug from dosage from
Higher inter-patient variability
What are some of the consequences of poor solubility for formulation? (3)
Severely limited choice of delivery technologies
Increasingly complex dissolution testing
Limited or poor correlation with in vivo absorption
What are the factors affecting solubility and permeability? (12)
Wettability Surfactants Particle size Solid dispersions Adsorbents Degradation Polymorphs pH solubility Soluble prodrug Complexation Viscosity enhancing agents Diluents
