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The Medicine Year 3 Sem 1 > Oral Dosage Form > Flashcards

Oral Dosage Form Flashcards

1
Q

Define dissolution

A

Disintegration of granules into fine particles so it can be solubilised and absorbed

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2
Q

When does [C] fall?

A

When absorption is dissolution rate limited due to absorption or partitioning of the drug.

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3
Q

Describe how are sink conditions maintained during dissolution.

A

As drug molecules diffuse away from the saturated diffusion layer into the bulk fluids, new drug molecules replace them, rapidly saturating the diffusion layer (sink conditions).

The further away you get from the diffusion layer, the lower the concentration.

Drug concentration gradient maintains the sink conditions (saturated diffusion layer maintained).

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4
Q

What is the significance of the pH diffusion layer?

A

Not considering the pH of the diffusion later may lead to overestimation of the rate of ionisation and dissolution of weak acids (intestine) and weak bases (stomach)

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5
Q

How do salts improve dissolution of WAs in the stomach?

A

The dissolution rate of weak acids in the stomach is low.
The drug is unionised (due to acidic pH) and therefore poorly soluble in the diffusion layer.

Alkaline salt of WA increases diffusion layer pH.
Na and K salts dissolve more rapidly than free acids.
Regardless of the local pH
They release OH ions which increases the pH of the diffusion layer, promoting drug ionisation.
Increases solubility and dissolution.

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6
Q

What does the pH partition hypothesis of absorption of ionised drugs depend on?

A 
Ka/pKa
Partition coefficient (P)
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7
Q

What is pKa defined as?

A

The pH at which 50% of the drug molecules are ionised

[ionised] = [unionised]

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8
Q

What is distribution coefficient (D) defined as?

What does it depend on?

A

The ‘effective’ partition coefficient, accounting for the degree ionisation.

Depends on pH
Related to P and logP
Can be approximated at any pH using pKa of a drug

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9
Q

What is the equation of carrier-mediated transport absorption rate?

A

Absorption rate = (Vmax x C)/(Km + C)

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10
Q

What is Vmax?

A

A constant

Relates to the maximum rate of transport or saturate of the carriers

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11
Q

What is Km?

A

A constant

Relates to the affinity of the carrier binding of the drug

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12
Q

What effect does food have on dissolution?

A

For both WA and WB drugs, food:
Delays gastric emptying and improves dissolution
Stimulates acid release, further reducing stomach pH
Blood flow increases when stimulated by gastric secretions

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13
Q

What happens when a weakly basic drug enters the stomach?

A

Weakly basic drugs are ionised and soluble in the acidic stomach.

However, charged base less lipophilic and less permeable. Also, the stomach has a low surface area (sub-optimal conditions for permeation).

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14
Q

What happens when a weakly basic drug enters the small intestine?

A

Small intestine is more basic
therefore the percentage of ionised drug species reduces.

Increased permeation due to increased lipophilicity, blood supply and high surface area.

Due to good blood flow in the gut, there is sink conditions which helps to establish a high concentration gradient

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15
Q

What happens when a weakly acidic drug enters the stomach?

A

WA drugs exists in unionised form in the acidic conditions of the stomach.

Stomach has a low SA = limited uptake of ionised drug in the stomach.

The molecule becomes more lipophilic and permeable but it’s solubility decreases and precipitation may occur

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16
Q

What happens when a weakly acidic drug enters the small intestine?

A

The percentage of uncharged acid reduces, ionisation increases and solubility increases.

The charged acid is less lipophilic and has a lower partition into liquid.

Rapid blood flow maintains high diffusion gradient for solubilised and permeable fraction of the drug

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17
Q

Discuss very weak acids (pKa>8) in terms of ionisation, solubility and permeability

A
  • Ionisation: Unionised at most pH values
  • Solubility: May be poor/not really affected by pH
  • Permeability: May be okay but may be affected by pH
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18
Q

Discuss moderately weak acids (pKa 2.5 - 7.5) in terms of ionisation, solubility and permeability

A
  • Ionisation: Unionised at gastric level, ionised at intestinal pH
  • Solubility: Poor in the stomach and improved in the small intestine
  • Permeability: May be okay in the stomach but may be decreased in the small intestine
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19
Q

Discuss stronger acids (pKa<2) in terms of ionisation, solubility and permeability

A
  • Ionisation: Ionised at most pH values

- Solubility and Permeability: May be okay or mildly affected by pH

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20
Q

Discuss very weak bases (pKa<7) in terms of ionisation, solubility and permeability

A

Ionisation: Unionised at most pH values
Solubility: May be poor and may be improved at acid pH
- Permeability: May be okay but decreases in the stomach

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21
Q

Discuss moderately weak bases (pKa 7 - 10) in terms of ionisation, solubility and permeability

A
  • Ionisation: Ionised as gastric pH, largely unionised at intestinal pH
  • Solubility: Okay in GI but decreased in the intestine
  • Permeability: Poor in the stomach but improves in the intestine
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22
Q

Discuss strong bases (pKa>11) in terms of ionisation, solubility and permeability

A

Ionisation: Ionised at most pH values
Solubility: Okay/mildly affected
Permeability: Poor permeability and isn’t really affected by pH

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23
Q

What properties do drugs in Class I of the BCS have?

A

High solubility

High permeability

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24
Q

What properties do drugs in Class II of the BCS have?

A

Low solubility

High permeability

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25
Q

What properties do drugs in Class III of the BCS have?

A

High solubility

Low permeability

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26
Q

What properties do drugs in Class IV of the BCS have?

A

Low solubility

Low solubility

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27
Q

When are drugs considered to be highly soluble?

A

When the highest dose required is soluble in <250ml of water over a pH range of 1 - 7.5

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28
Q

Why would a weakly basic BCS class II have low bioavailability when given as an immediate release orally?

A

Class II = Low solubility and high permeability

Decreased solubility means that it goes straight to the intestine undissolved
Should ideally be given with food to increase dissolution time

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29
Q

What are the issues associated with low drug solubility in vivo?

A
  • Decreased bioavailability
  • Increased chance of food effects
  • Increased issues with disease states (esp. GIT problems affecting blood flow)
  • Increased incomplete release
  • Higher interpatient variability
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30
Q

What are the issues associated with low drug solubility during formulation?

A
  • Limited choice of delivery technologies
  • Complex dissolution testing
  • Limited/poor correlation with in vivo and in vitro absorption
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31
Q

What are the factors affecting dissolution and absorption

A
  • Wettability (contact angle)
  • Surfactants (enhances wetting and solubilisation)
  • Particle size (small size increase SA)
  • Solid dispersions (Eutectic mixture)
  • Polymorphs (different solubility, MP and dissolution rates)
  • pH solubility
  • Soluble prodrugs (Clorazepate acid degraded to Nordiazapam)
  • Complexation (by excipients, food, GI mucin etc.)
  • Adsorbents (reduce amount of drug available)
  • Viscosity enhancers (increase retention time)
  • Degradation (hydrolysis reduces drug available)
    Diluents (improves solubility)
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32
Q

What are the major issues caused by poor drug solubility?

A
  • Poor bioavailability
  • Sub optimal dosing
  • Food effects (variation in bioavailability in fed vs fasting states)
  • Lack of dose-response proportionality
  • Inability to optimise lead compound selection based on efficacy and safety
  • Harsh excipients required (co-solvents)
  • Use of extreme basic/acidic conditions
  • Uncontrollable precipitation after dosing
  • Patient non-compliance due to inconvenient dosing/formulation
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33
Q

How are cyclodextrins formed?

A

Formed through supersaturating a cyclodextrin (CD) solution with a drug and mildly agitating the solution
OR
By kneading a drug/CD/solvent slurry to a paste, which is dried and sieved

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34
Q

What is the advantages and disadvantages of amorphous solids?

A

More soluble, but also more unstable and prone to recrystallization

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35
Q

How are amorphous solid dispersions formed?

A

Spray dry using solvents or replace solvent with supercritical fluids

OR

Hot melt extrusion:

  • Soften the polymer, add drug and mix as the dispersion flows through the extruder
  • Rapidly cool and extrude to form strands of polymeric glass with embedding API.
  • Mill the glass strands into a powder (increases SA)
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36
Q

Give examples of polar excipients

A

Polyethylene glycol (PEG)
Gelatin
Sugar glasses (e.g. Inulin)
Lipids

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37
Q

How is PEG used as a polar excipient?

A

Used as co-solvent in liquid formulations (e.g. topical, parenteral) to prevent precipitation of poorly soluble compounds

Acts as a dispersion-enhancer or as a wetting agent.

Incorporated by solvent evaporation or freeze drying.

Can be used in combination with other excipients e.g. stearic acid, sodium lauryl sulfate

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38
Q

How is gelatin used as a polar excipient?

A

Has both positive and negative charges, which bind to the poorly soluble compound

Improves the wettability of hydrophobic compounds when used as a granulating agent

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39
Q

How is sugar glass used as a polar excipient?

A

Inulin is a fructose polymer.
Inulin solution is mixed with a drug solution then freeze dried to form a sugar glass.

Improves the dissolution profile of the drug and protects it from physical and chemical degradation, increasing stability.

40
Q

How does re-crystallisation reduce particle size?

A

Uses liquid solvents and anti-solvents

41
Q

What is the disadvantage of communition and spray drying?

A

Rely on mechanical stress to disaggregate the active compound.

This may induce degradation or thermal stress on the product.
Not suitable for processing thermo-sensitive or unstable compounds.

42
Q

What is the ideal particle size to increase absorption by 41.5 fold?

A

5µm - 120nm

43
Q

Where in the GI is there higher absorption?

A

The small intestine because there is a higher surface area, there is a greater window absorption

44
Q

What are the benefits of nanoparticles?

A

Higher absorption in small intestine because of higher surface to mass ratio, and greater dissolution in the transit time through the small intestine
Results in:
- Greater bioavailability = higher Cmax and AUC
- Less variability with food: smaller difference between fed and fasted states
- Dose proportional to AUC

45
Q

Give examples of drugs that nanoparticulation is used for

A 
Dolargin
Loperamide
Tubocuranine
Doxorubicin
Ibuprofen
Diazepam
Naproxen
Carbimazole 
Nifedipine 
Phytosterol
46
Q

How far does micro milling operate?

A

Down to sub-micron sizes

47
Q

How do piston gap methods create drug nanoparticles?

A

Through hydrodynamic cavitation

48
Q

How do supercritical fluids create nanoparticles?

A

By controlling solubility using pressure and temperature in solvents such as carbon dioxide

49
Q

What properties do SCFs have?

A

Above the critical point, they have the properties of both a liquid and a gas (supercritical region).

They can diffuse through solids like a gas, and dissolve materials like a liquid.

At the Triple Point they have properties of a solid, liquid and gas.

50
Q

What does manipulation of SCFs allow?

A

Improves diffusivity and reduces viscosity and surface tension.

This allows liquids to behave like gases enabling precise control drug solubilisation

51
Q

What is the action of non-ionic surfactants in self-emulsifying systems?

A

Improve drug solubilisation and prevent drug precipitating out of the micro emulsion in vivo

52
Q

How do self-emulsifying systems increase bioavailability?

A

Drug dissolved in oil-surfactant mixture.

Lipid presence in duodenum stimulates secretion of biliary lipids, forming micelles and emulsion droplets.

The interaction of triglycerides and surfactants with the wall of the GI tract promotes solubilisation and absorption of the drug.

Drug absorbed through lymphatic system (the same way fats in our diet are absorbed) and then into systemic circulation, avoiding first pass metabolism.

53
Q

Why is digestion of lipids important?

A

Breakdown of lipids needed for good absorption and dissolution of lipid based formulations

54
Q

How are lipid based formulations prepared?

A

Through incorporation of a drug into an oil-surfactant mix, until a clear solution is formed, and filled into hard or soft gelatin capsules.

55
Q

How does drug co-adminstration with lipids enhance absorptions?

A

High lipophilicity facilitates absorption into the intestinal lymphatics and then into systemic circulation, avoiding first pass metabolism

56
Q

What is the rate limiting step during dissolution?

A

Rate of dissolution

57
Q

What is the assumption when you have sink conditions?

A

Where we have sink conditions, we can assume first order kinetics i.e. [drug in intestine] > [drug in blood]

Drug moves from intestines into the blood.

58
Q

What are the three methods of permeation?

A
  • Paracellular (between cells)
  • Transcellular (through cell membrane)
  • Membrane transporters
59
Q

What are the generalisations made for permeation of oral drugs? And what is the reality?

A

Small hydrophilic compounds permeate through paracellular water channels

Lipophilic compounds permeate by partition through the lipid bilayer of biological membranes (transcellular route)

Reality: most compounds permeate via membrane transporters

60
Q

What is logP?

A

Measure of lipophilicity
It is the partition coefficient of an unionised drug between aqueous and lipophilic phases

Considers only unionised drugs

61
Q

What is the equation for logD?

A

Weak acids: D = [HA org]/ {[HA aq] + [A- aq]}

Weak bases: D = [B org]/{[B aq] + [BHaq^+]}

62
Q

What is the equation for logD?

A

WB: logP - log(1+10^(pKa-pH))
WA: logP - log (1+10^(pH-pKa))

63
Q

What are the limitations of logD?

A
  • Unstirred conditions
  • Convective flow
  • Ionised drug may also be absorbed
  • pH at membrane surface may be different
  • Ionisation and absorption may be altered by secretions
  • Disruption to the lipid membrane
64
Q

What is carrier mediated transport?

A

For drugs which do not cross the gut wall by permeation.

The absorption rate is assumed to be the rate of carrier mediated membrane transport.

65
Q

What is C in the equation for carrier mediated transport?

A

Free (uncomplexed) drug concentration at the site of absorption (GI luminal side)

66
Q

What affects the rate of carrier-mediated transport?

A

Concentration - saturation of carriers limits rate

Affinity of molecule to carrier

67
Q

How do patient factors affect blood flow in the intestines?

A

At rest or during an illness, there is poor blood flow in the intestines

68
Q

How can the absorption of weakly acidic and weakly basic drugs be improved?

A

Taking with food

Delays gastric emptying which increases time for dissolution

Can also change the local pH to influence ionisation

69
Q

What does a negative logD mean?

A

Hydrophilic

70
Q

What is a biowaver and what class of drugs are eligible for one?

A

Means that the drug doesn’t need to show in vivo bioavailability data to get product approval
Can just use data from dissolution testing

Class I
Class II - weak acids which are highly soluble at pH 6.8
Class III - if very fast dissolution rate

71
Q

When are drugs considered highly permeable?

A

If >90% of the administered dose is absorbed

72
Q

What is considered a poor solubility?

A

<10mg/ml
<0.1 mg/ml = nearly insoluble

Will impair solubilisation during formulation and impede dissolution from the dosage form

73
Q

What is the difference between LogP and LogD?

A

LogP is independent of pH, LogD is pH dependent

74
Q

What is relationship between pKa and pH for a WA and WB drugs?

A

2 pH units > pKa of an acid – 99% ionised
2 pH units < pKa of an acid – 99% unionised

Opposite is true with pka of a basic group

75
Q

What will be seen if a drug has both an acidic and basic group?

A

Biphasic solubility profile (Solubility decreases then gradually increases again or vice versa)

Lowest solubility seen when drug is in zwitterionic form - when the highest proportion of both ionisable groups are in their unionised form

76
Q

Why are the release characteristics of the formulation important weakly basic drugs?

A

If a formulation demonstrates excellent release characteristics at gastric pH, then a decrease in solubility at duodenal pH may be of lower significance, as sufficient of the drug already in the dissolved state is absorbed, and replaced from the insoluble fraction.

77
Q

Why is dissolution testing become unreliable for predicting in vivo behaviour?

A

Fewer BCS class I compounds are being identified.

The molecular size and hydrophobicity of drugs is increasing leading to increasing solubility and permeability issues.

Results in compounds with poor oral bioavailability.

78
Q

How can you improve Class II drugs?

A

Requires solubility improvement

  • Reduce particle size
  • Soluble salts
  • Cyclodextrin
  • Solid dispersions
  • Surfactants
  • Nanoparticles
  • Change pH of diffusion layer
  • Self-emulsifying systems
79
Q

How can you improve Class III drugs?

A

Needs permeability improvement

  • Permeation enhancer
  • Lipid-filled capsules
  • GI motility consideration
  • Efflux inhibitors
  • Absorption enhancing excipients
80
Q

How can you improve Class IV drugs?

A

Solubility and permeation improvement

  • Prodrugs
  • Salt forms
  • Co-solvents
  • Surfactants
  • Nanoparticles
  • Lyophilisation
  • Liposomes
  • Lipid-filled capsules
81
Q

How do cyclodextrins work?

A

CDs have a hydrophobic interior and hydrophilic exterior.
They form a cylindrical cage formed around a poorly soluble drug, presenting hydrophilic group to the outside and increasing solubility.

82
Q

How can the effect of cyclodextrins be improved?

A

Formulating with hydrophilic polymers e.g. HPMC

Improve the solubilising effect of CDs, so less CD is needed to solubilise the same amount of drug

83
Q

Why is there only a few cyclodextrin based products on the market?

A

Cyclodextrins have toxicity and stability issues

84
Q

What are amorphous solid dispersions?

A

Drug formulated with polymers

85
Q

Sugar glasses are used in the formulation of which drugs?

A

Cyclosporin, diazepam, amoxicillin, bacitracin, tetrahydrocannabinol.

86
Q

In which formulation are lipids used as a polar excipient?

A

Self-emulsifying systems e.g. lymphatic delivery

87
Q

What is the disadvantage of recrystallisation?

A

Requires organic solvents for processing, increasing the complexity of manufacture

88
Q

What is the limitation of using traditional methods of comminution to create nanoparticles?

A

Grinding and milling

Often incapable of reducing the particle size enough for nearly insoluble drugs

89
Q

Why are supercritical fluids used?

A

Effective way of producing different sizes and shapes of drug particles

SCF-solubilised drug particles may be re-crystallised at greatly reduced particle sizes.

90
Q

At what particle size are SCF-solubilised drug particles recrystallised?

A

5 – 2000nm in diameter

91
Q

What are self-emulsifying systems?

A

Liquids packaged in soft or hard-shelled capsules

Non ionic surfactants used to improve drug solubilisation

92
Q

Give examples of non-ionic surfactants and explain their use.

A

Tweens (polysorbates) and Labrafil (polyoxyethylated oleic glycerides) with high hydrophile-lipophile balances (HLB) are used to ensure an immediate formation of oil-in-water droplets during production.

Co-solvents/surfactants e.g. ethanol, PEG, propylene glycol are used to increase the amount of drug dissolved into the lipid base.

93
Q

What is the purpose of drying suspensions?

A

To obtain stable drug particles in powder form which become liquid when in contact with bodily fluids.

Increases shelf-life.
E.g. Eurand’s nanolipispheres

94
Q

How are lipid formulations classified?

A

Poulton’s lipid formulation classification.

5 types: Type I - IV
Type III has two variations (A and B)

Type I is the biggest – the bigger delivery systems have triglycerides.

Larger particles are less likely to be affected by dissolution.

95
Q

Give examples of lipid based formulations

A

Solutions, emulsions and self-dispersing lipid formulations of poorly-soluble lipophilic drugs e.g. cyclosporin (Neoral), ritonavir (Norvir) and saquinavir (Fortovase)

96
Q

How much lipid is needed in the GIT for lipid-based formulations to work?

A

<2g (2 capsules)

Food can also increase the amount of lipids

97
Q

Why may intestinal absorption of a drug vary in the same patient and between different patients?

A

Patient diet
Underlying disease
Existing drug therapy
Pharmacogenetics

Can all play a role in P-gp expression

The Medicine Year 3 Sem 1 (7 decks)

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