Biopharmaceutics of oral dose formulation

Question 1

Is LogP dependent or independent of pH?

Answer 1

Independent

Question 2

Is LogD dependent or independent of pH?

Answer 2

dependent

Question 3

Process of dissolution?

Answer 3

• Disintegration of granules
• Deaggregation into fine particles
• Solubilised drug molecules absorbed
• Complexation of precipitation into fine particles

Question 4

When a drug is rapidly absorbed or partitioned into another compartment, the concentration [C] _______ with distance

Answer 4

decreases.

Question 5

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). What is the rate limiting step under these conditions?

Answer 5

Rate of dissolution

Question 6

What order of kinetics do we assume in sink conditions?

Answer 6

First order

Question 7

The pH of the diffusion layer around each drug particle may be different. Why is it important to consider this?

Answer 7

By not considering this, we may over-estimate rates of ionisation and dissolution of weak acids (intestine) and weak bases (stomach)

Question 8

Why is the dissolution rate of weak acids in the stomach low?

Answer 8

because the drug is unionised and therefore poorly soluble in the diffusion layer

Question 9

How to overcome a low dissolution rate of weak acid in the stomach?

Answer 9

• The pH of the diffusion layer may be increased by forming an alkaline salt of the weak acid
• Na and K salts dissolve more rapidly than free acids, regardless of the local pH because they release OH ions which promotes drug ionisation

Question 10

Generalisations made for oral drugs in terms of permeation include:

Answer 10

• Small hydrophilic compounds permeate through paracellular water channels = few drugs actually do this
• Lipophilic compounds permeate by partition into and through the lipid bilayer of biological membranes (transcellular route)  in some circumstances
• Some compounds permeate via membrane transporters  this is increasingly being observed and includes drug efflux transporters
• Transport through other epithelial and endothelial barriers (e.g. BBB) relies on more advanced understanding and novel drug delivery methods
• Large compounds e.g. synthetic peptides and protein-based biologics raise a number of problems

Question 11

What is Log P a measurement of?

Answer 11

Lipophilicity: it is the partition coefficient of an unionised drug between aqueous and lipophilic phases

Question 12

What is the dissociation constant?

Answer 12

• The dissociation constant Ka or pKa describes the extent to which a drug is ionised
• pKa is the pH at which [ionised] = [unionised]

Question 13

Log D (distribution coefficient) =

Answer 13

log P – log {1 + antilog (pKa - pH)}

Question 14

Limitations of log D approximation?

Answer 14

unstirred conditions, convective flow, absorption of ionised species, different pH at the membrane surface, disruption of the lipid membrane, but the equation gives a good approximation of Log D

Question 15

Absorption rate equation?

Answer 15

Absorption rate = Vmax C/ (Km+C)

Max = constant relating to the maximum rate of transport or saturation of the carriers

Question 16

How does food affect dissolution? (weakly basic drugs)

Answer 16

Food increases time for dissolution, acidity increases % protonated of (charged) base and solubility of drug.
- Charged (protonated) base less lipophilic and less permeable

Question 17

Consequences of emptying into increased pH (weakly basic).

Answer 17

Reduces % protonated base and solubility. Precipitate particles may form.

Uncharged base more lipophilic and permeable
Rapid blood flow maintains high diffusion gradient from particles.

Question 18

How does food affect dissolution? (weakly acidic drugs)

Answer 18

Food increases time for dissolution, acidity increases % uncharged (non ionised) acid.

More lipophilic and permeable but decreases solubility, precipitate particles may form. Less surface area.

Question 19

Consequences of emptying into increased pH (weakly acidic).

Answer 19

Emptying into increased pH reduces % uncharged acid, increases % ionised and solubility.

Charged (ionised) acid less lipophilic and lower partition into lipid.

Rapid blood slow maintain high diffusion gradient for solubilised and permeable fraction of drug.

Question 20

What is rifampicin and some of its issues?

Answer 20

One of the oldest effective TB treatments but major issue with variable oral bioavailability.

Question 21

Explain how changes in solubility, logD and permeability in the different gut regions affect its absorption and lead to variable bioavailability of Rifampicin (2 pka values so biphasic).

(as pH increases log D increases and Solubility starts really high at ph 1.4 decreases and once it gets to pH 4 starts to increase again)

Answer 21

DRUG SOLUBILITY
Biphasic pH-solubility profile
- due to drug possessing two pKa values: acidic pKa ~1.7 & basic pKa ~ 7.9
- Lowest solubility seen at pH 3.5
- Zwitterionic form of drug least soluble – when the highest proportion of both ionisable groups are in their unionised form

Effect of food
- drug solubility differs by a factor of 100 over pH range 1-3 - hence this may cause variable absorption, depending on the pH of the fasted or fed stomach of the patient

Effect of formulation
- wide difference in drug solubility over the pH range of 1–3 may cause differences in the rate &/or extent of dissolution from different formulations

DRUG LOG D & PERMEABILITY
In highly acidic conditions (i.e. stomach)
- drug exhibits high solubility yet unfavourable logD /permeability due to lower surface area of the stomach.
- In less acidic conditions (i.e. duodenum, pH 4-6) drug exhibits a moderate but lower solubility, yet a greater absorption in this region - due to an increased log D value and high permeability, when absorption provides sink conditions due to increase surface area
- In basic conditions (i.e. ileum & colon, pH 6-8) the moderate solubility and permeability in the ileum and the increased solubility and lower log D/permeability, in the colon are also expected to contribute to bioavailability

Effect of formulation

• if a formulation demonstrates excellent release characteristics at gastric pH, the decreased 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.
• The ratio of ionised and unionised molecules exists in an equilibrium

Question 22

Drugs are considered highly soluble when

Answer 22

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

Question 23

Drugs are considered highly permeable:

Answer 23

if >90% of the administered dose is absorbed

Question 24

Issue with low solubility:

Answer 24

Compounds with a solubility <0.1mg/ml cause significant problems; a solubility <10mg/ml will impair solubilisation during formulation and impede dissolution from the dosage form

Question 25

A weakly basic BCS class II drug has decreased bioavailability when administered in an immediate release oral dosage form. Which ONE of the following is a possible cause of the decreased bioavailability?

A:  Gastric solubility is less than intestinal solubility – most absorption occurs in intestine 
B:  The dose was taken with a meal – solubility is likely to increase due to presence of a meal 
C: The drug has poor intestinal permeability – class 2 compounds exhibit good permeability 
D: Gastric retention time was increased – solubility is likely to increase due to gastric retention 
E: The dose was taken on an empty stomach – less gastric fluid = less soluble and therefore increased bioavailability. Less dissolution on an empty stomach due to higher pH (and it’s a weakly basic drug)

Answer 25

E: The dose was taken on an empty stomach – less gastric fluid = less soluble and therefore increased bioavailability. Less dissolution on an empty stomach due to higher pH (and it’s a weakly basic drug)

Question 26

Drug solubility issues

Answer 26

• BCS class I drugs are generally clinically effective in immediate release or controlled release formulations
• Poorly soluble Class II and IV drugs cause problems for pharmaceutical development
• Increased use of combinatorial chemistry and high throughput drug screening means that up to 40% of new compounds are poorly soluble or lipophilic
• There is a greater reliance on patented formulation processes to address poor solubility
• In addition, more poorly soluble drugs are now off patent and require more cost-effective formulation solutions to make the products financially viable in a competitive and price-sensitive market

Question 27

Low solubility compounds create many problems during formulation, including:

Answer 27

• Severely limited choice of delivery technologies
• Increasingly complex dissolution testing
• Limited or poor correlation with in vivo absorption

The difficulties of achieving predictable and reproducible in vivo/in vitro correlations are often severe enough to halt product development

Question 28

Newly synthesised drug compounds may have solubility and permeability issues that halt drug development. Which ONE of the following would be LEAST likely in the case of a drug with poor solubility and high permeability?
A: Increased chance of food effects
B: Higher inter-patient variability
C: Limited correlation of dissolution testing with in vivo absorption
D: Increased bioavailability
E: More frequent incomplete release of the drug from the dosage form

Answer 28

D: Increased bioavailability

Question 29

Why are fewer new BCS class I compounds are being identified?

Answer 29

• The molecular size and hydrophobicity of drugs is increasing, as are the number of new drugs with solubility and permeability issues
• The resulting compounds have poor oral bioavailability and dissolution studies are becoming unreliable for predicting in vivo behaviour

Question 30

Factors affecting solubility and permeability?

Answer 30

• Wettability: measurement of contract angle
• Surfactants: wetting, solubilisation, and permeability enhancing
• Particle size: smaller size increases effective surface area
• Solid dispersions: eutectic mixture with water soluble carrier
• Polymorphs: diffrent solubility, melting point and dissolution rate
• pH solubility: weak acid and bases vary as a function of pH
• Soluble prodrugs: of poorly soluble drug e.g. nor diazepam replaced with clorazepate, acid degraded to nordiazepam
• Complexation: by excipients, GI mucin, food etc
• Adsorbents: reduced drug available, unless readily reversible
• Viscosity enhancing agents: complex drug, increase residence time
• Degradation: acid or enzymatic hydrolysis reduces drug available for absorption
• Diluents: hydrophilic dilutants for hydrophobic drugs

Question 31

Summary of approaches to improve solubility and permeability?

Answer 31

Solubility enhancement:
- particle size reduction, soluble salts, solid dispersions, self emulsifying systems, surfactants, nanoparticles, cycle dextrin and ph diffusion layer

Permeation enhancer:
Absorption enhancing excipients, efflux inhibitors, lipid filled capsules, GI motility considerations

Question 32

Major issues caused by poor drug solubility

Answer 32

• Poor oral bioavailability
• Suboptimal dosing
• Food effects: variation in bioavailability in fed vs fasting states
• Lack of dose response proportionality
• Inability to optimise lead compounds
• Harsh excipients required e.g. excessive use of co solvents
• Use of extreme basic or acidic conditions to enhance solubilisation
• Uncontrollable precipitation after dosing
• Patient non-compliance due to inconvenience of formulation and/or dosing regimen

Question 33

Describe cyclodextrins?

Answer 33

• CD have a hydrophobic interior and hydrophilic exterior, so form complexes with hydrophobic compounds
• They are formed by:
- Supersaturating a CD solution with drug, with agitation
- Kneading a drug/CD/solvent slurry to a paste, which is dried and sieved
• Hydrophilic polymers e.g. HPMC improve the solubilising effect of CDs, so less CD is needed to solubilise the same amount of drug
• Few oral CD-based drug products are on the market because they have toxicity and stability issues

Question 34

What are amorphous solid dispersions?

Answer 34

• Amorphous compounds are more soluble, but are more unstable and prone to recrystallization
• Amorphous compounds can be created by formulation with polymers
• Spray dry using solvents or replace with supercritical fluids
• Hot melt extrusion: soften polymer, add drug and mix as the dispersion flows through the extruder; rapidly cool and extrude to form strands of polymeric glass with embedded API; mill glass strands into a powder

Question 35

Uses of polar excipients and examples:

Answer 35

Polyethylene glycol (PEG)
• Liquid PEG can be used as a co-solvent in liquid-based dosage forms to prevent precipitation of compounds that are poorly soluble in aqueous formulations
• Suitable for topical and parenteral administration
• Acts as a wetting agent or enhances dispersion of solid dosage forms; incorporated by solvent evaporation or freeze drying
• Can be used in combination with other excipients e.g. stearic acid, sodium lauryl sulfate

Gelatin
• A naturally derived collagen extract with both positive and negative charges , which bind to the poorly soluble compound
• Can be used to improve the wettability of hydrophobic compounds when used as a granulating agent

Sugar glasses e.g. inulin
• A naturally occurring fructose polymer, safe for parenteral and pulmonary use, GRAS status for oral formulations
• Mixing an inulin solution with a drug solution, followed by freeze drying, creates a sugar glass
• Sugar glasses improve the dissolution profile of the drug and protect it from physical and chemical degradation, increasing stability
• Sugar glasses are used in the formulation of cyclosporin, diazepam, amoxicillin, bacitracin, tetrahydrocannabinol
Lipids
• Lipids are used as polar excipients in self emulsifying systems e.g. lymphatic delivery

Question 36

What is particle engineering?

Answer 36

• Reducing particle size increases surface area and usually improved dissolution properties, enabling the use of a wider range of formulations and delivery approaches
• Recrystallization of poorly soluble materials using liquid solvents and anti-solvents to reduce particle size requires organic solvents for processing, increasing the complexity of manufacture
• Conventional comminution and spray-drying rely upon mechanical stress to disaggregate the active compound
• This puts significant amounts of stress on the drug product and may induce degradation or thermal stress
• This approach is therefore not suitable for thermo-sensitive or unstable compounds

Question 37

Particle size and surface area effects on absorption:

Answer 37

Higher absorption in small intestine because of higher surface to mass ration of small particle suspension and greater dissolution in the transit time through the small intestine - window of absorption.

Question 38

Benefits of nanoparticle formulations on drug delivery:

Answer 38

Greater bioavailability (higher Cmax, AUC)

Less variability with food: smaller difference between fed and fasted bioavailabilities

Dose proportionality: AUC proportional to dose

Question 39

What is nanoparticulaiton?

Answer 39

• Used for several drugs such as loperamide, ibuprofen, diazepam, naproxen, carbamezapine etc.

Created by SCF’s - create nanoparticles by control of solubility using pressure and temperature in solvents such as carbon dioxide.

Question 40

Traditional methods of com munition:

Answer 40

• Such as grinding and milling, are often incapable of reducing the particle size sufficiently for nearly insoluble drugs.
• Micro-milling may operate down to sub micron sizes with physical and thermal stresses
• Piston gap methods create drug nano particles through hydrodynamic cavitation.

Question 41

What are supercritical fluids?

Answer 41

SCF’s are used in manufacture as an effective means of producing different sizes and shapes of drug particles.

SCF’s at a temp and pressure above their thermodynamic critical point assume the properties of both a liquid and a gas.

Question 42

Nanoparticle engineering using SCF:

Answer 42

• SCFs can diffuse though solids like a gas and dissolve materials like a liquid
• SCF-solubilised drug particles may be re-crystallised at greatly reduced particle sizes, often 5 – 2000nm in diameter
• At near critical temperatures SCFs are highly compressible, allowing moderate changes in pressure or temperature to greatly alter their density, mass transport and solvating power
• Manipulation of the pressure of SCFs improves diffusivity and reduces viscosity and surface tension
• This allows liquids to behave like gases, which enables precise control of drug solubilisation

Question 43

Supercritical fluid processes are emerging as alternatives to produce small drug particles by re-crystallization and precipitation processes. Identify which ONE of the following statements is correct:

A: SCFs are poorly compressible and allow large changes in temperature and pressure to be used to maintain density and solvation power
B: SCFs are poorly compressible and maintain uniform density during pressure and temperature changes, allowing good control of particle size
C: SCFs are poorly compressible and allow small changes in temperature and pressure to be used to alter density and solvation power
D: SCFs are highly compressible, allowing small changes in temperature and pressure to alter density and solvation power
E: SCFs are highly compressible, preventing large changes in temperature and pressure from altering their density and solvation power

Answer 43

D: SCFs are highly compressible, allowing small changes in temperature and pressure to alter density and solvation power

Question 44

What are self emulsifying systems

Answer 44

• Non-ionic surfactants improve drug solubilisation and prevent drugs from precipitating out of the micro-emulsion
• 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
• Solid products are suspension-dried to obtain stable drug particles in powder form e.g. Eurand’s nanolipispheres – a stable colloidal micro-emulsion suspension of sub-micron drug particles in a solid lipid matrix

Question 45

Self-emulsifying lipid-based formulations prep:

Answer 45

• Preparation involves incorporation of the drug into a oil-surfactant mixture, which is loaded into hard or soft gelatin capsules
• Lipid-based formulations include solutions, emulsions and self-dispersing lipid formulations of poorly-soluble lipophilic drugs e.g. cyclosporin (Neoral), ritonavir (Norvir ) and saquinavir (Fortovase )
• The presence of lipid in the duodenum (<2g; ~2 capsules; or food) stimulates secretion of biliary lipids, generating colloidal micelles, mixed micelles and emulsion droplets
• Digestion of the lipids is often an important step for the bioavailability enhancement of lipid formulations
• The interaction of triglycerides and surfactants with the wall of the GI tract promotes solubilisation and absorption of the drug
• Drugs are absorbed into the intestinal lymphatics (the same way fats in our diet are absorbed), then into the systemic circulation, avoiding first pass metabolism

Question 46

Which one of the following formulation approaches would be most appropriate to address variable and poor bioavailability upon oral administration, for an amphipathic, weakly basic drug with limited aqueous solubility and which is a known substrate for p-glycoprotein?

A: Delayed release colonic delivery solid dose form to reduce variable absorption in the upper intestine
B: Floating dose form to increase retention time in the stomach
C: Liquid filled capsule releasing a self-microemulsifying lipid formulation predominantly in the small intestine – as needs to dissolve and as soon as it is released it can be absorbed
D: Complexation with a hydrophilic anionic polymer matrix dosage form that disintegrates in the small intestine
E: Amorphous solid dispersion from a hot melt extrusion formulation micro-milled into small particles to release in the small intestine – incorrect as it is poorly insoluble so dissolution won’t be achieved

Answer 46

C: Liquid filled capsule releasing a self-microemulsifying lipid formulation predominantly in the small intestine – as needs to dissolve and as soon as it is released it can be absorbed

Question 47

Itraconazole is a triazol anti-fungal administered at 200mg (3 X daily). This weakly basic (pKa ~3.7) drug has a molecular weight of 706, a cLogP of 5.66 and a solubility of <3.5µg/ml. Which one of the following would you consider to be the most suitable oral dose formulation?

A: Immediate release tablet
B: Gastro-retentive dose form
C: Capsule of sugar spheres of drug – puts polar charge on drug
D: Delayed release dose form
E: Cyclodextrin-based liquid formulation (form hydrophilic shell but hydrophobic inside)

Answer 47

E: Cyclodextrin-based liquid formulation (form hydrophilic shell but hydrophobic inside)

• A meal enhances drug absorption
• Pre-systemic clearance by intestinal metabolism, mediated by P450 3A4 isoenzyme (CYP3A4) results in the production of both active and inactive metabolites
• Itraconazole is both an inhibitor and a substrate of CYP3A4
• Itraconazole is both an inhibitor and a substrate of P–glycoprotein
• Significant intra- and inter-patient variability is observed
• High oral doses may result in nausea and/or diarrhoea

Question 48

hy is itraconazole prescribed after a full meal?

Answer 48

• Delays gastric emptying dosage form in stomach longer increases solubility. Lower pH in presence of food, increases dissolution
  • Itraconazole has low solubility and as a very weak base, its protonationand dissolution in stomach is important in determining its absorption
  • Higher gastric emptying rates result in insufficient dissolution in the stomach before the drug is emptied into the intestine for absorption
  • Absorption improved by slower gastric emptying rates after full meal

Question 49

Why may IV itraconazole be considered in seriously ill and chemotherapy patients?

Answer 49

• Ill patients have reduced blood flow, seriously ill people may struggle eating, faster.
  • Difficulties in swallowing oral doses and eating meals
  • Reduced intestinal blood flow
  • IV benefits: rapid attainment of therapeutic levels
  • Avoid first pass metabolism and upregulation/activation of PGP
  • Gastric hypochlorhydria (pH > 4) leading to poor absorption of weak bases is a common condition in seriously-ill, chemotherapy & AIDS patients.

Question 50

Why may itraconazole not be prescribed with H2 antagonists (famotidine), proton pump inhibitors (omeprazole), antacids or didanosine tablets?

Answer 50

drugs interact by reducing gastric acidity, resulting in decreased dissolution & decreased absorption of itraconazole (acid beverage - protonation of weak base e.g. pH 2.5 with 500 mg ascorbic acid)

Question 51

Why may an acidic beverage be recommended?

Answer 51

to increase stomach pH

Question 52

• Why may the itraconazole dose be increased or not prescribed with rifampin, rifabutin, phenytoin, phenobarbital, carbamazepine?

Answer 52

These drugs are all known inhibitors of the PgP efflux pump and CYP
• Drugs induce CYP3A4 causing in decrease absorption
• These effects may last 1-2 weeks after the interacting drugs are stopped.

Question 53

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

Answer 53

Different expressions of protein receptors (Pgp and CY3A4), on other medication, what the patient has eaten in a day etc.
• The close location of P-gp & CYP 3A4 in enterocyte cells & the overlapping substrate specificity results in an an intestinal barrier to a variety of xenobiotics
• Patient diet, underlying disease, drug therapy, pharmacogenetics can all play a role in P-gp expression, resulting in significant person-to-person variation – as much as 4x variation in healthy volunteers and 10x in medical patients). As itraconazole is both an inhibitor & substrate of P-gp, intestinal absorption can change over a period of prolonged exposure.
• Intestinal CYP 3A4 metabolism produces both inactive & active itraconazole metabolites, e.g. the active metabolite hydroxy-itraconazole is ~ 2x as active as itraconazole.

Question 54

Why is there a 60% higher AUC for the oral cyclodextrin-itraconazole solution under fasting conditions, compared to the sugar-coated itraconazole capsule under fasted conditions, and only 30% higher AUC under fed?

Answer 54

Cyclodextrin better absorption because it is more soluble whereas capsule has to disintegrate then dissolve. Fed conditions higher AUC – increases gastric retention time more time for tablet to dissolve.
• sugar-coated drug - poor dissolution in the stomach under fasted conditions, improved after meal (longer gastric retention).
• encapsulation in lipophilic pocket of cyclodextrin improves water solubility.
• improved solubility means less reliance on weak base protonation & dissolution in the stomach, resulting in a large increase in AUC under fasted conditions, a smaller increase seen under fed conditions (higher absorption under these conditions).
• Little cyclodextrin (<3%) is absorbed from gut of healthy adults, 50-60% excreted unchanged in the faeces, the rest is broken down by gut microflora into molecules of glucose.
• Cyclodextrin passing through the gut stimulates intestinal secretion and gastrointestinal propulsion, and may cause nausea and/or osmotic diarrhoea.

Question 55

Sugar spheres compared to pure drug powder?

Answer 55

• sugar spheres dissolve more rapidly than pure drug powder
• amount of drug released from the nanoparticle suspension formulation was 90% within 10 min compared to ~10% from pure drug and ~17% from sugar spheres.
• increase in accessible surface area coupled with the hydrophilic surfactant coating of the smaller nanoparticles may be the reason for the 6x increase in dissolution rate.