Biopharmaceutics Flashcards
emptying stomach has around ____mL of gastric fluid
100
if pH >pKa of an acid. ionisation?
99% ionised
If pH< pKa of an acid?
99% unionsed
Log P is _______ of pH
LogD is _______ of pH
independent
dependent
effect of eating food on the stomach
increases gastric retention time and stimulates acid release, further reducing stomach pH
LogP only measures the ______ form of the drug
ionised
LogD measures….
both ionised and non-ionised which is not affected by pH but the fraction ionised will depend on pH
food ______ transit time of drugs in the stomach
increases
if you have a poorly soluble drug you should take it when in relation to food?
WITH food
you will have a greater time for dissolution to occur.
how can dissolution be aided by our saliva for basic drugs?
saliva is acidic
what is sink conditions?
• 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 in sink conditions?
rate of dissolution
where we have sink conditions what order kinetics are there?
first
[C] intestine >[C] blood
TF: the pH oft he diffusion layer around each particle is the same
no it can be different
if we don’t consider that the pH of the diffusion layer around each particle is different, what can happen?
we can overestimate rates of ionisation and dissolution of weak acids (intestines) and wet bases (stomach)
the dissolution rate of weak acids in the stomach is _____. why
low
because the drug is unionised and therefore poorly soluble in the diffusion layer
how can the pH of the diffusion layer 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 as they release OH ions which promotes drug ionisation
Na and K salts dissolve _____ rapidly than the free acids
MORE
release OH ions which promotes ionisation
TF: all small hydrophilic compounds permeate through paracellular water channels
false, not all do this. some do
Log P is a measure of?
what is it
lipophilicity
the partition coefficient of an unionised drug between aq and lipophilic bases
what does the dissociation constant Ka or pKa describe?
the extent to which a drug is ionised
the pKa is the pH at which [ionised] = [unionised]
what is the pKa
the pKa is the pH at which [ionised] = [unionised]
what is the distribution coefficient?
the effective partition coefficient accounting for the degree of ionisation
WA
D= [HAorg]/ ([HAaq]+ [A-aq])
WB
D= [Borg]/ ([Baq]+[BH+aq])
Distribution coefficient for weak acids equation
D= [HAorg]/ ([HAaq]+ [A-aq])
Distribution coefficient for weak bases equation
D= [Borg]/ ([Baq]+[BH+aq])
D and LogD are pH ______
dependent
and they’re related to P
equation that relates LogD to LogP?
Log D = log P – log {1 + antilog (pKa - pH)}
what is the limitations with the Log D = log P – log {1 + antilog (pKa - pH)} equation when trying to determine logD?
. unstirred conditions, convective flow, absorption of ionised species, different pH at the membrane surface, disruption of the lipid membrane
absorption rate equation?
Absorption rate = VmaxC/(Km+C)
C is the free (un-complexed) drug concentration at the site of absorption (ie GI luminal side of the bio membrane of the epithelial cell)
Km is a constant relating to the affinity of the carrier binding the drug (cf enzymes kinetics)
Vmax is a ‘constant’ relating to the maximum rate of transport or saturation of the carrier (cf enzyme kinetics)
acidicy in the stomach effects a weak base drugs permeability and solubility how?
acidity increases % protonated and hence the solubility increases
charged base is less permeable
when the weak base goes into the intestine what can happen in relation to solubility?
reduces % protonated as the pH increases
reduces solubility and a precipitate may form
the uncharged base is ______ lipophilic and permeable
more
acidicy in the stomach effects a weak acids drugs permeability and solubility how?
increases % uncharged acid
more lyophilic and permeable
decreased solubility- precipitate may form
when the weak acid goes into the intestine what can happen in relation to solubility?
reduces % uncharged acid
increases ionised and solubility
less lipophilic and lower partition into lipid
what maintains a high diffusion tradition for solubilised and permeable fractions of the drug
rapid blood flow
what equation for weak acid is favoured in the stomach?
RCOO- + H+ –> RCOOH
what equation for weak acid is favoured in the intestine?
RCOOH –> RCOO- + H+
what equation for weak bases is favoured in the stomach?
RNH2 + H+ –> RNH3+
what equation for weak bases is favoured in the intestine?
RNH3+ –> RNH2 + H+
effects of food on drug solubility?
can change pH.
drug solubility differs by a factor of 100 over pH range 1-3 hence can cause variable absorption.
if a formulation demonstrates excellent release characteristics at a gastric pH, then a decreased solubility at duodenal pH means what?
nothing
the decreased solubility has little consequence as it can all be absorbed in the stomach
drugs are considered highly soluble when…..
the highest dose required dissolves in <250mL water over a pH range 1-7.5
drugs are considered highly permeable if…..
90% of the administered dose is absorbed
BCS class I
high solubility and high permeability
BCS class II
low solubility
high permeability
BCS class III
high solubility
low permeability
BCS class IV
low solubility
low permeability
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 B: The dose was taken with a meal C: The drug has poor intestinal permeability D: Gastric retention time was increased E: The dose was taken on an empty stomach
E!!!!
A: Gastric solubility is less than intestinal solubility
B: The dose was taken with a meal – increase retention and acidity, this would improve solubility
C: The drug has poor intestinal permeability – doesn’t have this as it has high permeability
D: Gastric retention time was increased – this would improve as it is weakly basic the longer it is in the stomach the better
E: The dose was taken on an empty stomach – decreased solution and therefore decrease bioavailability
____% of new compounds are poorly soluble or lipophilic
40
low drug solubility consequences in the body?
Decreased bioavailability
Increased chance of food effects
Increased issues in patients with diseases, especially GIT problems relating to blood flow
More frequent incomplete release of the drug from the dosage form
Higher inter-patient variability
low drug solubility problems in formulation?
Severely limited choice of delivery technologies
Increasingly complex dissolution testing
Limited or poor correlation with in vivo absorption
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
D!!!
A: Increased chance of food effects
B: Higher inter-patient variability
C: Limited correlation of dissolution testing with in vivo absorption – even a poorly soluble drug is likely to act the same every time.
D: Increased bioavailability – this drug is poorly soluble so you might not get much absorption in the stomach
E: More frequent incomplete release of the drug from the dosage form
what is wettability
measurement of contact angle
what are solid dispersions
eutectic mixture with water soluble carriers
effect of adsorbents?
reduce drug available, unless readily reversible
hydro_____ diluents are used for hydrophobic drugs
hydrophillic
factors that effect solubility and permeability?
Wettability – measurement of contact angle
Surfactants – wetting, solubilisation and permeability enhancing
Particle size – smaller size increase effective surface area
Solid dispersions – eutectic mixture with water soluble carrier
Polymorphs – different solubility, melting point and dissolution rate
pH solubility – weak acid and bases vary as a function of pH
Soluble prodrugs – of poorly soluble drug eg nordiazepam replaced with clorazepate, acid degraded to nordiazepam
Complexation – by excipients, GI mucin, food etc
Adsorbents – reduce drug available, unless readily reversible
Viscosity- enhancing agents, complex drug, increase residence time
Degradation – acid or enzymatic hydrolysis (eg Penicillin G, erythromycin) reduce drug available for absorption
Diluents – hydrophilic diluents for hydrophobic drugs
major issues caused by poor drug solubility
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
Cyclodextrins have a hydro______ interior and a hydro ______ exterior
PHOBIC
PHILLIC
how are cyclodextrins formed?
by
Supersaturating a CD solution with drug, with agitation
Kneading a drug/CD/solvent slurry to a paste, which is dried and sieved
what improves the solubilising effect of Cyclodextrins? meaning?
hydrophilic polymers
so less CD is needed to solubilise the same amount of drug
why are there few oral CD based drugs on the market?
they have toxicity and stability issues
amorphous solid dispersions are _____ soluble
more
what are amorphous solid dispersions prone to?
recrystallisation as they’re more unstable
how can amorphous compounds be created?
by formulation with polymers
spray dry using solvents
hot melt extrusion
what is hot melt extrusion
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
name 4 types of polar excipients?
PEG
gelatin
sugar glasses e.g. insulin
lipids
use of liquid PEG in liquid based dosage forms?
co-solvent to prevent precipitation of compounds that are poorly soluble in aqueous formulations
use of PEG in solid dosage forms?
wetting agent or enhances dispersion
incorporated by solvent evaporation or freeze drying
what is gelatine, how is it polar?
• A naturally derived collagen extract with both positive and negative charges , which bind to the poorly soluble compound
what can gelatine be used for?
to improve the wettability of hydrophobic compounds when used as a granulating agent
what are sugar glasses?
A naturally occurring fructose
what administration is PEG in liquid dosage forms safe to use?
topical and parenteral administration
what administration are sugar glasses safe for use?
parenteral
pulmonary
how can sugar glass be created?
Mixing an inulin solution with a drug solution, followed by freeze drying
sugar glasses effect on drugs?
improve the dissolution profile of the drug and protect it from physical and chemical degradation, increasing stability
examples of drugs where sugar glass has been used?
Cyclosporin, diazepam, amoxicillin, bacitracin, tetrahydrocannabinol
when are lipids used as polar excipients?
Lipids are used as polar excipients in self emulsifying systems e.g. lymphatic delivery
effect of reducing particle size on dissolution?
Reducing particle size increases surface area and usually improved dissolution properties, enabling the use of a wider range of formulations and delivery approaches
what is needed for recrystallisation of poorly soluble materials using liquid solvents and anti-solvents to reduce particle size? effect of this
organ solvents for processing
means a more complicated manufacture
conventional comminution and spray drying rely upon? what is the effect of this?
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
what compounds is conventional comminution and spray drying not suitable for?
thermo sensitive or unstable compounds
why is there higher absorption and dissolution in the SI
absorption: higher SA to volume ratio
dissolution: greater transit time- window for absorption
benefits of nanoparticle formulations on drug delivery?
greater F- higher Cmax and AUC
less variability with food: small difference between fed and fasted F
dose proportionality: AUC proportional to dose
TF: comminution e.g. grinding and milling can reduce the particle size sufficiently for nearly insoluble drugs to <0.1mg/mL
false, these methods are often incapable of reducing the particle size sufficiently
what can micromilling do?
may operate down to sub-micron sizes, with physical and thermal stresses
what do piston gap methods create?
drug nanoparticles through hydrodynamic cavitation
how do supercritical fluids create nanoparticles?
by control of solubility using pressure and temperature in solvents such as CO2
what are supercritical fluids used in?
in manufacture as an effective means of producing different sizes and shapes of drug particles.
examples of supercritical fluids?
CO2 and water
what makes CO2 and water supercritical fluids?
at a temperature and pressure above their thermodynamic critical points, assume the properties of both a liquids and a gas.
properties of SCFs like a gas
properties of SCFs like a liquid
can diffuse through solids like a gas
can dissolve materials like liquids
how can SCFs reduce particle size?
• 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 ______. what does this allow.
compressible
allowing moderate changes in pressure or temperature to greatly alter their density
at near critical temperatures SCFs are highly compressible. what does this allow.
allows moderate changes in pressure or temperature to greatly alter their density
manipulation of the pressure of SCFs effects?
improves diffusivity and reduces viscosity and surface tension
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
D
in self emulsifying systems: non-ionic surfactants improve drugs _______. what does this prevent
solubilisation
prevents drugs from precipitating out of the microemulsion
what are tweens used for in self emulsifying systems?
polysorbates
they have high hydrophile-lipophile balances (HLB) are used to ensure an immediate formation of oil-in-water droplets during production
what are co-solvents/ surfactants used for in self emulsifying systems?
are used to increase the amount of drug dissolved into the lipid base
PEG, ethanol
what’s involved in the preparation of self emulsifying lipid based formulations?
involves incorporation of the drug into a oil-surfactant mixture, which is loaded into hard or soft gelatin capsules
the presence of lipid in the duodenum stimulates?
stimulates secretion of biliary lipids, generating colloidal micelles, mixed micelles and emulsion droplets
in self emulsifying lipid based formulations, what is the most important step for the bioavailability?
digestion of the lipids
in lipid formulations, what interactions promotes solubilisation and absorption of the drug
interactions of triglycerides and surfactants with the wall of the GIT
how are lipid formulations absorbed? do they undergo first pass?
into the intestinal lymphatics- like fats in our diet
then into systemic circulation
they dont undergo first pass
LogP of ____ facilitates absorption into the intestinal lymphatics
5
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.
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
C!!!
A: Delayed release colonic delivery solid dose form to reduce variable absorption in the upper intestine – solid dosage form only to be released in the colon
B: Floating dose form to increase retention time in the stomach – we do want absorption in stomach but it has limited aqueuous solubility as you won’t get complete dissolution
C: Liquid filled capsule releasing a self-microemulsifying lipid formulation predominantly in the small intestine. - Already dissolved so combated limited solubility. Lipid formulation will also promote absorption
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
