Biopharmaceutics of oral dose formulation Flashcards
What happens to drug formulations as they near dissolution?
Drug breaks up into small molecules which allow it to be solubilised and then absorbed
What can happen to drug molecules as they move further into the GI tract?
It is possible for molecules to become less soluble and precipitate out of solution
What layer surrounds the drug particle in solution?
Saturated diffusion layer with a high concentration. As you move further away from the diffusion layer down the concentration gradient, concentration decreases
What are sink conditions when describing the saturated diffusion layer?
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 sink conditions for dissolution?
The rate of dissolution
What can we assume when we have sink conditions in dissolution?
First order kinetics: [C] intestine > [C] blood
What is the dissolution rate of weak acids in the stomach?
Low, because the drug is unionised and therefore poorly soluble in the diffusion layer
How might the pH of the diffusion layer of a weak acid be increased?
By forming an alkaline salt of the weak acid. As it dissolves, hydroxide ions would be released, increasing pH and promoting dissolution
Why do Na and K salts dissolve more rapidly than free acids?
Because they release OH- ions which promotes drug ionisation (independent to local pH)
What route for drug molecules crossing the gut wall is most observed?
Most drug molecules cross the gut wall via a number of different drug transporters
What is Log P
Log P is a measure of lipophilicity: it is the partition coefficient of an unionised drug between aqueous and lipophilic phases
ONLY considers unionised drug, not drugs that may be partially ionised
What is pKa?
The dissociation constant, it describes the extent to which a drug is ionised
pKa is the pH at which …?
[ionised]=[unionised]
What is used instead of LogP to take into account ionised forms of drug?
LogD
What is D?
Distribution coefficient (D) is the “effective” partition coefficient accounting for the degree of ionisation
What is the equation for Weak acids D?
D = [HA org] / {[HA aq] + [A- aq]}
What is the equation for weak bases D?
D = [B org] / {[B aq] + [BH+ aq]}
What is D dependent on?
pH
What is the equation for logD?
Log D = log P – log {1 + antilog (pKa - pH)}
What are the limitations associated with log D?
- unstirred conditions
- convective flow
- absorption of ionised species
- different pH at the membrane surface
- disruption of the lipid membrane
What is required for carrier-mediated transport?
Energy
What is the absorption rate in carrier-mediated transport assumed to be?
It is assumed to be the rate of carrier mediated membrane transport
What is the absorption rate in carrier-mediated transport equal to?
Absorption rate = Vmax . C /(Km + C)
What is C?
C is the unbound drug concentration at the site of absorption (i.e. GI luminal side of the biomembrane of the epithelial cell)
What is Vmax?
Vmax is a constant relating to the maximum rate of transport or saturation of the carriers (cf enzyme kinetics)
What is Km?
Km is a ‘constant’ relating to the affinity of the carrier binding the drug (cf enzyme kinetics)
Where are weakly basic drugs soluble?
In the stomach
What conditions in the stomach alter the weakly basic drug?
Food increases time for dissolution, stays in the stomach for a longer period of time. Also, acidity increases % protonated base and solubility of drug. Protonated (charged) base is less lipophilic and less permeable.
RNH2 + H+ –> RNH3+
What happens to the weakly basic drug when it moves into the small intestine?
o Emptying into increased pH reduces % protonated base and solubility, precipitate particles may form (worse solubility)
o Uncharged base is more lipophilic and permeable
o Rapid blood flow maintains high diffusion gradient from particles (sink conditions) – good absorption
o Blood flow is variable between people – after food, blood flow is high in the intestine
o Decreases if resting or ill
RNH3+ –> RNH2 + H+
What happens to weakly acidic drugs in the stomach?
RCOO- + H+ –> RCOOH (HA)
Food increases time for dissolution, acidity increases % uncharged acid (further reduces pH) and further delays dissolution. More lipophilic and permeable, but decreases solubility, precipitate particles may form. Less surface area - poor absorption
What happens to weakly acidic drugs in the small intestine?
RCOOH –> RCOO- + H+
o Emptying into increased pH reduces % uncharged acid, increases % ionised and solubility – favourable o Charged (ionised) acid less lipophilic and lower partition into lipid – more soluble o Uncharged form is what is permeated through the gut wall – small proportion rapidly absorbed and replaced o Even though absorption is unfavourable because there is a higher amount of IONISED form, there is enough UNIONISED to be absorbed and create a concentration gradient o Rapid blood flow maintains high diffusion gradient for solubilised and permeable fraction of drug
What is the pKa of very weak acids?
> 8, unionised at most pH values
What is the pKa of moderately weak acids?
2.5-7.5, unionised at gastric pH, ionised at intestinal pH
What is the pKa of strong acids?
<2, ionised at most pH values
What is the pKa of very weak bases?
<7, unionised at most pH values
What is the pKa of moderately weak bases?
7-10, ionised at gastric pH, largely unionised at intestinal pH
What is the pH of strong bases?
> 11, ionised at most pH values
What is the effect of food on solubility?
In the stomach (low pH), variable absorption may be seen depending on pH of fed or fasted stomach of the patient
What is the effect of formulation on solubility?
If formulation allows good solubility in stomach – will have good solubility when it reaches intestine with a big surface area – drug in equilibrium, as soon as some absorbs – more will follow
What is the effect of highly acidic conditions (stomach) on drug log D and permeability?
Drug (rifampicin) exhibits high solubility yet unfavourable logD /permeability due to lower surface area of the stomach.
In highly acidic conditions, there is LOW permeability (negative log D)
What is the effect of less acidic conditions (duodenum pH4-6) on drug log D and permeability?
- 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
- LogD increases with increasing pH (increasing lipophilicity/permeability)
What is the effect of basic conditions (ileum & colon, pH 6-8) on drug log D and permeability?
- 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
- Good surface area and sink conditions
What is the effect of formulation on log D and permeability?
- 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
What is a Biowaiver?
When drug companies don’t need to show in vivo bioavailability waiver to get approval
What is BCS class 1?
High solubility and High permeability
*Eligible for biowaiver
What is BCS class 2?
Low solubility and High permeability
*Eligible for biowaiver only if weak acids, highly soluble at pH6.8, plus dissolution
What is BCS class 3?
High solubility, Low permeability
*Eligible for biowaiver if rapidly dissolving
What is BCS class 4?
Low solubility, Low permeability
*NOT eligible for biowaiver
When are drugs considered highly soluble?
When the highest dose required dissolves in 250ml or less water over a pH range of 1-7.5
When are drugs considered highly permeable?
If >90% of the administered dose is absorbed
What solubility of drugs will cause significant problems?
<0.1mg/ml
What is a possible cause for decreased bioavailability of a weakly basic BCS class 2 drug?
If the dose was taken on an empty stomach, there will be decreased solubility and therefore bioavailability
What problems during formulation do low solubility compounds create?
- 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
How would you enhance permeability of a drug?
Absorption enhancing excipients, efflux inhibitors, lipid-filled capsules, GI motility consideration
How would you enhance solubility of a drug?
Particle size reduction, soluble salts, solid dispersions, self-emulsifying systems, surfactants, nanoparticles, cyclodextrin, pH diffusion layer
How would you enhance permeability AND solubility of a drug?
Prodrugs, salt forms, co-solvents, solubilisation by surfactants, lipid-filled capsules, nanoparticles, liposomes, lyophilisation
What are some 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
List 5 different ways to improve solubility
- Cyclodextrins
- Amorphous solid dispersions
- Polar excipients
- Particle engineering
- Self emulsifying systems
What are cyclodextrins and why are they used to improve drug solubility?
They have a hydrophobic interior and hydrophilic exterior, so form cage-like complexes with hydrophobic compounds (drug hidden inside hydrophilic cage)
How are Cyclodextrin compounds formed?
By supersaturating a CD solution with drug, with agitation conditions OR by kneading a drug/CD/solvent slurry to a paste, which is dried and sieved
What can be used to improve the solubilising effect of CDs?
Hydrophillic polymers (e.g. HPMC) - so LESS CD is needed to solubilise the same amount of drug
What is the issue with oral CD-based drug products?
They have toxicity and stability issues
What are amorphous compounds?
More soluble, but more unstable and prone to recrystalisation
How are amorphous compounds created?
By formulating a drug with polymers:
• Spray dry using solvents or replace with supercritical fluids
• OR 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 polar excipients
- Polyethylene glycol (PEG)
- Gelatin
- Sugar glasses e.g. inuin
- Lipids
What is PEG used for and how does it work?
- 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
What is gelatin and how does it act?
- 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
What are sugar glasses and how do they work?
- 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
What are lipids and how doe they work?
Lipids are used as polar excipients in self emulsifying systems e.g. lymphatic delivery
What does reducing particle size during particle engineering do?
Reducing particle size increases surface area and usually improved dissolution properties, enabling the use of a wider range of formulations and delivery approaches
What does recrystallisation of poorly soluble materials using liquid solvents and anti-solvents to reduce particle size require ?
Organic solvents for processing, increasing the complexity of manufacture
What do conventional comminution and spray-drying techniques of particle reduction rely on?
Mechanical stresses to disintegrate 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
Why do nanoparticles have much better dissolution?
Because they have a high surface area to particle size ratio - drug is therefore absorbed faster
What are the benefits of nanoparticle formulations on drug delivery?
- Rapid increase in blood concentration of drug with time, higher bioavailability, Cmax and AUC
- less variability in fed/fasted responses in nanoparticle formulation
- AUC proportional to dose, good predictable response
What drugs are nanoparticulation used in?
Dolargin, Loperamide, tubocuraine, doxorubicin, ibuprofen, diazepam, naproxen, carbamazepine, griseofulvin, nifedipine, phytosterol
What methods of size reduction are often incapable of sufficiently reducing the particle size for nanoparticles?
Traditional methods of comminution, such as grinding and milling
What method may operate down to sub-micron sizes?
Micro-milling, with physical and thermal stresses - not appropriate for unstable or heat-sensitive drugs
What methods are there to create nanoparticles?
- Piston gap methods create drug nanoparticles through hydrodynamic cavitation
- Supercritical fluids (SCFs) create nanoparticles by control of solubility using pressure and temperature in solvents such as carbon dioxide (MORE COMMONLY USED)
Give examples of SCFs
Carbon dioxide, water
What properties do SCFs have?
- At a temperature and pressure above their thermodynamic critical points (above triple point and critical point), assume the properties of BOTH a liquid and a gas – important for formulation options
- They can diffuse through solids like liquids and dissolve materials like a liquid
- SCF-solubilised drug particles may be re-crystallised at greatly reduced particle sizes, often 5 – 2000nm in diameter – very controlled manor
At near critical temperatures what happens to SCFs?
They are highly compressible, allowing moderate changes in pressure or temperature to greatly alter their density, mass transport and solvating power
What are self emulsifying systems?
• 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
What does the preparation of a self emulsifying lipid-based formulation involve?
Involves incorporation of the drug into an oil-surfactant mixture, which is loaded into hard or soft gelatin capsules
What do 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 )
What does the presence of lipid in the duodenum stimulate?
Stimulates secretion of biliary lipids, generating colloidal micelles, mixed micelles and emulsion droplets
What in a lipid-based formulation promotes solubilisation and absorption of the drug?
The interaction of triglycerides and surfactants from formulation with the wall of the GI tract.
How are lipid-based formulation absorbed?
High lipophilicity (logP 5) facilitates absorption into intestinal lymphatics (same way fats in diet are absorbed) and then into systemic circulation, avoiding first pass metabolism
Why is itraconazole prescribed after a full meal?
o Itraconazole has low solubility and as a very weak base, its protonation
o and dissolution in stomach is important in determining its absorption
o - Higher gastric emptying rates result in insufficient dissolution in the
o stomach before the drug is emptied into the intestine for absorption
o - Absorption improved by slower gastric emptying rates after full meal
o Delayed gastric emptying – in stomach for longer, increased dissolution, increased acid secretion – more increased dissolution
o Weak base – ionised in the stomach – increases solubility
Why may IV itraconazole be considered in seriously ill and chemotherapy patients?
o Difficulties in swallowing oral doses and eating meals
o Reduced intestinal blood flow
o IV benefits: rapid attainment of therapeutic levels
o Avoid first pass metabolism and upregulation/activation of PGP
o Gastric hypochlorhydria (pH > 4) leading to poor absorption of weak bases is a common condition in seriously-ill, chemotherapy & AIDS patients
o Immediate absorption – straight into the blood – quicker therapeutic levels
o Reduced blood flow in intestine in seriously ill people
o Ill patients may not be able to swallow tablets
o Pgp effluxes many cancer drugs, IV wont inhibit Pgp
Why may itraconazole not be prescribed with H2 antagonists, PPIs, antacids or didanosine tablets, and why may an acidic beverage be recommended?
o 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)
o PPIs to prevent release of acid – so pH of stomach will be higher
o Need low pH to have a significant effect
Why may the itraconazole dose be increased or not prescribed with rifampicin, rifabutin, phenytoin, phenobarbital, carbamazepine?
o Drugs induce CYP3A4 causing in decrease absorption
o These effects may last 1-2 weeks after the interacting drugs are stopped.
Why may intestinal absorption of itraconazole vary in the same patient and between different patients?
o The close location of P-gp & CYP 3A4 in enterocyte cells & the overlapping substrate specificity results in an intestinal barrier to a variety of xenobiotics
o 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.
o Intestinal CYP 3A4 metabolism produces both inactive & active itraconazole metabolites, e.g. the active metabolite hydroxy-itraconazole is ~ 2x as active as itraconazole.
• 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 conditions?
o sugar-coated drug - poor dissolution in the stomach under fasted conditions, improved after meal (longer gastric retention).
o encapsulation in lipophilic pocket of cyclodextrin improves water solubility.
o 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).
o 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.
o Cyclodextrin passing through the gut stimulates intestinal secretion and gastrointestinal propulsion, and may cause nausea and/or osmotic diarrhoea.
What dissolves more rapidly, sugar spheres or pure drug powder?
Sugar spheres
