Oral Dosage Form Flashcards
Define dissolution
Disintegration of granules into fine particles
When does [C] fall?
When absorption is dissolution rate limited due to absorption or partitioning of the drug.
What happens when [C] falls?
Drug molecules are immediately replaced and rapidly saturate the diffusion layer, as drug diffuses away from the saturated layer into bulk fluids
What can cause the pH of the unstirred diffusion layer to be different
- Over predicting ionisation and dissolution of weak acids and weak bases
- Dissolution rate of weak acid in the stomach is low because of low solubility of the drug in the diffusion layer
How may the diffusion layer pH be increased?
By forming an alkaline salt of the weak acid
How do small hydrophilic compounds permeate?
Paracellularly
How do lipophilic molecules permeate?
Transcellularly
What does the pH partition hypothesis of absorption of ionised drugs depend on?
Ka or pKa and partition coefficient (P)
What is pKa defined as?
The pH at which [ionised] = [unionised]
What is distribution coefficient (D) defined as?
What does it depend on?
An ‘effective’ partition coefficient, accounting for the degree of ionisation
Depends on pH and is related to P for a weakly basic drug
Can be approximated at any pH using pKa of a drug
What is the equation of carrier-mediated transport absorption rate?
Vmax*C / Km + C
What is Vmax?
The constant relating to the maximum rate of transport or saturate of the carriers
What is Km?
The constant relating to the affinity of the carrier binding of the drug
What effect does food have on gastric emptying?
Decreases it
Blood flow increases when stimulated by gastric secretions
What happens when a weakly basic drug enters the stomach?
Food increases time for dissolution, the acidity increases the percentage protonated base and increases the solubility of the drug
The charged base is less lipophilic and is less permeable
What happens when a weakly basic drug enters the small intestine?
The percentage of the protonated based reduces, as does the solubility, therefore precipitates are more likely to form.
What happens when a weakly acidic drug enters the stomach?
Food increases time for dissolution, acidity of the stomach increases the percentage of uncharged acid.
The molecule becomes more lipophilic and permeable but it’s solubility decreases and precipitation may occur
What happens when a weakly acidic drug enters the small intestine?
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
Discuss very weak acids (pKa>8) in terms of ionisation, solubility and permeability
Unionised at most pH values
Solubility may be poor / not really affected by pH
Permeability is okay but may be affected by pH
Discuss moderately weak acids (pKa 2.5 - 7.5) in terms of ionisation, solubility and permeability
Unionised at gastric level, ionised at intestinal pH
Solubility poor in the stomach and improved in the small intestine
Permeability is okay in the stomach but may be decreased in the small intestine
Discuss stronger acids (pKa<2) in terms of ionisation, solubility and permeability
Ionised at most pH values
Solubility and Permeability may be okay or mildly affected by pH
Discuss very weak bases (pKa<7) in terms of ionisation, solubility and permeability
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
Discuss moderately weak bases (pKa 7 - 10) in terms of ionisation, solubility and permeability
Ionised as gastric pH, largely unionised at intestinal pH
Solubility okay in GI but decreased in the intestine
Permeability is poor in the stomach but improves in the intestine
Discuss strong bases (pKa>11) in terms of ionisation, solubility and permeability
Ionised at most pH values
Solubility is okay/mildly affected
Poor permeability and isn’t really affected by pH
What properties do drugs in Class I of the BCS have?
High solubility
High permeability
What properties do drugs in Class II of the BCS have?
Low solubility
High permeability
What properties do drugs in Class III of the BCS have?
High solubility
Low permeability
What properties do drugs in Class IV of the BCS have?
Low solubility
Low solubility
When are drugs considered to be highly soluble?
When the largest dose is soluble in <250ml of water over a range of pH’s
Why would a weakly basic BCS class II have low bioavailability when given as an immediate release ODF?
Goes straight to the intestine undissolved
Should ideally be given with food to increase dissolution time
What are the issues associated with low drug solubility in vivo?
- Decreased bioavailability
- Increased chance of food effects
- Increased issues with disease states
- Increased incomplete release
- Higher patient intervariability
What are the issues associated with low drug solubility in vitro?
- Limited choice of delivery technologies
- Complex dissolution testing
- Limited/poor correlation with in vivo absorption
What are the factors affecting dissolution and absorption
Wettability Surfactants Particle size Solid dispersions Polymorphs pH solubility Soluble prodrugs Complexation Adsorbents Viscosity enhancers Degradation Diluents
What are the major issues with poor drug solubility?
Poor bioavailability Sub optimal dosing Food effects Lack of dose-response proportionality Inability to optimise lead compound selection based on efficacy and safety Harsh excipients Use of extreme basic/acidic conditions Uncontrollable precipitation after dosing Patient non-compliance
How are cyclodextrins formed and how do they improve solubility?
Formed through supersaturating a CD solution with a drug and mildly agitating the solution OR by adding a mass of drug to a CD and solvent slurry
They allow non-polar molecules to be dispersed in water
What is the advantage and disadvantage of solid dispersions
They tend to be more soluble but can be unstable
How are amorphous soli dispersions formed?
Spray dry using solvents or replace supercritical fluids
Hot melt extrusions: soften the polymer, add API and mis to form strands of polymeric glass with embedding API and then mill the glass strands into a powder
Give examples of polar excipients
PEG
Gelatin
Sugar glasses
Lipids
How is PEG used as a polar excipient?
Helps to prevent precipitation of poorly aqueous materials. It is used as a dispersion-enhancer or as a wetting agent in SDFs
It may also be used in combination with other surfactants
How is gelatin used as a polar excipient?
Can improve the gettability of hydrophobic compounds when used as a granulating aid
How is sugar glass used as a polar excipient?
Inulin is a fructose polymer, it is mixed with a drug solution then freeze dried to form a sugar glass
They protect the API against physical and chemical degradation which increases stability
How does re-crystallisation reduce particle size?
Uses liquid solvents and anti-solvents
What is the disadvantage of communition and spray drying?
May induce degradation or thermal stress the processing thermo sensitive or unstable active compounds
What is the ideal particle size to increase absorption by 41.5 fold?
5µm - 120nm
Where in the GI is there higher absorption?
The small intestine because there is a higher surface area, there is a greater window absorption
What are the benefits of nanoparticles?
- Greater bioavailability = higher Cmax and AUC
- Less variability with food: smaller difference between fed and fasted states
- Dose proportional to AUS
Give examples of drugs that nanoparticulation is used for
Dolargin Loperamide Tubocuranine Doxorubicin Ibuprofen Diazepam Naproxen Carbimazole Nifedipine Phytosterol
How far does micro milling operate?
Sub micron states
How do piston gap methods creasy drug nanoparticles?
Through hydrodynamic cavitation
How do supercritical fluids create nanoparticles?
By control of solubility using pressure and temperature in solvents
What properties do SCFs have?
They can diffuse through solids like a fas, and dissolve materials like a liquid
At near critical temperatures they are high compressible allowing moderate changed in pressure or temperature to alter density, mass transport and solvating power
What does manipulation of SCFs allow?
Favourable characteristics of gases to be put in liquids to precisely control drug solubilisation
What do non-ionic surfaces allow for?
Higher degrees of drug solubilisation and avoid precipitation of the drug out of the micro emulsion in vivo
What do lipids in the duodenum stimulate?
Secretion of biliary lipids, generating colloidal micelles, mixed micelles and emulsion droplets
Why is digestion of lipids important?
Important for enhancing bioavailability of lipid solutions
What occurs when triglycerides and surfactants react with the walls of GIT
There is a solubilising effect
How do lipids increase solubilisation?
Lipids facilitate absorption into intestinal lymphatics and then into systemic circulation, avoiding 1st pass.
How are lipid based formulations prepared?
Through incorporation of a drug into an oil-surfactant mix, until a clear solution is formed, and filled into hard or soft gelatin capsules.
How does drug co-adminstration with lipids enhance absorptions?
High lipophilicity facilitates absorption into the intestinal lymphatics and then into systemic circulation, avoiding first pass metabolism
