Lecture 15- Biopharmaceutics II Flashcards
Importance of dissolution
Dissolution/solubilisation= key to bioavailability
Drug dissolution in the GI tract = primary step in the oral absorption process from a pharmaceutical dosage form
Only dissolved drug= permeates the mucosa at the absorptive sites of the GI tract
Drug solubility data= used as a rough predictor for bioavailability in the future
Definitions
Absolute/ intrinsic solubility= max amount of solute dissolved in a given solvent under standard conditions of temp, pressure + pH= static property
Dissolution= solid substance enters into a solvent to yield a solution; e.g. mass transfer from the solid surface to liquid phase = dynamic property
Rate of dissolution= amount of drug substance that goes into solution per unit time under standard conditions; pH, solvent composition + constant solid surface area
Dissolution and Noyes-Whitney Equation
Rate of dissolution of a solid in solvent = dc/dt
*go over maths
Slide 6,7 + 8
Improve dissolution
Increase the effective surface area
Reduce the thickness of the stagnant diffusion layer
Increase the concentration gradient
Equation- s10
Surface area should be increased;
= allows more access for water to surround the particles
Motility should be increased;
= takes away the dissolved drug to allow more to be dissolved by water
= stirring speeds up the process and makes a more homogenous mixture
Sink conditions
The ability of the dissolution media to dissolve at least 3 times the amount of drug that is in the dosage form
-improves robustness + is more physiologically relevant
Achieved by;
- increasing vol of dissolution fluid
- increasing the drug solubility by adding a water miscible solvent to the dissolution media
- replenishing the dissolution media constantly with a fresh solvent
- adding selective adsorbents to remove the dissolved drug
Slide 12,13 + 14
Factors affecting dissolution rate
Surface area of undissolved solid (particles size etc)
Polymorphism
Amorphous state
Free acid, free base + salt form
Complexation, solid solutions
Excipients; diluents, surfactants etc
Drug particle size vs Effective surface area
Inversely proportional to each other
Effective surface area- area of the solid surface exposed to the dissolution medium
-directly related to the dissolution rate
-greater the ESA = more intimate the contact between the solid surface + aqueous solvent and
the faster the dissolution
-micronisation + super critical fluid tech = increase the rate of absorption of drugs like = griseofulvin
Particle size issues
Nitrofurantoin was ground to reduce particle size
Sizes below 10um side effects; nausea, vomiting, GI irritation were observed= indicative of toxicity
Polymorphism
Substance that exists in more than one crystalline form
-Solubility may be affected by crystal form
-Stable polymorphs have lower energy state, higher mp + lower aqueous solubility
-Metastable polymorphs have higher energy state, lower mp + higher aqueous solubility
Amorphism
Form of drug that has no internal crystal structure
-represents higher energy state + greater aqueous solubility than crystalline forms
E.g. amorphous form of novobiocin is 10x more soluble than the crystalline form
-excipient may be used to stabilise the amorphous form e..g povidone
Amorphous > metastable > stable
Excipients in dissolution
Inert materials added to dosage forms to;
- improve manufacturability, appearance, texture, taste + bioavailability
Diluents; fillers/bulking agents
Allow formulation of a normal size tablet
Expected to have no effect on the bioavailability but certain diluents have an effect on the solubility of a drug
Surfactants
Wetting agents to aid the dissolution of poorly soluble drugs
-decrease aggregation thus increase dissolution
-disrupt membranes - increase absorption
*may also form micelles that prevent the drug from being absorbed
Viscosity enhancing agents
Used mainly for organoleptic purposes
Overall GI contents have increased viscosity;
-gastric motility is reduced
-reduced dissolution
-reduced GI emptying
Salt form of the drug
Some neutral compounds + some have an ionic charge
-physiological fluids= not neutral
-solubility of ionic material= highly dependent on the pH of the solvent
-ionised compounds= dissolve faster than unionised compounds
-disso rate of weak acids + bases= enhanced by converting them into their salt form
*weakly acid drugs= strong base salt is prepared
*weakly basic drugs= strong acid salt is prepared
pH, pKa + ionisation
pKa = acid dissociation constant to describe acidity of a particular molecule
Strong acids = low pKa values
Weak acids = higher pKa values
Weak acid= ionised; pH above the pKa value; neutral/basic conditions
Weak acid= unionised; pH below the pKa value; acidic conditions
Henderson-hasselbalch equation- slide 25,26 + 27
Salts to improve solubility
Slide 29
Compression force
Influence of compression force on dissolution rate of tablet
- increased density/ hardness, decreased porosity/ solvent penetrability
-increased deformation/ fracture, particle changes/ increased effective SA
