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
Slide 6,7 + 8
Improve dissolution
Increase the effective surface area
Reduce the thickness of the stagnant diffusion layer
Increase the concentration gradient
Slide 10
Increase rate of dissolution
The 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 homogeneous 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
