Drug Solubility and Dissolution Rate Flashcards
Why should a pharmacist understand solubility and dissolution rate ?
Most drugs will “function” in solution in the body.
Poorly soluble compounds tend to be eliminated from the GI tract before dissolution
Drugs must dissolve before being absorbed:
Need to determine the rate and extent of
absorption; bioavailability (BA).
Low aqueous solubility frequent BA problems
= Poor bioavailability
Solution
Molecular dispersion formed by 2 or more components which form a ‘one phase’ homogeneous system.
A mixture of two or more components that forms a single phase which is homogeneous down to the molecular level.
Can be applied to solid, liquid and gaseous state
miscibility
Solvent
The component that determines the phase of the solution is termed ‘solvent’.
Solvent usually constitutes the largest proportion of the system.
Solutes
Are other components of the solution.
Are dispersed as molecules or ions throughout the solvent.
i.e. Are dissolved in the solvent
Saturated solution
Solute is in equilibrium with the solid phase (solute).
Solubility (in quantitative terms)
The concentration of solute in a saturated solution at a certain temperature
Commonly as ‘the maximum mass or volume of solute that will dissolve in a given mass or volume of solvent at a particular temperature’.
e.g. The solubility of ‘nitrofurantoin’ (antibiotic for urinary infections) in water at 37oC is 174mg dm-3.
Solubility (in qualitative way)
The spontaneous interaction of 2 or more substances to form a homogenous molecular dispersion.
Unsaturated or subsaturated solution
The dissolved solute is in concentration below that necessary for complete saturation at a definite temperature.
Supersaturated solution
Contains more of the dissolved solute that it would normally contain at a definite temperature.
E.g. Salts such as sodium thiosulfate and sodium acetate
Dissolution in large amounts at an elevated temperature.
upon cooling, fail to crystallize from the solution.
DISSOLUTION
For a drug to be absorbed, it must first be dissolved in the fluid at the site of absorption.
e.g. Oral administered tablet -> dissolved/solubilized by the GI fluids -> absorption
Dissolution describes the process by which the drug particles dissolve.
Dissolution rate
The rate of dissolution is determined by the slower step.
The interfacial steps ( I& II) are virtually instantaneous.
The rate of dissolution is determined by the diffusion of the solute through the static boundary layer.
The rate of mass transfer of
solute molecules (or ions) through
a diffusion layer is:
Directly proportional to the
area available for migration
and the C across the
boundary layer
- Inversely proportional to the
thickness of the diffusion layer
in solution
Dissolution rate can be raised by:
increasing the surface area
of the drug by reducing
particle size
increasing drug solubility
in diffusing layer.
Increasing k
Schematic representation of the dissolution of a drug particle in the gastrointestinal (GI) fluids:
If dissolution fast/or drug delivered remained in solution:
The rate of absorption is primarily dependent upon its ability to traverse the absorbing membrane.
If drug dissolution slow (physicochem. properties/formulation factors):
Dissolution may be the rate-limiting step in absorption
-> influence drug bioavailability.
Factors affecting dissolution rate
A- size of particles, dispersibility, surfactants and bile salts
Cs- temp, solvent and solute, ph , crystalline from, micelles
C- volume of dissolution, any process that removes solute and solution
D- viscosity of solvent, Prescence of food
h- stirring GI mobility
The influence of Temperature- dissolution
Dissociation in water -> endothermic
Its solubility increases with rise in ToC until 32.5oC is reached.
Above 32.5oC, the solid is converted to the anhydrous form.
Dissolution-> exothermic
Change of slope from (+) to (-) as the ToC exceeds the transition value.
structure of solute - use of salt increases solubility
Salt form of a drug instead of the free acid (a weak acid).
The sodium salt has a higher degree of dissociation in water
Increased interaction with the solvent
Increased solubility
percentage Weak acids and bases in Pharmacy
~70% of drugs are weak bases- cocaine
metoclopramide
ropinirole
chlopromazine
many amine drugs
usually hydrochloride salts
~20% of drugs are weak acids-naproxen
non-steroidal anti-inflammatories
phenobarbital
barbiturates
nitrofurantoin
phenylbutazone
~5% are non-ionic, amphoteric, or alcohols
Changes in pH within the gastro-intestinal tract (pH 1-8)
changes in ionisation
ionised forms are more soluble than unionised
hence, solubility will change with pH
a drug must dissolve before it can be absorbed
drug solubility determines the rate and extent of absorption
weak acid A- > HA when
pH > pKa
weak acid HA > A- when
pH < pKa
weak base - B > BH+ when
pH > pKa
weak base- BH+ > B when
pH < pKa
Solubility of weak acids as a function of pH
HA equilibrium arrow H+ + A-
unionized (free) form,
low solubility (So)*
Decrease pH (add H+)
Increase proportion of unionised form (less soluble)
Low solubility
ionized form,
higher solubility
Increase pH (remove H+)
Increase proportion
of ionised form (more soluble)
High solubility
Weak acids can form salts with positive ions (cations
When, for example, Na+A- is dissolved in water, a different equilibrium is established:
Na+A- + H2O HA + NaOH
Dissolution of salt of a weak acid pH increased
The solubility of a weakly acidic drug can be predicted given: (a) the pH of the solution, (b) the pKa, and (c) the solubility of the free (unionised) form of the drug (its so-called intrinsic solubility, S0)
The solubility of a weakly acidic drug:
(a) increases by about 10x for each unit of pH above the pKa,
(b) approaches S0 as pH decreases below the pKa, and
(c) equals {2 x S0} when the pH equals the pKa.
If the salt of a weak acid is used instead of the free form
The pH of the solution increases
The solubility increases
BUT, if solution pH is lowered, precipitation of free acid form may occur
If the salt form of a weak base is used:
The pH of the solution falls
The solubility increases
BUT, if pH is increased, precipitation of the free base may occur
The solubility of a weakly basic drug:
(a) increases by about 10x for each unit of pH below the pKa,
(b) approaches S0 as pH increases above the pKa, and
(c) equals {2 x S0} when the pH equals the pKa.
What happens in the GI?
A weak base has a high dissolution rate in the stomach, but the dissolution rate falls as the pH of the GI tract rises.
A weak acid has minimal dissolution in the stomach but its dissolution rate increases down the gut.
