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.
Salts and pH of the diffusion layer
The use of the salt form modifies the pH of the diffusion layer.
Salt of a weak acid increase the pH of the diffusion layer
Salt of a weak base decrease the pH of the diffusion layer.
Cosolvency+++
Weak electrolytes may behave like strong electrolytes and like non-electrolytes in solution:
When at a given pH of solution, drug is in ionic form:
It behaves as a solution of strong electrolyte
The solubility does not constitute serious problem
When the pH of solution is adjusted to a value to produce mostly unionized molecules exceeding solubility of this form:
Then precipitation occurs.
The solubility of weak electrolytes or non-polar compounds in water can often be improved by the addition of water –miscible solvent in which the compound is soluble.
Vehicles used in combination with water to increase the solubility of a drug are called co-solvents.
The solubility in this mixed systems is greater than that of individual solvents.
cosolvency
Frequently a solute is more soluble in a mixture of solvents than in one alone. This phenomenon is known as
cosolvents.
The solvents that, in combination, increase the solubility of the solute are called
Organic compounds
Miscible with water
Better solvents than water for the drug
No single unique structural feature.
Hydrogen bond donor and acceptor groups
Small hydrocarbon regions
Most cosolvents are liquids:
Ethanol, glycerol, propylene glycol,
Some are solids that are highly soluble in water:
PEG, PVP, urea
Cosolvents decrease the hydrogen bond density of aqueous systems
Reduce the cohesive interactions of water
Reduce polarity of the solution
Exponential increase
in solubility with increasing
cosolvent concentration
The solubilization slope (usually) increases with decreasing the polarity of the solvent
Addition of a cosolvent increases the solubility of a nonpolar and semipolar solute in water.
As the solute becomes more polar, cosolvency becomes less efficient
It will DECREASE the solubility of a polar solute in water
Inclusion compounds: cyclodextrins
Result from the incorporation of the non-polar portion of one molecule into the non-polar cavity of another molecule (or group of molecules) that is water soluble.
The driving force is similar to the driving force in micellar solubilization: reduce the non-polar-water interfacial area by inserting the solute (guest) into the complexing agent (host)
Cyclodextrins
Cyclodextrins (CD) are enzymatically modified starches.
Their glucopyranose units form a ring:
–a-CD a ring of 6 units, b-CD, 7units and g-CD, 8units.
The ‘ring’ is cylindrical:
The outer surface being hydrophilic
The internal surface of cavity is non-polar
Appropriately sized lipophilic molecules can be accommodated wholly or partially in the complex in which the host guest ratio usually 1:1.
- Although other stoichiometries are possible: i.e. 1, 2 or 3 CD molecules
Complexing with 1 or more drugs.
Formation of crystalline complexes of the inclusion complexes
Dissolution-dissociation-recrystallisation process of a cyclodextrin (CD) complex of a poorly soluble guest
Surface Activity
The ability to reduce the surface tension at an interface without requiring large concentrations*
* large concentrations that could blur the distinction between solvent and
solute
The lower the concentration required for a given effect, the better surface-activity properties of a solute.
Most marked effects (highest reduction in interfacial tension) are obtained with solutes that combine in their molecule structure:
One element having a high affinity for the solvent
One element having minimal affinity for the solvent
Such a molecule has its lowest potential energy at the phase boundary.
Surfactant = Surface-active agent
Most surfactants have a molecular structure composed of
hydrophilic or polar head group:
nonionic
ionic
lipophilic or nonpolar chain.
These groups can be presented in different proportions.
The balance of these two regions determine:
The surfactant solubility in water and oil
Its applications
Its place on the scale of Hydrophile-Lipophile Balance is known as the HLB
Classification of surfactants
Charge carried by the polar part
anionic
cationic
non-ionic
zwitterionic
At Concentrated Solutions
They aggregate over a narrow concentration range.
These aggregates, which may contains 50 or more monomers, are called Micelles.
‘Critical Micelle Concentration’ or ‘CMC’.
The concentration of monomer at which micelles form is termed the
Aggregation Number’
The number of monomers that aggregate to form a micelle is known as the
‘Aggregation Number’ of the micelle
More properties of surfactants solutions
At CMC, there are abrupt changes in several physical properties of surfactants:
osmotic pressure
turbidity
electrical conductance
and surface tension
Micelles (association colloids)
This behaviour is explained by the formation of micelles or aggregates of the surfactant molecules in which:
the lipophilic chains are orientated towards the interior of the micelle
the hydrophilic groups are in contact with the aqueous medium
The concentration above which micelle formation is appreciable is the Critical Micelle Concentration (c.m.c.) or (CMC)
Factors affecting the CMC
CMC may increase with:
Increase in polarity of head group
CMC may decrease with
Temperature – cloud point
pH (surfactants are weak electrolytes)
A second surfactant
Addition of electrolytes and organic matter
Critical values for micelles
Critical micelle concentration-
Kraft point (critical micelle temperature)- This is known as the Kraft point or T at which the solubility becomes equal to the c.m.c.
At T < Kraft point,
the c.m.c. > solubility and micelles cannot form
Unassociated surfactant has a limited solubility
Micelles are highly soluble and can accommodate a large amount of surfactant
Cloud point- Non-ionic surfactants
Increase in temperature
dehydration of POE chains
decreased water solubility
Formation of very large micelles
The solution becomes cloudy
Reversible process:
cooling
formation of small micelles
clarification
Critical micelle pH- When the compound’s ionized state exhibits surface activity and the unionized state is surface inactive (or has a lower CMC than the ionized state), altering the pH can trigger micellization.
Geometric properties of micelles
At high concentration of surfactants, higher
viscosity systems may occur:
Cylindrical rods, flattened disks
Liquid crystals (hexagonal phase, middle phase)
Lamellar phase (neat phase)
Bilayers
Vesicles
Non-ionic surfactants
Hydroxyl and ether groups
Less polar than ionized groups
We will need “more” units to produce an effective polar moiety
Surfactant applications
Anionic
Widely use because they are cheap
Toxicity: Only for external applications
O/W emulsifiers
Cationic
Disinfectant, preservative properties
O/W emulsifiers
Toxicity
Nonionic
O/W and W/O emulsifiers
Low toxicity and low irritancy
Oral and parenteral use
Parenteral
Ionic:
hemolysis of RBC and destruction of T lymphocyte cells
Non-ionic
Phospholipids, lecithin 5%
Cremophor EL anaphylactic shock, restricted use
Toxicity of non-ionic related to residual contamination of ethylene oxide
Quantification of solubilisation
It is important to be able to quantify micellar solubilisation
There are several commonly used terms
The most commonly encountered term is
Solubilisation capacity (k)
Solubilization and surfactant structure
Non polar region directly related with solubilization capacity of low polarity solutes
Increase HC chain
larger nonpolar region: Solubilize more solute
decreased c.m.c
Introduction of a polar group, a double bond in the chain
Equivalent to decrease length of the chain
Branched surfactants: smaller micelles
Semipolar solutes: surface and palisade region
Largely unaffected by the nonpolar region
Surfactant selection
Amount of SURFACTANT that can be placed in water
Very long chain are not effective surfactants: low solubility
Ability to solubilize a solute
Very short chain: very high c.m.c. (require high [Surfactant])
chain length = CMC and solubility
Although the CMC is reduced it corresponds to a decrease in surfactant solubility which reduces the amount of surfactant that can be used
increasing chain length in two carbons decreases solubility 10 fold
In practice a balance is required
12-16 carbons or 18 with a double bond
Provides a low CMC and sufficient water solubility
As chain length increases:
The solubility decreases
Surface activity becomes more pronounced
The longer the hydrocarbon chain, the greater the tendency of the surfactant molecules to adsorb at the surface and lower the surface tension.
Lundelius’s rule
Any factor that tends to decrease solubility of the surfactant promotes surface activity
