Drug Solubility and Dissolution Rate

Question 1

Why should a pharmacist understand solubility and dissolution rate ?

Answer 1

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

Question 2

Solution

Answer 2

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

Question 3

Solvent

Answer 3

The component that determines the phase of the solution is termed ‘solvent’.
Solvent usually constitutes the largest proportion of the system.

Question 4

Solutes

Answer 4

Are other components of the solution.
Are dispersed as molecules or ions throughout the solvent.
i.e. Are dissolved in the solvent

Question 5

Saturated solution

Answer 5

Solute is in equilibrium with the solid phase (solute).

Question 6

Solubility (in quantitative terms)

Answer 6

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.

Question 7

Solubility (in qualitative way)

Answer 7

The spontaneous interaction of 2 or more substances to form a homogenous molecular dispersion.

Question 8

Unsaturated or subsaturated solution

Answer 8

The dissolved solute is in concentration below that necessary for complete saturation at a definite temperature.

Question 9

Supersaturated solution

Answer 9

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.

Question 10

DISSOLUTION

Answer 10

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.

Question 11

Dissolution rate

Answer 11

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

2. 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

Question 12

Schematic representation of the dissolution of a drug particle in the gastrointestinal (GI) fluids:

Answer 12

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.

Question 13

Factors affecting dissolution rate

Answer 13

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

Question 14

The influence of Temperature- dissolution

Answer 14

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

Question 15

percentage Weak acids and bases in Pharmacy

Answer 15

~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

Question 16

Changes in pH within the gastro-intestinal tract (pH 1-8)

Answer 16

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

Question 17

weak acid A- > HA when

Answer 17

pH > pKa

Question 18

weak acid HA > A- when

Answer 18

pH < pKa

Question 19

weak base - B > BH+ when

Answer 19

pH > pKa

Question 20

weak base- BH+ > B when

Answer 20

pH < pKa

Question 21

Solubility of weak acids as a function of pH

Answer 21

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.

Question 22

If the salt of a weak acid is used instead of the free form

Answer 22

The pH of the solution increases
The solubility increases
BUT, if solution pH is lowered, precipitation of free acid form may occur

Question 23

If the salt form of a weak base is used:

Answer 23

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.

Question 24

What happens in the GI?

Answer 24

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.

Question 25

Salts and pH of the diffusion layer

Answer 25

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.

Question 26

Cosolvency+++

Answer 26

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.

Question 27

cosolvency

Answer 27

Frequently a solute is more soluble in a mixture of solvents than in one alone. This phenomenon is known as

Question 28

cosolvents.

Answer 28

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

Question 29

Inclusion compounds: cyclodextrins

Answer 29

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)

Question 30

Cyclodextrins

Answer 30

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

Question 31

Surface Activity

Answer 31

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.

Question 32

Surfactant = Surface-active agent

Answer 32

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

Question 33

Classification of surfactants

Answer 33

Charge carried by the polar part

anionic
cationic
non-ionic
zwitterionic

Question 34

At Concentrated Solutions

Answer 34

They aggregate over a narrow concentration range.
These aggregates, which may contains 50 or more monomers, are called Micelles.

Question 35

‘Critical Micelle Concentration’ or ‘CMC’.

Answer 35

The concentration of monomer at which micelles form is termed the

Question 36

Aggregation Number’

Answer 36

The number of monomers that aggregate to form a micelle is known as the
‘Aggregation Number’ of the micelle

Question 37

More properties of surfactants solutions

Answer 37

At CMC, there are abrupt changes in several physical properties of surfactants:
osmotic pressure
turbidity
electrical conductance
and surface tension

Question 38

Micelles (association colloids)

Answer 38

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)

Question 39

Factors affecting the CMC

Answer 39

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

Question 40

Critical values for micelles

Answer 40

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.

Question 41

Geometric properties of micelles

Answer 41

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

Question 42

Non-ionic surfactants

Answer 42

Hydroxyl and ether groups
Less polar than ionized groups
We will need “more” units to produce an effective polar moiety

Question 43

Surfactant applications

Answer 43

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

Question 44

Quantification of solubilisation

Answer 44

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)

Question 45

Solubilization and surfactant structure

Answer 45

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

Question 46

Surfactant selection

Answer 46

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.

Question 47

Lundelius’s rule

Answer 47

Any factor that tends to decrease solubility of the surfactant promotes surface activity