(16-20) Drug Solubility and Dissolution Rate

Solvent definition

Component that determines the phase of a solution and constitutes the largest proportion

Solute definition

Other components of a solution dispersed as molecules or ions throughout the solvent

Saturated solution definition

A solution where the solute is in equilibrium with the solid phase at a particular temperature

Unsaturated solution definition

Solution where dissolved solute concentration is below saturation at a definite temperature

Supersaturated solution definition

Solution containing more dissolved solute than would normally be possible at a particular temperature

Solubility definition quantitative

Maximum mass or volume of solute that will dissolve in a given mass or volume of solvent at a particular temperature

Very soluble

Less than 1 part solvent per 1 part solute

Freely soluble

1 to 10 parts solvent per 1 part solute

Soluble

10 to 30 parts solvent per 1 part solute

Sparingly soluble

30 to 100 parts solvent per 1 part solute

Slightly soluble

100 to 1000 parts solvent per 1 part solute

Very slightly soluble

1000 to 10000 parts solvent per 1 part solute

Practically insoluble

Greater than 10000 parts solvent per 1 part solute

BCS Class I drugs

High solubility and high permeability

BCS Class II drugs

Low solubility and high permeability

BCS Class III drugs

High solubility and low permeability

BCS Class IV drugs

Low solubility and low permeability

Why is solubility clinically important

Drug must dissolve in fluid at site of absorption to be absorbed

Dissolution definition

Process by which drug particles dissolve into solution

Three steps of dissolution

1. Release of solute from solid phase 2. Formation of saturated solution around particles 3. Migration through diffusion layer

Diffusion layer definition

Saturated solution layer surrounding dissolving drug particles that acts as barrier to further dissolution

What determines the rate of dissolution

The slower step in the dissolution process

Rate-determining step in dissolution

Diffusion of solute through the static boundary layer following Ficks law

Noyes-Whitney equation components

dm/dt = k × A × (Cs - C)

dm/dt in Noyes-Whitney

Dissolution rate - mass of solute passed into solution per unit time

k in Noyes-Whitney

Dissolution rate constant with dimensions of length per unit area per unit time

A in Noyes-Whitney

Surface area of the dissolving solid

Cs in Noyes-Whitney

Concentration of drug in the saturated diffusing layer

C in Noyes-Whitney

Concentration of drug in the bulk dissolution medium at time t

Three ways to increase dissolution rate

1. Increase surface area by reducing particle size 2. Increase drug solubility in diffusing layer 3. Increase dissolution rate constant k

Particle size effect on solubility

When particle size is below 0.1 micrometres solubility itself increases

Micrometric range solubility behavior

In the micrometric range solubility increases markedly with decreasing particle size

Particle size effect on bioavailability example

Nitrofurantoin bioavailability is critically dependent on particle size control

Drugs benefiting from smaller particle size

Digoxin nitrofurantoin medoxyprogesterone acetate danazol tolbutamide aspirin sulphadiazine naproxen ibuprofen and phenacetin

Particle size reduction considerations

Must consider drug stability and potential for aggregation of hydrophobic drugs

Temperature effect on solubility example

Sodium sulphate solubility increases below 32.5 degrees Celsius then decreases above due to polymorph transition

Endothermic dissolution

Dissolution process that absorbs heat

Exothermic dissolution

Dissolution process that releases heat

Structure effect on solubility

Small changes in molecular structure can markedly change solubility - phenol is 100 times more soluble than benzene in water

Salt formation solubility enhancement weak acid

Using salt form instead of free acid increases aqueous solubility due to increased degree of dissociation

Salicylic acid solubility comparison

Sodium salt of salicylic acid is 550 times more soluble than free acid form

Ester formation for solubility reduction

Esterification of parent drug reduces aqueous solubility

Taste masking example

Chloramphenicol palmitate instead of chloramphenicol base masks unpleasant taste in pediatric suspensions

GI protection by esterification

Erythromycin propionate is less soluble and less readily degraded than erythromycin base

Enhanced absorption by esterification

Erythromycin propionate is more readily absorbed than erythromycin base

Polymorphism definition

Ability of a substance to exist in more than one crystalline form each with distinct crystal structure and unique physicochemical properties

Polymorphism frequency in drug classes

63 percent of barbiturates 67 percent of steroids 40 percent of sulphonamides

Polymorphism clinical significance

Different polymorphic forms exhibit dramatically different solubilities dissolution rates and bioavailability

Ritonavir polymorph problem

Initially marketed polymorph precipitated during shelf storage causing severe bioavailability problems

Tablet size pharmaceutical significance

Tablet size is deliberately designed for specific pharmacokinetic properties - disruption before oral administration may cause toxicity

Henderson-Hasselbalch equation weak acid

pH = pKa + log[conjugate base]/[weak acid]

Henderson-Hasselbalch equation weak base

pH = pKa + log[free base]/[conjugate acid]

Weak acid solubility behavior below pKa

Solubility decreases and approaches intrinsic solubility S0

Weak acid solubility at pKa

Solubility equals 2 times intrinsic solubility S0

Weak acid solubility above pKa

Solubility increases by approximately 10-fold for each unit of pH above pKa

Weak base solubility behavior above pKa

Solubility decreases and approaches intrinsic solubility S0

Weak base solubility at pKa

Solubility equals 2 times intrinsic solubility S0

Weak base solubility below pKa

Solubility increases by approximately 10-fold for each unit of pH below pKa

Intrinsic solubility definition

Solubility of the free unionised form of a drug designated as S0

pH range of GI tract

Approximately 1 in stomach to 8 in distal small intestine

Clinical significance of pH variation

pH changes in GI tract alter ionisation of weak acids and bases directly affecting solubility

Ionised vs unionised solubility

Ionised forms are typically more soluble than unionised forms

Weak acid salt form effects

When salt is used pH increases and solubility increases but precipitation of free acid may occur if pH lowers

Weak base salt form effects

When salt is used pH falls and solubility increases but precipitation of free base may occur if pH increases

Main pharmaceutical counterions for weak acids

Hydrochloride 43 percent sulphate 7.5 percent mesylate phosphate maleate salicylate tartrate lactate citrate and succinate

Main pharmaceutical counterions for weak bases

Sodium 62 percent potassium 11 percent calcium 10 percent lithium 14 percent magnesium diethanolamine zinc choline and aluminium

Regulatory significance of salt form

Salt form is considered a new chemical entity requiring toxicity testing

Weak base dissolution in stomach

High dissolution rate due to acidic pH promoting ionisation

Weak base dissolution in small intestine

Dissolution rate falls as pH rises reducing ionisation

Weak acid dissolution in stomach

Minimal dissolution due to acidic pH reducing ionisation

Weak acid dissolution in small intestine

Dissolution rate increases as pH rises promoting ionisation

Salt form vs free form dissolution

Dissolution of salt forms is generally greater than that of free forms

Phenobarbital case parameters

Weak acid with pKa of 7.41 solubility of free acid 0.0050 molar solution contains 1.3 percent weight by volume sodium phenobarbital

Thioridazine case parameters

Weak base with pKa of 9.5 free base solubility 1.5 times 10 to negative 6 molar hydrochloride salt solution contains 0.407 percent weight by volume

Factors affecting dissolution rate from Noyes-Whitney

Surface area solubility in medium concentration in bulk solution diffusion coefficient and boundary layer thickness

Secondary factors affecting dissolution

Temperature nature of solvent nature of solute pH co-solvents crystalline form presence of other compounds and solubility-enhancing agents

Factors affecting surface area

Particle size porosity and dispersibility

Factors affecting boundary layer

Stirring action and gastrointestinal motility

Factors affecting concentration in bulk

Absorption process and volume of available GI fluid

Factors affecting diffusion coefficient

Viscosity of solvent and GI fluids

Position and timing in GI tract effect

Affects pH fluid composition and drug dissolution

Food effect on dissolution

Food changes gastrointestinal pH affecting dissolution rate

Viscosity effect on dissolution

Taking drug with viscous substances like honey increases viscosity and may slow dissolution

IVIVC definition

In vitro and in vivo correlation predicting relationship between dissolution testing and drug absorption

BCS clinical utility

Helps predict bioavailability issues and guide design of in vitro dissolution tests

Permeability vs solubility modification

Far more difficult to modify drug permeability than to enhance solubilit