FACTORS AFFECTING THE RATE OF DISSOLUTION
1. Factors related to the physico chemical properties of the drug
2. Factors related to drug product formulation
3. Effect of processing factors on the dissolution rate
4. Factors related to dissolution test parameters
5. Miscellaneous
FACTORS RELATED TO PHYSICOCHEMICAL PROPERTIES
OF THE DRUG
Drug diffusivity
One of the key components of the Noyes–Whitney equation as well as
other equations that describe drug dissolution is the diffusion coefficient or
diffusivity (i.e. D) of a solute or drug. The Stokes–Einstein equation (Eq. (8))
permits the determination of the diffusivity as well as illustrating the
relationship between diffusivity and other peripheral physicochemical
properties not directly implicated in equations that describe drug dissolution.
Equation (8)
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where D is the diffusivity, T is the absolute temperature, h is the viscosity of the
liquid medium, r is the radius of the drug particle and K is Boltzmann’s
constant. It is apparent that an increase in the viscosity of the dissolution
medium can lower the drug diffusivity and the dissolution rate. There was a
decrease in the dissolution rate of benzoic acid in methylcellulose solution and
in the presence of high concentrations of a solubilizing agent polysorbate 80.
Powder properties: Available surface area Particle size
Surface area of the powder particle, in turn, is inversely related to the
particle size. The dissolution rate is directly proportional to the surface area of
powder available for dissolution. For poorly soluble drugs and many
hydrophobic drugs, reduction in the particle sizes of about 3–5 mm is frequently
employed as a successful strategy for enhancing drug dissolution rate.
It is important to note that for some drugs too much reduction in the
particle size can lead to exposure of surface charges, which can retard the drug
dissolution rate. The available effective surface area of the powder depends to
some extent on the ability of the dissolution fluid to wet the particle.
If the dissolution medium exhibits poor wetting properties, micronization
can produce agglomeration of powder particles, which can cause a decrease in
the dissolution rate owing to an increase in surface area.
Polymorphism
Many drugs are capable of existing in more than one crystalline form, a
property known as polymorphism; each polymorph possesses different energy
and, therefore, differs in physicochemical properties such as solubility, melting
point, heat of fusion, density, and refractive index.
Generally, the metastable form is preferred because it exhibits the faster
dissolution rate. There are a number of methods available for obtaining the
metastable form that include recrystallization from different solvents, melting or
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rapid cooling. Enhanced dissolution rate as a result of the right polymorph
selection, however, does not always translate into improved bioavailability.
In the case of the analgesic diflunisal , the solubility (26 mg/ml) of the
metastable form was twice as high as that of the stable form [the crystalline
form (14 mg/ml)]. However, no statistically significant differences in the in vivo
plasma profiles were reported.
Equilibrium solubility
The aqueous solubility of a drug is the major determinant of its
dissolution rate. The drug might be considered ‘poorly soluble’ when its
dissolution rate is slower than the time it takes to transfer past its absorption
sites, resulting in incomplete bioavailability. This generally is the case for drugs
where aqueous solubility is less than 100 mg/ml. The ratio of drug
dose:solubility is another parameter utilized to classify poorly soluble drugs.
The dose:solubility ratio can be defined as the volume of gastrointestinal
fluids required to dissolve the administered dose. If the desired volume is
greater than the volume of gastrointestinal fluid available to dissolve the
administered dose, one might anticipate incomplete bioavailability of a drug
from the solid dosage form. Griseofulvin is an excellent example. Its aqueous
solubility is 15 mg/ml at 37C and its usual dose is 500 mg. This results in a
dose:solubility ratio of approximately 33.
Equilibrium solubility (Cs) is also a key factor and an integral part of all
equations used to describe the dissolution of a drug along with the concentration
of drug (C) already dissolved and the thickness (h) of the boundary layer.
Various physicochemical and physiological factors influence the equilibrium
solubility of a drug in the gastrointestinal tract. These include crystallinity,
polymorphism and solubilization by the incorporation of surfactants.
Saturation solubility (Cs)
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Equilibrium solubility of a compound determines the concentration of a
drug dissolved in the thickness of the boundary layer and thus the concentration
gradient across the boundary layer, which is the driving force for dissolution. A
number of physicochemical and physiological factors influence the saturation
solubility of a drug in the gastrointestinal tract.
These include the crystalline form of a drug, its lipophilicity, the ability
of the drug to be solubilized by the surfactants present in the fluid and co-
ingested food, its aqueous solubility and pKa and its gastrointestinal pH profile.
Moreover, formation of a salt is likely to increase the water solubility of a drug,
as compared with that of the free base or free acid form.
pKa and the gastrointestinal pH profile
The solubility of weak acids and bases depends on their ionization
constants, Ka as well as the pH of the dissolution medium. Intrinsic solubility
can be defined as the solubility of a compound in its free acid or base form. For
weak acids this is approximated by the solubility at pH values greater than one
unit below its pKa. As the pH of the fluid increases, the solubility of the weak
acid increases owing to the contribution from the ionized species. At pH values
greater than pH = pKa + 1, a linear relationship between the logarithm of the
solubility and the pH is observed, until the limiting solubility of the ionized
form is reached.
The inverse of weak acidic drug relationship exists for weak bases (Fig.
10). The pH of the gastrointestinal fluids is, therefore, one of the most important
influences on the saturation solubility of ionizable drugs. The pH of the
gastrointestinal fluid varies widely with location in the gastrointestinal tract as
shown in Tables 1 and 2. Typical pH values in the fasted stomach are between 1
and 2, whereas in the upper small intestine the pH values usually lie between 5
and 6.5.
Factors related to the dissolution test parameters
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Method of granulation: Wet granulation has been shown to improve the
dissolution rates of poorly soluble drugs by imparting hydrophilic properties to
the surface of the granules. Additionally the use of fillers and diluents such as
starch, spray dried lactose, MCC tends to increase the hydrophilicity of the
active ingredients and thus improve dissolution. Consequently wet granulation
was considered superior to a dry or double compression procedure.
It must be notes that with the advent of newer tableting machines and materials,
it becomes more evident that the critical formulation and proper mixing
sequence and time of adding the several ingredients are the main criteria that
affect the dissolution characteristics of the tablets, not the method of
granulation.
Effect of compression force on dissolution rate:
T.Higuchi pointed out the influence of compression force employed in the
tableting process on the apparent density, porosity, hardness, disintegration
time, and average primary particle size of compressed tablets. There is always a
competing relationship between the enhancing effect due to the increase in
surface area through the crushing effect and the inhibiting effect due to the
increase in particle bonding that causes an increase in density and hardness and
consequently a decrease in solvent penetrability. The high compression may
also inhibit the wettability of the tablet due to the formation of a firmer and
more effective sealing layer by the lubricant under the high pressure and
temperature that usually accompanies a strong compressive force.
Factors related to dosage form:
Drug excipient interaction: These interactions can occur during any unit
operation such as mixing, blending, drying and granulating resulting in a change
in dissolution pattern of the dosage form in question.
The effect of magnesium stearate on the disintegration time of tablets
containing either potato starch or sodium starch glycolate was found to depend
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on the swelling characteristics of the Disintegrants. These results were
attributed to the formation of lubricant film during mixing, which resulted in an
increase in disintegration time and thus delayed dissolution.
Deaggregation:
Deaggregation is often a prerequisite or dissolution. In such cases it can control
dissolution. It was reported that two capsule formulations of sodium
diphenylhydantoin kshowed significant deaggregation, dissolution and therby
absorption rates. The formulation that deaggregated rapidly after the capsule
shell was dissolve resulted in exposure of large surface area. This resulted in
rapid dissolution at neutral pH but less rapid dissolution at neutral pH but less
rapid dissolution when both preparations were exposed to 0.1n HCL.
Aggregation of other formulation inhibited the conversion of most of its
sodium salt to the free acid in acidic medium where as such conversion
occurred readily with the rapidly disintegrating formulation. As a result, after
neutralization of the medium the latter dissolved and absorbed more readily and
rapidly than did the former.
Effect of test parameters on the dissolution rate
Eccentricity of the stirring device
USP 26/NF 21 specifies that the stirring shaft must rotate smoothly without
significant wobble. Eccentricity can be measured with a machinist’s indicator. It
is measured in terms of total indicator reading (TIR) which determines the sum
of the distance on both sides (180º C) of the axis of rotation.
Guiding the shaft:
The shaft of the stirring device extends about 6 inches beyond the chuck. An
eccentricity of 0.005 in at a distance of 1 in (25mm) from the chuck will be
barely perceptible but at 6 in will amount to 0.30 in (0.75 mm) which is the
maximum that can be tolerated.
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Vibration : Vibration is a common variable introduced into the dissolution
system from myriad causes. It has the effect of changing the flow patterns of the
liquid and of introducing energy to the dynamic system. Both effects may result
in significant changes in the dissolution rates. The speed of the rotational device
selected by official compendium are 50 – 100 rpm. Other speeds are specified
for certain drugs. Precise speed control is best obtained with a synchronous
motor that locks into the line frequency. Such motors are not only more rugged
but are far more reliable. Periodic variations in rpm might result in possible
disturbance in rotational devices, is commonly referred to as torsional vibration.
Such vibration indicates a variation in the velocity of rotation for short periods
of time although the average velocity is well within ±4% of the specified rate.
Alignment of the stirring element:
There are important factors to be considered here. These are as follows
Tilt: USP 26/NF21 states that the axis of the stirring element shall not deviate
more than 0.2 cm form the axis of the dissolution vessel, which defines centring
of the stirring shaft to within ± 2mm. It also constraints tilt. A series of tests
suggest that tilt in excess of 1.5(degree ) may increase dissolution rates using
Method 2 from 2-25% which is still a significant variation. The user should be
able to adjust his equipment to obtain alignment of the vertical spindles to
within 1(degrees) perpendicularly with the base of the drive to which the flasks
are mounted. Such alignment cannot be ensured in the factory. Adjustments for
perpendicularity must therefore be used in order to bring the equipment into
alignment in its final position.
Agitation intensity
The degree of agitation or the stirring conditions is one of hte most important
variables to consider in dissolution. Agitation conditions can markedly affect
diffusion controlled dissolution because the thickness of the diffusion layer is
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inversely proportional to agitation speed. Wurster and Taylor employed the
empirical relationship
K = a (N)b
Where N is the agitation rate, K the reaction rate. For diffusion controlled
processes b=1. Dissolution that is interfacial reaction rate controlled will be
independent of agitation intensity and thus b=0.
Agitation intensity within and between various in vitro dissolution testing
devices can be varied by the dimensions and geometry of the dissolution vessel,
volume of the dissolution medium, and the degree of agitation or shaking.
It is safe to predict that the two dosage forms having particles of differing sizes
and densities will not experience identical dissolution system, even though the
containers are being subjected to the same rate of rotation as of oscillation.
Temperature : because drug solubility is temperature –dependent ,careful
temperature control during the dissolution process is very important and should
be maintained during dissolution determinations. The effect of temperatures
variations of the dissolution medium depends mainly on the temperature
/solubility curves of the drug and excipients in the formulation.
For a dissolved molecule, the diffusion coefficient D, depends on the
temperature T according to the Stokes equation
D = kT/6r
Where k is the Boltzmann constant and 6r is the Stokes force a spherical
molecule
Dissolution medium:
pH of the dissolution medium: Acidic buffers such as sodium acid phosphate, to
maintain the required low pH.
Surface tension of the dissolution medium:
Surfactants and wetting agents lower the contact angle and consequently
improve penetration by the dissolution medium.
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E.g. measurable enhancement in the dissolution rate of salicylic acid from an
inert matrix was reported when the contact angle was lowered from 92º (water
) to 31º (using dioctyl sodium sulfosuccinate).
Viscosity of the dissolution medium
In case of diffusion controlled dissolution processes, it would be expected that
the dissolution rate decreases with an increase in viscosity. In the case of
interfacial controlled dissolution processes, however viscosity should have little
effect. The Stokes –Einstein equation describes diffusion coefficient D as a
function of viscosity.
E.g dissolution rate of benzoic acid is inversely proportional to the viscosity of
the dissolution medium using various concentrations of sucrose and
methylcellulose solutions.
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Factors related to drug product formulation
Effect of granulating agents and binders
Phenobarbitol tablets granulated with gelatine solution provide faster
dissolution rate in GI fluid than those prepared using SCMC or PEG 6000 as a
binder. The fact that gelatine impart hydrophilic characteristics to the
hydrophobic drug surface whereas PEG 6000 forms complex with poor
solubility and SCMC is converted to its less soluble acid form at low pH of the
gastric fluid
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