FACTORS AFFECTING THE RATE OF DISSOLUTION PDF/PPT

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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 37C 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/6r

Where k is the Boltzmann constant and 6r 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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