Workshop “Dissolution Test – The Important Parameter for Oral Dosage Form”

Jakarta, 20 March 2012

FORMULATION VIEWPOINT
TO DISSOLUTION RATE

Sigit Trawoco, M.Si., Apt.

PT. Kalbe Farma Tbk.
 OUTLINE

 Introduction
 Formulation Aspects on Increasing Dissolution Rate :
The Application
 Summary
 Introduction

 Bioavailability
– The rate and the extent to which the ingredients or
active moiety is absorbed from the drug product and
becomes available at the site of action.

 Drug with poor bioavailability :

– poor aqueous solubility
– slow dissolution rate in biological fluids
– poor stability of dissolved drug at physiological pH
– poor permeation through biomembrane
– extensive presystemetic metabolism.

 Bioavailability of poorly water soluble drugs is a major

problem.
DISSOLUTION RATE
The amount of active ingredient in a dosage form
dissolved in unit time under standardized
conditions of liquid / solid interface, temperature,
and media composition

 The dissolution rate of a drug is closely

associated with drug substance solubility.
Compounds with high solubility generally exhibit
significantly higher dissolution rates.
 Dissolution refers to the process solubilization of the drug
into the dissolution medium, and can be modeled as the
diffusion of the drug into the bulk liquid media as Noyes
Whitney’s equation below :

Dm/dt = K . (Cs – Ct)

dm/dt : mass rate of dissolution

K : dissoluttion constant
Cs : concentration at saturation or maximum solubility
Ct : concentration at time t
The process of drug product dissolution can be viewed as
proceeding through several steps

 Wetting and penetration of the dissolution medium into

the dosage unit
 Disintegration and/or deaggregation into granules or
fine particles of the drug substance
 Solubilization of the drug subtance into solution
In vitro drug product dissolution can be affected
by
• Intrinsic factors of drug substance
• Product formulation
• Manufacturing process
• Dissolution testing metodology

 Filler
 Granulating agents
 Surfactant
 Disintegrant
 Lubricant
 ...
 Formulation Aspects on Incrasing Dissolution
Rate : The Aplication

 Particle Size

The Effect of The Particle Size of The drug

on Dissolution Rate
Surface area
According to the equation

dw/dt = S . D/h (Cs – C)

• Dissolution rate is directly proportional to the surface area of the drug

• The surface area increases with decreasing particle size, higher
dissolution rates may be achieved through reduction of the particle size
If the drug is hydrophobic and the dissolution medium has
poor wetting properties, reduction of particle size may lead
to a smaller effective surface area and a slower dissolution
rate and a slower DR.
0.71 – 1 mm

0.50 – 0.71 mm

0.30 – 0.51 mm
Amount Disolved,

0.21 – 0.30 mm
MG in 500 ML

Time, Minutes

Figure 1. Effect of particle size on rate of dissolution of acetylsalicylic acid

(Finholt and coworkers, 1966)
• If 0.2% Tween 80 is added to the dissolution medium, phenacetin
disolves much faster and now the DR increases with decreasing particle
size.
0.11 – 0.15 mm
0.1N HCl + 0.2%
Tween 80
0.50 – 0.71 mm
0.1N HCl + 0.2%
Tween 80
Amount Disolved,
MG in 500 ML

0.50 – 0.71 mm
0.1N HCl
0.11 – 0.15 mm
0.1N HCl

Time, Minutes

Figure 2. Effect of particle size on rate of dissolution of phenacetin

 : particle size 0.30-0.50mm ________ : medium 0.1N HCl
 : particle size 0.11 -0.15 mm - - - - - - - - : medium 0.1 N HCl + 0.2% Tween 80
 : particle size 0.15-0.21 mm
 : particle size 0.21 -0.30mm
 : particle size 0.50-0.71mm
• Influence of particle size of drugs on their DR from granules. The granules were
prepared with potato starch as filler
• The granulation process has made the surface of the drug powders
hydrophilic, and as a result, reduction of particle size lead to increase in the
effective surface area.

0.11 – 0.15 mm
Amount Disolved,
MG in 500 ML

0.50 – 0.71 mm

Time, Minutes
Figure 3. Effect of particle size of phenacetin on DR of the drug from granules .
 : particle size 0.11-0.15 mm
 : particle size 0.15-0.21 mm
 : particle size 0.21-0.30 mm
 : particle size 0.30 – 0.50 mm
 : particle size 0.50 – 0.71 mm
The Effect of Drug Particle Size on its DR from Tablets
Fig. 5 demonstrate that the initial DR of phenacetin from tablets prepared with
potato starch as filler and gelatine as granulating agent increases with
decreasing particle size of the drug powder since the granulation process had
made the drug hydrophilic.
0.11 – 0.15
mm
Amount Disolved,

0.30 – 0.50
MG in 500 ML

mm

Time, Minutes

Figure 5. Effect of particle size of phenacetin on DR of the drug from tablet

 : particle size 0.11-0.15 mm
 : particle size 0.15-0.21 mm
 : particle size 0.30-0.50 mm
 : particle size 0.21 – 0.30 mm
The application...
that in most instances, reduction of the particle size of drugs contained
in tablets will enhance dissolution. Procedures employed in tablet
production, that is mixing of the drug with usually hydrophilic diluents
and a subsequent granulation, will make the surface of even originally
hydrophobic drug particles, more hydrophilic.
The application ..
Grind the material, Micronization

 Conventional methods of particle size reduction, such as comminution and

spray drying, rely upon mechanical stress to disaggregate the active
compound. Today, micronization of drugs is widely done by milling
techniques using a jet mill, rotor stator, colloidal mill, etc.

 Limitations. Micronization of sparingly or poorly soluble drugs is by no

means a guarantee of better dissolution and absorption.
– A hydrophobic powder with small particle size leads to aggregation,
making it difficult to disperse.
– The particles float on the dissolution medium because of entrapped air.
It is difficult to remove or wet these particles.
All these effects, in fact, reduce the rate of dissolution
  Filler

The Effect of Fillers on Dissolution Rate

Some experiments :
• Potato starch or a mixture of potato starch and lactose as fillers when
preparing tablets by wet granulation, have resulted in rapid dissolution.
Some exp. drugs : phenobarbital, phenacetin, sulfadiazine,
chloramphenicol, prednisone, nicotinic acid
• Triamterene Tablet (Yen, 1964)
Wet granulation. Compared four fillers.
Terra alba : poor DR
Filler starch, lactose, glycine : good DR. The reason is that the fillers
are either very soluble or hydrophilic.

• Sodium Salicylate Tablet (Marlowe and Shangraw, 1976)

Wet granulation using either lactose or a mixture of lactose and corn
starch as filler.
Presence of starch ‘dramatically’ increased the DR
• Phenobarbital Tab (Finholt et. al., 1966)
Difference in the method of production caused a great difference in the DR.

Dry Gran Dry Gran

Wet mixture Drug,
Granulation (drug+starch) + starch

I
II
III
Amount Disolved,
MG in 500 ML

Time, Minutes

Figure 6. Rate of dissolution of phenobarbital from tablets.

• Salicylic Acid Tab (Levy, 1963)
Dry granulation. Increasing the starch content from 5% to 20%
resulted in increase in the DR, probably because of more rapid
disintegration of the granules in the tablet.

The aplication...
If the drug is hydrophobic, a hydrophilic filler will tend to enhance
dissolution, especially if this filler at the same time as a disintegrant.
Starch has hydrophilic properties and is an effective disintegrant.
  Granulating Agent

The Effect of Granulating Agents on Dissolution Rate

If fast dissolution rate of a hydrophobic drug is wanted, that the

granulating agent has the ability to make the surface of the drug
powder hydrophilic.
If the binder forms a film around the particles upon drying of the
granules, it is important that this film is easily redisolved.
If the film is too thick as a result of employing to munch binder, the
dissolution rate may be diminished, even with hydrophilic granulating
agents.
Examples for application

Studies :
• Jacob and Plein (1968) compared gelatine with acacia, ethylcellulose,
hydroxyethyl cellulose. Phenobarbital as test drug. The fastest
dissolution rate in 0.1 N HCl was found with gelatine (2% of tablet
weight). DR was nearly independent of the tablets hardness. With 4%
gelatine the DR was slower and it decreased with increasing hardness of
the tablets. Satisfactory tablets were also obtained with acacia as
binding agent, whereas ethyl cellulose and hydroxy ethyl cellulose
produce tablets with poor DR.

• Yen (1964). With the water soluble granulating agent Plasdone a faster
DR was obtained than with gelatine. Film formation also take place upon
drying of the Plasdone granulation; but this film is more easily
redissolved.
  Lubricant

The Effect of Lubricants on Dissolution Rate

The effect of lubricants on rate of dissolution of drugs from tablets will

depend upon the properties of the granules and of the lubricant and
upon the amount of lubricant used. If the granule particles are
hydrophilic and fast disintegrating, a surface active lubricant will have
little effect. If the granule particles are less hydrophilic and not as fast
disintegrating, a surface active lubricant may enhance dissolution.

The stearates are hydrophobic of nature. They may therefore tend to

retard dissolution. However, if the amount of lubricant used is small, say
less than 1%, the retarding effect may be negligible.
  Surfactant

The Effect of Surfactants Incorporated in Tablets

on The Dissolution Rate

• Effect of polysorbate 80 on DR of Phenacetin tablets prepared with gelatine as

granulating agent 1% polysorbate 80 has a more pronounced effect than 0.1%.
The same amount of surfactant (0.1%) has a somewhat greater effect when
sprayed on the granules rather than dissolved in the granulating solution
....
 1% polysorbate 80 added,
dissolved in granulating sol

Dissolution medium 0.1 N HCl +

0.2% polysorbate 80

0.1% polysorbate 80 sprayed on

dried granules

0.1% polysorbate 80, dissolved

Amount Disolved,

in granulating sol
MG in 500 ML

Dissolution medium 0.1 N HCl

Time, Minutes

Figure 7. Effect of Polysorbate 80 on the dissolution rate of Phenacetin from tablet

Surfactants can and do increase the rate at which the solvent penetrates
the solid mass, thereby increasing its effective surface area and
ultimately the dissolution rate.

• Surfactants are molecules with distinct polar and nonpolar regions.

• Most surfactants consist of a hydrocarbon segment connected to a
polar group.
• The polar group can be anionic, cationic, zwitterionic or nonionic.
– Anionic surfactant : sodium dodecyl sulfate or SDS (sodium
lauryl sulfate or SLS)
– Cationic surfactant : Cetyl Trimethyl Ammonium Bromide or
CTAB
– Nonionic surfactant : Polysorbates or Tweens
 Compression Force

The Effect of Compression Force on Rate of Dissolution

of drugs from Tablets.

The effects of an increasing pressure on a tablet :

Particle bonding is affected. When particle bonding is the predominating
phenomenon, then dissolution rates will diminish with increasing
pressure.
Particle cleavage or crushing is affected. When this effect is predominating,
dissolution rates will increase with increasing pressure.

Different type response curves may result.

 I Phenytoin tablets prepared with gelatine as a binder.
Phenazon tablets prepared with gelatine as binder.

Sulfadimidine tablets prepared by wet granulation

DR II with starch paste as binder.
Phenazon tablets prepared with PEG 4000 as binder

III Sulfadimidine tablets prepared by wet granulation

with gelatine as binder.

Pressure
 Effect of pressure on DR of sulfadimidine was studied
IV from tablets prepared by wet granulation with methyl
cellulose as binder.
DR

Pressure

The application ...

effects of an increase in compression force on dissolution rate is
dependent on the pressure range and on the properties of the
drug, filler and binder used. In any case, the effect of pressure increase is
difficult to predict
  Granul Size

The Effect of Granule Size on Dissolution Rate

Study :
• Yen (1964). Triamterene tablets. DR increased with decreasing granule
size when terra alba or glycine was the filler. If starch was used as filler,
no effect of granule size on DR could be found. This probably is because
the starch containing granules are comparatively softer than the other
granules.

The application...
Granule size probably will have little influence on DR, if the granules are
relatively soft and disintegrate easily. If the granules are harder and
disintegrate more slowly, then granule size will be of importance,
and increase in size will cause a decrease in DR
  Capsule

The Effect of Additives (Fillers, lubricants and Surface Active

Agents) on The rate of Dissolution of Drugs From Capsules

The applications,
If the drug is hydrophobic an addition of a sufficient amount of a hydrophilic
diluent or a surface active agent will enhance dissolution. If the drug is
less hydrophobic, the addition of a hydrophilic diluent may be of no use
or even have an adverse effect. The addition of a hydrophobic lubricant
usually diminishes dissolution rate, provided the retarding effect is not
overcome by the simultaneous addition of a surface active agent.
  pH Modification, Salt
Formation

Weak acid
Diffusion Model

G = DA/h . (Co + K.Co/(H+) - C)

G : Dissolution rate

As the hydrogen ion concentration is decreased, that is, the pH raised, the
rate of dissolution is increased.
If the gastric fluid is made alkaline with NaHCO3 for example, a weak acid
will disolve faster.
 The application ..
Salt Formation

• The use of salt forms is a well known technique to enhanced

dissolution profiles. Salt formation is the most common and effective
method of increasing solubility and dissolution rates of acidic and
basic drugs.
• An alkaloid base is, generally, slightly soluble in water, but if the pH
of medium is reduced by addition of acid, and the solubility of the
base is increased as the pH continues to be reduced. The reason for
this increase in solubility is that the base is converted to a salt,
which is relatively soluble in water.
• The solubility of slightly soluble acid increased as the pH is
increased by addition of alkali, the reason being that a salt is
formed.
  Metastable Form

Use of Metastable Polymorphs

The presence of metastable, polymorphic crystalline forms, can exert a

great influence on the solubility, dissolution rate, and biological activity
of medicaments.

The separation and selective use of a specific polymorphic form that

possesses the highest solubility is a technique that can be applied, in
certain cases, for the increase of dissolution rates.

Melting followed by rapid cooling or recrystallization from different

solvents can produce metastable forms of a drug. For example, a
Metastable form of chloramphenicol palmitate is more water-soluble
than the A and C forms.

Polymorphic forms are often induced by methods of manufacture of the

drug, that is by solvent and temperature effect.
  Complexation

Inclusion Complexes

• Inclusion complexes are formed by the insertion of the nonpolar

molecule or the nonpolar region of one molecule (guest) into the
cavity of another molecule or group of molecules (host).

• Cyclodextrin inclusion is a molecular phenomenon in which usually

only one guest molecule interacts with the cavity of a cyclodextrin
molecule to become entrapped and form a stable association.

• The internal surface of cavity is hydrophobic and external is

hydrophilic; this is due to the arrangement of hydroxyl group within
the molecule.

• It was found that cyclodextrins increased the paclitaxel solubility by

950 fold.
  Dispersion within a
soluble carrier

Solid Dispersions

 The dispersion method allows the preparation of physically

modified forms of the drug that are much more rapidly soluble
in water than the pure compound.

 The most commonly used hydrophilic carriers for solid

dispersions include PVP, PEGs, and plasdone-S630.
Surfactants may also be used, like Tween-80, Myrj-52, and
Pluronic-F68 and sodium lauryl sulfate are used.

 Various newer strategies investigated : fusion (melting),

solvent evaporation, lyophilization (freeze drying), melt
agglomeration, extrusion, spray drying, surfactant use,
electrostatic spinning, and super critical fluid technology for
solid dispersions.
 The application ..
Example

• Kneading method
Mixture of Nevirapine and PVP was kneaded with small volume
water for 30 minutes to produce homogenous dispersion. Once
homogenous slurry was obtained, mixture was dried in at 45 C.
The dispersion after drying was pulverized and sifted.
 SUMMARY

 The solubility and dissolution properties of drugs play a important

role in the process of formulation development.

 Problem of dissolution rate are major chalenges for formulation

scientist which can be solved by different technological
approaches during the pharmaceutical product development work

 Some approaches to improve dissolution rate are the physical or

chemical modifications, product formulation, or the
manufacturing process, considering the properties of drug
substance and excipients and their interactions
Thank you
for your
attention