Techniques for enhancement of dissolution rate

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Techniques for
enhAnceMenT of DissoLuTion
rATe
Department of Pharmaceutics | Sagar savale
Mr. Sagar Kishor Savale
[Department of Pharmaceutics]
avengersagar16@gmail.com

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Contents
INTRODUCTION
PROCESS OF DISSOLUTION
METHODS TO ENHANCE DISSOLUTION RATE
CONCLUSION
REFERENCES

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INTRODUCTION
Dissolution
“ Dissolution is the process by which a solid phase goes into
solution”
Dissolution Rate
“Dissolution rate may be defined as the amount of drug substance that
goes in to solution per unit time under standardized conditions of
liquid-solid interface, temperature & solvent composition.”
Dissolution rate is given by Noyes-Whitney equation-
Under non sink condition
dc/dt = KS (Cs-C)
dc/dt =DS/h (Cs-C)

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Where ,
dc/dt = rate of drug dissolution,
K= dissolution rate constant,
S=surface area of the particle,
(Cs-C)=concentration gradient,
D= diffusion coefficient of drug in solution,
h= thickness of diffusion layer.
Under sink condition
dc/dt =DS/h Cs

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 Importance of dissolution study-
1) Necessary for predicting in-vivo absorption of drug.
2) Useful in product development.
3) Useful in Selection of excipient.
4) Help to study the rate of dissolution of drug.
5) Necessary for optimizing manufacturing process.
6) Useful in interpretation of solubility of poorly water
soluble drugs.

Process of dissolution :
Process of dissolution : The process of dissolution
involves breaking of inter-ionic or intermolecular bonds
in the solute, the separation of the molecules of the
solvent to provide space in the solvent for the solute,
and the interaction between the solvent and solute
molecule or ion.
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METHOD OF DISSOLUTION:
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Methods to Enhance Dissolution Rate Increase in the
effective surface area of the drug. Particle size
reduction Incorporation of surface active agents in
formulation. Solute-Solvent Complexation reactions.
Polymorphism. Molecular encapsulation with
Cyclodextrins or Complexation with Cyclodextrins.
Prodrug approach. Salt formation of drug.

Increasing the effective surface area of the
drug :
• Increasing the effective surface area of the drug The
size of the solid particle influences the solubility
because as particle becomes smaller, the surface area
to volume ratio increases. The larger surface area
allows a greater interaction with the solvent. The
effect of particle size on solubility can be described
by Where So is the solubility of infinitely large
particles and S is solubility of fine particles, V is
molar volume, γ is surface tension of solid and r is the
radius of fine particle.
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Particle size reduction :
• Particle size reduction Micronization technique:
Increasing dissolution by reducing particle size of
poorly water soluble drugs. Reduction is done by
variety of Micronization process such as grinding,
ball milling, air attrition, utilization fluid energy
mills. Micronization process usually results in 1-
10µm diameter. Kronblum and Hirschorn evaluated
two specific methods of Micronization, spray drying
and air attrition, which provided drug forms of
different specific surface areas and particle size
ranges, as well as other physical characteristics.
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Incorporation of Surface Active
Agents :
• Surfactants can also be used to enhance solubility. A
surfactant or surface active agent is amphipathic,
meaning it has polar end (the circular head) and a
nonpolar (the tail). When a surfactant is placed in
water it will form micelles. A nonpolar drug will
partition into the hydrophobic core of the micelle and
the polar tails will solubilize the complex.
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Solid Dispersions :
• Solid Dispersions These are generally prepared by
solvent or co-precipitation method where by both the
guest solute and the solid carrier solvent are dissolved
in a common volatile solvent like alcohol. The liquid
solvent is removed by evaporation under reduced
pressure or by freeze drying which results in
amorphous precipitation of guest in a crystalline
carrier. Thus the basic difference between the solid
dispersions and solid solutions/eutectics is that the
drug is precipitated out later; e.g.: amorphous
sulfathiazole in crystalline urea. Such dispersions are
often called as Co-evaporates or Co-precipitates. 11

Polymorphism :
• Polymorphism The capacity for a substance to exhibit
in more than one crystalline form is polymorphism. If
the change from one form to another is reversible, the
process is called enantiotropy. Use of metastable
forms help in increasing the dissolution rate.
Polymorphism A solid has a rigid form and a definite
shape . The shape or habit of a crystal of a given
substance may vary but the angles between the faces
are always constant. A crystal is made up atoms, ions,
or molecules in a regular geometric arrangement or
lattice constantly repeated in three dimensions. This
repeating pattern is known as the unit cell.
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The use of Metastable Polymorphs:
• The use of Metastable Polymorphs: The solid state
characteristics of drug are known to potentially exert
the significant influence on the solubility parameter.
As the presence of metastable, polymorphic
crystalline forms can exert a great influence on
solubility, dissolution rate and biological activity of
medicaments.
• Drugs which show met stability include
Chloramphenicol, Prednisolone, Barbiturates, and
Riboflavin.
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Molecular Encapsulation
• Molecular Encapsulation with Cyclodextrins
(Complexation with Cyclodextrins) The α-, β-, γ-
Cyclodextrins are cyclic oligosaccharides consisting
of six , seven and eight glucose units respectively.
Their important property is ability of forming
inclusion complexes with smaller molecules which fit
into their hydrophobic cavity of the Cyclodextrins.
The formation of inclusion complex alters a variety of
physico-chemical properties of the drug molecules
such as its solubility, dissolution rate, membrane
permeability, chemical reactivity and dissociation
constant. Solubility increases with increase in the
amount of cyclodextrin added. 14

Prodrug Approach :
• Prodrug Approach One method to increase the
solubility of a drug is to alter the structure of the
molecule. The addition of polar groups like
carboxylic acids, ketones and amines can increase
solubility by increasing hydrogen bonding and
interaction with water. Another structure modification
may be can be to reduce intermolecular forces. E.g. :
methyldopa (solubility ~10mg/ml) and methyldopa
(10-300 mg/ml depending on pH). The addition of
ethyl ester to methyldopa reduces the intermolecular
hydrogen bond between the carboxylic acid and
primary amine. There fore this addition reduces
melting point and increases solubility. 15

Salt form of the drug :
• Salt form of the drug Most of the drugs are either
weak acids or weak bases. One of the easiest method
to enhance dissolution rate of drugs is to convert
them into salt forms. At a given pH, the solubility of
a drug, whether acidic/basic or its salt form is a
constant. The influence of salt formation on the drug
solubility, rate of dissolution and the absorption can
be explained by considering the pH of the diffusion
layer and not the pH of the bulk of the solution.
Consider a case of a salt of weak acid at any given pH
of the diffusion layer of the salt of the weak acid will
be higher than that observable with the free acid from
the drug.
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Nanosuspension :
• Nanosuspension A Nanosuspension is a submicron
colloidal dispersion of drug particles which are
stabilized by surfactants. The poor water solubility of
drugs is major problem for drug formulation. To date,
nanoscale systems for drug delivery have gained
much interest as a way to improve the solubility
problems. The reduction of drug particles into the
sub-micron range leads to a significant increase in the
dissolution rate and therefore enhances
bioavailability. Nanosuspensions are promising
candidates that can be used for enhancing the
dissolution of poorly water soluble drugs.
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Ternary systems :
• Ternary systems Hydrophilic polymers have been
commonly used as carriers for preparing solid
dispersions. Among them, Polyvinylpyrrolidone
(PVP) was widely employed for its high aqueous
solubility, high physiological tolerance, and low
toxicity. In recent years, the interest in incorporating
a surface-active carrier into solid dispersion increased
greatly and a high improvement in drug dissolution
was reported.
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Conclusion :
• Conclusion For any drug to show proper efficacy and safety it
should reach the systemic circulation showing optimum
bioavailability that further depends upon the dissolution of the
drug dosage form in vivo and this dissolution should be
occurring at a required rate. The dissolution can be enhanced
to improve the bioavailability. Using proper surfactants,
increasing the surface area by reducing the particle size, etc,
can enhance the dissolution and the above discussed
parameters, thus improving bioavailability and therapeutic
efficacy of the medicament. Dissolution depends on the
chemistry of the active ingredients and physico-chemical
properties of the excipients used.
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References :
• D.M. Brahmankar, Sunil B Jaiswal. Biopharmaceutic and
pharmacokinetics 2005; pg no. 29, 290-296. Abdou.
Dissolution of pharmaceutical drugs 2001; pg no. 5, 56-68.
• V. Venkateshwar Rao “Biopharmaceutic and
pharmacokinetics 2005. Connors KA. The stability of
cyclodextrin complexes in the solution. Chem Rev. 1997;
97:1325-1357.
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Techniques for enhancement of dissolution rate

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