Download Enhancement on dissolution rate

Department of Pharmaceutics
Contents
Introduction
Process of dissolution
Methods for enhancing dissolution rate
Conclusion
References
Introduction
 Dissolution is the process by which a solid substance solubilizes in a given
solvent.
 Dissolution rate is defined as the amount of solid substance that reaches into
solution per unit time under standard conditions of temperature, pressure,
and pH.
 Concept of dissolution was introduced in 1897 by Noyes and Whitney,they
suggested that dissolution rate is controlled by the rate of diffusion of a very
thin layer of saturated solution that forms instantaneously around the solid.
 Noyes and Whitney have proposed an equation
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.
Methods to Enhance Dissolution Rate:
1.
2.
3.
4.
5.
6.
7.
8.
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.
1. 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.
2. 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.
Eg: In griseofulvin and several steroidal and sulphur drugs bioavailability
have been increased by micronization technique.
3.Incorporation of Surface Active Agents :
 This helps by enhancing dissolution by increasing wetting and penetration
properties of the dissolution medium through incorporation of surface-active
agent.
 Concentration usually employed is below the CMC(critical micellar
concentration) value since above CMC, the drug entrapped in the micelle
structure fails to partition in the dissolution fluid.
 Usually non-ionic surfactants like polysorbates are widely used.
Eg: steroids like Spironolactone.
4. Solute- Solvent Complexation Reactions:
 Molecular
complexation between molecules of dissolving solutes and
certain solvents have been known to effect dissolution rates. Higuchi
studied the dissolution rate of 2-napthol tablets in cyclo hexane. These
additives are known to react rapidly and reversibly forming soluble
complexes . Major complexation is hydrogen bonding. This can be called as
pseudo polymorphism.
 Dissolution kinetics are controlled by factors like diffusion coefficient of the
complexing component of the solvent and the stability constant of the
resulting complex.
 Solute solvent complexation reactions also improve dissolution by reducing
particle size of solid .
SOLID SOLUTIONS
 There are three means by which the particle size can be reduced to sub
micron level are:
1.
2.
3.

Solid solutions,
Eutectic mixtures, and
Solid dispersions.
In all these cases the solute is frequently a poorly water soluble drug
acting as a guest and the solvent is a highly water soluble compound or
polymer acting as a host or a carrier.
Solid solutions :
 It is a binary system comprising a solid solute molecularly dispersed in a
solid solvent. Since the two compartments crystallize together in a
homogenous one phase system, solid solutions are also called as molecular
dispersions or mixed crystals.
 By the reduction in particle size to the molecular level, solid solutions show
greater aqueous solubility and faster dissolution.
 Usually they are prepared by fusion method where by a physical mixture of
solute and solvent are melted together followed by rapid solidification.
Eg: Griseofulvin-succinic acid
 Solid solution of Griseofulvin dissolves 6 to 7 times faster than pure
griseofulvin.
Eutectic Mixtures:
 These systems are also prepared by fusion method. Such systems are
intimately blended physical mixture of two crystalline components.
 When the eutectic mixture is exposed to water, the soluble carrier dissolves
leaving the drug in a microcrystalline state which solubilizes rapidly.
 Examples of eutectic include paracetamol-urea, griseofulvin-urea,
griseofulvin- succinic acid, etc.
 Method cannot be applied to



Drugs which fail to crystallize from mixed melt,
Thermo labile drugs, and
Carriers such as succinic acid that decomposes at their melting point.
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. The
method is suitable for thermo labile substances.
 The carriers used are same as for eutectics and solid solutions. With glassy
materials, the dispersions formed are called as glass dispersions or glass
suspensions.
5. 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
enantiotropic.
 Use of metastable forms help in increasing the dissolution rate.
Amorphous> Metastable > Stable
Eg : Drugs which show metastability include Chloramphenicol,
Prednisolone, Barbiturates, and Riboflavin.
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. The separation and use of specific polymorphic form that
possesses the highest solubility is a technique that can be applied in certain
cases for the increase of dissolution rates.
 Drugs which show metastability include Chloramphenicol, Prednisolone,
Barbiturates, and Riboflavin.
6.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.
 Among the natural cyclodextrins β-cyclodextrin (βCD) is used widely
because of its unique cavity size (internal diameter about 6.5 °A).
Marketed preparations:
Alfaxalone
Steroid anesthetic
Incorporation : 100mg/g
CD used: THPB
Trappsol Hydroxypropyl Beta
Erythromycin 1
Antibiotic
Incorporation: 45mg/g
CD used: THPB
Hydrocortisone
Glucocorticoid
Incorporation: 90mg/g
CD used: THPB
Ibuprofen
Anti-inflammatory
Incorporation: 90mg/g
CD used: THPB
7. 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 methyldopate (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.
•Another method is complexation. Complexation lies on relatively weak forces
such as London forces, hydrogen bonding and hydrophobic interactions.c
Type
Example
Coordination
Hexamine cobalt (III) chloride
Chelates
EDTA
Metal-Olefin
Ferrocene
Inclusion
Choleic acid
Molecular complexes
Polymers
8. 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.
 Eg: Alkali metal salts of acidic drugs like pencillins and strong acid salts of
basic drugs like atropine are more water soluble than the parent drug
Newer techniques:
Self emulsification:
 Self emulsifying agent will act as dispersing or self emulsifying agent on
drug through which the dissolution of the drug can be increased by
preventing the formation of any water insoluble surface layer, although the
liberated drug remain undissolved in the dissolution medium.
 When its concentration exceed its saturation solubility, it will disperse or
emulsify into a finely divided state because of surface activity of the
dissolved vehicle the surface area will be made available which facilitate its
dissolution in gastrointestinal fluid.
Eg: Carmustine, Glycolides.
Nanosuspensions:
 A nanosuspension is a submicron colloidal dispersion of drug particles of
200-600 nm size which are stabilized by surfactants.
Eg : Amphotericin B
The three basic technologies currently in use to prepare nanoparticles are
1. Pearl milling
2. Homogenisation in water
3. Homogenisation in non-aqueous media
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.
 Eg: Dissolution of naproxen from solid dispersions in polyethylene glycol
(PEG) 4000, 6000, and 20000 could be further enhanced when Polysorbate
80 was incorporated into the system.
The dissolution profiles of original drug (OA), physical mixture,
and ternary solid dispersions.
References:
1.
2.
3.
4.
D.M. Brahmankar, Sunil B Jaiswal. Biopharmaceutics and
pharmacokinetics 2005; pg no. 29, 290-296.
Abdou. Dissolution of pharmaceutical drugs 2001; pg no. 5, 56-68.
V. Venkateshwar Rao “Biopharmaceutics and pharmacokinetics 2005.
Wikipedia.