BIOAVAILABILITY

ENHANCEMENT TECHNIQUES

For Class- B.Pharmacy 6th Semester

Subject- BIOPHARMACEUTICS AND PHARMACOKINETICS (BP604T)

RAMAKANT JOSHI
School of Studies in Pharmaceutical Sciences,
Jiwaji University, Gwalior
• DEFINITION : Solubility is defined in quantitative terms as
concentration of solute in concentrated solution at a certain
temperature, and in qualitative way it can be defined as a
spontaneous interaction of two or more substances to form a
homogenous molecular dispersion.

• Solubilization can be defined as a preparation of

thermodynamically stable isotropic solution of a substance
normally insoluble or slightly soluble in a given solvent by
introduction of an additional component or components.
The biopharmaceutical classification system
(BCS)
CLASS SOLUBILITY PERMEABILITY ABSORPTION RATE LIMITING
PATTERN STEP IN
ABSORPTION

I High High Well absorb Gastric

emptying

II Low High variable Dissolution

III High Low Variable Permeabilit

y

IV Low Low Poorly Case by

absorb case
The pharmacopoeia lists solubility in terms of number of
milliliters of solvent required to dissolve 1g of solute. The Indian
pharmacopoeia provides general terms to describe a given range.
These descriptive terms are given as:
DEFINITION PARTS OF SOLVENT REQUIRED
FOR 1 PART OF SOLUTE

Very soluble <1

Freely soluble 1 - 10
Soluble 10 – 30

Sparingly soluble 30 - 100

Slightly soluble 100 - 1000

Very slightly soluble 1000 – 10,000

Insoluble >10,000 6
• Therapeutic effectiveness of a drug depends upon the
bioavailability and ultimately upon the solubility of drug molecules.
• Solubility is one of the important parameter to achieve desired
concentration of drug in systemic circulation for pharmacological
response to be shown.
• Currently only 8% of new drug candidates have both high solubility
and permeability.
• Nearly 40% of the new chemical entities currently being discovered
are poorly water soluble.
• More than one-third of the drugs listed in the U.S. Pharmacopoeia
fall into the poorly water-soluble or water-insoluble categories.
• Low aqueous solubility is the major problem encountered with
formulation development of new chemical entities.
• Any drug to be absorbed must be present in the form of an
aqueous solution at the site of absorption.
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The process of solubilization involves the 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,
interaction between the solvent and the solute molecule or ion.
STEPS INVOLVED ARE :

1: Holes opens in the solvent

2. Molecules of the solid breaks away from the bulk.

3. The freed solid molecule is integrated into the hole.

I. Physical Modifications
A. Particle size reduction
1. Micronization 3.Sonocrystalisation
2. Nanosuspension 4.Supercritical fluid process
B. Modification of the crystal habit
1. Polymorphs 2. Pseudopolymorphs
C. Drug dispersion in carriers
1. Eutectic mixtures 2. Solid dispersions
3. Solid solutions
D. Complexation
Use of complexing agents
E. Solubilization by surfactants
Microemulsions
II. Chemical Modifications
1. Change in the pH
2. Use of buffer
3. Derivatization

III. Other methods

1.co-crystallisation
2. co-solvency
3.Hydrotrophy
4.Solubilizing agents
5.Selective adsorption on insoluble carrier
6.Solvent deposition
7.Using soluble prodrug
8.Functional polymer technology
9.Precipitation Porous
10.microparticle technology
11.Nanotechnology approaches
A.Particle size reduction:
Particle size reduction can be achieved by
a. Micronization
b. nanosuspension
c. Sonocrystalisation
d.Supercritical fluid process

1. Micronization: Colloid mill

• Micronization increases the dissolution rate of drugs through
increased surface area.
• Micronization of drugs is done by milling techniques using jet mill,
rotor stator colloid mills etc.
• Micronization is not suitable for drugs having a high dose number
because it does not change the saturation solubility of the drug .
• The process involves reducing the size of the solid drug particles
to 1 to 10 microns commonly by spray drying or by use of attrition
methods. The process is also called micro-milling.
2. Nanosuspension :

Nanosuspensions are sub-micron colloidal dispersion of

pure particles of the drug, which are stabilized by surfactants.
Nanosuspension technology is used for efficient delivery of
hydrophobic drugs . The particle size distribution of the
solid particles in nanosuspensions is usually less than one micron
with an average particle size ranging between 200 and 600 nm.

Advantage :
Increased dissolution rate due to larger surface area exposed.

Eg., Nanosuspension approach has been employed drugs like

paclitaxel, tarazepide, amphotericin B which are still on research
stage.
3.Sonocrystallisation :
Particle size reduction on the basis of crystallisation by
using ultrasound is Sonocrystallisation . Sonocrystallisation utilizes
ultrasound power for inducing crystallisation . It not only enhances
the nucleation rate but also an effective means of size reduction
and controlling size distribution of the active pharmaceutical
ingredients. Most applications use ultrasound in the range 20 kHz-
5 MHz.
4. Supercritical fluid process :
• A supercritical fluids are dense non-condensable fluid whose
temperature and pressure are greater than its critical
temperature ( Tc ) and critical pressure ( Tp ) allowing it to
assume the properties of both a liquid and a gas.
• Through manipulation of the pressure of SCFs, the favourable
characteristics of gases – high diffusivity, low viscosity and low
surface tension may be imparted upon the liquids to precisely
control the solubilisation of a drug with a supercritical fluid.
• Once the drug particles are solubilised within SCFs, they may be
recrystalised at greatly reduced particle sizes.
• A SCF process allows micronisation of drug particles within
narrow range of particle size, often to sub-micron levels.
B. Modification of the crystal habit:

Polymorphs

Enantiotropic Monotropic
One polymorphs form can No reversible transition
change reversibly into another is possible.
at a definite transition temperature
below the melting point.

• Metastable forms are associated with higher energy and thus

higher solubility. Similarly the amorphous form of drug is always
more suited than crystalline form due to higher energy associated
and increased surface area.
• The anhydrous form of a drug has greater solubility than the
hydrates. This is because the hydrates are already in interaction
 with water and therefore have less energy for crystal
breakup in comparison to the anhydrates.
• They have greater aqueous solubility than the crystalline
forms because they require less energy to transfer a
molecule into solvent. Thus, the order for dissolution of
different solid forms of drug is
Amorphous > metastable polymorph > stable polymorph
• Melting followed by a rapid cooling or recrystallization from
different solvents can produce metastable forms of a drug.
C. Drug dispersion in carriers:
The term “solid dispersions” refers to the dispersion of one or
more active ingredients in an inert carrier in a solid state, frequently
prepared by the

• Hot melt mehod

1.

• Solvent evaporation method

2.

• Hot melt extrusion method

3.
 1. Hot melt method :

Drug + vehicle (m.p low, organic solvent – insoluble)

(heating) Important
A molecular requisites :
dispersion can be 1. Miscibility of the
Melting
achieved or drug & carrier
.
not, depends on the in the molten
degree of form,
Freezing quickly
supersaturation and 2. Thermostability
rate of cooling used of the drug &
in the process. carrier.
Dosage forms

Suitable to drugs and vehicles with promising heat stability.

2. Solvent evaporation method:
Drug + vehicle ( both soluble in solvent)
organic solvent

solution The solvent

evaporation can
be done by spray
drying or freeze
evaporate the solvent
drying.

Temperatures used
coprecipitates for solvent
evaporation
generally lie in the
dosage forms range 23-65 C.

suitable
suitabletotodrugs
drugswith
withvolatility
volatilityororpoor
poorstability
stability
3.Hot-melt Extrusion:
Hot melt extrusion of miscible components results in
amorphous solid solution formation, whereas extrusion of an
immiscible component leads to amorphous drug dispersed in
crystalline excipient. The process has been useful in the
preparation of solid dispersions in a single step.
D. Complexation :
Complexation is the reversible association between
two or more molecules to form a nonbonded entity with a well
defined stoichiometry . Complexation relies on relatively weak
forces such as van-derwaal forces, hydrogen bonding and
hydrophobic interactions. Hydrophillic

Inclusioncomplexation
Inclusion complexation:: These are formed by
the insertion of the nonpolar molecule or the
nonpolar region of one molecule into the cavity
of another molecule or group of molecules. The
most commonly used host molecules are
cyclodextrins . Cyclodextrins are non- reducing,
crystalline , water soluble, cyclic,
oligosaccharides. Cyclodextrins consist of
Hydrphobic
glucose monomers arranged in a donut shape
ring. CYCLODEXTRIN
The surface of the cyclodextrin molecules makes them water
soluble, but the hydrophobic cavity provides a microenvironment
for appropriately sized non-polar molecules. Based on the structure
and properties of drug molecule it can form 1:1 or 1:2 drug
cyclodextrin complex. Three naturally occurring CDs are α
Cyclodextrin, β Cyclodextrin, and γ Cyclodextrin.
Staching complexation
Organic drug + water → Squeezed out by strong water-water interaction
force.

Forms aggregates

Reduces the contact b/w nonpolar hydrocarbon moieties & the polar
water molecule
Eg ., Large nonpolar regions
Nicotinamide,
Anthracene, Opposed by entropy
Caffeine,
Theobromine. Random arrangement

Complexes stached can be homogeneous or mixed

Self association complexation 25

E. Solubilization by surfactants:
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, zwitter ionic or
nonionic. The presence of surfactants
may lower the surface tension and increase the solubility of the
drug within an organic solvent .
Microemulsion : A microemulsion is a four-component system
composed of external phase, internal phase, surfactant and co
surfactant . The addition of surfactant, which is predominately
soluble in the internal phase unlike the co surfactant , results in the
formation of an optically clear, isotropic, thermodynamically stable
emulsion. It is termed as microemulsion because of the internal
phase is <0.1 micron droplet diameter.
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 The surfactant and the co surfactant alternate each other and
form a mixed film at the interface, which contributes to the
stability of the microemulsion .
Non-ionic surfactants, such as Tweens ( polysorbates ) and Labrafil
( polyoxyethylated oleic glycerides ), with high hyrophile-lipophile
balances are often used to ensure immediate formation of oil-in-
water droplets during production.
Advantages :
 Ease of preparation due to spontaneous formation.
 Thermodynamic stability,
transparent and elegant appearance,
enhanced penetration through the biological membranes,
increased bioavailability and
less inter- and intra-individual variability in drug
pharmacokinetics.
II. CHEMICAL MODIFICATIONS
1)By change of pH:
For organic solutes that are ionizable, changing
the pH of the system is the simplest and most effective means of
increasing aqueous solubility .

LOWER pH UNIONISED FORM INSOLUBLE PPT

HIGHER pH IONISED FORM MORE SOLUBLE DRUG

Lower pH Ionized form More soluble drug

Higher pH UNIONISED FORM INSOLUBLE PPT

2) Use of buffer: Buffer maintains the pH of the solution
overtime and it reduces or eliminate the potential for precipitation
upon dilution. On dilution pH alteration occurs that decrease
solubility . Change of pH by 1 fold increase solubility by 10 fold If it
changes by one pH unit ,that decrease ionization of the drug and
solubility decreases by 10 fold.

3) Derivatization : It is a technique used in chemistry which

transforms a chemical compound into a product of similar
chemical structure, called derivative. Derivatives have different
solubility as that of adduct. It is used for quantification of adduct
formation of esters and amides via acyl chlorides.

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III. OTHER METHODS.

1.Co-crystallization:
A co-crystal may be defined as a crystalline material
that consists of two or more molecular species held together by
non-covalent forces.
• Co-crystals are more stable, particularly as the co-crystallizing
agents are solids at room temperature.
• Co-crystals can be prepared by evaporation of a heteromeric
solution or by grinding the components together.
• Another technique for the preparation of co-crystals includes
sublimation, growth from the melt, and slurry preparation.
•Only three of the co-crystallizing agents are classified as generally
recognised as safe (GRAS) it includes saccharin, nicotinamide and
acetic acid limiting the pharmaceutical applications.
2. Cosolvency : Cosolvents are prepared by mixing miscible or
partially miscible solvents. Weak electrolytes and nonpolar
molecules have poor water solubility and it can be improved by
altering polarity of the solvent. It is well-known that the addition
of an organic cosolvent to water can dramatically change the
solubility of drugs. Cosolvent system works by reducing the
interfacial tension between the aqueous solution and hydrophobic
solute.
Aquous solvent - Etahnol, sorbitol, glycerin,
propylene glycol.
Non aquous solvent - glycerol dimethyl ketal,
glycerol formal, glycofurol,
dimethyl acetamide.
SOME PERANTRALPRODUCT THAT CONTAIN
COSOLVENT
1.Diazepam - 10% ethanol + propylene glycol
2.Digoxin - 10% ethanol + propylene glycol
 3. Hydrotrophy : Hydrotrophy designate the increase in solubility
in water due to the presence of large amount of additives. The
mechanism by which it improves solubility is more closely related
to complexation involving a weak interaction between the
hydrotrophic agents (sodium benzoate, sodium acetate, sodium
alginate, and urea).
4. Solubilizing agents: The solubility of poorly soluble drug can also
be improved by various solubilizing materials. PEG 400 is improving
the solubility of hydrochlorthiazide85. Modified gum karaya (MGK),
a recently developed excipient was evaluated as carrier for
dissolution enhancement of poorly soluble drug, nimodipine .

5. Selective adsorption on insoluble carriers: A highly active

adsorbent such as inorganic clays like Bentonite can enhance the
dissolution rate of poorly water-soluble drugs such as griseofulvin,
indomethacin and prednisone by maintaining the concentration
gradient at its maximum. 2 reasons suggested for rapid release of
drugs from the surface of clays :-
1. weak physical bonding between adsorbate and adsorbent.
2. hydration and swelling of the clay in the aqueous media.
6. Solvent deposition: In this method,the poorly aqueous soluble
drug such as Nifedipine is dissolved in an organic solvent like alcohol
and deposited on an inert , hydrophilic, solid matrix such as starch or
microcrystalline cellulose and evaporation of solvent is done.

7. Use of soluble prodrug :

Prodrug stratergy involves the
incorporation of polar or
ionizable moiety into the
parent compound to improve
aqueous solubility. Example :
prodrug of established drugs
has been successfully used to
improve water solubility of
corticosteroids
benzodiazepines.
8. Functional Polymer Technology : Functional polymer enhances
the dissolution rate of poorly soluble drugs by avoiding the lattice
energy of the drug crystal, which is the main barrier to rapid
dissolution in aqueous media. The dissolution rate of poorly
soluble , ionizable drug like cationic, anionic and amphoteric
actives can be enhanced by this technology. Applied to heat
sensitive materials and oils also.
9. Precipitation: In this method, the poorly aqueous soluble drug
such as cyclosporine is dissolved in a suitable organic solvent
followed by its rapid mixing with a non-solvent to effect
precipitation of drug in nano size particles. The product so
prepared is also called as hydrosol.
10. Porous microparticle technology: The poorly water soluble drug
is embedded in a microparticle having a porous, water soluble,
sponge like matrix, dissolves wetting the drug and leaving a
suspension of rapidly dissolving drug particles. These drug particles
provide large surface area for increased dissolution rate . This is the
core technology applied as HDDS.
11. Nanotechnology approaches : For many new chemical entities
of very low solubility ,oral bioavailability enhancement by
micronization is not sufficient because micronized product has a
tendency of agglomeration, which leads to decreased effective
surface area for dissolution . Nanotechnology refers broadly to
the study and use of materials and structures at the nanoscale
level of approximately 100 nanometers (nm) or less .

NANOCRYSTAL: Size: 1-1000 nm Crystalline material with

dimensions measured in nanometers. There are two distinct
methods used for producing nanocrystals . 1 . bottom-up. 2. top-
down . The top-down methods (i.e. Milling and High pressure
homogenization ) start milling down from macroscopic level, e.g.
from a powder that is micron sized. In bottom-up methods (i.e.
Precipitation and Cryo -vacuum method), nanoscale materials are
chemically composed from atomic and molecular components.
NanoMorph :
• The NanoMorph technology is to convert drug substances with
low water-solubility from a coarse crystalline state into amorphous
nanoparticles .
•A suspension of drug substance in solvent is fed into a chamber,
where it is rapidly mixed with another solvent. Immediately the
drug substance suspension is converted into a true molecular
solution. The admixture of an aqueous solution of a polymer
induces precipitation of the drug substance. The polymer keeps the
drug substance particles in their nanoparticulate state and prevents
them from aggregation or growth. Using this technology the coarse
crystalline drug substances are transformed into a nanodispersed
amorphous state, without any physical milling or grinding
procedures. It leads to the preparation of amorphous nanoparticles
.