2. DEFINITION:
The term ‘solubility’ is defined as maximum amount of
solute that can be dissolved in a given amount solvent.
Solute is the substance being
dissolved – powder
Solvent is the dissolving agent –
water
3. Solubility can also be defined
quantitatively as well as
qualitatively.
Quantitatively it is defined as the
concentration of the solute
in a saturated solution at a certain
temparature.
Qualitatively it may be defined as the
spontaneous
interaction of two or more substances
to form a homogenous molecular
dispersion.
A saturated solution is one in which
the solute is in equilibrium with
solvent.
The solubility of drug is represented
through various concentration
expression such as
parts,percentage,molarity,molality,vo
lume fraction,mole fraction
4. Solubility is one of the important parameters to achieve desired
concentration of drug in systemic circulation for achieving required
pharmacological response.
These poorly water soluble drugs having slow drug absorption leads to
inadequate and variable bioavailability and gastrointestinal mucosal
toxicity.
Most of the drugs(>40%) belongs to BCS class II (low solubility and
high permeability).
As for BCS class II drugs rate limiting step is drug release from the
dosage form and solubility in the gastric fluid, so increasing the solubility
in turn increases the bioavailability for BCS class II drugs.
5.
6. Solubility improvement techniques can be categorized
into physical modification, chemical modifications of the
drug substance, and other techniques.
Physical Modifications —Particle size reduction like
micronization and nano-suspension, modification of the
crystal habit like polymorphs, amorphous form and co-crystallization,
drug dispersion in carriers like eutectic
mixtures, solid dispersions and solid solutions.
Chemical Modifications —Change of pH, use of buffer,
derivatization, complexation, and salt formation.
Miscellaneous Methods —Supercritical fluid process, use
of adjuvant like surfactant, solubilizers,
cosolvency,hydrotropy etc.
7. Step 1 Step2 Step 3
Holes open in the
solvent
Molecules of the solid
breaks away from
the bulk
The freed solid
molecule is integrated
into the hole in the
solvent
9. Micellar solubilizatiion:
Surfactants can lower surface tension & improve the
dissolution of lipophilic drugs in the aqueous medium.
When the concentration of surfactants exceeds their
critical micelle concentration (CMC, which is in a
range of 0.05-0.10% for most surfactants), micelle
formation occurs,entrapping the drugs within the
micelles.
This process is known as micellisation and generally
results in enhanced solubility of poorly soluble drugs.
10. Micellar solubilization is a powerful alternative for
dissolving hydrophobic drugs in aqueous
environments.
Surfactants are known to play a vital role in many
processes of interest in both fundamental and applied
science.
One important property of surfactants is the formation
of colloidal-sized clusters in solutions, known as
micelles, which have particular significance in
pharmacy because of their ability to increase the
solubility of sparingly soluble substances in water
11. Micelles are known to have an anisotropic water
distribution within their structure
Micellar systems can solubilize poorly soluble drugs and
thus increase their bioavailability
12. Surfactants are amphiphilic molecules composed of a
hydrophilic or polar moiety known as head and a hydrophobic
or nonpolar moiety known as tail.
The surfactant head can be charged (anionic or cationic),
dipolar (zwitterionic), or non-charged (nonionic).
Ex: SDS, DTAB, Ethylene oxide, dioctanoyl phosphatidyl
choline etc.
The surfactant tail is usually a long chain hydrocarbon residue
and less often a halogenated or oxygenated hydrocarbon or
siloxane chain.
13. A surfactant, when present at low concentrations in a system,
adsorbs onto surfaces or interfaces significantly changing the
surface or interfacial free energy
Surfactants usually act to reduce the interfacial free energy,
although there are occasions when they are used to increase it.
When surfactant molecules are dissolved in water at
concentrations above the critical micelle concentration (cmc),
they form aggregates known as micelles.
14. In a micelle, the hydrophobic tails flock to the interior in order
to minimize their contact with water, and the hydrophilic heads
remain on the outer surface in order to maximize their contact
with water.
15. The micellization process in water
results from a delicate balance of
intermolecular forces, including
hydrophobic, steric, electrostatic,
hydrogen bonding, and van der
Waals interactions.
The determination of a surfactant
cmc can be made by use of several
physical properties, such as surface
tension(γ), conductivity (κ) – in case
of ionic surfactants, osmotic pressure
(π), detergency, etc.
When these properties are plotted as
a function of surfactant concentration
(or its logarithm, in case of surface
tension), a sharp break can be
observed in the curves obtained
evidencing the formation of micelles
at that point
16. Another important parameter that characterizes micelles is the
aggregation number, Nag, that corresponds to the average
number of surfactant monomers in each micelle of a micellar
solution.
Micelles are labile entities formed by the noncovalent
aggregation of individual surfactant monomers. Therefore, they
can be spherical, cylindrical, or planar (discs or bilayers).
Micelle shape and size can be controlled by changing the
surfactant chemical structure as well as by varying solution
conditions such as temperature, overall surfactant
concentration, surfactant composition (in the case of mixed
surfactant systems), ionic strength and pH
17. An important property of
micelles that has particular
significance in pharmacy is
their ability to increase the
solubility of sparingly soluble
substances in water.
Solubilization can be defined as
the spontaneous dissolving of a
substance by reversible
interaction with the micelles of
a surfactant in water to form a
thermodynamically stable
isotropic solution with reduced
thermodynamic activity of the
solubilized material.
18. From the thermodynamic point of view, the solubilization can
be considered as a normal partitioning of the drug between two
phases, micelle and aqueous, and the standard free energy of
solubilization (ΔGS º) can be represented by the following
expression
ΔGS º= -RTlnP
where R is the universal constant of the gases, T is the
absolute temperature, and P is the partition coefficient between
the micelle and the aqueous phase.
Usually, the solubilization of a molecule by a surfactant can be
evaluated based on two descriptors that are the molar
solubilization capacity, χ, and the micelle water partition
coefficient, P
19. The χ value is defined as the number of moles of the solute
(drug) that can be solubilized by one mol of micellar surfactant,
and characterizes the ability of the surfactant to solubilize the
drug.
Where Stot is the total drug solubility, SW is the water drug
solubility, Csurf is the molar concentration of surfactant in
solution, and cmc is the critical micelle concentration.
The micelle-water partition coefficient is the ratio of drug
concentration in the micelle to the drug concentration in water
for a particular surfactant concentration, as follows:
20. Combining Equations we can relate the two solubility
descriptors. Accordingly, for a given surfactant concentration
As can be seen, P is related to the water solubility of the
compound, in contrary to χ . In order to eliminate the
dependence of P on the surfactant concentration, a molar
micelle-water partition coefficient (PM), corresponding to the
partition coefficient when Csurf = 1 M, can be defined as
follows
The lower is the cmc value of a given surfactant, the more
stable are the micelles.
21. Hydrophilic drugs can be adsorbed on the surface of
the micelle.
Drugs with intermediate Solubility should be located
in intermediate positions within the micelle such as
between the hydrophilic head group of Peo Micelles
In the Palisade Layer between the hydrophilic group
and the first few carbon atoms of the hydrophobic
group , that is the outer core.
Completely insoluble hydrophobic drugs may be
located in the Inner Core of the micelle.
22. Examples of poorly soluble compounds that
use micellar solubilization are
Anti-diabetic drugs,
Gliclazide,
Glipizide,
Gluburide,
Glimepride,
Repaglinide,
Pioglitazone,and
Rosiglitazone.
23.
24. INTRODUCTION:
The term Hydrotropic agent was first introduced by Neuberg(1916)
to designate anionic organic salts.
Hydrotropy is defined as a solubilisation process where by addition
of a large amount of second solute results in an increase in the
aqueous solubility of another solute and the chemicals which are
used in hydrotropy are called hydrotropes.
Ex: sodium benzoate, urea, sodium salicylate, ibuprofen sodium etc.
The chemical structure of the conventional Neuberg’s hydrotropic
salts consists of two essential parts, an anionic group and a
hydrotropic aromatic ring or ring system.
25. Hydrotropic agents are ionic organic salts.
Additives or salts that increase solubility in given solvent are
said to “salt in” the solute & those salts that decrease solubility
“salt out ” the solute.
Several salts with large anions or cations that are themselves
very soluble in water result in “salting in” of non electrolytes
called “hydrotropic salts” a phenomenon known as
“hydrotropism”.
Hydrotropic solutions do not show colloidal properties and
involve a weak interaction between the hydrotropic agent and
solute.
26. A hydrotrope is a compound that solubilises
hydrophobic compounds in aqueous solutions.
Typically, hydrotropes consist of a hydrophilic part and
a hydrophobic part, but hydrophobic part is too small
to cause self aggregation.
Hydrotropes do not have a critical concentration above
which self aggregation 'suddenly' starts to occur.
Ex: Paracetamol with urea as hydrotropic agent.
27. The more is the concentration of hydrotrope, more is the aqueous solubility
of poorly water-soluble drugs. Distilled water was used in making
hydrotropic solutions.
To select suitable hydrotropes for various poorly water soluble drugs
following method is used.(approx solubility can be determined)
25ml of H2O/Hydrotropic soln 50ml beaker Gross weight was
noted.(1)
Gross weight is same operation is Add drug and shake
noted (2) continued till excess
drug remain undissolved.
From the difference in two readings, solubility was determined.
29. The determination of interference of hydrotropic agents in
the spectrophotometric estimation of the standard
solutions of drugs were determined in distilled water alone
and in the presence of the maximum concentration of the
hydrotropic agent employed for spectrophotometric
analysis.
The absorbances were recorded against respective reagent
blanks at appropriate wavelengths
Enhancement ratios can be determined by the formula
Enhancement ratio = solubility in hydrotropic solution/
solubility in distilled water.
30. Hydrotropy is suggested to be superior to other
solubilization method, such as miscibility, micellar
solubilization, co solvency and salting in, because the
solvent character is independent of pH, has high
selectivity and does not require emulsification
It only requires mixing the drug with the hydrotrope in
water.
It does not require chemical modification of
hydrophobic drugs, use of organic solvents, or
preparation of emulsion system
31. Mixed hydrotropic solubilization technique is the
phenomenon to increase the solubility of poorly water-soluble
drugs in the blends of hydrotropic agents which
may give miraculous synergistic enhancement effect on
solubility of poorly water soluble drugs.
Utilization of it in the formulation of dosage forms of
water insoluble drugs and to reduce concentration of
individual hydrotropic agent to minimize the side
effects.
32. It may reduce the large total concentration of hydrotropic
agents necessary to produce modest increase in solubility by
employing combination of agents in lower concentration.
It is new, simple, cost-effective, safe, accurate, precise and
environmental friendly method for the analysis (titrimetric
and spectrophotometric) of poorly water-soluble drugs
titrimetric and spectrophotometric precluding the use of
organic solvents.
It precludes the use of organic solvents and thus avoids the
problem of residual toxicity, error due to volatility,
pollution, cost etc
33. Quantitative estimations of poorly watersoluble drugs
by UV-Visible spectrophotometric analysis precluding
the use of organic solvents.
Quantitative estimations of poorly watersoluble drugs
by titrimetric analysis.such as ibuprofen, flurbiprofen
and naproxen using sodium benzoate[29] .
Preparation of hydrotropic solid dispersions of poorly
water-soluble drugs precluding the use of organic
solvents. Such as felodipine[30] using poly ethylene
glycol 6000 and poly-vinyl alcohol.
34. Preparation of injection of poorly water soluble drugs.
The use of hydrotropic solubilizers as permeation enhancers.
The use of hydrotropy to give fast release of poorly water-soluble
drugs from the suppositories.
Application of mixed- hydrotropy to develop injection dosage
forms of poorly water-soluble drugs.
Application of hydrotropic solubilization in nanotechnology
(by controlled precipitation).
Application of hydrotropic solubilization in extraction of active
constituents from crude drugs (in pharmacognosy field).
Hydrotropic solutions can also be tried to develop the
dissolution fluids to carry out the dissolution studies of dosage
forms of poorly water soluble drugs.
35. Solubility of the drug is the most important
factor that controls the formulation of the drug
as well as. Therapeutic efficacy of the drug,
hence the most critical factor in the formulation
development.
The various techniques described above alone or
in combination can be used to enhance the
solubility of the drug
Because of solubility problem of many drugs the
bioavailability of them gets affected and hence
solubility enhancement becomes necessary.
36. International journal of pharmaceutical
sciences review and research,vol5,issue1,
varun raj vemula, article007 nov-dec2010.
J pharm pharmaceutical sciences,CarlotaO.
July2005.
Journal of drug delivery & therapeutics
2012,Md.Ali sajid.
International journal of drug development
research, vol3, issue2, apr-jun2011
International journal of pharmaceutical
research & bio-science.
