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Solubility in Liquids
Definition of Solubility
Solubility Determination
Importance of Solubility
Methods of Solubility Improvement
Cosolvency
Definition of Solubility
In quantitative terms :
as the concentration of the solute in a saturated
solution at a certain temperature.
In qualitative terms: solubility may be defined as
the spontaneous interaction of two or more
substances to form a homogeneous molecular
dispersion.
Solubility Determination
…………………
Importance of Solubility
The Biopharmaceutical Classification System (BCS) groups poorly soluble
compounds as Class III and IV drugs, compounds which feature poor
solubility and high permeability, and poor solubility and poor
permeability, respectively.
Drug substances are considered highly soluble when the largest dose of a
compound is soluble in <250mL water over a range of pH from 1.0 to
7.5; highly permeable compounds are classified as those compounds that
demonstrate >90 per cent absorption of the administered dose.
In contrast, compounds with solubilities below 0.1mg/mL face significant
solubilisation obstacles, and often even compounds with solubilities
below 10mg/mL present difficulties related to solubilisation during
formulation.
Up to 40 per cent of new chemical entities discovered by the pharmaceutical
industry today are poorly soluble or lipophilic compounds. So solubility
issues complicating the delivery of these new drugs also affect the delivery
of many existing drugs.
Some of the consequences of low drug solubility:
in vitro
- severely limited choices of formulation and delivery technologies,
- increasingly complex dissolution testing with limited or poor correlation to
the in vivo absorption.
……..
in vivo
decreased bioavailability
Increased chance of food effect,
more frequent incomplete release from the dosage form and
higher inter- patient variability,
………
Methods of Solubility Improvement
The major approaches for increasing drug solubility are alteration of the solute or alteration
of the solvent.
Solvent modification is the most effective means of producing a thermodynamically stable
increase in solubility.
The most commonly used types of solubilizing agents are:
• cosolvents,
• surfactants,
• complexation ligands, and
• pH control by buffer.
With each technique, there is a maximum in the solubility that can be obtained.
The choice of a solubilization technique also depends on many other factors:
the physicochemical property of the drug molecule, the desired concentration,
the effectiveness of the method, the safety and the cost of solubilizing agents and possible
precipitation upon injection.
Cosolvency.
Cosolvency is one of the most popular approaches for improving the solubility of poorly aqueous soluble drugs
in pharmaceutical liquid formulations.
Cosolvents are the mixtures of miscible solvents often used to water which can dramatically change the
solubility of poorly aqueous soluble drugs.
The most frequently used low-toxicity cosolvents for parenteral use are:
propylene glycol, ethanol, glycerin, polyethylene glycol (PEG), dimethylsulfoxide (DMSO),
and dimethylacetoamide (DMA).
How cosolvent works?
The cosolvent reduces the polarity of water by weakening its intermolecular hydrogen bonding
network. The solubilization efficiency of a cosolvent depends upon the extent to which it weakens
the structure of water.
Cosolvents reduces the interfacial tension between the aqueous solution and hydrophobic solute. Most
cosolvents have hydrogen bond donor and/or acceptor groups as well as small hydrocarbon regions.
Their hydrophilic hydrogen-bonding groups ensure water miscibility, while their hydrophobic
hydrocarbon regions interfere with waters hydrogen bonding network, reducing the overall
intermolecular attraction of water. By disrupting waters self-association, cosolvents reduce waters
ability to squeeze out nonpolar, hydrophobic compounds, thus increasing solubility.
Cosolvents decreases the dielectric constant (DEC) of water. Nonelectrolyte drugs are more soluble in
low dielectric environment. (See Tables&Fig.)
Calculation of the solvent mixture DEC values:
Ideally, the dielectric constant of a mixed solvent system is the
weighted mean of the individual solvents,
DEC = ( % A x DEC A + % B x DEC B +…..)/100
assuming no or little interaction between the molecules.
I f the above equation is valid, a plot of the dielectric constant
versus the composition of the solvent should yield a straight
line.
90.0000
DEC
80.0000
Solvent mixture DEC
70.0000
60.0000
50.0000
y = 0.6591x + 12.433
R² = 1
40.0000
30.0000
20.0000
10.0000
0.0000
0
20
40
60
PEG 400 %V/V
80
100
120
Dielectric Requirement
Because lowering of the DEC is the most known mechanism, but not the only one, it
was found in certain cases that the maximum solubility occurs in a mixed solvent
system rather than in the pure solvent of lower DEC. Such phenomena has
described as "dielectric requirement" for maximum solubility for a specific drug.
What the "dielectric requirement" means ?
Certain solutes may be more soluble in mixed solvent of higher DEC than pure solvent
of lower DEC due to the presence of solvent-cosolvent complexation or interactions
that might produce any of the following changes in the nature of the solvent
mixture:
• changes in the surface tension,
• changes in the drug partition coefficient,
• changes in the intermolecular interactions,
• changes in the solvent solubility parameter,
• changes in the molecular size or the molecular shape of the solvent, this affects the
solvent solubilizing power,
• overall changes in the solute-solvent-cosolvent interaction.
Solubility
2.5000
2.0000
Drug Solubility, mg/ml
y = -0.0358x + 2.6658
R² = 0.9452
1.5000
1.0000
0.5000
0.0000
0.0000
-0.5000
10.0000
20.0000
30.0000
40.0000
50.0000
Solvent Mixture DEC
60.0000
70.0000
80.0000
90.0000
SOLUBILITY PARAMETER
THE HILDEBRAND SOLUBILITY PARAMETER
The solubility parameter (δ) is a numerical value that indicates the relative solvency behavior of a specific solvent.
It is derived from the cohesive energy density of the solvent, which in turn is derived from the heat of
vaporization.
Joel H. Hildebrand proposed the square root of the cohesive energy density as a numerical value indicating the
solvency behavior of a specific solvent.
The cohesive energy density δ2 between two substances based on dispersive force, polar interaction and
hydrogen bond interaction, as follow:
Where,
D = dispersive force ,
P = polar interaction,
H = hydrogen bond interaction
A low molar mass compound can be described by the three parameter values,
δD, δP, and δH.
VAPORIZATION
When a liquid is heated to its boiling point, energy (in the form of heat) is
added to the liquid, resulting in an increase in the temperature of the liquid.
Once the liquid reaches its boiling point, however, the further addition of
heat does not cause a further increase in temperature.
The energy that is added is entirely used to separate the molecules of the
liquid and boil them away into a gas. Only when the liquid has been
completely vaporized will the temperature of the system again begin to rise.
If we measure the amount of energy (in calories) that was added from the
onset of boiling to the point when all the liquid has boiled away, we will
have a direct indication of the amount of energy required to separate the
liquid into a gas, and thus the amount of van der Waals forces that held the
molecules of the liquid together.
It is important to note that we are not interested here with the temperature at
which the liquid begins to boil, but the amount of heat that has to be added
to separate the molecules. A liquid with a low boiling point may require
considerable energy to vaporize, while a liquid with a higher boiling point
may vaporize quite readily, or vise versa. What is important is the energy
required to vaporize the liquid, called the heat of vaporization.
The correlation between vaporization and van der Waals forces also
translates into a correlation between vaporization and solubility
behavior.
This is because the same intermolecular attractive forces have to be
overcome to vaporize a liquid as to dissolve it.
This can be understood by considering what happens when two liquids
are mixed: the molecules of each liquid are physically separated by
the molecules of the other liquid, similar to the separations that
happen during vaporization.
The same intermolecular van der Waals forces must be overcome in
both cases.
Since the solubility of two materials is only possible when their
intermolecular attractive forces are similar, one might also expect
that materials with similar cohesive energy density values would be
miscible.
COHESIVE ENERGY DENSITY
From the heat of vaporization, in calories per cubic centimeter of liquid, we can
derive the cohesive energy density (c) by the following expression
and
Where:
C = Cohesive energy density
∆H = Heat of vaporization
R = Gas constant
T=Temperature
Vm = Molar volume
δ = solubility parameters,
CED= ∆H-RT/Vm
δ = [CED] 1/2
In other words, the cohesive energy density of a liquid is a numerical value that
indicates the energy of vaporization in calories per cubic centimeter, and is a
direct reflection of the degree of van der Waals forces holding the molecules of
the liquid together.
Units of solubility parameter measurement
Tables below list several solvents in order of increasing
Hildebrand parameter.
Values are shown in both the common form which is derived
from cohesive energy densities in calories/cc,
and a newer form which, conforming to standard international
units (SI units), is derived from cohesive pressures.
The SI unit for expressing pressure is the pascal, and SI
Hildebrand solubility parameters are expressed in megapascals (1 mega-pascal or mpa=1 million pascals).
Conveniently, SI parameters are about twice the value of
standard parameters.
How to make use of the solubility parameter values?
In looking over the tables, one can rank the solvents
according to solubility parameter and a solvent
"spectrum" is obtained.
If, for example, acetone dissolves a particular material,
then one might expect the material to be soluble in
neighboring solvents, since these solvents have similar
internal energies.
Theoretically, there will be a contiguous group of solvents
that will dissolve a particular material, while the rest of
the solvents in the spectrum will not.
How to make use of the solubility parameter values? Cont.
For a solvent mixture, the Hildebrand value can be determined by
averaging the Hildebrand values of the individual solvents by
volume.
For example, a mixture of two parts toluene and one part acetone will
have a Hildebrand value of :
18.7= (18.3 x 2/3 + 19.7 x 1/3),
About the same as chloroform.
Theoretically, such a 2:1 toluene/acetone mixture should have
solubility behavior similar to chloroform.
If, for example, a resin was soluble in one, it would probably be soluble
in the other.
Introduction
DMI is water-miscible liquid, with low viscosity, used as pharmaceutical
vehicle, cosolvent and absorption enhancer in novel drug delivery.
Addition of DMI significantly increases the solubility of water-insoluble
drugs while not adversely affecting drug stability.
Experimental
Measurement of the solubility of Prednisolone.
Solubility measurements were carried in triplicate, at 25 ±0.5 deg. Screwcapped glass vials containing suspension of drug in appropriate solvent
were mounted on a rotating apparatus in a bath for 24 hour. Periodic
sampling was carried out to insure equilibrium solubilization. Analysis
was carried out using UV spectrophotometer. Dielectric constants were
measured using chemical oscillometer.
Results and Discussion
DEC measurements
DEC values were calculated using the equation:
DEC = ( % A x DEC A + % B x DEC B +…..)/100
assuming no or little interaction between the molecules.
Results as shown in the following figures indicated that:
DMI- PEG 400 solvent mixture: no interaction
DMI-Water, and DMI- PG: interaction present,
Break point was observed in the relation.
DMI-solvent interaction was proved using NMR measurements.
Results and Discussion-cont.
Solubility measurements
For DMI-PG, and DMI-water solvent mixture: maximum solubility was
observed at the break point in the dielectric constant.
For DMI-PEG solvent mixture: the solubility decreases with increasing
dielectric constant.
Conclusion
The DEC may be considered as indicator when complexation of solvent
molecules is negligible (DMI-PEG) system, otherwise it is not a good
predictor.