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 ImprovementThe 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.

0 20 40 60 80 100 1200.0000

10.0000

20.0000

30.0000

40.0000

50.0000

60.0000

70.0000

80.0000

90.0000

f(x) = 0.659127272727273 x + 12.4327272727273R² = 0.999998595353168

DEC

PEG 400 %V/V

Solv

ent m

ixtu

re D

EC

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.

0.0000 10.0000 20.0000 30.0000 40.0000 50.0000 60.0000 70.0000 80.0000 90.00000.0000

0.5000

1.0000

1.5000

2.0000

2.5000

f(x) = − 0.0357649810321316 x + 2.66583997542933R² = 0.945228776350272

Solubility

Solvent Mixture DEC

Dru

g So

lubi

lity,

mg/

ml

SOLUBILITY PARAMETERTHE 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

CED= ∆H-RT/Vmand δ = [CED] 1/2

Where:C = Cohesive energy density∆H = Heat of vaporizationR = Gas constantT=TemperatureVm = Molar volume δ = solubility parameters,

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 mega-pascals (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.

IntroductionDMI 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. Screw-capped

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 measurementsDEC 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 interactionDMI-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.