Solubility and Solubility Phenomenon

Contents
Solvent-solute interactions Solubility of gases in liquids Fractional distillation Solubility of solids in liquids

Henrys law
Solubility of liquids in liquids Ideal solutions

Definition, Determination, Factors

influencing solubility
Colligative properties Molecular weight determination Partition coefficient

- Raoults law
Real solutions

Distillation of
Binary mixtures
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Azeotropic mixtures

Relationship b/w VP & composition of binary liq phases is the underlying principle in distillation.

Depends on relative volatilities of the components of the liquid mixture. In case of miscible liqs, instead of plotting VP v/s comp; it is more useful to plot boiling point of various mixtures, determined at atmospheric pressure, against comp.

Higher the VP of a liq, the more volatile it is & lower the BP. Since the vapor of a binary mixture is always richer in more volatile constituent, the process of distillation can be used to separate more volatile from less volatile constituent.

Simple distillation

Separating a volatile liquid from non volatile component of the mixture. A process of converting a single constituent from a liquid into its vapors

and then condensing the vapors at other place.

Based on the difference between the volatility of two components.

Examples:
1. 2.

Simple distillation for preparation of distilled water and Water for injection. Separation of Non volatile solids from volatile liquids.

Fractional Distillation/ Rectification

It is a process in which vaporization of liq mixture gives a mixture of constituents

from which desired one is separated in pure form.

Used to separate miscible volatile liquids with close boiling points. It is a mass transfer process involving counter current diffusion of components at

each equilibrium stage.

A fractionating column introduced between still & condenser.
Partial condensation of vapor is allowed to occur in a fractionating column

through which the vapor must pass before reaching the condenser.
In the column, ascending vapor from the still is allowed to come in contact with

the condensing vapor returning to the still.

6 This results in enrichment of vapor with more volatile component.

 By condensing the vapor & reheating the liq repeatedly, eqm b/w liq & vapor is

set up at each stage, which ultimately results in the separation of more volatile component.
Condensate can be re-circulated to achieve further separation. It is a mass transfer process involving counter current diffusion of components at

each equilibrium stage.

Consider a mixture of high boiling liq A & low boiling liq B.

A mixture of these subs having comp a is distilled at boiling point b.

Comp of vapor v1 in eqm with liq at this temp is c; which is also the comp of distillate when it is condensed.

Vapor is thus richer in B than the liq from which it was distilled.
If a fractionating column is used, A & B can be completely separated. The vapor rising in the column is met by condensed vapor or downward-flowing liq.

As the rising vapor is cooled by contact with the liq, some of the lower-boiling fraction condenses, & the vapor contains more of the volatile component than it

did when it left the retort.

Thus, as the vapor proceeds up the fractionating column, it becomes progressively richer in more volatile component B, & the liq returning to distilling retort

becomes richer in less volatile component A.

Construction of BOILING POINT composition curve for Type I Miscible liquids

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Fractional distillation is suitable for a system when the BP of the mixture is always

intermediate b/w those of pure components.

There is neither a maximum or minimum in vapor composition curves. These systems are known as Zeotropic mixtures.

E.g. Benzene-Toluene;
Carbon tetrachloride-Cyclohexane & Water-Methanol

Application: Fractional distillation is used for separation of miscible liquids.

Disadvantage: It cannot be used to separate miscible liquids, which form Azeotropic mixtures.

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Liquids forming Azeotropic mixtures

If the VP curves can show maxima & minima, it follows that the BP curves will show corresponding maxima & minima resp.

With these mixtures, distillation produces either pure A or pure B plus mixture of

constant comp & constant BP.

This is known as Azeotrope ( Greek Boil unchanged) or Azeotropic mixture. It is not possible to separate such a mixture completely into 2 pure components by

simple fractionation.

If VP curve shows a minimum (i.e. negative deviation from Raoults law), the azeotrope has highest BP of all mixtures possible; it is thus least volatile &

remains in the flask, whereas either pure A or pure B is distilled off.

If VP curve shows a maximum (i.e. positive deviation from Raoults law), the azeotrope has lowest BP & forms the distillate. Either pure A or pure B is remains

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in the flask.

Minimum boiling point Azeotropic solutions Type II mixtures (Nonideal Solution)

Boiling point is lower than either of the components.

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Minimum boiling point Azeotropic solutions Type II mixtures (Nonideal Solution)

These mixtures have a Minimum BP or Maximum VP. The azeotropic mixture has a lower BP than that of the component with least BP.

At min BP, the comp remains constant.

It follows that the vapor comp must be identical to liq comp. Thus, liq comp curve & vapor comp curve coincides at the trough, Cmin. All mixtures of comp lying b/w A & Cmin can be separated by continuous fractional distillation. In this process, pure liq A is recovered from still & mixture with constant comp (at Cmin) is obtained as distillate from condenser.

In the same way, all mixtures of comp lying b/w Cmin & B can be separated by continuous
fractional distillation. In this process, pure liq B is recovered from still & mixture with constant comp (at Cmin) is
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collected as condensate.

Consider a hypothetical case in which the mixture contains more of liq B than A,
represented by M. If the mixture is distilled, the vapor has a comp of x. When this vapor is condensed, the liq comp is represented by M1, which is richer in B than C. When this liq is redistilled, the vapor has comp of x1. When this vapor is condensed, the liq has comp of M2. Thus on repeated distillation, the liq B will be in pure form & remains in still. Similar arguments can be proposed for fractional distillation of component A by considering left-side curve to Cmin.

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Example: Ethanol and water form a constant boiling mixture (95.6% ethanol, 4.4% water) with a minimum boiling point of 78.2oC (lower than that of pure ethanol, 78.5oC, or pure water, 100oC).

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Maximum boiling point Azeotropic solutions Type III mixtures (Nonideal Solution)
Boiling point is higher than either of the components.

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Maximum boiling point Azeotropic solutions Type III mixtures (Nonideal Solution)
These mixtures have a Maximum BP or Minimum VP. The azeotropic mixture has a higher BP than that of the component with highest BP.

At max BP, the comp remains constant.

It follows that the vapor comp must be identical to liq comp. Thus, liq comp curve & vapor comp curve coincides at the peak, Cmax. All mixtures of comp lying b/w Cmax & D can be separated by continuous fractional distillation. In this process, pure liq D is obtained as distillate & mixture with constant comp (at Cmax) is obtained in the still.

In the same way, all mixtures of comp lying b/w E & Cmax can be separated by continuous
fractional distillation. In this process, pure liq E is obtained as distillate & mixture with constant comp (at Cmax) is
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collected in the still.

Consider a hypothetical case in which the mixture contains more of liq D than E, represented by L. If the mixture is distilled, the vapor has a comp of v, which is richer in liq D & poorer in E.

At this stage, liq residue retained in still will be richer in E & poorer in D.
When the vapor at v is condensed, the liq comp is represented by L1. When this liq is redistilled, the vapor has comp of v1 is still richer in liq D &

poorer in E.
When this vapor is condensed, the liq has comp of L2. Thus on repeated distillation, the liq D will be in pure form & obtained as distillate. But the residue left in the stillis always a mixture of D & E of constant comp. Similar arguments can be proposed for fractional distillation of component E by considering left-side curve to Cmax.
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Example: Formic acid and water also form a constant boiling mixture (22.6%

formic acid, 77.4% water) with a maximum boiling point of 107.2oC (higher
than that of formic acid, 100.8oC or water).

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Azeotropic distillation
Azeotropic solns cannot be completely separated by fractional distillation, becoz

either the vapor or the liq has a mixture of components.

Azeotropic distillation is a distillation method in which azeotropic mixture is

broken by the addition of a 3rd subs, which forms a new azeotrope with one of the components.
A 3rd subs is added to the mixture in order to increase the relative volatility, so

that separation of components becomes relatively easy.

Azeotropic ternary mixtures with minimum BP (Max VP) are imp.

Applications:
1. 2.
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Prep of Absolute alcohol. Petroleum refineries employ azeotropic distillation.

E.g. Ethyl alcohol & water form an azeotropic mixture.

When

benzene is added, it breaks water-ethanol mixture & forms a new

azeotrope b/w benzene & ethanol.

Volatility of water is enhanced.

On distillation, water distills at 65.85C leaving alcohol & benzene behind in the

still.
This binary mixture has a BP of 68.2C, & benzene gets distilled leaving pure

alcohol behind.
It can be distilled off at 78.3C.

Similarly, when glycerin is added to ethanol-water system, VP of water is

lowered. Practically pure ethanol can be obtained from the fractionating tower.

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Steam distillation
Distillation carried out with the aid of steam. Used for the separation of immiscible liquids and high boiling liquids from the

non volatile impurities.

Steam distillation is preferred when: 1. 2. 3.

Impurities are difficult to be removed by other methods. When a liq decomposes at high temps, mainly in high boiling liqs. When other components are not volatile.

Applications: 1.

Used to separate/extract oils like clove, anise, eucalyptus etc.

2.
3. 4.
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Used for the separation of immiscible liqs s.a. water-turpentine; toluene-water.

Used in preparation of aromatic waters. Used to purify camphor.

Principle: A mixture of immiscible liquids begin to boil when the sum of their vapor pressures is equal to atmospheric pressures. In case of mixture of water & turpentine, mixture boils below the BP of pure water, though turpentine boils at a much higher temp than that of water

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Advantage:
Volatile oils can be separated at lower temperatures, without any decomposition.

Disadvantage:
Not suitable when two liquids interact with each other.
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Applications:

Mfr of liquid orals Mfr of iv, im & sc injections Solubility of drug in GI fluids is an imp step for better absorption. Release & absorption of drug from ointment or im injection depends on

degree of saturation of drug in solvent.

Serves as a std test for purity. Provides information regarding intermolecular forces of interaction.

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Saturation soln theory is imp for crystallization of drugs from solvent.

For determining physicochemical properties s.a. dissociation constant, solubility parameter.

When a solid is placed in contact with a liq, particles leave the surface of the solid & pass into liq. Initially, particles consist of blocks of few molecules which ulimately breakdown into molecules & ions. Dissolved material diffuses through liq in all directions & some of them return to the solid. This process continues until eqm is established b/w particles leaving the solid & those returning to it. Drug molecules in solid Drug molecules in soln

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Solubility of a solute in a solvent occurs in 3 steps: 1st step: Removal of a molecule from solute phase at a definite temp.

2nd step: Creation of a hole in the solvent just large enough to accept a solute molecule.

3rd step: Placement of solute molecule in the hole in the solvent.

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Dissolution process occurs only if the solute & solvent are mutually attracted to a

degree that is sufficient to overcome the solute-solute & solvent-solvent

attractions. No. of solvent molecules that can pack around the solute molecule is considered in

the calculation of thermodynamic properties of soln.

The molecular surface area of the solute is thus a key parameter. Good correlation is obtained b/w aqueous solubility & molecular surface area or volume.

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Procedure to determine the solubility of drugs in liqs can be explained in the foll steps: 1. Selection of drug, medium & exptal conditions 2. Prep of saturated soln at constant temp 3. Separation of undissolved drug from saturated soln 4. Determination of conc of drug in soln by analytical methods

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Selection of drug, medium & exptal conditions:

Selection of drug: If a drug is in pure state, the phase-solubility diagram will be

represented as follows.

Here, upto point C along the solubility line OC, all solute dissolves I available solvent. At point C saturation occurs. Thereafter no more dissolution & slope of line CC become zero. Extrapolation back to the ordinate yields True solubility.
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When a sample contains impurity, the phase-solubility diagram will be represented

as follows.

Initial line represents dissolution of solute & impurity. The next line shows dissolution of impurity alone.
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AT intersection, solute has reached the limit of its solubility.

Selection of liquid medium:

Selection of liq medium depends on intended purpose.

From preformulation point of view, intrinsic solubility is essential. Solubility of drug is determined in water, 0.1N HCl & 0.1 N NaOH. When purity of sample is assured, then:
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Value obtained in acid represents intrinsic solubility for weak acid. Value obtained in alkali represents intrinsic solubility for weak base.

This is because drug is available in unionized form in respective media. From biopharmaceutics point of view, solubilities of drugs are determined in

different buffers ranging from pH 1 to 7.

Thus, pH profile is desirable.
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Selection of experimental conditions:

Atmospheric pressure is used for solubility determinations.

Solubility is ideally measured at 2 temps. 4C To ensure physical stability & to extend short-term storage 37C To support biopharmaceutical evaluation (body temp)

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Preparation of saturated soln at constant temp :

Procedure: Excess of solid is agitated continuously with the solvent until eqm is
achieved, at a reqd temp using a constant temp water-bath.

Rate of dissolution of a subs can be enhanced in the following ways: 1. Increase the temp of solution. (prepare a supersaturated soln & filter the excess solid). Care should be taken to see that the drug is not decomposed at higher temp.

2. Reduce the particle size of solid.

36 Add 3.

a small amt of immiscible solvent in which solid is freely soluble.

Separation of undissolved drug from saturated soln:

1. Allow the excess solid to sediment & decant the supernatant liq.
2. Filter the solution. (Care must be taken to maintain temp during filtration) 3. Guarded pipette can be used to withdraw samples. (A simple variation can be done by using a tapered piece of glass tubing containing small pieces of glass wool or cotton wool) 4. Cellulose membranes can be used. Disadv: they adsorb large qtys of aq soln. Other membranes Oxoid cellulose acetate & Millipore membrane filter. Saturated soln is freed from solids & is used for analysis.
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Determination of conc of drug in soln by analytical methods :

Method of estimation used must be able to distinguish the subs in question from
impurities present in soln. 1. Gravimetric method: If solvent is volatile & solute is non-volatile, amt of solute can be determined by heating the sample to constant wt. Alternatively, solute may be converted to an insol compd by a chemical rexn. The wt of subs may be determined after filtration & drying. 2. Volumetric method: Acid-base titration can be used to estimate the amt of solute present in a solvent. 3. Other methods: Spectrophotometric & HPLC (High performance liquid chromatography). These methods provide accurate estimations.

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Solute related: Nature of solute Size, Shape & Surface area Physicochemical properties Melting point, Heat of fusion, Molar volume, pKa Physical forms Salt, Crystalline state, Polymorphism Solvent related:

Nature of solvent Polarity, pH of the medium, Volume of solvent employed

Environment related: Temperature & Pressure Formulation related: Effect of other ingredients
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Influence of Particle size, shape & surface area:

Solubility increase with decreasing particle size.

Because, surface area of solid in contact with the medium increases. But, increase in solubility ceases when particle size reaches a particular point. Hence, particle size is critical & beyond a particular value, solubility of solid decreases. Such a change arises because of presence of electrical charge on the particle, which is predominant in small particles. Shape Symmetric molecules may be less soluble than asymmetric ones.

If crystals are compact, they posses high lattice energy & thus lowered solubility.
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Influence of Physicochemical properties of drugs:

Dissociation constant of drug is useful in predicting the extent of ionization

depending on the pH of environment. In general, ionized species have greater aqueous solubility than unionized species.

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Influence of Physical forms:

- Amorphous forms of drugs have greater aq solubility than the crystalline forms.
E.g. Amorphous form of Novobiocin has greater solubility than crystalline form. - Among crystals, metastable form of drug has greater aq sol. than stable form. E.g. Metastable form of Riboflavin has greater solubility than stable form. - Anhydrous forms of drugs have greater aq solubility than the hydrate forms. E.g. Glutethimide anhydrate sol 0.42mg/ml & hydrate 0.26mg/ml. - Organic solvates of drugs have greater aq solubility than unsolvated forms. - Salt forms of drugs have greater aq solubility than the non-salt forms. (provided

common ion effect is not influenced)

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Influence of Solvents: Structural features & presence of non-polar & polar groups in the molecule are imp to determine the solubility of the drug. There are two types of solvents Polar & Non-polar Guiding principle for solubility is like-dissolves like.

Solvent Polar (water)

Nature of Solute Polar subs Strong electrolyte Weak electrolyte Non-electrolyte

Non-polar (oil)

Non-polar subs

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In most of the cases, a mixture of solvents is used for maximum solubility of drugs.

Influence of pH of the medium:

Most of the drugs are weak electrolytes.

Weak acids & weak bases undergo ionization in soln. Drugs are more sol in water when they are in ionized form. Unionized drugs are poorly water-soluble. The extent of ionization of drug in a soln depends on dissociation constant & pH of the medium. E.g. Alkaloidal salts are more sol in acidic pH & begin to precipitate as pH increases. Whereas, Phenobarbitone is more sol in alkaline pH & begins to precipitate as pH decreases.

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Influence of cosolvents:

A solute is more soluble in a mixture of solvents rather than a single solvent.

Solvents used to increase the solubility of a drug in water are called as cosolvents & the phenomena is known as cosolvency. E.g. Ethanol, propylene glycol, glycerin, PEG 300 & PEG 400. Undissociated phenobarbitone is soluble in water to the tune of 1.2g/l; while its solubility in ethanol is 13g/l. Hence, ethanol can be used as a cosolvent in case of Phenobarbitone. In addition, solvents s.a. benzyl alcohol, dimethyl sulphoxide (DMSO), dimethyl acetamide (DMA), dimethyl formamide (DMF) are used as Supplementary solvents.

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Solubility of phenobarbital in a mixture of water, alcohol & glycerine at 25C.

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Influence of temperature:

Increase in temp involves the absorption of heat & influences solubility of drugs.
- If dissolution involves positive heat of soln (endothermic reaction), a rise in temp increases solubility of solid. E.g. Potassium nitrate in water. - If dissolution involves negative heat of soln (exothermic reaction), a rise in temp decreases solubility of solid. E.g. Calcium acetate in water. - In some cases, abs of heat has little effect. E.g. Sodium chloride in water.

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Influence of other ingredients:

Several ingredients of diverse nature are added in formulation of DF.

Common ion effect Solubility of sparingly soluble electrolyte is decreased by the addition of a second electrolyte that possesses a similar ion to the first. This phenomena is known as Common ion effect. Effect of other electrolytes Solubility of sparingly soluble electrolyte may be increased by the addition of a second electrolyte that does not possess same ion. The ions produced by dissociation of electrolytes are strongly associated with oppositely charged ions.

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Influence of surfactants:

Surface active agents enhance the solubility of poorly water-soluble drugs due to
the formn of micelles. This phenomena is known as Micellar solubilization. E.g. Solubility of procaine is enhanced by 25% in aq buffer by surfactants.

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ASSIGNMENT 1. What is Simple, Fractional and Steam Distillation. 2. Explain in detail Azeotropic mixture and their Distillation with suitable examples.

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