+

Solubility and DistributionPhenomena

Aseel Samaro

+Objectives of the Chapter

After completion of this chapter, the student should be able to:

1. Understand the various types of pharmaceutical solutions.

2. Define solubility, saturated & unsaturated solutions and polar & non polar solvents.

3. Understand the factors controlling the solubility of strong & weak electrolytes.

4. Define partition coefficient & its importance in pharmaceutical systems.

+Importance of studying the phenomenon of solubility

Understanding the phenomenon of solubility helps the pharmacist to:

1. Select the best solvent for a drug or a mixture of drugs.

2. Overcome problems arising during preparation of pharmaceutical solutions.

3. Have information about the structure and intermolecular forces of the drug.

4. Many drugs are formulated as solutions, or added as powder or solution forms to liquids.

5. Drugs with low aqueous solubility often present problems related to their formulation and bioavailability.

+Definitions

Solution: is a mixture of two or more components that form a homogenous mixture. The components are referred to the solute and/or solutes & the solvent and/or solvents .

Solute: is the dissolved agent . (less abundant part of the solution )

Solvent : is the component in which the solute is dissolved (more abundant part of the solution).

A saturated solution: is one in which an equilibrium is established between dissolved and undissolved solute at a definite temperature. Or A solution that contains the maximum amount of solute at a definite temperature

An unsaturated solution: or subsaturated solution is one containing the dissolved solute in a concentration below that necessary for complete saturation at a definite temperature.

+Solubility

A supersaturated solution: contains more of the dissolved solute than it would normally contain in a saturated state at a definite temperature.

Solubility:

In a quantitative way: it is the concentration of solute in a saturated solution at a certain temperature

In a qualitative way: it is the spontaneous interaction of two or more substances (solute & solvent) to form a homogeneous molecular dispersion

+Degree of saturation

Unsaturated, Saturated or Supersaturated?

How much solute can be dissolved in a solution?

+Solubility Curve

Any solution can be made saturated, unsaturated, or supersaturated by changing the temperature.

+Thermodynamic solubility of drugs

The thermodynamic solubility of a drug in a solvent is the maximum amount of the most stable crystalline form that remains in solution in a given volume of the solvent at a given temperature and pressure under equilibrium conditions.

The equilibrium involves a balance of the energy of three interactions against each other:

(1) solvent with solvent

(2) solute with solute

(3) solvent and solute

+

Steps of solid going into solution.

1. Step 1: Hole open in the solvent

2. Step 2: One molecule of the solid breaks away from the bulk

3. Step 3: The solid molecule is enter into the hole in the solvent

+Solubility process

A mechanistic perspective of solubilization process for organic solute in water involves the following steps:

1. Break up of solute-solute intermolecular bonds

2. Break up of solvent-solvent intermolecular bonds

3. Formation of cavity in solvent phase large enough to accommodate solute molecule

4. Transfer of solute into the cavity of solvent phase

5. Formation of solute-solvent intermolecular bonds

+Tree types of interaction in the solution process

1. solvent – solvent interaction 2. solute – solute interaction3. solvent solute interaction

ΔH sol = ΔH 1 + ΔH 2 + ΔH 3

+Enthalpy

The enthalpy change of solution refers to the overall amount of heat which is released or absorbed during the dissolving process (at constant pressure).

The enthalpy of solution can either be positive (endothermic reaction) or negative (exothermic reaction).

The enthalpy of solution is commonly referred to as ΔH solution.

+ Expression Symbol Definition

Molarity M, c Moles (gram molecular weights) of solute in 1 liter

(1000 ml) of solution.

Molality m Moles of solute in 1000 gm of solvent.

Normality N Gram equivalent weights of solute in 1 liter of

solution

Mole Fraction x Ration of moles of solute to total moles of solute+

solvent

Percentage by

Weight

% w/w gm of solute in 100 gm of solution

Percentage by

Volume

%v/v ml of solute in 100 ml of solution

Percentage

Weight in Volume

% w/v gm of solute in 100 ml of solution Solu

bilit

y e

xp

ressio

ns

+Solubility expressions

The USP lists the solubility of drugs as: the number of ml of solvent in which 1g of solute will dissolve.

E.g. 1g of boric acid dissolves in 18 mL of water, and in 4 mL of glycerin.

Substances whose solubility values are not known are described by the following terms:

Term Parts of solvent required for 1 part of solute

Very soluble Less than 1 part Freely soluble 1 to 10 parts

Soluble 10 to 30 parts Sparingly soluble 30 to 100 parts Slightly soluble 100 to 1000 parts Very slightly soluble

1000 to 10 000 parts

Practically insoluble More than 10 000 parts

+Biopharmaceutics Classification System (BCS)

BCS is a scientific framework for classifying Drug substances according to their aqueous solubility and their intestinal permeability

+Solubility expressions: BCS

High solubility

The highest single unit dose is completely soluble in 250 ml or less of aqueous solution at pH 1 - 6.8 (37 °C)

Xanax (alprazolam) anxiety disorder

+Solvent - Solute Interactions

In pre - or early formulation, selection of the most suitable solvent is based on the principle of

“like dissolves like”

That is, a solute dissolves best in a solvent with similar chemical properties. Or two substances with similar intermolecular forces are likely to be soluble in each others

Polar solutes dissolve in polar solvents. E.g salts & sugar dissolve in water .

Non polar solutes dissolve in non polar solvents. Eg. naphtalene dissolves in benzene.

+POLAR SOLUTE - POLAR SOLVENT

Ammonia Dissolves in Water:

Polar ammonia molecules dissolve in polar water molecules.

These molecules mix readily because both types of molecules engage in hydrogen bonding.

Since the intermolecular attractions are roughly equal, the molecules can break away from each other and form new solute (NH3), solvent (H2O) hydrogen bonds.

+

Alcohol Dissolves in Water:

The -OH group on alcohol is polar and mixes with the polar water through the formation of hydrogen bonds.

A wide variety of solutions are in this category such as sugar in water, alcohol in water, acetic and hydrochloric acids.

+Solute-Solvent interactions

If the solvent is A & the solute is B, and the forces of attraction are represented by A-A, B-B and A-B,

One of the following conditions will occur:

1. If A-A >> A-B The solvent molecules will be attracted to each other & the solute will be excluded. Example: Benzene & water, where benzene molecules are unable to penetrate the closely bound water aggregates.

2. If B-B >> A-A The solvent will not be able to break the binding forces between solute molecules. Example NaCl in benzene, where the NaCl crystal is held by strong electrovalent forces which cannot be broken by benzene.

3. If A-B >> A-A or B-B, or the three forces are equal The solute will . form a solution. Example: NaCl in water.

+Classification of solvents & their mechanism of action

1. Polar solvents

2. Non polar solvents

3. Semi polar solvents

+Polar solvents

The solubility of a drug is due in large measure to the polarity of the solvent, that is, to its dipole moment. Polar solvents dissolve ionic solutes and other polar substances.

The ability of the solute to form hydrogen bonds is a far more significant factor than is the polarity as reflected in a high dipole moment

Water dissolves phenols, alcohols and other oxygen & nitrogen containing compounds that can form hydrogen bonds with water.

+

The solubility of a substance also depends on structural features such as the ratio of the polar to the nonpolar groups of the molecule.

As the length of a nonpolar chain of an aliphatic alcohol increases, the solubility of the compound in water decreases

Straight-chain monohydroxy alcohols, aldehydes, ketones, and acids with more than four or five carbons cannot enter into the hydrogen-bonded structure of water and hence are only slightly soluble.

Polar solvents

+

When additional polar groups are present in the molecule, as found in propylene glycol, glycerin, and tartaric acid, water solubility increases greatly.

Branching of the carbon chain reduces the nonpolar effect and leads to increased water solubility. Tertiary butyl alcohol is miscible in all proportions with water, whereas n-butyl alcohol dissolves to the extent of about 8 g/100 mL of water at 20°C.

tert-Butanol n-Butanol

Polar solvents

+

Hydrogen bonding is the attractive interaction of a hydrogen atom with an electronegative atom, such as nitrogen, oxygen

Dipole-dipole forces are electrostatic interactions of permanent dipoles in molecules.

+Non polar solvents

Non-polar solvents are unable to reduce the attraction between the ions of strong and weak electrolytes because of the solvents' low dielectric constants.

They are unable to form hydrogen bonds with non electrolytes.

Non polar solvents can dissolve non polar solutes through weak van der Waals forces

Example: solutions of oils & fats in carbon tetrachloride or benzene.

Polyethylene glycol 400

Castor oil

+Semi polar solvents

Semi polar solvents, such as ketones can induce a certain degree of polarity in non polar solvent molecules. For example, benzene, which is readily polarizable, becomes soluble in alcohol

They can act as intermediate solvents to bring about miscibility of polar & non polar liquids.

Example: acetone increases solubility of ether in water.

Propylene glycol has been shown to increase the mutual solubility of water and peppermint oil and of water and benzyl benzoate

+Polarity as Dielectric Constant of Solvent, ε decrease , the solubility also decrease

+

+Polarity

The solubility of the drug substance is attributable in large part to the polarity of the solvent, often expressed in terms of dipole moment, related to the dielectric constant.

Solvents with high dielectric constants dissolve ionic compounds (polar drugs) readily because of ion–dipole interactions,

Solvents with low dielectric constants dissolve hydrophobic substances (non-polar drugs)

polar solvents, with examples such as water and glycerin;

non-polar solvents, with example such as oils.

Solvents with intermediate dielectric constants are classified as semipolar.

+ Types of solutions

Solutions of pharmaceutical importance include:

Gases in liquids

Liquids in liquids

Solids in liquids

+

When the pressure above the solution is released (decreases), the solubility of the gas decreases

As the temperature increases the solubility of gases decreases

Solubility of gases in liquids

+ Solubility of liquids in liquids

Preparation of pharmaceutical solutions involves mixing of 2 or more liquids

Alcohol & water to form hydroalcoholic solutions

volatile oils & water to form aromatic waters

volatile oils & alcohols to form spirits , elixirs

Liquid-liquid systems may be divided into 2 categories:

1. Systems showing complete miscibility such as alcohol & water, glycerin & alcohol, benzene & carbon tetrachloride.

2. Systems showing Partial miscibility as phenol and water; two liquid layers are formed each containing some of the other liquid in the dissolved state.

The term miscibility refers to the mutual solubility of the components in liquid-liquid systems.

+Solubility of liquids in liquids

Complete miscibility occurs when: The adhesive forces between different molecules (A-B) >> cohesive forces between like molecules (A-A or B-B).

Polar and semipolar solvents, such as water and alcohol, glycerin and alcohol, and alcohol and acetone, are said to be completely miscible because they mix in all proportions.

Nonpolar solvents such as benzene and carbon tetrachloride are also completely miscible.

+Solubility of liquids in liquids

Partial miscibility results when: Cohesive forces of the constituents of a mixture are quite different, e.g. water (A) and hexane (B). A-A » B-B.

When certain amounts of water and ether or water and phenol are mixed, two liquid layers are formed, each containing some of the other liquid in the dissolved state.

The effect of temperature on the miscibility of two-component liquids is expressed by phase diagrams.

In the phase diagrams of two-component liquids, the mixture will have an upper critical solution temperature, a lower critical solution temperature or both.

+Three-Component Systems

waterPeppermint oil

Polyethylene glycol

+Three-Component Systems

waterMethyl salicylate

IPA

+

Solubility of solids in liquids

+ Solubility of solids in liquids Factors influencing solubility

1- Particle size (surface area) of drug particles

↓Particle size → ↑ surface area→ ↑Solubility

+

o So is the solubility of large particles o S is the solubility of fine particles o γ is the surface tension of the particleso V is molar volume o T is the absolute temperature o r is the radius of the fine particle o R is the gas constant

Solubility of solids in liquids Factors influencing solubility

+Example

A solid is to be comminuted so as to increase its solubility by 10%, that is s/so is to become 1.10

What must be the final particle size, assuming that the surface tension of the solid is 100 dynes/cm and the volume per mile is 50 cm3? The temperature is 27oC

Answer: 0.042µm

+

2- Molecular size

Molecular size will affect the solubility.

The larger the molecule or the higher its molecular weight the less soluble the substance.

Larger molecules are more difficult to surround with solvent molecules in order to solvate the substance.

In the case of organic compounds the amount of carbon branching will increase the solubility since more branching will reduce the size (or volume) of the molecule and make it easier to solvate the molecules with solvent

Solubility of solids in liquids Factors influencing solubility

+

3- The boiling point of liquids and the melting point of solids:

Both reflect the strengths of interactions between the molecules in the pure liquid or the solid state.

In general, aqueous solubility decreases with increasing boiling point and melting point.

Solubility of solids in liquids Factors influencing solubility

+

4-The influence of substituents on the solubility of molecules in water can be due to their effect on the properties of the solid or liquid (for example, on its molecular cohesion, or to the effect of the substituent on its interaction with water molecules.

Substituents can be classified as either hydrophobic or hydrophilic, depending on their polarity

Solubility of solids in liquids Factors influencing solubility

+

Polar groups such as –OH capable of hydrogen bonding with water molecules impart high solubility

Non-polar groups such as –CH3 and –Cl are hydrophobic and impart low solubility.

Ionization of the substituent increases solubility, e.g. –COOH and –NH2 are slightly hydrophilic whereas –COO– and –NH3 are very hydrophilic.

Influence of substituents on the solubility

+

The position of the substituent on the molecule can influence its effect on solubility, for example the aqueous solubilities of o-, m- and p-dihydroxybenzenes

Influence of substituents on the solubility

+

5-Temperature

Temperature will affect solubility. If the solution process absorbs energy then the solubility will be increased as the temperature is increased.

If the solution process releases energy then the solubility will decrease with increasing temperature.

Generally, an increase in the temperature of the solution increases the solubility of a solid solute.

A few solid solutes are less soluble in warm solutions.

For all gases, solubility decreases as the temperature of the solution increases.

Solubility of solids in liquids Factors influencing solubility

+

6-Crystal properties

Polymorphic Crystals, Solvates, Amorphous forms

Solubility of solids in liquids Factors influencing

solubility

Polymorphs have the same chemical structure but different physical properties, such as solubility, density, hardness, and compression characteristics

A drug that exists as an amorphous form (non crystalline form) generally dissolves more rapidly than the same drug in crystalline form

+

7- PH

is one of the primary influences on the solubility of most drugs that contain ionizable groups

Large number of drugs are weak acids or weak base.

Solubility depends on the degree of ionization.

Degree of ionization depends on the pH

Solubility of solids in liquids Factors influencing

solubility

About 85% of marketed drugs contain functional groups that are ionised to some extent at physiological pH (pH 1.5 – 8).

+carboxyl group (RCO2H)

Carboxylic acids containing more than five carbons are relatively insoluble in water, they react with dilute sodium hydroxide, carbonates and bicarbonates to form soluble salts.As the number of carbons in a carboxylic acid series becomes greater, the boiling point increases and the solubility in water decreases.

+

Carboxylic acids with 12 to 20 carbon atoms are often referred to as fatty acids

Fatty acids containing more than 10 carbon atoms form soluble soaps with the alkali metals. They are soluble in solvents having low dielectric constants; for example, oleic acid (C17H33COOH) is insoluble in water but is soluble in alcohol and in ether.

Benzoic acid is soluble in sodium hydroxide solution

Phenol is weakly acidic and only slightly soluble in water but quitesolution in dilute NaOH solution.

Organic compounds containing a basic nitrogen atomMost of these weak electrolytes are not very soluble in water but aresoluble in dilute solutions of acids

+

][

]][[ 3

HP

POHK a

)][

][log(]log[log 3 HP

POHKa

)][

][log(log]log[ 3 HP

PKOH a

S The total solubility of drug ( un-ionized + ionized) ][][ PHPS

solubility of the un-ionized form of drug in solution ][HPS S

S

SSpKpH ap

log

POHOHHP 32

+The equation relating the solubility, S, of an acidic drug to the pH of the solution

is:

S

SSpKpH a

log

S The total solubility of the drug (un-ionized + ionized)

The solubility of the un-ionized form of the drug S

Acidic drugs

pH is the pH below which the drug separates from solution as the undissociated acid.

From equation we can calculate:If the pH of the solution is known then we can calculate the solubility of an acidic drug at that pH.minimum pH that must be maintained in order" to prevent precipitation from a solution of known concentration.

Henderson-Hasselbalch

+

][

]][[

B

OHBHKb

)][

][log(]log[log

B

BHOHKb

)][

][log(log]log[

B

BHKOH b

S The total solubility of (phenobarbital) un-ionized + ionized ][][ BHBS

concentration of the un-ionized form in solution ][BS S

)][

][log(

B

BHpKpOH b

dissociation constant or basicityconstant for a weak base

SS

SpKpH a

log

bK)][

][log(1414

B

BHpKpH a

)][

][log(

BH

BpKpH a

+The equation relating the solubility, S, of an basic drug to the pH of the solution is:

SS

SpKpH a

log

S The total solubility of the drug (un-ionized + ionized)

The solubility of the un-ionized form of the drug S

Basic drugs

apK

From equation we can calculate:If the pH of the solution is known then we can calculate the solubility of an basic drug at that pH.minimum pH that must be maintained in order" to prevent precipitation from a solution of known concentration.

The pH is the pH above which the drug begins to precipitate from solution as the free base

Henderson-Hasselbalch

+ Ionization of drugs

For acidic drug

pH = pKa + log [ionized drug] [un-ionized drug]

For basic drug

pH = pKa + log [un-ionized drug] [ionized drug]

POHOHHP 32

)][

][log(

HP

PpKpH a

OHBHOHB 2

)][

][log(

BH

BpKpH a

S

SSpKpH a

log

SS

SpKpH a

log

][][ PHPS

][HPS

][][ BHBS

][BS

+

+

LitergmLL

gm/50

11.0

5

LitermoleWeightMolecular

WeightMolarity /1968.0

254

50

.

S

SSpKpH ap

log

826.515841.736.38log41.7005.0

005.01968.0log41.7

ppH

Below what pH will phenobarbital begin to separate from a solution having an initial concentration of 5% (w/v)?The molar solubility of phenobarbital, So, is 0.005 and the pKa is 7.41 at 25°C. The molecular weight of sodium phenobarbital is 254.

+Calculate the pHp of a 1% sodium phenobarbital solution. From Merck Index:

(i.e. 1% phenobarbital will precipitate at or below a pH of 8.3)

S

SSpKpH ap

log

+What is the pH below which sulfadiazine (pKa = 6.48) will begin to precipitate in an infusion fluid, when the initial molar concentration of sulfadiazine sodium is 4X 10 -2 mol/ dm 3 and the solubility of sulfadiazine is 3.07X 10 -4 mol/ dm 3 ?

The pH below which the drug will precipitate is calculated using equation

S

SSpKpH a

log

Example

+ ExampleExample:If 8.66 mg/ml procaine solution stable (i.e., no ppt.) at pH 7.4 given that 1 gm dissolves in 200 ml water and pka = 8.05.

SS

SpKpH a

log

S

S = 8.66 mg/ml

pka = 8.05

= 1gm/ 200ml = 1000mg/200 ml =5 mg/ ml

pH = 8.05 + log (5/ 8.66 – 5)

pH = 8.05 + log 1.37

pH = 8.19

This is maximum pH and 7.4 is less than 8.19, therefore solution is

stable and no ppt. occurs.

+Ionization and pH

Strong vs. weak acids and bases

1. Strong – ionized at all pHs2. Weak – only ionized at certain pHs (most drugs are weak acids or weak bases3. Ionized drugs are not very lipid soluble- only nonionized form of drug crosses membrane readily4. Percent ionization is pH dependent5. pKa is the negative log of the ionization constant and isequal to the pH at which a drug is 50% ionized6. Weak acids become highly ionized as pH increases7. Weak bases become highly ionized as pH decreases

+Computing Ionization Ratios

According to the Henderson-Hasselbalch equation, the difference between the pH of the solution and the pKa of the drug is the common logarithm of the ratio of ionized to unionized forms of the drug.

For acid drugslog(ionized/unionized) = pH - pKa, orratio of ionized to unionized is 10X / 1, whereX = pH – pKa

)][

][log(

HP

PpKpH a

+Computing ionization ratios

For basic drugs, everything is the same except that the ratio reverses:

Log(unionized/ionized) = pH – pKa, or

Ratio of unionized to ionized is 10X / 1, where

X = pH – pKa

)][

][log(

HP

PpKpH a

)][

][log(

BH

BpKpH a

+)

][

][log(

HP

PpKpH a

)][

][log(

BH

BpKpH a

Acidic drugs Basic drugs

+ Lipoid diffusion- weak acids and weak bases

Henderson-Hasselbalch equation

Determines extent of ionization

pKa = pH at which 50% of drug is ionized.

WEAK ACIDS:

log (ionized form/nonionized form)= pH – pKa

WEAK BASES:

log (nonionized form/ionized form)= pH – pKa

)][

][log(

HP

PpKpH a

)][

][log(

BH

BpKpH a

+ PASSIVE DIFFUSION

•water soluble drug (ionized or polar) is readily absorbed via aqueous channels or pores in cell membrane.•Lipid soluble drug (nonionized or non polar) is readily absorbed via cell membrane itself.

+

Examples

P weak acid, has a pKa of 5.5. Taken orally, it is in a stomach solution of pH 3.5.

pH – pKa = 3.5 – 5.5 = -2

Since it is an acid drug, we use the alphabetical formula ionized/unionized.

ionized/unionized = 10-2/1= 1/100

For every 1 molecule of P that is ionized, 100 are unionized. P in the stomach is highly fat soluble.

+

But look what happens…

The highly fat soluble P readily crosses the stomach membranes and enters blood plasma, which has a pH of 7.5

pH – pKa = 7.5 – 5.5 = 2

ionized/unionized = 102/1= 100/1

For every 100 molecules of P that are ionized, only 1 is unionized. P in the blood is not very fat soluble.

P will be subject to ion trapping.

+

+ Percent Ionization of Aspirin [Stomach]pKa of Aspirin [weak acid] = 3.4 (50% HA and A- at pH 3.4)pH stomach = 1.4 pH blood = 7.4pH = pKa + log (A-)/(HA) [ H-H equation]pH - pKa = log (A-)/(HA)1.4 – 3.4 = - 2 log of 0.01= -2 (stomach)A- / HA= 0.01/ 1 so HA is 100 fold greater than AHA moves from the stomach into the blood (good absorption)

Percent Ionization of Aspirin [Blood]Stomach (pH=1.4) Blood (pH=7.4)

pH - pKa = log (A-)/(HA)

7.4 – 3.4 = 4 log of 10,000 = 4 (blood)A- / HA= 10,000/ 1so A- is 10,000 fold greater than HA

+

Another example

M, a weak base with a pKa of 7.5 is dissolved in the stomach, pH 3.5

pH – pKa = 3.5 – 7.5 = -4

Since M is a base drug, we use the ratio backwards: unionized/ionized.

unionized/ionized = 10-4/1= 1/10,000

In the stomach, M will be mostly ionized, and not very fat soluble.

+

But…

If we inject M intravenously into the blood, with a pH of 7.5,

pH – pKa = 7.5 – 7.5 = 0

unionized/ionized = 100 = 1/1

In the blood, M will be equally ionized and unionized.

+Percent Ionization of Codeine [Stomach]

• CODEINE (weak base) pKa = 7.9• Stomach pH=1.9 Blood pH =7.4

pH - pKa = log(B)/(BH+) [H-H equation]

1.9 - 7.9 = -6 log 0.0000001 = -6 [Stomach]

B/ BH+ = 0.000001/1 so BH+ is 1,000,000 fold greater than B.

Little B (codeine) is absorbed into the blood (poor absorption)

+An oddity

Caffeine is a base drug, but it has a pKa of 0.5

pH – pKa = 3.5 – 0.5 = 3

Since caffeine is a base drug, we use the ratio backwards: unionized/ionized.

unionized/ionized = 103/1= 1000/1

In the stomach, caffeine will be mostly unionized, and fat soluble!

In the blood, caffeine will be even more unionized and fat soluble:

pH – pKa = 7.5 – 0.5 = 7, ratio = 107/1= 10,000,000/1.

+WEAK ACIDS

log (ionized form/nonionized form)= pH – pKa

A drug is a weak acid.

pKa is 3.5.

If stomach pH is 1.5, what percentage of drug will be in absorbable form?

pH – pKa = 1.5 – 3.5 = - 2

pH = pKa + log [ionized drug] / [un-ionized drug] (pH) – (pKa) -2 -1 0 1 2 Weak acid % nonionized

99

90

50

10 1

+Remember – absorbable means nonionized !

pH – pka = -2

This (-2) in the table for weak acid matches to 99%.

And this is supposed to be the nonionized form, which is same as “absorbable form” that is asked in this problem.

Hence the absorbable form is 99%.

+Weak bases

log (nonionized form/ionized form)= (pH) – (pKa)

A drug is a weak base.

pKa is 8.

At pH 6, what percentage of drug will be in the ionized form?

pH – pKa = 6 – 8 = - 2

(pH) – (pKa) -2 -1 0 1 2 Weak base % nonionized

1 10

50

90 99

+Please remember – ionized means nonabsorbable !

pH – pka has come as -2.

In the table for weak base, -2 matches with 1%. But this 1% is nonionized form. What is asked is – ionized.

So, ionized is 100 – 1 = 99%.

+Co-solvent effect on solubility

The presence of a co-solvent can increase the solubility of hydrophobic organic chemicals

Co-solvents can completely change the solvation properties of “water”

The nonelectrolytes and the undissociated molecules of weak electrolytes more soluble in a mixture of solvents than in one solvent alone. This phenomenon is known as cosolvency, and the solvents that, in combination, increase the solubility of the solute are called cosolvents.

+

Fig. 9-5. The influence of alcohol concentration on the dissociation constant of phenobarbital.

+

States that a solute will distribute itself between two immiscible solvents so that the ratio of its concentration in each solvent is equal to the ratio of its solubility in each one

CO

Kd = ---------

CW Co= molar conc in organic layerCw= molar conc in aqueous layerKd= distribution constant, distribution ratio, distribution coefficient, or partition coefficient

Distribution of Solutes between Immiscible Solvents

1-Octanol is the most frequently used lipid phase in pharmaceutical research. This is because:

It has a polar and non polar region (like a membrane phospholipid) Po/w is fairly easy to measure Po/w often correlates well with many biological properties

Xaqueous Xoctanol

P

Partition coefficient P (usually expressed as log10P or logP) is defined as:

P =[X]octanol

[X]aqueous

P is a measure of the relative affinity of a molecule for the lipid and aqueous phases in the absence of ionisation.

Partition coefficients

+Application

Extraction

Preservative action of weak acids in o/w systems

Drug absorption/distribution/action

+Application

Extraction

it is used to determine the efficiency with which one solvent can extract a compound from a second solvent

extract natural drugs from a solvent with several portions of an immiscible solvent

+Application

Preservative action

the concentration of preservative to be used in an emulsion can be calculated from the distribution law to give the effective antimicrobial concentration in the water phase

+Drug

Absorption/Distribution/Action

Hydrophobic drugs (high partition coefficients) are preferentially distributed to hydrophobic compartments such as lipid bilayers of cells

Hydrophilic drugs (low partition coefficients) preferentially are found in hydrophilic compartments such as blood serum.

+

If only the undissociated form is present at low pH then we need to find S0.

What is the solubility of benzylpenicillin G at a pH sufficiently low to allow only the nondissociated form of the drug to be present?The pKa of benzylpenicillin G is 2.76 and the solubility of the drug at pH 8.0 is 0.174 mol/ dm 3

(From R. E. Notari, Biopharmaceutics and Pharmacokinetics, 2nd edn, Marcel Dekker, New York, 1978.)

S

SSpKpH a

log

24.5174.0

log76.20.8

S

S

360 /101 dmmolS

Example

+In general

solubility increases exponentially as cosolvent fraction increases.

need 5-10 volume % of cosolvent to see an effect.

extent of solubility enhancement depends on type of cosolvent and solute effect is greatest for large, nonpolar solutes more “organic” cosolvents have greater effect

propanol>ethanol>methanol