9.Solubility(보충) - Physical Pharmacy Laboratory

SKKU Physical Pharmacy Laboratory

성균관대학교 물리약학연구실

• Drug solubility affects



Drug concentration in GI tract



Drug absorption through GI tract



Consideration for drug formulation





Solution

Solubility

Saturated

Solution

Sub-saturated

Solution

Supersaturated

Solution

A system in which molecules of a solute are dissolved in a solvent vehicle

The concentration of solute in a saturated solution at a certain temperature and pressure

A solution contains a solute at the limit of its solubility at any given temperature and pressure

A solution containing the dissolved solute in a concentration below that necessary for complete saturation

A Solution containing the dissolved solute above its normal solubility limit

The maximum equilibrium solubility of a drug

 It dictates the rate of solution of the drug

 Of practical pharmaceutical interest !

Physicochemical principles of Pharmacy. Alexander T Florence & David Attwood. 4 th edition.

Physical pharmacy. Alfred Martin. 4 th edition, p.212



1. A solute molecule is ‘removed’ from its crystal.

 Breaking the cohesive forces between solute molecules in its structure

2. A cavity for the molecule is created in the solvent.

3. The solute molecule is inserted into this cavity.

 Forming the adhesive forces between solute and solvent molecule

Surface area 

Size 

Boiling point or melting point 

Key parameters







Physicochemical principles of Pharmacy. Alexander T Florence & David Attwood. 4 th edition.

Solubility 

Solubility 

Solubility 



1.

Surface area of solute

• The equation reveals the relationship between solubility and surface area

S : molal solubility

A: total surface area in nm 2

• For polar molecules and weak organic electrolytes, the greater the area of the hydrophilic portion , the greater is the aqueous solubility




2.

Structural features of solute

 Shape

• The shape and size of non-polar groups and polar groups as well as the interaction between them affect the solubility of solute

• Chain branching of hydrophobic groups influences the aqueous solubility

• Boiling point & melting point  indicators of molecules cohesion

 guide to the orders of solubility in a closely related series of compounds




Factors influencing solubility (3)

2.

•

•

•

•

•


 Substituents

Influence on the molecular cohesion and its interaction with water molecules.

Polar groups (-OH) are capable of hydrogen bonding with water molecules impart high solubility.

Nonpolar groups (- CH

3

, - Cl) are hydrophobic and impart low solubility.

Ionisation of the substituents increases solubility: - COOH and – NH

2

; - COO and – NH

3

+ .

For inorganic electrolytes : the solubility is influenced by their crystal properties and the interaction of their ion with water (hydration).





2.


 Substituent



The polarity is guide to the solvent interactions so it enables to expect approximate solubility





2. Structural features of solute

 Substituent

Melting point

Solubility

105 o C

4 mol.dm

-3

111 o C

9 mol.dm

-3

170 o C

0.6 mol.dm

-3

•

• p–dihydroxyl benzen: greater stability of its crystalline state o–dihydroxyl benzen: possibility of intramolecular hydrogen bonding in aqueous solution




3.

Solvation and hydration

• Solvation

 The process of binding of solvent to solute molecules

 An interaction of a solute with the solvent, which leads to stabilization of the solute species in the solution

 Distinct from dissolution and solubility



Dissolution is a kinetic process

 Solubility quantifies the dynamic equilibrium state

• Hydration

 Solvation that solvent is water

 The clustering of water molecules around a solute particle




4. Additive

 Solubility product (Ksp)









For slightly soluble electrolytes the product of the upper limit of the product of the concentration of the soluble ions

If the product of the concentration of the ions exceed the value of Ksp

 they will form a precipitate in order to reduce the concentrations of the ions in solution back to the equilibrium value

Additives which can change concentration of ions affect on the solubility of solute




5.

pH of solution

The solubility of weak electrolytes is strongly influenced by the pH of the solution







[Acidic Drugs]

In acidic solutions

Drugs cannot exist as the ionised form

Undissociated specie has a limited solubility in water

Less soluble in acidic condition




5.

pH of solution

[Basic Drugs]

 Contrary to acidic drugs,

Basic drugs are more soluble in acidic solutions

[Amphoteric Drugs]


 pH < pI

 pH > pI









Mixed solvent is used when



 drugs have limited solubility the stability of drugs is low

Phenobarbital in mixed solvent

 Solubility : 0.12 % w/v in water

 Solubility is slightly higher in glycerol



 and much higher in ethanol

Solubility is much higher in ethanol-water and ethanol-glycerol mixed solvents

Drug dissolves in ‘pockets’ of the cosolvent

An expected Problem A : glycerol in water

B : ethanol in water





Reduction in ionisation may occur

This will favour decreased solubility

C : ethanol in glycerol

 The greater affinity of the undissociated species to cosolvent can overcome this effect




Solubility of drug in mixed solvents (2)

 Mixtures of acidic and basic compound

 For optimal solubility of each drugs, basic and acidic solutions required respectively

 High degree of incompatibility

 Mutual precipitation occurs on mixing



How can we optimize mutual dissolution ?

Infusion formulation : an aqueous solution includes 40% propylene glycol

 pH between 9.5 - 11.0

 Precipitation can be occurred by

Dilution pH change ionic composition any drug additives




Solubility of drug in mixed solvents (3)



Choice of drug salt to optimize solubility

 The solubility in water may be markedly dependent on the salt form

 Formation of water-soluble entities from poorly soluble drugs

 By the use of hydrophilic counterions

 Limit factors : Common ion effect and pH




Solubility of drug in immiscible solvents (1)



•

•

•

Partitioning of drugs between immiscible solvents

Examples of partitioning o Drugs partitioning between aqueous phases and lipid biophases o Preservative molecules in emulsions partitioning between aqueous and oil phase o Antibiotics partitioning into microorganisms o Drugs and preservative molecules partitioning into the plastic of containers or giving sets

Partition coefficient or distribution coefficient (P) : P = C

0

/ C w

Expression of partitioning as logP : logP >>>  high lipid solubility




Solubility of drug in immiscible solvents (2)

 Partitioning of drugs between immiscible solvents

• P app is apparent partition coefficient calculated by assay of solute in both phases

• For amphoteric drugs, the pH dependence of partition coefficient is complex and P app is maximal at the isoelectric point




Solubility of drug

• In single solvent

 Nature of drug : structure, hydrophobic/hydrophilic properties, substituent, ionization (pKa value)

 pH of medium

 pKa of drug is the indicator to predict its solubility in certain pH medium

 pH of medium is adjusted to get the optimal solubility of drug

• In mixed solvents

 Selection of co-solvents

• In immiscible solvents

 Partition coefficient of drug in two immiscible solvents




Osmotic properties

Thermodynamics

Solution properties of drugs

Ionization of drugs in solution

Diffusion of drugs in solution



•

Physicochemical properties of drugs in solution are of relevance to liqu id dosage forms: injections, solutions and eye drops

 Thermodynamic activity  an important parameter in determining drug potency

 Osmotic pressure of drug solution  an important parameter in formulation of isotonic parenteral solutions

 Ionization of drug in solution  effect of pH of solution on ionization of drug and calculation pH of drug solution




•

•

•

•

•

 Activity

Description of the departure of the behaviour of a solution from ideality

Way of describing the effective concentration

In ideal solution/ initial stage of dilution in real solution: activity = conce ntration

Activity coefficient:

Kinds of γ depend on concentration expression: γ m

, γ c

, γ x




•

•

•

 Activity of ionized drugs

For electrolytes, the activity of each ion: a

+

= γ

+ m

+ and a

-

= γ m m

-

The mean ionic activity :

 a : ionic activity



 m : ionic molality

 γ : ionic activity coefficient



The γ

± is calculated by using Debye-Hϋckel equation: z

+

/ z

-

: valencies of ions

 A : constant ( A = 0.509 in water at 298K )

I : total ionic strength.




 Chemical potential ( µ

2

)

 Extensive properties : depend on the quantity of substance such as volume, enthalpy, f ree energy, and entropy

 Intensive properties : do not depend on the amount of substance such as temperature, density, and refractive index

 Chemical potential : the effective free energy per mole of each component in the mixt ure  < free energy of the pure substance

 In two phases system, chemical potential is the driving force ( low  high ) between t wo phases

 Non-ionized substances :

 Strong electrolytes ( 1:1 ) :




•

•

 Chemical potential ( µ

2

)

Non-ionized substances :

Strong electrolytes ( 1:1 ) :

 µ2ᶿ : Chemical potential of the component in its standard state

 M1 : Molecular weight of the solvent

 R : Gas constant

 T : Temperature ( K )




• Determination of drug potency

• Example

 S-ibuprofen is an active entities while R-ibuprofen is a non

-active entities

 These always present in raw synthesis material

 The content of Ibuprofen is calculated on the S-ibuprofen




• Osmotic phenomenon : only solvent molecules move from the low conc entration of solutes  high concentration through semi-permeable me mbrane

• The driving force for movement - different chemical potential: solvent molecule/ solution < pure solvent




 Osmotic pressure

• Pressure differential develops across the semi-permeable membrane

• Value depends on the number of ions in solution ( including counterions of electrolytes )  colligative property

• Van’t Hoff equation

▪

 Π : Osmotic pressure of solution

 V : The molar volume of the solute

 n

2

: The number of moles of solute




•

•

 Osmotic pressure

Pressure differential develops across the semi-permeable membrane

Red blood cell membrane: semi-permeable membrane o Isotonic solution: Π solution

= Π blood serum o Hypertonic solution: Π solution

> Π blood serum o Hypotonic solution: Π solution

< Π blood serum

•

• n

  Administration of solution (i.e. injection) to delicate membranes of body (i.e. eyes): isotonic sol ution  avoid discomfort feeling

For preparing of isotonic solution, osmotic pressure is usual to use the freezing – point depressio

The freezing - point depression of blood serum is

∆T f

= 0.52˚ C




• Plays an important role in formulation and preparation of parenteral s olutions

• Administration of solution (i.e. injection) to delicate membranes of body

(i.e. eyes): isotonic solution  avoid discomfort feeling

• Freezing point depression is used to prepare isotonic solution






Acid

Base

Arrhenius

Tends to increase H + when dissolved in water

Bronsted

Able to donate H +

HCl  H + + Cl -

Tends to increase OH when dissolved in water

CH

3

COOH + H

2

-

O

+ H

3

O +

CH

3

COO

Able to accept H +

H

2

O + NH

3

NH

4

+ + OH -

NaOH  Na + + OH -

Conjugate acid – base pair

Lewis

Accepts lone pair electron

Donates lone pair electron

•

• An acid and base represent by an equilibrium

In the below figure, acid 1 - base 1 and acid 2 – base 2 is a conjugate acid – base pair

Physicochemical principles of Pharmacy. Alexander T Florence & David Attwood. 4 th edition

Mark E. Tuckerman 2006-11-16 http://www.nyu.edu/classes/tuckerman/honors.chem/lectures/lecture_21/node2.html



Ionization of drug in solution (2)

 Weakly acidic drugs and their salts

•

•

•

The lower p K a

 the stronger acid

At given pH:

Salts of weak acids: completely ionized in solution.





 Weakly acidic drugs and their salts





• Drugs are ionised in range of pH ± 2 of solution and completely unionised out of this range





 Weakly basic drugs and their salts

•

•

•

The lower p K b

At given pH:

 the stronger basic

Salts of weak basics: completely ionized in solution.





 Weakly basic drugs and their salts





•

 The relationship between p K a and p K b

The p K a values refer to both weak acids and bases

•

•

 p K a and p K b values of conjugate acid – base pairs p K a

+ p K b

= pK w

At 25˚ C, pK w

= 14.00 and decreases with increasing of temperature





 Amphoteric drugs

• Can function as either weak acids or weak bases in aqueous solution

 Odinary ampholytes: o When pH of solution increases, the basic group loses H + first o Counterions: cation, unionised and anion






 Odinary ampholytes






 Zwitterionic ampholytes: o Models: amino acids, peptides and proteins o o Depend on value of

∆ pKa, there are two kinds of zwitterionic ampholytes

 Large

∆ pKa : Existence form of cation, zwitterion and anion

 Small

∆ pKa : Existence form of cation, unionised , zwitterion and anion





 Zwitterionic ampholytes

 Large

∆ pKa



Over the range of pH 3 – 9, glycine exists in the zwitterionic form acting as both of acid a nd base

 Distribution of ionic species: similar to m-aminophenol

 pH i

– isoelectric pH or isoelectric point : is the pH at which the effective charge on the mo lecule is zero






 Small

∆ pKa (<< 2 pH units)

 Four electrical states: cation, unionised form, zwiterion and anion due to the o verlap of the ionisation of acidic and basic groups

 At pH i the Zwitterion and unionised forms coexist






 Small


 Four electrical states: cation, unionised form, zwiterion and anion due to th ov erlap of the ionisation of acidic and basic groups

 At pH i the Zwitterion and unionised form coexist





 Small










 Polyprotic drugs

• Polyprotic or polybasic acids : capable of donating > 1 proton

• Examples: tartaric acid, citric acid, phosphoric acid

• Polyprotic bases : capable of accepting > 1 proton

• Each stage of ionisation equilibrium, they have specific pK a and pK b value




 pH of drug in solution can be calculated as follow

 Strong acid : pH = -log [H + ]

 Weakly acidic drug :

 Weakly basic drugs :

 Salts of a weak acid and a strong base :

 Salts of a weak base and a strong acid :

 Salts of a weak acid and a weak base :




Ionization of drug in solution

• Most important properties of drug in solution

• In GI tract, most drugs are partially ionised at physiological pH providing biologically active forms of drugs

• At certain pH of medium, drug solubility can be predicted with known p

Ka value via the ionization of drug

• pH of drug solution can be calculated at certain concentration and pKa v alue of drug



•

•

•



Mixture of a weak acid and its salt (conjugate base) or weak base and i ts conjugate acid

Is used to minimize the change of drug solubility in certain solution

Buffer of HA and its salts (Na) o H + addition,

 o OH addition,

Buffer of weak base and its salts o o

H + addition,

OH addition,

Henderson-Hasselbalch equation




• o

Buffer capacity -

β

The effectiveness of a buffer in reducing changes in pH

• o βmax at pH = pKa o

 o

βmax = 0.576 cₒ cₒ : total buffer concentration

For polyprotic drugs, βmax of each stage is different

Universal buffer: effective over a wide range of pH




9.Solubility(보충) - Physical Pharmacy Laboratory

• Drug solubility affects

Drug concentration in GI tract

Drug absorption through GI tract

Consideration for drug formulation

Structural features of solute

Factors influencing solubility (3)

Structural features of solute

Factors influencing solubility (4)

Structural features of solute

Factors influencing solubility (5)

4. Additive

[Acidic Drugs]

pH of solution

[Basic Drugs]

[Amphoteric Drugs]

Solubility of drug in mixed solvents (2)

Solubility of drug in mixed solvents (3)

Choice of drug salt to optimize solubility

Solubility of drug in immiscible solvents (1)

Solubility of drug in immiscible solvents (2)

Solubility of drug

Solution properties of drugs

•

Ionization of drug in solution (2)

Ionization of drug in solution (3)

Ionization of drug in solution (4)

Ionization of drug in solution (5)

Ionization of drug in solution (6)

Ionization of drug in solution (7)

Ionization of drug in solution (8)

Ionization of drug in solution (10)

Ionization of drug in solution (11)

Ionization of drug in solution (12)

Ionization of drug in solution (13)

Ionization of drug in solution (14)

Ionization of drug in solution (16)

Ionization of drug in solution (17)

Ionization of drug in solution

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