1. Chapter 9. SOLUBILITY & SOLUTION PROPERTIES of DRUGS

2. The importance of drug solubility
Drug solubility affects
Drug concentration in GI tract
Drug absorption through GI tract
Consideration for drug formulation

3. Additives Ionisation Solubility pKa of drug Medium pH Surface area
Crystalline form
Hydrophobicity
Additives
Surface area
Ionisation
Medium pH

4. Definition The maximum equilibrium solubility of a drug
Solution
A system in which molecules of a solute are dissolved in a solvent vehicle
Solubility
The concentration of solute in a saturated solution at a certain temperature and pressure
Saturated Solution
A solution contains a solute at the limit of its solubility at any given temperature and pressure
Sub-saturated Solution
A solution containing the dissolved solute in a concentration below that necessary for complete saturation
Supersaturated Solution
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. 4th edition.
Physical pharmacy. Alfred Martin. 4th edition, p.212

5. Boiling point or melting point 
Dissolution Process
A solute molecule is ‘removed’ from its crystal.
Breaking the cohesive forces between solute molecules in its structure
A cavity for the molecule is created in the solvent.
The solute molecule is inserted into this cavity.
Forming the adhesive forces between solute and solvent molecule
Key parameters
Surface area 
Size 
Boiling point or melting point 
 Solubility 
 Solubility 
Physicochemical principles of Pharmacy. Alexander T Florence & David Attwood. 4th edition.

6. Factors influencing solubility (1)
Surface area of solute
S : molal solubility
A: total surface area in nm2
The equation reveals the relationship between solubility and surface area
For polar molecules and weak organic electrolytes, the greater the area of the hydrophilic portion, the greater is the aqueous solubility
Physicochemical principles of Pharmacy. Alexander T Florence & David Attwood. 4th edition.

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

8. Factors influencing solubility (3)
Structural features of solute
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 (- CH3, - Cl) are hydrophobic and impart low solubility.
Ionisation of the substituents increases solubility: - COOH and – NH2 ; - COO- and – NH3+.
For inorganic electrolytes: the solubility is influenced by their crystal properties and the interaction of their ion with water (hydration).
Physicochemical principles of Pharmacy. Alexander T Florence & David Attwood. 4th edition.

9. Factors influencing solubility (4)
Structural features of solute
Substituent 
The polarity is guide to the solvent interactions
so it enables to expect approximate solubility
Physicochemical principles of Pharmacy. Alexander T Florence & David Attwood. 4th edition.

10. Factors influencing solubility (5)
Structural features of solute
Substituent
p–dihydroxyl benzen: greater stability of its crystalline state
o–dihydroxyl benzen: possibility of intramolecular hydrogen bonding in aqueous solution
Melting point
105oC
111oC
170oC
Solubility
4 mol.dm-3
9 mol.dm-3
0.6 mol.dm-3
Physicochemical principles of Pharmacy. Alexander T Florence & David Attwood. 4th edition.

11. Factors influencing solubility (6)
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
Physicochemical principles of Pharmacy. Alexander T Florence & David Attwood. 4th edition.

12. Factors influencing solubility (7)
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
Additive
Solubility product (Ksp)
Ex) Silver chloride, barium sulfate.
The Ksp value is the product of the upper limit of the product of the concentration of the soluble ions. When the product of the concentration of the ions exceed the value of Ksp they cannot exist in equilibrium anymore. They will form a precipitate in order to reduce the concentrations of the ions in solution back to the equilibrium value.
Physicochemical principles of Pharmacy. Alexander T Florence & David Attwood. 4th edition.

13. Factors influencing solubility (8)
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
The solubility of weak electrolytes is strongly influenced by the pH of the solution.
pH is one of the primary influences on the solubility of most drugs that contain ionisable groups
Acidic drugs are less soluble in acidic solutions than in alkaline solutions
Martin’s Physical Pharmacy 233p
Physicochemical principles of Pharmacy. Alexander T Florence & David Attwood. 4th edition.

14. Factors influencing solubility (9)
pH of solution
[Basic Drugs]
Contrary to acidic drugs,
Basic drugs are more soluble in acidic solutions
[Amphoteric Drugs]
pH < pI
There are two dissociation constants
Figure :Determination of pKa values of some sulfonamides by LC and LC-PDA methods in acetonitrile-water binary mixtures
Nurullah ŞanliI,*; Senem ŞanliI; Güleren ÖzkanII; Adil DenizlicIII
pH > pI
Physicochemical principles of Pharmacy. Alexander T Florence & David Attwood. 4th edition.

15. Solubility of drug in mixed solvents (1)
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
Reduction in ionisation may occur
 This will favour decreased solubility
 The greater affinity of the undissociated species to cosolvent can overcome this effect
A : glycerol in water
B : ethanol in water
C : ethanol in glycerol
Many pharmaceutical preparations are complex systems.
Common water-miscible solvents used in pharmaceutical formulations include glycerol, propylene glycol, ethyl alcohol ….
drugs have limited solubility or the stability of drugs is low in one solvent.
It is naïve to assume that the drug dissolves in ‘pockets’ of the cosolvent (ex. Ethanol in ethanol-water mixtures)
Physicochemical principles of Pharmacy. Alexander T Florence & David Attwood. 4th edition.

16. How can we optimize mutual dissolution ?
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
Precipitation can be occurred by
Dilution pH change ionic composition any drug additives
Sulfamethoxaxole pKa=6.03
Trimethoprim pKa=7.05
Physicochemical principles of Pharmacy. Alexander T Florence & David Attwood. 4th edition.

17. 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
The chemical stability rather than the solubility may be a criterion
Increase in ion concentration (ex. Na, Cl salt form) will cause the equilibrium, push the reaction to the reverse direction. That lower the solubility of salt form.
Salt can change the pH of medium. So if the drug is basic, use acidic salt form like HCl.
Physicochemical principles of Pharmacy. Alexander T Florence & David Attwood. 4th edition.

18. Solubility of drug in immiscible solvents (1)
Partitioning of drugs between immiscible solvents
Examples of partitioning
Drugs partitioning between aqueous phases and lipid biophases
Preservative molecules in emulsions partitioning between aqueous and oil phase
Antibiotics partitioning into microorganisms
Drugs and preservative molecules partitioning into the plastic of containers or giving sets
Partition coefficient or distribution coefficient (P) : P = C0 / Cw
Expression of partitioning as logP : logP >>>  high lipid solubility
Physicochemical principles of Pharmacy. Alexander T Florence & David Attwood. 4th edition.

19. Solubility of drug in immiscible solvents (2)
Partitioning of drugs between immiscible solvents
Papp is apparent partition coefficient calculated by assay of solute in both phases
For amphoteric drugs, the pH dependence of partition coefficient is complex and Papp is maximal at the isoelectric point
Physicochemical principles of Pharmacy. Alexander T Florence & David Attwood. 4th edition.

20. Solubility of drug In single solvent In mixed solvents
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
Physicochemical principles of Pharmacy. Alexander T Florence & David Attwood. 4th edition.

21. Solution properties of drugs
Osmotic properties
Ionization of drugs in solution
Diffusion of drugs in solution
Thermo- dynamics

22. The importance of properties of drug solution
Physicochemical properties of drugs in solution are of relevance to liquid 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
Physicochemical principles of Pharmacy. Alexander T Florence & David Attwood. 4th edition.

23. Thermodynamics (1) 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 = concentration
Activity coefficient:
Kinds of γ depend on concentration expression: γm, γc, γx
Physicochemical principles of Pharmacy. Alexander T Florence & David Attwood. 4th edition.

24. Thermodynamics (2) Activity of ionized drugs
For electrolytes, the activity of each ion: a+ = γ+ m+ and a- = γm 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 = in water at 298K )
I : total ionic strength.
Physicochemical principles of Pharmacy. Alexander T Florence & David Attwood. 4th edition.

25. Thermodynamics (3) Chemical potential ( µ2 )
Extensive properties: depend on the quantity of substance such as volume, enthalpy, free 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 mixture  < free energy of the pure substance
In two phases system, chemical potential is the driving force ( low  high ) between two phases
Non-ionized substances :
Strong electrolytes ( 1:1 ) :
Physicochemical principles of Pharmacy. Alexander T Florence & David Attwood. 4th edition.

26. Thermodynamics (4) Chemical potential ( µ2 ) 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 )
Physicochemical principles of Pharmacy. Alexander T Florence & David Attwood. 4th edition.

27. Thermodynamics (5) 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
Physicochemical principles of Pharmacy. Alexander T Florence & David Attwood. 4th edition.

28. Osmotic properties (1)
Osmotic phenomenon: only solvent molecules move from the low concentration of solutes  high concentration through semi-permeable membrane
The driving force for movement - different chemical potential:
solvent molecule/ solution < pure solvent
Physicochemical principles of Pharmacy. Alexander T Florence & David Attwood. 4th edition.

29. Osmotic properties (2) 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
n2 : The number of moles of solute
Physicochemical principles of Pharmacy. Alexander T Florence & David Attwood. 4th edition.

30. Osmotic properties (3)
Osmotic pressure
Pressure differential develops across the semi-permeable membrane
Red blood cell membrane: semi-permeable membrane
Isotonic solution: Π solution = Π blood serum
Hypertonic solution: Π solution > Π blood serum
Hypotonic solution: Π solution < Π blood serum
 Administration of solution (i.e. injection) to delicate membranes of body (i.e. eyes): isotonic solution  avoid discomfort feeling
For preparing of isotonic solution, osmotic pressure is usual to use the freezing – point depression
The freezing - point depression of blood serum is ∆Tf = 0.52˚ C
Physicochemical principles of Pharmacy. Alexander T Florence & David Attwood. 4th edition.

31. Osmotic properties (4)
Plays an important role in formulation and preparation of parenteral solutions
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
Physicochemical principles of Pharmacy. Alexander T Florence & David Attwood. 4th edition.

32. Ionization of drug in solution (1)
Arrhenius
Bronsted
Lewis
Acid
Tends to increase H+ when dissolved in water
HCl  H+ + Cl-
Able to donate H+
CH3COOH + H2O CH3COO- + H3O+
Accepts lone pair electron
Base
Tends to increase OH- when dissolved in water
NaOH  Na+ + OH-
Able to accept H+
H2O + NH NH4+ + OH-
Donates lone pair electron
Conjugate acid – base pair
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. 4th edition
Mark E. Tuckerman

33. Ionization of drug in solution (2)
Weakly acidic drugs and their salts
The lower pKa  the stronger acid
At given pH:
Salts of weak acids: completely ionized in solution.
Physicochemical principles of Pharmacy. Alexander T Florence & David Attwood. 4th edition.

34. Ionization of drug in solution (3)
Weakly acidic drugs and their salts
Physicochemical principles of Pharmacy. Alexander T Florence & David Attwood. 4th edition.

35. Ionization of drug in solution (4)
Drugs are ionised in range of pH ± 2 of solution and completely unionised out of this range
Physicochemical principles of Pharmacy. Alexander T Florence & David Attwood. 4th edition.

36. Ionization of drug in solution (5)
Weakly basic drugs and their salts
The lower pKb  the stronger basic
At given pH:
Salts of weak basics: completely ionized in solution.
Physicochemical principles of Pharmacy. Alexander T Florence & David Attwood. 4th edition.

37. Ionization of drug in solution (6)
Weakly basic drugs and their salts
Physicochemical principles of Pharmacy. Alexander T Florence & David Attwood. 4th edition.

38. Ionization of drug in solution (7)
The relationship between pKa and pKb
The pKa values refer to both weak acids and bases
pKa and pKb values of conjugate acid – base pairs
pKa + pKb = pKw
At 25˚ C, pKw = and decreases with increasing of temperature
Physicochemical principles of Pharmacy. Alexander T Florence & David Attwood. 4th edition.

39. Ionization of drug in solution (8)
Amphoteric drugs
Can function as either weak acids or weak bases in aqueous solution
Odinary ampholytes:
When pH of solution increases, the basic group loses H+ first
Counterions: cation, unionised and anion
Physicochemical principles of Pharmacy. Alexander T Florence & David Attwood. 4th edition.

40. Ionization of drug in solution (10)
Amphoteric drugs
Odinary ampholytes
Physicochemical principles of Pharmacy. Alexander T Florence & David Attwood. 4th edition.

41. Ionization of drug in solution (11)
Amphoteric drugs
Zwitterionic ampholytes:
Models: amino acids, peptides and proteins
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
Physicochemical principles of Pharmacy. Alexander T Florence & David Attwood. 4th edition.

42. Ionization of drug in solution (12)
Zwitterionic ampholytes
Large ∆pKa
Over the range of pH 3 – 9, glycine exists in the zwitterionic form acting as both of acid and base
Distribution of ionic species: similar to m-aminophenol
pHi – isoelectric pH or isoelectric point : is the pH at which the effective charge on the molecule is zero
Physicochemical principles of Pharmacy. Alexander T Florence & David Attwood. 4th edition.

43. Ionization of drug in solution (13)
Zwitterionic ampholytes
Small ∆pKa (<< 2 pH units)
Four electrical states: cation, unionised form, zwiterion and anion due to the overlap of the ionisation of acidic and basic groups
At pHi the Zwitterion and unionised forms coexist
Physicochemical principles of Pharmacy. Alexander T Florence & David Attwood. 4th edition.

44. Ionization of drug in solution (14)
Zwitterionic ampholytes
Small ∆pKa (<< 2 pH units)
Four electrical states: cation, unionised form, zwiterion and anion due to th overlap of the ionisation of acidic and basic groups
At pHi the Zwitterion and unionised form coexist
Physicochemical principles of Pharmacy. Alexander T Florence & David Attwood. 4th edition.

45. Ionization of drug in solution (15)
Zwitterionic ampholytes
Small ∆pKa (<< 2 pH units)
Physicochemical principles of Pharmacy. Alexander T Florence & David Attwood. 4th edition.

46. Ionization of drug in solution (16)
Physicochemical principles of Pharmacy. Alexander T Florence & David Attwood. 4th edition.

47. Ionization of drug in solution (17)
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 pKa and pKb value
Physicochemical principles of Pharmacy. Alexander T Florence & David Attwood. 4th edition.

48. pH of drugs in solution
pH of drug in solution can be calculated as follow
H of drugs in solution:
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 :
Physicochemical principles of Pharmacy. Alexander T Florence & David Attwood. 4th edition.

49. 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 pKa value via the ionization of drug
pH of drug solution can be calculated at certain concentration and pKa value of drug

50. Buffer solution (1) Henderson-Hasselbalch equation
Mixture of a weak acid and its salt (conjugate base) or weak base and its conjugate acid
Is used to minimize the change of drug solubility in certain solution
Buffer of HA and its salts (Na)
H+ addition,
OH- addition,
Buffer of weak base and its salts
Henderson-Hasselbalch equation
Physicochemical principles of Pharmacy. Alexander T Florence & David Attwood. 4th edition.

51. Buffer solution (2) Buffer capacity - β
The effectiveness of a buffer in reducing changes in pH
βmax at pH = pKa
βmax = cₒ
cₒ : total buffer concentration
For polyprotic drugs, βmax of each stage is different
Universal buffer: effective over a wide range of pH
Physicochemical principles of Pharmacy. Alexander T Florence & David Attwood. 4th edition.