IONIZATION

Ionization is the process of converting an atom or molecule into an ion by adding or removing
charged particles such as electrons or other ions.
A positively charged ion is produced when an electron bonded to an atom (or molecule) absorbs
enough energy to escape from the electric potential barrier thus breaking the bond and freeing
it to move. The amount of energy required is called the ionization potential. A negatively
charged ion is produced when a free electron collides with an atom and is caught inside
releasing any excess energy.
ACID-BASE THEORIES:
1- ARRHENIUS THEORY:
According to Arrhenius an acid is a substance that supplies hydrogen ions (H+) and base is a
substance that supplies hydroxyl ions (OH‾) on dissociation. E.g. HCl, H2SO4, H3PO4 are acids
and NaOH, KOH, NH4OH are bases.
2- BRONSTED-LOWRY THEORY:
An acid is a substance, charged or uncharged that is capable of donating a proton, and a base
is a substance, charged or uncharged capable of accepting a proton from acid. According to
Bronsted –Lowry classification, acids and bases are of following types:
a) ANIONS: HSO4‾, CH3COO‾
b) CATIONS: NH4+, H3O+
c) NEUTRAL: HCl, NH3
Water can act either as an acid or a base and thus is called amphiprotic.
Acid-base reactions occur when an acid reacts with a base to form a new acid and base. Because
such reactions involve a transfer of proton they are called as protolytic reaction or protolysis.
E.g.
HCl + H2O H3O+ + Cl‾
Acid1 + Base2 Acid2 + Base1
3- LEWIS ELECTRONIC THEORY:
An acid is a molecule or an ion that accepts an electron pair to form a covalent bond, and a
base is a molecule or an ion that provides a pair of unshared electron by which the base
coordinates with an acid.

H
H
+
H N H H NH
H H
ACID BASE

pH

pH is defined as the negative logarithm of the hydrogen ion (H+) concentration.

The concept of pH was introduced by Danish chemist Sørensen in 1909. Sørensen suggested
the notation "pH", standing for "power of hydrogen", using the logarithm of the reciprocal of
the concentration of hydrogen ions in solution.

pH = log 1__
[H+]
+
Where, [H ] represents the concentration of hydrogen ions.
According to rules of logarithm, the above equation can be written as
pH= log 1 - log[H+] and since log 1 zero therefore
pH= - log[H+]

pH of a solution have numerical values from 0 to 14. The acidity increases from 7 to 0 and
alkalinity increases from 7 to 14. The value 7 at which the concentration of H+ and OH- are
equal at room temperature and is known as neutral pH. Pure water is said to be neutral. The pH
for pure water at 25°C is close to 7.0. Solutions with a pH less than 7 are said to be acidic and
solutions with a pH greater than 7 are said to be basic or alkaline.

Pure water ionizes through a process known as auto protolysis in the following manner:

2H2O H3O+ + OH-

Water can act as an acid or a base and is amphoteric i.e. act as proton acceptor and proton
donor. Law of Mass action give the equilibrium expression of the above equation:

K= [H3O+] [OH-] / [ H2O2]

Where K is equilibrium constant for the reaction. Since the concentration of H2O is very much
greater than [H3O+] or [OH-] so it can be considered to be constant and can be combined with
K to give new constant Kw known as ion product of water or dissociation constant.

Kw= [H3O+] [OH-]

The value of Kw is 1x10-14 at 25°C. It has different values at different temperatures. In pure
water H3O+ and OH- are equal and each has value of 1x10-7 mole/liter at 25°C

[H3O+] = [OH-] = 1x10-7

Or

Kw = 1x10-7 x 1x10-7 = 1x10-14

A solution in which [H3O+] is equal to [OH-] is termed as neutral solution.

pOH
pOH is sometimes used as a measure of the concentration of hydroxide ions, OH−. pOH is not
measured independently, but is derived from pH. The concentration of hydroxide ions in water
is related to the concentration of hydrogen ions by

[OH-] = KW /[H+]

pH INDICATOR

A pH indicator is a chemical detector for Hydrogen ions (H+). Normally, the indicator causes
the color of the solution to change depending on the pH. (A halochromic material is a material
which changes color when pH changes occur.)

Theory

pH indicators themselves are frequently weak acids or bases. When introduced into a solution,
they may bind to H+ (Hydrogen) or OH- (hydroxide) ions. For example, litmus is red in acidic
solutions (pH<7) and blue in alkaline (pH>7) solutions.

Applications

pH indicators are frequently employed in titrations in analytic chemistry and biology

experiments to determine the extent of a chemical reaction. For applications requiring precise
measurement of pH, a pH meter is frequently used.

Commercial preparations

pH measurement with indicator paper.

Universal indicator

Universal indicator consists of a mixture of indicators such that there is a continuous color
change from about pH 2 to pH 10. Universal indicator paper is simple paper that has been
impregnated with universal indicator.

Universal indicator components

 Transition pH
Indicator Low pH color High pH color
range

Thymol blue (first transition) red 1.2–2.8 orange

Methyl red red 4.4–6.2 yellow

Bromothymol blue yellow 6.0–7.6 blue

Phenolphthalein colorless 8.3–10.0 purple

pKa and drug absorption

pKa is the negative logarithm of acid dissociation constant of a solution.
pKa=-log10Ka
Difference Between pKa and pH
pKa pH
pKa gives details of the dissociation of an pH gives details about the concentration of
acid in aqueous solution. H+ ions in a system.
pKa indicates whether an acid is a strong acid pH indicates whether a system is acidic or
or a weak acid. alkaline.
If the pKa of an acid is high, it is a weak acid, If the pH of a system is high, the system is
and if the pKa of an acid is low, it is a strong alkaline. If the pH is low, then the system is
acid. The lower the pKa value, the stronger acidic.
the acid. pKa < 3 is strong acid and pKa > 7 is
strong base

Drug Absorption Factors

According to pH-partition theory for drugs which are mainly transported across GIT by passive
diffusion, the process of absorption depends upon three important factors like:
1. The pKa of the drug. The pKa value for weak acidic or basic drug indicates the amount
of unionized drug available for absorption. The lower the pKa value of the acidic drug,
stronger is the acid i.e. greater is the proportion of ionized form at a particular pH.
2. The lipid solubility of the unionized drug i.e. lipid-water partition coefficient (K).
When a drug is ionized it will not be able to cross the lipid membrane. But only when
it is unionized (non-polar), it has higher lipid solubility.
3. pH at the absorption site.
As a general rule:
For acidic drugs, ionization will be lower in stomach while absorption per unit area will be
higher than intestine.
For basic drugs, ionization of a basic drug will be lower in intestine and absorption per unit
area will be higher than stomach.
If taken orally, a drug that is a weak acid will be absorbed in the stomach (acidic environment)
whereas, a drug that is a weak base will be absorbed in the small intestines (alkaline
environment).

BUFFERS

A buffer solution is an aqueous solution consisting of a mixture of a weak acid and its salt or
a weak base and its salt which resist changes in pH. It has the property that the pH of the solution
changes very little when a small amount of acid or base is added to it.

Types of Buffers:

1- Alkaline buffer solutions

An alkaline buffer solution has a pH greater than 7. Alkaline buffer solutions are commonly
made from a weak base and one of its salts. For example: mixture of ammonia solution and
ammonium chloride solution. If these were mixed in equal molar proportions, the solution
would have a pH of 9.25.

2- Acidic buffer solutions

A mixture of acetic acid (weak acid) and sodium acetate (salt)

If we add OH- or base in this buffer, acetic acid which exists largely in non ionized
form combines with OH- to form acetic ion and H2O

CH3COOH + OH- CH3COO- + H2O

If acid or H3O+is added, the acetate ion which is a base combines with H3O+ to form non
ionized acetic acid and water

CH3COO- +H3O+ CH3COOH + H2O

Other Examples of Buffers:

Boric acid: Sodium borate

Citric Acid: Sodium citrate
Mono basic Potassium phosphate: Dibasic Potassium phosphate
Mono basic Sodium phosphate: Dibasic Sodium phosphate
FACTORS INFLUENCING THE pH OF BUFFER SOLUTION

1. DILUTION
Dilution of acidic buffer shows an increase in pH while dilution of a basic buffer shows a
decrease. This change due to dilution can be quantitatively described as dilution value, i.e.
change in pH brought about on diluting the buffer solution with an equal volume of water.

2. TEMPERATURE
Temperature also influence buffers pH.
pH of acetate buffer----- increases with temperature
Boric acid-sodium borate--- decreases with temperature

BUFFER CAPACITY
The ability of a buffer system to resist pH changes is its buffer capacity and denoted β:

= ∆B/∆pH
Buffer capacity= number of moles of OH- or H3O+ added per L of buffer solution/ pH change
Where:
Buffer capacity is the magnitude of resistance of a buffer to pH changes and is also termed as
Buffer index or Buffer efficiency or buffer value.
The greater the buffer capacity, the smaller is the change in pH due to the addition of a given
amount of strong acid or base.

Henderson-Hasselbalch equation:

The Henderson-Hasselbalch equation relates pKa and pH. For a typical weak acid, the
dissociation equilibrium is represented as:

HA→H+ + A-

Dissociation constant of above reaction will be

Ka= [H+] [A-] /[HA]

Or [H+]= ka [HA]/ [A-]

Taking -log of both sides

-log[H+]= -log ka - log[HA]/ [A-]

pH= pKa - log[HA]/ [A-]

Invert negative log[HA]/ [A-]

pH= pKa + log [A-]/[HA]

or

pH= pKa + log [salt]/[acid]

Buffer capacity is dependent on the total concentration of the buffer system and on the
[Salt]/[Acid] ratio. Buffer capacity is increased by the following factors:

1- Increasing the concentration of the buffer system components (e.g. doubling the total molar
concentration of the buffer system will double the buffer capacity at a given pH).

2- Using equimolar concentrations of the acid (CH3COOH) and its conjugate base(CH3COO-
).

pH= pKa + log 1 log1= 0

Therefore,

pH = pKa

Buffer capacity is maximum when pH = pKa or ([Acid] = [Salt]).

Why use buffers in pharmacy?

Solubility - The ionized form of a drug is more water-soluble than the unionized form. Buffers
can be used to maintain a drug in its ionized (salt) form for aqueous solutions.

Absorption - The unionized form of a drug is a more lipid soluble than the ionized form. The
unionized form therefore penetrates biological membranes much more efficiently than the ionized
form. Buffers can also be used to maintain the drug in its unionized form.

Stability - pH can affect the stability of a drug in an aqueous solution. For example, ester drugs
are very susceptible to hydrolytic reactions. Buffering formulations at low pH (pH 3-5) can
reduce the rate of hydrolysis.

Tissue irritation - High or low pH can cause tissue irritation. Buffering a formulation to near
neutral pH can reduce tissue irritation. Ophthalmic products are least irritating at pH 7-9.
Drug Activity – Some drugs may be active only either in ionized or unionized form. They need
optimum pH range for maximum activity. E.g. benzoic acid and salicylic acid have antibacterial
activity in unionized form but are inactive in ionized form. They need acidic pH for this
function. On the other hand, some antibacterial agents including quaternary ammonium
compounds (e.g. Benzalkonium chloride, Benzethonium chloride) are active in cationic form.

Buffers and the Body:

• Body fluids contain buffering agents and buffer systems that maintain pH at or near
pH=7.4. Important natural buffer systems include carbonic acid/sodium bicarbonate and
sodium phosphate in the plasma; and hemoglobin, and potassium phosphate in the cells.
• Value of pH < 7.0 or pH > 7.8 can be life threatening. Pharmaceutical solutions generally
have a low buffer capacity and unable to change the pH of the body fluids.
• Buffer concentrations of between 0.05 and 0.5 M and buffer capacities between 0.01
and 0.1 are usually sufficient for pharmaceutical solutions.

ISOTONIC SOLUTIONS:
Solutions having same osmotic pressure as that of body fluids.
e.g. 0.9 % NaCl aqueous solution
PARATONIC SOLUTIONS:
Solutions not having same osmotic pressure as that of body fluids. They have two types:
a- Hypertonic solutions: Solutions having higher osmotic pressure than that of body fluids.
b- Hypotonic solutions: Solutions having lower osmotic pressure than that of body fluids.

Undesirable effects of abnormal tonicity:

Ophthalmic Preparations:
Medications not isotonic to eye fluids (lachrymal fluids) cause eye irritation.
Parenteral Preparations:
Excessive infusion of hypotonic fluids may cause swelling of RBC’s, hemolysis, water
invasion of body cells and edema.
Excessive infusion of hypertonic fluids may cause loss of water, dehydration, diuresis, loss of
electrolytes and coma.

METHODS OF ADJUSTING TONICITY:

These methods are used only for hypotonic drug solutions in which other substances can be
added to increase their tonicity up to body fluids. If the drug solution is hypertonic than the
reference solution, it can be adjusted to isotonicity only by dilution, which is not favorable on
therapeutic grounds. Any of the methods can be used to calculate the quantity of sodium
chloride, dextrose, glycerin, propylene glycol or any other tonicity adjusting substance that may
be added to solutions of drugs to make them isotonic. These methods are classified as follows:

I. Freezing point depression method or Cryoscopic method

In these methods, sodium chloride or any other tonicity adjusting agent is added to the solution
of the drug to lower the freezing point of the solution to – 0.52 °C and thus to make it isotonic
with body fluids. Osmotic Pressure of blood and lachrymal fluids = 7.65 atm
i) Non Electrolyte (Boric Acid)
One M solution of Boric Acid is prepared by dissolving 61.8g in1000ml water
Freezing point of 1M Boric Acid= -1.86°C
Freezing point of blood and lachrymal fluids = - 0.52 °C
The amount of boric acid required for making isotonic solution can be calculated by ratio-
proportion as follows:
1.86/0.52=61.8/Xg
X=61.8x0.52/1.86= 17.3g/1000ml or 1.73g/100ml is isotonic
ii) Electrolytes (Sodium Chloride)
1M solution NaCl=58.5g/1000ml
F.P depression of = -1.86°Cx i (i-dissociation constant, its value is 1.8)
The amount of NaCl required for making isotonic solution can be calculated by
1.86x1.8/0.52=58.5/Xg
X= 9.09g/1000ml or 0.909g/100ml

II. Sodium chloride equivalent method (E Value)

In this method E value of drugs are used, which is the weight of sodium chloride that will
produce the same osmotic pressure as 1 g of the drug. E.g. dexamethasone has an E value 0.18,
which means that 0.18 g NaCl will produce an osmotic pressure equal to that produced by 1 g
dexamethasone.
In the given prescription, Calculate the amount of NaCl required to make the solution
isotonic.
Atropine So4 =1%
NaCl q.s.
Purified water= 100ml
E value= 0.12
Step 1
For 100ml, amount of Atropine So4 = 1.0g (1% )
Step 2
Amount of NaCl required for 100ml to form isotonic solution= 0.9g
Step 3 We know E value
Osmotic pressure of one gram Atropine So4 =0.12g NaCl
Step 4
Amount of NaCl to be added to make 100ml solution isotonic would be
Difference of NaCl in Step 2 & 3= 0.9-0.12= 0.78g NaCl
We have to add 0.78g NaCl in the above prescription to make solution isotonic.

III. White-Vincent method

In this method volume of water is determined by the following equation.
Vol = w × E × 111.1
Where,
Vol = volume of water required to dissolve drug
w = weight of drug
E = E value of drug
The drug is dissolved in required amount of water which is then made up to the final volume
with another isotonic solution such as 0.9% NaCl solution or 5.0 % dextrose solution. e.g.
Atropine So4 =1%
NaCl q.s.
Purified water= 30ml
E value= 0.12
W=Weight of drug for 30ml (Atropine So4)= 1.0/100x30= 0.3g
Vol of water= 0.3x0.12x111.1=3.9996 0r 4.0ml
Dissolve drug in 4.0ml of water and the makeup volume up to 30ml with 0.9% NaCl