Ionization

Contents:

• pH,
• pH indicators,
• pka,
• buffers,
• buffer’s equation,
• isotonic solutions and their applications in
pharmacy.
Electrolytes and Nonelectrolytes

3
 Solutes and Ionic Charge
In water,
• strong electrolytes produce ions and conduct an electric current
• weak electrolytes produce a few ions
• nonelectrolytes do not produce ions

4
 Strong Electrolytes
Strong electrolytes
• dissociate in water, producing positive and negative ions
• dissolved in water will conduct an electric current
• in equations show the formation of ions in aqueous (aq)
solutions
H2O 100% ions
NaCl(s) Na+(aq) + Cl(aq)
H2O
CaBr2(s) Ca2+(aq) + 2Br(aq)
5
 Weak Electrolytes
A weak electrolyte
• dissociates only slightly in water
• in water forms a solution of a few ions and mostly
undissociated molecules

HF(g) + H2O(l) H3O+(aq) + F(aq)

NH3(g) + H2O(l) NH4+(aq) + OH(aq)

6
 Nonelectrolytes

Nonelectrolytes
• dissolve as molecules in water
• do not produce ions in water
• do not conduct an electric
current

7
Classification of Solutes in
Aqueous Solutions

8
Electrolytes in IV replacement solutions

9
 Theory of Ionization
• This theory explains the differences in conductivity of different substances.
It is also called theory of electrolytic dissociation or ionic theory.
• This theory was developed by Arrhenius in 1887 and makes following
postulates.
1. Electrolytes when dissolved in water, dissociate into particles called ions.
2. The ions carry a charge of electricity, one set being negatively charged and
the other set positively charged.
3. The ions may be elementary or compound.
4. The valency of the atom or radical and the number of charges assigned to
it are the same.
5. Electrical equilibrium exists in the solution. 10
 Degree of Ionization -
Ostwald’s dilution Law
• Ionization is a reversible reaction and is therefore governed by
the law of mass action.
• Inthe case of ionic equilibrium, the equilibrium constant is
called the dissociation constant or ionization constant and
the formula is ;
Product of conc. of ions
Ionization constant = ----------------------------------------
Conc. of undissociated
molecules
11
 Ionization of water
• Based on chemical equilibrium, the ionization of water and its equilibrium constant
can be written as
H2O+H2O = H3O+ + OH-
K= [H3O+][OH-] / [H2O]2
• Here because the concentration of hydronium and hydroxide ions are much smaller
than the concentration of water, [H2O] is essentially a constant. The equilibrium
constant for ionization of water is defined as K w, according to following equation
Kw= [H3O+][OH-] = 1 x 10-14
• In pure water, Kw is 1.008 x 10-14 at 25 ◦C and hydronium ion and hydroxyl ion
concentrations are equal and have a value of 10 -7 M.
 pH and Indicators
• In 1909, Sorenson introduced a logarithmic scale through which
the concentration of hydronium ion was expressed using the term pH
defined as “positive number of the power when concentration is
expressed in base 10” that is
pH = -log [H3O+]
• In a similar fashion, concentration of hydroxide ions and the
constant Kw can be defined as pOH and pKw in that
pOH = -log [OH-]
pKw = -log Kw
• With these designations, the equilibrium of water can be written as
pKw = pH + pOH =14
• The pH of a solution can be considered in terms of a
numeric scale having values from 0 to 14, which expresses
in a quantitative way the degree of acidity (7 to 0) and
alkalinity (7–14).
• The value 7 at which the hydrogen and hydroxyl ion
concentrations are about equal at room temperature is
referred to as the neutral point, or neutrality.
pKw = pKa + pKb
• The pK values of weak acidic and basic drugs are ordinarily
determined by ultraviolet spectrophometry and
potentiometric titration. They can also be obtained by
solubility analysis and by a partition coefficient method
Basic
14>pH>7

Neutral
pH=7

Acidic
1<pH<7
 pKa concepts
• Ionization is the complete separation of the ions in a crystal lattice when
the salt is dissolved.
• Dissociation is the separation of the ions of an electrovalent compound as
a result of the action of a solvent (usually water)
• Most drugs are weak acids or bases and are present in solution as both the
non-ionized and ionized forms.
• The extent of ionization depends on the pKa of the drug and the pH of the
medium.
• The ionized form is more polar , and therefore more water soluble, than
the nonionized form and is excreted faster.
• The non-ionized molecules being lipid soluble diffuse across the cell
membrane and is better absorbed.
The Henderson-Hasselbalch equation

• The Henderson-Hasselbalch equation describes the relation between the ionized and the
nonionized forms of a drug as a function of pH and pKa.
• When the pH of the medium equals the pKa of the drug, 50% of the drug in solution is nonionized
and 50% is ionized, as can be shown from the following equations:
• (1) For weak acids:

• (2) For weak bases:

• When pH = pKa, the charged and uncharged species have
equal concentrations.
• When pH > pKa, the un-ionized form is dominant (weakly
basic drugs)
• When pH < pKa, the un-ionized, uncharged form is
dominant (weakly acidic drugs)

• Weakly acidic drugs are less ionized in acid media than in alkaline media.
• When the pKa of an acidic drug is greater than the pH of the medium in
which it exists, it will be > 50% in its nonionized (molecular ) form and thus
more likely to cross lipid cellular membranes.
• Weakly basic drugs are less ionized in alkaline media than in acid media.
• When the pKa of a basic drug is less than the pH of the medium in which it
exists, it will be > 50% in its nonionized (molecular ) form and thus more
likely to cross lipid cellular membranes.
• The ratio of nonionized and ionized fractions of a drug is thus influenced by
pH of the medium thereby affecting its absorption and excretion through
process of passive diffusion.
• In the stomach weak acids e.g. aspirin, phenobarbitone will be mostly
nonionized hence lipid soluble and would be better absorbed than from the
alkaline medium of the intestine.
• On the other hand weak bases e.g. quinidine, ephedrine, would be highly
ionized in the stomach and therefore, poorly absorbed from the stomach but
would be better absorbed from the intestine with alkaline medium.
• In the kidneys a weak acid is ionized by making the urine alkaline,
therefore, its tubular reabsorption is decreased and its excretion in urine is
increased.
• Similarly a weak base is ionized by making the urine acidic and its excretion
is increased through decrease in tubular reabsorption.
 Applications of the Henderson-
Hasselbalch equation
• The equation allows
1. Preparation of drug solution at a desired pH because pH
maintains drug’s solubility and stability.
2. Determination of pKa of an acid or base.
3. Helps in prediction of dominating form of drug (ionized or non-
ionized) to get desirable effects (better absorption or better
excretion).
20
 Determination of pH values

• pH can be determined by
1. Colorimetric method:
• The colorimetric method is less expensive. Several indicators are
used for this purpose that show a specific colour with respect to a
specific pH.
2. Electrometric method
• In this method, indicator electrodes are used to determine pH. Glass
electrode is more common.
1-pH Indicators /colorimetric method

• Chemical indicators are typically

compounds with chromophores that can
be detected in the visible range and
change color in response to a solution’s
pH.
• Indicators may be considered as weak
acids or weak bases that act like buffers
and also exhibit color changes as their
degree of dissociation varies with pH.
• HIn is the un-ionized form of the indicator, which gives the
acid color, and In− is the ionized form, which produces the
basic color. KIn is referred to as the indicator constant.
• If an acid is added to a solution of the indicator, the hydrogen ion
concentration term on the right-hand side of equation is increased, and
the ionization is repressed by the common ion effect. The indicator is
then predominantly in the form of HIn, the acid color.
• If base is added, [H3O+] is reduced by reaction of the acid with the
base, reaction proceeds to the right, yielding more ionized indicator
In−, and the base color predominates. Thus, the color of an indicator is
a function of the pH of the solution. A number of indicators with their
useful pH ranges are listed below.
• Choosing the correct indicator for an acid-base titration
1. For titrations of strong acids and strong bases (and vice versa),
any indicator with a pKin between 4 and 10 will do
2. For the titration of a weak acid, the pH at the equivalence point
is greater than 7, and an indicator such as phenolphthalein or
thymol blue, with pKin > 7, should be used
3. For the titration of a weak base, where the pH at the
equivalence point is less than 7, an indicator such as methyl red
or bromcresol blue, with pKin < 7, should be used.
 Range and Color Changes of Some Common Acid-Base
Indicators

pH Scale
1 2 3 4 5 6 7 8 9 10 11 12 13 14
Indicators

Methyl orange red 3.1 – 4.4 yellow

Methyl red red 4.4 6.2 yellow

Bromthymol blue yellow 6.2 7.6 blue

Neutral red red 6.8 8.0 yellow

Phenolphthalein colorless 8.0 10.0 red colorless beyond 13.0

 Universal Indicator
• Most chemicals used as indicators respond only to a narrow pH
range.
• A universal indicator is a pH indicator made of a solution of
several compounds that exhibits several smooth colour changes
over a wide range pH values to indicate the acidity or alkalinity
of solutions.
• A universal indicator is usually composed of water, 1-Propanol,
phenolphthalein sodium salt, sodium hydroxide, methyl red,
bromothymol blue monosodium salt, and thymol blue
monosodium salt.
• These universal indicators are available as liquids or test papers.
Litmus Paper
 pH Paper
pH 0 1 2 3 4 5 6

pH 7 8 9 10 11 12 13
 2-pH meter /Electrometric method
• The pH is measured by measuring EMF.
• To measure pH, the bulb of glass
electrode and a suitable reference
electrode is immersed in a sample
solution, connected to a pH meter and
pH is read from the meter.
• Thereference electrode has a constant
potential irrespective of the pH.
• Several standard solutions are available
for calibration of pH meters. The most
popular is 0.05 M potassium hydrogen
phthalate solution.
 Significance of pH in pharmacy

1. Glass is used for storage of medicines but it imparts alkalinity to the products. Special glass
types are available for making containers of pharmaceutical preparations that comply with
tests which limit the alkalinity to acceptable proportions.
2. Precipitation of drugs can occur if pH is changed significantly e.g., sodium benzoate or
salicylate will deposit benzoic acid or salicylic acid when pH changes.
3. The pH of proteins drugs is also important e.g., insulin precipitates from aqueous solutions at
pH 5-6.
4. Biological activities of medicaments are also pH dependent since ionized and unionized forms
have different activities. Unionized can penetrate cell membranes more readily than ions e.g.,
increased antimicrobial activity of benzoic acid at acidic pH.
5. Enzymes have maximum activity and stability at a specific pH and they may be inactive or
destroyed by pH change beyond the limit.
6. Many compounds are unstable in aqueous solutions due to hydrolysis. So they are stabilized
by adjusting pH.
 Buffers
• Buffers are compounds or mixtures of compounds that, by their
presence in solution, resist changes in pH upon the addition of
small quantities of acid or alkali or on dilution with a solvent.
• Most of the buffers consist of a mixture of a weak acid and one
of its salt or a weak base and one of its salt.
• The resistance to a change in pH upon addition of an acid or a
base is known as buffer action.
• The expression
pH = pKa + log [salt]
[acid]
is buffer equation or the Henderson Hasselbalch equation for a
weak acid and its salt.
• Itis used in preparation of buffered pharmaceutical solutions
suitable for pH range 4-10.
 Buffer capacity

• The magnitude of the resistance of a buffer to pH changes upon the addition

of a strong acid, a strong base, or other agents that tend to alter the
hydrogen ion concentration is referred to as the buffer capacity, β. It is also
known as buffer efficiency, buffer index, buffer coefficient and buffer
value.
• It is the ratio of the increment of strong base (or acid) to the small change in
pH brought about by this addition.
• It is given by the formula

• ∆B is the small increment in gram equivalents (g Eq)/liter of strong base

added to the buffer solution to produce a pH change of ∆pH.
 BUFFERS IN PHARMACEUTICAL
AND BIOLOGIC SYSTEMS

• In Vivo Biologic Buffer Systems:

1. Blood is maintained at a pH of about 7.4 by the so-called primary
buffers in the plasma and the secondary buffers in the erythrocytes.
The plasma contains carbonic acid/bicarbonate and acid/alkali
sodium salts of phosphoric acid as buffers. Plasma proteins, which
behave as acids in blood, can combine with bases and so act as
buffers. In the erythrocytes, the two buffer systems consist of
hemoglobin/oxyhemoglobin and acid/alkali potassium salts of
phosphoric acid.
2. Lacrimal fluid, or tears, have been found to have a great
degree of buffer capacity, allowing a dilution of 1:15 with
neutral distilled water before an alteration of pH is noticed.
The pH of tears is about 7.4, with a range of 7 to 8 or slightly
higher. It is generally thought that eye drops within a pH
range of 4 to 10 will not harm the cornea. However, discomfort
and a flow of tears will occur below pH 6.6 and above pH 9.0.
3. Urine:The 24-hr urine collection of a normal adult has a pH
averaging about 6.0 units; it may be as low as 4.5 or as high
as 7.8. When the pH of the urine is below normal values,
hydrogen ions are excreted by the kidneys. Conversely, when
the urine is above pH 7.4, hydrogen ions are retained by
action of the kidneys in order to return the pH to its normal
range of values.
 Pharmaceutical Buffers

• Buffer solutions are used frequently in pharmaceutical practice,

particularly in the formulation of ophthalmic solutions.
• They also find application in the analytical procedures and pH
calibrations ,dissolution testing of solid dosage forms, preparations
of isotonic solutions and establishment of solubility and stability
monographs of drugs and dosage, colorimetric determination of pH
and for research studies in which pH must be held constant.
1. Buffers like sodium bicarbonate, magnesium carbonate and sodium
citrate are used in tablet formation to reduce gastric irritation.
2. Most of ophthalmic drugs are weakly acidic or basic. At low pH they
dissociate and remain stable but exert low therapeutic effect since
undissociated form is able to penetrate the lipid membrane so
buffers are added to adjust pH in the range which is suitable for
stability, solubility and eye comfort. These agents are borate,
phosphate or carbonate buffers. These preparations are also made
isotonic with ophthalmic fluids.
3. In parenteral preparations, pH is also maintained since high pH
(above 9) will cause tissue necrosis while low pH (below 3) results in
extreme pain at the site of injection. The ideal pH is 7.4 (that of
blood). Acetate, phosphate, citrate buffers are used in parenterals.
4. Creams and ointments during storage undergo pH change that
affects drug stability so buffers are added like citric acid and its salts.
 BUFFERED ISOTONIC SOLUTIONS

• In addition to carrying out pH adjustment, pharmaceutical solutions that

are meant for application to delicate membranes of the body should also be
adjusted to approximately the same osmotic pressure as that of the body
fluids.
• Isotonic solutions cause no swelling or contraction of the tissues with which
they come in contact and produce no discomfort when instilled in the eye,
nasal tract, blood, or other body tissues.
• Isotonic sodium chloride is a familiar pharmaceutical example of such a
preparation.
• For example, if a small quantity of blood, defibrinated to prevent clotting, is
mixed with a solution containing 0.9 g of NaCl per 100 mL, the cells retain
their normal size. The solution has essentially the same salt concentration
and hence the same osmotic pressure as the red blood cell contents and is
said to be isotonic with blood.
• In hypertonic solution, outward passage of water causes the cells to shrink
and become wrinkled or crenated.
• Finally, if the blood is mixed with hypotonic solution, water enters the
blood cells, causing them to swell and finally burst, with the liberation of
hemoglobin. This phenomenon is known as hemolysis.
METHODS OF ADJUSTING TONICITY AND pH

• One of several methods can be used to calculate the quantity of

sodium chloride, dextrose, and other substances that may
be added to solutions of drugs to render them isotonic.
• In these methods, sodium chloride or some other substance is
added to the solution of the drug to lower the freezing point of
the solution to −0.52◦C and thus make it isotonic with body
fluids. Under this class are included the cryoscopic method
and the sodium chloride equivalent method.
 1-Cryoscopic Method

• Isotonic solutions can be made in terms of data relating to

colligative properties of solutions.
• Freezing point depression is easily used for adjusting tonicity.
• The freezing point of human blood and lacrimal fluid is
-0.52◦C. This temperature corresponds to freezing point of
0.9% sodium chloride solution which is considered to be
isotonic with blood and lacrimal fluids.
• In this method, an amount of tonicity adjuster (NaCl) is added
to drug solution such that final freezing point lowering is that
of blood or serum (-0.52 ◦C ).
 2-Sodium chloride equivalent method

• The Sodium Chloride Equivalent (E value) of a drug is the amount of

sodium chloride which has the same osmotic effect as 1 gram of the
drug.
• Calculations for determining the amount of sodium chloride
or other inert substance to render a solution isotonic
involve multiplying the quantity of each drug in the prescription by its
sodium chloride equivalent and subtracting this value from the
concentration of sodium chloride that is isotonic with body
fluids, namely, 0.9 g/100 mL
• Most medicinal salts approximate the dissociation of NaCl.
• If the number of ions is known so:
1. Nonelectrolytes and substances of slight dissociation i =1
2. Substances that dissociate into 2 ions i = 1.8
3. Substances that dissociate into 3 ions i = 2.6
4. Substances that dissociate into 4 ions i = 3.4
5. Substances that dissociate into 5 ions i = 4.2

Mwt of NaCl i factor of subs tan ce

  Sodium Chloride equivalent
i factor of NaCl Mwt ofsubs tan ce
 Applications of tonicity
1. Istonic ophthalmic solutions are better tolerated by patients than hypo or hyper
tonic solutions. In ophthalmic drugs, tonicity is maintained to avoid irritation in
eye. Isotonic preparation duplicates tears for patient’s comfort.
2. Contact lenses must be placed in isotonic solution during storage to avoid dryness
or burning sensation in the eye.
3. Injections that are not isotonic should be administered slowly and in small
amount to minimize tissue irritation, pain and cell fluid imbalance. Large volume
parenterals in hypertonic conc. will lead to loss of water and electrolytes,
dehydration and coma while in hypotonic form, swelling of RBCs and hemolysis will
occur.
4. When parenterals are formulated, tonicity of hypotonic solutions is adjusted by
adding dextrose or sodium chloride which is also applied for TPN.
 References

1. Bentley’s Textbook of Pharmaceutics by Sanjay K. Jain.

2. Basic Physical Pharmacy by Joseph K. H. Ma and Boka W.
Hadzija.
3. Remington: Essentials of Pharmaceutics edited by Linda Felton.
4. Martin’s Physical Pharmacy and Pharmaceutical Sciences 6 th ed.
5. Physical Pharmacy by S.P. Agarwal and Rajesh Khanna.
6. Theory and practice of Physical Pharmacy by Gaurav Kumar Jain.