Pharmaceutical Analytical

Chemistry

Lecture -3

Dr. Mohammed Abbas HAmidaddin.

 Main Topics
 Introduction to analytical chemistry
 Theories of acids and bases.
 Acid-base equilibrium in water.
 pH of acid, base, and salt solution.
 Buffer solutions: definition, types & importance in pharmacy.
 Neutralization indicators: colour, turbidity, & fluorescence.
 Neutralization titration curves: definition, types, & importance.
 Acid-base titrations in non-aqueous medium.
 Introduction
 Analytical chemistry is the branch of chemistry that deals with the
separation, identification and determination of components in a
sample.

 It also traditionally includes coverage of chemical equilibrium and

statistical treatment of data.

 Analytical chemistry plays an important role in all aspects (agricultural,

clinical, environmental, forensic, manufacturing, and pharmaceutical).

3
Analytical chemistry can be classified into two general areas of analysis:

 Qualitative Analysis
Attempting to identify what materials are present in a sample.

 Quantitative Analysis
Determining how much of a material is present in a sample.

4
 Common Analytical Techniques

Quantitative Qualitative

Volumetric Gravimetric Instrumental Organic Inorganic

analysis analysis analysis analysis analysis

Acid-base
titrations

Precipitation Anions
titrations

Complexometric
Cations
titrations

Redox titrations
 Volumetric Analysis (Titrations)

 Titration, also known as titrimetry, is a common laboratory

method of quantitative chemical analysis that is used to
determine the unknown concentration of an
identified analyte.

 Since volume measurements play a key role in titration, it is

also known as volumetric analysis. A reagent, called
the titrant or titrator is prepared as a standard solution.

 A known concentration and volume of titrant reacts with a

solution of analyte or titrand to determine concentration of
analyte.

 The volume of titrant reacted is called titre.

 Volumetric Analysis (Titrations)

 A typical titration begins with a beaker or flask containing a very precise

volume of the analyte and a small amount of indicator placed
underneath a calibrated burette containing the titrant.

 The process involves the determination of the volume of a

solution of known concentration (standard solution) which is
required to react quantitatively with the solution of the
substance being determined, reflecting arrival at the endpoint of
the titration.
 Depending on the endpoint desired, single drops or less than a single drop of the
titrant can make the difference between a permanent and temporary change in
the indicator.

 When the endpoint of the reaction is reached, the volume of reactant consumed is
measured and used to calculate the concentration of analyte by: C a= Ct * V t /
Va where Ca and Ct are conc. of analyte and titrant respectively and V a and V t
are vol. of analyte and titrant respectively .

 Reactions involved in titrations include: acid-base, precipitation, complexation

and oxidation-reduction (redox) reactions

8
 ACID-BASE TITRATIONS
Reference:
Gary D. Christian, Analytical Chemistry, 7th edition.
 Theories of Acids and Bases
1. Arrhenious Theory

+ +
An acid is a substance that produces H in water (H3O )

-
A base is a substance that produces OH in water

Arrhenius theory is limited to water solvent only

10
 Acid-Base Theories
2. Brönsted-Lowry Theory
An acid is the substance, which produces or donates H+.
Acid  Proton + Conjugate base
HCl  H+ + Cl—
H2O  H+ + OH—
A base is the substance, which accept H+
NH3 + H+  NH4+
The solvent in this theory, is involved in the reaction as acid or base,
Examples:
HCl + H2O  H3O+ + Cl—
NH3 + H2O  NH4+ + OH—
11
 Acid-Base Theories
3. Lewis Theory
 Acid is the substance that accepts an electron Pair.

 A base is the substance that accepts to share this electronic pair (e.g. N,
O, S, P). eg. HCl + :NH3  NH4+ + Cl—
 Acid-Base Theories
 Lewis Theory is the most convenient theory for explanation the acidity
and alkalinity of compounds that do not contain H + or OH - group

Neutralization is the formation of a co-ordinate bond between acid

and base.

Compounds with no OH- are alkaline (NH3):

HCl + :NH3  NH4+ + Cl—

Compounds with no H+ are acids (BCl3):

BCl3 + :NEt3  Cl3B NEt3

13
Pharmaceutical Analytical
Chemistry

Lecture -4
pH of Acids, Bases and Salts
Dr. Mohammed Abbas HAmidaddin.
 Acid-Base Equilibria in Water

Strong Weak
HCl CH3COOH (acetic acid)
HClO4 NH3
H2SO4a C6H5OH (phenol)
HNO3 HCHO2 (formic acid)
NaOH C6H5NH2 (aniline)
CH3COONa
a The first proton is completely ionized in dilute solution, but the second

proton is partially ionized (K2

= 10−2).

15
 Acid-Base Equilibria in Water

 When an acid or base is dissolved in water, it will dissociate, or ionize.

 A strong acid or base is completely ionized.

e.g. HCl H+ + Cl- (a strong acid)
NaOH Na+ + OH- ( a strong base
 A weak acid or base is partially ionized.
Ka
 e.g. HOAC H+ + OAC—

*HOAC = Acetic acid

[H+] [OAC—]
= Ka (Ionization or dissociation constant or
[HOAC] molar equilibrium constants)
Dissociation of Water:

Kw [H+] [OH ]
H2O H+ + OH Kw =
[H2O]

Since water is slightly ionised, the value of [H2O] may be regarded as unity,
hence: [H+][OH ] = KW (ionic product of water = 1 1014 at 25 °C).
In pure water, [H+] = [OH ] = 1  10 7

[H+] > [OH ] [H+] = [OH ] [H+] < [OH ]

Solution Acidic Neutral Alkaline

pH <7 7 >7
pH Scale 0 7 14
Hydrogen ion exponent ―pH‖
pH = —log [H+] pOH = —log [OH ] [H+][OH ] = KW = 1014 pKw = —log Kw = 14
pH + pOH = 14
Solution pH [H+] mole/L [OH ] mole/L

Acid 0 1.0 0.00000000000001

1.0 0.1 0.0000000000001
2.0 0.01 0.000000000001
3.0 0.001 0.00000000001
4.0 0.0001 0.0000000001
5.0 0.00001 0.000000001
6.0 0.000001 0.00000001

Neutral 7.0 0.0000001 0.0000001

Alkaline 8.0 0.00000001 0.000001

9.0 0.000000001 0.00001
10.0 0.0000000001 0.0001
11.0 0.00000000001 0.001
12.0 0.000000000001 0.01
13.0 0.0000000000001 0.1
14.0 0.00000000000001 1.0
 pH of Acids and Bases Solutions

1. pH of Strong Acid or Bases: eg. HCl, HNO 3 and NaOH , KOH

Strong acids or bases are completely dissociated, the [H+] or [OH]:

0.1 N HCl gives [H+] = 1/10 = 10—1,
pH = — log 10—1 = 1.0

0.1 N NaOH, pOH= - log 0.1 = 1

pKW = pH + pOH, 14 = pH + 1 pH =14-1 = 13

A 1.0 × 10−3 M solution of hydrochloric acid is prepared.
What is the hydroxide ion concentration?
Since hydrochloric acid is a strong electrolyte and is
completely ionized, the H+ concentration is 1.0 × 10−3 M.
Thus,
−3 − −14
(1.0 × 10 ) [OH ] = 1.0 × 10
− −11
[OH ] = 1.0 × 10 M

20
Calculate the pH of a 2.0 × 10−3 M solution of HCl.

Solution

HCl is completely ionized, so

−3
[H+] = 2.0 × 10 M
−3
pH = −log (2.0 × 10 ) = 3 − log 2.0 = 3 − 0.30 = 2.70

21
 −2
Calculate the pOH and the pH of a 5.0 × 10 M solution of
NaOH at 25 ◦C.

22
Calculate the pH of a solution prepared by mixing 2.0mL of
a strong acid solution of pH 3.00 and 3.0mL of a strong
base of pH 10.00.

−3
[H+] of acid solution = 1.0 × 10 M
−3 −3
mmol H+ = 1.0 × 10 M × 2.0 mL = 2.0 × 10 mmol
OH
p of base solution = 14.00 − 10.00 = 4.00
− −4
[OH ] = 1.0 × 10 M
− −4 −4
mmol OH = 1.0 × 10 M × 3.0 mL = 3.0 × 10 mmol

23
There is an excess of acid.

mmol H+ = 0.0020 − 0.0003 = 0.0017 mmol

Total Volume = (2.0 + 3.0) mL = 5.0 mL

−4
[H+] = 0.0017 mmol/5.0 mL = 3.4 × 10 M
−4
pH = −log 3.4 × 10 = 4 − 0.53 = 3.47

24
The pH of a solution is 9.67. Calculate the hydrogen
ion concentration in the solution.

Solution

−log [H+] = 9.67

−9.67 −10 0.33

[H+] = 10 = 10 × 10

[H+] = 2.1 × 10−10 M

25
 pH of Acids and Bases Solutions

2. pH of Weak Acids: (Acetic acid)

Ka
HOAC H+ + OAC
Ka = [H+] [OAC ] / [HOAC]
Since [H+] = [OAC-] and the degree of dissociation is very low
Ka = [H+]2 / C ( C is total acid concentration).

[H+]2 = C  Ka [H+] = C  K a pH = ½ pC + ½ pKa

pH = 1/2 (pka – log C)

26
Calculate the pH and pOH of a 1.00 × 10−3 M solution of
acetic acid.

27
 pH of Acids and Bases Solutions

3. pH of Weak Bases: (NH4OH)

Base concentration is C .
Dissociation constant of base is Kb.

pH = pKW– ½ pC – ½ pKb

pH = pKw-1/2 (pKb-logC)

28
29
 pH of Salt Solutions

1. Salts of Strong Acids and Strong Bases (KCl, NaCl) : Neutral, pH = 7.

2. Salts of Strong Acids and Weak Bases (NH4Cl) : Acidic, pH  7.

pH = 1/2 (pkw – pKb -log Cs)

3. Salts of Weak Acids and Strong Bases (NaOAC) : Alkaline, pH  7.

CH3COONa + H2O CH3COOH + NaOH
pH = 1/2 (pkw + pKa +log Cs)
4. Salts of Weak Acids and Weak Bases : Acidic or alkaline ?. It
depends on the dissociation constant of the acid or base.
AB + H2O AH + BOH
pH = 1/2 (pkw + pKa - pKb)
31
 pH at Elevated Temperatures

A neutral solution has pH < 7 above room temperature.

Example 1:
At 100 ℃, for example, Kw = 5.5 × 10−13, and a neutral solution has
[H+] = [OH−] = 5.5 × 10−13 = 7.4 × 10−7 M
pH = pOH = 6.13
pKw = 12.26 = pH + pOH

Example 2:
The pH of blood at body temperature (37 ◦C) is 7.35 to 7.45. This
value represents a slightly more alkaline solution relative to
neutral water than the same value would be at room
temperature. (give an explanation )
32
 213 PHC
Pharmaceutical Analytical
Chemistry

Lecture -5
Buffer Solutions
 Buffer Solutions
1. Definition: Solutions that resist change in pH, upon the addition of small
amounts of acids or alkalies or when the solution is diluted

2. Types:
- First Type : Weak acid and its salt (acetic acid and sodium acetate)
- Second Type Weak base and its salt ( ammonium hydroxide and ammonia
chloride)
3. Importance of buffer solutions
a- Control of pH of liquid formulations (syrups, pH of 2.0 – 8.0),
parenteral, (pH 4.0 – 9.0), eye drops (pH of 7.4, optimize stability,
solubility or biological compatibility of the dissolved drug).
b- The pH of blood is very well buffered ( carbonic acid + bicarbonate)
 Buffer Solutions

4. Mechanism of Buffer Action:

a. First Type of Buffer

H+ + OAC HOAC

OH + HOAC OAC + H2O

b. Second Type of Buffer

H+ + NH4OH NH4+ + H2O

OH + NH4Cl NH4OH + Cl

 Henderson-Hasselbalch Equations for Buffer Solutions
1. For Weak Acid & its Salt (CH3COOH/CH3COONa): HA A + H +

Ka = [H+][A ]/[HA] — log Ka = — log [H+] — log [A ]/[HA]

log [A ] /[HA] — log Ka = — log [H+]

log [A ] /[HA] + pKa = pH

pH = pKa + log [A ]/[HA] [A ] = salt concentration
pH = pKa + log [salt]/[Acid] [salt]/[acid] is the buffer ratio

When [salt] = [acid], pH = pKa

2. For Weak Base & its Salt (NH4OH/NH4Cl):

pOH = pKb + log [salt] / [base] & pH = pKW – pKb – log [salt] / [base]
 Buffer Capacity
Definitions:
- Is the limit to how much acid or base can be added to a given buffer
solution before any appreciable change in pH results.

- The number of gm equivalent of strong acid or strong base required to

change the pH of 1 L of buffer solution by one pH unit.

In general, the buffer capacity is maintained within the range 1:10 to 10:1.
pH = pKa + log [salt]/[Acid], pH = pKa + log [1]/[10] = pKa -1
pH = pKa + log [salt]/[Acid], pH = pKa + log [10]/[1] = pKa +1

The approximate pH range of a weak acid buffer is: pH = pKa ± 1.

Buffers show maximum buffering action when: pH = pKa
Pharmaceutical Analytical
Chemistry

Lecture -4
Acid-Base Indicators and Titration Curves
Detection of the end point indicators: Acid-Base Indicators

Definition
Weak acid or weak base that is highly colored whose colour changes with
the change in pH.

Ostwald Theory for change of indicator’s colour

Indicators are either weak organic acids or bases, in which undissociated
molecules differ in colour from their ions.

HIn H+ + In (Acidic indicator as phenolphthalein)

InOH OH + In+ (Basic indicator as methyl orange)
Indicator Constant : eg. Acidic indicator

HIn H+ + In
Unionized ionized
(acidic) (basic colour)

KIn = [In][H+]/[HIn] [H+] = KIn [HIn]/[In ]

pH = PKIn + log [In ]/[HIn]
pH = PKIn + log [basic colour]/ [acidic colour]

When [basic colour] = [acidic colour] pH = PKIn

Middle tint of an indicator
Effective transition Range of an Indicator: pH = PKIn  1 Ratio =1:10 & 10:1

pK - 1 pK pK + 1

acidic colour %
99.99 99 91 70 60 50 40 30 9 1 0.1 0.01

0.01 1 9 30 40 50 60 70 91 99 99.9 99.99

basic colour %

U seful range

Transition interval
Is the interval during which shades of colour are produced extending between the
two coloured forms
Acid-Base Indicators

42
Indicator pH range Basic colour Acidic colour
Phthalein Indicators
Phenolphthalein 8.2 – 10.0 Colourless Pink
o-Cresolphthalein 9.3 – 10.5 Colourless Blue
Thymolphthalein 3.3 – 4.4 Red Yellow
Sulphonephthalein Indicators
Thymol blue (acid range) 1.2 – 2.8 Red Yellow
Thymol blue (basic range) 8.0 – 9.6 Yellow Blue
Bromophenol blue 3.0 – 4.6 Yellow Blue-violet
Bromophenol red 4.8 – 6.4 Yellow Red
Bromothymol blue 6.0 – 7.0 Yellow Blue
Phenol red 6.4 – 8.0 Yellow Red
Cresol red 7.2 – 8.8 Yellow Red
Azo Indicators
Methyl yellow 2.9-4.0 Yellow Red
Methyl orange 3.1-4.4 Yellow Red
Methyl red 4.2-6.2 Yellow Red
Alizarin yellow R 10.1-12.0 Violet Yellow
Universal (multi-range) indicators
 A mixture of indicators, its colour change extends over
a considerable pH range.
 Used for rough determination of pH, but not suitable
for titration.
Screened Indicators
A mixture of an indicator and a dye for more sharper colour change.

Example: methyl orange & indigo carmine

Colour changes: at pH 4.1, from green (in alkaline) to violet (in acid).

45
 Acid-Base Titration Curves

 The titration curve is a plot of pH values versus the volume of titrant.

 They are constructed to study the feasibility of the titration and to help in
choosing an indicator for the titration.
 Graphical determination of the End Point and the pH at this point.
1. Strong Acid vs Strong Base (HCl , 40 mL , 0.1 N vs NaOH, 0.1 N)

pH before addition of NaOH, During the titration (before and after the end point)
is calculated as the following:
 Before addition of any NaOH:
pH = pCa = — log [H+] = — log 0.1 = 1

 Before reaching equivalence point

(After addition of 10 mL of NaOH)
pH = pCa = — log [H+] = — log (0.1 30 / 50) = — log 0.06 = 1.22
After addition of 20 mL of NaOH
pH = pCa = — log [H+] = — log (0.1 20 / 60) = — log 0.033 = 1.48
 At the equivalence point ( After addition of 40 mL of NaOH )
pH = pOH = ½ pKW =7.0
 After the equivalence point (after addition of 50 mL NaOH):
pH = pKW – pCb = 14 – ( — log 0.110/90)
pH = 14 – ( — log 0.01) = 14 – 1.95) = 12.05
 AY

PP

PR

MR

MO

Titration Curve for Strong Acid – Strong Base (HCl – NaOH)

2. Weak Acid vs Strong Base (CH3COOH, 40 mL, 0.1 N vs NaOH, 0.1 N)
pH is calculated before addition of any NaOH, before reaching the equivalent
point, at the equivalent point after the equivalent point (pKa = 4.74)
 Before addition of any NaOH:
pH = 1/2 (pka – log C) ½ (4.74-log 0.1) = 2.87

 Before reaching equivalence point (After addition of 20 mL of NaOH

(Buffer):
pH = pKa + log [salt] / [acid] = 4.74 + log 20 /20 = 4.74 + log 1
= 4.74 + 0 = 4.74
 At the equivalence point (after addition of 40 mL of NaOH) (Salt)
pH = 1/2 (pkw + pKa +log Cs) Cs = 40/80 X 0.1 = 0.05
½(14 +4.74 + log 0.05) = 8.72
 After the equivalence point (after addition of 50 mL NaOH):
pH = pKW – pOH = 14 – (- log 0.110/90)
pH = 14 – ( — log 0.01) = 14 – 1.95) = 12.05
50
Titration Curves for Strong Acid ( – ) or Weak acid ( – ) with Strong Base
Effect of Ka on the shape of the titration curve of titration of 0.10 M weak acid

The sharpness of the end point decreases as K decreases. As in Figure 8.6, the
a

sharpness will also decrease as the concentration decreases. Generally, for titration
at significant concentrations (ca. 0.1 M), acids with K values as low as 10 can be
a −6

titrated accurately with a visual indicator.

Effect of concentration on the shape of the titration curve of titration of
weak acid
3. Weak Base vs Strong Acid (NH4 OH, 40 mL, 0.1 N vs HCl, 0.1 N)
pH of the solution before and during the course of titration (pKb = 4.74)

 Before addition of any HCl:

pH = pKw-1/2 (pKb-log C)
pH = 14 – ½ (4.74 — log 0.1) = 11.13

 Before the equivalence point (after addition of 20 mL of HCl (Buffer):

pH = pKW – pKb + log [base] / [salt] = 14 – 4.74 + log (20/20 )
pH = 9.26 + 0 = 9.26

 At the equivalence point (after addition of 40 mL of HCl ) (Salt):

pH = 1/2 (pkw – pKb -log Cs) Cs = 40/80 X 0.1 = 0.05
= ½ (14 – 4.74 – log 0.05 = 5.28

 After the equivalence point (after addition of 60 mL HCl):

pH = – log [H+] = – log (0.1 20 / 100) = 1.7
 4-7 pH
transition range

Titration Curve for Weak Base – Strong Acid (NH4 OH – NaOH)

 Titration curves for 100mL 0.1 M weak base of different Kb values versus 0.1 M HCl.
 Methyl red could not be used as an indicator in dilute solutions.
 In titrations involving significant concentrations (ca. 0.1 M), one can
accurately titrate a base with a K of 10-6 using a visual indicator.
b 56
4. Diprotic Acid (H2A) with Strong Base (NaOH)

 Diprotic acids can be titrated stepwise

 Ka1 should be at least 104 × Ka2 (why) In order to obtain good end-point breaks for
titration of the first proton.
4. Diprotic Acid (H2A) with Strong Base (NaOH)

 If Ka2 is in the required range of 10−7 to 10−8 for a successful titration, an end-
point break is obtained for titrating the second proton.
 pH at 1 st E.P. = ½ (pK1 + pK2 ) = ½ (2.12 + 7.12) = 4.66 (M.O.)
 pH at 2 st E.P. = ½ pKW + ½ pKa — ½ pCs = 9.94 (Ph.Ph.)
4. Diprotic base (Sodium carbonate) with Strong acid (HCL)

Sodium carbonate is a Brønsted base that is used as a primary

standard for the standardization of strong acids. It hydrolyzes in
two steps:

Titration curve for

50mL 0.1 M Na2CO3
versus 0.1 M HCl.
Dashed line represents
a boiled solution with
CO2 removed.
 213 PHC
Pharmaceutical Analytical
Chemistry

Lecture -5
Titrations in Non-aqueous Media
 Uses and Theory of Non-Aqueous Titrations
 Too weak bases that can not be titrated in aqueous acids.
 Weak acids, which can not be titrated in water with strong bases, can be
titrated if a basic non-aqueous solvent is used.
 Many water-insoluble acidic or basic organic compounds of analytical interest.

H+ + H2O H3O+ + NH3 H2O + NH4+

H+ + CH3COOH CH3COOH2+ + NH3 CH3COOH + NH4+

— Glacial HOAC is a much more acidic than H2O = H2O is more basic than HOAC.
— NH3 is more basic (better proton acceptor) in glacial HOAC than it is in H2O
because CH3COOH2+ is a much better proton donor than H3O+.
— A solvent that is more acidic than H2O (HOAC) will enhance the strength of weak
bases because such a solvent has a greater affinity for giving protons.
— A solvent that is more basic than H2O (pyridine, ether) will enhance the strength
of a weak acid because such solvent has a greater affinity for protons.
 Solvents for Non-Aqueous Titrations

1. Amphiprotic Solvents. Accept or donate protons (bases or acids):

water, alcohol and acetic acid with high dielectric constant.

Autoprotolysis
2 H2O H3O+
2 CH3COOH CH3COOH2+
2 CH3OH CH3OH2+

2. Protophillic Solvents. Accept protons (basic): acetone, ether and pyridine.

They behave as differentiating solvents for weak acids.

3. Protogenic Solvents. Donate protons (acidic): sulphonyl chloride.

4. Aprotic Solvents. Neither accept nor donate protons (inert): chloroform and
benzene. They act as a medium for the titrations.
 Leveling and Differentiating Effect of Solvents
Leveling effect. The inability to distinguish any difference between the strength of
two acid as perchloric and hydrochloric acids:
Both acids are much stronger acids
than H3O+ (or H2O is a stronger base HClO4 + H2O ClO4— + H3O+
than either HCIO4 or HCl). HCl + H2O Cl— + H3O+

Differentiating effect. The ability to differentiate the difference between the

strength of two acid as perchloric and hydrochloric acids:
CH3COOH2+ is a
stronger acid than H3O+ HClO4 + CH3COOH ClO4— + CH3COOH2+
(or acetic acid is a much HCl + CH3COOH Cl— + CH3COOH2+
weaker base than water).

HClO4 in acetic acid, shows a stronger acidity than HCl in acetic acid.
 Applications of Non-Aqueous Titrations

1. Determination of Bases
Titrated with HClO4 in HOAC
Crystal violet indicator: Violet  green

Sample: AR—NH2 + CH3COOH AR—NH3+ + CH3COO— (1)

Titrant: HClO4 + CH3COOH ClO4— + CH3COOH2+ (2)
Reaction: CH3COO — + CH3COOH2+ 2 CH3COOH (3)
Overall: AR—NH2 + HClO4 AR—NH3+ + ClO4— (4)
 Applications of Non-Aqueous Titrations

2. Determination of Acids (Benzoic acid)

Titrated with lithium methoxide in dimethylformamide
Thymol blue indicator: Violet  Blue

CH3 CH3
Sample: ArCOOH + HCO-N
CH3
HCO-N
CH3
+ ArCOO-
H

CH3 - CH3
Reaction: HCO-N CH3
+ CH3O HCO-N
CH3
+ CH3OH

Overall: ArCOOH + CH3OLi ArCOOLi + CH3OH