COMPLEXOMETRY

Pharmaceutical Analysis for Liquid and Semisolid Preparation

2015

DEFINITION
TITRIMETRIC METHODS THAT ARE
BASED UPON COMPLEX FORMATION
REACTIONS

Application :
1)Calcium determination in food using EDTA titration
2)Water hardness (Ca, Mg)
3) Ca or Al content of drugs such as calcium pantothenate or
alumina.
4) Metal content in every kind of matrix

Typical kit for testing for water hardness

in household water.

Terms in Complex-Formation Reaction

Ligand : an ion or molecule that forms a covalent

bond with a cation by donating a pair of electron,
which are then shared by the ligand and the
cation
Coordination number : number of covalent bonds
it tends to form with electron donor species
Complex : compound formed when metal ion
combines with a molecule which can donate
electron
Chelate : cyclic complex formed when a cation is
bonded by two or more donor groups contained
in single ligand

Complexation equilibria

Complexation reactions involve a metal-ion M

reacting with a ligand L to form a complex ML.
M + L ML
This is followed by:
ML + L ML2
ML2 + L ML3

and so on

These have overall formation constants

designated by the symbol n

METAL-CHELATE COMPLEXES
Synthetic Aminocarboxylic Acid Chelating
Ligands
Ethylenediaminetetraacetic acid (EDTA)
Trans-1,2-diaminocyclohexanetetraacetic acid
(DCTA)
Diethylenetriaminepentaacetic acid (DTPA)
Bis(aminoethyl)glycolether-N,N,N,Ntetraacetic acid (EGTA)
- Form 1:1 complexes with metal ions
(but not with monodentate ions like Li +, Na+,
K+)

EDTA
It is hexaprotic in the form H6Y2+

HO2CH2C

CH2CO2H

HNCH2CH2NH

HO2CH2C

CH2CO2H

CHEMISTRY AND PROPERTIES OF EDTA

Ethylenediaminetetraacetic acid, or EDTA is

an aminocarboxylic acid
EDTA is a lewis base
Has six potential binding sites (the four
carboxylate groups and the two amino groups)
The resulting metal-ligand complex, in which
EDTA forms a cage-like structure around the
metal ion is very stable
All metal-EDTA complexes have a 1:1
stoichiometrically

EDTA

Six pKa values

First four apply to carboxyl protons (COOH)
Next two apply to ammonium protons (NH +)
pKa1 = 0.0 (CO2H)
pKa3 = 2.00 (CO2H)
pKa5 = 6.13 (NH+)
(NH+)

pKa2 = 1.5 (CO2H)

pKa4 = 2.69 (CO2H)
pKa6 = 10.37

Neutral EDTA is a tetrabasic acid

H 4 Y H H 3Y

[H
]
[H
Y
]
-2
3
K a1 1.0 10
[H 4 Y]

H 3Y H H 2 Y 2

2
[H
]
[H
Y
]
-3
2
K a2 2.2 10
[H 4 Y]

H 2 Y 2 H HY 3

3
[H
]
[HY
]
-7
K a3 6.9 10
[H 4 Y]

HY H Y

4
[H
]
[Y
]
-11
K a4 5.5 10
[H 4 Y]

Disodium EDTA

Since Y4- is the ligand species in complex

formation, the complexation equilibria are
affected markedly by the pH.

H4Y has a very low solubility in water, and so that

disodium salt Na2H2Y,2H2O is used.

This salt dissociates in solution to give H2Y2-, pH of

this solution is approximately 4 to 5.

EDTA
Complexometric Titration
- Titration based on complex formation
Formation constant (stability constant)
-Equilibrium constant for complex formation (Kf)
Mn+ + Y4- MYn-4

[MY n 4 ]
Kf
[M n ][Y 4 ]

- EDTA complexes have large Kf values

- Higher for more positively charged metal ions

EDTA
- Metal-EDTA complex is unstable at very low pH
-H+ competes with metal ion for EDTA
- Metal-EDTA complex is unstable at very high pH
- OH- competes with EDTA for metal ion
- Unreactive hydroxide complexes may form
- Metal hydroxide may precipitate

Titration Curves
In most cases, a titration is performed by addition of
the titrant (EDTA) to the metal ion solution adjusted to
appropriate pH and in presence of a suitable indicator.
The break in the titration curve is dependent on:
1. The value of the formation constant.
2. The concentrations of EDTA and metal ion.
3. The pH of the solution
As for acid-base titrations, the break in the titration
curve increases as kf increases and as the
concentration of reactants is increased. The pH effect
on the break of the titration curve is such that sharper
breaks are obtained at higher pH values.
15

Example :
Ca 2 Y 4 CaY 2
[CaY 2 ]
Kf
[Ca 2 ] [Y4-]

Minimum pH for effective titrations

of various metal ions with EDTA.
16

Table of Formation Constants for EDTA Complexes

Cation

Kf

Log Kf

Ag+

2.1 x 107

7.32

Mg2+

4.9 x 108

8.69

Ca2+

5.0 x 1010

10.70

Sr2+

4.3 x 108

8.63

Ba2+

5.8 x 107

7.76

Mn2+

6.2 x 1013

13.79

Fe2+

2.1 x 1014

14.33

Co2+

2.0 x 1016

16.31

Ni2+

4.2 x 1018

18.62

Cu2+

6.3 x 1018

18.80

Zn2+

3.2 x 1016

16.50

Cd2+

2.9 x 1016

16.46

Hg2+

6.3 x 1021

21.80

Pb2+

1.1 x 1018

18.04

Al3+

1.3 x 1016

16.13

Fe3+

1.3 x 1025

25.1

V3+

7.9 x 1025

25.9

Th4+

1.6 x 1025

23.2

Titrations
EDTA solution

Sample + indicator+buffer

Detection of the end point

Using indicator

Example indicator : EBT (eriochrome black T)

contains three ionizable protons.
can be used for the titration of Mg 2+ with EDTA.
a small amount of indicator is added to the sample solution and it forms a red
complex with part of the Mg 2+; the color of the uncomplexed indicator is blue.
as soon as all the free Mg 2+ is titrated, the EDTA displaces the indicator from
magnesium, causing a change in the color from red to blue.
MgIn+ HIn
red
blue

+ H2Y22+ H

MgY

2-

colorless

colorless

The metal indicator complex must be less stable than

that of the metal-EDTA complex, or else the EDTA will
not displace it from the metal
The metal indicator complex must not be too weak, or
the EDTA will start replacing it at the beginning of the
titration
The metal-indicator complex should be 10-100 times
less -stable than the metal-titrant complex

Metal Ion Indicators

Metal ion indicators are compounds whose color changes when they
bind to a metal ion. Useful indicators must bind metal less strongly than
EDTA does.
A typical titration is illustrated by the reaction of Mg2+ with EDTA, using
Eriochrome black T as the indicator.
MgIn
(red)

EDTA

MgEDTA

(colorless)

+ In

(colorless)

(blue)

Structure and molecular model of Eriochrome Black T(left) and

Calmagite (right).

most indicator for complexation titration are organic

dyes, form stable complexes with metal ions
Most of these dyes (metalochromic indicators) are
weak acids or weak bases
Conditional formation constant for metal-indicator
depends on pH

EDTA Titration Techniques

Direct titration: analyte is titrated with

standard EDTA.
Back titration: a known excess of EDTA is
added to the analyte.
Displacement titration: For metal ions that
do not have a satisfactory indicator.

Techniques of EDTA Titration

Direct titration
the solution containing the metal ion to be determined is buffered
to the desired pH and titrated directly with the standard EDTA
solution. It may be necessary to prevent precipitation of the
hydroxide of the metal by addition of some auxiliary complexing
agent, such as tartrate or citrate or triethanolamine

 Back titration
many metals cannot be titrated directly; thus they
may precipitate from the solution in the pH range
necessary for the titration or they may form inert
complexes, or a suitable metal indicator is not
available. In such cases an excess of standard EDTA
solution is added, the resulting solution is buffered to
the desired pH and the excess of the EDTA is back
titrated with a standard metal ion solution; a solution
of zinc chloride or sulphate or of magnesium chloride
or sulphate is often used for this purpose. The end
point is detected with the aid of the metal indicator
which responds to the zinc or magnesium ions
introduced in the back titration

 Replacement or substitution titration

May be used for metal that do not react (react unsatisfactory) with metal indicator, or for
metal ion which form EDTA complexes that are more stable than those of other metals
such as magnesium and calcium.
Example :
In titration of calcium. In the direct titration of calcium ions, solochrome black gives poor
end poin; if magnesium is present, it is displaces from its EDTA complex by calcium and
improved end point results

Effect of other compound on complexes

There is excess EDTA, and

vitually all the metal ion is in the
form Myn-4
There is exactly as much EDTA as
metal in the solution. [Mn+ ] =
[EDTA]
In this region, there is excess Mn+
left in solution after the EDTA has
been consumed.

Three regions in an EDTA titration illustrated for reaction of 50.0mL of 0.050

0M Mn+ with 0.050 0M EDTA, assuming Kf = 1.15 1016.

Laboratory Modul

Ion Pb2+ = Pb-asetat . C4H6O4 .Pb.3H2O

400 mg zat tambahkan 100 mL aquadest, 3 mL
asam asetat Pekat (32%), setelah larut
tambahkan 1 gram heksamin, 0,4 mL indikator
jingga xylenol, titrasi dengan komplekson III
0,05 M sampai warna kuning.
HgCl2
300 400 mg zat, larutkan dalam 100 mL
aquadest tambahkan 40 mL komplekson III 0,05
M tambahkan 5 mL buffer salmiak, indikator
EBT titrasi dengan ZnSO4/ZnCl2 0,05 M. (Becket)

Home Works

1. Derive the titration curve for 30 mL of

0,015 M Fe2+ with 0,03 M EDTA in a solution
buffered to pH 7,0. Calculate pFe values
after the addition of 0 ; 10 ; 15 and 25 mL
of titrant. KMY value for Fe-EDTA 2,1 x 1012
and Y4- for pH 7 = 4,8 x 10-4

Home Works
2. Calculate the concentration of Mg 2+ in a solution
prepared by mixing 100 mL of 0,03 M Mg 2+ with
100 mL of 0,05 M EDTA. The mixture is buffer to
a pH of 3.
4 at pH 3 = 2,5 x 10-4. KMg-Y4- = 4,9x 108