PHARMACEUTICAL ANALYTICAL CHEMISTRY I

Code No: PHCH323

Lecturer: Dr.Zeinab A. Sheribah

Course Schedule:
Lecture, Wednesday All groups , 3rd & 4th Slots

Practical, Saturday, group 2, 1st & 2nd Slots

group 1, 3rd & 4th Slots

Course

Assessment (Evaluation)

Practical course 30%

lab. reports & attendance 10%

Three practical exams. 20%

Theoretical course 70%

Quizzes

(20%) (2 quizzes).

{Announced one week in advance}

Final term exam. (50%)

Text books
Analytical

Chemistry by Gary D. Christian Publisher: Wiley.

of Analytical chemistry by Skoog /West /Holler.

Fundamental

Scheme for Analytical Chemistry. Define volumetric (titrimetric) reaction. Standard solutions, Types & preparations. Define neutralization reaction. Undergo calculations involving acid-base mixtures. Aqueous Acid Base Theories. Hydrogen exponent pH. Buffer solutions. Neutralization Indicators. Construct titration curves of strong acids with strong bases. Applications.

3

Objectives

Analytical Chemistry
Science dealing with the qualitative and quantitative analysis of substances

Quantitative analysis
deals with the determination of the quantity of substances

Qualitative analysis
deals with the identification of inorganic substances

Instrumental

Manual

Anions

Cations

Gravimetry by weighing

Volumetry by titration

Acid Base Titration

Redox Titration

Preciptimetric Titration

Complexometric Titration

Volumetric analysis
To understand volumetric analysis, we must understand the types of reaction that happen in it.

Types of reactions used in volumetric analysis : I- Ionic combination reactions:-The reaction goes to completion due to formation of slightly ionized or slightly insoluble products. a- Neutralization reaction : In which acid reacts with base to form slightly ionized water. H+ + OH- (H2O) H2O (H3O+) b- Formation of precipitate : Ag+ + ClAgCl

c- Formation of slightly ionizable complex : Ag+ + 2 CNCa+2 + H2Y-2 [EDTA] [Ag(CN)2]2H+ + CaY-2 [Ca-EDTA complex]

II- Electron transfer reactions : -In which electron transfer from one reactant to another. It is called (oxidation -reduction reactions) eg: Ce+4 + Fe+2 Ce+3 + Fe+3

i.e.

Fe+2 Ce+4 + e

Fe+3 + e Ce+3

oxidation (loss of electrons) reduction (gain of electrons)

Requirements for titrimetric reactions

The reaction must be simple and can be expressed by chemical equation.

A single reaction must occur between the desired sample and titrant. The reaction must be instantaneous. If slow it must be catalyzed.

Suitable standard solution must be available as titrant

The end point of the reaction should be easily detected either by the use of indicator which changes its color at the end point.

Standard solutions
Standard solution is a solution of exactly known concentration
Types of Standard Solutions 1-Molar solution
Molecular weight (M.wt) / liter (L) 1M e.g. 1 M NaCl (atomic wt. Na=23, Cl=35.5) = 58.5 gm NaCl in 1 litre

2- Normal solution (N)

Equivalent weigh/liter 1N Equivalent wt. of acid = mol.wt / no. of replaceable H+ Equivalent wt of base = mol.wt./ no. of replaceable OHEquivalent wt. of salt =mol.wt./no.of replaceable cations x its valance or no.of anions x its valance

3- Empirical solution

1mL of it reacts with a definite amount of the substance to be analyzed

Preparation of standard solutions

a. Direct method
Accurately weighed amount of the solute is transferred into a volumetric flask, dissolved in the solvent then completed to the required volume

b- Indirect method
Prepare solution of approximate concentration which is standardized against 1ry standard

The solute is not primary standard

The solute must be a chemical of primary standard quality.

1-They must be easily obtained in very high grade of purity and of known composition

6- They must be readily soluble in the solvent

2-They must be easily tested for impurity by simple test

Characteristics of primary standard chemicals

6- They should have high equivalent weight to minimize error due to incomplete transfer during weighing.
3-They must react with other substances quantitatively according to a balanced chemical equation. i.e. react stoichiometrically

4-They must be stable, i.e. not absorbing water or CO2

Volume consumed

Standard solution

By measuring volume of standard solution

(titrant)
complete

used

for

reaction

with the sample

Sample solution

Acid-base reactions

An acid-base reaction is often called neutralization reaction.When just enough base is added to react exactly with the acid in a solution, we say the acid has been neutralized. Performing calculations for acid-base reactions Write the balanced equation for the reaction resulting from the species present in solution. Calculate the moles of reactants. Determine the limiting reactant or product. Calculate the moles of the required reactant or product. Convert to grams or volume if required in the problem.
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Example

What volume of a 0.100M HCl solution is needed to neutralize 25.0 mLof 0.350M NaOH? HCl + NaOH NaCl + H2O The No. of moles of NaOH = MV= 25.0 x 0.350= 8.75 milli mole The No. of moles of HCl should be the same as that of NaOH and since they react in a 1:1ratio, 8.75 milli moles of HCl are required. (MV)HCl = 8.75, substitute by the HCl concentration (0.100 V) = 8.75, thus the volume of HCl = 87.5 mL
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ACID BASE Acid- Base Theories

1- Arrhenius theory :Acid : Is the substance which ionize to give H+ Base : Is the substance which ionize to give OH eg: HCl eg: NaOH

2- Brnsted - Lowry theory :Acid : Is the substance which loses or donates proton. Base : Is the substance which gains or accepts proton. Every acid has a conjugate base and the base has a conjugate acid. eg. HCl + H2 O Cl+ H3O+ Acid base conj.base conj.acid

eg.

NH3 + H2O NH4+ + OHbase acid conj.acid conj.b N.B. Water behave as acid or base because it is neutral (AMPHOTERIC).
Water as both base and acid. One H2O acts as a base and gains H+ to become H3O+; the other H2O acts as an acid and loses H+ to become OH-.

3- Lewis theory :Acid : Is a substance which accepts lone pair of electrons eg. BF3, AlCl3. Base : Is a substance which donates lone pair of electrons eg NH3, amines.

Al
Cl Cl

Cl

+ H

adduct

Lewis acid

Lewis base

Acid-Base Titration in Aqueous Medium

Solutions are classified into :Electrolytes : Which dissociate (ionize) and conduct electricity. Non electrolytes : Which doesn't ionize and doesn't conduct electricity.

Dissociation of water
H2O H+ + OHDissociation const. Kw = [ H+] [OH-] / [H2O] - Since H2O is weakly dissociated , therefore; H2O is considered unity. therefore; Kw = [H+] [OH-] = 10 -14 at 25oc Kw : it is called ionic product of water. At 25oc [H+] =[OH-] = 10-7 If [H+] = [OH-] , therefore; solution is neutral If [H+] > 10-7 eg 10-6, 10-5 , therefore; solution is acidic If [H+] < 10-7 eg 10-8, 10-9 , therefore; solution is alkaline.

Hydrogen Exponent : pH
pH = -log [H+] i.e. If [H+] = 10-7 pH = - log 10-7 = 7 In acidic side i.e. If [H+] = 10-6 pH = - log 10-6 = 6 In basic side i.e. If [H+] = 10-8 pH = - log 10-8 = 8 i.e. as pH value increase [H+] conc. decrease. Therefore; acid solution has pH less than 7 alkaline solution has pH more than7 neutral solution has pH = p OH = 7

pH of Acids and Bases

1- pH of strong acids :Since strong acids are strongly ionized. Therefore; pH = pCa where; Ca ( conc. of acid) i.e. 0.1 N HCl pH = - log 0.1= - log 10-1 = 1

2- pH of strong bases :Since strong bases are completely ionized. Therefore; pOH = pCb where; Cb (conc.of base) pH = pKw pOH i.e. pH = pKw pCb. i.e. 0.1 N NaOH pH = 14 _ 1 = 13

3- pH of weak acids :
pH = 1/2 pCa + 1/2 pKa

4- pH of weak bases :pH =pKw - 1/2 pCb - 1/2 pKb

5- pH of salts :a- Salt of strong acid and strong base eg. NaCl Always neutral i.e. pH = 7 b- Salt of strong acid and weak base eg.NH4Cl Always pH is in the acidic side , calculated from eq. pH = 1/2 pKw - 1/2 pKb + 1/2pCs where; Kb (dissociation constant of weak base) Cs (conc. of salt) c- Salt of weak acid and strong base eg. Na Ac Always pH is in the alkaline side, calculated from eq.: pH = 1/2 pKw + 1/2 pKa - 1/2pCs where; Ka (dissociation constant of weak acid) Cs (conc. of salt) d- Salt of weak acid and weak base eg. NH4Ac pH is calculated from eq. : pH = 1/2 pKw + 1/2 pKa - 1/2pKb

Buffer Solutions
-Definiton : They are solnution which resist changes in pH upon addition of small amount of acid or base. -They consist of weak acid and its salt or weak base and its salt Type 1: weak acid and its salt eg. HAc and Na Ac pH of this buffer is calculated from the eq.: pH = pKa + log [salt] / [acid]

Type 2: weak base and its salt eg. NH4OH and NH4Cl
pH of this buffer is calculated from the eq.: pH = pKw - pKb - log [salt]/[base] log [salt]/[acid] or log [salt/base] is called buffer ratio if [salt] = [acid] therefore; pH =pKa Examples 1- Calculate the pH of a buffer solution containing 0.1 M acetic acid and 0.1 M sodium acetate pKa =4.76 solution. pH = pKa + log [salt] / [acid] pH = 4.76 + log 0.1 / 0.1 = 4.76

Neutralization Indicators
Color indicators:
- Substance which change their color with change in pH are used as neutralization indicators. eg. Phenolphthalein ph.ph" (one color indicator), methyl orange "M.O" (2 color indicator) eg. ph.ph. = 8-10 M.O. = 3.3-4.4 M.R. = 4-6 N.B. the indicator is chosen according to pH of the product.

Titrations and pH curves

A titration is commonly used to determine the amount of acid or base in a solution.

This process involves solution of known concentration (the titrant) delivered from a burette into the unknown solution until the substance being analyzed is just consumed. The stoichiometric (equivalence point) is often signaled by the color change of the indicator.

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Titrations and pH curves (cont.)

In this section, we will discuss the changes that occur in pH during an acid base titration.

The progress of an acid-base titration is often monitored by plotting the pH of the solution being analyzed as a function of the amount of titrant added. Such a plot is called a pH curve or a titration curve.
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Neutralization Titration Curves

For neutralization reaction. The titration curve is plot of pH versus the mL of titrant.

Types of neutralization curves:

1- Strong acid -strong base titration :eg. HCl and NaOH we have sample of 100 mL HCl and titrate against NaOH.
a.Before the titration pH is due to the sample i.e. HCl (strong acid) Therefore; pH = pCa b. At the equivalence point :

HCl +NaOH NaCl + H2O pH is due to NaCl i.e. pH= 7 (salt of strong acid and strong base) c. After the equivalence point : pH is due to excess titrant i.e. NaOH (strong base) pH = pKw-pCb N.B. The pH rises slowly till 99.9 % of acid is titrated by adding 0.1 mL NaOH, pH rises from 4 to 7 then another 0.1 mL after equivalence point pH rises from 7 to 10 i.e. at equivalence point pH rises from 4 to 10. So we can use M.O.(3.3 - 4.4), M.R.(4 - 6), and ph.ph.(8 - 10) indicators

2- Weak acid - Strong base titration :eg. CH3COOH (pKa = 4.74) and NaOH We have sample of 100 mL 0.1 N HAc and titrate against 0.1 N NaOH a.Before the titration pH is due to the sample i.e. HAc (weak acid) Therefore; pH = 1/2pKa + 1/2 pCa = 2.37 + 0.5 = 2.87 b. During titration: eg. after adding 40 mL NaOH HAc + NaOH NaAc + H2O HAc will be present ( not completely neutralized) and NaAc i.e. weak acid and its salt. (acidic buffer) Therefore; pH is calculated from pH = pKa + log [salt]/ [acid] = 4.74 + log 40/60 = 4.53 c. At the equivalence point : all HAc is neutralized and only NaAc is present i.e.(salt of weak acid and strong base) Therefore; pH is calculated from: pH = 1/2 pKw + 1/2 pKa -1/2 pCs =7 + 2.37 -1/2 (- log 100 x 0.1 /200) = 8.72 d- After equivalence point the pH is calculated from excess titrant i.e. NaOH (strong base). N.B. The end point is at the alkaline side and abrupt change in the curve is from pH 7 to pH 11. i.e. M.O and M.R. indicator are not suitable. Therefore; use ph.ph. indicator or any other of pH range on the alkaline side.

3- Strong acid - weak base titration :eg. NH4OH (pKb = 4.74)and HCl We have sample 100 mL 0.1 N NH4OH and titrate against 0.1 NHCl a. Before titration: pH is due to the sample i.e. NH4OH (weak base) Therefore; pH is calculated from eq. of. pH = pKw - 1/2 pKb -1/2 pCb = 14 2.37 - 0.5 =11.13 b. During titration: eg. After adding 90 mL HCl NH4 OH + HCl NH4Cl + H2O NH4OH will be present(not completely neutralized) and NH4Cl i.e. weak base and its salt.(basic buffer) Therefore; pH is calculated from: pH = pKw -pKb - log [salt]/ [base] = 14 - 4.74 - log 90/10 = 8.31 c. At the equivalence point: all NH4OH is neutralized and NH4Cl is only present i.e.( salt of strong acid and weak base) Therefore; pH is calculated from : pH = 1/2 pKw- 1/2 pKb + 1/2 pCs =7 - 2.37 + 1/2 (- log 100 x 0.1 /200) = 5.13 d. After the equi.point: the pH is calculated from excess titrant i.e. HCl N.B. The end point is at the acidic side = 5.13 .The abrupt change is From pH 6 to 4 , i.e. ph.ph. indicator cannot be used. Therefore; use M.O. or M.R. or any indicator of pH range at acidic side.

Strong Acid- Strong Base titrations

The net ionic reaction for a strong acid-strong base titration is H+(aq) + OH-(aq) H2O(l)
To compute [H+] at a given point in the titration, we must determine the amount of H+ that remains at that point and divide by the total volume of solution.

Since titrations usually involve small quantities (burettes are graduated in milliliters) we are going to use the mmoles = volume (in mL) X molarity.

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CASE STUDY: Consider the titration of 50.0 mL of 0.2M HNO3 with 0.1M NaOH. We will calculate the pH of the solution at selected points during the course of the titration, where specific volumes of 0.1M NaOH have been added. A. No NaOH has been added. Since HNO3 is a strong acid, the major species are H+, NO3- and H2O [H+] = 0.2 M and pH = 0.669

B. 10.0 mL of 0.1M NaOH has been added. H+ + OHH2O Before reaction 50.0x0.2 10x0.1 = 10.0 mmol =1.0 mmol After reaction 10.0-1.0 1.0-1.0 =9.0 mmol =0 After reaction, [H+] = mmol of H+ left/ volume of solution mL = 9.0/ (50.0+10.0) = 0.15 M pH = - log (0.15) = 0.82
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(cont.)

C. 20 mL (total) of 0.1 M NaOH has been added. H+ + OHH2O Before reaction 50.0x0.2 20x0.1 = 10.0 mmol =2.0 mmol After reaction 10.0-2.0 2.0-2.0 =8.0 mmol =0 After reaction, [H+] = mmol of H+ left/volume of solution mL = 8.0/ (50.0+20.0) = 0.11 M pH = - log (0.11) = 0.942

D. 50.0 mL (total) of 0.1M NaOH has been added. Proceeding exactly as for point B and C, the pH is found to be 1.301

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(cont.)

E. 100.0 mL (total) of 0.1M NaOH has been added.

At this point the amount of NaOH that has been added is 100mL x 0.1M = 10.0 mmol. The original amount of nitric acid was 50.0 mL x 0.2M = 10.0 mmol Enough OH- has been added to react exactly with the H+ from the nitric acid. This is the stoichiometric point or equivalence point, of the titration.
At that point, the major species are Na+, NO3and H2O, since Na+ has no acid or base properties and NO3- is the anion of strong acid and therefore is a very weak base, neither NO3- nor Na+ affects the pH and the solution is neutral. (The pH is 7.0)
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(cont.)

F. 150 mL (total) of 0.1m NaOH has been added

H+ + OH= 10.0 mmol H2O

Before reaction 50.0x0.2 After reaction After reaction, 10.0-10.0

= 0 mmol

150x0.1
=15.0 mmol

15.0-10.0
= 5.0(excess OH- added)

[OH-]= mmol of OH- excess/volume of solution mL = 5.0/ (50.0+150.0) = 0.025 M [H+] = 1.0x10-14/2.5x10-2 = 4.0x10-13M pH = 12.40

G. 200.0 mL (total) of 0.1 M NaOH has been added Proceeding as for point F, the pH is found to be 12.60
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(cont.)

The results of the previous steps are summarized by the pH curve shown in fig.
Note that the pH changes very gradually until the titration is close to the equivalence point, where a dramatic change occurs. This behavior is due to the fact that early in the titration, there is relatively a large amount of H+ in the solution, and the addition of a given amount of OH- thus produces a small change in pH. However, near the equivalence point [H+] is relatively small and the addition of a small amount of OH- produces a large change.
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1- Direct titration methods

Direct titration is useful for :A- Strong acid B- Strong base C- Weak acid or base if Ka and Kb not less than 10-7

Determination of acids

1. Strong acids can be titrated against strong alkali using ph.ph. or M.O. On titrating weak acid only ph.ph. is suitable. 2. Acids like benzoic acid , salicylic acid which are not insoluble in water are dissolved in neutral ethanol then add water and titrate against NaOH using Ph.ph. as indicator. 3. Boric acid: weak acid is a monobasic acid i.e. release 1 H+,can be titrated against NaOH only after potentiation by adding any poly hydroxy compound eg. glycerol using ph.ph. as indicator.

Determination of bases
1- Strong base can be titrated against strong acids using M.O. or ph.ph . For weak bases we use M.O. indicator or any indicator of pH range on the acidic side.

2- Displacement titration methods

It is used for easily hydrolysable salts :A- Salt of strong base and weak acid eg. borax, Na2CO3 B- Salt of weak base and strong acid eg. FeCl3, Al2(SO4)3 N.B. Always titrate the strong part of the salt. eg.1. KCN We titrate KOH by standard acid eg. HCl eg.2. Borax Na2B4O7
Borax hydrolyze in water to give: 4H3BO3 + 2 NaOH v.weak acid tit. 2 HCl using M.O titrate HCl using M.O indicator.(let reading = x) eg.3. Na2CO3 sodium carbonate. Na2CO3 pH =
HCl

Na2B4O7 + 7 H2O

NaHCO3 8.3 ph.ph

HCl

NaCl + H2O +CO2 3.8 M.O.

Na2CO3 can be determined by titration against HCl by 2 methods : a- Using M.O. as indicator it will give total CO3-2 b- Using ph.ph. as indicator it will give 1/2 CO3-2 and considered as half neutralization step. But care that the 1st step to NaHCO3 takes place on 2 separate steps; Na2CO3 + 2HCl
Na2CO3 +CO2 + H2O

2NaCl + CO2
2 NaHCO3

+H2O

2Na2CO3 +2HCl

2NaHCO3 + 2 NaCl

Therefore; For 1/2 neutralization, we must prevent the escape of CO2 by : 1- cooling 2- dilution 3-stirring

4- dipping the nozzle of burette under the surface of the solution.

3- Indirect or back (residual titration)

- In it we add Known excess of standard to the sample and titrate the excess non-reacted standard. Conc. of sample A = Known excess standard - b

When do we use back titration ?

1. When sample is volatile .eg. NH4+ salts, formic acid. 2. When sample is insoluble eg. ZnO, CaO, CaCO3, BaCO3 3. When reaction require heat of standard solution. 4. When reaction proceed only in presence of excess reagent eg. lactic acid.

eg.1: Determination of inorganic ammonium salts

NH4Cl + NaOH NaCl + NH3 + H2O Add known excess NaOH , then boil to remove NH3 and titrate excess NaOH using HCl and M.R. as indicator.

eg.2: Determination of nitrogen in organic compounds : (by Kjeldahl's method) :

Organic compound Conc.H2SO4 NH3 (NH4)2SO4 -Nitrogen of organic compound is reduced to NH3 by digestion with conc. H2SO4 in the presence of K2SO4 or Na2SO4 (to raise the boiling point of acid) and CuSO4 or HgO as a catalyst.

-The organic compound is oxidized to CO2 and the acid is reduced to SO2 and nitrogen to NH3 which is fixed with excess acid as (NH4)2SO4 then add known excess NaOH and titrate excess unreacted alkali against HCl as before.

4- Other indirect Titrations :

Determination of esters:e.g Aspirin Esters are hydrolyzed by reflux with known excess of NaOH, cool and the excess unreacted NaOH is titrated against standard HCl using Ph.Ph. indicator.

Determination of ammonium salt and amino acids (Formol titration) Another method for determination of ammonium salts is formol titration . When formaldehyde is added to the sample, hexamethylene tetramine (hexamine) which is neutral is formed and equivalent amount of acid which can be titrated against NaOH.
4NH4Cl + 6HCHO (CH2)6N4 + 4HCl + 6H2O

4(NH4)2SO4 + 6HCHO

(CH2)6N4 + 2H2SO4 + 6H2O

N.B. HCHO must be neutralized from any formic acid which formed due to aerial oxidation. .