OUR LADY OF FATIMA UNIVERSITY

COLLEGE OF PHARMACY

QUALITY CONTROL I
An Introduction
Session 1
¨  Enumerate the 3 incidents that led to the formulation
of GMP?

¨  designed to minimize the risks involved in any

pharmaceutical production

¨  Cross contamination ¨  Gross/Particulate

¨  Errors and mix-ups ¨  Biological

¨  Chemical

QUALITY product
GMP (Good Manufacturing Practice)

à is part of a quality system covering the

manufacture and testing of pharmaceutical dosage
forms or drugs and active pharmaceutical ingredients,
diagnostics, foods, pharmaceutical products, and
medical devices. GMPs are guidance that outlines the
aspects of production and testing that can impact the
quality of a product
What is Quality?
a distinctive attribute or
characteristic
possessed by someone
or something.

a measure of excellence
or a state of being
free from defects,
deficiencies and
significant variations
Quality
¨  The combination of attributes or characteristics
of a product which, when compared to a
standard, serves as a basis for measuring the
uniformity of the product and determines its
degree of acceptability.

Quality is a universal concept

Quality is subjective
 Quality
7

¨  ISO 9000:2015: Quality management systems—

Fundamentals and vocabulary defines QUALITY as the  
“degree to which a set of inherent characteristics of
an object  fulfils requirements.”

¨  Simply stated, quality is meeting customer

requirements.
Quality as summarized by Harvey &
Green (1993) as:

¨  Exception: distinctive, embodies in excellence,

passing a minimum set of standards.
¨  Perfection: zero defects, getting things right the
first time (focus on process as opposed to inputs and
outputs).
¨  Fitness for purpose: relates quality to a
purpose, defined by the provider.
Quality as summarized by Harvey &
Green (1993)
¨  Value for money: a focus on efficiency and
effectiveness, measuring outputs against inputs. A
populist notion of quality (government).

¨  Transformation: a qualitative change (Ex. in

education àabout doing something to the student
as opposed to something for the consumer. Includes
concepts of enhancing and empowering:
democratisation of the process, not just outcomes.
 QC/QA in Pharmaceutical Industry
10

¨  Quality assurance - all the planned and systematic

activities implemented within the quality system that
can be demonstrated to provide confidence that a
product or service will fulfill requirements for
quality (American Society for Quality or ASQ)
11

¨  Quality control - the operational techniques and

activities used to fulfill requirements for quality
12

¨  Quality Assurance - refers to all the planned and

systematic activities implemented in a quality
system , and demonstrate as needed, to provide
adequate confidence that an entity will fulfill the
requirements for quality (American National Standards
Institute or ANSI)
13

¨  Quality Control - those quality assurance actions

which provide a means to control and measure the
characteristics of an item, process, or facility to
established requirements
QA vs. QC
¨  “A part of quality management focused on providing
confidence that quality requirements will be fulfilled”
¨  A strategy of prevention

¨  Pro-active

¨  “A part of quality management focused on fulfilling

quality requirements”
¨  A strategy of detection

¨  Reactive
Quality Control

¨  A tool, which gives the assurance that a product

conforms to standards and specifications through a
system of inspection, analysis, and action.

¨  Established at the conception of a new product,

during production of the batch, and during
distribution of the commercial package.
Quality Control
¨  Guarantees that the drug product is:
¤  Free from impurities
¤  Physically and chemically stable

¤  Having the amount of active ingredient as stated on

the label
¤  Providing an optimal release of active ingredients
when the drug product is administered
Benefits of QC system
¨  The system minimizes or eliminates the risk of
marketing unsafe products.
¨  It guarantees conformance to regulatory

requirements.
¨  It guarantees product efficacy.

¨  It reduces operating costs.

Benefits of QC system
¨  It reduces operating losses.
¨  It produces higher employee morale.

¨  It motivates the pharmaceutical/medical professions

to sell or prescribed the product.

Other Related Terms

TQM: a management approach for an organization,

centered on quality, based on the participation of
all its members and aiming at long-term success
through customer satisfaction, and benefits to all
members of the organization and to society.
Related Terms
ISO
¨  Popular name for International Organization For

Standardization (IOS), a voluntary, non-treaty

federation of standards setting bodies of some 130
countries. Founded in 1946-47 in Geneva as a UN
agency, it promotes development of
standardization and related activities to facilitate
international trade in goods and services, and
cooperation on economic, intellectual, scientific, and
technological aspects
ISO certification:  public statement by a certified
auditor that an organization lives up to the ISO
standards.
With regard to quality management, ISO 9000’s
conception of quality is linked to ‘quality as
perfection’ or ‘zero errors’ and demands adherence
to explicitly described business processes
Basic Control Functions
¨  Audit function
¨  Record Review and Release Function

¨  Monitor function

¨  Analysis function
Control Functions
¨  Audit function

It is the function of QC to see to it that employees

and all persons involved in the practice comply with
SOPs.
Control Functions
¨  Record Review and Release Function

Release of the material or product takes place only

after the full assurance of the completeness and
accuracy on the results of the tests performed and it
is done after thorough examination and review of
records.
Control Functions
¨  Monitor function

This is to assure that quality is maintain throughout

the production until after the release of the material
or product.

This may be done by lot or time basis, by continuous

random sampling and testing.
Control Functions
¨  Analysis function

It is one of the control functions that assure the

acceptability of a material or a product by
performing various tests and comparing the values
with that of the specifications given.
Drug References
Official Compendia : Approved sources
of guidelines for drug quality required
by certain practitioners or agencies.

It comprises LIST of Pharmacopoeia: the word derives from the

pharmaceutical
substances, formula
ancient Greek φαρμακοποιϊ α
along with their (pharmakopoiia), from φαρμακο-
description and (pharmako-) ′′drug′′, followed by the
standards
verb-stem ποι- (poi-) ′′make′′ and
finally the abstract noun ending -ια (-ia).
These three elements together can be rendered
as ′′drug-mak-ing′′ or ′′to make a
drug′′.
Philippine Pharmacopeia
Exec. Order 302 – Declaring and adopting the Phil
Pharmacopeia as the Official book of Standards and
Reference for Pharmaceutical Products and Crude
plant drugs in the Philippines
Dr. TH Pardo de Tavera – published in 1901 a book
on the Philippines flora and its medicinal uses.
1978 – Published Philippine National Formulary
Philippine Pharmacopeia
Nov 1998 – May 26, 1999 – Creation to signing of
the first Philippine Pharmacopeia in cooperation with
the Japanese Government through the initiatives of Dr.
Conrado S Dayrit and Prof Akira Hamada.
BP, USP/NF
¨  1864 – Medical Act of 1858 published the first
combined Pharmaceopeia (London, Edinburgh and
Dublin)
¨  2018 Edition – revision is annual and is made
official every 1st of January each year.
¨  1820 - Foundation of US Pharmacopeial
Convention headed by: Dr. Lyman Spalding, Dr.
Samuel Mitchill and Dr. Jacob Bigelow
¨  1888 – First National Formulary was published by
American Pharmacists Association (APhA)
USP/NF
¨  1975 – USP acquires NF and Drug standards
Laboratory from APhA
¨  1980 – First combined USP-NF was published

¨  2002 – USP revised and published annually, made

official every 1st of May each year.

Monographs
¨  API and FPP
¨  provides a specification by way of a name,
definition, description, tests, procedures, and
acceptance criteria and sometimes packaging and
labeling requirements.
¨  Sample Raw Material (RM) monograph
file://localhost/Users/tinasabroso/Desktop/Screen Shot 2018-11-13 at 2.07.09 PM.png
Official Compendia (USP)
The complete monograph of a raw material or a
finished dosage form includes the following
information:
1. chemical structure
2. chemical name
3. purity rubric
4. packaging and storage
5. reference standard
 Official Compendia
¨ The complete monograph of a raw material or a
finished dosage form includes the following information:
6. Identification tests
7. Corresponding tests for chemical
and physical constants such as melting range,
rotatory power, refractive index etc.
8. Water content
9. Assay procedure
Sample monograph
..\..\Acetaminophen Monograph A.docx
OUR LADY OF FATIMA UNIVERSITY
COLLEGE OF PHARMACY

QUALITY CONTROL I
METHODS OF ANALYSIS
Session 2
Analysis

¨  Pharmaceutical Analysis - branch of practical

chemistry that involves a series of process for
identification, determination, quantification
purification of a substance, separation of the
components of a solution or mixture, or
determination of structure of chemical compounds
 1. Qualitative Chemistry

¨  What is in the sample?

Identification
Composition determination
Ascertainment of impurities
2. Quantitative chemistry
¨  How much is in the sample?
determination of the proportion of
components in a substance
Qualitative–Quantitative Chemistry in
Pharmacy
¨  Analysis of purity and quality of drugs and
chemicals used in practice.
¨  Others: applied in throughout industry, medicine,

environment
- Analysis of the chemical constituents found in
human body.
- Analysis of medicinal agents and their
metabolites found in biological systems
Classification of Analysis
I. Based on sample size
II. Based on the extent of determination
III. Based on nature of methods
IV. Based on materials used
 I. Based on sample size

¨  Ultramicroanalysis < 1 mg
¨  Microanalysis 1 mg – 10 mg
¨  Semi-microanalysis 10 mg – 100 mg
¨  Macroanalysis 100 mg – 1 g
II. Based on the extent of determination
¨  Proximate analysis
Total amount of a class or a group of
active plant principles in a given sample.

¨  Ultimate analysis
Amount of a specific constituent or a single
chemical species present in the sample
II. Based on the extent of determination
III. Based on the nature of methods
A.  Classical method
B.  Instrumental method
C.  Miscellaneous or special method
III. Based on the nature of methods
A. Classical method
¤  also known as general/ chemical/ wet/
stoichiometric method
¤  example : titrimetric analysis

gravimetric analysis
III. Based on the nature of methods
B. Instrumental method
¤  more accurate
¤  based on specific physical or chemical
properties of the analyte
¤  Examples: spectrometry
polarimetry
chromatography
III. Based on the nature of methods
C. Miscellaneous or special method
¤  Involves the crude drugs and other natural
products
¤  Examples: Acid value
Ash content
Water content
IV. Based on materials used
¨  Chemical = titrimetric method
¨  Physical = instruments and special apparata

¨  Biological = use of microorganism and animals

and parts thereof

Example
An assay using 0.125 g sample, determined for its
total acid constituent using HPLC. Determine the
specific classification based on size, extent, nature
of methods and material used

macroanalysis
proximate
instrumental
physical
Example
A 0.5g sample of glycerin was used to determine the heavy
metals content of the sample. After preparing presence of
heavy metals were tested by comparing the sample solution
with the standard. Determine the specific classification
based on size, extent, nature of methods and material used.
Types of Quantitative Analysis
A. Volumetric Analysis
B. Gravimetric Analysis
C. Special Methods
D. Physico-Chemical Methods
Types of Quantitative Analysis
A. Volumetric Analysis
analysis involving the measurement of
volume of a solution of known
concentration required to react with the
desired constituent.
Types of Quantitative Analysis
Divisions of volumetric analysis:
I. Neutralization
II. Precipitation
III. Compleximetry
IV. Oxidation-reduction
permanganate
ceric sulfate
iodometry
iodimetry
bromine
potassium iodate
diazotization assay with nitrite
Types of Quantitative Analysis
B. Gravimetric Analysis
Analysis involving the accurate
measurement of weight of substance
being determined which may be isolated in
pure form or converted to another substance
of known composition by making it react
quantitatively with another substance usually a
precipitant.
Types of Quantitative Analysis
C. Special Methods
analysis which require a distinct type of
technique such as analysis of crude drugs,
assay of fats and fixed oils, assay of volatile
oils and assay of alkaloids.
Types of Quantitative Analysis
D. Physico-Chemical Methods
Analysis based on some specific physical or
chemical property or properties of the
substance being analyzed with the use of
instruments such as: spectrophotometer,
chromatograph units, polarographer,
polarimeter, flourometer.
Specialized Analytical Methods
Results and Errors
¨  No analysis is free of errors
¨  When can you say that your results are reliable?

A. Determinate (Systematic Error)

B. Indeterminate (Random Errors)
Determinate Errors
¨ The error is reproducible and can be discovered
and corrected.
1. Instrument errors - failure to calibrate, degradation
of parts in the instrument, power fluctuations,
variation in temperature.
2. Method errors - errors due to no ideal physical or
chemical behavior - completeness and speed of
reaction, interfering side reactions, sampling
problems
Determinate Errors
¨  3. Personal errors - occur where measurements
require judgment, result from prejudice, color acuity
problems
Indeterminate Errors
¨  Caused by uncontrollable variables, which can not
be defined/eliminated.
¨  A plot of indeterminate error would show a normal
frequency curve
¨  We are 95% certain that the

true value falls within

2 (infinite population),
IF there is no
systematic error.
Accuracy and precision
¨  Accuracy
pertains to agreement of an experimental
results with true value

¨  Precision
is the measure of reproducibility of data within
a series of results.
Accuracy and Precision
Accuracy and Precision
REVIEW
1.  The density of water at 20°C is 0.9982 g/ml.
From the 2 sets of determination, which is more
accurate

A. 0.9989 0.9993 0.9991

B. 0.9981 0.9980 0.9982
¨  The density of ethanol at 20°C is 0.7893 g/ml.
From the 2 sets of determination, which is more
precise?

A. 0.790 0.788 0.789

B. 0.7890 0.7880 0.7880
Data Analysis
–  The Mean- measure of central tendency
–  The Range- difference between largest/smallest
observations in a set of data
–  Average Deviation measures the difference of the
actual values with the mean value
–  Relative average deviation – determined by
dividing the average deviation by the mean in %
–  Variance – sum of squares/total number of
samples
– Standard Deviation square root of variance
 Example 1
1.  The density of water at 20°C is 0.9982 g/ml.
B. 0.9981 0.9980 0.9982
Mean = 0.9981
Range = 0.9982 – 0.9980 = 0.0002
Mean deviation = (0.9981-0.9981)+(0.9980- 0.9981)+(0.9982-0.9981)
--------------------------------------------------
3
= 0.0001
Relative mean deviation = 0.0001/ 0.9981 x 100 = 0.01%
Variance = sum of squares of deviation/ data
S = 0.0001
 Percentage Relative Error (E) is a measure of the
71 accuracy of the method.
100 x relative error

Absolute Error= [True value - Observed value]

Relative error = Abs error/True value
Ideal %E is ≤ 2.5

Percentage Relative Deviation (D) is a measure of

the precision of method.
100 x SD / mean
Assay using 2 samples
Sd = mean sample deviation
Practice problem 1
Group 1 of QC lab has prepared and standardized
a solution of sodium hydroxide. The values obtained
are 0.01965 N, 0.01976 N and 0.01960 N.
1.  Compute for average, average deviation and %

rad
Assuming that the true concentration of the solution is
0.01970 N, what is the % E
If a fourth value is 0.01949 is available, is it
acceptable?
Answer
Mean = 0.01967N
Average deviation = = 0.00006
%rad = 0.3%
%E = 0.15%
Precision and Accuracy

¨  Determine the precision of the results by computing

for mean, mean deviation and %rad
Precision and Accuracy

¨  Determine the precision of the results by computing for

mean, mean deviation and %rad
¨  Determine the data accuracy from the given labeled amount
Significant figures
1.  All non-zero numbers are significant
2.  All zero between non-zero numbers are significant. 2016
3.  Leading zeros are not significant
àall zeros to the Left of the expressed decimal point and
to the right of a non zero digit are not significant. 0.54 and
0.0025
4. all zeros to the right of a decimal point and to the right of a
non-zero digit are significant. 95.00
 Illustration of Rounding Numerical Values
for Comparison with Requirements (USP/NF)

Compendial Unrounded Rounded

Requirement Value Result Conforms
Assay limit 97.96% 98.0% Yes
98.0%
97.92% 97.9% No

97.95% 98.0% Yes

Limit test 0.025% 0.03% No

0.02%
0.015% 0.02% Yes
Assignment
¨  Memorize the atomic weights of the following
elements
¤  C H O N K S I Na Cl Ca Ba Fe Mn Mg Ag
OUR LADY OF FATIMA UNIVERSITY
COLLEGE OF PHARMACY

QUALITY CONTROL I
A. VOLUMETRIC METHODS
Session 3
Volumetric Method
¨  The determination of the volume of a solution of
known concentration required to react with a given
amount of a substance to be analyzed.

¨  NEUTRALIZATION
¤  Acid and base combine to form SALT and WATER
¤  The principle involved in volumetric method
ESSENTIAL TERMS
¨  Analyte
the chemical substance being analyzed or the
active constituent, in the sample.
¨  Standard solution (titrant)
one whose concentration is accurately known
¨  Titration
process by which a standard solution is brought
into reaction until the desired reaction is accomplished
ESSENTIAL TERMS
¨  Indicator
a chemical, which changes color at or very near
the endpoint.
¨  Endpoint (practical)

shown by the change of color of the indicator.

¨  Equivalence point or stoichiometric point or
theoretical endpoint
is the theoretical point at which equivalent
amounts of each substance have reacted
Equivalence point
Equivalent Weight
Equivalent - number of moles of reactive unit in a
compound
- that which reacts or takes the place of
one mole of Hydrogen ion.

¨  weight that is chemically equivalent to the reacting

power of one of one atomic weight of hydrogen
TITER
¨  Strength in grams per milliliter solution or the weight
of a substance chemically equivalent to 1 ml of a
standard solution.

mL x N = g/meq
“or
g/mL = N x meq
“each ml of 0.1 N HCl is equivalent to 3.705 mg of
Ca(OH)2
Indicators
¨  Chemical substance, which changes color at or very
near the endpoint.
¨  Referred to as TS or Test solutions

¨  Used to avoid errors during titration

¨  Usual concentration is 0.05%, with 0.1 to 0.2 ml of

indicator used for 10 ml of the analyte.

 Indicators for NEUTRALIZATION

Color change
Indicator pH range Acid Base
Malachite green 0 – 2.0 Yellow Green
Methyl orange 3.2 -4.4 Pink Yellow
Methyl red 4.2 – 6.2 Red Yellow
Bromothymol blue 6.0 – 7.6 Yellow Blue
Phenolphthalein 8 - 10 Colorless Pink or red
Thymol blue 8 – 9.2 yellow blue

Methyl orange and methyl orange follow the color of acids

Malachite green, bromothymol blue and thymol blue follow the color of bases
Indicators
¨  Use only 3 drops of indicators unless otherwise
specified
¨  When weak acid is titrated with strong alkali, use
phenolphthalein
¨  When weak alkali is titrated with strong acid, use
methyl red
¨  When a strong acid is titrated with a strong alkali,
methyl red, methyl orange or Pp may be used
¨  Weak alkali should never be titrated with weak
acid, indicator will not give a sharp endpoint
Indicators

Pp and Mo Equivalence point

Indicators
 Indicators (OTHERS)

Precipitation Complexometry REDOX

• Dichlorofluorescein •  Dithiazone •  Iodine TS
• Eosin Y •  Eriochrome black •  Potassium
• Potassium chromate •  Hydroxynaphthol blue permanganate VS
• FAS •  Starch TS
Sample problems
Compute for the molecular weight, equivalent per mole,
equivalent weight, milliequivalent weight and weight in
milligrams of solute per milliliter of 0.15N solution

Nitric acid Barium hydroxide

Sulfuric acid Phosphoric acid
Silver nitrate Magnesium sulfate
Potassium hydroxide Calcium carbonate
Sample problems
Compute for the molecular weight, equivalent per mole,
equivalent weight, milliequivalent weight and weight in
milligrams of solute per milliliter of 0.15N solution

Sulfuric acid Barium hydroxide

Boric acid Phosphoric acid
Acetic acid Nitric acid
Potassium hydroxide Ammonium hydroxide
OUR LADY OF FATIMA UNIVERSITY
COLLEGE OF PHARMACY

QUALITY CONTROL I
VOLUMETRIC SOLUTIONS
Session 4
Expressions of Concentration
¨  A normal solution contains one gram equivalent weight
of solute in a liter of solution or one gram
milliequivalent weight in a milliliter of solution.

no. of g-eq wt g solute/ eq wt g solute

N = -------------------- = -------------------- = ------------------
L of soln L of soln (eq wt) (L of soln)

- that which reacts or takes the place of one mole of Hydrogen ion
- number of moles of reactive unit in a compound
1 N – A normal solution
2N – Double normal
0.5N – Half normal

Tenth-normal – 0.1N
Fiftieth-normal – 0.02N
Hundredth-normal – 0.01N
Thousandth-normal - 0.001N
Expressions of Concentration
¨  A molar solution contains a mole (one gram
molecular weight) in a liter of solution or one
millimole per milliliter of solution. A mole is the
molecular weight expressed in grams. A millimole is
one thousandth part of a mole.
  no. of mol solute g solute/ molar mass g solute
M = ---------------------- = ------------------------ = ---------------------
no. of L of soln L of soln (molar mass) (L of
soln)
Normality and Molarity

N= M x Eq
Expressions of Concentration
¨  A molal solution contains a mole (one gram
molecular weight) in one thousand grams of solvent.

no. of mol solute g solute/ mol wt g solute

m = ---------------------- = ------------------------ = --------------------------
Kg of solvent Kg of solvent (mol wt) (Kg of
solvent)
Standard solution
¨  a solution of known concentration or a solution
whose exact concentration is known.

¨  Standard Acid solutions – HCl, H2SO4, HClO4

¨  Standard alkali solutions – NaOH and KOH,

CH3ONa
Standardization
¨  Process of determining exact concentration of a
solution.
Types of Volumetric solutions:
1. Primary standard
2. Secondary standard
STANDARD SOLUTIONS
¨  Primary Standard
- chemically pure solid substance almost 99.9%
pure used in the standardization of a solution
STANDARD SOLUTIONS
¨ Primary Standard
other requirements for primary standard are:

1. it must be easy to prepare and pure

2. it must be of definite known composition
3. it must be stable
4. it must react stoichiometrically with the
substance present in the solution
5. it must be soluble in water and
6. it must have a fairly high equivalent
weight
STANDARD SOLUTIONS
¨  Primary Standard
¨  For acid solutions - Anhydrous pure sodium
carbonate, Calcium carbonate and THAM
(trihydroxymethylaminomethane)
¨ 
STANDARD SOLUTIONS
¨  For Alkali solutions, the most commonly used
are benzoic acid, potassium biphthalate and
sulfamic acid.
STANDARD SOLUTIONS
¨  Secondary Standard
¨  Substance that is not necessarily pure but
whose exact purity is known.
¨  A standard solution is a commonly used
secondary standard
¨  Common practice - to standardize only one of
the solutions by using a primary standard and
the other is standardized by using a secondary
standard
Sample problems
¨  Compute for the amount in grams of the solute in
each of the following solutions:
¤  2 liters HCl 2.5 N
¤  3 liters H2SO4 1.5 N
¤  150 ml HCl 0.25 N
¤  1.5 liters of KOH 2.0 N
¤  125 ml NaOH 1.5 N
1.  A sample of sodium carbonate (anhydrous)
weighing 2.125 grams required 40.2 mL of
sulfuric acid for neutralization. Express the
concentration of the solution in Normality and
Molarity

2.  What is the Molarity and Normality of a solution

prepared by dissolving 8.050g Ba(OH)2 in
1500ml of solution?
Assignment
Give the primary standards and indicators used for
the following VS
¨  Sulfuric acid Iodine
¨  Ceric sulfate

¨  Hydrochloric acid Oxalic acid

¨  Sodium hydroxide Potassium permanganate
¨  Perchloric acid Edetate disodium
¨  Potassium hydroxide Ammonium thiocyanate
¨  Sodium methoxide Silver nitrate
Standardization of Acid Solution using a
Primary Standard.
Standardization of Acid Solution using a
Primary Standard.
¨  Using Primary Standard

no. of equivalents (titrant) = no. of equivalents (analyte)

ml x N = gm/ meq
Normality
1. Weight of pure Na2CO3 = 1.6250g
Vol HCl consumed during titration = 30.20 ml
Equivalent weight Na2CO3 =
Normality of HCl =

1.0152N
2. Prepare a 1 N Hydrochloric solution in which:
HCl has a density of 1.18
Contains 36.5 per cent hydrochloric acid by weight

36.5 grams
84.75 ml
3. A sample of sodium carbonate (anhydrous)
weighing 2.125 grams required 40.2 mL of sulfuric
acid for neutralization. Compute for: (a) normality
of the acid solution; (b) the sodium carbonate titre
of the acid.

0.05286 g
N = 0.9974
Standardization of the Alkali Solution
using Primary Standard.
Dissolve 45 g NaOH pellets in 950 ml of water
Standardization of the Alkali Solution
using Primary Standard.
5 g KHP
Standardization of the Alkali Solution using
Secondary Standard.

Run down from a burette a measured volume of the

standard acid solution
Dilute with distilled water
Add the indicator
Titrate with the alkali solution
endpoint is reached
Take note of the total volume consumed
Calculate the normality of the solution.
1. In the standardization of NaOH solution, 24.25 ml
of the solution was consumed in the titration of the
sample. The dried KHP sample weighed 4.9651g.
Compute for the Normality.

N = g KHP/ mEqKHP x ml NaOH

N = 4.9651/ 0.20423 x 24.25 ml
N = 1.0025
Working Formula
ENDPOINT
no. of equivalents (titrant) = no. of equivalents (analyte)

ml x N = gm/ mEq
2. What is the normality of NaOH solution which upon
titration with 25 ml of 0.075 N HCl consumed
25.52ml of the base? 0.0735N

3. What volume of 0.075 M HCl is required to

neutralize 100 ml of 0.01 M Ca(OH)2 solution?
13.33 ml
4. 42.5 mL of 1.3M KOH are required to neutralize
50.0 mL of H2SO4. Find the molarity and of H2SO4.
1.105M
5. A 50-ml sample of calcium hydroxide solution
required 19.50ml of 0.1050 N hydrochloric acid
solution to neutralize it. Calculate the amount of
Ca(OH)2 in 100 ml of the solution. 0.1515 g

6. During the standardization of hydrochloric solution,

25.20 ml of 0.9505 N NaOH is required in the
titration of 25.00 ml of the acid solution. Compute
for the normality 0.9581N
7. A solution of sodium hydroxide was standardize
and the following data were obtained:
¤  35 ml of NaOH
¤  5 g of KHC8H4O4 is used
Compute for the normality 0.6995N

8. What is the Molarity of a solution prepared by

dissolving 8.050g Ba(OH)2 in 1500ml of solution?

0.0314M
9. How many grams of pure sodium hydroxide are
needed for the preparation of 500 ml of
0.1000N solution?
2g

10. How many milligrams of sodium carbonate will

react with 50 ml of 0.2 N HCl?
530 mg
Assignment
Answer the problems in the book on
p. 75 (2,3,4,5,6)
Application of acid-base Titrimetry

-  Analysis of compounds
-  Acidimetry (table 4.1, 4.2)
-  Alkalimetry (table 5.1, 5.2)
-  Direct
-  Residual
DIRECT – a base is being assayed using a
standard acid solution
RESIDUAL – a base is being assayed with a
known excess of a standard acid, where
the excess acid is determined by standard
base
WHY Residual Titration?
à Sample is insoluble in water
à Reaction with standard solution is slow
à Sample does not give a distinct endpoint
with an indicator by direct titration
ACIDIMETRIC ANALYSIS
Acidimetry is the analysis of a base using an
accurately measured volume of standard acid
solution.

¤  DIRECT if using an accurately measured volume of a

standard acid solution
¤  RESIDUAL if the process requires adding an excess of
the standard acid solution and determining the amount
in excess by residual titration with standard alkali
solution
Assay of Sodium Bicarbonate –
DIRECT ACIDIMETRIC ASSAY
3 g of NaHCO3 dissolved in 25 ml of water
Add the indicator
Titrate with 1 N Sulfuric acid

% assay – percentage potency, strength or

percentage purity of a drug or preparation.
- amount per 100
 no. of equivalents (titrant) = no. of equivalents (analyte)

ml x N = g/ meq

Amount of substance (g) = ml x N x meq

% Assay = ml x N x meq
------------------- x 100
wt/ vol of sample
Titer use in Assay
NOTE: titer is the weight (in grams or milligrams) of a
substance chemically equivalent to 1 ml of a
standard solution. For uniformity of units, convert the
mg to grams.
 PROBLEM
If a 0.2800g of sodium bicarbonate is titrated with
0.9165 N sulfuric acid and 3.51 ml is consumed
during the titration, what is the amount sodium
carbonate in the sample? What is its % assay?
N x ml = g/mEq
g = N x ml x mEq the percentage purity
g = N x ml x mEq 0.280 g
3.51 mL
----------------- X 100
g of sx 0.9165 N Sulfuric acid
% NaHCO3= 0.9165 N x 3.51 ml x 0.084
--------------------------------- x 100
0.280 g
= 96.51%
Assay of Zinc Oxide –
RESIDUAL ACIDIMETRIC ASSAY
2nd Std Solution
accurately weighed
NaOH VS sample of zinc oxide
add
Acidammonium chloride the basic
titrates (neutralize)
dissolved in 50+mLexcess
sample of 1-Nacid
sulfuric acid
Indicator is added
excess acid isNaOH
titratedtitrated excess
with sodium std acid
hydroxide until the
solution
endpoint is reached.
Calculate the percentage purity of zinc oxide.
Sample – ZnO

50ml Std Acid solution

 Number of equivalents
Reacted with sample plus = ml x N acid
Excess acid

Number of equivalents
Equal to excess acid = ml x N base

Number of equivalents
that reacted with the sample = (ml x N) acid - (ml x N) base

Grams of pure in the = (ml x N) acid - (ml x N) base x meq sample

sample

% Assay
Amount of pure per
= (ml x N) acid - (ml x N) base x meq sample
1 g sample
X 100
----------------------------------------------
wt of sample
PROBLEM
What is the percentage purity of ZnO sample which
weighs 1.2500 and treated with 50 ml of 1.1230 N
sulfuric acid if it consumed 27.48 ml of 0.9746N
sodium hydroxide during back titration.
Given: 1.25g ZnO, 50ml of 1.1230N H2SO4
27.48ml NaOH, 0.9746N
Unknown: % purity ZnOà g
g = N x ml x mEq à
(N x ml )H2SO4 – (N x ml) NaOH x mEq
 (ml x N) acid - (ml x N) base x meq sample
% = ----------------------------------------------x 100
wt of sample
= 95.15%
ALKALIMETRIC ANALYSIS
¨  Alkalimetry is the analysis of an acid , acid salt or
other acidic substance
¤  DIRECT if using an accurately measured volume of a
standard alkali solutions
¤  RESIDUAL if the process requires adding an excess of
the standard alkali solution and determining the amount
in excess by residual titration with standard acid
solution
Assay of Hydrochloric acid –
DIRECT ALKALIMETRIC ASSAY
accurately weighed sample of HCl in
glass stoppered flask
Dilute with 25 ml of water
Add the indicator
Titrate with 1-N sodium hydroxide
Calculate the percentage purity of the acid in the
sample.
Assay of Acetic acid –
DIRECT ALKALIMETRIC ASSAY
accurately weighed sample of acetic acid
add 40 mL of water
Add the indicator
Titrate with 1-N sodium hydroxide
Calculate the percentage purity of acetic acid in the
sample.
Amount of substance (g) = ml x N x meq
% Assay = ml x N x meq
------------------- x 100
wt/ vol of sample
PROBLEM
What is the percentage purity of acetic acid if 3
grams require 20.5 mL of 0.105-N NaOH solution
to reach the endpoint?

N x ml = g/mEq the percentage purity

3 grams
g = N x ml x mEq
20.5 mL
g = N x ml x mEq 0.105-N NaOH
----------------- X 100
g of sx
% acetic acid = 0.105 N x 20.5 ml x 0.060
--------------------------------- x 100
3g
= 4.31%
If exactly 15 ml of 0.1 N NaOH is consumed during
the titration of 2 g acetic acid, what is the
percentage purity of the acid sample?

Given: 15 ml of 0.1 N NaOH, 2 g acetic acid sample

Unknown: percentage purity
% = N x ml x mEq / wt of sample x 100
= 4.5%
Assay of Aspirin capsule –
RESIDUAL ALKALIMETRIC ASSAY
accurately weighed sample of aspirin
Add 50 mL of 0.1-N NaOH
boil gently for 10 minutes and allow to cool.
Add the indicator
Titrate the excess sodium hydroxide
with 0.1-N sulfuric acid
Perform a blank determination (same quantities of the
reagent and in the same manner)
Titrate and calculate the percentage purity of aspirin.
 g of sample = ml x N x meq
(g) = (ml x N) acid - (ml x N) base x meq sample
RESIDUAL ACIDIMETRIC ----------------------------------------------

wt of sample

IN RESIDUAL ALKALIMETRIC

% sample = (ml blank – ml actual)Acid NAcid x meq sample

------------------------------------------- x100
wt of sample
 ml in the blank titration = ml of acid = total base
___
ml in actual = ml of acid = base found in excess
---------------------------------------------------------------
ml of acid that reacted with sample = ml of the
base that reacted with the sample
Blank Determination
¨  Blank test is carried in the same manner as the
actual test
¤  Correct
for the presence of impurities in the reagents,
changes in volume at different temperature, absorption
of carbon dioxide by the alkali or by the alkalinity
imparted by the glass
Analysis
1. If a 50ml Ca(OH2 reacts equally with 19.50 ml of
0.1050 N HCl. What is the normality of the
solution
How much in grams Ca(OH)2 is present in 50 ml of
the solution
What is the percentage w/v of the resulting
Ca(OH)2 solution
2. What weight of 98.5% KHC8H4O4 is equivalent
to 35 ml, 0.01N NaOH?

3. A 2.2g methylparaben (mEq of 0.152) was

assayed using 50 ml of Sodium Hydroxide,1.250 N
and it consumed 31 ml to of 1.100N sulfuric acid to
titrate the excess. In the blank, 42ml of the same
acid solution was consumed. What is the percentage
purity of Methyparaben?
KJELDAHL Method
Nitrogen determination by Kjeldahl method
-  A method designed to determine and quantify

ammonia in ammonium sulfate obtained by

decomposing organic substance with sulfuric acid
-  àK2SO4, anhy Na2SO4, CuSO4, Se

-  à if N is as NO3, salicylic acid is added

-  USP Methods

-  Method I for macroanalysis

-  Method II for semimicroanalysis
Kjeldahl set-up
 Sx in Kjeldahl flask
Add, H2SO4
Add K2SO4 or anhy Na2SO4 (digestants) and/or
CuSO4 or Se (catalyst)
Heat to boiling
Add NaOH
Distill
Ammonia gas in boric acid solution
 % sample = (ml x N) acid - (ml x N) base x meq sample
------------------------------------------ x 100
wt of sample
Table 4.3 – Acidimetric assay, Nitrogen determination
Ex. Protein in food, fertilizer, blood, assays of
Heparin, insulin, urea, povidone
Practice problems (p. 101)
2. The ammonia from 6.150 g sample of an organic
nitrogen compound was distilled into 50.0 ml of
0.1246 N H2SO4, and the mixture was titrated
with 22.42 ml of 0.0962N NaOH. Calculate the
percentage N in the sample.
Ans: 0.927%
3. A 2.500 g sample of acetanilid(98.5%) was
assayed by Kjeldahl method. If the ammonia from
the sample were distilled into 50 ml 1N H2SO4,
what volume of 1.245N NaOH would be required
in the titration?

Ans: 24.95 ml
4. Calculate the % urea in a 0.50 g sample, if 15.35
ml of 0.4967N NaOH were required in the titration
after the ammonia from the sample had been
distilled into 50.0 ml of 0.4861N H2SO4.
Ans: 100.08%
Assignment
Answer the following problems found in Jenkins
p. 86 (4,5,6)
no. 4 on p. 90
no. 2 on p.91
no. 3 on p. 95
No. 3, 4, 5p.104
p 75 (2 – 6)
113
p. 75
2. What weight of 98.5% KHC8H4O4 is equivalent
to a. 35 ml, 0.01N NaOH b. 35 ml, 0.1M Ba(OH)2
.
3.  Given: 50ml Ca(OH2 , 19.50 ml of 0.1050 N HCl
Unknown: N of Ca(OH)2, g Ca(OH)2 in 50 ml,
%w/v Ca(OH)2

N = 0.1050N x 19.50ml HCl/ 50ml Ca(OH)

N = 0.04095
g Ca(OH)2 = 0.04095N x 50ml x 0.037
= 0.07576 g
% w/v = 0.07576g/50ml x 100 à 0.1515%
4. Given: 25 ml, HCl, 0.650g Na2CO3 à N
Unknown: wt of the reagents equivalent to 25 ml
HCl a. NaHCO3 b. KOH c. Ba(OH)2 d. CaO
N = 0.650 g Na2CO3/ 0.053 x 25ml
= 0.490566N
a. g NaHCO3 = 0.490566N x 25ml x 0.084
= 1.030
b. g KOH = 0.490566N x 25ml x 0.056 à 0.6868g
c. g Ba(OH)2 = 0.490566N x 25ml x 0.0855à1.049g
d. g CaO = 0.490566N x 25ml x 0.028à0.3434g
5. Given: 25 ml NaOH, 40 ml H2SO4
25 ml H2SO4, 0.3060g Na2CO3 à N
Unknown: N NaOH?

N = 0.3060g/ 0.053 x 25 ml
= 0.2309N

N NaOH = 40 ml x 0.2309N H2SO4/ 25 ml

= 0.3694N
6. Given: 25 ml H2SO4, 20.50 ml NaOH,
35ml NaOH, 0.7140 g KHP
Unknown: wt of BaSO4 produced from 50 ml H2SO4?
N NaOH = 0.7140g/ 0.20423 x 35 ml
= 0.099887N
N H2SO4 = 0.099887N x 20.50ml/ 25ml
= 0.0819076N
g BaSO4 = 0.0819076N x 50ml x 0.1165
= 0.4771g
p. 86
4. 3 g of NaHCO3 is dissolved in 25 ml of water,
what is the normality of the solution?
5. If 2.8 g NaHCO3 (96.5%) is titrated with 0.9165
N HCl, what volume is required to reach endpoint?
6. Compute for titer values for 1N H2SO4
KHCO3
K2CO3
CaCO3
p. 90, #3
Given: Dibasic organic acid mol wt 215
0.2500N, 35 ml
Unknown: wt of sample

g = 0.250N x 35ml x (215/2000)

p. 90, #4
Given: 20 tablets x 325 mg in 200 ml
15.0 ml aliquot
29.11 ml of 0.1N HCl
unknown: amount per tablet?, % labeled amount
20 x 325 mg = x mg àwt of sample
200 ml 15 ml
g = 0.1N x 29.11ml x mEq C7H5NaO3
Titer value = each ml of 0.1N HCl is equivalent to 16.01

% = 0.1N x 29.11ml x 0.1601/0.4875g x 100

 p. 95, #3
Given: 50ml of1.0340 N 12.32g sample
24.60 ml of 1.1255N
unknown: % Mg(OH)2
(ml x N) acid - (ml x N) base x meq sample
% = ----------------------------------------------x 100
wt of sample
= (50ml x 1.0340N) – (24.60ml x 1.1255N) x 0.029
----------------------------------------------------------- x 100
12.32 g
Sample problem (p.113)
¨  20 aspirin capsules was dissolved in 100 ml of
alcohol. If a 10-ml aliquot was found to contain
0.4880 g aspirin, what was the % labeled amount
in 5 grains of aspirin capsule?

¨  Weight of the sample used?

¨  % labeled amount
5. Compute for percent purity of Methylparaben
Data are as follows:
Wt of sx: 2.1000g
ml of 1N taken for 40 ml
Sample and blank
ml of 1.1000N H2SO4 41.0ml
Required for blank
ml of 1.1000N H2SO4 31.0 ml
Required for sample titration
Each ml of 1N NaOH consumed is equivalent to 152.2 mg of methylpa
raben
Assignment
Answer problems :
No. 3, 4, 5p.104
Non – Aqueous Titration
¨  Most organic acids and bases are insoluble in water
¨  Most organic acids and bases are weak acids and

bases
¨  Moisture must be avoided or at least limited to

0.05%
¤  Titrants
n  Acid – Perchloric acid in glacial acetic acid or dioxane
n  Base – Sodium methoxide, Lithium methoxide in
ethylenediamine, n-butylamine, morpholine
¤  Indicators

¤  ACIDIMETRY)
n  Crystalviolet, malachite green, quinaldine red,
methylrosaniline (weak bases)
n  Methyl orange, methyl red, Thymol blue (relatively stronger)
q ALKALIMETRY
q Azoviolet ( weak acids)
q Thymol blue (strong acids)
q  potentiometric methods – most preferred
n  Table 6-1 and 6-2 – List of Compound Assayed by acidimetric and alkalimetric
methods (e.g Methacholine, Phenytoin)
DOUBLE INDICATOR TITRATION
¨  To determine composition of certain mixtures
¨  To account for the total alkalinity of NaOH

¤  Certain indicators change color at different stages of

neutralization
¤  Certain compounds react in two stages

¤  NaOH and Na2CO3 or Na2CO3 and NaHCO3

¤  Phenolphthalein changes in color within the pH range of
8.0 to 10, Methyl orange within 3.2 to 4.4
General Procedure
¨  An accurately weighed sample is dissolved in 40 mL of
distilled water
¨  Add 2-3 drops of phenolphthalein
¨  Titrate with 1-N hydrochloric acid until the pink color is
discharged.
¨  Record the volume of hydrochloric acid consumed.
¨  To the resulting mixture, add 2-3 drops of methyl orange
¨  Titrate with the acid is until the endpoint is reached.
¨  The volume of the acid consumed is recorded.
¨  Compute for the percentage purity of each component in
the mixture.
 Pp Mo
NaOH + HCl -à NaCl + H2O
Na2CO3 + HCl -à NaHCO3 + NaCl NaHCO3 + HCl -àNaCl + CO2 + H2O

v1 > v2 = NaOH, Na2CO3

Pp Mo

Na2CO3 + HCl -à NaHCO3 + NaCl NaHCO3 + HCl -àNaCl + CO2 + H2O

NaHCO3 + HCl -àNaCl + CO2 + H2O

v1 < v2 = Na2CO3, NaHCO3

Percentage assay
NaOH, Na2CO3
% NaOH = (mL HCl Pp - mL HCl Mo) x N HCl
x meq
------------------------------------- x 100
wt of sample
% Na2CO3 =2 (ml HCl Mo) X N HCl X meq
------------------------------------- x 100
wt of sample
Na2CO3, NaHCO3

% Na2CO3 =2 (ml HCl Pp) x N HCl x meq

------------------------------------- x 100
wt of sample
% NaHCO3 = (mL HCl Mo - mL HCl Pp) x N HCl x
meq
------------------------------------- x 100
wt of sample
 !. A 5.0 ml mixture required 28.8 ml of 0.5000N HCl
to Pp endpoint and 14.4 ml to reach Mo endpoint.
What composes the mixture? Give the % assay of
each.
5.76%
15.26%
Answer p. 89
¨  Problems 1 -4
Practice problems p. 89
1. In the titration of 1.090-g sample of sodium
carbonate (98.5%) with 0.9050N H2SO4, what
volumes would be necessary to produce the Pp and
Mo endpoints?
11.19ml
22.38ml
2. In the titration of a mixture of 0.50g of pure
Na2CO3 and 0.40 g pure NaHCO3 with 1.1050N
acid solution. What volume of the acid would be
necessary to produce the Pp and Mo endpoints?
4.27ml
8.58ml
4. Calculate the sodium carbonate and sodium
bicarbonate content of a 1.2500-gram sample
requiring 13.80 ml of 0.5250N HCl on titration to a
phenolhthalein endpoint and additional 16.30 ml on
further titration to Mo endpoint.

61.4%
8.82%
2. Calculate the percentage composition in mixture
which required 13.80 ml of 0.5250 N HCl on
titration Pp endpoint and additional 16.30 ml to Mo
endpoint using 1.2500 g sample.
A 250 mg NaCO3 reacts with 9.0 ml of the HCl
solution.
3. A 2.4671 g sample was titrated with 0.5282M of
HCl. It consumed 47.2 ml of the acid to reach Pp
endpoint and additional 23.4 m to reach Mo
endpoint. What is the identity of the sample and its
% composition?
Theories on Acids and Bases

Arrhenius Theory
Acids – produce hydrogen ions in
solution
Bases – produce hydroxide ions in
solution
Lewis Theory
Acids – an electron pair acceptor
Bases – electron pair donor
Bronsted – Lowry Theory
Acids – proton donor
Bases – proton acceptor

¤ Strong
acids and bases – ionize completely
¤ Weak acids and bases – dissociate
Strong Acids – nitric acid, perchloric acid, sulfuric acid,
hydrocloric acid, hydrobromic acid, hydroiodic acid
Strong Bases – sodium hydroxide, lithium hydroxide,
potassium hydroxide, hydroxides of cesium, calcium,
strontium and barium

Weak Acids – acetic acid, phosphoric, carbonic,

hydrofluoric
Weak bases – ammonia, magnesium and aluminum
hydroxide, Lime, soda ash
¨  Strong acid + strong base = neutral salt
¨  Strong acid + weak base = acid salt

¨  Strong base + weak acid = basic salt

¨  Ex. Fe (NO3)3
¤  Na2SO4
¤  Ni(ClO4)2
 H2O ßà H+ + OH –

Kw = [H+ ] [OH – ] = 1.00 x 10 -14

¤  pH refers to the measure of acidity or alkalinity

n  Measure of the hydrogen ion concentration
n  pH = - log [H+ ]
n  For water at equilibrium ,[H+ ] is 1.00 x10 -7
n  pH = - log [H+ ] = 7
Computing for pH, H+, pOH and pKa

¨ pH = -log [H+ ]

¨ [H+ ] = inv log (-pH)

¨ pOH = -log [OH – ]

¨ [OH – ] = inv log [-pOH]

¨  pH = 14 – pOH
¨  pka = - log ka

Compute for pH of weak acid

- determine pka
- compute for pH using:
pH = 1 [pka – log C]
--------------------
2
BUFFERS
¨  Compounds that resist changes in pH upon the addition
of limited amounts of acids or bases.
¨  pH of a buffer system is given by Henderson –
Hasselbach eq:
[salt]
¨  pH= pka + log ------
[acid]
[base]
¨  pH= pkw - pkb + log --------
[salt]
Buffer capacity
¨  Measure of the efficiency of a buffer in resisting
changes in pH
¨  Van slyke equation gives the relationship between
buffer capacity and buffer concentration:
ka [H3O+]
β = 2.3 C -------------------
(ka + [H3O+]) 2
C = sum of the molar concentrations of acid and
salt)
Sample Computation (p.54)
¨  Compute for hydronium ion concentration
¤  HCl,
pH 3.41
¤  NaOH, pH 9.20

¨  Compute for pH of solutions

¤  0.0035 M HCl
¤  0.0089 M NaOH
p.54
¨  pH of weak acid with concentration of 0.1M and ka
of 1 x 10 -5
¨  pka = - log ka

=5
¨  pH = (pka – log C) / 2

=3
Summary
Volume- Standardi- Compound Type of assay meq
tric Soln zation s assayed
Method
HCl 1° - Na2CO3 NaHCO3 - Aqueous, Direct
Mo
NaOH

H2SO4

HClO4

CH3ONa